CA2295469A1 - Analgesic with controlled active substance release - Google Patents

Analgesic with controlled active substance release Download PDF

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Publication number
CA2295469A1
CA2295469A1 CA002295469A CA2295469A CA2295469A1 CA 2295469 A1 CA2295469 A1 CA 2295469A1 CA 002295469 A CA002295469 A CA 002295469A CA 2295469 A CA2295469 A CA 2295469A CA 2295469 A1 CA2295469 A1 CA 2295469A1
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Prior art keywords
preparation according
release
analgesic
microtablets
morphine
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CA002295469A
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French (fr)
Inventor
Johannes Bartholomaus
Jurgen Betzing
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4468Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/451Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/4808Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

This invention relates to an orally administered preparation with controlled release of at least one analgesic from microtablets with a diameter of < 3 mm.

Description

Patent App.l_icati.or~, C~r_unerzthal GrnbH, D-5>0'78 1\aWnen Interna7_ ref . : G ~''I10 Analgesic with controlled active substance release The present invent:i.on relates to a ptnarmaceutic.al formulation from whiclo the analgesic active substance i.s released in a controlled manner.
Many formulations of analgesic painkillers which provide controlled release of the activa sulostanc.e are known from the prior art.
EP-A-0647448 W nter alia lras thus already descr.it~ect am analgesically active preparation with delayed active substance release which consists of a plurality of substrates containing opio:i_d in cotltrol7_ed re lease form having a dia-meter of 0.1 to 3 nuu as a single daily close.
Substrates suitable for this purpose may assume the form of spheroids, m:icrobeads, pe7_-lets or granules. The ~>rodric.tion.
of this type of substrate entails relatively elaborate formulation methods, suclu as for example layer ac.c,ret ion agglomeration processes for_ pe.Llets or the exi=rusion/
spheronisation process fo:r splterc>ids .
'There is furthermore a requirement in many therapeutic applications to provide ind~_vidua:L doses of a pharruaceutical containing an analgesic, as is possible witt-r orally administered, 7.iquic7 dosage forrus in 1le foxzn of drops and to be able to make use of convent-Tonal, uncomplicated formu7.atioo metluocts, such as talc-left i.ncf, during the producti..on ttnereof .
The ob-ject of tt~e present. imvent.:lon was aCCOrdimgly t0 provide an orally adrnirristerecl preparation w.i tlu colitrolled release of at= least one ana7gesir, which preparat-i_on permits individual, precise dosing, comparable to tlne admiruistration o.f drops, for example from storacze containers or makes it: possible to subdivide a certain quantity of active substance into a rea.di7_y atml accurately controllable numberof substrates, and which ~n~zy be produced using standarc~i, straightforwat:d fortnulat:ia>n methods.
Thi s obj ect is achieved acco .riling to tlue invention by the provision of an orally administered preparation with controlled release of at least one analgesic-, from a rnic.rotal:>let wi.ttn a diameter of < 3 mm.
These micro tablets preLerabl_y have clsameters ref 1 to ~ mrn, particularly preferably of 1.5 to 3 mm.
The microtablets according to the invention preferably contain at =least one op_i_oid as the ana~_gesic active substance. Ilydrotnor_phone, oxycodone, mo~:phine, levorploanol, methadone, di.hydrocodeine, codeine, feet=any.t, cliltydro-morphine, pethidine, piri.tramide, buprenorph_i.ne, ti lvic~ine, tramadol, the part_i cu lar salts thereof or mini-u.res thereof are preferably used as tt~e pop-i_oid.
Tramadol, tramadol hydroclu pride, morphine, morpr~i_ne hydrochloride and/or morphine sulfate are very pa.rtict.rlarl_y preferably used as l=he arialgesir_.
Apart from the stated op:ioic~ atialge.,ics, t=he preparal.ion according to the invention may contain non-opioid analgesics which optionally exhibit a synergistic action with the opio.id analgesics. 'These nom-opioid analqesi.cs include ibuprofet.i, ~etopr_ofen, fJi.~rbiproten, paracetamol, naproxen, propyphectazcme, acematacin, acetylsa7icyli_c acid, metamizol and/or the salts thereof.
The micr_otablets used according to the irnvention are distinguished by cotttro~_l.ed release of the analgesic.

