EP2224806A1 - Pharmaceutical composition - Google Patents

Pharmaceutical composition

Info

Publication number
EP2224806A1
EP2224806A1 EP08862226A EP08862226A EP2224806A1 EP 2224806 A1 EP2224806 A1 EP 2224806A1 EP 08862226 A EP08862226 A EP 08862226A EP 08862226 A EP08862226 A EP 08862226A EP 2224806 A1 EP2224806 A1 EP 2224806A1
Authority
EP
European Patent Office
Prior art keywords
antagonist
release
naltrexone
opioid
sequestering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08862226A
Other languages
German (de)
French (fr)
Other versions
EP2224806A4 (en
Inventor
Alfred Liang
Frank Matthews
Garth Boehm
Lijuan Tang
Frank Johnson
Joseph Stauffer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alpharma Pharmaceuticals LLC
Original Assignee
Alpharma Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alpharma Pharmaceuticals LLC filed Critical Alpharma Pharmaceuticals LLC
Publication of EP2224806A1 publication Critical patent/EP2224806A1/en
Publication of EP2224806A4 publication Critical patent/EP2224806A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine

Definitions

  • This invention pertains Io composotions and methods useful for treating pain m human patients.
  • One such composition contains both an opioid antagonist and an opioid agonist formulated such that the agonist is released over time with minimal release of the antagonist.
  • OA osteoarthritis
  • OA is the most common form of arthritis in the United States (Hochberg et al., 1995a) ? affecting more than 21 million people. It is a disease of primarily middle-aged and older adults and is a leading cause of disability (American College of Rheumatology, 2000a).
  • OA results from degeneration of the joint cartilage, and usually involves the neck, low back, knees, hips, and fingers. The prevalence of OA of the hip and knee increases progressively with age (Peloso et al., 2000).
  • inflammation if present, is usually mild and localized to the joint.
  • the cause of OA is unknown, but biomechanicaJ stresses affecting the articular cartilage and subchondral bone, biochemical changes in the articular cartilage and synovial membrane, and genetic factors are significant in its pathogenesis (Hochberg et al., 1995b; American College of Rheumatology, 2000b).
  • OA is characterized by pain dial typically worsens with activity and weight bearing and improves with rest, as well as morning stiffness, and pain and stiffness that ease after a few minutes of movement
  • Clinical examination often reveals tenderness to palpation, bony enlargement, crepitus, and/or limited joint motion (American College of Rheumatology, 2000b).
  • OA patients experience increasing pain and loss of function, with pain intruding at periods of rest (Peloso et al., 2000). Since no
  • Nonpharmacologic and pharmacologic tteatme ⁇ for O ⁇ are used in conjunction to reduce pain and to improve functional status
  • Nonpharmacologic therapies include patient education, weight loss (if overweight), occupational therapy, physical therapy, and aerobic exercise psograrm to restore joint and increase strength and aerobic capacity ( American College of Rheumatology. 2000a)
  • the initial pharmacologic therapies for O ⁇ include nonopioid analgesics (e.g.. acetaminophen) and topical analgesics, folkmcd by treatment with nonsteroidal ami- inflammatory drugs (NSAf Ds) and judicious use of intra-articuiar steroid injections (JHoetrherg et al., 1995a).
  • naltrexone Although well absorbed orally, naltrexone is subject to significant first-pass metabolism, with oral bioavailability estimates ranging from 5Vo to 40°' « (Naltrexone H(I 1 ablets. I 1 SP Package Insert) The activity of naltrexone is believed to be due to both the parent compound and the o- ⁇ nalUexol metabolite.
  • ⁇ UC area under the concentration-time curve
  • C nm maximum plasma concentration
  • Kadi an contains polymer-coated extended-release pellets of morphine sulfate, to deliver up to 24 hours of continuous pain relief
  • This formulation lacks an immediate-release component, on Iv prov iding a slow release of the analgesic
  • This slow-release technology serves to mmirmzc plasma peaks and troughs, thereby providing a lelatnelv fiat pharmacokinetic U 3 K) curve upon multiple closing
  • Phis dehxeiy mechanism is ideally suited for chrome pain patients
  • Kadian capsules aie an extended-release oral formulation of morphine sulfate indicated foi the management of moderate to pam when a continuous, atou ⁇ d-the-clock opioid analgesic is needed for an extended pei iod of time
  • Kadian KT (morphine sulfate plus naltrexone hydiochloude extended-release capsules), is a product that is intended to be used as an opiate analgesic for raodeiate to sexeie pam Its abuse-detenence feature incoipoiat.es an immediate release of naltrexone upon illicit manipulation this is intended to neuUalue the euphoric potential of morphine and ui ⁇ ease safetv afici ingestion of the tamp ⁇ cd product If Kadian NT is used as duected.
  • a patient should receive a dose of morphine equivalent to the same n ⁇ dose of Kadi an if the drug pioduct is tampered w ith and ingested b ⁇ a patient who is opioio dependent, the patient may be exposed to a dose of naltiexone sufficient to produce w ithdiawai symptoms
  • Abusc-tesisstant, sustamed-release dosage fomis of products intended to treat pain !ki ⁇ e been described in the ait (see, for ex ⁇ mpfe. V S Application Mos 2003 0124185 and 200 > 0044458) that substantial amounts of the opioid antagonist oi othei antagonist found m these sequesteied f ⁇ ns ase released ume (usual Iv less than 24 hours) due to flic osmotic pressure that builds up m the core of the sequestered form as watei peuneates thiough the sequesieied foim mto the cot ⁇ I he high osmotic pi ⁇ ssute inside the coie of the sequesteied foini causes the opioid antagonist oi antagonist to be pushed out of the sequesteted form, theieby causing the opioid antagonist oi antagonist to be released fiom the sequesteied foim ⁇ s sliuwn below, certain embodiments described hcicin prov ide improved
  • Proxided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit and wherein the seal coat forms a layet physically separating the antagonist from the agonist from one another.
  • the methods described herein prov ide methods fot substantially ielicwng pain (e.g. puruduig an analgesic effect) for time pcuods of at least one week (e.g , two, four, eight, 12, 16. 20, 24, 2S, 32. 36, 40 and 100 weeks) with regular administration ⁇ e.g., once, twice, three or four times daily).
  • Pan ided heiehi are compositions and methods for adn ⁇ nisteting a multiple actne agents to a mammal in a form and manner that minimizes the effects of either acme ayeni upon the other hi vivo
  • at least two active agents are formulated as part of a pharmaceutical composition.
  • a first aclKe agent may pi oxide a therapeutic effect m vivo
  • the second active agent may be an antagonist of the first acme agent, and may be useful in preventing misuse of the composition.
  • the second aethe aj ⁇ etit may be an antagonist of the narcotic
  • the composition remains intact during normal usage patients and the antagonist is not released However, upon tampering with the composition, ⁇ he antagonist rnav be steleased theiet ⁇ presenting the naieotic from hav ing its intended effect.
  • the active agents arc both contained within a single unit, such as a bead, in the form of layers.
  • the acme agents may be formulated with a substantially impermeable barrier as. for example, a co ⁇ trolled-release composition, such that release of the antagonist from the composition is minimized.
  • the antagonist is released in //; assays but is substantially not released m vivo In v ⁇ fro and in vhv release of the active agent from the composition ma ⁇ be measured by any of ⁇ hv ielease may be determined by measuring the plasma levels of the active agent or metabolites thereof ( ⁇ .e, ⁇ U( ⁇ Cmaxl
  • one of the active agents is an opioid receptoi agonist.
  • opioid agonists are commercially available or in clinical ttials and be administered as described herein such that the alcohol effects arc minimized.
  • Opioid agonists include, foi example, alfenta ⁇ il, aily ⁇ piodme, alphapiodine, amie ⁇ dine, bcHzylnio ⁇ hine, bezitramidc. buprenorpliine.
  • butorphanol clonitazene, codeine, cvcla/ocine desomorphsne, dextroinoratnide, dezocine, dianipiomide, dthydrocodeme, ⁇ hydroetorpiurte dihydromorphine, dimenoxadol, dimepheptanoK dimetln ithiambutene, dioxaphetyl butjuue, dipipanone.
  • epta/ocine ethohepta/me, ethyl methylthiarnb ⁇ tene, ethylmo ⁇ hine, etonitazene, etorphine, fentanyi, heroin, hydiocodone, hydromoiphone, hydroxypethidine, isomethadonc kctobenudone, lcv allorphan, levorphanol, lofentani), mepeiidine, mepta/inol, raeta/ocine.
  • the opioid agonist is selected from the group consisting of hydrocodone, bydromorphone, oxycodone, dihydrocodeiue. codeine, dihydromoiphine, morphine, buprenorphme.
  • the opioid agonist is morphine, hydr ⁇ morphone, oxycodone or hydrocodone
  • Eqmanalgesic doses of these opioids, m comparison to a 15 mg dose of hydrocodonc, are as follows oxycodone ⁇ $ 5 mg ⁇ , codeine (90 0 mg ⁇ , hydiocodone ( 15 0 mg), hydromorpho ⁇ e (3,375 n ⁇ K (! 3 ragK meperidine ( 135.0 mg). methadone (90 rag), and morphine l2 7 0 rngh
  • a common dosage form of hydrocodone is in combination w ith acetaminophen and is commercially available, for example, as L ⁇ rtab ⁇ in the United States from UCB Pharara, ⁇ c Belgium! as 2.5 500 mg, 5 500 mg, 7.S/5OO mg and 10 500 rag hydrocodone/ ' acetammophen tablets. Tablets ate also available m the ratio of 7.5 rag hydrocodone bitartrate and 650 mg acetaminophen and a 7.5 mg hydrocodone bitanrate and 750 mg acetaminophen Hydrocodone, in combination with aspirin, is given in an oral dosage form io adults generally in 1 -2 tablets every 4-6 hours as needed to alicxiate pain.
  • Hie tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with 32 mg caffeine, or 5 mg hydrocodone bitartrate ami 500 mg aspirin.
  • Another formulation comprises hydrocodone bitartrate and ibuprofcn Vicopiofen®, cotnnicrc tally available in the U.S. from Knoll Laboratories ⁇ Mount Oine, N.J. ⁇ , is a tablet containing n 5 mg hydiocodone bitartrate and 200 nm ibuprofen lhe invention is contemplated to encompass all such formulations, with the inclusion of the opioid antagonist and or antagonist in sequestered form as part of a subunit comprising an opioid agonist.
  • Oxycodone chemically known as 45-epoxy-I4-hydro ⁇ y-3-methoxy-17- mcthylm ⁇ rphman- ⁇ -o ⁇ e. is an opioid agonist whose principal therapeutic action is analgesia
  • Other therapeutic effects of ONjcodone include anxiolysis, euphoria and feelings of relaxation
  • the precise mechanism of its analgesic action ⁇ s not known, but specific CNS opioid receptors for endogenous compounds with opioid-like aethil ⁇ been identified thioughout the biain and spinal cord and p!a> a role in the analgesic effects of this drug.
  • Oxycodone is commercial iy available in the United States, e.g., as Gxycctiivls horn Purdue Pharma L.P. ⁇ Stamford, Conn.), as control I ed ⁇ rel ease tablets for oral administration containing 10 mg, 20 ing, 40 mu. or 80 mg oxycodone hydrochloride, and as OxylRTM, also from Purdue Pharma L.F., as immediate-release capsules containing 5 mg oxycodone hydrochloride.
  • the invention is contemplated to encompass all such formulations, with the inclusion of an opioid antagonist and'Or antagonist in sequestered form as pan of a subimit comprising an opioid agonist
  • Oral bydroraorphone commercial! ⁇ available in the United States, e.g., as Dilaudid'D from Abbott Laboratories ⁇ Chicago, III), Oral morphine is commercially available in the United States, e.g., as Kadianl' from faulding Laboratories (Piscataway. NJ ⁇
  • the sustained-release oral dosage forms can include analgesic doses from about 8 rag to about 50 mg of hydrocodone per dosage unit.
  • sustained-release oiai dosage forms where iiydromo ⁇ boiie is the therapeutically active opioid it is included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride.
  • the opioid agonist comprises morphine
  • the sustained-release oral dosage forms of the imetition include from about 2.5 nig to about 800 ⁇ morphine, by weight.
  • the opioid agonist comprises oxycodone and the sustained-release oral dosage forms include from about 2.5 mg to about 800 mg oxycodone.
  • the sustained-release oral dosage forms include from about 20 mg to about 30 mg oxycodone.
  • Controlled release oxycodone formulations are known in the ait. The following documents des ⁇ ibe various control led ⁇ release oxycodone formulations suitable for use in the invention described herein, and processes for their manufacture; U.S. Pat. Nos. 5,266,331 ; 5,549,912; 5,508,042; and 5,656,295, which are incorporated herein by reference.
  • the opioid agonist cart comprise tramadol and the sustained-release oral dosage forms can include from about 25 mg to 800 mg tramadol per dosage unit.
  • another active agent contained within the composition may be an opioid receptor antagonist.
  • the agonist and antagonist are administered together, either separately or as part of a single pharmaceutical unit.
  • the antagonist preferably is an opioid antagonist, such as naltrexone, naloxone, ⁇ almeiene, cycliuaeine, levallorphan, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof.
  • opioid antagonist is naloxone or naltrexone
  • opioid antagonist is meant to include one or more opioid antagonists, either alone or in combination, and is further meant to include partial antagonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof.
  • the pharmaceutically acceptable salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like: alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as triethyiamine salt pyridine salt, picoline salt, ethanotamine salt, t ⁇ ethanolamine salt, dicyclohexylamine salt, N,N-dibenzyleihylenediarnine salt, and the like; inorganic acid sails, such as hydrochloride, hydrobromidc, sulfate, phosphate, and the like; organic acid salts, such as formate, acetate, trifluoroacelate.
  • alkaline earth metals such as calcium salt, magnesium salt, and the like
  • organic amine salts such as triethyiamine salt pyridine salt, picoline salt, ethanotamine salt, t ⁇ ethanolamine salt, dicyclohexylamine salt, N,N-dibenzyleihyl
  • the amount of the opioid antagonist can be about 10 ng to about 275 nig.
  • the antagonist when the antagonist is naltrexone, it is preferable that the intact dosage form releases less than 0.125 mg or less within 24 hours, with 0.25 mg or greater of naltrexone released after 1 hour when the dosage form is crushed or chewed,
  • the opioid antagonist comprises naloxone.
  • Naloxone is an opioid antagonist, which is almost void of agonist effects. Subcutaneous doses of up to 12 mg of naloxone produce no disce ⁇ iabie subjecihe effects, and 24 mg naloxone causes only slight drowsiness. Small doses (0.4-0.8 mg ⁇ of naloxone given intramuscularly or intravenously in man prevent or promptly reverse the effects of morphine-like opioid agonist. One mg of naloxone intravenously has been reported to block completely the effect: of 25 mg of heroin. The effects of naloxone are seen almost immediately after intravenous administration.
  • the dntg is absorbed after oral administration, but has been reported to be metabolized into an inactive form rapidly in its first passage through the such that it has been reported to have significantly lower potency than when parenteral Iy administered. Oral dosages of more than I g have been reported to be almost completely metabolized in less than 24 hours tt has been repotted that 25% of naloxone admin isteied sublingualis is absorbed (Weinberg ct al, Clin. Pharmacol, flier 44 335-340 U 988))
  • the opioid antagonist comprises naltrexone
  • naltrexone In the tieatmeut of patients iously addicted to opioids, naltrexone has been used in large oral doses (over 100 mg) to prevent eupho ⁇ aenic effects of opioid agonists Naltrexone has been reported to exert strong preferential blocking action against mu over delta sites Naltrexone is known as a synthetic congener of oxymorpho ⁇ e ⁇ Uh no opioid agonist properties, and differs in structure from oxymorprione by the replacement of the methyl group located on die nitrogen atom of oxymorphone w ith a cyciopropyimethyl group The hydrochloride salt of naltrexone is soluble in w afer up to about 100 mg,cc The pharmacological and pharmacokinetic properties of naltrexone have been evaluated m multiple animal and ciimcai studies.
  • naltrexone is rapidly absorbed (within 1 hour) and has an oral bioavailability ianging from 5-40% Naltrexone's protein binding is approximately 21% and the volume of distribution following single-dose administration is 16.1 L ⁇ g
  • Naltrexone is commercially available in tablet form ( Revia ⁇ DuPont (Wilmington, Del )) for the treatment of alcohol dependence and for the blockade of exogenous! ⁇ administered opioids. See, e.g.. ia (naltrexone hydrochioiide tablets), Physician's Desk Reference. 51 * ed . Montvale, N J., and Economic 51 957-059 (1997) A dosage of 50 mg blocks the pharmacological effccb of 25 rag IV administered heroin for up to 24 hours. It is known that, when coadministered with moiphine, heiom OJ other opioids on a chronic of physical dependence to opioids.
  • naltrexone blocki the effects of heroin h by competitively binding at the opioid receptors Naltrexone has been used to treat narcotic addiction by complete blockade of the effects of opioids. It has been found that the most successful use of naltrexone for a narcotic addiction is w ith narcotic addicts good prognosis, as part of a compreheashe occupational or rehabilitathe program involving behavioral control or other compliance- enhancing methods For treatment of naicotic dependence with naltrexone, n is desirable that the patient be opk ⁇ d-fiee foi at least 7-10 days.
  • naltrexone for such purposes lias typically been about 25 tng, and if no withd ⁇ awal signs occur the dosage may be ii ⁇ cascd to 50 mg pei day. A daily dosage of 50 mg is considered to produce adequate clinical blockade of the actions of parenteral ⁇ administered opioids.
  • Naltrexone also has been used for the treatment of alcoholism as an adjunct v, ith social and psychotherapeutic methods.
  • opioid antagonists include, for example, cydazocine and naltrexone, both of which rune cyclopropy t methyl substitutions on the nitrogen, retain ⁇ uich of the «' the ora! route, and last longer, with durations approaching 24 hours after oral administration
  • the antagonist may also be a bitter ⁇ g agent.
  • bittering agent refers to any agent that provides an unpleasant taste to the host upon inhalation and or swallowing ⁇ f a tampered dosage form comprising the sequestering subunit
  • the intake of the tampered dosage form produces a bitter taste upon inhalation or oral administiatio ⁇ , which, in certain embodiments, spoils or hinders the pleasure of obtaining a high from the tampered dosage form, and preferably presents the abuse of the dosage form
  • bittering agents can be employed, including, for example, and without limitation, riatmal, artificial and synthetic flavot oils and flavoring aromaticb and oi oik, oleoiesiiis and extracts derrved from plants, leases, flowers, fruits, and so forth, and combinations thereof.
  • Nonhmiting representative flavor oils include spearmint oil, peppeimint oil, eucalyptus oil, oil of nutmeg, auspice, mace, oil of bittei almonds, menthol and the like.
  • Also useful buttering agents are artificial natural and synthetic fruit flavors such as alms oils, including lemon, orange, lime, and gtapefr ⁇ it, fruit essences, and so forth Additional bitiering agents include sucrose demat ⁇ es (e.g., sucrose octaacetate), ehlorosucrose derh arrves., quinine sulphate, and the like
  • sucrose demat ⁇ es e.g., sucrose octaacetate
  • ehlorosucrose derh arrves. ehlorosucrose derh arrves.
  • quinine sulphate e.g., quinine sulphate
  • a preferred bitteri ⁇ g agent for use in the unention is Denatoninra Beozoate NF- Anhydrous, sold under the name BitrexTM ⁇ Macfarian Smith Limited, Edinburgh, I'Kj.
  • a brttermg agent can be added to the formulation in an amount of less than about 50 1 O by weight, preferably less than about 10% by weight, more preferably less than about 5% b> weight of die dosage form, and most pieferabiy in an amount ranging from about 0 I to LO peicent by weight of the dosage form, depending on the particular bitteiing agent(s) used.
  • the antagonist may be a dye
  • tefers to any agent ⁇ hat causes discoloration of the tissue in contact In this iegaui if (he sequestering subunit is tampered with and the contents are snorted, the dye w ill discolor the nasal tissues and surrounding tissues thereof.
  • Prefe ⁇ ed dyes are those that can bind strongly with subcutaneous tissue proteins and are well-known m the art.
  • D) es useful in applications ranging firom, for example, food coloring to tattooing, are exemplar) dyes suitable for the invention.
  • Food coloiing dyes include, but are not limited to FD&C G teen £ and FD&C Blue 41 , as well as any other F ⁇ ) &C os D&C color
  • Such food aie commercially available through companies, such as Yoigt Global Distribution (Kansas City. Mo.).
  • the antagonist may alternatively be an irritant.
  • the terra 'irritant' 1 as used herein includes a compound used to impart an irritating, e g , burning or uncomfortable, sensation to an abuser administering a tampered dosage form of the invention.
  • Use of an irritant will discourage an abuser from tasnpeitng with the dosage form and thereafter inhaling, injecting, oi swallowing the tampered dosage form
  • the irritant is released when the dosage form is tampered urth and provides a burning or irritating effect to the abuser upon inhalation, injection, and/or swallowing the tampeied dosage form
  • Various irritants can be employed including, for example, and without limitation, capsaicin, a capsaicin analog w ith similar type properties as capsaicin, and the IiIe.
  • capsaicin analogues or derivatives include, for example, and without limitation, lesiniferat ⁇ xm, tinvatoxin, bepianoylisobuty ⁇ araide, bcptanoyl jaiaiacylamkie, othet isobisty S amides or giiamcylamides.
  • Na 4,S l 2,446 describes capsaicin analogs and methods for their preparation Furthermore.
  • U S Pat. No 4,424205 cites Newman, 11 INaUa a! and Synthetic Pepper- Flavored Substances, " ' published m 1954 as listing pungency of capsaiein-l ⁇ ke analogs. Ton et al , Hrit&h J ⁇ untat o/ I'hatvnaa>hg ⁇ ⁇ 10 175-182 (1955), discusses pharmacological actions of capsaicin and its analogs.
  • Suitable capsaicin compositions include capsaicin (tians 8 ⁇ mel1iyl-N ⁇ vanill ⁇ l ⁇ 6-:i ⁇ iieamide) ot analogues thereof in a concentration between about 0 00125% and 50% b ⁇ weight, preferably between about 1% and about 7,5% by weight, and most preferably, between about !°b and about 5% by weight
  • the antagonist may also be a ueUina asent.
  • celling asenf as used herein refers to any agent that prov ides a gel-like quality to the tampered dosage form, which slows the absorption of the therapeutic agent, which is foimulaled with the sequestering subunit, such that a host is less likeh to obtain a rapid '"high "
  • the dosage form when the dosage form is tampeied with and exposed to a small amount (e.g., less than about 10 mt) of an aqueous liquid (e.g., water), the dosage form will be unsuitable for injection and oi inhalation Upon the addition of the aqueous liquid, the tampered dosage form preferably becomes thick and rendering it unsuitable for injection.
  • the term '"unsuitable for injection is defined foi purposes of the .mention to mean that one would have substantia! difficult ⁇ injecting the dosage form (e.g., due to pam upon administration or difficulty pushing the dosage form through a syringe) due to the uscosity imparted on the dosage form, thereby reducing the potential for abuse of the therapeutic agent in the dosage form
  • the gelling agent ss present in such an amount in the dosage form that attempts at evaporation (by the application of heat) to an aqueous mixture of the dosage form in an effort to produce a higher concentration of the therapeutic agent, pi educes a highly ⁇ beous substance unsuitable foi injection.
  • the gelling agent can become gei ⁇ hke upou administration to the nasal passages, due to the moisture of the mucous membranes.
  • This aiso makes such formulations to nasal administration, as the gel w ⁇ l stick to the nasal passage and minimize absorption of the abitsable substance
  • Various gelling agents may can be employed including, for example, and without limitation, sugars or sugar-derived alcohols, such as mam ⁇ tol, sorbitol, and the like, staich and starch deriv atives cellulose dematnes, such as im ⁇ ocrysialline cellulose, sodium caboxymethyl cellulose, methylceil ⁇ lose. ethyl cellulose, hydroxyethyl cellulose.
  • hydroxypiop cellulose
  • hyckoxv propyl metihylceilulose.
  • aitapulgties bentonites, dext ⁇ ns, alginates, catragee ⁇ ao, gum tragacant, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and caibopols.
  • the gelling agent is xauthan gum
  • the gelling agent of the invention is pectin, I he pectin or pectic substances useful for this invention include not only purified oi isolated pcctaics but also crude natural pectin sources, such as apple.
  • the pectins used in this invention are derived ftom citrus fruits, such as lime, lemon, grapefruit, and orange
  • the gelling agent preferably imparts a gel-hke quality to the dosage form upon tampering that spoils or hinders the pleasure of obtaining a rapid high from due to the gel-hke consistent; ⁇ of the tampered dosage form in contact with the mucous membrane, and in certain embodiments, prevents the abuse of the dosage form by minimizing absorption, e.g., in the nasal passages
  • ⁇ gelling agent can be added to the formulation m a ratio of gelling agent to opioid agonist of from about 1:40 to about 40' 1 by w eight, preferably from about i i to about 3Oi by weight, and more
  • the dosage fotm forms a gel haung a viscosity of at least about 10 cP after the dosage form is tampered uith by dissolution in an aqueous ⁇ quid (ftom about 0.5 to about 10 ml and pieferably from 1 to about 5 ml) Most preferably, the resulting mixture will ha ⁇ c a viscosity of at least about ⁇ O eP.
  • the antagonist can comprise a single type of antagonist (e g , a capsaicin), multiple forms of a single type of antagonist (e g, a capashi and an analogue thereof), or a combination of different types of antagonists (e g , one or more bittering agents and one or mojte gelling agents).
  • a single type of antagonist e g , a capsaicin
  • multiple forms of a single type of antagonist e g, a capashi and an analogue thereof
  • a combination of different types of antagonists e g , one or more bittering agents and one or mojte gelling agents.
  • the amount of antagonist in a unit of the ⁇ nentkm is not toxic to die host
  • the invention proudes a sequestering subimit comprising an opioid antagonist and a blocking agent, wherein the blocking agent substantially prevents telease of the opioid antagonist ftom the sequestering subumt in the gastioimesiinai tract for a time peiiod that is gieatei than 24 hours.
  • This sequestering subimit is mcoiporated into a single pharmaceutical unit that also includes an opioid agonist lhe pharmaceutical unit thus includes a core portion to which the opioid antagonist is applied.
  • ⁇ seal coat is then optionally applied upon the antagonist Upon the seal coat is then applied a composition comprising the pharmaceutically acthe agent.
  • the term "sequestering subunif as used herein refers to any means for containing an antagonist and presenting or substantially preventing the release thereof in the gastrointestinal tract when intact, i e.. when not tampered with.
  • blocking agent refers to the means by which the sequestering subumt k able to prevent substantially the antagonist from being released
  • the blocking agent may be a sequestering polymet, for instance, as described in greater detail below .
  • the dosage form is orally administered to a host e.g , a mammal (e.g., a human), as Intended.
  • a mammal e.g., a human
  • the blocking agent substantially prevents or pr ⁇ enfs the release of the antagonist to the extent that at least about 80% of the antagonist is prevented from being released from the sequestering subu ⁇ it in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the blocking &gcnt prevents i ⁇ iea& ⁇ of at ieast about 90" n of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the blocking agent prevents release of at least about 95" o of the antagonist ftom the seqtiesteting subumt. Most pteferab!> ⁇ the blocking agent pt events ielease of at least about 99% of the antagonist fiom the sequestering subunit in the gastrointestinal tract for a time period ⁇ bat is greater than 24 hours.
  • the amount of the antagonist released after oral administration can be measured in-vjtro by dissolution testing as described in the United States Pharmacopeia (USP26) in chapter ⁇ 7 ⁇ 1 ⁇ Dissolution i-or example, using Q OO mL of 0.1 N HCi, Apparatus 2 ⁇ Paddle ⁇ , 7 5 ⁇ m, at 3? '" C to measure release at times fiom the dosage unit.
  • Other methods of measuring the release of an antagonist from a sequeste ⁇ ng subunit o ⁇ er a given period of time are known m the ait (see e g., USP26).
  • the sequestering subun.it of the invention overcomes the limitation 1 ; of the sequestered forms of an antagonist known in the art in that the sequestering subunit of the invention reduces osm ⁇ tically-d ⁇ ven release of the antagonist from the sequestering subunit. Furthermore, it is believed that the present inventive sequestering subunit reduces the release of the antagonist fur a longer period of time (e.g.. greatci than 24 horns) in companson to the sequestered forms of antagonists known in the art.
  • the sequestered subunit of the invention provides a longer pre ⁇ ention of release of the antagonist is particularly relevant, since precipitated withdrawal could occur after the time for which the therapeutic agent is released and acts It is well known thai the gastrointestinal tract tia ⁇ sit time for indiv iduals ⁇ aries great! within the population, Hence, the residue of the dosage form may be retained in the tract for longer than 24 hours, and in some cases for longer than 48 hours.
  • Ii is further well known that opioid analgesics cause decreased bowel motility, further prolonging gastrointestinal tract transit time
  • the sequestering subunit of the invention is designed to prevent substantially the ieiease of the antagonist when imacl
  • 'imacf is meant that a dosage form has not undergone tampering.
  • tampering is meant to include am manipulation by mechanical, thermal and or chemical means, which changes the physical properties of ⁇ he dosage form.
  • the tampeiing can be, for example, crushing, shearing, g ⁇ nding. chewing, dissolution in a solvent, heating (for example, greater than about 45 a C), or any combination thereof
  • the antagonist is immediately released from the sequestering subimlt.
  • s ⁇ bunit is meant to include a composition, mixture, particle; etc., that can provide a dosage form (e.g., an. orai dosage form) when combined with another sulnmit.
  • the subimit can be in the form of a bead, pellet, granule, spheroid, or the like, and can be combined with additional same or different sub ⁇ nits, in the form of a capsule, tablet or the like, to provide a dosage form, e.g., an oral dosage form.
  • the subun.it may also be part of a larger, single unit, forming part of that unit, such as a layer.
  • the subun.it may be a core coated with an antagonist and a seai coat; this summit may then be coated with additional compositions including a pharmaceutically active agent such as an opioid agonist.
  • the antagonist can be any agent that negates the effect of the therapeutic agent or produces an unpleasant or punishing stimulus or effect, which will deter or cause avoidance of tampering with the sequestering subuntt or compositions comprising the same.
  • the antagonist does not harm a host by its administration or consumption but has properties that deter its administration or consumption, e.g., by chewing and swallowing or by crushing and snorting, for example.
  • the antagonist can have a strong or foul taste or smell provide a burning or tingling sensation, cause a fachrymation response, nausea, vomiting, or any other unpleasant or repugnant sensation, or color tissue, for example.
  • the antagonist is selected from the group consisting of an antagonist of a therapeutic agent, a bittering agent, a dye, a gelling agent, and an irritant.
  • exemplary antagonists include capsaicin, dye, bittering agents and emetics.
  • antagonist of a therapeutic agent is meant any drug or molecule, naturally- occurring or synthetic, that binds to the same target molecule (e.g., a receptor) of the therapeutic agent, yet does not produce a therapeutic, intracellular, or in vivo response
  • the antagonist of a therapeutic agent binds to the receptor of the therapeutic agent, thereby preventing the therapeutic agent from acting on the receptor, thereby preventing the achievement of a "high" in the host hi the instance when the therapeutic agent is an opioid agonist
  • the antagonist whilrat% is an opioid antagonist, such as naluexone, naloxone, naimciene, cyclazacine, dernatnes or complexes thereof pharmaceutically acceptable salts thereof, and combinations thereof.
  • opioid antagonist is naloxone 01
  • opioid antagonist ' ts meant to include one or mote opioid antagonists, either alone oi in combination and is further meant to include partial antagonists, pharmaceutically acceptable salts thereof, steteots ⁇ mors tbeieof etheis thcieof, esters thereof, and combinations thereof
  • pharmaceutically acceptable sails include metal salts, such as sodium salt, potassium salt cesium salt, and the like, alkaline earth metals, such as calcium sait. magnesium salt, and the iike.
  • organic amine salts such as trieth ⁇ lar ⁇ ne !>att, pyiidioe salt, picoline salt, cthanolaminc salt, metlianoiamine salt, dic>clohexylai ⁇ une salt, K N-dsben/ylethyle ⁇ edtarai ⁇ c bah and the like, inorganic acid salts, such as hvdiochioride. hydrobromide.
  • sulfate phosphate, and the like
  • oiganic acid salts such as fo ⁇ nate, acetate, tiifiuoioacetate, maleate, taitiate, and the like
  • sulfonates such as methanesuifbnate.
  • the amount of the opioid antagonist present m sequestered fotm can be about 10 ng to about 275 nig
  • the antagonist is naltrexone, it is ptefeiahle that the intact dosage fomi ieleases less than 0, 125 mg or less vnthm 24 houis, with 0 25 mg or greatci of naltrexone icleased after 1 hour when the dosage form is ciushed or chewed
  • the antagonist can comprise a single type of antagonist (e.g , a capsaicin), multiple forms of a single type of antagonist (e g , a capasm and an analogue theteof), oi a combmatiofl of diffeient types of antagonists (e g , one oi moie hiUe ⁇ ng agents and one oi more gelling agents)
  • a single type of antagonist e.g , a capsaicin
  • multiple forms of a single type of antagonist e.g , a capasm and an analogue theteof
  • oi a combmatiofl of diffeient types of antagonists e g , one oi moie hiUe ⁇ ng agents and one oi more gelling agents
  • the amount of antagonist in the sequestering sobunit of the invention is not toxic to the host
  • the blocking agent cuts or substantially cuts the release of the antagonist in the gastiouHestinal tract foj a time peu ⁇ d that is gteatet than 24 houis, e g , between 24 and 25 hours. 30 hours. 35 hours. 40 hours 45 hours, 48 hours, 50 hours 55 houis. 60 hours, 65 kouis. 70 hoius, 72 houis, 75 htiuTs. 80 houis, 85 houis, 90 hours. 95 hours o? 100 hours, etc.
