WO2011008298A2 - Novel axomadol dosage forms - Google Patents

Abstract

The present invention provides a slow release dosage form comprising a therapeutically effective amount of at least one form of axomadol, at least one pharmaceutically acceptable excipient wherein the said dosage form is suitable for once or twice daily administration. This invention also provides a method of treating a mammal by administering such slow release dosage forms. The present invention also provides a dosage form comprising a therapeutically effective amount of at least one form of axomadol, at least one pharmaceutically acceptable excipient, and at least one second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSADD, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor for treating a patient in need thereof and a method of treating a human comprising administration of such combination dosage forms of axomadol and at least one second active agent.

Description

NOVEL AXOMADOL DOSAGE FORMS RELATED APPLICATIONS

[0001] This application claims priority from a U.S. provisional patent application serial no. 61/270,986 filed on July 16, 2009, which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention is related to a slow release axomadol dosage form and to a method of using such dosage forms. It is also related to combinations of axomadol with an additional active agent such as acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor that are useful for treating a therapeutic disorder in a mammal.

BACKGROUND

[0003] Axomadol, (6-Dimethylaminomethyl-l-(3-methoxyphenyl)-cyclohexane-l, 3-diol, with other Names: (1R,3R, 6R)-6-(dimethylaminomethyl)-l-(3-methoxyphenyl)cyclohexane-l,3-diol or

(lRS,3RS,6RS)-6-[(dimethylamino)methyl]-l-(3-methoxyphenyl)cyclohexane-l,3-diol or

(lRS^RS.όRS^ό-Kdimetilamino^etilJ-l-^-metoxifeniOciclohexano-l, 3-diol and having a Molecular Weight:C₂₆H₂₅Nθ₃, , Referred hereafter as Axomadol or axomadol) known from EP 0 753 506 Bl or U.S. Pat. No. 5,733,936 is of interest for its therapeutic properties. Axomadol formulations are undergoing clinical trials for treating pain.

[0004] There are a number of classes of therapeutic compounds that are used for treating various disorders including pain, Alzheimer's disease, depression etc. These include acetaminophen, NSAIDs such as naproxen, CENODS such as naproxcinod, Opiates such as morphine, tramadol, tapentadol, oxycodone etc, Antiepileptics such as pregabalin, NMDA (N-methyl-D-aspartic acid) Receptor antagonists like memantine and SNRIs such as duloxetine etc.

[0005] However, all these classes of drugs have one or more side effects that limit their use in treating a disorder for example-pain particularly over a long period of time. For Example- NSAIDs also have unwanted effects on the upper gastrointestinal tract (GI). It is reported, the prevalence of serious events such as symptomatic ulcers, bleeding, and perforation. Antiepileptic drug like Pregabalin has shown to increase suicidal behavior among its users and thus drugs that reduce such side effects are very helpful in managing pain. Similarly, opioids have certain commonly reported side effects that include nausea, constipation, dizziness, headache, drowsiness, and vomiting. Thus, it is desirable to prevent these side effects by prescribing lower doses of drugs without compromising the extent of relief.

[0006] To address this unmet need for better drug products, it is desirable to develop novel slow release Axomadol dosage forms and combinations of axomadol with other classes of therapeutic drugs such as an acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor etc so that they could be used as longer acting drugs for treating a disorder, especially pains such as fibromyalgia, arthritis and diabetes neuropathy, depression or neurodegenerative disorders.

[0007] Slow release pharmaceutical dosage forms are well known and provide distinct advantages for delivery of drugs which act optimally at certain levels of plasma concentration over extended periods of time. These are particularly suited for chronic conditions such as neurodegenerative disorders, metabolic diseases, pain and pain related conditions by providing drugs in a sustained released manner that only requires administration either once or twice daily instead of every four to eighteen hours as may be indicated for a particular drug.