p J
Controlled release of flue analgesic is ta>;en to mean 1->otlr non-delayed and delayed release. The opi_oid active substance is preferably released in a delayed marnner.
Release may be achieved by immobil_i_sinc~ the ac_-.ti.ve substance in a controlled release matrix. Incorporation into a matrix material ensures that controlled, delayed release of the active su.bst.am'e is achie~ec~ over the desired petviod of t_~rne. ~t is preferably endeavc>i.rred to 1.0 adjust 1:1e release <_~l ttoe a~t~.ve su'<>statua.e in smclu a wanner flat it is suf f icvi.ent t:o take (_he ~>rel>ara L i oo t~3i c«, pl~eferab_Ly only once, per a4 loours.
Suitable matrix mater_i_a1s are pharmaceuLica 1:ly cc>mpatib:l.e hydrophilic materials which are mown to ttie person s>ii7lecl in the art. Polymers, such as for example cellulose ethers, cellulose esters or acry_ic resins are preferably used as hydrophilic: matrix materials. L~,l.lLylcel7Lllose, hydroxypropylmethylce7. l_u_I_~se, hyr_lroxypropylce ll_u lose, hydroaymetr~ylc:el lulose, l~c~=ly (meth) ac:,ry7ic acp cl a rrd/or the derivatives thereof, sue:h a,:, Clue salts, amides or eaters, are «ery part-i.cmlarl_y preferred as matrix nmteria7s.
The matrix material may, however, a_l_so consist or hydrophobic materia7_s, suclu as fc~.r example hyc~rophob~ c~
polymers, waxes, fats, oils, lonc7-clnaln fatty ac-i.d,~, fal_.ty alcolols or cornespomdinq esters or mixtures t-L~ereof. Morm-or di.glycer_ides of C .__~~a and/or C,.-Cz., Catty alcohols and/or waxes are preferably used as hydrcy>l~obic materials.

It is also possible to use a miyture «f tle stated lydropli=l is and lydrophob:i c materials as a cor~trol~ec~
releas a matrix mater i.<~7.
The microtablets ac:c~_ording to the invention may furtlmrmore contain pharmaceutical_Ly conventional auxiliaries as additional constituents, s~_ic1 as extenders, for example lactose, microcrystal l i ne c.e7_lulose or calcium hydrogen phospOate, a.s wel.l as s l.ip a<Ldi l=ivies, luhr icant..s and :Glow control agents, such as for example hiclhl_y disperse silia,~m dioxide, talcum, maqne sium stearate and/or stearic' acid.
A particularly preferred pharmaceutically compatil~~te matrix mater_ia7_ comprises at least one ce11u1ose ether and/o:r cellulose ester, a 2 wi . ", aqueous solution of wl-rich has a Viscosity at 20°C of 3000 to 150000 mPas, preferably of 10000 to 150000 mPas, optionally in combination with an extender which is not swe11ab7_e in an aqueous medium, such as for example calc~_um hyc~roc~eu ptwsphate, or with at1 insoluble ex t:etlder swe liable _i_ n an aqueous meth i um, suc~1 a s for exatnyl_e rnic~rocrystall i_ue c:ellule~:~e, or ao extencder soluble in aqueous mecii a, such a:,~ for example 1 actose.
The content of anale~esic, preferably of_ opic.>icl anal~esi.c, is adjusted as a function of the desired duration of release and quantity of analgesic to be releasers. The active substance content= i_s preferably between 10 and 85 wt.°r, particularly prefer-ably bei~ween 2.5 and 7a wt.',, relative to the complete m.ixt-ure. On the basis of the action of opioid and non-opioid analges i_cs, tire person s>iilled in Clue art is aware of ttue mixilrg ratios ito which these should be used in order t-~_> ac~h i eve the cles i recJ
release of ac::tive stzl>at:ar~~~F:~s.
In the case of_ the preparations ac~cor_ding to the invention, which comprise microtablets, controlled release of the active substance may also hoe achieved by c~oat.iroq tl~e irndividua.l tab7_ets witlo at least c>ne c~oati_ry ~.Jlic1 permits controlled, genera Lly de.layea, release of tire active substance in am aqueo~_is medium. Su i_table controlled release coatings comprise water-insolub.l a waxes or polymers, such as for examp Le ac_:ryli c: res i rus, r>re ~erably x>c~ l_ y (m~ttl) _ ac.rylates c~r_ water-irm~olubJe cel_7_~.rlcoaes, p.reTerab:Ly ethylcell.ulose. These tnateria7_s are 1>nowm from the prior art, for example Bauer, L~elnnann, Os terwa7 d, Rotlgang "Uberzogene Arzr~eifointien", Wissensclaftliche Verla~as-gesellschaft mbH, Stutt~~art, 1993, pages 69 et sect. , and are hereby included by way of reference.