  • the time pe ⁇ od for which the release of the antagonist is prevented 01 substantially presented in the gastrointestinal tract is at least about 48 hours More preferably, the blocking agent prevents or substantially prev ents the release for a time period of at least about 72 hours
  • the blocking agent of the present sequestering siibunit can be a system comprising a first antagonisi-rmpe ⁇ neabfe material and a core "'antagotnst- impermeable material " ' is meant any materia! that is substantially impermeable to the antagonist, such that the antagonist is substantially not released from the sequestering subunit I he term ''substantially rmpenn ⁇ able " as used herein does not necessa ⁇ l ⁇ imply complete or 100% impermeability.
  • the antagonist- impermeable material substantially presents or pme ⁇ ts the release of the antagonist to an extent that at least about 80% of the antagonist ts prevented ftom being released from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the a ⁇ tagonist-impeimeable material prevents release of at least about 90% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours More preferably, the antagonist-impermeable material prevents ieiease of at least about 95° « of the antagonist from the sequestering subunit Most pieferably, the antagonist-impermeable material release of at least about 99% of the antagonist from the sequesteung subunil m the gastrointestinal tract for a time period that is greater than 24 hours.
  • tiie autagonisi-mipeimeabie material prevents ⁇ r substantialii the release of the ad ⁇ ersne agent ftom the sequestennit subunit for a time period of at least about 72 hours
  • the first antagonist-impermeable material comprises a hydrophobic material, such that the antagonist is not released or substantially not released during its ttansit tbough the gasfiointestinai tiact when ad ⁇ iinisieied orally as intended, without having been tampered with Suitable hydrophobic materials for use in the invention are described herein and sd forth below
  • the hydrophobic material is prefeiably a pharmaceutical!) acceptable hydiophobic material P ⁇ eferahk, the pharmaceutically acceptable hydrophobic material comprises a celiutose poh mer.
  • the first antagonist-impermeable material comprises a polymei insoluble in the gastrointestinal tract.
  • a polymer that is insoluble m the gastrointestinal tract will prevent the release of the antagonist upon ingestion of the sequestering s ⁇ bunit I foe polymer can be a cellulose or an acrylic polymer
  • the cellulose is selected from the group consisting of ethyfcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, and combinations thereof
  • btln lcelhilose includes, for example, one that has an ethoxy content of about 44 to about 55 0 O.
  • Ethylcelluiose can be used in the form of an aqueous dispersion, an alcoholic solution, or a solution in other suitable sohents.
  • the cellulose can ha ⁇ c a degree of substitution I D. S ⁇ on the anhydroglucose unit, from greater than £ ⁇ iio and up to 3 inclusive.
  • degree of substitution is meant the aveiage number of hydroxy! groups on the anhydro. glucose unit of the cellulose polymer that are replaced by a substituting group.
  • Representative materials include a polymer selected from the group consisting of cellulose acylate. cellulose diacylate.
  • cellulose vriaevSate cellulose acetate, cellulose diacetate, cellulose triacetate, monocelhii ⁇ se alkanylate, diceSlulosc alkanylate, tucelSulose alkaaj late, monocellulose alk ⁇ n lates, dicellulose adenylates, t ⁇ eellulose alkcnylates, monocellulose aro ⁇ latcs, dicellulose aroylates, and tricellulose ar ⁇ ylatcs
  • More specific celluloses include cellulose propionate having a D S of 1 S and a propyl content of 39.2 to 45 and a hydroxy content of 2,8 to 5.4%; cellulose acetate butyrate ha ⁇ iug a D.S of LS 1 an acetyl content of 13 to 15° a and a butuyl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxy content of 0 5 to 47%, cellulose triacj late hav ing a D S of 2$ to 3, such as cellulose triacetate, cellulose tmalerate, cellulose trilaurate.
  • cellulose tripatmitatc, cellulose trisuccioate, and cellulose trioctan ⁇ ate cellulose diacylatcs having a D.S of 2.2 to 2 6.
  • cellulose disuccioate, cellulose dipalmitate cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose such as cellulose acetate but ⁇ rate, cellulose acetate octanoate vafytate, and cellulose acetate p ⁇ op ⁇ nate.
  • Additional cellulose polymers useful for pieparing a sequestering suhur ⁇ t of the invention includes aeetaldehyde dimethyl cellulose acetate, cellulose acetate ethyfcarbamate, cellulose acetate methycarbamate and cellulose acetate dimethylaminocei lulose acetate
  • the acrylic polymer preferably ts selected from the group consisting of r ⁇ ethacryhc polymers, acry lic acid and mefhacrylic acid copolymers, methyi metrsaciylate copolymers, ethoxyethyl mothacryiates, cya ⁇ oetliyi methacrylate.
  • pol ⁇ (acrylic a ⁇ d ⁇ poh(raethacryi?c acid), methacryiic acid a ⁇ kylarmde copolymer, poly ⁇ mcthyl methacryiateK polymethacryiatc, poly(methyl methacrylatei copoly mer, polya ⁇ ylamsde, a ⁇ unoalkyi methac ⁇ ylate copolymer, po!y ⁇ methacryiic acid anhydride), glycidyi methacrylate copolymers, and combinations thereof.
  • An aenlie polymer useful for preparation of a sequestering sub ⁇ r ⁇ f of the imention includes awjlic resins comprising copolymers synthesized from acrylic and methacryiic acid esters ⁇ c g , the copoKnici of aery Hc acid lower aikyi ester and raeihacryhc acid lower alky! ester) containing about 0,02 to about 0 03 mole of a rri (Sower alkyl) ammonium group per mole of the acrylic and methacryhc monomer used.
  • a suitable acrylic resin is amnionic methacrvlate copolymer NF2L a polymer manufactured by Rohm Pharma GmbH, Darmstadt, Germany, and sold under the Eudnigik ⁇ trademark Tudragit RS30D is prefeired hudrauitO ⁇ is a water-insoluble copolymer of ethyl acrylaie (HA), methyl methaciylatc (MM) and tnmethylaimnonimnetiiyl methacrvlate chloride (TAM) in which the molar ratio of TAM to the remaining components (FA and MM) ⁇ s I 40
  • Acrylic resins such as Eudi'agitl-, can be used in the form of an aqueous dispersion or as a solution in suitable solvents
  • the antagonist-impermeable material is selected from the group consisting of polylactic acid, poiygiycolic acid, a co ⁇ polj mer of poiylactic acid a «d poiygiycolic acid, and combinations thereof,
  • the hydrophobic material includes a biodegradable polymer comprising a polytlactic glycolic aeid) ⁇ '"P ⁇ .GA"'), a polylactide, a polyglycokle, a polyanhydtide. a poiycaprolac tones, polypbosphazenes. polysaccharides, proteinaceous polymers.
  • the biodegradable polymer comprises a poly (lactic glycolic acid), a copolymer of lactic and glycolic acid, having ft molecular weight of about 2,000 to about
  • the ratio of lactic acid to giycoiie acid is preferably from about 10Oi to about 25:75, with the ratio of lactic acid to glycolic acid of about 65,35 being more prefer ⁇ ed
  • Poly(lactic glycolic acid) can be prepared by the procedures set forth in I 5 S Pat No 4,293,539 ⁇ Ludvv ig ct al ). which is incorporated herein by reference
  • I udwig prepares the copolymer by condensation of lactic acid and glycolic acid in ⁇ be presence of a readily removable polymerization catalyst (e.g . a strong ion-exchange resin such as Dowex HCR- W2-H)
  • a readily removable polymerization catalyst e.g a strong ion-exchange resin such as Dowex HCR- W2-H
  • the amount of catalyst is not critical to the polymerization, but typically is from about 0.0] to about 20 part?, by weight re lathe to the total weight of combined lactic acid and giyc ⁇ lic acid.
  • the polymerization reaction can be conducted without solvents at a temperature from about 10CP C.
  • Suitable plastickers for example, acetyl triethyi citrate, acetyl triburvl citrate, triethyl curate, diethyl phthalate, dibutv l phthalate. or ⁇ biitvl sebacate, also can be admixed with the polymer u ⁇ ed to make the sequestering subunit.
  • Addit ⁇ es. such as coloring agents, talc and/ ⁇ r magnesium stearate, and othei additives also can be i ⁇ ;>ed in making the present inventive sequestering subunit
  • additiv es may be included m the compositions to imprm e the sequestering characteristics of the sequestering subunit ⁇ s deset ibed below , the ratio of additives or components with respect to other additiv es or components may be modified to enhance or delay improve sequestration of the agent contained within the subunit
  • a functional additiv e i.e.. a charge-neutralizing additive
  • a water-soluble core i.e.. a sugar sphere
  • a swfactant may serve as a charge-neutralizing Such neutralization may in certain embodiments i educe the swelling of the sequestering poKmer by hydration of positively charged groups contained therein.
  • Surfactants s ionic or non-ionic) oiay also be used in preparing the sequestering subunit It is preferred that the surfactant he ionic Suitable exemplary agents include, for example, alkylary! sulphonates, alcohol sulphates, sulphosuccmates, sulphosuccinamates. sarcosi ⁇ ates or taurates and others.
  • Additional examples include but are not limited to ethoxylated castor oil, ben/aikonmni chloride, poSyglycoiyzed glyce ⁇ des acerylated rnonoglyce ⁇ des, sorbitasi fatty acid esters, poloxamers, polyc ⁇ yethylene fatty acid esters, polyox ⁇ ethylene derivatives, moaoglycerides or ethoxylated derivatives thereof, dighce ⁇ des or poK'oxycthylene derivatives thereof, sodium docusate, sodium lauryl sulfate, dioct ⁇ ⁇ sodium sulphosuccinate, sodium lauryl sarcosinate and sodium methyl cocoyl taurate, magnesium lauryl sulfate, t ⁇ ethanolarnine.
  • cetrimide sucrose laurate and other sucrose esters, glucose (devtiose) estei.s, .simethicone, ocoxv ⁇ ol, di ⁇ ctyl sodiumsiilfosuceinate, poiyglycolyzed giycerides, sodiumdodecylbenzene sulfonate. dialkyl sodmr ⁇ siilfosuccmatc, fatty alcohols such as lauryl. cetyl, and ster ⁇ Lglyceryl esters, cholic acid or derivatives thereof, lecithins, and phospholipids. These agents are Upicaily ehatacten/ed as ionic (i e .
  • anionic or catio ⁇ ic) oi nonionic In ccttain einbodiinenls described herein, ant anionic surfactant such as sodium iaurxl sulfate (SLS) is preferably used (U S. Pat. No. 5,725,883; U.S. Pat Ko. 7,201,920, EP 502642A1; Shokri et al. Pharra Sci. 2003. The effect of sodium loury!
  • SLS sodium iaurxl sulfate
  • Sl. S is particularly useful in combination with Fudragit RS when the sequestering subunit is built upon a sugar spheie substrate.
  • SI S at iess than approximately 6 3% on a basis ieiatKe to the sequestering poly met may provide a chaige neuUaSi-dng function (theoretically 20% and 41% neutralization, respectfulh), and thereby significantly slow the release of the acme agent encapsulated thereby (i.e.. the antagonist naltrexone), Inclusion of more than approximately 6 3% SLS relativ e to the sequestering polymer appears to increase release of the antagonist from the sequestering subimit.
  • SLS used m conjunction w ith Kudragit x RS, it is piefe ⁇ ed that die SLS is present at approximates) 1 %, 2V 3%, 4 c !o ot 5 0 O. and typically less than 6% on a w w basis ieiatne to the sequestering polymer ⁇ i e.. Eudragit' RS).
  • SLS may be present at approximately Lt% or approximately 3 3*?O ielame to the sequestering polymer
  • agents i e., soifactants
  • u&cful agents include those that may physically block migration of the antagonist from the subun.it and / or enhance the hydrephohiciiy of the barrier.
  • One exemplary agent is talc, which is commonly used in pharmaceutical compositions (Pawar et al Agglomeration of Jbf ⁇ rqfen With Talc by Xovel ( rystallo-Co- ⁇ ggbwcnrtion fevln ⁇ que ⁇ AFS PharmSci Tech. 2004; 5(4)- article 55). As shown in the Examples, talc is especially useful where the sequestering subunit is built upon a sugar sphere core.
  • talc ⁇ n> form of talc be used, so long as it does not detrimentally affect the function of the composition
  • Most talc results from the alteration of dolomite (CaMg(CO ⁇ h or magnesite (MgO) in the presence of excess dissolved silica (SiO;) oi by altering serpentine or quartzite Tale may be include minerals such as trcmolite ( CaMgI(SiOOO, seipenline J 3MgO 2S?0; 2 ⁇ R ) )_ anthophylhie ( Mg- (OHb ( SMOH):), magoesite.
  • talc mica, chlorite, dolomite, the caicite form of calcium carbonate (CaCOO- iron oxide, carbon, quart/, and - or manganese oxide.
  • the presence of such impurities may be acceptable m the compositions described herein provided the function of the talc is maintained, ⁇ t is preferred that that talc be USP grade.
  • the function of talc as described herein is to enhance the hydrophobic ⁇ and therefore the functionality of the sequestering polymer.
  • Mam substitutes for talc may be utilized in die compositions described herein as may be determined b ⁇ one of skill in die art It has been determined thai the ratio of taic to sequestering polymer may make a diamatic diiVeience m the functionality of the compositions described hoi em.
  • the Fxamples described below demonstrate that the taic to sequestering polymei ratio ( ⁇ i ⁇ ) is important with respect to compositions designed to present the release of naltrexone therefrom, it is shown therein that inclusion of at) equiv alent amount (on a weight-In -weight basis) of talc and E ⁇ tdragit ⁇ RS results m a very low naltrexone release profile in contrast, significantly km ei oi higher both a lower ⁇ 69 IS ⁇ Wu) and a lnghei ( 151% w w) RS ratios result in increased release of naltrexone ielcase Thus, where talc and Eudragit* RS are utilized, it is preferred that talc is present at approximately 75%.
  • the most beneficial ratio for other additives or components will vary and may be determined using sHindaul experimental procedures in certain embodiments, such as where a watet-soiuble coie is utilised, ii is useful to include agents that may affect the osmotic pressure of the composition (i.e , an osmotic pressure regulating agent) (see, m general WO 2005 046561 A2 and WO 2005/046649 ⁇ 2 relating to fcudfamode*).
  • osmotic pi cssiit e iegiilatitig agent is pieferabl) positioned immcdiatclj beneath the actne agent layci.
  • Suitable osmotic press ⁇ ie regulating agents may include, foi instance, hydrox>piOpy!mcthyi cellulose ⁇ HPMC) or chloride ions (i.e . from NaCl), or a combination of !
  • HPMC may have a molecular weight ranguig from about 10,000 to about L500.000. and typicalh from about 5000 to about ⁇ 0,000 (low molecular weight HPMC).
  • the specific of HPMC is typically from about I ! *? to about 1 31, with an .specific giaw.y of about 1 26 and a v iscositv of about 3600 to 5600.
  • HPMC may be a water-soluble synthetic polymei. Examples of suitable.
  • lcelluiose polymers include Methocel R lOO LV ami Mclhocel K4M (Dow).
  • Othci IiPMC addithes arc known in the art and may be suitable ui preparing the compositions described herein ⁇ $ shown in the Examples, the inclusion of NaCl (w ith HPMC) was found to have posifrveh affect sequestration of RS in certam embodiments, it is preferred ihai the charge- neutraliziog addstne ⁇ i e.. KaC i) is included at less than approximately I 2, 3. 4, 5. 6, 7.
  • a sequestering subunit buiit upon a sugar sphere substrate is prov ide d comprising a sequestering polymei ⁇ ?
  • the therapeutic agent of the present inventive compositions can be any medicinal agent used for the treatment of a condition or disease, a pha maceutically acceptable salt thereof, or an analogue of either of the foregoing
  • the therapeutic agent can be, for example, an analgesic (e g , an opioid agonist, aspirin, acetaminophen, nonsteroidal aoti-mflarar ⁇ aton drags ("NSAIDS”), N-meth>l-D-aspartate (“"NMDA”) receptor antagonists eycooxjgenase-II inhibitois pCO ⁇ -H inhibitors”), and gi) curse ieceptor antagonists), an antibaeteiial agent an agent, an anti-microbial agent,
  • an analgesic e g , an opioid agonist, aspirin, acetaminophen, nonsteroidal aoti-mfl
  • the therapeutic agent is one that is addicth e (physically and/or psychologically) upon repeated use and typically leads to abuse of the thesapeutic agent, In ibis regard, the therapeutic agent can he M ⁇ y opioid agonist as discussed herein
  • the therapeutic agent can be an opioid agonist.
  • 'Opioid ' ' is meant to include a diug. hormone. 01 other chemical ot biological substance, natural or synthetic, having a sedat ⁇ e, narcotic, or otherwise simiiai effect(s) to those containing opium or its natural or synthetic derivatives
  • opioid agonist,' sometimes used herein interchangeabi ⁇ with terms “opioid 1” and ' " opioid analgesic, " is meant to include one or more opioid agonists, either alone or in combination, and is tbrther meant to include the base of the opioid, mixed or combined agomsi-amag ⁇ nists, partial ago ⁇ isb, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof.
  • Opioid agonists include, for example, alfentantl, alls Iprodi ⁇ e. alphapiodine. anileridine, henzylmurphme, bezitramide, buprenorphine, butorphanol, domtazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromtde, dihvdrocodeiiie dilrydroetorphinc, dihydinmorphine, dimcnoxadol, dimcphcptanol, dimethylthiambutene, dioxaphetv! butyrate.
  • the opioid agonist is selected from the group consisting of hydrocodone, hydromoi phone, oxycodone, di ⁇ n drocodeme, codeine, dih> dromo ⁇ hine, morphine, buprenorphine, or complexes thereof, pharmaceutical!) acceptable salts thereof, and combinations theieof Most prefejabh, the opioid agonist is morphine, hydtoniorphone, oxycodone or hydrocodone. in a ptei ' e ⁇ ed embodiment, the opioid agonist compiles oxycodone or hydrocodcme and is present in the dosage form in an araoimt of about ! 5 to about 45 mg, and the opioid antagonist compnses naltrexone and is present in the dosage form in an amount of about 0.5 to about 5 mg
  • Hydtocodoiie is a semisynthetic narcotic analgesic and antitussive with multiple nervous system and gastrointestinal action?. Chemically, hydrocodone is 4.5 ⁇ e ⁇ oxy-3- r»etlioxy-17 ⁇ tnethyhnorphinan-A-one, and is also known as dihydrocodeiiione ⁇ ike other opioids, hydrocodone am be habit-forming and can produce drug dependence of the morphine type. Like other opmm h ⁇ drocodone will depress i aspiration.
  • Oral tndfocodone is also available in Europe (e.g , Belgium, Germany, Greece. KaI) , Luxembourg, Norway and Swit/edaud) as an antitusshe agent
  • a pendederal formulation is also av ailable in Germany as an antitussive agent For use as an analgesic,
  • ⁇ common dosage form of h ⁇ d ⁇ ocodone is m combination with acetaminophen and is commeieially a ⁇ atlable, foi example, as I onab4* m the. United Slates from LUB Phaima, inc (Btussels, Belgium), as 2 5/500 mg ?
  • Owcodono chemicalh known as 7 - is an opioid agonist whose p ⁇ nc ⁇ al therapeutic action is analgesia
  • Othei therapeutic effects of oxycodone include anxiohsis euphoria and feelings of iciavatson.
  • the piecibo mechanism of us analgesic action is> not known but specific CNS opioid receptors for endogenous compounds with opioid-hke acttsity been identified throughout the biain and spmai cotd and pla) a ⁇ ole ⁇ n the analgesic effects of this di ug Oxycodone ss eommcicuilh a% as!
  • Oxx lRTM 40 nig or 80 nig oxycodone hydrochloride, and as Oxx lRTM, also from Puidue Phaima L P as tminediate-telease capsules containing 5 mg oxycodone indrochJorsde f lie un entjon is contemplated to encompass all such fotmulatious with the inclusion of an opioid antagonist and ot antagonist m sequesteied form as pan of a subunit composing an opioid agonist Oral hydiomoiphone is commercially in the United States, e g,, as Dilaiidid-I; from Abbott Laboratories ⁇ Chicago, III ⁇ . Ota!
  • morphine is conimeiciaily in the United States, e g , as Kadiaiv ⁇ from Fauldmg Laboratories ( Pbcataway, NJ.), hxemplary NS ⁇ iDS Include ibuprofen, diclofenac, naproxen, flurbiprofen, fenoprofen. flubufen, ketoprofen, indoprofen, piroprofen, carprofen. oxapio/in, pramoprofcn, nu ⁇ oprofe ⁇ , trioxaprofen, stiproten. aminoprofcn, tiaprofemc acid, fiuprafen. bucloxic acid, indomettaaem.
  • Exemplary NMDA receptor medicaments include moiphmans, such as dcxotronicthorphan or dextrophan, ketaminc, d-methadone, and pharmaceutically acceptable baits tbe.eof, and encompass dmgs that block a major intfaccilukr consequence of NMD ⁇ -receptor actuation, e.g though a gaiiglioside, such as (6-ammothexyU- 5-chloro-l -naphtbaienesuifbnamide.
  • moiphmans such as dcxotronicthorphan or dextrophan, ketaminc, d-methadone, and pharmaceutically acceptable baits tbe.eof, and encompass dmgs that block a major intfaccilukr consequence of NMD ⁇ -receptor actuation, e.g though a gaiiglioside, such as (6-ammothexyU- 5-chloro-l -n
  • narcotic analgesics such as moiphinc, codeine, etc in U S Pat Nos 5,321 012 and 5,556,838 (both to Mayer cl al ), both of which are incorporated herein by leference. and to tieat chronic pain in U S Pat. No. 5.502,05 S (Mayer et a!.), incorporated herein bv reference.
  • the N MDA agonist can be included alone or in. combination with a ⁇ oca! anesthetic, t>uch as lidocame, as described m these patents by Ma ⁇ er et al.
  • COX- 2 inhibitor include celeco. ⁇ b (SC-58o35X DL'P-697, OosuHde (C ⁇ iP-28238), meloxicam, 6-methoxy-2-naphth ⁇ lacetic acid (6-NMA), V ⁇ K-966 (also known as Vioxx). nabumetone ⁇ pjodrug fo ⁇ 6-MNA), nimesuhde, NS-398. SC-5766. SC-5S215. " 1-614. o» combinations thereof.
  • COX-2 inhibitoi on the oidei of tiorn about 0.005 iiig to about 140 rag per kilogram of body weight per day been shown to be therapeutically effective in combination with an opioid analgesic.
  • about 0 25 mg to about 7 g per patient per day of a COX-2 inhibitor can be administered in combination with an opioid analgesic.
  • the treatment of chrome pain ⁇ ia the use of glycine receptor antagonists and the identification of such drugs is described in ILS. Pat. No. 5,5 S 4,6BO (Weber et al ). which is incorporated herein by reference.
  • K acceptable salts of the antagonist or agonist agents discussed hciein include metal salts, such as sodium salt, potassium salt, cesium salt, and the like, alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as t ⁇ ethviamine salt, pyridine salt, picolme salt ethanolamine salt, methanoiamine salt, ⁇ cyclohexUaramc salt, N,N' ⁇ diben/ylcthylenedtam ⁇ ne sail, and the like; inorganic acid salts, such as hydrochloride, hvdrobromide, sulfate, phosphate, and the like: organic acsd salts, such as foimate.
  • metal salts such as sodium salt, potassium salt, cesium salt, and the like, alkaline earth metals, such as calcium salt, magnesium salt, and the like
  • organic amine salts such as t ⁇ ethviamine salt, pyridine salt, picolme salt ethanolamine salt
  • acetaie trifluot ⁇ aeetate, maieaie, taruatc, and the like
  • sulfonates such as methanes ⁇ lfonate, benzenesitlfonate, p-tolueaesulfonate, and the like
  • amino acid salts such as argmate. asparginate, glutarnate, and the like
  • the sustained-relcavc oial dosage forms car? include analgesic doses from about 8 mg to about 50 mg of hydiocodone pet dosage unit, In sustained-release oial dosage foims where hydromorphone is the therapeutically active opioid, it is included m an amount from about 2 mg to about 64 mg bydromorphonc hydrochloride
  • the opioid agonist comprises morphine
  • the sustained-release oral dosage forms of the invention include from about 2.5 mg to about SOO mg morphme. by weight
  • the opioid agonist comprises oxycodone and the sustained-release oral dosage forms include from about 2 5 nig to about HOO mg oxycodone.
  • die sustained-release oral dosage forms include fioni about 20 mg to about 30 mg oxycodone
  • Controlled release oxycodone formulations are known in the ait
  • the following documents describe various conti oiled-release oxy codone formulations suitable for use in the invention described herein, and processes for their manufacture.
  • the opioid agonist can comprise uamadol and the sustained-ie ⁇ ease oral dosage foims can include fiom about 25 nig to 800 mg uamadol par dosage unit.
  • Spheroids oi beads, coated ⁇ ⁇ h an active ingredient can be piepaied for example, by dissoh mg the acme ingiedient in water and then spra>mg the solution onto a sohstsate, for example, n ⁇ pane! 18 20 beads, lining a Wurster insert.
  • the resulting substtate-activc material optionally can he ovcicoated with a bamei material to separate the therapeutical Iv actne agent from the next coat of material e.g , ⁇ e-!eas>e- ⁇ eta ⁇ d» ⁇ g material Pieteiably, the batriei mateiial ib a matetial comptisi ⁇ g methj lcef ttilose
  • the barrier material does not affect the dissolution rate of the final product
  • Pellets comprising an actne ingredient can be prepared, for example, by a melt pclleti/ation technique Typical of such techniques is when the actne mgiedierst in finely divided foira Ls combined with a bmdei (also m paniculate foim) and olbei optional inert ingredients, and thereafter the mixture is pcllchzed. e.g . by mechanically the mixture in a high shear mixei io form the pellet (e g.. pellet, gia ⁇ ule&, spheres, heacta. etc .
  • a melt pclleti/ation technique Typical of such techniques is when the actne mgiedierst in finely divided foira Ls combined with a bmdei (also m paniculate foim) and olbei optional inert ingredients, and thereafter the mixture is pcllchzed. e.g . by mechanically the mixture in a high shear mixei io form
  • Suitable binder substances include for example, h) dr ⁇ genated castoi oil, hydrogemited vegetable oil, other hjdrogenated fats, fatty alcohols. fatt> acid esters, fatty acid glycetides, and the like.
  • the diameter of the extruder aperture or exit port also can be adjusted to vary the thickness of the extruded stiands Fiirtheunoie, the exit part of the extruder need not be round; it can be oblong, rectangular; etc fhe exiting strands can be reduced to particles using a hot ⁇ ire Bingoi , guillotine, etc
  • the melt-extruded multiparticulate system can be, fot example in the form of gianules. spheroids, pellets, 01 the like, depending upon the extruder exit orifice.
  • melt-extruded and " 'melt-extruded multiparticulate system(s) "1 and melt-extruded particles” are used interchangeably herein and include a plurality of subunits. preferably within a range of similar si/e and'or shape
  • the melt-extruded multiparticulates are preferably in a range of from about 0.1 to about 12 mm in length and c a diameter of from about O. I to about 5 mm in addition, the melt-extruded multiparticulates can be any geometrical shape within this ssze range. Alternately the extredate can simply be cut into desired lengths and div ided into unit doses of the therapeutically active agent without the need of a spheronization step.
  • the substrate also can be prepared via a granulation technique
  • rnelt- granulation techniques invoke melting a normally solid hydrophobic material, e g , a wax, and incorporating an acm e ingredient therein.
  • a coatmg composition can be applied onto a substrate by spraying it onto the substrate using any suitable spraj equipment.
  • a W ⁇ rstcr fiuidized-bed system can be used m which an air flow from underneath. fjuidizes the coated material and effects drying, while the insoluble poiymci coating is sprayed on
  • the thickness of the coating will depend on the characteristics of the particular coating composition, and can be determined by using routine experimentation
  • a su bun it in the form of a pellet or the like can be prepared by co-extruding a material c ⁇ mp ⁇ siug the opioid agoinst and a material comprising the opioid antagonist and/or antagonist in sequestered form.
  • the opioid agonist composition can cover, e.g , ov ercoat, the material comprising the antagonist and or antagonist in sequestered form.
  • ⁇ bead for example, can be prepared by coating a substrate comprising an opioid antagonist and ' Or an antagonist in sequestered form with a solution comprising an opioid agimist.
  • the sequestering subunits of the are particularly well-suited for use in compositions comprising the sequestering suhunit and a theiapeutic agent in re ⁇ easable form.
  • the invention also prov tdes a composition comprising any of the sequestering subunits of the invention and a therapeutic agent in releasabie form.
  • Yeleasable form is meant to include immediate release, intermediate release, and sustained-release forms.
  • the therapeutic agent can be formulated to provide immediate release of the therapeutic agent, in preferred embodiments, the composition provides sustained-release of the therapeutic agent
  • the therapeutic agent in sustained-release form is preferably a particle of therapeutic agent that is combined with a release-retarding material.
  • the release-retarding material is preferably a material that permits release of the therapeutic agent at a sustained rate in an aqueous medium.
  • the release-retarding material can be selectively chosen so as to achieve, in combination with the other stated properties, a desired in vitro release rate.
  • the oral dosage form of the invention can be formulated to provide for an increased duration of therapeutic action allowing once-daily dosing.
  • a release-retarding material is used to provide the increased duration of therapeutic action.
  • the once-daily dosing is provided by the dosage forms and methods described in U.S. Patent Application Pob. No. 20050020613 to Boehm, entitled “Sustained-Release Opioid Formulations and Method of Use. " filed on Sep. 22, 2003, and incorporated herein by reference.
  • Preferred release-retarding materials include acrylic polymers, alkylceJluloses, shellac, zein. hydrogenated vegetable oil, hydrogenated castor oil, and combinations thereof.
  • the release-retarding material is a pharmaceutically acceptable acrylic polymer, including acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl rnethacryiates, cynao ⁇ thyi methacryiate, aminoaikyi methacrylate copolymer, polytacrylic acid), poly(methacryi ⁇ c acid), methacrylic acid aikylamide copolymer, poly ⁇ methyl methacrylate), poiyjmethacrylic acid anhydride), methyl metha ⁇ ylate, polymemacryiate, poly(methyi methacrylate) copolymer, poiyacrylamide, aminoaikyi merhacrylate copolymer, and j
  • die acrylic polymer comprises one or more ammonio r ⁇ ethacryiate copolymers.
  • Ammonio methacrylate copolymers are well-known in the art, and are described in NRUl 1 the 21"' edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockvili ⁇ , Md.), as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary aoimonium groups.
  • the release-retarding materia! is an alkyl celSul ⁇ sic material, such as ethyicelhilose.
  • cellulosie polymers including other alky! cellulosic polymers, can be substituted for part or all of the ethylcellulose.
  • the release-modifying agent functions as a pore-former.
  • the pore-fcrmer can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • the pore-former can comprise one or more hydrophilic polymers, such as hydroxypropylmethylcelluiose.
  • the release- modifying agent is selected from hydroxypropylmethylcellulose, lactose, .metal stearates, and combinations thereof.
  • the release-retarding material can also include an. erosion-promoting agent, such as starch and gums; a release-modifying agent useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain; and/or a semipermeable polymer.
  • an erosion-promoting agent such as starch and gums
  • a release-modifying agent useful for making microporous lamina in the environment of use such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain
  • a semipermeable polymer such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
  • the release-retarding material can also include an exit means comprising at least one passageway, orifice, or the like.
  • the passageway can be formed, by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; »044,088,864, which are incorporated herein by reference.
  • the passageway can have any shape, such as round, triangular, square, elliptical, irregular; etc,
  • Ae therapeutic agent in sustained-release form can include a plurality of substrates comprising the active ingredient, which substrates are coated with a sustained-release coating comprising a release-retarding material
  • the sustained-release preparations of the invention can be made in conjunction with any multiparticulate system, such as beads, ion-exchange resin beads, spheroids, microspheres, seeds, pellets,, granules, and other multiparticulate systems in order to obtain a desired sustained-release of die therapeutic agent.
  • the multiparticulate system can be presented i ⁇ a capsule or in any other suitable unit dosage form, hi eeitam pr ⁇ fe ⁇ ed embodiments, moie than one multiparticulate system can be used, each exhibiting different characteristics, such a:> pl f dependence of release, time for release in in ⁇ ho size and composition.
  • the therapeutic agent can be coated "w nh an amount of release-retarding material sufficient to obtain a weight gain from about 2 to about 30V although the coat can be greater or lesser depending upon the physical properties of the particular therapeutic agent utilized and the desired release rate, among other things.
  • the coat can be greater or lesser depending upon the physical properties of the particular therapeutic agent utilized and the desired release rate, among other things.
  • Solvents typically used for the release-retarding material include pharmaceutically acceptable solvents, such as water, methanol, ethanol, methylene chloride and combinations thereof !n certain embodiments of the invention, the release-retarding material is m the form of a coating comprising an aqueous dispersion of a hydrophobic polymer
  • a plasticizer in the aqueous dispersion of hydrophobic polvmcr will further improve the physical properties of the Him foi example, because ethylcelkilose has a relatively high glass transition tempeiature and does not form flexible films under norma!
  • the amount of plasticizer included in a coating solution is based on the concentration of the fi!m- former, e g., most often from about 1 to about 50 peicenl by weight of the film-former Concentrations of the plastict/er. howeser, can be determined by routine experimentation, Examples of plastici/ers for ethj leellolo ⁇ e and other celluloses include dibutj l sebacate, diethyl pbiiiaiate, triethyl citrate, tributy!
  • plasticizers such as acetylated monoglycc ⁇ des, phthalatc esters, castor oil, etc
  • plasticizers for the acrvUc polymers include citric acid esters, such as trieth)! citrate NI-21, tiihuiv! citrate, dibufyl phthalate, and possibly 1,2-p ⁇ opylene glycol, po! ⁇ eth ⁇ iene gKcols, piopv!ene glycol, diethyl phthalate, castor oil.
  • the formulations of the invention can be atteied for example, by using more than one release - retarding material, varying the thickness of the release-retarding maLenal chaa ⁇ ia ⁇ the particular release- retarding material used, altering the relative amounts of release- tetardi ⁇ g material, altoting the manner in which the plastiei/ei is added ⁇ e g , when ⁇ he sustained-release coating is demed from an aqueous dispersion of hydrophobic polymer), by relative to retardant material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture: etc
  • the oral dosage form can utilize a multiparticulate sustained-release matrix
  • the sustained-release matrix comprises a hulropMlie and'or hydrophobic polymer, such as gums, cellulose ethers, acrylic renins and protein-derh ed materials Of these pohmeis, the cellulose ethers, specifically hydroxyalkylcelluioses and carboxyaikyleel.uloses, are preferred
  • the oral dosage form can contain between about 1% and about 80% ⁇ by weight) of at least one hvdrophilic or hydrophobic polymer
  • the hydrophobic materia! is preferably selected fiom the group consisting of alkylcellulose, acrylic and methaeiylic acid polymers and copolymers, shellac, zein. hydrogenated cantor oil, oil, ur mixtures theieof