[0008] For Example: The art describes controlled release or sustained release formulations in U.S. Pat. No. 5,478,577, U.S. Pat. No. 5,637,320, U.S. Pat. No. 5,591,452, U.S. Pat. No. 6,254,887, U.S. Pat. No. 6,068,858, U.S. Pat. No. 5,601,842, U.S. Pat. No. 5,580,578, U.S. Pat. No. 5,639,476, U.S. Pat. No. 5,811,126, U.S. Pat. No. 5,849,240, U.S. Pat. No. 6,077,533, U.S. Pat. No. 5,891,471, U.S. Pat. No. 5,965,163, U.S. Pat. No. 5,958,452, U.S. Pat. No. 5,965,161, U.S. Pat. No. 6,254,887, U.S. Pat. No. 5,478,577, U.S. Pat. No. 5,580,578, U.S. Pat. No. 5,648,096, U.S. Pat. No. 5,672,360, U.S. Pat. No. 5,811,126, U.S. Pat. No. 5,879,705, U.S. Pat. No. 5,968,551, U.S. Pat. No. 5,980,941, U.S. Pat. No. 6,077,532, U.S. Pat. No. 5,395,626, U.S. Pat. No. 5,474,786 and, U.S. Pat. No. 5,645,858. More recently U. S. Pat. 6,285,887 disclose the controlled release oral formulations containing tramadol. U.S. Pat 7,410,965 provides a delayed release pharmaceutical formulation containing l-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol or a pharmaceutically acceptable salt thereof in a matrix.

[0009] Similarly fixed dose combinations are known in the art to provide additive or synergistic effects. . It has been reported that some of these combination products also have a synergistic analgesic effect. U.S. Patent No. 4,571,400 discloses a combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic. See also U.S. Patent Nos. 4,587,252 and 4,569,937, which disclose other ibuprofen opioid combinations. Combinations of non-opioid analgesics have also been prepared to avoid the side effects associated with opioids, and the combinations are noted to have the benefit of requiring less of each ingredient and may provide additive effects, U.S. Patent. No. 4,260,629, U.S. Patent No. 4,132,788. A number of sustained release formulations for the delivery of a combination of

acetaminophen and tramadol have been described, for example, in U.S. Pat. No. 7,374,781 and U.S. Patent Publication No. US2003/0092724 Al. U.S Pat. App. No. 6,558,701 describes a combination of tramadol and diclofenac. U.S. Pat. No. 20090130183 describes a sustained release formation of tramadol and acetaminophen and U.S. Pat. No. 20100015222 discloses a dosage form of acetaminophen and an opioid for delivery of the drugs to the upper gastrointestinal tract ("GI") of a mammal for an extended period of time.

[0010] The prior art, however, does not disclose useful novel slow release dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the dosage form is suitable for once or twice daily oral administration. Nor does the art describe a dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient, and at least one second active agent, the said second active agent is selected from a group consisting of acetaminophen, an NSAK), an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor, for treating a patient in need thereof wherein the dosage form is suitable for once or twice daily oral administration.

[0011] Further, the prior art does not disclose a method of treating a mammal comprising administration of slow release dosage forms of axomadol and the combinations of axomadol and at least one second active agent, wherein the said second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl- D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor.

[0012] Towards achieving this objective, this invention discloses a slow release dosage form, comprising a therapeutically effective amount of at least one form of axomadol, and at least one pharmaceutically acceptable excipient, suitable for once or twice daily oral administration. The invention further discloses a method of treating a disorder in a mammal with a slow release dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once daily or twice daily administration. [0013] Further towards achieving the objectives of finding novel combinations, this invention further discloses a pharmaceutical dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent useful for treating a mammal, wherein the said second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor for treating a disorder in a mammal. Further, the invention discloses a method of treating mammal by administering to a mammal in need thereof, a dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent useful for treating a mammal, wherein the said second active agent is selected from a group consisting of acetaminophen, an NSAED, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRT), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a FIT Agonist and a Proton Pump Inhibitor. The invention also provides such combinations wherein at least one of the active agent is in slow release form.

BRIEF DESCRIPTION OF THE INVENTION

[0014] The present invention provides a slow release dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once daily or twice daily administration.

[0015] The present invention provides a method of treating pain, by administering a dosage form comprising, a therapeutically effective amount of at least one form axomadol and at least one

pharmaceutically acceptable excipient, the said dosage form is suitable for once daily or twice daily administration.

[0016] A slow release dosage form comprising at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once or twice daily oral administration and provides equivalent clinical effect to an immediate release form of same dosage.