rl In addition to the water-irrsolmbJ_e polymers, i.t= is optionall y possible to ad j us t l he ac~l. ive sups lance re k ease rate by ~>refer_ahly a.Lso using quantities of u~ to ~~0 wt.:~.
S of non-control_Led release, preferab)_y water-soluh7_e polyruers, such as for a xampl a polyvirnyl.pyrro Lidone or water-soluble ce7_luloses, prel-erak~ly hydroxy-propylmettnylcellulose or hydroxypropylcellulose, and/or l~nown plastici.sers.
In addition to the controlled release coati m.~, the rnicrotabl.ets accordi_ncr to the invention may addil.ionally he provided W tli furt~luer c:~~atrocks . 1 t i~~ thus pass i~~:l.e to apply a coating contail~.W g the actioe substancJe, feom wl~:ir_-h coating the ac,ti.ve substance is released in a non-contrc~llee~ manner after oral administration. Suck1 multilayer microtablet.s rrray after administration very rapidly provide an initia7dose of the analgesic for alleviating the pain, wherein the level of_ tle analgesic may be maintained by the subsectuent delayed release o C the active substance.
Apart f_rmr.~ the cc>ntrc>1l.ec-1 release c:cmtiru~l, the m i c-:rotahlel.:s may furthermo.r_e also additi_orral.ly have acoat.Lng whic°.h dissolves in a pH-dependent manner. It is thus puss-i_k.~le, for example, to ensure that a c~ertaimum~~er of the microtablets of a preparat~ om pass undisaolved tllrou~~h t1e gastric tract and are not .released mnti7_ t=hey reach the intestinal tract-.
Anottler pre (erred embodiment of the prepay-a lions accorc.ling to tlue invemt_i_on consists irr t.hr~ rnicr_ota>_~lets', w1i_ch are proVi_ded with a control led release arlcl opt ionai. ly further coatings, already comta iri i rah tkre aci. ive sums tanc.ve io a matrix which erusur_es controlled, delayed release of the active subs lance, o:r in t:Ue ruatrix controlled release microtabl.ets' having no controlled release coating, but at least one of the stated coatings which erasure an initial dose and/or pH-dependent release.