  • the hydrophobic mate ⁇ al is a pharmaceuticalh acceptable acrylic polymer, including acn lic acid and methacrylic acid copolymers * , methyl meihaciyiate, methj l m ⁇ thaciylaie copoKmers, ethoxyeihyl raetliacrvlate, animoalkyl methacrylatc copolymer, poly(aciy licacid).
  • poiyt methacrylic acid methacrylic acid alkylamine copoi ⁇ nier. poiy(methy! methactylate), poly (methacrv tic acid ) ⁇ anhydride), polymcthacryiate, polyacrylainide, poiyfmethacA'hc acid anhydride), and glycidyi metha ⁇ ylate copolymers.
  • the hydrophobic material can also include hydroox ⁇ aik ⁇ lce!luloses such as hydroxypropyJmethykeUiilose and mixtures of the foregoing Piefeired lndiophobic mateiials ate watei-insoluble uith mote or less pio ⁇ ouneed heliophobic fiends Picfciabls, the hydrophobic materia! ha:> a melting point fi ⁇ rn about K ) ' C to about 200° C , more prefeiahiv fiom about 4 ⁇ ° C to about 90° C I he h ⁇ dtoph ⁇ bie material can include neima!
  • oi svnthetsc waxes fatty alcohols (such as Luu)i, tnyusty!, steaiyi, cet>) ot piefetably cetosieat) ! alcohol), fatty acids, mchtdnig fattv a ⁇ d esteis, fattv acid ghceudes (mono-, di-, and tn-giyceudes), hydiogenated fats, hydiocaiboiis normal waxes, stearic acid, stearyl alcohol and hvdiophobic and h ⁇ diophihc raate ⁇ ah mg hydrocaibon backbones
  • Suitable waxes include beeswax, ghcowax, castor wax, carnauha wax and wax-tike substances, e g , material normally solid at room tempeiature and ing a melting point of from about 3O 1- C to about 100
  • Ptcf ⁇ iabiv a combination of oi ntoie hydtophobic mate ⁇ als are included m the matrix formulation_. It an additional matcnal is included, it is prefeiabK a ⁇ atmai or svnthctic wax, a fatty acid, a tatty alcohol oi mixtures theieof. Examples include beeswax, carnauba stearic acid and steai ⁇ -1 alcohol
  • the sustained-release matrix comprises digestible, iong-cham
  • the sustaiued-ielease malax can contain up t ⁇ 60° a f bv weight) of at least one polvalkylene ghcol ⁇ n a prefers ed embodiment, the mat ⁇ x comprises at least one water-soluble hydtowalkvl cellulose, at least one i ⁇ :-( ⁇ ., ptefeiabh Cu-( ⁇ , aliphatic alcohol and, optionally at least one polyaikylenc glycol
  • the at least one hydio ⁇ yalk ⁇ l cellulose is prefeiably a hvdtoxv (C ⁇ -C f) ) alkvl cellulose such as and, preferabh .
  • cellobse T he amount of die at least one l cellulose m the oial dosage f ⁇ u will be determined, amongst other tluogs. by the precise iate of opioid jelease required
  • the amount of the at lea.st one aliphatic aicoho! in the present oral dosage form will be determined by the piocise iate of opioid release required. However, if will also depend on whether ⁇ lie at least one polyalkylene glycol is absent from the oral dosage fomi.
  • a spheromzing agent together with the active ingredient, can be &pheroni/ed to form spheroids
  • Microcrysiailme cellulose and hydrous lactose impalpable are examples of such agents.
  • the spheroids cart contain a watei-insoluble poly mer, preferab ' ⁇ an acrylic polymer, an acrylic copolymer, such as a methacrylic a ⁇ d-ethx- i acrylate copolymer or eth> !
  • the sustained-release coating will generally include a water-in soluble materia! such as (a) a wax, either alone or in admixture with a fatty alcohol or O)) shellac or zein
  • the sequestering subunit compiles the therapeutic agent in sustained- release form.
  • the sustained-release subunit can be prepared by any suitable method.
  • a plasticized aqueous dispe.si ⁇ i. of the iulease-tetaulmg materia! can be applied onto the subunit comprising the opioid agonist.
  • a sufficient amount of the aqueous dispersion of release-retarding material to obtain a predetermined sustained -release of the opioid agonist when the coated substrate is exposed to aqueous solutions, e g , gastric fluid, is preferably applied, taking into account the phvsical characteristics of the opioid agonist, the manner of incorporation of the plastici/er, etc.
  • a fuither cn ercoat of a f ⁇ iffl-formcr. such as Opadry (Colorcon, West Point, VaJ, can be applied after coating ⁇ * ith the release-retarding material
  • the subunit can be cured m order to obtain a stabilized release rate of the therapeutic agent
  • a stabilized product can be pieierably obtained by subjecting the subunit to ox en curing at a temperature abo ⁇ e the glass transition temperature of the plast ⁇ ci?ed acrylic poij mer for the required time period.
  • the optimum temperature and time for the particular formulation can be determined by routine experimentation.
  • a sustamed-relea.se matrix also can contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, fkvorants and glidants that are comentionai ni the pharmaceutical art.
  • the mechanical fragility of of the sequestering siibunits described herein is the same as the mechanical fragility of the therapeutic agent in reieasable tbroi.
  • tampering with the composition of the im ention in a manner to obtain the therapeutic agent will result m the destruction of the sequestering subunit such that the antagonist is released and mixed in with the therapeutic agent Consequently, the antagonist cannot be separated from the therapeutic agent, and the therapeutic agent cannot be administered in the absence of the antagonist.
  • Methods of assaying the mechanical fragilit ⁇ of the sequestering subunit and of a therapeutic agent are known in the art.
  • composition of the invention can be in any suitable dosage form or formulation, (see, e.g.. Pharmaceutic* and Pharmacy Practice, J. B. Lippincoit Company, Philadelphia, Pa., Banker and Chalmers, eds , pages 238-250 ( 19S2)).
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the inhibitor dissohed in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lo/enges. and troches, each containing a predetermined amount of the acthe ingredient as solids ot giamiles.
  • Liquid formulations may include diluents, such as water and alcohols, for example, cthano ⁇ , ben/yi alcohol and the polyethylene alcohols, either with or w ithout the addition of a pharmaceutically acceptable suifactant
  • Capsule forms can he of the oidinaiy hard- or soft-shelled gelatin type contaminu, for example, surfactants, lubricants, and ineit fillers, such as lactose, sucrose, calcium phosphate, and corn starch Tablet forms can include one or more of lactose, sucrose, ma ⁇ mtoL corn starch, potato starch, algink acid, microcrystalline cellulose, acacia, gelatin, g ⁇ ar gum, colloidal silicon dioxide, croscarrneibse sodium, talc, magnesium stearate, calcium sleaiate, /inc
  • Lozenge forms can comprise the active ingredient in a flavor, usualh sucrose and acacia or tiagacanth, as well as pastilles comprising the acthe ingredient in an ineit base, such as gelatin and giyeeiin, 01 sucrose and acacia, emulsions, gels, and the like containing, in addition to the acthe ingtedient such excipients as are known in the an
  • compositions of the invention can be modified in any number of ways, such that the therapeutic efficacy of the composition is increased through the modification.
  • the therapeutic agent oi sequestering subunu could be conjugated either directly oi indirectly through a linker to a targeting moiety
  • the therapeutic agent oi sequestering subunu could be conjugated either directly oi indirectly through a linker to a targeting moiety
  • targeting moiety refers to a ⁇ v molecule or agent that specifically recognizes and binds to a cell-surface receptor. such that the targeting moiety directs the deliv ery of the tlie ⁇ tpeutie agent or sequestering subumt to a population of cells on which the receptor is expressed
  • Taigeiing moieties include, but are not limited to. antibodies, or fragments theieof, peptides, hormones, growth factors, cytokines, and am other naturallv- or non- ⁇ atuialiy- hgarsds, which bind to cell-surface receptors.
  • linker ' refers to any agent or molecule that bridges the therapeutic agent or sequestering subumt to the targeting moiety
  • sites on the theiapeutk agent or sequestering subunil which are not necessary foi the function of the agent or sequestering subunit are ideal sites for attaching a linker and or a targeting moiety, provided that the linker and oi targeting moiety, once attached to the agent or sequestering subunit, do(es) not interfere w ith the function of the therapeutic agent or sequestering s ⁇ hunn
  • the composition is preferably an oral dosage form
  • oral dosage form' is meant to include a unit dosage form prescribed oi intended for oral adr ⁇ imsrjation comprising subu ⁇ its Desiiably.
  • the composition comprises the sequestering subunit coated with the therapeutic agent in ⁇ deasable form, thereby founing a composite subunit comprising the sequestering subunit and the therapeutic agent,
  • the invention further pros ides a capsule suitable for otal administration comprising a plurality of such composite subimits. Akematheiy.
  • the oral dosage form can comprise any of the sequestering subumts of the im ention in combination with a therapeutic agent subun ⁇ t the lheiapeutic agent subunit comprises the therapeutic agent in releasahle form
  • the ⁇ mention provides a capsule suitable for oral adramisttaticm comprising a plurality of sequestering subunits of the imentson and a pluraht) of therapeuuc subumts, each of which comprises a therapeutic agent in reieasable form
  • the invention furthei provides tablets comprising a sequestering subunit of (he invention and a therapeutic agent m ieleasable foim
  • the invention provides a tablet suitable for oral administration comprising a first layer comprising any of the sequestering subumts of the invention and a second layer comprising therapeutic agent m re leasable form, wherein tlie first layer is coated with the second layer
  • the first layer can comprise a plurality of sequestering subunits
  • the frtsi layer can be or can consist of a single sequestering subunit.
  • the therapeutic agent in releasable form can be in the f ⁇ rni of a therapeutic agent subun.it and the second layer can comprise a plurality of therapeuuc subunits. Alternately, the second layer can comprise a single substantially homogeneous layer comprising the therapeutic agent in releasable form.
  • the sequestering s ⁇ bumi ⁇ in be in one of several different foims
  • the system can further comprise a second antagonsst-mipetmeable materia ⁇ , m which case tlie sequestering unit comprises an antagonist, a first antagonist-impermeable matetiai, a sec ⁇ nd antagonisHrnpeimeabie material and a coie.
  • the core is coated with the first antagonist-impermeable material which, in turn, is coated with the antagonist, which, in u»n, ts coated wiih the second antagonist-impermeable material Hie first antagonist-impermeable material and second antagonist-impermeable material substantially prevent release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the first antagonist-impermeable material is the same as the second antagonist-impermeable materia! In otiiei instances, the fust antagonist-impermeable materia!
  • the second antagonist-impermeable material is different from the second antagonist-impermeable material It is within the skill of the oidinary artisan to deteimine whether oi not the Hist and second antagonist- impermeable materials should be the same cu diffeient. Factors that influence the decision as to whether the first and second antagonist-impermeable materials should be the same or different can include whether a layer to be placed over the antagonist- impermeable material requires certain properties to prevent dissolving pait or all of the antagonist-impermeable layer when applyiug the next layer or properties to promote adhesion of a layer to be applied over the antagonist- impermeable layer.
  • the antagonist can he incorporated into the core, and the core is coated with the first antagonist-impermeable material.
  • the invention provides a sequestering subunit comprising an antagonist, a core and a first antagonist- impermeable material wherein the antagonist is incorporated into the core and the core is coated with the first antagonist-impermeable material and wherein the first antagonist- impermeable material substantially prevents release of the antagonist from the sequestering subunii in the gastrointestinal tract for a time period that is greater than 24 hours.
  • 'incorporate' ' and words stemming therefrom is meant to include any means of incorporation, e.g.. homogeneous dispersion of the antagonist throughout the core, a single layer of the antagonist coated on top of a core, or a multilayer system of the antagonist, which comprises the core.
  • the core comprises a water-insoluble material and the core is coated with the antagonist, which, in lorn, is coated with the first antagonist-impermeable material.
  • the indention further provides a sequestering subunit comprising art antagonist, a first antagonist-impermeable materia!, and a core, which comprises a water-insoluble material, wherein the core is coated with the antagonist, which, in turn, is coated with the first antagonist-impermeable material and wherein the first antagonist-impermeable materia! substantially presents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • water-insoluble material as used herein means any material mat is substantially water-insoluble.
  • substantially water- insoluble does not necessarily refer to complete or 100% wafer-insolubility. Rather, there are varying degrees of water insolubility of which one of ordinary skill in the art recognizes as having a potential benefit.
  • Preferred water-insoluble materials include, for example, microcrystalline cellulose, a calcium salt, and a -wax.
  • Calcium salts include, but are not limited to. a calcium phosphate (e.g., hvdroxyapatite, apatite: etc), calcium carbonate, calcium sulfate, calcium stearate, and the like.
  • Waxes include, for example, cauiuba wax, beeswax, petioleum wax, canddilSa wax. and the like.
  • the sequestering subunit includes an antagonist and a sea! coat where the sea! coat forms a layer physically separating the antagonist within the sequestering suhunu from the agonist which is layered upon the sequestering subunit.
  • the seal coat comprises one or more of an osmotic pressure regulating agent, a chaige-noutiaii/iitg additive, a sequestering polymer hydrophohicHy-enhaneing additn e, and a first sequestering polymei (each haung been desciibed abo ⁇ e). in such embodiments, it is preferred that the osmotic pressure regulating agent, charge- neutralizing addime.
  • Standaul tests may be utilized io ascettam the antagonist's effect on agonist function (i e., reduction of pain ⁇ .
  • the sequestering subunit of the can hav e a blocking agent that is a tether to which the antagonist is attached.
  • the teim "tether" as used herein iefers to am means by which the antagonist is tethered or attached to the interior of the sequestering subimit, such that the antagonist is not released, unless the sequestering subunii is tampered with. Ui this instance, a tether-antagonist complex is formed.
  • the complex is coated with a tether-irnpeimeable mateiiah thereby substantially pies en ting release of the antagonist furni the subunit.
  • the terra "tethei-impeimeable material" as ms ⁇ herein refers to any material that substantially presents or the teihef from petmeating through the mate ⁇ al.
  • the tether pieferably is an too exchange resin bead.
  • l he imenuoti further provides a tablet suitable for oral administration composing a single la ⁇ er comprising a therapeutic agent in releasable form and a plurality of any of the sequestering suhunils of the im enium dispersed throughout the layer of the therapeutic agent in releasabie form.
  • Hie im ention also ⁇ ro ⁇ ides a tablet in which the therapeutic agent in releasable form is in the form of a therapeutic agent subitnit and the tablet comprises an at least substantially homogeneous mi ⁇ tuie of a plurality of sequestering subunits and a plurality of subunits comprising the therapeutic agent !
  • oral dosage forms ate prepared to include an effective amount of melt-extruded sub ⁇ mts in the form of raultipartic ⁇ es % ithin a capsule
  • a plurality ⁇ f the melt-extruded muliparticulates can be placed m a gelatin capsule in an amount sufficient to provide an effects e release dose when ingested and contacted by gastric fluid.
  • the subunits e.g , in the form of multiparticulates
  • Exciptents in tablet formulation can include, for example, an inert diluem such as lactose, granulating and disintegrating agents, such as cornstarch, binding agents, such as starch, and lubricating agents, such as magnesium stearate.
  • the subunits are added during the extrusion process and the ettrudate can be shaped into tablets as set forth in U. S Pat. No 4, ⁇ 57,681 (Klimesch et al. ⁇ , which is incorporated herein by reference.
  • the sustamed-reicasc. melt-extruded, multiparticulate systems or tablets can be coated, or the geJatm capsule can be fuithei coated, uuh a sits ⁇ anied- reiease coating, such as the sustained-release coatings described herein
  • Such coatings are panicdaily useful when the subunil comprises an opioid agonist in ieleasabie fo ⁇ n, but ⁇ c*t ia sustained-release form.
  • the coatings preferably include a sufficient amount of a hydrophobic materia! to obtain a weight gam foira about 2 to about 30 percent, although the overcoat can be greater, depending upon the physical properties of the particular opioid analgesic utilized and the desired release rate, among other things
  • the raelt-extruded dosage forms can further include combinations of melt- extruded multiparticulates containing one o ⁇ more of the therapeutically active agents before being encapsulated Furthermore, the dosage forms can also include an amount of an immediate ieleasc ⁇ hetape ⁇ tic agent for prompt tbeiapemie effect
  • the immediate release therapeutic agent can be incorporated oi coated on the surface of the subunits after preparation of the dosage forms (e.g . control led -release coating or matrix-based). Tiie dosage forms cast also contain a combination of control led-release beads and matrix multiparticulates to a desired effect.
  • the sustained-release formulations preferably slowly release the the ⁇ eittie agent, e g.. when ingested and exposed to gastric fluids, and then to intestinal fluids
  • the sustained-release profile of the niek-ex.ruded formulations can be altered, for example, by the amount of retardatrt, e.g.. hydrophobic material by the amount of plastiC ⁇ zer relative to hydrophobic material, by the inclusion of additional ingredients or e ⁇ cipients. by altering the method of manufacture; etc.
  • the melt-extruded material is prepared without the inclusion of the subunits, which are added thereafter to the extrudate
  • Such formulations can ha ⁇ e the subunits and other drugs blended together with the extruded matrix material, and then the miviuie is tabieted in order to ide a slow ielease of the therapeutic agent or other drugs.
  • Such formulations can be particularly advantageous, for example, when the therapeutically active agent included m the formulation is sensitne to temperatures needed for softening the hydrophobic materia!
  • the release of the antagonist of the sequestering sobunit or composition is expiessed in terms of a ratio of the release achieved after tampering, eg , by crushing or chew ing, relative to the amount released from the intact formulation
  • the iatio is, thetefoie, expiessed a& [Cr ⁇ nhedj.[Wholej, and it is desired that tins ratio have a numerical range of at least about 4 1 or greater [e.u. , crushed release within I hour/intact release iu 24 hours).
  • the iatio of the therapeutic agent and the antagonist present ⁇ n the sequesteiing subunit, is about I J, about 50.1, about 75 1, about 100 1 , about 150 I , or about 200" I, foi example, b> weight, preferably about 1 .1 to about 20.1 by weight oi !5 ! to about 30.1 by weight.
  • the weight tatio of the therapeutic agent to antagonist refers to the weight of the active ingredients HUB, for example, the w eight of the therapeutic agent excludes the weight of the coating, matrix, or other component that renders the antagonist sequestered, or other possible exc ⁇ ients associated with the antagonist particles, in certain preferred embodiments, the ratio is about 1.1 to about 10 1 by weight.
  • the amount of such antagonist wnhm the dosage form can be more w idely than the therapeutic agent antagonist combination dosage forms, where both are available for release upon administration, as tlte formulation does not depend on differential metabolism or hepatic clearance for proper functioning.
  • the amount of the antagonist present in a substantially n ⁇ n-releasabie form is selected as not to be harmful to humans, even if fully released under conditions of tampering
  • the composition;? of the [mention are particularly well-suited foi use in presenting abuse of a therapeutic agent, hi this regard, the (m ention also presides a method of preventing abuse of a therapeutic agent by a human benig.
  • the method comprises incorporating the therapeutic agent into any of the compositions of the imeniion Upon administration of the composition of the invention to the person, the antagonist is substantial!) from being released in the gastrointestinal tract for a time period that is grcatei than 24 hours.
  • the sequestering subunit which is mechanically fragile, v ⁇ ili break and thereby allow the antagonist to be released. Since the mechanical fragility of the sequestering subunit is the same as the therapeutic agent in releasable form, the antagonist will be mixed with the therapeutic agent such that separation between the two components is virtually impossible
  • the effectiveness of treatment of chronic moderate to severe pain is typically measured by mean change in diary Brief Pain Inventory (BPl) seoie of av erage pain (daily scores of average pain averaged over 7 days, in-clinic BP! and/or dailv diary BPI ⁇ worst, least, and current pain)), WOMAC Osteoarthritis Index, Medical Outcomes Study (MOS) Sleep Scale, Beck Depression Inventory, and Patient Global impression of Change (PGlC).
  • BPl diary Brief Pain Inventory
  • MOS Medical Outcomes Study
  • PHS Patient Global impression of Change
  • BPi is typically measured using 11 -point BPl system as follows L Ptease pain circling the one number that best describes your pain at its worst in the last 24 hours.
  • the Reek Depression inventory is a self-admin&tered, 2 i -item test in multiple-choice format that measures the presence and degree of depression (Beck et al. An im entory for measuring depression ⁇ teh (Jen Psych 1%1 :4 561 -571 ).
  • Lach of the inx entoiy questions corresponds to a specific category of depressive symptom and or attitude. Answers are scored on a 0 to 3 scale, where " v 0 " ' is minimal and u ⁇ i6 severe A scote of -- 15 indicates raild depression, a score of 15-30 indicates moderate depression, and a score >30 indicates depression
  • the WOMAC Osteoarthritis index consists of questions on three subscaies' Pain, Stiffness, and Physical Function (Bellamy et al. Validation stixis of WOMAC : a health status instrument for measuring clinically important patient ant outcomes to antirheumatic drug tlierap ⁇ in patients with osteoarthritis of the hip or knee, J Rheumatol 1988; 15 1833-1840; Bellamy K Pain assessment in osteoarthritis: experience with the WOM ⁇ C osteoarthritis index Semin Arthritis Rheum.
  • the PGIC is based on the Clinical Global Impression of Change (CGIC) (Guy W. M. ' DL-li assessment manual for psychopharmacology. Washington. DC: Department of Health, Education and Welfare, 197 ⁇ ;217-222, Publication Number (ADM) 76-338), which is a validated scale.
  • CGIC Clinical Global Impression of Change
  • ADM Publication Number
  • Prcn iced herein are methods for treating pain in a person comprising administering thereto a multilayer pharmaceutical composition as described herein such that pain is substantially relieved m the patient.
  • substantially relieved is meant that the person reports a decrease in pain as measured by any of several known methods (including but not limited to those described herein) for determining pain. This decrease may be in comparison to no treatment, a placebo, or another form of treatment Including but not limited to another composition, either one described herein or otherwise available to one of skill in the art.
  • pain is considered substantially relieved where the decrease is significant (e.g., ⁇ 0.05).
  • the methods described herein provide methods for substantially relieving pain (e.g, providing an analgesic effect ⁇ for time periods of at least one week ⁇ eg , two, four, eight, 52, 16, 20, 24, 28, 32, 36, 40 and 100 weeks) by admimsteiing a multi-lavei pharmaceutical composition as descnbed liejein in one ei ⁇ bodiiuciit.
  • the method includes icguiativ adnimistcting (e g , at least once, twice, three, or four times ) & multi-k> ⁇ pharmaceutical composition comprising an agonist and an atagooist as descnbed herein for at least one week le g., one, two, four, eight 12, 16, 20, 24, 28, 32, 36. 40 and 100 week** ⁇ wherein no substantial release (e g , zero, or less than about 10% 20V or 30° o release) of the antagonist is observ ed, in some embodiments, administration of the composition to a population once daily for a tune pe ⁇ od of at least one week results m no substantial ⁇ e ⁇ ease in at least about Wo, 80% v 70 0 O, ft ⁇ %. or 5Q% of the making up the population Release ma> be measured by detecting naltrexone or (1-naltrexoi in plasma.
  • Exemplary KadianNT formulations and methods described below in Examples 1 - 4 may also be found in PCT/US2OO7/014282 (WO 2007/149438 A2), PCT/US2007/021627 (WO 2008/063301 A2), and PCT/US08/ 10357.
  • Kadian NI pellets with naltrexone pellet coat thickness of I5 ⁇ m had comparable naltrexone release as KT pellets with 90 um coat thickness
  • This comparable NT ielease may also be attributed ftom the presence of 50 ⁇ m seal coat on the sugar spheres used in Kadian NT pellets
  • Significant NT sequestering was observ ed, both at fasting (>97%) and fed states ( ⁇ "-%%)
  • Kadian NT pellets conia ⁇ nng sodium chloiide above the naltrexone pellet coat (Fi-H 1 J?) had half the release of naltrexone compared to Kadian NT pellet without sodium chloride (PI- 1496), consistent with in vitro results There is again food effect observed. Lag time was significantly reduced.
  • C max Relative bioavailability based on Cmax ::: Dose-adjusted ratio of Cmax (NT/KNT pellet) to Cmax (NT soin)
  • BA (AUC inf) ⁇ Relative bioavailability based on AUC inf ⁇ Dose-adjusted ratio of AUC iuf (NT/KNT pellet)
  • components (a), (b) and / or (c) may be included as described below;
  • Kadian KT ⁇ 60mg morphine sulfate.
  • 2.4i ⁇ g naltrexone H(T) was administered io humane and compared to the piewously described product Kadian
  • Each Kadian sustained release capsule contains either 20. 30, 50. 60. or 100 mg of Morphine Sulfate USP and the following inactive ingtcdients common io ail strengths.
  • naltrexone (parent ⁇ is iapidly absoibcd and coin cited to the metabolite is a opioid antagonist than naltrexone. ing onl> 2 to 4°o the antagonist potencv Most patients had quantifiable levels ⁇ > U 25 pg/mL) of 6- ⁇ -naitrexol The incidental piescnce of 6- ⁇ - ⁇ aitrexol m the plasma had no effect on pain scores
  • Oth ⁇ measuteraents including hi-Chmc Pain, WOM ⁇ C Pam, WOM ⁇ C Stiffness, WOM ⁇ C Daily Activ ities, and BP! Pain w cie albo made. It was ⁇ etct mined that the diffeiences in these measuiements in those taking Kadmn and those taking Kadian .N I ' was not significant as shown belcnv .
  • COWS Oimcal Opsale Wuhdiawal Scale
  • This long-term, open-label study evaluated the safety of Kadian NT administered once or twice daily (QD oi BID) o ⁇ ei a 12-month period Kadian ⁇ S T was used in dosage strengths of 20 rag, 30 mg, 40 nig, 50 mg, 60 mg, 80 mg and 100 mg. There no maximum allowable daily dose set for this study Subjects wete titrated upward as needed in a manner consistent with the current Kadian" labeling and in accordance with the investigator's best medical judgment for the most effective pain management Multiples of the a ⁇ aiiable dosage strengths were combined as needed to achiev e the intended necessity daily dose.
  • Subjects currently taking opioids who will have their opioid dose converted to a Kadian NT dose should be scheduled for a morning clinic appointment (before noon) for the Drug Dispensing Visit. Additionally, subjects were instructed to refrain from taking the morning dose of their current opioid pain medication on the day of their Drug Dispensing clinic visit. It was recommended that subjects who are already taking opioid medication be started on a Kadi an NT dose equivalent to 50% to 75% of the current daily opioid dose rounded to the lowest available Kadi an NT dosage strength due to potential for incomplete cross tolerance. The dose was determined utilizing the conversion table provided in Appendix V of this protocol; investigators were free to choose an alternate opioid conversion seiieduie at their own discretion. Opioid dose requirements were based on the subject ' s average combined daily opioid consumption for chronic and rescue dosing over the week prior to study entry.
  • a subject Even if a subject is experiencing a Pl " ⁇ 3, the subject was free io choose not to have the dose increased. For example, a subject may have been satisfied with having his or her pain level reduced to a PI level of 4, If a subject's dose was increased and the subject repotted unacceptable AEs or an opioid-expe ⁇ eticed subject was convened to a dose that results in unacceptable AEs, the dose was decreased. If a subject expediences inadequate pain relief and desired to have bis or her dose increased prior to a scheduled clinic visit, the subject was allowed to telephone the site and request a dose increase after a minimum of three days at the previous dosage !e ⁇ e!
  • Subjects were required to return for a post-treatment follow-up appioximately 28 to 32 days aftet the final dose of sluch medication to record AEs and concomitant medications and to assure that appropriate taperuig from study medication and transition to standard of care has been accomplished
  • Subjects wishing to discontinue opioid medication were converted to Kadian ⁇ for the taper penod, fhe suggested mechanism for tapering was for the subject to take half of hib oi bet last effective dose of stud> medication in divided doses of Kadian (BID) for three days, and then to take half of that i educed dose in divided doses ⁇ BID ⁇ for the next three days, on the sev enth day, all dosing will discontinue.
  • Subjects weie also allowed to convert to c ⁇ rrently-approv ed extended release opioid per investigator discretion
  • the Interactive Voice Response S stem (iVRS) was used to identify up to 20 subjects in each of the follow ing daily dosing categories to undergo PK sample collection at their scheduled visits. 40 mg to 60 ing, 80 rag to 120 ma, and y 120 nig, I p to 20 subjects aged 65 years atid above v>e ⁇ e also identified to participate in the PK sample collection. I be primary focus of this PK sampling was to quantify naltrexone, 6-beia naltrcxol and rr ⁇ rpbine concentrations. Study medications were in the form of orally administered capsules Study medications were. I )
  • a subject was eligible for study participation if he she meets the following criteria: 1. The subject was I S to 70 years of age and exhibited sufficient literary skills to complete study assessments. 2 The subject agreed to refrain from taking am opioid medications other than study medication during the study period, and agreed to report all non-opioiti analgesic medications taken;
  • Sujbect had a histoiy of chronic moderate to seven c pain caused by a notimalignam condition for ai least thiee months prior to Baseline Visit Conditions include. but are not limited to. osteoarthritis of any joint, chronic km back pain ⁇ ith or without radiculopathy, diabetic peripheral neuropathy, and post-he ⁇ etic neutalgia. Subject was directed to choose the most painful joint or body area to serve as the target joint atea for this stud) ⁇ target joint. ⁇ *as not to contain any type of orthopedic sod oi prosthetic device.
  • a subject v iil be excluded from the s ⁇ xh if he she meets any of the following critciia:
  • Subject had a documented histoty of an allergic reaction (hives, rash, etc ⁇ or a clinically significant intolerance to morphine ot other opioids, such that treatment with morphine is coiuxanidicaied. 2. Subject was pregnant or breast-feeding,
  • Subject had a documented histoiy of ⁇ iusf abuse dependence misuse or naieotic analgesic abuse/dcpciidcnce.'misusc within live years ptioi to the Baseline Visit.
  • Subject had a documented histoiy of alcohol abuse ( ⁇ 2 glasses/day) and'or dependence within fix e years prior to the Baseline Visit, which, in the opinion of the investigator, may ha ⁇ e influenced subject compliance w ith the study
  • Subject was considered b> the im estigator. for any reason, to be an unsuitable candidate to receive extended-release morphine sulfate with naltrexone, including ( but not limited to) the risk(s) in terms of precautions, warnings, and contraindications in the Investigator's Brochure for Kadian KT. 8. Subject had a Bod ⁇ Mass Index (BMf) -- 45 kg m : .
  • Subject had a psyehiatiie illness or medical iiinoss'condition, and or abnormal diagnostic finding, that, m the opinion of the hn estimator, would interfere with the completion of the study, confound the results of the studs, or pose risk to the subject
  • Subjects with settled claims were allowed to participate,
  • Subject had a histor> of impairment of pislmo ⁇ an fimction, hypercarbia, b) chronic obstructive pulmonary disease, cor pulmonale, uncontrolled asthma, sleep apnea s ⁇ ndrome, or respiratory deptession.
  • Subject had a history of gastiie or small intestine surgery leading to din seal malabsorption (e g , gastric tnpassL oi ain othet disease that causes chnical malabsorption, 2 !
  • Subject had active cardiac disease or other health conditions s) that pose a significant health risk m the event of opioid withdrawal 22 Subject was taking phcnothia/incs oi high doses of sedatives, hypnotics, oi tranquilizers. Chronic low dose sleep aids or anxiolvtks were allowed with
  • Safety endpoims wei ⁇ the incidence of treatment-emergent AI j .s, changes from pre-treatment to post-treatment tor s ital signs, ECGs. physical examination findings, and clinical laboratory test results, and opioid tovicity assessments.
  • the efficacy endpoints were Pain Intensity (PI) within trie past 24 hours, and. Global Assessment of Study Drug.
  • Three subject analysis populations * were defined as follows 1 ) the "safety population” " consisting of ail subjects who take study medication, used for safety analyses. 2) the “mtem-to-treaf " (ITT) population consisting of all subjects who take study medication and Io ⁇ emon , or Global Assessment of Study Drug observation: the !TT population will be used for efficacy analyses; 3 ⁇ the pharmacokinetic ⁇ PK) population will consist of ail subjects w ith PK samples ami will be used for PK, analyses.
  • TFAEs resulting in discontinuation of treatment was observed in approximate! 30" ⁇ of patients admmtsteied less than 80 ma Kadian Nl pet day: approximately 10% of patients administered between 80 and 120 mg Kadian NT per and, approximate! ⁇ - 9 0 O of patients administered more than 120 mg Kadian NT pet day Oveiall, TB AEb were obseived m approximately 24° ⁇ of patients
  • Seuoifo AEs resulting in djsconiimiation of Kadian KT tteamicnt were m approximately 2% of patients admmisteied less than 80 mg Kadsao Kl per dav, approximately 8° ⁇ of patients administered between 80 and 120 mg Kadian KT per day, and approximately 2% of patients administered more than 120 n ⁇ kadian K F per da) Overall SF AFs vu'ie obseived in approximate!) ⁇ 0 O of patients