[0017] The present invention provides a method of treating pain, by administering a slow release dosage form comprising at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once or twice daily oral administration and provides equivalent clinical effect to an immediate release form of same dosage. [0018] The present invention provides a pharmaceutical dosage form comprising a therapeutically effective amount of at least one form of axomadol, at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor.

[0019] The present invention provides a method of treating a disorder, by administering a dosage form comprising a therapeutically effective amount of at least one form of axomadol, at least one

pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo- oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor.

[0020] The present invention provides a pharmaceutical dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor,

[0021] The present invention provides a pharmaceutical dosage form comprising a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor, wherein at least one of the active agents is in slow release form.

[0022] The present invention is related in part to a therapeutic dosage forms administered orally, via implant, transdermal Iy, parenterally, sublingually, rectally, buccally, topically, via inhalation, etc. In other embodiments of the invention, axomadol can be administered separately from the second analgesic, as set forth in more detail below. [0023] The invention provides a dosage form comprising a therapeutically effective amount of at least one form of axomadol, at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting acetaminophen, an NSAlD, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D- aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor that allows the use of lower doses of the second active agent or the, or lower doses of both drugs than would normally be required when either drug is used alone. By using lower amounts of either or both drugs, the side effects associated with effective pain management in humans are significantly reduced.

[0024] The invention further relates to the use of a pharmaceutical combination of at least one form of axomadol, at least one pharmaceutically acceptable excipient, at least one second active agent, wherein the dosage form is suitable for once daily or twice daily administration.

[0025] The invention further relates to the use of a pharmaceutical combination of at least one form of axomadol together with an antiepileptic to provide effective treatment of pain.

[0026] The invention further relates to the use of a pharmaceutical combination of at least one form of axomadol together with 5-HT agonist to provide treatment of head ache including migraine.

[0027] The invention further relates to the use of a pharmaceutical combination of at least one form of axomadol together with an NMDA antagonist to provide treatment of a disorder such as pain, neurodegenerative disorder or metabolic disease.

[0028] The invention further relates to the use of and at least one form Axomadol and at least one second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl- D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor, for the treatment of a disorder.

BRIEF DESCRIPTION OF FIGURES

[0029] FIGURE 1 is the dissolution profile of a slow release Axomadol dosage form according to

Examples 1, 2 and 3.

[0030] FIGURE 2 is the dissolution profile of a slow release Axomadol dosage form according to

Examples 6.

[0031] FIGURE 3 is the dissolution profile of a slow release Axomadol dosage form according to

Examples 10, 1 1 and 12. [0032] FIGURE 4 is the dissolution profile of a slow release Axomadol dosage form according to

Examples 13, 14 and 15.

[0033] FIGURE 5 is the dissolution profile of a slow release Axomadol dosage form according to

Examples 16, 17 and 18.

[0034] Figure 6 shows the VAS Pain scores for Slow Release Axomadol (Example 1) and Immediate

Release Axomadol (Reference Example 2).

[0035] FIGURE 7 shows the VAS Pain Score for the treatment involving Axomadol (Reference

Example 1), Pregabalin, Fixed Dose Combination of Axomadol and Pregabalin (Example 38) and

Placebo.

DETAILED DESCRIPTION OF THE INVENTION

[0036] The term " axomadol " as used herein is defined to mean at least one form of axomadol chosen from axomadol salt, the individually optically active enantiomers of axomadol, such as for example, (+) or (-) forms of axomadol, racemic mixtures thereof, active metabolites, pharmaceutically acceptable salts thereof, such as for example, acid addition or base addition salts of axomadol. Acids commonly employed to form acid addition salts are inorganic acids, such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,

monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fiimarate, maleate, butyne-l,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,

methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, g-hydroxybutylate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1- sulfonate, napththalene-2-sulfonate, mandelate and the like. Base addition salts include those derived from inorganic bases, such as for example, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. [0037] The term "Active Agent" as used in this invention means axomadol, acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D- aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump

Inhibitor and their respective pharmaceutically equivalent salts, and isomers.

[0038] The term "administration or ingestion" used herein means administration of dose of a formulation containing an active ingredient administered to a patient or subject.