The rnicrotablets are produced usincf known metluoc~s, as ~~r~~
de.scribec~, for example, in I~,t-~1-016631_5. 'The corresponding disclosure is heretoy iz~cluc~ed by way of reference.
Tyre mi_crotablets are pxeLerably produced by sc:reeni_ug all the tablet constituents, preferably tl~rottgln a 0.6 mm screen, and then homogeneously mixing them. Tl-re mixture may be converted into granules, wherein the screening step is then preferably performed after granu.l.ati.on. Where granulation is performed, s.l.ip additives and/or lubricants are preferab=Ly incorporated before compression. The homogeneous mixture is wompression moulded in a 1_ablett:img press, preferably a 1-ovary tab l.etL.incJ x>r_ess, to for_tn tablets having a diameter of 7.. Lo ~ nun, preferably of 1.5 to ~ rrnn. This method is prefer-ak_>ly a Iso perfor-rned whet-r producing micro tablets with matrix cc>ntrolled re=Lease, wherein melt granulation. is a prefer-red production process for hydrophobic matrix materials fusible at < 1.00°C. Methods suitable for this purpose ara known to the person sl~~i1leel in tine art .
In the event that t..he prepaz:aL=iotrs acw>rding to tire invention contain microtabl_ets with coatings, these may t'>e applied using convent=i <.>na 1 metro~c~s, such as for example by sugar coating, sprayi.rog with solutions, di.spersio,ns or_ suspensions, by melt processing or by powder appl~_cation processes.
The orally administered preparations according to the invention consisting of mie-rc~taVlets moreover Crave the major advantage that floe desirec.~ dose of ana7_cJesic may be st.~.bdivicled into a strai.~~lo 1. f~> r~,mr-ci ly co~.tnta.ble cumber o f utrits. In this manner, it is possLb7_e to fortnu7ate the ~5 oral:Ly administered prepa-ration in accordance with individual patient r_equirernents by, for_ example, taking the desired number of microtablets from a supply of microtablets using a rneter_i_ng unit, preferably a c~ispeoser, in accordance with tlue individual duration of release and quantity of analgesic Forrelease wlticvh are to be achie~red.
The present invention accorditngly also provides individually meter_able, orally adtnin.i.ste.r_ed preparations, the tnrtnber of rnicrotablets of which is deLertnined in accordance with the ind:ividuall_y cle,,.ired duration of release and quantity of analgesic for release.
The present invention also provides the orally admi_nisterec~
preparations according to the i.ovention in capsules which contain a defined number of the m-icrotablets with controlled .release of the analgesic in accordance with the inclividttal duration of release and quant.i.ty of allalges~.c for release which are to he acb ieVecl . The nutnher of micr_otablets in a capsule is preferably selected such that the dose is suffp c_ient for_ administration once or tw-i.ce dally. It is advantageous in tluis dosage form too for the dose of the analgesic; t=o be subdivided between a straightforwardly countable number of microtablets, but= the patient is relieved of the task of counting by t1e dose being determined iu a capsule.
The ora=11y admin_istere~~ preparations acco.rolit~~~r t« tkoe invention may furthermore assume flue ~o.rm of a so-called macrota.blet, i. e. a tal~l.et of conventiona.ldimensions, iruto which a defined nunrbe.r o.f microtablets in accordance with the individual duration of rrelease and. qu.arrt.ity of analgesic fo.r release which are to be achieved are compression moulded with conventional tablet auxiliaries and additives to form a tablet. In this ease, too, it i_s advantageous if the number of microtab7_ets const.itut~ng t.le macrotablet is selected such that flue duration ~f release and quantity of analc,es~c for re.l_ea;;e is cuffiwi_ent for admin._istrat-ion once or twice daily.
The present invention accordingly also provides orally administered preparations with controlled release of at least one analgesic comprising rni_crotablets, wherein a F~
certain number of microLabJ-ets in accordance wz.tli Olle individual duration of rE~lease anc~ quantity of analgesic for release which are to be achieved are compression moulded with convent=i_onal au~ i.l_iaries and a<lditives to form a tablet.

Examples The release profi7.e of the preparations prodmced in l: he Examples was determinec7 as follows:
True preparations were placed in 600 m1 of artificial gastric juices (pN 7.2j in a rotai=ing basket, apparatu;~
(according t.o the F~uropean fluarrrracopoeia) at a I=ernperature of the release medium of ~ 7°C and a rotational speed of the rotating basket of 10~i ruin-' . After 1_20 minutes, the plI
value of the .r_elease medimn U~as raised to pII 7.2 )~y addition of phosphate buffet- soJtrtiotl. 'L'his pII va1_ue was maintained unti7_ the end of the testing. TOe quant=ity of active substance released at a parLic:ula.r point i.n tune is determined spectrophotorneLrical7.y.
Exarnple 1:
Composition:
per_ tablet per_ c:apsul.e c.ontai n incJ

1_-rI~7ets _ Components of Trarnadol HC1 10.0 mg 1_00 rmJ

the micro- Mic.rocrystal.l.ine 4.0 rng 40 mg tablets cellulose Povic)on!i h ~0--_ 0. 8 rng 8 rng - _ Magnesium sLearvate 0. ~ mg 2 rtlg Total _-- 15 rng - 7_50 tng -'l he tramadol. salt and rnicm~c-vrysi_ al line cellulose were granulated with an aqueous so_Lution of Povidonl~ K30, dried, screened, mixed with magnes iorn st.earate, compression moulded to form tablet..; loavirlg a d_i_arrret~er of ~ rnnr arid a height of approx. 2 rnrn and packaged in Capsu:Les each containing 10 tablets.
The release prof.i=I_e was as fol_1ows:

after 15 minutes ? 80J. act=ive m_h.~,~tance release.
Example 2:
Composition:
per tablet per capsule c:ontainin~~
lU
tab7..el_s Components of_ Trarnac~o7_ IiCl LO_0 mg 7_00 Ing -the micro- Microcrystal7.ine 4.0 mg 40 mg tablets cellulose Povpdon!t Is3 C~ 0 . a rug 8 Ing MaC~Iles::llllTl (_l.c' Illg ~ Irlg ;~tF'3Tal~e Coating fthylcel7.l_ilose 0. f3 rug fi mc~
components (Aquacoat lz ) I_)ibu ty.l:sel_aac-atatn . 2 Ing 2. mg Tota1 - _ 16 rng 1.60 m<J --_-__.

The tramadol sal t and rn i_cvrocrys to 71 i ne cel.lu7ose were granulated whir an ac~ue~>os s~-, I uli_on of E~ov i.doroC> I~ ~~i (poly--vinylpyrrolidone) , dry eci, scr-eenecl, miyec_i w_itlu rrragnes Turn stearate, compression Ino~_a1c_ie<~ to forms tablets having a diameter of ~ mm and coated with an adUeot.rs ethylc~el.lulo.,e/
dibuty7. sebacate dis~>ersion in a 4:1 quantity ratio in a fl.tridised bed apparatus by spraying on tire d.i_spersion with continuous drying. 10 rnir~rotab.l_ets ~:~ere packaged in each capsule.

l.1 Ttne average release pro.fi1a was:
Time after Act-ive substance release in of ori..cJinal a~~tive substance concentration 30 minutes 1',' 240 minutes I<<'', 480 minutes 2 9", Example 3:

Microtabl_et:s of a diameter o f 2 rnln and hei ght of ax~pr ox .
2 nun of the following c~pcupc>;;ition were produced and c-o~atect in a similar manner Lo h;xarnple ; . ?0 rni ct:otablet.~ were pac)>aged in each. capsu le .
per tablet per capsule ~ontain.inr4 ~ 0 talol et:s Components of '1'rarnado 1Lf~' 'p . 0 m_g l0 mg l 1_lie micro- Microc~ry~~ t:a.l ___ _ tah7_ei~s l ine 2 . 0 mg 40 rni.J
cellulose PovidnC~y I~~'c) O_4 rn'J ~ m~
_ _-__ _-_ -_-_ r~a'~jres iy_uz~ i~. 7_ nrg nuJ
shear-ate Coating E;Lllylcel1uJc_~se _ 8 rn~,I
components (Aduacoai_ !~ ) 0.4 rnc~

Dibutyl set~ar_ate 0.1 mg 2 mg 'Total __ _ 8 . O mg 1_ 60 rng _ -Example 4:
Matriy controlled r_elPase mi croi._.ahlets were produced by screenirng t.rarnadol 11~.'=L ( '~ un_~/ t-.ate let) and gl_yceryJheluenat=a (Compritol 880 ato~t) (5 rng/tabiet) through a 0.6 mm mesh screen. The homogenised mixture was then compression moulded with 2 nun punches to fomm corresponding micro tablets. These e:~hibitecl t=he fo_Llowing re7_ease 2U profile:

Tirne alter IIc:L i_ve suhstar~ce .release _i-n '.
~T

~ot-i~ioal acV'tivf~ substance c:nc:entral..ion 60 minutes 4c~"-.

120 minutes 6(n', 240 minutes -~~,~, -_ 480 minutes ~zr'=',

Claims (20)