Abstract

Provided herein is a pharmaceutical composition composing an antagonist, an agonist, a seal coat, and a sequestering polymer, w herein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from the agonist from one another. Methods for manufacturing such a pharmaceutical composition are also provided. Methods for dealing pain using such compositions is also demonstrated.

Description

PHARMACEUTICAL COMPOSITION RELATED APPLICATIONS
This application claims priority to U.S. Ser. No. 60/007,882 filed December 17, 2007.
EtELP OF STUDY
This invention pertains Io composotions and methods useful for treating pain m human patients. One such composition contains both an opioid antagonist and an opioid agonist formulated such that the agonist is released over time with minimal release of the antagonist.
BACKqRQUNP
Improved methods for treating pain are desired by those of skill in the art. A disease in which pain is a major symptom is osteoarthritis (OA). OA is the most common form of arthritis in the United States (Hochberg et al., 1995a)? affecting more than 21 million people. It is a disease of primarily middle-aged and older adults and is a leading cause of disability (American College of Rheumatology, 2000a). OA results from degeneration of the joint cartilage, and usually involves the neck, low back, knees, hips, and fingers. The prevalence of OA of the hip and knee increases progressively with age (Peloso et al., 2000). Unlike rheumatoid arthritis and other inflammatory arthritides, inflammation, if present, is usually mild and localized to the joint. The cause of OA is unknown, but biomechanicaJ stresses affecting the articular cartilage and subchondral bone, biochemical changes in the articular cartilage and synovial membrane, and genetic factors are significant in its pathogenesis (Hochberg et al., 1995b; American College of Rheumatology, 2000b).
OA is characterized by pain dial typically worsens with activity and weight bearing and improves with rest, as well as morning stiffness, and pain and stiffness that ease after a few minutes of movement Clinical examination often reveals tenderness to palpation, bony enlargement, crepitus, and/or limited joint motion (American College of Rheumatology, 2000b). As the disease advances, OA patients experience increasing pain and loss of function, with pain intruding at periods of rest (Peloso et al., 2000). Since no
SUBSTITUTE SHEET (RULE 26) cuie for OΛ is available, the pnmary goal of O \ treatment is to reduce pain while maintaining or improving ]oint mobiluy and limiting functional impairment.
Nonpharmacologic and pharmacologic tteatmeππ for OΛ are used in conjunction to reduce pain and to improve functional status, Nonpharmacologic therapies include patient education, weight loss (if overweight), occupational therapy, physical therapy, and aerobic exercise psograrm to restore joint and increase strength and aerobic capacity ( American College of Rheumatology. 2000a) The initial pharmacologic therapies for OΛ include nonopioid analgesics (e.g.. acetaminophen) and topical analgesics, folkmcd by treatment with nonsteroidal ami- inflammatory drugs (NSAf Ds) and judicious use of intra-articuiar steroid injections (JHoetrherg et al., 1995a). Although these medications mav provide temporary pain relief, the beneficial effect may be offset by other factors. Use of nonopioid analgesics to treat moderate to se\ere OA pain is limited by a ceiling effect for analgesia { Roth et aL 2000). Additional!}, NSAIDs can be toxic to the gastrointestinal tract, and NSAIDs and acetaminophen cat) ptoduce renal toxicity, especially in the elderly ( Peloso et ai . 2000). Thus, a need exists for additional analgesic treatment options for pain associated with OA,
Recent efforts have been made to liberalize the use of opioids for the treatment of chionic nonmalignaπt pain (Sullivan et a! , 2005) Sullήan proposes subject-centered principles to guide efforts to relieve chronic nonmalignam pain, including the acceptance of all subject pain reports as but negotiation of treatment goals early in care, avoidance of subject harm, and ineoipoiation of chionic opioids as one part of the treatment plan if they improve the subject's oxeralϊ health-related quality of lite Prescribing opiates in the treatment of chionic noninaHgnant pain may pose a challenge to the primary caie physician (Qi sea et at. 2004), Although an outright ban on opioid use in chronic nonmaiignant pain is no longer ethically acceptable, ensuring that opioids provide overall benefit to subjects requires significant physician time and skill Subject with chronic nomrmϋgnant pain should be assessed and treated foi concurrent psychiatric ώsoiders: those with dϊsotders are entitled to equhalent efforts at pain relief The essential question is not whether chronic nomnalignant pain is ieai or proponioual to objective disease se\eutγ. but how it should be managed so that the subject's quality of life is optimized. As early as the raid 1990s, naltrexone has been shown to etϊeetnek block morphine effects in humans {Kaiko et al.. 1995). Morphine effects in. normal volunteers were blocked by three 100-røg doses of naltrexone. I he fust dose of naltrexone was given 24 hours before closing with controlled release morphine sulfate (MS Contirr), followed b) a second dose at the time of NfS Coπtin dosing and a third dose 24 hours after MS Co nt in administration Single 200 nig doses of MS Contin gi\ en with {he naltrexone blockade were generally well tolerated, and adverse effects w ere similar to those reported for naltievone alone and for lower closes of morphine without naluexone. Naltrexone proved safe and effective in blocking the effects of controlled release morphine, permitting bioequi valence studies of a high dose of morphine in normal "volunteers.
Although well absorbed orally, naltrexone is subject to significant first-pass metabolism, with oral bioavailability estimates ranging from 5Vo to 40°'« (Naltrexone H(I 1 ablets. I1SP Package Insert) The activity of naltrexone is believed to be due to both the parent compound and the o-β nalUexol metabolite. Both patent ώug and metabolites, are exαeted pπrnauly by the kidney (53Vo to "7O0Z0 of the dose), however, uiirmrv excretion of unchanged naltrexone accounts for less than 2° o of an oral dose and fecal excretion is a minor elimination pathway The mean elimination terminal half-life (tj ;) values for naltrexone and are 4 houis and 13 houis. respectively Naltrexone and 6-β-ϊiaitrcxo! are dose-proportional in terms of area under the concentration-time curve (ΛUC) and maximum plasma concentration (Cnm) o\ eι the uiπge of 50 to 200 mg and do not accumulate aftei 100 rag daily doses.
Various formulations of opioids aie in development that have a ieduced risk of dhersion and non-medical use and can be used to treat patients with chronic, aonmahgnam conditions Kadian& (morphme sulfate extended-release capsule) Λ\ as developed for use in subjects with chronic pain who require repeated dosing with a potent opioid analgesic, and has been tested in subjects with pain due Io malignant and nonmabgnant conditions. Kadi an contains polymer-coated extended-release pellets of morphine sulfate, to deliver up to 24 hours of continuous pain relief This formulation lacks an immediate-release component, on Iv prov iding a slow release of the analgesic This slow-release technology serves to mmirmzc plasma peaks and troughs, thereby providing a lelatnelv fiat pharmacokinetic U3K) curve upon multiple closing Phis dehxeiy mechanism is ideally suited for chrome pain patients Kadian capsules aie an extended-release oral formulation of morphine sulfate indicated foi the management of moderate to pam when a continuous, atouπd-the-clock opioid analgesic is needed for an extended pei iod of time
Hkwevei, persons abusing opioids aie to tarapei vuth controlled-ielease fotmuϊations m hopes of obtaining the ciitite dose to induce an immediate euphoπa To fuithei deter non-medical opioid use foπmiSauons containing opioid antagonists aie bcmg developed 4s described herein. Kadian KT (morphine sulfate plus naltrexone hydiochloude extended-release capsules), is a product that is intended to be used as an opiate analgesic for raodeiate to sexeie pam Its abuse-detenence feature incoipoiat.es an immediate release of naltrexone upon illicit manipulation this is intended to neuUalue the euphoric potential of morphine and uiαease safetv afici ingestion of the tampαcd product If Kadian NT is used as duected. a patient should receive a dose of morphine equivalent to the same nψ dose of Kadi an if the drug pioduct is tampered w ith and ingested b\ a patient who is opioio dependent, the patient may be exposed to a dose of naltiexone sufficient to produce w ithdiawai symptoms
Abusc-tesisstant, sustamed-release dosage fomis of products intended to treat pain !ki\e been described in the ait (see, for exεmpfe. V S Application Mos 2003 0124185 and 200 > 0044458) that substantial amounts of the opioid antagonist oi othei antagonist found m these sequesteied fυπns ase released ume (usual Iv less than 24 hours) due to flic osmotic pressure that builds up m the core of the sequestered form as watei peuneates thiough the sequesieied foim mto the cotε I he high osmotic piεssute inside the coie of the sequesteied foini causes the opioid antagonist oi antagonist to be pushed out of the sequesteted form, theieby causing the opioid antagonist oi antagonist to be released fiom the sequesteied foim Λs sliuwn below, certain embodiments described hcicin prov ide improved forms of sequestered opioid antagonists and contiolled-jelease opioid agonists
In \ lew of the fotegouiy di aw backs of the sequesteted forrøs of the poor ait there e\tsts a need in the an foi methods of seating pam a sequestered foim of an opioid antagonist or othei antagonist that is not released fiom the sequesteied foim due to osmotic pressure The indention prov ides such a sequesteung form of an opioid antagonist or antagonist. This and other objects and adx aπtages of the invention, as well as additional inventive features, will be apparent from the description of tbe invention provided hereto.
BRtEF DESCRIPTION OV THK DRAW INGS
Figure J, Mean BPI Score Over Time by Treatment Group-Worst Pain in Past 24 Hours,
Figure 2, Mean BPΪ Score Over Time by Treatment Group-Least Pain in Past 24 Hours.
Figure 3, Mean BPI Score Over Time b> Treatment Group-Λverage Pain in Past 24
1 lours.
Figure 4, Mean BPI Score Cher Time by Treatment Growp-Carrent Pain Le\el.
BRIEF SDΛ1MΛRY
Proxided herein is a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit and wherein the seal coat forms a layet physically separating the antagonist from the agonist from one another. The methods described herein prov ide methods fot substantially ielicwng pain (e.g. puruduig an analgesic effect) for time pcuods of at least one week (e.g , two, four, eight, 12, 16. 20, 24, 2S, 32. 36, 40 and 100 weeks) with regular administration {e.g., once, twice, three or four times daily). In certain embodiments, no substantias release of tbe antagonist from the intact form of the composition is observed. Methods for manufacturing such a pharmaceutical composition arc also provided A)I references referred to or cited in this application are hereby incorporated by reference iti their entirety.
PETAtLEP DESCRIPTION Pan ided heiehi are compositions and methods for adnύnisteting a multiple actne agents to a mammal in a form and manner that minimizes the effects of either acme ayeni upon the other hi vivo In ceitairt embodiments, at least two active agents are formulated as part of a pharmaceutical composition. A first aclKe agent may pi oxide a therapeutic effect m vivo The second active agent may be an antagonist of the first acme agent, and may be useful in preventing misuse of the composition. For instance, wheie the first active agent is a narcotic, the second aethe aj∑etit may be an antagonist of the narcotic The composition remains intact during normal usage patients and the antagonist is not released However, upon tampering with the composition, {he antagonist rnav be steleased theietπ presenting the naieotic from hav ing its intended effect. In certain embodiments, the active agents arc both contained within a single unit, such as a bead, in the form of layers. The acme agents may be formulated with a substantially impermeable barrier as. for example, a coαtrolled-release composition, such that release of the antagonist from the composition is minimized. In certain embodiments, the antagonist is released in //; assays but is substantially not released m vivo In vι fro and in vhv release of the active agent from the composition ma} be measured by any of \hv ielease may be determined by measuring the plasma levels of the active agent or metabolites thereof (ϊ.e, ΛU(\ Cmaxl
In certain embodiments, one of the active agents is an opioid receptoi agonist. Several opioid agonists are commercially available or in clinical ttials and be administered as described herein such that the alcohol effects arc minimized. Opioid agonists include, foi example, alfentaπil, ailyϊpiodme, alphapiodine, amieπdine, bcHzylnioφhine, bezitramidc. buprenorpliine. butorphanol, clonitazene, codeine, cvcla/ocine desomorphsne, dextroinoratnide, dezocine, dianipiomide, dthydrocodeme, ώhydroetorpiurte dihydromorphine, dimenoxadol, dimepheptanoK dimetln ithiambutene, dioxaphetyl butjuue, dipipanone. epta/ocine, ethohepta/me, ethyl methylthiarnbυtene, ethylmoφhine, etonitazene, etorphine, fentanyi, heroin, hydiocodone, hydromoiphone, hydroxypethidine, isomethadonc kctobenudone, lcv allorphan, levorphanol, lofentani), mepeiidine, mepta/inol, raeta/ocine. methadone, metopon, morphine, m>τophme, nalbuphine, narceine, nieomorptiine, not methadone, nalorphine, normorphiue. norpipauone, opium, oxycodone, oxymoiphone, papav eremm, pentazocine, phenadoxoαe. phertazocine, phenomoφhart, phenoperidine. pirainodine. pirmannde, prophepta/ine, promedol, propeπdine, propiiam propoxyphene, sufentanil, tramadol, tilidmc, derivatives 01 complexes thereof, pharmaceutically acceptable salts thereof and combinations thereof Preferably, the opioid agonist is selected from the group consisting of hydrocodone, bydromorphone, oxycodone, dihydrocodeiue. codeine, dihydromoiphine, morphine, buprenorphme. dernatn es or corapiexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof Most preferably, the opioid agonist is morphine, hydrυmorphone, oxycodone or hydrocodone Eqmanalgesic doses of these opioids, m comparison to a 15 mg dose of hydrocodonc, are as follows oxycodone {\ $ 5 mg}, codeine (90 0 mg}, hydiocodone ( 15 0 mg), hydromorphoπe (3,375 nψK (! 3 ragK meperidine ( 135.0 mg). methadone (90 rag), and morphine l270 rngh
A common dosage form of hydrocodone is in combination w ith acetaminophen and is commercially available, for example, as LαrtabΦ in the United States from UCB Pharara, ϊπc Belgium! as 2.5 500 mg, 5 500 mg, 7.S/5OO mg and 10 500 rag hydrocodone/'acetammophen tablets. Tablets ate also available m the ratio of 7.5 rag hydrocodone bitartrate and 650 mg acetaminophen and a 7.5 mg hydrocodone bitanrate and 750 mg acetaminophen Hydrocodone, in combination with aspirin, is given in an oral dosage form io adults generally in 1 -2 tablets every 4-6 hours as needed to alicxiate pain. Hie tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with 32 mg caffeine, or 5 mg hydrocodone bitartrate ami 500 mg aspirin. Another formulation comprises hydrocodone bitartrate and ibuprofcn Vicopiofen®, cotnnicrc tally available in the U.S. from Knoll Laboratories {Mount Oine, N.J.}, is a tablet containing n 5 mg hydiocodone bitartrate and 200 nm ibuprofen lhe invention is contemplated to encompass all such formulations, with the inclusion of the opioid antagonist and or antagonist in sequestered form as part of a subunit comprising an opioid agonist.
Oxycodone, chemically known as 45-epoxy-I4-hydro\y-3-methoxy-17- mcthylmϋrphman-ό-oϊϊe. is an opioid agonist whose principal therapeutic action is analgesia Other therapeutic effects of ONjcodone include anxiolysis, euphoria and feelings of relaxation The precise mechanism of its analgesic action \s not known, but specific CNS opioid receptors for endogenous compounds with opioid-like aethil} been identified thioughout the biain and spinal cord and p!a> a role in the analgesic effects of this drug. Oxycodone is commercial iy available in the United States, e.g., as Gxycctiivls horn Purdue Pharma L.P. {Stamford, Conn.), as control I ed~rel ease tablets for oral administration containing 10 mg, 20 ing, 40 mu. or 80 mg oxycodone hydrochloride, and as OxylR™, also from Purdue Pharma L.F., as immediate-release capsules containing 5 mg oxycodone hydrochloride. The invention is contemplated to encompass all such formulations, with the inclusion of an opioid antagonist and'Or antagonist in sequestered form as pan of a subimit comprising an opioid agonist
Oral bydroraorphone commercial!} available in the United States, e.g., as Dilaudid'D from Abbott Laboratories {Chicago, III), Oral morphine is commercially available in the United States, e.g., as Kadianl' from faulding Laboratories (Piscataway. NJΛ
In embodiments in which the opioid agonist comprises hydrocodone, the sustained-release oral dosage forms can include analgesic doses from about 8 rag to about 50 mg of hydrocodone per dosage unit. In sustained-release oiai dosage forms where iiydromoφboiie is the therapeutically active opioid, it is included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride. In another embodiment, the opioid agonist comprises morphine, and the sustained-release oral dosage forms of the imetition include from about 2.5 nig to about 800 πψ morphine, by weight. In yet another embodiment the opioid agonist comprises oxycodone and the sustained-release oral dosage forms include from about 2.5 mg to about 800 mg oxycodone. In certain preferred embodiments, the sustained-release oral dosage forms include from about 20 mg to about 30 mg oxycodone. Controlled release oxycodone formulations are known in the ait. The following documents desαibe various control led~release oxycodone formulations suitable for use in the invention described herein, and processes for their manufacture; U.S. Pat. Nos. 5,266,331 ; 5,549,912; 5,508,042; and 5,656,295, which are incorporated herein by reference. The opioid agonist cart comprise tramadol and the sustained-release oral dosage forms can include from about 25 mg to 800 mg tramadol per dosage unit.
In certain embodiments, another active agent contained within the composition may be an opioid receptor antagonist. In certain embodiments, the agonist and antagonist are administered together, either separately or as part of a single pharmaceutical unit. In the instance when the therapeutic agent is. an opioid agonist, the antagonist preferably is an opioid antagonist, such as naltrexone, naloxone, πalmeiene, cycliuaeine, levallorphan, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. More preferably, the opioid antagonist is naloxone or naltrexone, By "opioid antagonist" is meant to include one or more opioid antagonists, either alone or in combination, and is further meant to include partial antagonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof. The pharmaceutically acceptable salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like: alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as triethyiamine salt pyridine salt, picoline salt, ethanotamine salt, tπethanolamine salt, dicyclohexylamine salt, N,N-dibenzyleihylenediarnine salt, and the like; inorganic acid sails, such as hydrochloride, hydrobromidc, sulfate, phosphate, and the like; organic acid salts, such as formate, acetate, trifluoroacelate. maieate, tartrate, and the like; sulfonates, such as methanesuifoπate, benzetiesuiibnate, p-toiuenesuifoπate, and the like; amino acid salts, such as argmate, asparginate, gliu&rmue, and the like. In certain embodiments, the amount of the opioid antagonist can be about 10 ng to about 275 nig. In a preferred embodiment, when the antagonist is naltrexone, it is preferable that the intact dosage form releases less than 0.125 mg or less within 24 hours, with 0.25 mg or greater of naltrexone released after 1 hour when the dosage form is crushed or chewed,
In a preferred embodiment, the opioid antagonist comprises naloxone. Naloxone is an opioid antagonist, which is almost void of agonist effects. Subcutaneous doses of up to 12 mg of naloxone produce no disceπiabie subjecihe effects, and 24 mg naloxone causes only slight drowsiness. Small doses (0.4-0.8 mg} of naloxone given intramuscularly or intravenously in man prevent or promptly reverse the effects of morphine-like opioid agonist. One mg of naloxone intravenously has been reported to block completely the effect: of 25 mg of heroin. The effects of naloxone are seen almost immediately after intravenous administration. The dntg is absorbed after oral administration, but has been reported to be metabolized into an inactive form rapidly in its first passage through the such that it has been reported to have significantly lower potency than when parenteral Iy administered. Oral dosages of more than I g have been reported to be almost completely metabolized in less than 24 hours tt has been repotted that 25% of naloxone admin isteied sublingualis is absorbed (Weinberg ct al, Clin. Pharmacol, flier 44 335-340 U 988))
In another preferred embodiment, the opioid antagonist comprises naltrexone In the tieatmeut of patients iously addicted to opioids, naltrexone has been used in large oral doses (over 100 mg) to prevent euphoπaenic effects of opioid agonists Naltrexone has been reported to exert strong preferential blocking action against mu over delta sites Naltrexone is known as a synthetic congener of oxymorphoπe ^Uh no opioid agonist properties, and differs in structure from oxymorprione by the replacement of the methyl group located on die nitrogen atom of oxymorphone w ith a cyciopropyimethyl group The hydrochloride salt of naltrexone is soluble in w afer up to about 100 mg,cc The pharmacological and pharmacokinetic properties of naltrexone have been evaluated m multiple animal and ciimcai studies. See, e g., Gonzalez et al Dntgs 35:192-213 (1988). Following oral administration, naltrexone is rapidly absorbed (within 1 hour) and has an oral bioavailability ianging from 5-40% Naltrexone's protein binding is approximately 21% and the volume of distribution following single-dose administration is 16.1 LΛg
Naltrexone is commercially available in tablet form ( Revia^\ DuPont (Wilmington, Del )) for the treatment of alcohol dependence and for the blockade of exogenous!} administered opioids. See, e.g.. ia (naltrexone hydrochioiide tablets), Physician's Desk Reference. 51 * ed . Montvale, N J., and Economic 51 957-059 (1997) A dosage of 50 mg blocks the pharmacological effccb of 25 rag IV administered heroin for up to 24 hours. It is known that, when coadministered with moiphine, heiom OJ other opioids on a chronic of physical dependence to opioids. It is believed that the method bs which naltrexone blocki the effects of heroin h by competitively binding at the opioid receptors Naltrexone has been used to treat narcotic addiction by complete blockade of the effects of opioids. It has been found that the most successful use of naltrexone for a narcotic addiction is w ith narcotic addicts good prognosis, as part of a compreheashe occupational or rehabilitathe program involving behavioral control or other compliance- enhancing methods For treatment of naicotic dependence with naltrexone, n is desirable that the patient be opkύd-fiee foi at least 7-10 days. The initial dosage of naltrexone for such purposes lias typically been about 25 tng, and if no withdϊawal signs occur the dosage may be iiκτcascd to 50 mg pei day. A daily dosage of 50 mg is considered to produce adequate clinical blockade of the actions of parenteral^ administered opioids. Naltrexone also has been used for the treatment of alcoholism as an adjunct v, ith social and psychotherapeutic methods.
Other preferred opioid antagonists include, for example, cydazocine and naltrexone, both of which rune cyclopropy t methyl substitutions on the nitrogen, retain πuich of the«' the ora! route, and last longer, with durations approaching 24 hours after oral administration The antagonist may also be a bitterήϊg agent. I be term "foittering agent" as used herein refers to any agent that provides an unpleasant taste to the host upon inhalation and or swallowing υf a tampered dosage form comprising the sequestering subunit With the inclusion of a bittemig agent, the intake of the tampered dosage form produces a bitter taste upon inhalation or oral administiatioπ, which, in certain embodiments, spoils or hinders the pleasure of obtaining a high from the tampered dosage form, and preferably presents the abuse of the dosage form,
Various bittering agents can be employed, including, for example, and without limitation, riatmal, artificial and synthetic flavot oils and flavoring aromaticb and oi oik, oleoiesiiis and extracts derrved from plants, leases, flowers, fruits, and so forth, and combinations thereof. Nonhmiting representative flavor oils include spearmint oil, peppeimint oil, eucalyptus oil, oil of nutmeg, auspice, mace, oil of bittei almonds, menthol and the like. Also useful buttering agents are artificial natural and synthetic fruit flavors such as alms oils, including lemon, orange, lime, and gtapefrαit, fruit essences, and so forth Additional bitiering agents include sucrose dematήes (e.g., sucrose octaacetate), ehlorosucrose derh arrves., quinine sulphate, and the like A preferred bitteriπg agent for use in the unention is Denatoninra Beozoate NF- Anhydrous, sold under the name Bitrex™ {Macfarian Smith Limited, Edinburgh, I'Kj. A brttermg agent can be added to the formulation in an amount of less than about 501O by weight, preferably less than about 10% by weight, more preferably less than about 5% b> weight of die dosage form, and most pieferabiy in an amount ranging from about 0 I to LO peicent by weight of the dosage form, depending on the particular bitteiing agent(s) used. Altematheiy. the antagonist may be a dye The term as used herein tefers to any agent {hat causes discoloration of the tissue in contact In this iegaui if (he sequestering subunit is tampered with and the contents are snorted, the dye w ill discolor the nasal tissues and surrounding tissues thereof. Prefeπed dyes are those that can bind strongly with subcutaneous tissue proteins and are well-known m the art. D) es useful in applications ranging firom, for example, food coloring to tattooing, are exemplar) dyes suitable for the invention. Food coloiing dyes include, but are not limited to FD&C G teen £3 and FD&C Blue 41 , as well as any other FΪ)&C os D&C color Such food aie commercially available through companies, such as Yoigt Global Distribution (Kansas City. Mo.).
The antagonist may alternatively be an irritant. The terra 'irritant'1 as used herein includes a compound used to impart an irritating, e g , burning or uncomfortable, sensation to an abuser administering a tampered dosage form of the invention. Use of an irritant will discourage an abuser from tasnpeitng with the dosage form and thereafter inhaling, injecting, oi swallowing the tampered dosage form Preferably, the irritant is released when the dosage form is tampered urth and provides a burning or irritating effect to the abuser upon inhalation, injection, and/or swallowing the tampeied dosage form Various irritants can be employed including, for example, and without limitation, capsaicin, a capsaicin analog w ith similar type properties as capsaicin, and the IiIe. Some capsaicin analogues or derivatives include, for example, and without limitation, lesiniferatυxm, tinvatoxin, bepianoylisobutyϊaraide, bcptanoyl jaiaiacylamkie, othet isobisty S amides or giiamcylamides. dϊhydrocapsaicin, oetyiestcr. nonanoyl x anillylainidε, ot other compounds of the class known as Resmiferatoxin is descnbed, for example, in IJ S Pat No 5,290,816, L1 S Pat. Na 4,S l 2,446 describes capsaicin analogs and methods for their preparation Furthermore. U S Pat. No 4,424205 cites Newman, 11INaUa a! and Synthetic Pepper- Flavored Substances,"' published m 1954 as listing pungency of capsaiein-lϊke analogs. Ton et al , Hrit&h Jυuntat o/ I'hatvnaa>hg\< 10 175-182 (1955), discusses pharmacological actions of capsaicin and its analogs. With the inclusion of an irritant (e.g., capsaicin) in the dosage form, the irritant imparts a burning or discomforting quality to the abuser io dϊseoiuage the inhalation, injection, or oral administration of the tampered dosage form, and preferably to the abuse of the dosage form Suitable capsaicin compositions include capsaicin (tians 8~mel1iyl-N~vanill} l~6-:iϋiieamide) ot analogues thereof in a concentration between about 0 00125% and 50% b\ weight, preferably between about 1% and about 7,5% by weight, and most preferably, between about !°b and about 5% by weight
The antagonist may also be a ueUina asent. The term "celling asenf as used herein refers to any agent that prov ides a gel-like quality to the tampered dosage form, which slows the absorption of the therapeutic agent, which is foimulaled with the sequestering subunit, such that a host is less likeh to obtain a rapid '"high " In certain preferred embodiments, when the dosage form is tampeied with and exposed to a small amount (e.g., less than about 10 mt) of an aqueous liquid (e.g., water), the dosage form will be unsuitable for injection and oi inhalation Upon the addition of the aqueous liquid, the tampered dosage form preferably becomes thick and rendering it unsuitable for injection. The term '"unsuitable for injection" is defined foi purposes of the .mention to mean that one would have substantia! difficult} injecting the dosage form (e.g., due to pam upon administration or difficulty pushing the dosage form through a syringe) due to the uscosity imparted on the dosage form, thereby reducing the potential for abuse of the therapeutic agent in the dosage form In certain embodiments, the gelling agent ss present in such an amount in the dosage form that attempts at evaporation (by the application of heat) to an aqueous mixture of the dosage form in an effort to produce a higher concentration of the therapeutic agent, pi educes a highly \ beous substance unsuitable foi injection. W hen nasally inhaling the tampered dosage form, the gelling agent can become gei~hke upou administration to the nasal passages, due to the moisture of the mucous membranes. This aiso makes such formulations to nasal administration, as the gel wϋl stick to the nasal passage and minimize absorption of the abitsable substance Various gelling agents may can be employed including, for example, and without limitation, sugars or sugar-derived alcohols, such as mamπtol, sorbitol, and the like, staich and starch deriv atives cellulose dematnes, such as imαocrysialline cellulose, sodium caboxymethyl cellulose, methylceilυlose. ethyl cellulose, hydroxyethyl cellulose. hydroxypiop)! cellulose, and hyckoxv. propyl metihylceilulose. aitapulgties, bentonites, dextήns, alginates, catrageeπao, gum tragacant, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and caibopols. polyethylene glycol, polyethy lene oxide, polyv inyl alcohol, silicon dioxide, surfactants, mixed surfactant, w etting ageat systems, errmlsifiers, other polymeric materials, and mixtures thereof, etc, In certain preferred embodiments, the gelling agent is xauthan gum In other preferred embodiments, the gelling agent of the invention is pectin, I he pectin or pectic substances useful for this invention include not only purified oi isolated pcctaics but also crude natural pectin sources, such as apple. citius or sugar beet residues, which have been subjected, when necessary, to esteπficatton or de-esterification, e g,, by alkali or enyymes Preferably, the pectins used in this invention are derived ftom citrus fruits, such as lime, lemon, grapefruit, and orange With the inclusion of a gelling agent in the dosage form, the gelling agent preferably imparts a gel-hke quality to the dosage form upon tampering that spoils or hinders the pleasure of obtaining a rapid high from due to the gel-hke consistent;} of the tampered dosage form in contact with the mucous membrane, and in certain embodiments, prevents the abuse of the dosage form by minimizing absorption, e.g., in the nasal passages Λ gelling agent can be added to the formulation m a ratio of gelling agent to opioid agonist of from about 1:40 to about 40' 1 by w eight, preferably from about i i to about 3Oi by weight, and more prcfetably ftom about 2 1 to about 10 1 b\ weight of the opioid agonist. In certain othei embodiments, the dosage fotm forms a gel haung a viscosity of at least about 10 cP after the dosage form is tampered uith by dissolution in an aqueous ϋquid (ftom about 0.5 to about 10 ml and pieferably from 1 to about 5 ml) Most preferably, the resulting mixture will ha\c a viscosity of at least about βO eP.
The antagonist can comprise a single type of antagonist (e g , a capsaicin), multiple forms of a single type of antagonist (e g, a capashi and an analogue thereof), or a combination of different types of antagonists (e g , one or more bittering agents and one or mojte gelling agents). Desirably, the amount of antagonist in a unit of the ύnentkm is not toxic to die host,
Iu one embodiment, the invention proudes a sequestering subimit comprising an opioid antagonist and a blocking agent, wherein the blocking agent substantially prevents telease of the opioid antagonist ftom the sequestering subumt in the gastioimesiinai tract for a time peiiod that is gieatei than 24 hours. This sequestering subimit is mcoiporated into a single pharmaceutical unit that also includes an opioid agonist lhe pharmaceutical unit thus includes a core portion to which the opioid antagonist is applied. Λ seal coat is then optionally applied upon the antagonist Upon the seal coat is then applied a composition comprising the pharmaceutically acthe agent. An additional layer containing the same or a different blocking agent ma\ then be applied such thai the opioid agonist is released in the digestive tract over time U e , controlled release) Fhus. the opioid antagonist and the opioid agonist are both contained within a single pharmaceutical unit, winch is typical l\ in the foim of a bead
The term "sequestering subunif as used herein refers to any means for containing an antagonist and presenting or substantially preventing the release thereof in the gastrointestinal tract when intact, i e.. when not tampered with. The term "blocking agent"" as used herein refers to the means by which the sequestering subumt k able to prevent substantially the antagonist from being released The blocking agent may be a sequestering polymet, for instance, as described in greater detail below . The terms "substantially prevents.-' "'ptes ents,"" or an> v\ ords stemming therefrom, as used herein, means that the antagonist is substantially not released from the sequestering subumt in the gastrointestinal tract. B> "substantial Iv not released" is meant that the antagonist may be released in a small amount, but the amount released does not affect or does not significant!) affect the analgesic efficacy w hen the dosage form is orally administered to a host e.g , a mammal (e.g., a human), as Intended. The teims Substantial i) pi events,*' "prev ents," or any wouls stemming therefrom, as used herein, docs not necessarily imph a complete or 100% prevention. Rather, there are varying degiees of of which one of oidinaiy skill m the ait recognizes as hav ing a potential benefit in this regard, the blocking agent substantially prevents or prø enfs the release of the antagonist to the extent that at least about 80% of the antagonist is prevented from being released from the sequestering subuαit in the gastrointestinal tract for a time period that is greater than 24 hours. Preferably, the blocking &gcnt prevents iβiea&ε of at ieast about 90" n of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. More preferably, the blocking agent prevents release of at least about 95" o of the antagonist ftom the seqtiesteting subumt. Most pteferab!>\ the blocking agent pt events ielease of at least about 99% of the antagonist fiom the sequestering subunit in the gastrointestinal tract for a time period {bat is greater than 24 hours.
For purposes of this invention, the amount of the antagonist released after oral administration can be measured in-vjtro by dissolution testing as described in the United States Pharmacopeia (USP26) in chapter <7{ 1 ^ Dissolution i-or example, using QOO mL of 0.1 N HCi, Apparatus 2 {Paddle}, 75 φm, at 3?'" C to measure release at times fiom the dosage unit. Other methods of measuring the release of an antagonist from a sequesteπng subunit o\er a given period of time are known m the ait (see e g., USP26).
Without being bound to any particular theory, it is believ ed that the sequestering subun.it of the invention overcomes the limitation1; of the sequestered forms of an antagonist known in the art in that the sequestering subunit of the invention reduces osmυtically-dπven release of the antagonist from the sequestering subunit. Furthermore, it is believed that the present inventive sequestering subunit reduces the release of the antagonist fur a longer period of time (e.g.. greatci than 24 horns) in companson to the sequestered forms of antagonists known in the art. The fact that the sequestered subunit of the invention provides a longer pre\ ention of release of the antagonist is particularly relevant, since precipitated withdrawal could occur after the time for which the therapeutic agent is released and acts It is well known thai the gastrointestinal tract tiaπsit time for indiv iduals \aries great!) within the population, Hence, the residue of the dosage form may be retained in the tract for longer than 24 hours, and in some cases for longer than 48 hours. Ii is further well known that opioid analgesics cause decreased bowel motility, further prolonging gastrointestinal tract transit time Currently, sustaincd- ιeiea&e foiras hax iny a» effect over a 24 hour time peπod ha\e been approved the hood and Drug Administration in this regaid, the present imentή e sequestering subunit ρro\ ides prevention of release of the antagonist for a time period that is greater than 24 hours when the sequestering subunit has not been tampered.