[0039] The term "Acetylcholinesterase inhibitor " as used in this inventions means an entity that inhibits cholinesterase enzyme and they include, but not limited to, Metrifonate, Physostigmine,

Neostigmine, Pyridostigmine, Ambenonium, Demarcarium, Rivastigmine, Galantamine, Donepezil,

Tacrine, Edrophonium, Huperzine A, Ladostigil and Ungeremine.

[0040] The term "analgesic" as used in this invention means to include any drug used to relieve pain including paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, oxycodone, etc synthetic drugs with narcotic properties such as tramadol and tapentadol, CINODS such as naproxcinod, SNRIs like duloxetine, GABA analogues like pregabalin , gabapentin and various others classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants.

[0041] The term " Antiepileptic or Antiepileptics" as used herein refers to class of compounds also referred to as anticonvulsants and they include , but not limited to, aminobutyric acid, beclamide, barbexaclone, brivaracetam, clonazepam, carbamazepine, ethotoin, ethadione, ethosuximide, eslicarbazepine, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, lacosamide, mephenytoin, methylphenobarbital, metharbital, mesuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, paramethadione, phenacemide, pheneturide, phensuximide, pregabalin, progabide rufinamide, selectracetam, stiripentol, sultiame, topiramate, trimethadione, tiagabine, valproic acid, amino(diphenylhydantoin) valeric acid, valpromide, vigabatrin and zonisamide and the term encompasses all the modulators of voltage gated calcium channels.

[0042] The term "area under curve or AUC" as used herein refers to the area under the plasma

(serum, or blood) concentration versus time curve as per the FDA guidelines.

[0043] The term "bioequivalence or bioequivalent" is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. There is being about a 90% or greater probability that the bioavailability (AUC) of axomadol as determined by standard methods is about 80 to about 125% of the second orally administrable dosage form comprising the same dose of at least one form axomadol and that there is a about 90% or greater probability that the maximum blood plasma concentration (C_m3x) of at least one form axomadol as measured by standard methods is about 80 to about 125% of the second orally administrable dosage form. It means the bioequivalence or bioequivalent under FDA guidelines.

[0044] The term "binding agent" as used in this specification, refers to any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polymethacrylate, polyvinylalcohol, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents are water soluble materials such as polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent may comprise approximately about 0 to about 40% of the total weight of the core and preferably about 3% to about 15% of the total weight of the core. In one embodiment, the use of a binding agent in the core is optional.

[0045] The term "Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator" or "CINODs" as used herein have a nitric oxide (NO)-releasing group and are also designated No-NSAIDs and includes naproxcinod.

[0046] The term "clinical effect" as used herein as clinical efficacy with respect to pain experienced by study subjects measured using a suitable scale, for example; in treating pain, clinical effect is measured by WOMAC global score, Likert-scale, or VAS score.

[0047] The term "C_m3x" as used herein means the mean maximum plasma concentration of at least one form axomadol.

[0048] The term "controlled release" as used herein is defined to mean a substantially gradual rate of release of the drug. The controlled-release dosage form with the at least one means for controllably releasing at least one form axomadol in a substantially controlled manner per unit time in-vivo. The rate of release of the drug is controlled by features of the dosage form and/or in combination with physiologic or environmental conditions rather than by physiologic or environmental conditions alone.

[0049] The term "controlled-release dosage forms" or dosage forms which exhibit a "controlled- release" of at least one form axomadol as used herein is defined to mean dosage forms administered once daily that release drug at a relatively constant rate and provide plasma concentrations of the active drug that remain substantially invariant with time within the therapeutic range of the active drug over about a 12 to 24-hour period.

[0050] The term "candidate for sustained release" encompasses all the characteristics of a drug which make it a candidate for formulating it into an extended release fashion like a short elimination half life and consequent dosing of more than once a day, a single dose product given in an extended fashion to achieve better clinical results and avoid side effects associated with an immediate release etc.

[0051] The term "delayed-release dosage forms" or dosage forms which exhibit a delayed-release of the drug. The dosage forms administered once daily that do not substantially release drug immediately following administration but at a later time. Delayed-release dosage forms provide a time delay prior to the commencement of drug-absorption. Such dosage forms will desirably be coated with a delayed- release coat.