1. Orally administered preparation with controlled release of at least one analgesic from microtablets with a diameter of < 3 mm.
2. Preparation according to claim 1, characterised in that the microtablets have a diameter of 1 to 3 mm, preferably of 1.5 to 3 mm.
3. Preparation according to claim 1 or 2, characterised in that the analgesic is at least one opioid.
4. Preparation according to claim 3, characterised in that hydromorphone, oxycodone, morphine, leborphanol, methadone, dihydrocodeine, fentanyl, codeine, dihydro-morphine, pethidine, piritramide, bupronorphine, tilidine, tramadol, the particular salts thereof or mixtures thereof are used as the opioid.
5. Preparation according to claim 4, characterised in that tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate are used as the opioid.
6. Preparation according to one or more of claims 1 to 5, characterised in that the microtablets contain the analgesic uniformly distributed in a controlled release matrix.
7. Preparation according to claim 6, characterised in that the matrix comprises at least one polymer, a wax, a fat, an oil, a fatty acid, a fatty alcohol or a corresponding ester.
8. Preparation according to claim 7, characterised in that that cellulose ethers, cellulose esters and/or acrylic resins are used as the polymers.
9. Preparation according to one of claims 6 to 8, characterised in that ethylcellulose, hydroxpropyl-methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, mono- and/or diglyceridles of C12-C~ fatty acids and/or C12-C~~ fatty alcohols are used as the matrix material.
10. Preparation according to one of claims 1 to 5, characterised in that the microtablets are provided with at least one coating.
11. Preparation according to claim 10, characterised in that the coating provides controlled release.
12. Preparatiom according to claim 10 or 11, characterised in that the coating is based on a water-insoluble polymer or wax.
13. Preparation according to claim 12, characterised in that an acrylic resin or cellulose derivative, preferably alkylcellulose, is used as the polymer.
14. Preparation acccording to claim 13, characterised in that ethylcellulose and/or a poly(meth) acrylate is used as the coating material.
15. Preparation according to one or more of claims 1 to 14, characterised in that the microtablets are in a capsule.
16. Preparation according to claim 15, characterised in that the capsules each contain a defined number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
17. Preparation according to claim 16, characterised in that the number of microtablets in the capsule is sufficient for administration once or twice daily.
18. Preparation according to one of claims 1 to 14, characterised in that the microtablet(s) may be taken from a supply of microtablets using a metering unit, preferably a dispenser, in a countable number in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved.
19. Preparation according to one or more of claims 1 to 14, characterised in that a certain number of microtablets in accordance with the individual duration of release and quantity of analgesic for release which are to be achieved are compression moulded with conventional auxiliaries and additives to form a tablet.
20. Preparation according to one or more of claims 1 to 5, characterised in that more than 75% of the analgesic is released within 30 minutes.
CA002295469A 1999-01-18 2000-01-14 Analgesic with controlled active substance release Abandoned CA2295469A1 (en)

Applications Claiming Priority (2)

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DE19901683.6 1999-01-18
DE19901683A DE19901683B4 (en) 1999-01-18 1999-01-18 Controlled-release analgesic

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7988998B2 (en) 2002-10-25 2011-08-02 Labopharm Inc. Sustained-release tramadol formulations with 24-hour efficacy
US8414919B2 (en) 2005-09-09 2013-04-09 Angelini Labopharm, Llc Sustained drug release composition
US8487002B2 (en) 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
US8883205B2 (en) 2006-02-10 2014-11-11 Biogenerics Pharma Gmbh Microtablet-based pharmaceutical preparation
US10076498B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19901687B4 (en) * 1999-01-18 2006-06-01 Grünenthal GmbH Opioid controlled release analgesics
SK285128B6 (en) * 1999-12-28 2006-07-07 Zentiva, A. S. A remedy with controlled release comprising tramadol hydrochloride and method for preparation thereof
US20020044962A1 (en) * 2000-06-06 2002-04-18 Cherukuri S. Rao Encapsulation products for controlled or extended release
UA81224C2 (en) * 2001-05-02 2007-12-25 Euro Celtic S A Dosage form of oxycodone and use thereof
AU2002314968B2 (en) * 2001-06-08 2006-12-07 Endo Pharmaceuticals, Inc. Controlled release dosage forms using acrylic polymer, and process for making the same
PE20030527A1 (en) 2001-10-24 2003-07-26 Gruenenthal Chemie DELAYED-RELEASE PHARMACEUTICAL FORMULATION CONTAINING 3- (3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL) PHENOL OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND ORAL TABLETS CONTAINING IT
MY135852A (en) 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
EP1479381A1 (en) * 2003-05-19 2004-11-24 Euro-Celtique S.A. Pharmaceutical dosage form comprising a solid solution
CN100336501C (en) * 2003-08-06 2007-09-12 健乔信元医药生技股份有限公司 Cuyantong slow-releasing round-particle composition and preparation method
US6984403B2 (en) * 2003-12-04 2006-01-10 Pfizer Inc. Azithromycin dosage forms with reduced side effects
DE102008056312A1 (en) 2008-11-07 2010-05-12 Biogenerics Pharma Gmbh Use of micro-tablets as food and feed additive
KR101378973B1 (en) * 2012-04-13 2014-03-28 한미약품 주식회사 Composite formulation comprising multi-unit spheroidal tablet(must) encapsulated in a hard capsule and method for preparing the same