The sequestering subunit of the invention is designed to prevent substantially the ieiease of the antagonist when imacl By 'imacf is meant that a dosage form has not undergone tampering. I he term "tampering" is meant to include am manipulation by mechanical, thermal and or chemical means, which changes the physical properties of {he dosage form. The tampeiing can be, for example, crushing, shearing, gπnding. chewing, dissolution in a solvent, heating (for example, greater than about 45 a C), or any combination thereof When the sequestering suhunit of the invention has been tampered with, the antagonist is immediately released from the sequestering subimlt.
By "sυbunit" is meant to include a composition, mixture, particle; etc., that can provide a dosage form (e.g., an. orai dosage form) when combined with another sulnmit. The subimit can be in the form of a bead, pellet, granule, spheroid, or the like, and can be combined with additional same or different subυnits, in the form of a capsule, tablet or the like, to provide a dosage form, e.g., an oral dosage form. The subun.it may also be part of a larger, single unit, forming part of that unit, such as a layer. For instance, the subun.it may be a core coated with an antagonist and a seai coat; this summit may then be coated with additional compositions including a pharmaceutically active agent such as an opioid agonist.
For purposes of the invention, the antagonist can be any agent that negates the effect of the therapeutic agent or produces an unpleasant or punishing stimulus or effect, which will deter or cause avoidance of tampering with the sequestering subuntt or compositions comprising the same. Desirably, the antagonist does not harm a host by its administration or consumption but has properties that deter its administration or consumption, e.g., by chewing and swallowing or by crushing and snorting, for example. The antagonist can have a strong or foul taste or smell provide a burning or tingling sensation, cause a fachrymation response, nausea, vomiting, or any other unpleasant or repugnant sensation, or color tissue, for example. Preferably, the antagonist is selected from the group consisting of an antagonist of a therapeutic agent, a bittering agent, a dye, a gelling agent, and an irritant. Exemplary antagonists include capsaicin, dye, bittering agents and emetics. By "antagonist of a therapeutic agent" is meant any drug or molecule, naturally- occurring or synthetic, that binds to the same target molecule (e.g., a receptor) of the therapeutic agent, yet does not produce a therapeutic, intracellular, or in vivo response, In this regard, the antagonist of a therapeutic agent binds to the receptor of the therapeutic agent, thereby preventing the therapeutic agent from acting on the receptor, thereby preventing the achievement of a "high" in the host hi the instance when the therapeutic agent is an opioid agonist, the antagonist pielerat% is an opioid antagonist, such as naluexone, naloxone, naimciene, cyclazacine, dernatnes or complexes thereof pharmaceutically acceptable salts thereof, and combinations thereof. VIoie pieferabh, the opioid antagonist is naloxone 01 By "opioid antagonist'" ts meant to include one or mote opioid antagonists, either alone oi in combination and is further meant to include partial antagonists, pharmaceutically acceptable salts thereof, steteotsυmors tbeieof etheis thcieof, esters thereof, and combinations thereof I he pharmaceutically acceptable sails include metal salts, such as sodium salt, potassium salt cesium salt, and the like, alkaline earth metals, such as calcium sait. magnesium salt, and the iike. organic amine salts, such as trieth\larαιne !>att, pyiidioe salt, picoline salt, cthanolaminc salt, metlianoiamine salt, dic>clohexylaiτune salt, K N-dsben/ylethyleπedtaraiπc bah and the like, inorganic acid salts, such as hvdiochioride. hydrobromide. sulfate, phosphate, and the like, oiganic acid salts, such as foπnate, acetate, tiifiuoioacetate, maleate, taitiate, and the like, sulfonates, such as methanesuifbnate. benzenesulfonate, p-toluenesulfonate, and the like, amsnu acid salts, such as alginate, asparginate, glutama+e, and the like in certain embodiments, the amount of the opioid antagonist present m sequestered fotm can be about 10 ng to about 275 nig In a preferred embodiment when the antagonist is naltrexone, it is ptefeiahle that the intact dosage fomi ieleases less than 0, 125 mg or less vnthm 24 houis, with 0 25 mg or greatci of naltrexone icleased after 1 hour when the dosage form is ciushed or chewed
The antagonist can comprise a single type of antagonist (e.g , a capsaicin), multiple forms of a single type of antagonist (e g , a capasm and an analogue theteof), oi a combmatiofl of diffeient types of antagonists (e g , one oi moie hiUeπng agents and one oi more gelling agents) Desirably, the amount of antagonist in the sequestering sobunit of the invention is not toxic to the host
The blocking agent cuts or substantially cuts the release of the antagonist in the gastiouHestinal tract foj a time peuυd that is gteatet than 24 houis, e g , between 24 and 25 hours. 30 hours. 35 hours. 40 hours 45 hours, 48 hours, 50 hours 55 houis. 60 hours, 65 kouis. 70 hoius, 72 houis, 75 htiuTs. 80 houis, 85 houis, 90 hours. 95 hours o? 100 hours, etc. Fieferabh , the time peπod for which the release of the antagonist is prevented 01 substantially presented in the gastrointestinal tract is at least about 48 hours More preferably, the blocking agent prevents or substantially prev ents the release for a time period of at least about 72 hours
The blocking agent of the present sequestering siibunit can be a system comprising a first antagonisi-rmpeπneabfe material and a core "'antagotnst- impermeable material"' is meant any materia! that is substantially impermeable to the antagonist, such that the antagonist is substantially not released from the sequestering subunit I he term ''substantially rmpennεable" as used herein does not necessaπl} imply complete or 100% impermeability. Rather, there are v arying degrees of impermeability of which one of ordinary skill m the art recognizes as haung a potential benefit In tins regard, the antagonist- impermeable material substantially presents or pmeπts the release of the antagonist to an extent that at least about 80% of the antagonist ts prevented ftom being released from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. Prefeiably, the aπtagonist-impeimeable material prevents release of at least about 90% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours More preferably, the antagonist-impermeable material prevents ieiease of at least about 95°« of the antagonist from the sequestering subunit Most pieferably, the antagonist-impermeable material release of at least about 99% of the antagonist from the sequesteung subunil m the gastrointestinal tract for a time period that is greater than 24 hours. The antagonist- impemieable materia! presents or substantially piesents the release of the antagonist in the gastrointestinal tract for a time period that is greater than 24 hours, and dcssrabh, at least about 48 hours More desπably, tiie autagonisi-mipeimeabie material prevents υr substantialii the release of the ad\ ersne agent ftom the sequestennit subunit for a time period of at least about 72 hours
Preferably, the first antagonist-impermeable material comprises a hydrophobic material, such that the antagonist is not released or substantially not released during its ttansit tbough the gasfiointestinai tiact when adπiinisieied orally as intended, without having been tampered with Suitable hydrophobic materials for use in the invention are described herein and sd forth below The hydrophobic material is prefeiably a pharmaceutical!) acceptable hydiophobic material Pϊeferahk, the pharmaceutically acceptable hydrophobic material comprises a celiutose poh mer.
It is preferred that the first antagonist-impermeable material comprises a polymei insoluble in the gastrointestinal tract. One of ordiπars skill in the ait appreciates that a polymer that is insoluble m the gastrointestinal tract will prevent the release of the antagonist upon ingestion of the sequestering sυbunit I foe polymer can be a cellulose or an acrylic polymer Desirably, the cellulose is selected from the group consisting of ethyfcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, and combinations thereof btln lcelhilose includes, for example, one that has an ethoxy content of about 44 to about 550O. Ethylcelluiose can be used in the form of an aqueous dispersion, an alcoholic solution, or a solution in other suitable sohents. The cellulose can ha\ c a degree of substitution I D. S } on the anhydroglucose unit, from greater than £<iio and up to 3 inclusive. By "degree of substitution" is meant the aveiage number of hydroxy! groups on the anhydro. glucose unit of the cellulose polymer that are replaced by a substituting group. Representative materials include a polymer selected from the group consisting of cellulose acylate. cellulose diacylate. cellulose vriaevSate, cellulose acetate, cellulose diacetate, cellulose triacetate, monocelhiiυse alkanylate, diceSlulosc alkanylate, tucelSulose alkaaj late, monocellulose alkε÷n lates, dicellulose adenylates, tπeellulose alkcnylates, monocellulose aroλlatcs, dicellulose aroylates, and tricellulose arυylatcs
More specific celluloses include cellulose propionate having a D S of 1 S and a propyl content of 39.2 to 45 and a hydroxy content of 2,8 to 5.4%; cellulose acetate butyrate ha\iug a D.S of LS1 an acetyl content of 13 to 15° a and a butuyl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxy content of 0 5 to 47%, cellulose triacj late hav ing a D S of 2$ to 3, such as cellulose triacetate, cellulose tmalerate, cellulose trilaurate. cellulose tripatmitatc, cellulose trisuccioate, and cellulose trioctanøate; cellulose diacylatcs having a D.S of 2.2 to 2 6. such as cellulose disuccioate, cellulose dipalmitate cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose, such as cellulose acetate but} rate, cellulose acetate octanoate luifytate, and cellulose acetate pϊopωnate. Additional cellulose polymers useful for pieparing a sequestering suhurύt of the invention includes aeetaldehyde dimethyl cellulose acetate, cellulose acetate ethyfcarbamate, cellulose acetate methycarbamate and cellulose acetate dimethylaminocei lulose acetate The acrylic polymer preferably ts selected from the group consisting of røethacryhc polymers, acry lic acid and mefhacrylic acid copolymers, methyi metrsaciylate copolymers, ethoxyethyl mothacryiates, cyaπoetliyi methacrylate. pol\ (acrylic aαd\ poh(raethacryi?c acid), methacryiic acid aϊkylarmde copolymer, poly{mcthyl methacryiateK polymethacryiatc, poly(methyl methacrylatei copoly mer, polyaαylamsde, aπunoalkyi methacϊylate copolymer, po!y{ methacryiic acid anhydride), glycidyi methacrylate copolymers, and combinations thereof. An aenlie polymer useful for preparation of a sequestering subυrπf of the imention includes awjlic resins comprising copolymers synthesized from acrylic and methacryiic acid esters <c g , the copoKnici of aery Hc acid lower aikyi ester and raeihacryhc acid lower alky! ester) containing about 0,02 to about 0 03 mole of a rri (Sower alkyl) ammonium group per mole of the acrylic and methacryhc monomer used. An example of a suitable acrylic resin is amnionic methacrvlate copolymer NF2L a polymer manufactured by Rohm Pharma GmbH, Darmstadt, Germany, and sold under the Eudnigik^ trademark Tudragit RS30D is prefeired hudrauitO^ is a water-insoluble copolymer of ethyl acrylaie (HA), methyl methaciylatc (MM) and tnmethylaimnonimnetiiyl methacrvlate chloride (TAM) in which the molar ratio of TAM to the remaining components (FA and MM) \s I 40 Acrylic resins, such as Eudi'agitl-, can be used in the form of an aqueous dispersion or as a solution in suitable solvents
In anothei preferred embodiment, the antagonist-impermeable material is selected from the group consisting of polylactic acid, poiygiycolic acid, a co~polj mer of poiylactic acid a«d poiygiycolic acid, and combinations thereof, In certain other embodiments, the hydrophobic material includes a biodegradable polymer comprising a polytlactic glycolic aeid) {'"PΪ.GA"'), a polylactide, a polyglycokle, a polyanhydtide. a poiycaprolac tones, polypbosphazenes. polysaccharides, proteinaceous polymers. poKesters, polydioxanone, polyglucorsate, polylactic-acid-polyethylene oxide copolymets, polythydioxybυtyrate). pohphosphαester oi combinations thereof Preferably, the biodegradable polymer comprises a poly (lactic glycolic acid), a copolymer of lactic and glycolic acid, having ft molecular weight of about 2,000 to about
500,0(XJ daltotis. The ratio of lactic acid to giycoiie acid is preferably from about 10Oi to about 25:75, with the ratio of lactic acid to glycolic acid of about 65,35 being more prefer} ed
Poly(lactic glycolic acid) can be prepared by the procedures set forth in I5 S Pat No 4,293,539 {Ludvv ig ct al ). which is incorporated herein by reference In brief, I udwig prepares the copolymer by condensation of lactic acid and glycolic acid in {be presence of a readily removable polymerization catalyst (e.g . a strong ion-exchange resin such as Dowex HCR- W2-H) The amount of catalyst is not critical to the polymerization, but typically is from about 0.0] to about 20 part?, by weight re lathe to the total weight of combined lactic acid and giycυlic acid. The polymerization reaction can be conducted without solvents at a temperature from about 10CP C. to about 250° C. for about 4 S to about % hours, pieferabiy under a reduced piessure to facilitate removal of watei and by- products, Polyøactic gSycohc acid) is then recovered by filtering the molten reaction mixture in an organic so Kent such as dichloromethane or acetone, and then filtering to remove the catal) st
Suitable plastickers, for example, acetyl triethyi citrate, acetyl triburvl citrate, triethyl curate, diethyl phthalate, dibutv l phthalate. or ώbiitvl sebacate, also can be admixed with the polymer u^ed to make the sequestering subunit. Additήes. such as coloring agents, talc and/υr magnesium stearate, and othei additives also can be iι;>ed in making the present inventive sequestering subunit
Iu certain embodiments, additiv es may be included m the compositions to imprm e the sequestering characteristics of the sequestering subunit Λs deset ibed below , the ratio of additives or components with respect to other additiv es or components may be modified to enhance or delay improve sequestration of the agent contained within the subunit Various amounts of a functional additiv e (i.e.. a charge-neutralizing additive) may be included to vary the release of an antagonist, particukriy vvheie a water-soluble core (i.e.. a sugar sphere) is utilized. I- or instance, it has been determined that the inclusion of a low amount of diarge-ueutralizmg additiv e relative to sequestering pohmer on a basis may cause decreased release of the antagonist.
09 hi certain embodiments, a swfactant may serve as a charge-neutralizing Such neutralization may in certain embodiments i educe the swelling of the sequestering poKmer by hydration of positively charged groups contained therein. Surfactants s ionic or non-ionic) oiay also be used in preparing the sequestering subunit It is preferred that the surfactant he ionic Suitable exemplary agents include, for example, alkylary! sulphonates, alcohol sulphates, sulphosuccmates, sulphosuccinamates. sarcosiπates or taurates and others. Additional examples include but are not limited to ethoxylated castor oil, ben/aikonmni chloride, poSyglycoiyzed glyceπdes acerylated rnonoglyceπdes, sorbitasi fatty acid esters, poloxamers, polycκyethylene fatty acid esters, polyox} ethylene derivatives, moaoglycerides or ethoxylated derivatives thereof, dighceπdes or poK'oxycthylene derivatives thereof, sodium docusate, sodium lauryl sulfate, dioct} } sodium sulphosuccinate, sodium lauryl sarcosinate and sodium methyl cocoyl taurate, magnesium lauryl sulfate, tπethanolarnine. cetrimide, sucrose laurate and other sucrose esters, glucose (devtiose) estei.s, .simethicone, ocoxvπol, diυctyl sodiumsiilfosuceinate, poiyglycolyzed giycerides, sodiumdodecylbenzene sulfonate. dialkyl sodmrπsiilfosuccmatc, fatty alcohols such as lauryl. cetyl, and ster\ Lglyceryl esters, cholic acid or derivatives thereof, lecithins, and phospholipids. These agents are Upicaily ehatacten/ed as ionic (i e . anionic or catioπic) oi nonionic In ccttain einbodiinenls described herein, ant anionic surfactant such as sodium iaurxl sulfate (SLS) is preferably used (U S. Pat. No. 5,725,883; U.S. Pat Ko. 7,201,920, EP 502642A1; Shokri et al. Pharra Sci. 2003. The effect of sodium loury! sulphate on the release of diazepam from solid ώψcrvom prepared hy awn' ninig tei hntφie* Wells, et al Effect of Anionic SurfiϊL kmts on the Release of Chlorpheniramine Maleate From an inert, Heterogeneous Matm Drug Development and industrial Pharmacy 18(2) (1992) 175- 18(J. Rao. et al "Fffect of Sodium Lauryl Sulfate on the Release of Rifampicin from Guar Gum Matrix " Indian Journal of Pharmaceutical Science (2000), 404-406; Knop, et al. Influence of surfactants of different charge and concentration on drug release from pellets coated with an aqiieom dispersion of quaternary acrylic polymers SlP Pharnia Sciences. VoI 7, JSo. 6, (1997) 507-512). Other suitable agents are known in the art. As shown herein, Sl. S is particularly useful in combination with Fudragit RS when the sequestering subunit is built upon a sugar spheie substrate. The inclusion of SI S at iess than approximately 6 3% on a basis ieiatKe to the sequestering poly met (i.e , Fiυdragit RS) may provide a chaige neuUaSi-dng function (theoretically 20% and 41% neutralization, respectfulh), and thereby significantly slow the release of the acme agent encapsulated thereby (i.e.. the antagonist naltrexone), Inclusion of more than approximately 6 3% SLS relativ e to the sequestering polymer appears to increase release of the antagonist from the sequestering subimit. With respect to SLS used m conjunction w ith Kudragitx RS, it is piefeπed that die SLS is present at approximates) 1 %, 2V 3%, 4c!o ot 50O. and typically less than 6% on a w w basis ieiatne to the sequestering polymer {i e.. Eudragit' RS). In preferred embodiments, SLS may be present at approximately Lt% or approximately 3 3*?O ielame to the sequestering polymer As discussed above, many agents (i e., soifactants) may substitute foi SLS in the compositions disclosed herein
Additionally u&cful agents include those that may physically block migration of the antagonist from the subun.it and / or enhance the hydrephohiciiy of the barrier. One exemplary agent is talc, which is commonly used in pharmaceutical compositions (Pawar et al Agglomeration of Jbfφrqfen With Talc by Xovel ( rystallo-Co- Λggbwcnrtion fevlnύque ΛAFS PharmSci Tech. 2004; 5(4)- article 55). As shown in the Examples, talc is especially useful where the sequestering subunit is built upon a sugar sphere core. Λn> form of talc be used, so long as it does not detrimentally affect the function of the composition Most talc results from the alteration of dolomite (CaMg(CO^h or magnesite (MgO) in the presence of excess dissolved silica (SiO;) oi by altering serpentine or quartzite Tale may be include minerals such as trcmolite (CaMgI(SiOOO, seipenline J 3MgO 2S?0; 2ΪR))_ anthophylhie ( Mg- (OHb ( SMOH):), magoesite. mica, chlorite, dolomite, the caicite form of calcium carbonate (CaCOO- iron oxide, carbon, quart/, and - or manganese oxide. The presence of such impurities may be acceptable m the compositions described herein provided the function of the talc is maintained, ϊt is preferred that that talc be USP grade As mentioned above, the function of talc as described herein is to enhance the hydrophobic^ and therefore the functionality of the sequestering polymer. Mam substitutes for talc may be utilized in die compositions described herein as may be determined b\ one of skill in die art It has been determined thai the ratio of taic to sequestering polymer may make a diamatic diiVeience m the functionality of the compositions described hoi em. For instance, the Fxamples described below demonstrate that the taic to sequestering polymei ratio (\\i\\ ) is important with respect to compositions designed to present the release of naltrexone therefrom, it is shown therein that inclusion of at) equiv alent amount (on a weight-In -weight basis) of talc and Eιtdragitκ RS results m a very low naltrexone release profile in contrast, significantly km ei oi higher both a lower {69ISΌ Wu) and a lnghei ( 151% w w) RS ratios result in increased release of naltrexone ielcase Thus, where talc and Eudragit* RS are utilized, it is preferred that talc is present at approximately 75%. 8M o. 85° O, QO0O, 95° 0. 100%. 105%, ϊ 10%, 115° ... i20% or w/w relative to Eudtagit* RS As described above, the most beneficial ratio for other additives or components will vary and may be determined using sHindaul experimental procedures in certain embodiments, such as where a watet-soiuble coie is utilised, ii is useful to include agents that may affect the osmotic pressure of the composition (i.e , an osmotic pressure regulating agent) (see, m general WO 2005 046561 A2 and WO 2005/046649 Λ2 relating to fcudfamode*). 1 his agent is preferably applied to the Hudragu*' RS talc layer described above In a pharmaceutical unit comprising Ά sequestering subunit overlayed an actne agent (i.e , a con.rolled-reiease agonsst pieparation). the osmotic pi cssiit e iegiilatitig agent is pieferabl) positioned immcdiatclj beneath the actne agent layci. Suitable osmotic pressυie regulating agents may include, foi instance, hydrox>piOpy!mcthyi cellulose { HPMC) or chloride ions (i.e . from NaCl), or a combination of ! IPMC and chloiide ions {i.e . from KaC!) Othet tons that ma} be useful include bromide or iodide. The combination of sodium chloride and HPMC may be prepared in \\ ater or m a mixture of ethanol and u ater, for instance h PMC is commonly utilized m pharmaceαucai compositions (set. for example. Ii, S, Pat. Nos. ,22(>,ύ2Q and 7,229,982). In certain embodiments, HPMC may have a molecular weight ranguig from about 10,000 to about L500.000. and typicalh from about 5000 to about ϊ 0,000 (low molecular weight HPMC). The specific of HPMC is typically from about I ! *? to about 1 31, with an .specific giaw.y of about 1 26 and a v iscositv of about 3600 to 5600. HPMC may be a water-soluble synthetic polymei. Examples of suitable.
*>Λ cαmmeiαally av ailable l meth> lcelluiose polymers include Methocel R lOO LV ami Mclhocel K4M (Dow). Othci IiPMC addithes arc known in the art and may be suitable ui preparing the compositions described herein \$ shown in the Examples, the inclusion of NaCl (w ith HPMC) was found to have posifrveh affect sequestration of RS in certam embodiments, it is preferred ihai the charge- neutraliziog addstne {i e.. KaC i) is included at less than approximately I 2, 3. 4, 5. 6, 7. 8, 9, or 10% of the composition on a basis, In other ptefeπed embodiments, the charge-neutrah/rng additrve is present at approximately 4% of {he composition on a basis. Thus, m one embodiment, a sequestering subunit buiit upon a sugar sphere substrate is prov ide d comprising a sequestering polymei {? e , Eiidragif" R.S) in combination with several opimti/mg agents, including sodium launl ^uifaie (SLS) as a charge-neutral izmg agerst to reduce swelling of the film by hydration of the posnrveK charged groups on the polymer, talc to create a solid impermeable obstacle to naltrexone transport through the film and as a h\ drophobicity-enhacing agent, and a chloπde ion (i e , as NaClI as an osmotic pressure reducing agent The ratio of each of the additional ingredients relative to the sequestering polymer was suφπsinylv found to be important to the function of the sequestering subitnit Fot instance, the Examples provide a sequestering subunit including a sequester ing polvmet and the optims/uig agents SLS at less than 6%, preferably 1-4%, and even more preferabK 1 60O or 3 3% on a WΛV basis relative to Hudragil R.S. talc in an amount approximate!) equal to Rudiagii*' RS (on a w'w basis); and. NaCl present at approximate^ 4% on a w w basis relatis e to Eudragst^ RS
The therapeutic agent applied upon the sequestering subunit ma> be any medicament The therapeutic agent of the present inventive compositions can be any medicinal agent used for the treatment of a condition or disease, a pha maceutically acceptable salt thereof, or an analogue of either of the foregoing The therapeutic agent can be, for example, an analgesic (e g , an opioid agonist, aspirin, acetaminophen, nonsteroidal aoti-mflararπaton drags ("NSAIDS"), N-meth>l-D-aspartate (""NMDA") receptor antagonists eycooxjgenase-II inhibitois pCOλ-H inhibitors"), and gi) curse ieceptor antagonists), an antibaeteiial agent an agent, an anti-microbial agent,
2(> anti-infective agent, a chemotherapeutic, an immunosuppressant agent, an antitussiv e, an evpectorant, a decongestant, an antihistamine dtugs, a decongestant, antihistamine drugs, and the like. Preferably, the therapeutic agent is one that is addicth e (physically and/or psychologically) upon repeated use and typically leads to abuse of the thesapeutic agent, In ibis regard, the therapeutic agent can he M\y opioid agonist as discussed herein
The therapeutic agent can be an opioid agonist. By 'Opioid'' is meant to include a diug. hormone. 01 other chemical ot biological substance, natural or synthetic, having a sedatπe, narcotic, or otherwise simiiai effect(s) to those containing opium or its natural or synthetic derivatives By "opioid agonist,'" sometimes used herein interchangeabi} with terms "opioid1" and '"opioid analgesic," is meant to include one or more opioid agonists, either alone or in combination, and is tbrther meant to include the base of the opioid, mixed or combined agomsi-amagυnists, partial agoπisb, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof. Opioid agonists include, for example, alfentantl, alls Iprodiπe. alphapiodine. anileridine, henzylmurphme, bezitramide, buprenorphine, butorphanol, domtazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromtde, dihvdrocodeiiie dilrydroetorphinc, dihydinmorphine, dimcnoxadol, dimcphcptanol, dimethylthiambutene, dioxaphetv! butyrate. dipipanone, eptazocine ethohepta/ine. etliyfmcthylthiambutene, ethyimorphine, etonitazene, etoφhine, fcπtam l, heroin, hydrocυdone, hydiomorphone, hydroxypethidine, bαmeihadone, ketobemidυnc, levailorphan, levoφhanol, levoplicnacylmorpiian, lofentaitil. meperidine, meptaήnol, meta/ocine, methadone, metopon, morphine, muøphme, nalbuphine, narceme, nicomorphπie. normethadone, nabφhine, normorphine norpipanone, opium, oxycodone, oxymorphone, paptiveretum, pentazocine, phenadoxonc, pheπazocine, phenomorphan, phenoperidine, piminodiαe, piritramide, propheptazine, promedol properidinc, propiram, propoxyphene, sufentanil tramadol tilidine, or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the opioid agonist is selected from the group consisting of hydrocodone, hydromoi phone, oxycodone, diϊn drocodeme, codeine, dih> dromoφhine, morphine, buprenorphine, or complexes thereof, pharmaceutical!) acceptable salts thereof, and combinations theieof Most prefejabh, the opioid agonist is morphine, hydtoniorphone, oxycodone or hydrocodone. in a ptei'eπed embodiment, the opioid agonist compiles oxycodone or hydrocodcme and is present in the dosage form in an araoimt of about ! 5 to about 45 mg, and the opioid antagonist compnses naltrexone and is present in the dosage form in an amount of about 0.5 to about 5 mg
Fquianalgesic doses of these opioids, m comparison to a 15 mg doδe of hydrocodone, are set forth in I able 1 below
Fable I
Equi analgesic Doses of Opioids
Opioid Calculated Do^e (mg)
Oxycodone 13.5
Codeine 90,0 lhdrocodone 15 0 lϊydrυmυφhone 3 375
Levorphanoi 1.8
Meperidine 135.0
Methadone 9,0
Morphine 27 0
Hydtocodoiie is a semisynthetic narcotic analgesic and antitussive with multiple nervous system and gastrointestinal action?. Chemically, hydrocodone is 4.5~eρoxy-3- r»etlioxy-17~tnethyhnorphinan-A-one, and is also known as dihydrocodeiiione ϊ ike other opioids, hydrocodone am be habit-forming and can produce drug dependence of the morphine type. Like other opmm h\ drocodone will depress i aspiration.
Oral tndfocodone is also available in Europe (e.g , Belgium, Germany, Greece. KaI) , Luxembourg, Norway and Swit/edaud) as an antitusshe agent A paienteral formulation is also av ailable in Germany as an antitussive agent For use as an analgesic,
2$ lrydiocodone hitaπrate is commonly av ailable in the United States oni> as a fixed combination with non-opiate diugs (e g , ibuprofen, acetaminophen, aspnin, etc ) foi iehef of moderate to moderately seΛere pain
Λ common dosage form of h\dιocodone is m combination with acetaminophen and is commeieially a\ atlable, foi example, as I onab4* m the. United Slates from LUB Phaima, inc (Btussels, Belgium), as 2 5/500 mg ? SOO mg, 7 V^t)O mg and 10'500 rag hydiocodone/acetammophen tablets Tablets are aiso available in the tatiα of 7 5 mg h^ώocodone bitaitiate and 6^0 mg acetaminophen and a ^ mg hvdiocodone bi tartrate and 750 mg acetaminophen H\ drocodone, in combination Λv ith aspirin, is gKen m an oral dosage form to adults generally in 1-2 tablets 4-t> hours as needed to alienate pain The tablet form is 5 mg hvdrocodont* bitaitiate and 224 mg asp inn with 32 mg caffeine oi S rag !i>drocodoπe bitaiπate and 500 me aspiim Λootbei foπnulauon comprises hydrocodone bi tartrate and ibuprofen a\ ailable Jn the U S flora Knoi! Laboiatoπcs {Mount Oine, N1 J 1, b a tablet cαntammg 7 5 rag iTydiocodotte bitartrate and 200 mg ibiφiofeπ I he indention, is contemplated to encompass all such formulations, with the inclusion of the opioid antagonist and or antagonist in sequesteied form as pait of a subunit comprising an opioid agonist
Owcodono chemicalh known as 7- is an opioid agonist whose pπncφal therapeutic action is analgesia Othei therapeutic effects of oxycodone include anxiohsis euphoria and feelings of iciavatson. The piecibo mechanism of us analgesic action is> not known but specific CNS opioid receptors for endogenous compounds with opioid-hke acttsity been identified throughout the biain and spmai cotd and pla) a τole \n the analgesic effects of this di ug Oxycodone ss eommcicuilh a% as! able tn the Lm ted States, e g , as Ocycotm^ fiαm Put due Pharma L P (Stamfoid, Conn X as controlled-teiease tablets for υral adrniniitratioii containing 10 mg, 20 mg. 40 nig or 80 nig oxycodone hydrochloride, and as Oxx lR™, also from Puidue Phaima L P as tminediate-telease capsules containing 5 mg oxycodone indrochJorsde f lie un entjon is contemplated to encompass all such fotmulatious with the inclusion of an opioid antagonist and ot antagonist m sequesteied form as pan of a subunit composing an opioid agonist Oral hydiomoiphone is commercially in the United States, e g,, as Dilaiidid-I; from Abbott Laboratories {Chicago, III}. Ota! morphine is conimeiciaily in the United States, e g , as KadiaivΦ from Fauldmg Laboratories ( Pbcataway, NJ.), hxemplary NSΛiDS Include ibuprofen, diclofenac, naproxen, flurbiprofen, fenoprofen. flubufen, ketoprofen, indoprofen, piroprofen, carprofen. oxapio/in, pramoprofcn, nuπoprofeπ, trioxaprofen, stiproten. aminoprofcn, tiaprofemc acid, fiuprafen. bucloxic acid, indomettaaem. sulindac, tolmetm. /omepirac, tiopmac, /idoHietaciri, aceractacin, fentia^ac, clidaπac, oxpinac, motenamic acid, medofetiamic acid, flufenamic acid, nifimnk acid, tolfenamic acid, difluπsaL tlufeαisal piroxicam. or isosicam, and the like. 11SeM dosages of these drugs are well-known
Exemplary NMDA receptor medicaments include moiphmans, such as dcxotronicthorphan or dextrophan, ketaminc, d-methadone, and pharmaceutically acceptable baits tbe.eof, and encompass dmgs that block a major intfaccilukr consequence of NMDΛ-receptor actuation, e.g „ a gaiiglioside, such as (6-ammothexyU- 5-chloro-l -naphtbaienesuifbnamide. These drugs are stated to inhibit the development of toieraiice to and/or dependence on addictive drugs, e.g., narcotic analgesics, such as moiphinc, codeine, etc in U S Pat Nos 5,321 012 and 5,556,838 (both to Mayer cl al ), both of which are incorporated herein by leference. and to tieat chronic pain in U S Pat. No. 5.502,05 S (Mayer et a!.), incorporated herein bv reference. The N MDA agonist can be included alone or in. combination with a ϊoca! anesthetic, t>uch as lidocame, as described m these patents by Ma\er et al.
{X)X-2 inhibitors been reported m the an, and niatiy chemical compounds are known to produce inhibition of c>c!ooxygenase-2. t'OX-2 inhibitors are described. for example, in U S Pat Nos. 5,616,601 , 5,604,260, 5,593,994, 5.550,142: 5.536.752; 5,521.213, 5.475,095; 5,639,780; 5 604.253: 5,552,422; 5,510.368, 5,436,265, 5,409,044 and 5.130,3 ! 1 , all of which are incorporated herein by reference Certain preferred COX- 2 inhibitor include celeco.ύb (SC-58o35X DL'P-697, OosuHde (C<iP-28238), meloxicam, 6-methoxy-2-naphthγlacetic acid (6-NMA), VϊK-966 (also known as Vioxx). nabumetone {pjodrug foϊ 6-MNA), nimesuhde, NS-398. SC-5766. SC-5S215. "1-614. o» combinations thereof. Dosage of COX-2 inhibitoi on the oidei of tiorn about 0.005 iiig to about 140 rag per kilogram of body weight per day been shown to be therapeutically effective in combination with an opioid analgesic. Alternativ ely, about 0 25 mg to about 7 g per patient per day of a COX-2 inhibitor can be administered in combination with an opioid analgesic. The treatment of chrome pain \ ia the use of glycine receptor antagonists and the identification of such drugs is described in ILS. Pat. No. 5,5 S 4,6BO (Weber et al ). which is incorporated herein by reference.
Pharmaceutical K acceptable salts of the antagonist or agonist agents discussed hciein include metal salts, such as sodium salt, potassium salt, cesium salt, and the like, alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as tπethviamine salt, pyridine salt, picolme salt ethanolamine salt, methanoiamine salt, ώcyclohexUaramc salt, N,N'~diben/ylcthylenedtamιne sail, and the like; inorganic acid salts, such as hydrochloride, hvdrobromide, sulfate, phosphate, and the like: organic acsd salts, such as foimate. acetaie, trifluotυaeetate, maieaie, taruatc, and the like; sulfonates, such as methanes αlfonate, benzenesitlfonate, p-tolueaesulfonate, and the like; amino acid salts, such as argmate. asparginate, glutarnate, and the like
In embodiments in which the opioid agonist comprises bydiocodone, the sustained-relcavc oial dosage forms car? include analgesic doses from about 8 mg to about 50 mg of hydiocodone pet dosage unit, In sustained-release oial dosage foims where hydromorphone is the therapeutically active opioid, it is included m an amount from about 2 mg to about 64 mg bydromorphonc hydrochloride In another embodiment, the opioid agonist comprises morphine, and the sustained-release oral dosage forms of the invention include from about 2.5 mg to about SOO mg morphme. by weight, In yet another embodiment the opioid agonist comprises oxycodone and the sustained-release oral dosage forms include from about 2 5 nig to about HOO mg oxycodone. Tn certain preferred embodiments, die sustained-release oral dosage forms include fioni about 20 mg to about 30 mg oxycodone Controlled release oxycodone formulations are known in the ait The following documents describe various conti oiled-release oxy codone formulations suitable for use in the invention described herein, and processes for their manufacture. U.S. Pat. Nos 5,266,331; 5,549,012, 5,508.042, and 5.056,295, which me incorpouited herein by reference. The opioid agonist can comprise uamadol and the sustained-ieϊease oral dosage foims can include fiom about 25 nig to 800 mg uamadol par dosage unit.
Methods of making am of the sequestering suburuts of the {mention are known in the art See, for example. Remington fhe Si fence ωaJPructhe of Pharmacy, Alfonso R Genωo {eά\ 20lh edituMi, and bvample 2 set forth below The sequestering subumts can be prepared b\ an\ suitable method to provide, for example, beads, pellets granules, spheioids and the hke. Spheroids oi beads, coated Λ\ ιιh an active ingredient can be piepaied for example, by dissoh mg the acme ingiedient in water and then spra>mg the solution onto a sohstsate, for example, nυ pane! 18 20 beads, lining a Wurster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the actn c ingredient in binding to the substrates, and or to color the solution, etc The resulting substtate-activc material optionally can he ovcicoated with a bamei material to separate the therapeutical Iv actne agent from the next coat of material e.g , ιe-!eas>e-ϊetaιd»πg material Pieteiably, the batriei mateiial ib a matetial comptisiπg methj lcef ttilose However, an> film-former m the art can be used Preferably, the barrier material does not affect the dissolution rate of the final product
Pellets comprising an actne ingredient can be prepared, for example, by a melt pclleti/ation technique Typical of such techniques is when the actne mgiedierst in finely divided foira Ls combined with a bmdei (also m paniculate foim) and olbei optional inert ingredients, and thereafter the mixture is pcllchzed. e.g . by mechanically the mixture in a high shear mixei io form the pellet (e g.. pellet, giaτιule&, spheres, heacta. etc . collectn ely referred to herein as '"pellets'") Tliereafter, the pellets can be sieved in order to obtain pellets of the jeqiusue Mze I he bmdet material is prefeiabiy in paiticuhue form and has a nielUng point about 40 '' C Suitable binder substances include for example, h) drυgenated castoi oil, hydrogemited vegetable oil, other hjdrogenated fats, fatty alcohols. fatt> acid esters, fatty acid glycetides, and the like.
The diameter of the extruder aperture or exit port also can be adjusted to vary the thickness of the extruded stiands Fiirtheunoie, the exit part of the extruder need not be round; it can be oblong, rectangular; etc fhe exiting strands can be reduced to particles using a hot \\ ire cutiei , guillotine, etc The melt-extruded multiparticulate system can be, fot example in the form of gianules. spheroids, pellets, 01 the like, depending upon the extruder exit orifice. The terms "melt-extruded and "'melt-extruded multiparticulate system(s)"1 and melt-extruded particles" are used interchangeably herein and include a plurality of subunits. preferably within a range of similar si/e and'or shape The melt-extruded multiparticulates are preferably in a range of from about 0.1 to about 12 mm in length and c a diameter of from about O. I to about 5 mm in addition, the melt-extruded multiparticulates can be any geometrical shape within this ssze range. Alternately the extredate can simply be cut into desired lengths and div ided into unit doses of the therapeutically active agent without the need of a spheronization step.