[0052] The term "dosage form" as used herein is defined to mean a solid oral pharmaceutical preparation or system in which doses of medicine or active drug are included. A dosage form will desirably comprise, for example, at least one slow release dosage form including various slow release forms such as, osmosis controlled-release dosage form, erosion controlled-release dosage form, dissolution controlled-release dosage form, diffusion controlled-release dosage form, controlled-release matrix core, controlled-release matrix core coated with at least one release-slowing coat, enteric coated dosage form, one sustained dosage, dosage form surrounded by at least one delayed-release coat, capsules, minitablets, caplets, uncoated microparticles, microparticles coated with release-slowing coat, microparticles coated with delayed-release coat or any combination thereof.

[0053] The term "enhanced absorption dosage forms" or dosage forms which exhibit an "enhanced absorption" of the drug as used herein is defined to mean dosage forms that when exposed to like conditions, will show higher release and/or higher absorption of the drug as compared to other dosage forms with the same or higher amount of drug.

[0054] The term "effective amount" as used herein means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.

[0055] The term "extended release material" as present in the inner solid particulate phase and the outer solid continuous phase refers to one or more hydrophilic polymers and/or one or more hydrophobic polymers and/or one or more other type hydrophobic materials, such as, for example, one or more waxes, fatty alcohols and/or fatty acid esters.

[0056] The term "extended-release dosage forms" or dosage forms which exhibit an "extended release" of drug as used herein is defined to mean dosage forms administered once daily that release drug slowly, so that plasma concentrations of the drug are maintained at a therapeutic level for an extended period of time such that the sustained-release dosage form provides therapeutic benefit over a 12-24-hour period.

[0057] The term "hydrophilic polymers" as used in this specification include, but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium, carboxymethyl- cellulose, carboxymethylcellulose calcium, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinylalcohol, povidone, carbomer, potassium pectate, potassium pectinate, etc

[0058] The term " hydrophobic polymers" as used in this specification include, but are not limited, to ethyl cellulose, hydroxyethylcellulose, ammonio methacrylate copolymer (Eudragit RL™ or Eudragit

RS™), methacrylic acid copolymers (Eudragit L™ or Eudragit S™), methacrylic acid-acrylic acid ethyl ester copolymer (Eudragit L 100-5™), methacrylic acid esters neutral copolymer (Eudragit NE 30D™), dimethylaminoethylmethacrylate-methacrylic acid esters copolymer (Eudragit E 100™), vinyl methyl ether/malefic anhydride copolymers, their salts and esters (Gantrez™) etc.

[0059] The term "immediate release coat" as used herein, is defined to mean a coat, which has substantially or appreciably no influence on the rate of release of axomadol from the dosage form in-vitro or in-vivo. The excipients comprising the immediate release coat have no substantial slow release, swelling, erosion, dissolution, or erosion and swelling properties, which means that the composition of the coat has no substantial influence on the rate of release of the axomadol.

[0060] The term "medicament" as used herein means a dosage form suitable for administration of the pharmaceutically active compound to a patient.

[0061] The term "mean maximum plasma concentration" (C_max) as used herein means the arithmetic mean of maximum plasma concentration of at least one form axomadol.

[0062] The term "mean plasma concentration" as used herein means the arithmetic mean blood plasma concentration of at least one form axomadol.

[0063] The term "modified-release dosage forms" or dosage forms which exhibit drug release characteristics of time course and/or location are designed to accomplish therapeutic or convenience objectives not offered by an immediate-release dosage forms. Modified-release dosage forms or dosage forms are typically designed to provide a quick increase in the plasma concentration of the drug which remains substantially constant within the therapeutic range of the drug for at least a 12-24-hour period.

[0064] The term "multiparticulate" or "microparticle" as used herein is defined to mean a plurality of drug-containing entities, such as for example microspheres, spherical particles, microcapsules, particles, microparticles, granules, spheroids, beads, pellets, or spherules.