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR5138M (en) * 1966-01-26 1967-06-05
CA1341504C (en) * 1988-03-25 2006-04-11 Jun Akimitsu Substituted superconductive bi-sr-ca-cu oxide and bi-sr-ca-ln-cu oxide compositions
IT1230576B (en) * 1988-10-20 1991-10-28 Angeli Inst Spa ORAL PHARMACEUTICAL FORMULATIONS WITH SELECTIVE LIBERATION IN THE COLON
IT1243341B (en) * 1990-07-13 1994-06-10 Farcon Ag PHARMACEUTICAL COMPOSITION FOR ORAL USE WITH MODIFIED RELEASE OF NON STEROID ANTI-INFLAMMATORS
HU218673B (en) * 1993-10-07 2000-10-28 Euroceltique S.A. Controlled release pharmaceutical composition for orally administration comprising opioid analgesic and process for producing its
DK0654263T3 (en) * 1993-11-23 2002-04-29 Euro Celtique Sa Process for the preparation of a sustained release preparation
WO1999001111A1 (en) * 1997-07-02 1999-01-14 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
US6156342A (en) * 1998-05-26 2000-12-05 Andex Pharmaceuticals, Inc. Controlled release oral dosage form

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8487002B2 (en) 2002-10-25 2013-07-16 Paladin Labs Inc. Controlled-release compositions
US7988998B2 (en) 2002-10-25 2011-08-02 Labopharm Inc. Sustained-release tramadol formulations with 24-hour efficacy
US9439866B2 (en) 2005-09-09 2016-09-13 Angelini Pharma, Inc. Trazodone composition for once a day administration
US8795723B2 (en) 2005-09-09 2014-08-05 Angelini Pharma Inc. Sustained drug release compositions
US8962019B2 (en) 2005-09-09 2015-02-24 Angelini Pharma, Inc. Sustained drug release composition
US8414919B2 (en) 2005-09-09 2013-04-09 Angelini Labopharm, Llc Sustained drug release composition
US8883205B2 (en) 2006-02-10 2014-11-11 Biogenerics Pharma Gmbh Microtablet-based pharmaceutical preparation
US10076498B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US10076499B2 (en) 2006-08-25 2018-09-18 Purdue Pharma L.P. Tamper resistant dosage forms
US11298322B2 (en) 2006-08-25 2022-04-12 Purdue Pharma L.P. Tamper resistant dosage forms
US11304908B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11304909B2 (en) 2006-08-25 2022-04-19 Purdue Pharma L.P. Tamper resistant dosage forms
US11826472B2 (en) 2006-08-25 2023-11-28 Purdue Pharma L.P. Tamper resistant dosage forms
US11904055B2 (en) 2006-08-25 2024-02-20 Purdue Pharma L.P. Tamper resistant dosage forms

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DE19901683B4 (en) 2005-07-21
RU2244541C2 (en) 2005-01-20
HU0000137D0 (en) 2000-03-28
CO4910117A1 (en) 2000-04-24
EP1020183A3 (en) 2000-09-20
HUP0000137A3 (en) 2001-03-28
AU1010700A (en) 2000-07-20
NZ502260A (en) 2002-02-01
KR20000071245A (en) 2000-11-25
HUP0000137A2 (en) 2001-02-28
ZA200000171B (en) 2000-08-07
PL337868A1 (en) 2000-07-31
SK652000A3 (en) 2000-08-14
IL134075A0 (en) 2001-04-30
CN1270028A (en) 2000-10-18
AR021934A1 (en) 2002-09-04
AU777330B2 (en) 2004-10-14
PE20001453A1 (en) 2000-12-23
EP1020183A2 (en) 2000-07-19
JP2000212069A (en) 2000-08-02

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