The substrate also can be prepared via a granulation technique Generally, rnelt- granulation techniques invoke melting a normally solid hydrophobic material, e g , a wax, and incorporating an acm e ingredient therein. To obtain a sustained-release dosage form, it can be necessary to incorporate an additional hydrophobic materia!. A coatmg composition can be applied onto a substrate by spraying it onto the substrate using any suitable spraj equipment. For example, a Wαrstcr fiuidized-bed system can be used m which an air flow from underneath. fjuidizes the coated material and effects drying, while the insoluble poiymci coating is sprayed on The thickness of the coating will depend on the characteristics of the particular coating composition, and can be determined by using routine experimentation
Any mannoi of prepaiing a subun.it can be employed. By of example, a su bun it in the form of a pellet or the like can be prepared by co-extruding a material cαmpπsiug the opioid agoinst and a material comprising the opioid antagonist and/or antagonist in sequestered form. Optional!), the opioid agonist composition can cover, e.g , ov ercoat, the material comprising the antagonist and or antagonist in sequestered form. Λ bead, for example, can be prepared by coating a substrate comprising an opioid antagonist and'Or an antagonist in sequestered form with a solution comprising an opioid agimist.
The sequestering subunits of the are particularly well-suited for use in compositions comprising the sequestering suhunit and a theiapeutic agent in reϊeasable form. In this regard, the invention also prov tdes a composition comprising any of the sequestering subunits of the invention and a therapeutic agent in releasabie form. By "Yeleasable form" is meant to include immediate release, intermediate release, and sustained-release forms. The therapeutic agent can be formulated to provide immediate release of the therapeutic agent, in preferred embodiments, the composition provides sustained-release of the therapeutic agent
The therapeutic agent in sustained-release form is preferably a particle of therapeutic agent that is combined with a release-retarding material. The release-retarding material is preferably a material that permits release of the therapeutic agent at a sustained rate in an aqueous medium. The release-retarding material can be selectively chosen so as to achieve, in combination with the other stated properties, a desired in vitro release rate.
In a preferred embodiment, the oral dosage form of the invention can be formulated to provide for an increased duration of therapeutic action allowing once-daily dosing. In general, a release-retarding material is used to provide the increased duration of therapeutic action. Preferably, the once-daily dosing is provided by the dosage forms and methods described in U.S. Patent Application Pob. No. 20050020613 to Boehm, entitled "Sustained-Release Opioid Formulations and Method of Use." filed on Sep. 22, 2003, and incorporated herein by reference.
Preferred release-retarding materials include acrylic polymers, alkylceJluloses, shellac, zein. hydrogenated vegetable oil, hydrogenated castor oil, and combinations thereof. In certain preferred embodiments, the release-retarding material is a pharmaceutically acceptable acrylic polymer, including acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl rnethacryiates, cynaoεthyi methacryiate, aminoaikyi methacrylate copolymer, polytacrylic acid), poly(methacryiιc acid), methacrylic acid aikylamide copolymer, poly{methyl methacrylate), poiyjmethacrylic acid anhydride), methyl methaαylate, polymemacryiate, poly(methyi methacrylate) copolymer, poiyacrylamide, aminoaikyi merhacrylate copolymer, and jilycidyl methacrylate copolymers. In. certain preferred embodiments, die acrylic polymer comprises one or more ammonio røethacryiate copolymers. Ammonio methacrylate copolymers are well-known in the art, and are described in NRUl1 the 21"' edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockviliε, Md.), as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary aoimonium groups. In. other preferred embodiments, the release-retarding materia! is an alkyl celSuløsic material, such as ethyicelhilose. Those skilled to. the an will appreciate that other cellulosie polymers, including other alky! cellulosic polymers, can be substituted for part or all of the ethylcellulose.
Release-modifying agents, which affect the release properties of the release- retarding material also can be used. In a preferred embodiment, the release-modifying agent functions as a pore-former. The pore-fcrmer can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore-former can comprise one or more hydrophilic polymers, such as hydroxypropylmethylcelluiose. In certain preferred embodiments, the release- modifying agent is selected from hydroxypropylmethylcellulose, lactose, .metal stearates, and combinations thereof.
The release-retarding material can also include an. erosion-promoting agent, such as starch and gums; a release-modifying agent useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain; and/or a semipermeable polymer.
The release-retarding material, can also include an exit means comprising at least one passageway, orifice, or the like. The passageway can be formed, by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; »044,088,864, which are incorporated herein by reference. The passageway can have any shape, such as round, triangular, square, elliptical, irregular; etc,
In certain embodiments, Ae therapeutic agent in sustained-release form can include a plurality of substrates comprising the active ingredient, which substrates are coated with a sustained-release coating comprising a release-retarding material
The sustained-release preparations of the invention can be made in conjunction with any multiparticulate system, such as beads, ion-exchange resin beads, spheroids, microspheres, seeds, pellets,, granules, and other multiparticulate systems in order to obtain a desired sustained-release of die therapeutic agent. The multiparticulate system can be presented iα a capsule or in any other suitable unit dosage form, hi eeitam prεfeπed embodiments, moie than one multiparticulate system can be used, each exhibiting different characteristics, such a:> pl f dependence of release, time for release in in \ ho size and composition. fo obtain a sustained-release of the therapeutic agent in a manner sufficient to prm ide a therapeutic effect for the sustained durations, the therapeutic agent can be coated "w nh an amount of release-retarding material sufficient to obtain a weight gain from about 2 to about 30V although the coat can be greater or lesser depending upon the physical properties of the particular therapeutic agent utilized and the desired release rate, among other things. Moreover, there can be more than one release-retarding materia! used in the coat, as well as various other pharmaceutical exdpients
Solvents typically used for the release-retarding material include pharmaceutically acceptable solvents, such as water, methanol, ethanol, methylene chloride and combinations thereof !n certain embodiments of the invention, the release-retarding material is m the form of a coating comprising an aqueous dispersion of a hydrophobic polymer The inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polvmcr will further improve the physical properties of the Him foi example, because ethylcelkilose has a relatively high glass transition tempeiature and does not form flexible films under norma! coating conditions, it ;s necessary to plasticize the ethylccllulose befoie using the same as a coating maternal General!} , the amount of plasticizer included in a coating solution is based on the concentration of the fi!m- former, e g., most often from about 1 to about 50 peicenl by weight of the film-former Concentrations of the plastict/er. howeser, can be determined by routine experimentation, Examples of plastici/ers for ethj leellolo^e and other celluloses include dibutj l sebacate, diethyl pbiiiaiate, triethyl citrate, tributy! citrate, and triacetio, although it is possible that other plasticizers (such as acetylated monoglyccπdes, phthalatc esters, castor oil, etc) can be used hsaoipies of plastic izers for the acrvUc polymers include citric acid esters, such as trieth)! citrate NI-21, tiihuiv! citrate, dibufyl phthalate, and possibly 1,2-pϊopylene glycol, po!\eth\iene gKcols, piopv!ene glycol, diethyl phthalate, castor oil. and niacetm, although it is possible that otliei piasUcizers (such as aeetylated monoglyeendes, phthalate esters, castor oil, etc.) can be used. l he sustained-release profile of drug release m the formulations of the invention (either in "vivo or in vitro) can be atteied for example, by using more than one release - retarding material, varying the thickness of the release-retarding maLenal chaa^ia^ the particular release- retarding material used, altering the relative amounts of release- tetardiπg material, altoting the manner in which the plastiei/ei is added {e g , when {he sustained-release coating is demed from an aqueous dispersion of hydrophobic polymer), by relative to retardant material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture: etc
In certain other embodiments, the oral dosage form can utilize a multiparticulate sustained-release matrix, In certain embodiments, the sustained-release matrix comprises a hulropMlie and'or hydrophobic polymer, such as gums, cellulose ethers, acrylic renins and protein-derh ed materials Of these pohmeis, the cellulose ethers, specifically hydroxyalkylcelluioses and carboxyaikyleel.uloses, are preferred The oral dosage form can contain between about 1% and about 80% {by weight) of at least one hvdrophilic or hydrophobic polymer
The hydrophobic materia! is preferably selected fiom the group consisting of alkylcellulose, acrylic and methaeiylic acid polymers and copolymers, shellac, zein. hydrogenated cantor oil, oil, ur mixtures theieof Preferably, the hydrophobic mateπal is a pharmaceuticalh acceptable acrylic polymer, including acn lic acid and methacrylic acid copolymers*, methyl meihaciyiate, methj l mεthaciylaie copoKmers, ethoxyeihyl raetliacrvlate, animoalkyl methacrylatc copolymer, poly(aciy licacid). poiyt methacrylic acid), methacrylic acid alkylamine copoi\nier. poiy(methy! methactylate), poly (methacrv tic acid ){ anhydride), polymcthacryiate, polyacrylainide, poiyfmethacA'hc acid anhydride), and glycidyi methaαylate copolymers. In other embodiments, the hydrophobic material can also include hydroox\aik\ lce!luloses such as hydroxypropyJmethykeUiilose and mixtures of the foregoing Piefeired lndiophobic mateiials ate watei-insoluble uith mote or less pioπouneed heliophobic fiends Picfciabls, the hydrophobic materia! ha:> a melting point fiαrn about K) ' C to about 200° C , more prefeiahiv fiom about 4^° C to about 90° C I he hΛdtophøbie material can include neima! oi svnthetsc waxes. fatty alcohols (such as Luu)i, tnyusty!, steaiyi, cet>) ot piefetably cetosieat) ! alcohol), fatty acids, mchtdnig fattv aαd esteis, fattv acid ghceudes (mono-, di-, and tn-giyceudes), hydiogenated fats, hydiocaiboiis normal waxes, stearic acid, stearyl alcohol and hvdiophobic and h}diophihc raateπah mg hydrocaibon backbones Suitable waxes include beeswax, ghcowax, castor wax, carnauha wax and wax-tike substances, e g , material normally solid at room tempeiature and ing a melting point of from about 3O1- C to about 100° C
Ptcfεiabiv, a combination of oi ntoie hydtophobic mateπals are included m the matrix formulation_. It an additional matcnal is included, it is prefeiabK a πatmai or svnthctic wax, a fatty acid, a tatty alcohol oi mixtures theieof. Examples include beeswax, carnauba stearic acid and steaiχ-1 alcohol
Jn other embodiments, the sustained-release matrix comprises digestible, iong-cham
(e g , Cs-(So, piefeiabH C Z-C4J)K substituted or unsubstUuled hydrocarbons, such as fattv acids fattv alcohols glycenϊ c_.tcis of fattv acids> mineral and vegetable of K and waxes lhdiocaibons ιng a melting point of between about 25" C and about 90" C" are piefened Of these Song-chain hjdrocaibon matenah fattv (aliphatic) alcohols aie piefeπed The oul dosage loiπi tan contain up to about 60% (by weight) of\u least one digestible, long-chain hydioeaibcm
Kinher, the sustaiued-ielease malax can contain up tυ 60° a f bv weight) of at least one polvalkylene ghcol ϊn a prefers ed embodiment, the matπx comprises at least one water-soluble hydtowalkvl cellulose, at least one i\:-(\ ., ptefeiabh Cu-( ^, aliphatic alcohol and, optionally at least one polyaikylenc glycol The at least one hydio\yalk\l cellulose is prefeiably a hvdtoxv (C<-Cf)) alkvl cellulose such as and, preferabh . cellobse T he amount of die at least one l cellulose m the oial dosage fυπu will be determined, amongst other tluogs. by the precise iate of opioid jelease required The amount of the at lea.st one aliphatic aicoho! in the present oral dosage form will be determined by the piocise iate of opioid release required. However, if will also depend on whether {lie at least one polyalkylene glycol is absent from the oral dosage fomi.
In certain embodiments, a spheromzing agent, together with the active ingredient, can be &pheroni/ed to form spheroids Microcrysiailme cellulose and hydrous lactose impalpable are examples of such agents. Additionally (or alternatheh). the spheroids cart contain a watei-insoluble poly mer, preferab'} an acrylic polymer, an acrylic copolymer, such as a methacrylic aαd-ethx- i acrylate copolymer or eth> ! cellulose in such embodiments, the sustained-release coating will generally include a water-in soluble materia! such as (a) a wax, either alone or in admixture with a fatty alcohol or O)) shellac or zein
Preferabl), the sequestering subunit compiles the therapeutic agent in sustained- release form. The sustained-release subunit can be prepared by any suitable method. For example, a plasticized aqueous dispe.siυi. of the iulease-tetaulmg materia! can be applied onto the subunit comprising the opioid agonist A sufficient amount of the aqueous dispersion of release-retarding material to obtain a predetermined sustained -release of the opioid agonist when the coated substrate is exposed to aqueous solutions, e g , gastric fluid, is preferably applied, taking into account the phvsical characteristics of the opioid agonist, the manner of incorporation of the plastici/er, etc. Optionally, a fuither cn ercoat of a fϊiffl-formcr. such as Opadry (Colorcon, West Point, VaJ, can be applied after coating \* ith the release-retarding material
The subunit can be cured m order to obtain a stabilized release rate of the therapeutic agent In embodiments employing an acrylic coating, a stabilized product can be pieierably obtained by subjecting the subunit to ox en curing at a temperature abo^e the glass transition temperature of the plastιci?ed acrylic poij mer for the required time period. The optimum temperature and time for the particular formulation can be determined by routine experimentation.
Once prepared, the subunit can be combined with at least one additional subunit and, optionally, other excipients or drugs to an oral dosage form hi addition to the above ingredients, a sustamed-relea.se matrix also can contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, fkvorants and glidants that are comentionai ni the pharmaceutical art.
Optional!} and preferably, the mechanical fragility of of the sequestering siibunits described herein is the same as the mechanical fragility of the therapeutic agent in reieasable tbroi. In this regard, tampering with the composition of the im ention in a manner to obtain the therapeutic agent will result m the destruction of the sequestering subunit such that the antagonist is released and mixed in with the therapeutic agent Consequently, the antagonist cannot be separated from the therapeutic agent, and the therapeutic agent cannot be administered in the absence of the antagonist. Methods of assaying the mechanical fragilitλ of the sequestering subunit and of a therapeutic agent are known in the art.
The composition of the invention can be in any suitable dosage form or formulation, (see, e.g.. Pharmaceutic* and Pharmacy Practice, J. B. Lippincoit Company, Philadelphia, Pa., Banker and Chalmers, eds , pages 238-250 ( 19S2)). Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the inhibitor dissohed in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lo/enges. and troches, each containing a predetermined amount of the acthe ingredient as solids ot giamiles. «e) powders; id) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, cthanoϊ, ben/yi alcohol and the polyethylene alcohols, either with or w ithout the addition of a pharmaceutically acceptable suifactant Capsule forms can he of the oidinaiy hard- or soft-shelled gelatin type contaminu, for example, surfactants, lubricants, and ineit fillers, such as lactose, sucrose, calcium phosphate, and corn starch Tablet forms can include one or more of lactose, sucrose, maπmtoL corn starch, potato starch, algink acid, microcrystalline cellulose, acacia, gelatin, gυar gum, colloidal silicon dioxide, croscarrneibse sodium, talc, magnesium stearate, calcium sleaiate, /inc stearaie, stearic acid, and other excipients. colorants, diluents, buffering agents, disintegrating agents, moistening agents. piesen athes. flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usualh sucrose and acacia or tiagacanth, as well as pastilles comprising the acthe ingredient in an ineit base, such as gelatin and giyeeiin, 01 sucrose and acacia, emulsions, gels, and the like containing, in addition to the acthe ingtedient such excipients as are known in the an
One of ordinary skill in the art will readily appreciate that the compositions of the invention can be modified in any number of ways, such that the therapeutic efficacy of the composition is increased through the modification. For instance, the therapeutic agent oi sequestering subunu could be conjugated either directly oi indirectly through a linker to a targeting moiety I he practice of conjugating thetapeutic agents or sequestering suhunits to targeting moieties is known in the art See, for instance. Wadwa et al , J. Dn>g Targeting 3' 1 1 1 (1W5). sod U S Pat No. 5,087,616. The teiisn "targeting moiety" as used herein, refers to aαv molecule or agent that specifically recognizes and binds to a cell-surface receptor. such that the targeting moiety directs the deliv ery of the tlieπtpeutie agent or sequestering subumt to a population of cells on which the receptor is expressed Taigeiing moieties include, but are not limited to. antibodies, or fragments theieof, peptides, hormones, growth factors, cytokines, and am other naturallv- or non-αatuialiy- hgarsds, which bind to cell-surface receptors. The term 'linker' as used herein, refers to any agent or molecule that bridges the therapeutic agent or sequestering subumt to the targeting moiety Otic of ordinary skill in the art recognizes that sites on the theiapeutk agent or sequestering subunil which are not necessary foi the function of the agent or sequestering subunit, are ideal sites for attaching a linker and or a targeting moiety, provided that the linker and oi targeting moiety, once attached to the agent or sequestering subunit, do(es) not interfere w ith the function of the therapeutic agent or sequestering sυhunn
With respect to the present imentne compositions, the composition is preferably an oral dosage form By "oral dosage form'" is meant to include a unit dosage form prescribed oi intended for oral adrøimsrjation comprising subuπits Desiiably. the composition comprises the sequestering subunit coated with the therapeutic agent in ϊdeasable form, thereby founing a composite subunit comprising the sequestering subunit and the therapeutic agent, Accordingly, the invention further pros ides a capsule suitable for otal administration comprising a plurality of such composite subimits. Akematheiy. the oral dosage form can comprise any of the sequestering subumts of the im ention in combination with a therapeutic agent subunϊt the lheiapeutic agent subunit comprises the therapeutic agent in releasahle form In this respect, the {mention provides a capsule suitable for oral adramisttaticm comprising a plurality of sequestering subunits of the imentson and a pluraht) of therapeuuc subumts, each of which comprises a therapeutic agent in reieasable form
The invention furthei provides tablets comprising a sequestering subunit of (he invention and a therapeutic agent m ieleasable foim For instance, the invention prov ides a tablet suitable for oral administration comprising a first layer comprising any of the sequestering subumts of the invention and a second layer comprising therapeutic agent m re leasable form, wherein tlie first layer is coated with the second layer The first layer can comprise a plurality of sequestering subunits Alternatively, the frtsi layer can be or can consist of a single sequestering subunit. The therapeutic agent in releasable form can be in the fυrni of a therapeutic agent subun.it and the second layer can comprise a plurality of therapeuuc subunits. Alternately, the second layer can comprise a single substantially homogeneous layer comprising the therapeutic agent in releasable form.
When the blocking agent is a system comprising a first antagonist-impermeable material and a core, the sequestering sυbumi αin be in one of several different foims For example, the system can further comprise a second antagonsst-mipetmeable materia}, m which case tlie sequestering unit comprises an antagonist, a first antagonist-impermeable matetiai, a secυnd antagonisHrnpeimeabie material and a coie. In this instance, the core is coated with the first antagonist-impermeable material which, in turn, is coated with the antagonist, which, in u»n, ts coated wiih the second antagonist-impermeable material Hie first antagonist-impermeable material and second antagonist-impermeable material substantially prevent release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. In some instances, it is preferable that the first antagonist-impermeable material is the same as the second antagonist-impermeable materia! In otiiei instances, the fust antagonist-impermeable materia! is different from the second antagonist-impermeable material It is within the skill of the oidinary artisan to deteimine whether oi not the Hist and second antagonist- impermeable materials should be the same cu diffeient. Factors that influence the decision as to whether the first and second antagonist-impermeable materials should be the same or different can include whether a layer to be placed over the antagonist- impermeable material requires certain properties to prevent dissolving pait or all of the antagonist-impermeable layer when applyiug the next layer or properties to promote adhesion of a layer to be applied over the antagonist- impermeable layer.
Alternatively, the antagonist can he incorporated into the core, and the core is coated with the first antagonist-impermeable material. In this case, the invention provides a sequestering subunit comprising an antagonist, a core and a first antagonist- impermeable material wherein the antagonist is incorporated into the core and the core is coated with the first antagonist-impermeable material and wherein the first antagonist- impermeable material substantially prevents release of the antagonist from the sequestering subunii in the gastrointestinal tract for a time period that is greater than 24 hours. By 'incorporate'' and words stemming therefrom, as used herein is meant to include any means of incorporation, e.g.. homogeneous dispersion of the antagonist throughout the core, a single layer of the antagonist coated on top of a core, or a multilayer system of the antagonist, which comprises the core.
In another alternative embodiment, the core comprises a water-insoluble material and the core is coated with the antagonist, which, in lorn, is coated with the first antagonist-impermeable material. In this case, the indention further provides a sequestering subunit comprising art antagonist, a first antagonist-impermeable materia!, and a core, which comprises a water-insoluble material, wherein the core is coated with the antagonist, which, in turn, is coated with the first antagonist-impermeable material and wherein the first antagonist-impermeable materia! substantially presents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. The term "water-insoluble material" as used herein means any material mat is substantially water-insoluble. The term "substantially water- insoluble" does not necessarily refer to complete or 100% wafer-insolubility. Rather, there are varying degrees of water insolubility of which one of ordinary skill in the art recognizes as having a potential benefit. Preferred water-insoluble materials include, for example, microcrystalline cellulose, a calcium salt, and a -wax. Calcium salts include, but are not limited to. a calcium phosphate (e.g., hvdroxyapatite, apatite: etc), calcium carbonate, calcium sulfate, calcium stearate, and the like. Waxes include, for example, cauiuba wax, beeswax, petioleum wax, canddilSa wax. and the like.
In one embodiment, the sequestering subunit includes an antagonist and a sea! coat where the sea! coat forms a layer physically separating the antagonist within the sequestering suhunu from the agonist which is layered upon the sequestering subunit. hi one embodiment, the seal coat comprises one or more of an osmotic pressure regulating agent, a chaige-noutiaii/iitg additive, a sequestering polymer hydrophohicHy-enhaneing additn e, and a first sequestering polymei (each haung been desciibed abo\e). in such embodiments, it is preferred that the osmotic pressure regulating agent, charge- neutralizing addime. and / or sequestering polymer hydrophobidty-enhanάng additn e. respectively where present, are present in proportion to the first sequestering polymer such that no more than 10% of the antagonist is released from the intact dosage form Where an opioid antagonist is used in the sequestering submit and the intact dosage form includes an opioid agonLst, it it> preferred that ratio of the osmotic piessiπe tegulatmg agent, charge-neutralizing and or sequestering polymer hydrophobtcuy- enhanenig additne, respectively where present, m relation to the first sequestering pohmer is such that the physiological effect of the opioid agonist is not diminished when the composition is in its intact dosage form oi during the normal course digestion in the patient Release may be detei mined as described abose using the USP paddle method (opticmail) using a buffer containing a surfactant such as Triton X-IOO) or measured from plasma aftei administration to a patient in the foά or non-fed state, ϊn one embodiment, plasma naltrexone levels are determined; in others, plasma 6-bcta aaitrexol ϊc\ els are detei mined. Standaul tests may be utilized io ascettam the antagonist's effect on agonist function (i e., reduction of pain}. The sequestering subunit of the can hav e a blocking agent that is a tether to which the antagonist is attached. The teim "tether" as used herein iefers to am means by which the antagonist is tethered or attached to the interior of the sequestering subimit, such that the antagonist is not released, unless the sequestering subunii is tampered with. Ui this instance, a tether-antagonist complex is formed. The complex is coated with a tether-irnpeimeable mateiiah thereby substantially pies en ting release of the antagonist furni the subunit. The terra "tethei-impeimeable material" as msά herein refers to any material that substantially presents or the teihef from petmeating through the mateπal. The tether pieferably is an too exchange resin bead. l he imenuoti further prov ides a tablet suitable for oral administration composing a single la\er comprising a therapeutic agent in releasable form and a plurality of any of the sequestering suhunils of the im enium dispersed throughout the layer of the therapeutic agent in releasabie form. Hie im ention also ρro\ ides a tablet in which the therapeutic agent in releasable form is in the form of a therapeutic agent subitnit and the tablet comprises an at least substantially homogeneous miλtuie of a plurality of sequestering subunits and a plurality of subunits comprising the therapeutic agent !n preferred embodiments oral dosage forms ate prepared to include an effective amount of melt-extruded subυmts in the form of raultiparticϊes % ithin a capsule For example, a plurality υf the melt-extruded muliparticulates can be placed m a gelatin capsule in an amount sufficient to provide an effects e release dose when ingested and contacted by gastric fluid. !tt another preferred embodiment, the subunits, e.g , in the form of multiparticulates, can be compressed into an oral tablet using conventional tableting equipment using standard techniques Techniques and compositions for making tablets (compressed and molded), capsules (hatd and soft gelatin) and pills aie also described in Remington's Pharmaceutical Sciences. (Λuπher Osol . eduoi K 1553-15^3 ( 198O)5 which is incorporated herein b> reference Exciptents in tablet formulation can include, for example, an inert diluem such as lactose, granulating and disintegrating agents, such as cornstarch, binding agents, such as starch, and lubricating agents, such as magnesium stearate.
In \et another preferred embodiment., the subunits are added during the extrusion process and the ettrudate can be shaped into tablets as set forth in U. S Pat. No 4,^57,681 (Klimesch et al. }, which is incorporated herein by reference.
Optionally, the sustamed-reicasc. melt-extruded, multiparticulate systems or tablets can be coated, or the geJatm capsule can be fuithei coated, uuh a sitsΛanied- reiease coating, such as the sustained-release coatings described herein Such coatings are panicdaily useful when the subunil comprises an opioid agonist in ieleasabie foπn, but αc*t ia sustained-release form. The coatings preferably include a sufficient amount of a hydrophobic materia! to obtain a weight gam foira about 2 to about 30 percent, although the overcoat can be greater, depending upon the physical properties of the particular opioid analgesic utilized and the desired release rate, among other things
The raelt-extruded dosage forms can further include combinations of melt- extruded multiparticulates containing one oτ more of the therapeutically active agents before being encapsulated Furthermore, the dosage forms can also include an amount of an immediate ieleasc ϊhetapeυtic agent for prompt tbeiapemie effect The immediate release therapeutic agent can be incorporated oi coated on the surface of the subunits after preparation of the dosage forms (e.g . control led -release coating or matrix-based). Tiie dosage forms cast also contain a combination of control led-release beads and matrix multiparticulates to a desired effect.
The sustained-release formulations preferably slowly release the theπφeittie agent, e g.. when ingested and exposed to gastric fluids, and then to intestinal fluids The sustained-release profile of the niek-ex.ruded formulations can be altered, for example, by the amount of retardatrt, e.g.. hydrophobic material by the amount of plastiCϊzer relative to hydrophobic material, by the inclusion of additional ingredients or eκcipients. by altering the method of manufacture; etc.
In other embodiments, the melt-extruded material is prepared without the inclusion of the subunits, which are added thereafter to the extrudate Such formulations can ha\ e the subunits and other drugs blended together with the extruded matrix material, and then the miviuie is tabieted in order to ide a slow ielease of the therapeutic agent or other drugs. Such formulations can be particularly advantageous, for example, when the therapeutically active agent included m the formulation is sensitne to temperatures needed for softening the hydrophobic materia! and or the retardanl material ϊn certain embodiments, the release of the antagonist of the sequestering sobunit or composition is expiessed in terms of a ratio of the release achieved after tampering, eg , by crushing or chew ing, relative to the amount released from the intact formulation The iatio is, thetefoie, expiessed a& [Crιnhedj.[Wholej, and it is desired that tins ratio have a numerical range of at least about 4 1 or greater [e.u. , crushed release within I hour/intact release iu 24 hours). In certain embodiments, the iatio of the therapeutic agent and the antagonist, present ϊn the sequesteiing subunit, is about I J, about 50.1, about 75 1, about 100 1 , about 150 I , or about 200" I, foi example, b> weight, preferably about 1 .1 to about 20.1 by weight oi !5 ! to about 30.1 by weight. The weight tatio of the therapeutic agent to antagonist refers to the weight of the active ingredients HUB, for example, the w eight of the therapeutic agent excludes the weight of the coating, matrix, or other component that renders the antagonist sequestered, or other possible excφients associated with the antagonist particles, in certain preferred embodiments, the ratio is about 1.1 to about 10 1 by weight. Because in certain embodiments the antagonist is in a sequestered from, the amount of such antagonist wnhm the dosage form can be more w idely than the therapeutic agent antagonist combination dosage forms, where both are available for release upon administration, as tlte formulation does not depend on differential metabolism or hepatic clearance for proper functioning. For safety reasons, the amount of the antagonist present in a substantially nυn-releasabie form is selected as not to be harmful to humans, even if fully released under conditions of tampering
The composition;? of the [mention are particularly well-suited foi use in presenting abuse of a therapeutic agent, hi this regard, the (m ention also presides a method of preventing abuse of a therapeutic agent by a human benig. The method comprises incorporating the therapeutic agent into any of the compositions of the imeniion Upon administration of the composition of the invention to the person, the antagonist is substantial!) from being released in the gastrointestinal tract for a time period that is grcatei than 24 hours. However, if a person tampers w ith the compositions, the sequestering subunit, which is mechanically fragile, v\ ili break and thereby allow the antagonist to be released. Since the mechanical fragility of the sequestering subunit is the same as the therapeutic agent in releasable form, the antagonist will be mixed with the therapeutic agent such that separation between the two components is virtually impossible
The effectiveness of treatment of chronic moderate to severe pain (focusing on osteoarthritis of the hip or kneel is typically measured by mean change in diary Brief Pain Inventory (BPl) seoie of av erage pain (daily scores of average pain averaged over 7 days, in-clinic BP! and/or dailv diary BPI {worst, least, and current pain)), WOMAC Osteoarthritis Index, Medical Outcomes Study (MOS) Sleep Scale, Beck Depression Inventory, and Patient Global impression of Change (PGlC). The safety and tolerabihty of opioid medications such as Radian Nl ;ue compared Io placebo using Adverse Kvents (A£s), clinical laboratory data, vital signs, and two meabutes of opioid wilhdiawai" Subjective Opiate Withdrawal Scale (SOWS) and Clinical Opiate Withdrawal Scale (COWS),
BPi is typically measured using 11 -point BPl system as follows L Ptease pain circling the one number that best describes your pain at its worst in the last 24 hours.
0 1 2 3 4 5 6 7 8 9 10 Kid as
\(>!i tan iftupiBC
2. Please rate pain at Hs least in the last 24 hours.
0 1 2 ^ 4 5 6 7 8 9 10
\u patl) P1I)I! JSi bad ,JS
uwtdiimiasirui.
3, Please rate your pain by circling the one number tbat best describes your pain on the ayerage in the last 24 hours.
0 I 2 3 4 S 6 7 8 O 10
No pam i'am a> bύi a>
4, Please rate your pain by circling the one number that tells how much pain you have right turn.
0 1 2 3 4 5 6 7 Z 9 10
No {vjiii i'aii) j!, bά$ as
lhe MOS Sleep Scale n a self-admnmtered. subject-rated questionnaire consisting of 12 items that assess Le> components of sleep (R. D., & Stewart, A. L, (Ϊ992) Sleep πieasiues in Λ L, Stew an & J B Waie (eds.). Measuring funciioning and well-being. Hie Medical Outcomes Stud) approach (pp 235-25Q), Durham, NC" Duke Press). When scoied, the instiunient provides seven siibscale seo.es (sleep disturbance, snoring, awaken shoit of breath or with a headache, quantity of sleep, optima! sleep, sleep adequacy, and somnolence) as well as a nine-item ox em!! sleep problems mdex. Higher scores reflect more impairment in all subscales except for sleep adequac}, where a higher score reflects less impairment. A typical representation of the MOS Sleep Scale is shown below
i 1 low long did it usual!} take for you to fall asleep during the past four v> eeks?
(Circle One}
O 15 minutes 1
16 30 rmniueb
31 45 minutes 3
46 - 60 minuter 4
More than 60 minutes 5
2 Ou the as erage, how many hows did >ou sleep each.niglu dun tig the past lout weeks'1
Write in the number of hows per night 1 low often during the past four weeks did you...
(Ciicle One "Number On Each Line)
All of Most A Good Some A LϊUle None the of the Bit of of the of the of the
Time lime the Time I ime fime
Time
▼ T T ψ T T
3 feel that your sleep was not 4 5 6 quiet (moving restlessly, feeliug tense, speaking, etc., while sleeping)?
4. get enough sleep to fee! jested upon waking m the morning''1 5 awaken short of breath or with a headache?
6 feel drowsy or sleepy during i 2 3 4 5 6 the da\ 1J
7. have trouble failing asleep? 1 > 3 4 5 6 awakeu dυπiiu vour sleen 1 2 3 4 5 6 time and hav e trouble falling asleep again?
9. have trouble staying av\ ake 1 2 3 4 5 6 during the day9
10 snore during youi sleep? 1 2 3 4 5 6
1 1 take naps (5 minutes or 1 2 3 4 5 ft longer} duπng the daV'
12. get the amount of sleep you 1 2 3 4 5 6 needed?
The Reek Depression inventory is a self-admin&tered, 2 i -item test in multiple-choice format that measures the presence and degree of depression (Beck et al. An im entory for measuring depression Λteh (Jen Psych 1%1 :4 561 -571 ). Lach of the inx entoiy questions corresponds to a specific category of depressive symptom and or attitude. Answers are scored on a 0 to 3 scale, where "v0"' is minimal and u¥~ i6 severe A scote of -- 15 indicates raild depression, a score of 15-30 indicates moderate depression, and a score >30 indicates depression