[0065] The term" NMDA antagonists or NMDA Antagonist" as used herein means inhibitors or modulators of NMDA (N-methyl-D-aspartic acid) receptors including Amantadine, Dextromethorphan,

Dextrorphan, Ketamine, Ketobemidone, Memantine, Methadone, Nitrous oxide, Phencyclidine and

Rilutek, etc. [0066] The term "NSAID" means Nonsteroidal anti-inflammatory drugs such as Ibuprofen,

Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin, Indomethacin, Sulindac, Etodolac,

Diclofenac, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib etc.

[0067] The term " Serotonin Norepinephrine Reuptake inhibitors (SNRIs)" means the class of antidepressant used in the treatment of clinical depression and other affective disorders including

Venlafaxine, duloxetine, milnacipran and desvenlafaxine etc.

[0068] The term "Norepinephrine Reuptake inhibitors (NRI, NERJ) or adrenergic reuptake inhibitor (ART)" means the class of drug which acts as a reuptake inhibitor for the neurotransmitters

norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter. They include, but limited to, Atomoxetine/Tomoxetine, Mazindol, Reboxetine, and

Viloxazine.

[0069] The term "optimal" us used herein means an amount which is the optimal dosage for that compound when used in single-compound therapy.

[0070] The term "Opioids or Opiates" as used herein means any entity that brings out biological response by acting on opioid receptors. These include but not limited to opioid agonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, faxeladol, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomoφhine, norlevorphanol, normethadone, naloφhine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tapentadol, and, tramadol, mixtures or salts of any of the foregoing,.

[0071] The term "osmotic dosage form", "osmotic delivery device", as used herein is defined to mean dosage forms which forcibly dispense the drug all or in partially by pressure created by osmosis or diffusion of fluid into a core which forces the drug to be dispensed from the osmotic dosage form.

[0072] The term "prevention of a disease" as used herein is defined as the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The piupose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders.

[0073] The term "pain and pain related conditions" as used herein is defined as any pain due to a medical conditions including but not limited to neuropathic pain, osteoarthritis, rheumatoid arthritis, fibromyalgia, and back, musculoskeletal pain, Ankylosing spondylitis, juvenile rheumatoid arthritis, migraines, dental pain, abdominal pains, ischemic pain, postoperative pain or because of an anesthetic or surgical contrition.

[0074] The term "pharmaceutically acceptable derivative" means various pharmaceutical equivalent isomers, enantiomers, salts, hydrates, polymorphs, esters etc of at least one form axomadol.

[0075] The term" Proton Pump Inhibitor or PPI" as used herein means any active agent that blocks hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase,) of the gastric parietal cell including Omeprazole, Lansoprazole, Esomeprazole, Pantoprazole and Rabeprazole

[0076] The term "5-HTagonists" as used herein means drugs that act on 5-HT receptor including sumatriptan, rizatriptan, zolmitriptan, almotriptan and frovatriptan.

[0077] The term "second active agent" as used herein means an active agent selected from a group consisting acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor.

[0078] The term "sub-optimal or sub-therapeutic" as used herein means an amount which is below the optimal dosage for that compound when used in single-compound therapy.

[0079] The term "slow-release" here applies to any release formulation that is other than an immediate release wherein the release of the active ingredient is slow in nature. This includes various terms used interchangeably in the pharmaceutical context like extended release, delayed release, sustained release, controlled release, timed release, specific release, prolonged release and targeted release etc.

[0080] The term "sustained-release dosage forms" or dosage forms which exhibit a "sustained- release" of the drug as used herein is defined to mean dosage forms administered once daily that provide a release of the drug sufficient to provide a therapeutic dose after administration, and then a gradual release over an extended period of time such that the sustained-release dosage form provides therapeutic benefit over a 12 to 24-hour period.

[0081] The term "treatment of a disease" as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

[0082] The term "twice daily oral pharmaceutical composition" as used herein is defined as any axomadol formulation administered two times a day to a patient in need of.

[0083] The term "therapeutically effective amount" means an amount that elicits a biological response in a mammal including the suboptimal amount.

[0084] The term "T_1113x" as used herein means a mean time to maximum plasma concentration of at least one form of axomadol.