The WOMAC Osteoarthritis index consists of questions on three subscaies' Pain, Stiffness, and Physical Function (Bellamy et al. Validation stixis of WOMAC : a health status instrument for measuring clinically important patient ant outcomes to antirheumatic drug tlierap\ in patients with osteoarthritis of the hip or knee, J Rheumatol 1988; 15 1833-1840; Bellamy K Pain assessment in osteoarthritis: experience with the WOM ΛC osteoarthritis index Semin Arthritis Rheum. N89; 18; 14- π, Beliamy et al Double bund randomized controlled trial of sodium mcclofcnaniale (Mcclomen) and diclofenac sodium {Voltaren}: post validation reappiication of the WOMAC Osteoarthritis index. J Rheumatol. 1992; 19: 153- i 59). Questions are typically completed by the subject before any other efficacy assessments are performed, A typical WOMAC* survey is reproduced below; The PCJIC IS a self-administered instrument that measures change in patient's overall status on a scale ranging from 1 (\ery much improved) to 7 (very much worse). The PGIC is based on the Clinical Global Impression of Change (CGIC) (Guy W. M.'DL-li assessment manual for psychopharmacology. Washington. DC: Department of Health, Education and Welfare, 197ό;217-222, Publication Number (ADM) 76-338), which is a validated scale. A typical form of the PGlC sun ey is shown below:
How would you rate your overall status since vour last visit?
(Please circle one)
Very Much Improved I
Much Improved 2
Minimally Unproved 3
Ko Change 4
Minimal Iy Worse 5
Much Worse 6
Very Much Worse 7
Any or all of these measures of effectn eπess may be used alone or in combination to determine the efficacy of various formulations or treatment regimens. Prcn iced herein are methods for treating pain in a person comprising administering thereto a multilayer pharmaceutical composition as described herein such that pain is substantially relieved m the patient. By "substantially relieved" is meant that the person reports a decrease in pain as measured by any of several known methods (including but not limited to those described herein) for determining pain. This decrease may be in comparison to no treatment, a placebo, or another form of treatment Including but not limited to another composition, either one described herein or otherwise available to one of skill in the art. Typically but not necessarily, pain is considered substantially relieved where the decrease is significant (e.g., ρ<0.05). The methods described herein provide methods for substantially relieving pain (e.g, providing an analgesic effect} for time periods of at least one week {eg , two, four, eight, 52, 16, 20, 24, 28, 32, 36, 40 and 100 weeks) by admimsteiing a multi-lavei pharmaceutical composition as descnbed liejein in one eiπbodiiuciit. the method includes icguiativ adnimistcting (e g , at least once, twice, three, or four times ) & multi-k>α pharmaceutical composition comprising an agonist and an atagooist as descnbed herein for at least one week le g., one, two, four, eight 12, 16, 20, 24, 28, 32, 36. 40 and 100 week**} wherein no substantial release (e g , zero, or less than about 10% 20V or 30° o release) of the antagonist is observ ed, in some embodiments, administration of the composition to a population once daily for a tune peπod of at least one week results m no substantial ϊeϊease in at least about Wo, 80%v 700O, ftθ%. or 5Q% of the making up the population Release ma> be measured by detecting naltrexone or (1-naltrexoi in plasma.
A bettci understanding of the piescnt imention and of its many advantages will be had frotn the following examples, given by way of illustration.
EXAMPLES
Exemplary KadianNT formulations and methods described below in Examples 1 - 4 may also be found in PCT/US2OO7/014282 (WO 2007/149438 A2), PCT/US2007/021627 (WO 2008/063301 A2), and PCT/US08/ 10357.
Example 1
Optimization Study #4, KadianftiT, Morphine sulfate and Naltrexone HO 6Umg/4,Hmg
/29-780-1 N)
A. Method of preparation
1 Dissolve Ethylccllulosc and ώbutyl scbacatc into etbanol, then disperse talc and magnesium stearate into the solution
2. Spra) the dispersion from I onto sugar spheres in a Wurster to form seal-coated sugar spheres (50μm seal coat)
3. Dissohe Kluce! LF and ascorbic actd into 20,80 mixture of water and cthanol Disperse nalϊietone HCl and (ale into ihe sohitioπ
4. Spra> the naltrexone dispersion from 3 onto scal-coatcd sugar spheres from 2 in a Wurster tυ foim naltrexone cores.
5. Dissohe Ludragn RS, sodium laurvl sulfate and dibutsl debacate into ethaπol Disperse talc into the solution
6. Spray the dispersion from 5 onto naltrexone cores from 4 in a Wurster to form naltieλonc pellets.
7 1 he Naltrexone pellets ate diied at 50 X " for 4S hours. 8, Resulting pellets a Eudragit RS eβai thickness of 150μm for both PΪ-1495 Pl-1496.
9 (Only foi Pi- 14*?5) Dissolve sodium chloride and hypromeilose into water. 10. Dissolve hyproraellose into !0;90 mixture of water and ethanoi. Disperse 5 morphine sulfate into the solution
! 3 (OnH tor PI- 1495) Spray the solution from 9 followed by the dispersion from 10 onto naltrexone pellets in 7 in a rotor to form nallroxoπe-morphine cores. 12 (Only for PI- 1496) Spray the dispersωn fiom 10 onto naltrexone peilets in 7 in a rotoi to form naltrexone-morphine cores 10 13 Dissolve ethj lcellulose. PEG 6000, budragit LI 00-55 and diethyl phthalate into ethanol Disperse talc into the solution. 14 Spray the dispersion from 12 onto na.trexυne-røorphine cores in i 1 or 12 to form naltrcxone-morphme pellets 15, The pellets me filled into capsules. 35
B jn-Λ.jttro...drug .release -
1 Method - I'SP paddle method at 37T and lOOrpm
- 1 hour in (UN ItCl then 72 hours in 005M pll 7,5 phosphate buffer 20 Results - Pes cent of KT released at 73 hours for PΪ- J495 l)%
- Pcrccm υf NT teleased at 73 hout s for ?l- 14% 0θ ό
2 Method - I'SP paddle method at 3TX ' and 1 OOrpm
- 72 hrs in 02\ Triton X-100/0.2% sodium acetate<0.0G2N HCL pH 25 5 5
Results - Percent of NT released at 73 houis for Pl-14^5 - 0%
- Percent of NT released at 73 hours for PI-14% - 0%
M)
*n
This is a single-dose, open-label, tw o period stud) in which two gioups of eight subjects one dose of either PI- 1495 or Pl -14% Each subject recehed an assigned treatment sequence based on a randomization schedule nodes fasting and non- fasting conditions Blood samples were drawn prior to dose administration and at O 5 to 16B hours post-dose Limits of quantitation are 4.00 pg roL for naltrexone and 0 250 pg ml. foi 6-beta-naltrexol A summary of ώe pharmacokinetic results is shown in the following tables
Naltrexone
N S, unless specified otherwise
N=S, unless specified otherwise
Kadian NI pellets with naltrexone pellet coat thickness of I5θμm had comparable naltrexone release as KT pellets with 90 um coat thickness This comparable NT ielease may also be attributed ftom the presence of 50μm seal coat on the sugar spheres used in Kadian NT pellets Significant NT sequestering was observ ed, both at fasting (>97%) and fed states ("-%%) Kadian NT pellets coniaπnng sodium chloiide above the naltrexone pellet coat (Fi-H1J?) had half the release of naltrexone compared to Kadian NT pellet without sodium chloride (PI- 1496), consistent with in vitro results There is again food effect observed. Lag time was significantly reduced.
Optimization Study US, KadianNT, Morphine sulfate and Naltrexone HCl 60mg/2*4mg
(20'9(B-AV) B. Method of preparation ~~
1 Dissolve Kthylcellulose and dibutvl sebacate into ethanol, then disperse talc and magnesium stearate into the solution, 2 Spray the dispersion from 1 onto sugar spheres in a Wmster to form seal- coated sugar spheres (50μm sea! coat).
3 Dissolve Klucei LF and ascorbic acid into 20.80 mixture of w atei and ethatiol. Disperse naltrexone LlCl and talc into the solution.
4 Spray the naltrexone dispersion from 3 onto seal-coated sugar spheres from 2 in a Wurster to form naltrexone cores.
5. Dissolve Eυdragit RS, sodium lauryl sulfate and dibutyl sebacate into etlianol Dispei so talc into the .solution
6, Spray the dispersion from 5 onto naltrexone cores from 4 in a Wurster to form nalUe.vone pellets. 7. The Naltrexone pellets are dried at 5O0C for 48 hours
8 Resulting pellets have a Eudragit RS coat thickness of 150μm.
9. Dissolve sodium chloride and hypromellose into water.
10 Dissnhe hypionieilose into 10 90 mixtαic of watct and eihanol Dispose morphine sulfate into the solution 11 Spray the solution from 9 followed by the dispersion from 10 onto naltrexone pellets in 7 in a roioi to form naltrexoπe-morpbiπe cores.
12 Dissolve ethyiceliitiose, PEG 6000, Eudragit L 100-55 and dicth\ l phthalatc into ethanol Disperse talc πuo the solution
13 Spray the dispersion from \2 onto iiaitrexone-morphine cores in I I or 12 to foHTi naitrexonomorphinc pellets
14. The pellets ai-e filled into capsules.
B lnA nro diog relea.se
1. Method - USP paddle method at 37T and lOOrpm - 1 hour in 0 1 M HCi, (hen 72 hours in 0 05M pi 1 7.5 phosphate bufiej
Results - Percent of NT released at ^3 hours foi = 0% 2 Method - \J%? paddle method at 37T ami 1 OGJ pm
- 72 his m 0 2°o Fπtcui X-I OO 0 2°B sodium acetate/0 002N HO pH
5. S Results - Percent of Nl teleased at 73 houis 0%
C Ifhyno suuiy
I his is a smgle-dose open-label, two peuod study ui which eight subjects weie landomi/ed to receive one dose of PMMO under either fasted or foό state during Stud) Period 1 and alternate fasted or ted state feu Study Period 2 Blood samples were ά&wn ptiot to dose admimstianon and at 0 5 to 16S horns pob>t-dosc Limits, of quantitation aie 400 pg mL foi naltrexone and 0 250 pg/roϊ for 6-beta-naUτexoi A bumman of the phaimacokinetic raeasuiemente is provided m the follow ing tables
»8, unless specified otherwise
It was concluded that Fi-1510 and PI- i.495 aie eurapaiable The teductum in loading in the pellets (from 1 5% m PI- 1495 to 0 7% m Pl-I S 10} does not seem to affect KT release Significant NT beqυesteπng \\άh υksened both at fasting ( "-9M o) and fed states (>95° o) The food effect obsen εd w as modest in terms of total N T ielcasc , the lag tsme was s»jgnjficantly seduced in the ptescπce of food Theie Vv ere subjects w ith multiple peaks of iclease. Summar^of NT
BA (C max) ::: Relative bioavailability based on Cmax ::: Dose-adjusted ratio of Cmax (NT/KNT pellet) to Cmax (NT soin)
BA (AlJC last) = Relative bioavailability based on AUC last = Dose-adjissted ratio of AUC last { NT/KNT pellet) to AU
BA (AUC inf) ~ Relative bioavailability based on AUC inf ~ Dose-adjusted ratio of AUC iuf (NT/KNT pellet)
Total in-vivo cumulative NT release can be extrapolated from BA {AUC inf) calculations from 6~beta-Naltrt'xo! plasma levels
Example 3 Kadian XT Formulation M6 (Al-ϋl)
In certain embodiments, components (a), (b) and / or (c) may be included as described below;
(a) preferably a matrix polymer insoluble at pH of about 1 to about 7.5: preferably ethylcellulose; preferably at least 35 % by weight of a+b÷e;
(b) preferably an enteric polymer insoluble at pH of about i to about 4 but soluble at pH of about 6 to about 7.5; preferably røethacrylic acid-ethyl acrylate copolymer (methacrylic acid copolymer type C) preferably about ϊ to about 30% of\a÷b+c; and, (c) compound soluble at a pH from about I to about 4: preferably polyethylene glycol with a molecular weight from about 1700 to about 20,000; preferably from about 1% to about 60% by weight of a+b+e.
C, Method of prepare ikm L Ethylceϊiiilose and Dibutyl Sebacate were dissolved into Alcohol SDA3A.
Tale and Magnesium. Stearate were then dispersed into the solution. The percent solid of the dispersion was 20%. 2, The dispersion from 1 was sprayed onto Sugar Spheres in a Wurster to fomi
Seal-coaled Sugar Spheres (approx. 50μ,m sea! coat). 3. Hydroxypropyl Cellulose and Ascorbic Acid were dissolved into a 20:80 mixture of Water and Alcohol SDA3A. Naltrexone HCl and Talc were then dispersed into the solution. The percent solid of the dispersion is 20.4%. 4. The Naltrexone HCl dispersion from 3 was sprayed onto Seal-coated Sugar Spheres from 2 in a Wurster to form Naltrexone HCI cores.
5. Ammottio Methacryiate Copolymer. Sodium Lairryl Sulfate and Dibutyl Sebacate were dissolved into a 22:7S mixture of Water and Alcohol SDA3A, Talc was dispersed inlo the solution. The percent solid of the dispersion was
20%.
6. The dispersion from S was sprayed onto Naltrexone HCl cores from 4 in ι\ Wurster to form Naltrexone HC! Intermediate Pellets.
7. The Naltrexone BCl intermediate Pellets were dried in an oven at 5O0C for 24 hours.
8. Amnionic Methacrylate Copolymer, Sodium Lauryl Sulfate and Dibutyl Sebacate were dissolved into a 22:78 mixture of Water and Alcohol SD A3 A. Talc was dispersed into the solution. The percent solid of the dispersion was 20%. cλ The dispersion from 8 was sprayed onto Naltrexone HCI Intermediate Pellets from 7 in a Wurster to form Naltrexone HCI Finished Pellets.
10. The Naltrexone HC! Finished Pellets were dried in an oven at 50°C for 24 ho LiI S.
11. The resulting pellets had a pellet coat thickness of approximate!)' ! 5()μm. 12. Sodium Chloride (NaCl) and Hydroxypropyl Cellulose were dissolved into
Water, The percent solid in the solution was 6%. 13. The Sodium Chloride solution from 12 was sprayed onto Naltrexone HCl
Finished Pellets from 10 in a Wurster to form Sodium Chloride (Na(I)
Over. coaled Naltrexone HCI Pellets, 14. Hydroxypropyl Cellulose was dissolved into Alcohol SDA3A, and Morphine
Sulfate dispersed into the solution. The percent solid in the dispersion was
24.4%. 15. The Morphine Sulfate dispersion from 14 was sprayed onto NaCI Overcoated
Naltrexone HCI Pellets in 13 in a rotor to form Morphine Sulfate Cores with Sequestered Naltrexone HCl. 16 Htlnieeilulose, Polyethylene Glycol. Methaeryhc Acid Copohmer and Diethyl Phthalatc were dissolved into Alcohol SDA3A. Talc \uιs dispersed into the solution The percent solid in the dispeisϊon was 14,3C O
P The Dispersion from lή was sprayed onto Morphine Sulfate Cores with 5 Sequestered Naltrexone HCI m 15 to form Morphine Sulfate Intended-release v. ith Sequestered Naltrexone HCI Pellets
18 The pellets were filled into capsules.
Example 4
I O Methods for Treating Pain (2ύ2)
As an example, Kadian KT {60mg morphine sulfate. 2.4iπg naltrexone H(T) was administered io humane and compared to the piewously described product Kadian Each Kadian sustained release capsule contains either 20. 30, 50. 60. or 100 mg of Morphine Sulfate USP and the following inactive ingtcdients common io ail strengths.
15 hydroxyprop} 1 methyleeikilose. ethyleellolosc. methacryhe add copolymer, polyethylene glycol, diethyl phthalafe, tale, corn starch, and sucrose, In these studies, the effects of Kadian were compared to those of Kadian NI .
Patients already being tieated with Kadian were subjected to a '^ ashouf period of approximately 14 da>s during which Kadian was not administered. Immediately 0 follow tng this washout period, the trial was> begun. Patients were eithei adininisteied Kadian oi Kadian NT at day 0, After a period of up to 28 days treatment v. ith Kadianf , patients were then "crossed-o\ef* to Kadian NT or continued taking KadianEλ The amount of Kadian NI wa& individually adjusted such that each patient was tecen iny: approximately the same amount of morphine they had been receiving while 5 taking Kadian This cross-ox er was then repeated after 14 days Various physiological responses were measured at different timepoints, as discussed below. These responses included morphine blood levels, naltrexone blood levels, 6-β-natrexol blood levels and pain scores.
Mean morphine concentiations were measuied and deteπninεd to be
30 approximately the same for Kadian-S" and Kadian NT, This, observation confirms that the new fomuiktϊoα effecm elv ieleases morphine into the blood of patients I his is shown in the table below.
It js urφoitant that the Kadmα \τl fctmυlation not release significant amounts of antagonist {i e . naltiexone ot auves tlieteof) mto the bloodstieam such that the actϊ\ ity of moiphiαe is diminished Only 14 of 69 patients had quantifiable (v 4 0 pg/rnL) nahtexυnc concentrations The range of quantifiable coϊicentidtions was 4 4-25 5 pg/raL However, the teiease of some naltrexone into the bioodstieam did not affect the pa«i scoics (sec below)
*Λ pain score of 0-3 is considered "imlcT and 4-7 is considered "moderate"
When presided m an immediate formulation, naltrexone (parent} is iapidly absoibcd and coin cited to the metabolite is a opioid antagonist than naltrexone. ing onl> 2 to 4°o the antagonist potencv Most patients had quantifiable levels { > U 25 pg/mL) of 6-β-naitrexol The incidental piescnce of 6-β- πaitrexol m the plasma had no effect on pain scores
It was aJso important to confirm that Radian NT did not result in a significantly different type, number oi severity of common atheisc events. This was confύmed, as shown below
!tt addition, it was important to note whether Kadian NT functioned similarly to Kadian with respect to adverse events typically associated with withdrawal symptoms. I his v. as confirmed as shown below;
Othα measuteraents, including hi-Chmc Pain, WOMΛC Pam, WOM ΛC Stiffness, WOMΛC Daily Activ ities, and BP! Pain w cie albo made. It was ϋetct mined that the diffeiences in these measuiements in those taking Kadmn and those taking Kadian .N I' was not significant as shown belcnv .
In-( KBk PaJH (ITT Papulation, Completers)
WOMAC Pain (ITT Population, Compfcters)
WOMΛC Stiffness ClTT Population, Completers)
W OMAC Paih Activities (I I f Population, ConipleterVt
In conclusion, plasma moiphme levels foi Kadmn and Kadian KT are le\els of naltrexone Of the 14 patients with measurable levels of naltiexone, theie was no iicgatne effect on pain seoses Se\en of these 14 patients had a measurable level at onl\ one ume poπit Most patients bad some of 6-β-naltt≤λθl. however there was no negatne effect on pam scores in addϊtior, there was no difference m pain scoies m mdniduals iakmg Kadiau oi Kadian MI
Long-Term Safety Study of Kadian ST (302) A. METHODS
The pϋαwy objective of this study ^s as to e\ aluate the long-term safety of Kadian N I administered for op to 12 months The secondary ohjectn es of this study were to
• evaluate the long-term efficacy of Kadian NT during a 12-month period by assessing pain intensity (Pi) in the past 24 horns using the Brief Pain [memory (BPl) Short Form, and the Global Assessment of Study Drug;
• evaluate opioid withdrawal symptoms in subjects who receive Kadian NT upon completion of ! 2 -months exposure or earh termination from the stud> using the
Oimcal Opsale Wuhdiawal Scale (COWS); and,
and morphine concentrations at Visits 2 through 15 m selected male and female subjects for pharmacokinetic study
This long-term, open-label study evaluated the safety of Kadian NT administered once or twice daily (QD oi BID) o\ ei a 12-month period Kadian \ST was used in dosage strengths of 20 rag, 30 mg, 40 nig, 50 mg, 60 mg, 80 mg and 100 mg. There no maximum allowable daily dose set for this study Subjects wete titrated upward as needed in a manner consistent with the current Kadian" labeling and in accordance with the investigator's best medical judgment for the most effective pain management Multiples of the a\aiiable dosage strengths were combined as needed to achiev e the intended necessity daily dose.
Subjects w ith chronic moderate to severe noitmaltgnant pain who meet al! inclusion/exclusion criteria weie enrolled Into the long-term study Each subject WΛS provided with Kadiasi NT at each clinic visit m the form of capsules to be administered BID approximately 12 hours apart or QD at 24-hour intervals Opioid-nane subjects began at a tola! daily dose of 40 rag Kadian KT adminbieied as 20 mg BID. Opioid- naϊve subjects who fully qualify for study and have documented normal labs witfiin the previous thice months were enrolled and dosed on the Baseline Visit day All other subjects were to return within seven days for enrollment and dosing. Subjects currently taking opioids who will have their opioid dose converted to a Kadian NT dose should be scheduled for a morning clinic appointment (before noon) for the Drug Dispensing Visit. Additionally, subjects were instructed to refrain from taking the morning dose of their current opioid pain medication on the day of their Drug Dispensing clinic visit. It was recommended that subjects who are already taking opioid medication be started on a Kadi an NT dose equivalent to 50% to 75% of the current daily opioid dose rounded to the lowest available Kadi an NT dosage strength due to potential for incomplete cross tolerance. The dose was determined utilizing the conversion table provided in Appendix V of this protocol; investigators were free to choose an alternate opioid conversion seiieduie at their own discretion. Opioid dose requirements were based on the subject's average combined daily opioid consumption for chronic and rescue dosing over the week prior to study entry.
All subjects were to return to the clinic one week after the Drug Dispensing Visit and then monthly for the remainder of the study. Pain Intensity and Global Assessment of Study Drug were collected at each scheduled visit. Urine drag screens, adverse events (AEs), concomitant medications, and vital signs were collected at all clinic visits. Urine pregnancy tests will be performed monthly on females of child-bearing potential. Drug accountability was conducted at all clinic visits- The occurrence of withdrawal symptoms for subjects taking Kadian NT was assessed utilizing the Clinical Opiate Withdrawal Scale (COWS). The COWS was administered at every visit from Visit 3 through 16. or at early termination (whichever comes first).
Dose titration was allowed throughout the duration of the study. At each clinic visit, the dose of Kadian NT was increased where all of the following criteria were met:
• Subject was tolerating study medication (no unacceptable AEs): ♦ Pain intensity (Pl) within the past 24 hours is > 3; and,
♦ Both investigator and subject agreed that the dose should be increased.
Even if a subject is experiencing a Pl "~ 3, the subject was free io choose not to have the dose increased. For example, a subject may have been satisfied with having his or her pain level reduced to a PI level of 4, If a subject's dose was increased and the subject repotted unacceptable AEs or an opioid-expeπeticed subject was convened to a dose that results in unacceptable AEs, the dose was decreased. If a subject expediences inadequate pain relief and desired to have bis or her dose increased prior to a scheduled clinic visit, the subject was allowed to telephone the site and request a dose increase after a minimum of three days at the previous dosage !e\e! The subject was then to return to the site for an unscheduled clinic v isit to return study medication and to receive new study medication at the increased dose Opioid toxicity assessments and drug accountability were conducted, but a complete battery of efficacy assessments was not necessary for these unscheduled visits
Investigators piox ided a stimulating bowel segirnen foi prophylactic treatment of constipation, the most common opioid side effect. ( American Pain Society . 2OO3J If unacceptable opjoid-related AEs were experienced prior to a scheduled clinic visit subjects were allow ed to return to the clinic for a dose reduction and to obtain treatment for opsoul-related ATs.
Subjects were required to return for a post-treatment follow-up appioximately 28 to 32 days aftet the final dose of sluch medication to record AEs and concomitant medications and to assure that appropriate taperuig from study medication and transition to standard of care has been accomplished Subjects wishing to discontinue opioid medication were converted to Kadian^ for the taper penod, fhe suggested mechanism for tapering was for the subject to take half of hib oi bet last effective dose of stud> medication in divided doses of Kadian (BID) for three days, and then to take half of that i educed dose in divided doses {BID} for the next three days, on the sev enth day, all dosing will discontinue. Subjects weie also allowed to convert to cυrrently-approv ed extended release opioid per investigator discretion
Safety was evaluated by v ital signs (heart rate, respiratory rate, blood pressure after sitting for three minutes, and oral temperature K physical examinations, electrocardiograms (ECGs), clinical laboratory tests and Adverse Events Clinical laboratory tests were pei formed at Baseline and at the end of months 3, 6, 9, and 12 or at early termination Qualitative urine drug screens were performed monthly and included reflex testing to identify specific opiates takers by subjects during study participation Urine pregnancy tests w ere performed monthly for female subjects of child-bearing potential VCG was perfoimed at Baseline, at the end of months ύ and 12 or early termination. Population pharmacokinetic (PK) sampling was also pei formed in this study monthly after the Baseline Visit. The Interactive Voice Response S) stem (iVRS) was used to identify up to 20 subjects in each of the follow ing daily dosing categories to undergo PK sample collection at their scheduled visits. 40 mg to 60 ing, 80 rag to 120 ma, and y 120 nig, I p to 20 subjects aged 65 years atid above v>eτe also identified to participate in the PK sample collection. I be primary focus of this PK sampling was to quantify naltrexone, 6-beia naltrcxol and rrørpbine concentrations. Study medications were in the form of orally administered capsules Study medications were. I )
Kadian NT 20, 30, 40. 50, fiO, 80 and 100 mg capsules; or, 2) acetaminophen up to tw o (2) grams per day ( 500 mg every 6 hours as needed) as rescue medication
A subject was eligible for study participation if he she meets the following criteria: 1. The subject was I S to 70 years of age and exhibited sufficient literary skills to complete study assessments. 2 The subject agreed to refrain from taking am opioid medications other than study medication during the study period, and agreed to report all non-opioiti analgesic medications taken;
3 Sujbect had a histoiy of chronic moderate to seven c pain caused by a notimalignam condition for ai least thiee months prior to Baseline Visit Conditions include. but are not limited to. osteoarthritis of any joint, chronic km back pain \\ ith or without radiculopathy, diabetic peripheral neuropathy, and post-heφetic neutalgia. Subject was directed to choose the most painful joint or body area to serve as the target joint atea for this stud) Λ target joint. \*as not to contain any type of orthopedic sod oi prosthetic device. 4 If female, subject w as either not of child-bearing potential (defined as postmenopausal for at least one year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy}} ehildbcanng potential and practicing one of the follow ing methods of biith conttol
* total abstinence from sexual intercourse (minimum one complete menstrual cycle befoie study enuy1),
* a vasectorøized partner. * contraceptives (otal, paiemeral, or transdeimal) for tlnee consecuth e months prior to investigational product administration.
* intrauterine dev ice { LU D), or
* double-barrier method (condoms, sponge diaphragm or vaginal ring with jellies or cream).
5. If female of childbearing potential, subject had a negative urine pregnancy test at screening (urine specimen must be obtained within !4 days prior to randomization) and monthly throughout study participation, o Subject was able to undet stand and cooperate with stud) procedures, was to be easily reached by telephone, and signed a written informed consent prior to entering the stud>
A subject v iil be excluded from the sπxh if he she meets any of the following critciia:
1 Subject had a documented histoty of an allergic reaction (hives, rash, etc } or a clinically significant intolerance to morphine ot other opioids, such that treatment with morphine is coiuxanidicaied. 2. Subject was pregnant or breast-feeding,
3 Subject was receiving systemic chemotherapy or has an acme malignancy of any type, or has been diagnosed with cancer w ithin the past three years {excluding squamous or basal cell carcinoma of the skin)
4. Subject had a documented histoiy of άiusf abuse dependence misuse or naieotic analgesic abuse/dcpciidcnce.'misusc within live years ptioi to the Baseline Visit.
5. Subject had a documented histoiy of alcohol abuse (^ 2 glasses/day) and'or dependence within fix e years prior to the Baseline Visit, which, in the opinion of the investigator, may ha\ e influenced subject compliance w ith the study
6. Subject had a pαsime urine drug screen at the Baseline \ isit NOT caused by any therapeutic concomitant medication rεpoued by ihe subject.
7. Subject was considered b> the im estigator. for any reason, to be an unsuitable candidate to receive extended-release morphine sulfate with naltrexone, including ( but not limited to) the risk(s) in terms of precautions, warnings, and contraindications in the Investigator's Brochure for Kadian KT. 8. Subject had a Bod\ Mass Index (BMf) -- 45 kg m:.
9. Subject had a psyehiatiie illness or medical iiinoss'condition, and or abnormal diagnostic finding, that, m the opinion of the hn estimator, would interfere with the completion of the study, confound the results of the studs, or pose risk to the subject
10 Subject had abnormalities on physical examination, or abnormal \ ital signs or F(Xi findings that judged to be clinically significant by the im estimator.
11 Subject had clinically significant abiiotmalities in chmcai eherntstn, hematology or urinalysis, including serum glutamic-oxaloacetic transaminase; aspartate aminotransferase (AST) or serum transaminase alanine aminotransferase {ALT} > 3.0 times the upper limit of the reference range oi a serum creatinine >_ ^ 0 tng dl at the Baseline Visit.
12 Subject had pain in the target area due to conditions such as malignancy, fibromyalgia, migraine, recent tiauma oi fracture, or infection. 13 Subject was involved in an unsettled claim such as automobile accident, civil lawsuit, oi woiker'sj compensation pet taming to a specific injury Subjects with settled claims were allowed to participate,
14 Subject received intraspinal infusion of any medication within one month of {he Baseline Visit, had an implanted spinal cord stimulate! , oi had plans for such tieatmem during the proposed study period.
15 Subject recehed epidural or local corticosteroid injections in target joint w ithin two months of the Baseline Visit, or target joint viscosupplementation. within {he past three months,
16. Subject recehed oral or intramuscular corticosteroids within the past W days. (Topical, nasal and inhaled corticosteroids were permitted and low. stable doses e.g. MO mg prednisone, provided were no changes in dosing within the previous foui weeks.) 17 Subject had suigical intervention to the back within six months of study entn or plans for surgical intervention while in the study 18 Subject undement an electi\e surgical procedure within eight weels priot to the
Baseline Visit, or was scheduled for an elective surgical procedure during the course of the study
19. Subject had a histor> of impairment of pislmoπan fimction, hypercarbia, b) chronic obstructive pulmonary disease, cor pulmonale, uncontrolled asthma, sleep apnea s\ ndrome, or respiratory deptession. 20 Subject had a history of gastiie or small intestine surgery leading to din seal malabsorption (e g , gastric tnpassL oi ain othet disease that causes chnical malabsorption, 2 ! Subject had active cardiac disease or other health conditions s) that pose a significant health risk m the event of opioid withdrawal 22 Subject was taking phcnothia/incs oi high doses of sedatives, hypnotics, oi tranquilizers. Chronic low dose sleep aids or anxiolvtks were allowed with
Medical Monitoi approval 23 Subject w as historical Iy non-responsK e ( no therapeutic response ) to morphine
24. Subject had reeened treatment w ith an investigational product m the 30 days prior to Baseline Visit.
Safety endpoims weiε the incidence of treatment-emergent AIj.s, changes from pre-treatment to post-treatment tor s ital signs, ECGs. physical examination findings, and clinical laboratory test results, and opioid tovicity assessments. The efficacy endpoints were Pain Intensity (PI) within trie past 24 hours, and. Global Assessment of Study Drug.
Three subject analysis populations* were defined as follows 1 ) the "safety population"" consisting of ail subjects who take study medication, used for safety analyses. 2) the "mtem-to-treaf" (ITT) population consisting of all subjects who take study medication and Io\ emon , or Global Assessment of Study Drug observation: the !TT population will be used for efficacy analyses; 3} the pharmacokinetic ^PK) population will consist of ail subjects w ith PK samples ami will be used for PK, analyses. Safety was assessed based on the incidence of tieatmejni-emergent AFs, changes flora pie-tteattnent to post-tieatrnent fm vital signs, ECGs, physical examination findings and clinical laboraton test iesuits Changes on a weie captuied as i he mrnibei and peicentage of subjects with ΛH wύl be displaced bv Nvstem Organ ( lass and prefeued Cemi using the Medical Dictsonarv foi Regulatory Activities* (MedDR \ ) Suinrøanes m teims υf seventy and ielatsomhϊp to stitch medication were also prov ided S 4Es and \k% causing discontinuation of stud} medication were summau/ed separately in a similai niamiei Subject listings υf \Fs causing discontinuation of studv medication and of selected opioid-assoαated λfv, including άr\ mouth, constipation, dbsπness, somnolence pruatm, nausea and weie also be tabulated Vital signs were suounaπzed at each \ mt in teims of descπptnc statistics jncludmg the mean median, ^andaid dc\ iatioii minimum κia\imum and quaniies Actual sallies and change fioπi Baseline v\ere sυrnmaπzed ECG^ v^ere pcrfoimcd at Baseline, Visit 8 (end of month 6) and Visit ! *> (end of month 12) oi Eat Iy Term in a u on Changes fiυra Baseline were summarized Quanutatn e laboiatorv test results w eie summarized at each \ isit in teims of de^ctiptπc btatϊβtics Actual v alues, and change fiom BabcSme were summarized For qualitative laboiaton tests, the numbei and petcentage of subjects, in each categotv weie produced at each visit For all lahoiatorv tests, Ά shift table w as produced summarizing changes fiom noimal iai Baseline) to abnoimai and vice- versa l he numbei and percentage of subjects with norma! and abnoimai findings m the phssical examination at each s wι vseie dsbpla>ed A bhift table was produced summarizing changes* from normal fat Baseline) to abnoimai and vicc-xcisa COWS were summaπzed at each beginning vs ith \ IM( and change tluough stud\ petiod sveie summaπ/ed Selected anahses weie iepeated b\ subgroups based on age sex, and i ace
Efticacv v\as assessed based on the BPI Short Fotra, and subject's Global Assessment of Study Drug A.11 efficacy analy ses VH CIC descnptne, with no formal testing of statistical hypotheses, although or confidence unienah vveie presented to aid in mteqDretation bach of the fbui items of the BPl Short Form v\ese anahzed at eath visu m terms of the values themselves as well as m teims of change and percent change from Baseline Desuφtne statistics weϊe calculated, and pairv\ ιse t-test p-\ alues used to summarize the difference between each post-Baseline time point and Baseline. Global Assessment of Study Drug was summarized descriptivelv Rescue medication (additional analgesic medication) was summarized All efficacy analyses are consideied secondary. Sparse blood samples (one trough blood sample taken from each subject participating in the PK. study, total 14 blood samples) ^ ere taken at selected visits for morphine, naltrexone, and 6-β-naltrexol determinations
Schedule of Observations and Procedures
OO O te v
B, RESl LTS I. Adverse Events Λhs (TJiAEs) occurring in more than 5% of patients included constipation., nausea, vomiting, headache, somnolence, dianhea. pruπtis and fatigue These are al! tvpical opicnd-ielated ABs A summary of the numbei of
Ijeatmem-F.metgeni Adveise Hx ersis, Serious Adverse l-λ enis and Deaths (none) iesuiUng from Ueatmem with Kadi an N f is shovn below
TFAEs resulting in discontinuation of treatment was observed in approximate!) 30" α of patients admmtsteied less than 80 ma Kadian Nl pet day: approximately 10% of patients administered between 80 and 120 mg Kadian NT per and, approximate!}- 90O of patients administered more than 120 mg Kadian NT pet day Oveiall, TB AEb were obseived m approximately 24° ό of patients
Seuoifo AEs (SEAEs) resulting in djsconiimiation of Kadian KT tteamicnt were m approximately 2% of patients admmisteied less than 80 mg Kadsao Kl per dav, approximately 8°Ό of patients administered between 80 and 120 mg Kadian KT per day, and approximately 2% of patients administered more than 120 nψ kadian K F per da) Overall SF AFs vu'ie obseived in approximate!) ^0O of patients
Summary of Treatment-Emergent Advene Events, Serious Adverse Events and Death - Safety Population
2. Efficacy
As shown in Figs, J -4, daily administration of Kadian NT to patients included in this trial results m lower mean BPl scores for up to six months The data indicates that
5 the affects of morphme in this population is not affected by the concomitant administration of both morphine and nalttexone tn an intact dosage form (Kadtan NT) ϊhus, Kadtan N I ma\ be used to effectnεly Ueat pain in human patients for long periods of time (i e., greater than two weeks) Prcuouslv Kadian N l was only shown to be effecth e lot periods up to two weeks ϊt was not know n vϋiether the cumulative effect of
!0 repeatedK administering a composition containing a morphine antagonist over a period of greater than two weeks would eventually negate ely affect the actions of morphine m the patient Suφiisimdy. the data indicates that Kadian N' T may be used to alleviate pain for long periods of time {i e . greatet than two weeks) The data also indicates that Kadian NT may be most effecth e at the lowest dose tested (i e , less than 80 mg per day).
15 Pharmacokinetic (PK) data was also analyzed as shown below. The results demonstrate thai naltrexone was indeed sequestered the course of the trial While there were a couple of outliers, the data indicates sequestration is possible over long periods of time (i e , greater than two weeks and out to 100 weeks)
M
9!
While the present inv ention has been described m terms of the preferred embodiments, it is understood that variations and modifications will occur to those skilled in the art Therefore, if is intended that the appended claims cover all such equivalent variations that come withm the scape of the imention as claimed

Claims

What is claimed is.
1 A method of treating a condition in a host that is sesponsne to an agonist the method comprising administering a multi-iayer pharmaceutical composition comprising an agonist and an antagonist thereof that are not m direct contact with one another in the intact form of the composition, therein administration of the intact form of the composition to the host once 01 tw ice daily toi at least one week results m /eτo release of the antagonist.
2 The method of claim ! wherein administration of the intact form of the composition to the host once daily for at least a time period selected from the group consisting of four, eight. 12. 16, 20, 24, 2S, 32. 36. 40 and 100 weeks results m zero release of antagonist
3. The method of either claim 1 or 2 wherein the antagonist is naltrexone.
4. The method of either claim 3 wherein release of naltrexone is determined by mca-oiri ng plasma ie\ els of β-naitrex o!
5. A method of treating a condition in a host that is responsive to art agonist the method comprising administering a lnulti-iajor pharmaceutical composition comprising an agonist and an antagonist thereof that are not in direct contact with one another in the intact form of the composition, wherein administration of the mtact form of the composition to a population once dash for a time period of at least one week results in zero release of the antagonist in about 90% of the population.
6. The method of claim 1 wherein the time period is selected fiom the group consisting of four, eight, 12, 16, 20, 24, 28, 32, 36, 40 and 100 weeks results in zero release of antagonist 7, The method of either claim 1 or 2 wherein the antagonist is nalπexone.
8 The method of cither claim 1 wherein release of naltrexone is determined by measuring plasma leΛels of β-na!tiελθl
9. A method of treating a condition m a host that is tesponsne to an agonist, the method comprising administering a multi-iajer pharmaceutical composition comprising an agonist and an antagonist thereof that are not in direct contact with one another in the intact form of the composition, wherein administration of the intact form of the composition to the host once or twice clash for a tsroe peuod of at leas! two weeks piovides arc analgesic effect. iθ. The method of claim 9 wherein the time period is selected from the group consisting of four, eight, 12, 16, 20, 24. 28, 32, 36. 40 and 100 weeks.
EP08862226.1A 2007-12-17 2008-12-16 Pharmaceutical composition Withdrawn EP2224806A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US788207P 2007-12-17 2007-12-17
PCT/US2008/087030 WO2009079518A1 (en) 2007-12-17 2008-12-16 Pharmaceutical composition

Publications (2)

Publication Number Publication Date
EP2224806A1 true EP2224806A1 (en) 2010-09-08
EP2224806A4 EP2224806A4 (en) 2014-02-19

Family

ID=40795902

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08862226.1A Withdrawn EP2224806A4 (en) 2007-12-17 2008-12-16 Pharmaceutical composition

Country Status (4)

Country Link
EP (1) EP2224806A4 (en)
AU (1) AU2008338439A1 (en)
CA (1) CA2709903A1 (en)
WO (1) WO2009079518A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2092936E (en) 2000-02-08 2013-06-20 Euro Celtique Sa Tamper-resistant oral opioid agonist formulations
MY135852A (en) 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
EP2224808A4 (en) * 2007-12-17 2013-11-27 Alpharma Pharmaceuticals Llc Pharmaceutical composition
CA2709950A1 (en) * 2007-12-17 2009-07-09 Alpharma Pharmaceuticals, Llc Pharmaceutical composition

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033566A2 (en) * 1996-03-12 1997-09-18 Alza Corporation Composition and dosage form comprising opioid antagonist
WO2001058451A1 (en) * 2000-02-08 2001-08-16 Euro-Celtique, S.A. Tamper-resistant oral opioid agonist formulations
WO2004026283A1 (en) * 2002-09-20 2004-04-01 Alpharma, Inc. Sequestering subunit and related compositions and metohds
US20040202717A1 (en) * 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
US20050191244A1 (en) * 2002-10-25 2005-09-01 Gruenenthal Gmbh Abuse-resistant pharmaceutical dosage form
US20070269505A1 (en) * 2003-12-09 2007-11-22 Flath Robert P Tamper Resistant Co-Extruded Dosage Form Containing An Active Agent And An Adverse Agent And Process Of Making Same
WO2007149438A2 (en) * 2006-06-19 2007-12-27 Alpharma, Inc. Pharmaceutical compositions
WO2008027442A2 (en) * 2006-08-30 2008-03-06 Theraquest Biosciences, Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
WO2008063301A2 (en) * 2006-10-11 2008-05-29 Alpharma, Inc. Pharmaceutical compositions
WO2009032270A2 (en) * 2007-09-04 2009-03-12 Alpharma, Inc. A multilayer pharmaceutical composition comprising an antagonist in a first layer and an agonist in a second layer
WO2009085778A1 (en) * 2007-12-17 2009-07-09 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
WO2009088673A2 (en) * 2007-12-17 2009-07-16 Alpharma Pharmaceuticals, Llc Pharmaceutical composition

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8790689B2 (en) * 2003-04-30 2014-07-29 Purdue Pharma L.P. Tamper resistant transdermal dosage form
WO2007013975A2 (en) * 2005-07-20 2007-02-01 Pharmorx Inc. Composition containing an opioid agonist and a partial opioid agonist, preferably buprenorphine , for controlling abuse of medications

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033566A2 (en) * 1996-03-12 1997-09-18 Alza Corporation Composition and dosage form comprising opioid antagonist
WO2001058451A1 (en) * 2000-02-08 2001-08-16 Euro-Celtique, S.A. Tamper-resistant oral opioid agonist formulations
WO2004026283A1 (en) * 2002-09-20 2004-04-01 Alpharma, Inc. Sequestering subunit and related compositions and metohds
US20050191244A1 (en) * 2002-10-25 2005-09-01 Gruenenthal Gmbh Abuse-resistant pharmaceutical dosage form
US20040202717A1 (en) * 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
US20070269505A1 (en) * 2003-12-09 2007-11-22 Flath Robert P Tamper Resistant Co-Extruded Dosage Form Containing An Active Agent And An Adverse Agent And Process Of Making Same
WO2007149438A2 (en) * 2006-06-19 2007-12-27 Alpharma, Inc. Pharmaceutical compositions
WO2008027442A2 (en) * 2006-08-30 2008-03-06 Theraquest Biosciences, Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
WO2008063301A2 (en) * 2006-10-11 2008-05-29 Alpharma, Inc. Pharmaceutical compositions
WO2009032270A2 (en) * 2007-09-04 2009-03-12 Alpharma, Inc. A multilayer pharmaceutical composition comprising an antagonist in a first layer and an agonist in a second layer
WO2009085778A1 (en) * 2007-12-17 2009-07-09 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
WO2009088673A2 (en) * 2007-12-17 2009-07-16 Alpharma Pharmaceuticals, Llc Pharmaceutical composition

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOHNSON F ET AL: "(236) Relative bioavailability of plasma naltrexone from crushed ALO-01 (an investigational, abuse-deterrent, extended-release, morphine sulfate formulation with sequestered naltrexone) to a naltrexone oral solution", JOURNAL OF PAIN, SAUNDERS, PHILADELPHIA, PA, US, vol. 9, no. 4, 1 April 2008 (2008-04-01), page 35, XP025871409, ISSN: 1526-5900, DOI: 10.1016/J.JPAIN.2008.01.157 [retrieved on 2008-04-01] *
See also references of WO2009079518A1 *

Also Published As

Publication number Publication date
EP2224806A4 (en) 2014-02-19
AU2008338439A1 (en) 2009-06-25
WO2009079518A1 (en) 2009-06-25
CA2709903A1 (en) 2009-06-25

Similar Documents

Publication Publication Date Title
US8623418B2 (en) Pharmaceutical composition
CN103347495B (en) Treat the opioid agonist of Parkinson&#39;s and the combination of opioid antagonists
US20130122065A1 (en) Pharmaceutical Composition
JP2004515455A (en) Opioid antagonist compositions and dosage forms
US20140328930A1 (en) Pharmaceutical Compositions
JP6550157B2 (en) Novel gastric retention dosage form comprising a GABA analogue and an opioid
WO2009085778A1 (en) Pharmaceutical composition
EP2224805A1 (en) Pharmaceutical composition
US20150104519A1 (en) Pharmaceutical Compositions
WO2009079518A1 (en) Pharmaceutical composition
AU2014216032B2 (en) Pharmaceutical composition
AU2018202217A1 (en) Pharmaceutical composition
AU2019202760A1 (en) Pharmaceutical composition
AU2014250614B2 (en) A multilayer pharmaceutical composition comprising an antagonist in a first layer and an agonist in a second layer
AU2014216026A1 (en) Pharmaceutical composition
AU2015200402A1 (en) Pharmaceutical composition

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20100624

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

RIN1 Information on inventor provided before grant (corrected)

Inventor name: STAUFFER, JOSEPH

Inventor name: JOHNSON, FRANK

Inventor name: TANG, LIJUAN

Inventor name: BOEHM, GARTH

Inventor name: MATTHEWS, FRANK

Inventor name: LIANG, ALFRED

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20140122

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/50 20060101AFI20140116BHEP

Ipc: A61K 31/485 20060101ALI20140116BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140819