[0085] Optionally, the oral solid dosage form includes a sustained release carrier which causes the sustained release of the second active agent, or both the second active agent and at least one form of axomadol when the dosage form contacts gastrointestinal fluid. The sustained release dosage form may comprise a plurality of substrates which include the drugs. The substrates may comprise matrix spheroids or may comprise inert pharmaceutically acceptable beads which are coated with the drugs. The coated beads are then preferably over coated with a sustained release coating comprising the sustained release carrier. The matrix spheroid may include the sustained release carrier in the matrix itself; or the matrix may comprise a normal release matrix containing the drugs, the matrix having a coating applied thereon which comprises the sustained release carrier. In yet other embodiments, the oral solid dosage form comprises a tablet core containing the drugs within a normal release matrix, with the tablet core being coated with a sustained release coating comprising the sustained release carrier. In further embodiments, the tablet contains the drugs within a sustained release matrix comprising the sustained release carrier. In further embodiments, the tablet contains the opioid analgesic within a sustained release matrix and at least one form of axomadol coated into the tablet as an immediate release layer.

[0086] The present invention discloses a slow release pharmaceutical composition comprising axomadol and at least one pharmaceutically acceptable excipient, According to the invention, the composition preferably contains a therapeutically effective amount of axomadol or a pharmaceutically acceptable salt thereof, wherein the axomadol is suitably in the range of from 5 to 2000 mg, especially about 250, 500,

750, 1000, 1250 to 1500 mg per dosage unit.

[0087] Granules, spheroids, pellets, multiparticulates, capsules, patches tablets, sachets, controlled release suspensions, or in any other suitable dosage form incorporating such granules, spheroids, pellets or multiparticulates are also a part of the present invention.

[0088] The one or more of active ingredient in the composition according to the present invention may suitably be incorporated in a matrix. This may be any matrix, known to a person skilled the art, that affords slow release axomadol over at least a twelve hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of axomadol within the therapeutically effective ranges. The formulation according to the present invention may preferably use a slow release matrix. Alternatively, normal release matrices having a coating which provides for slow release of the axomadol may be used. This may be any matrix that affords axomadol released over at least a twelve hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of axomadol within the ranges specified above. Preferably the matrix is a controlled release matrix. Alternatively, normal release matrices having a coating which provides for controlled release of the active ingredient may be used.

[0089] The slow release matrix employed in the composition of this invention may also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colorants, flavourants, surfactants, pH adjusters, anti- adherents and glidants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica. Any known diluent e.g. microcrystalline cellulose, lactose and dicalcium phosphate may be used to prepare this combination. Suitable lubricants are e.g. magnesium stearate and sodium stearyl fumarate. Suitable binding agents are e.g. hydroxypropyl methyl cellulose, polyvidone and methyl cellulose. Suitable disintegrating agents are starch, sodium starch glycolate, and crospovidone and croscarmellose sodium.

[0090] The slow release matrix employed in the composition of this invention may also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colorants, flavourants, surfactants, pH adjusters, anti- adherents and glidants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica. Any known diluent e.g. microcrystalline cellulose, lactose and dicalcium phosphate may be used to prepare this combination. Suitable lubricants are e.g. magnesium stearate and sodium stearyl fumarate. Suitable binding agents are e.g. hydroxypropyl methyl cellulose, polyvidone and methyl cellulose. Suitable disintegrating agents are starch, sodium starch glycolate, and crospovidone and croscarmellose sodium.

[0091] Slow release matrix of present invention includes materials such as Polyalkylene glycols, Long Chain Hydrocarbons and Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, acrylic resins and protein derived materials. Of these polymers, the cellulose ethers, especially alkyl celluloses are preferred. The preparation may conveniently contain between 1% and 80% (by weight) of one or more hydrophilic or hydrophobic polymers. Still further Digestible, long chain (C.8 -C50), substituted or un-substituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The preparation may conveniently contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon. [0092] Surface actives that are suitable for this invention are Poloxamer 188.RTM, polysorbate 80 and sodium lauryl sulfate. The suitable flow aids for this invention are talc colloidal anhydrous silica.

Similarly, the suitable water soluble polymers that may be used to prepare the matrix are PEG with molecular weights in the range 1000 to 6000. The combination comprising the slow release axomadol according to the invention may conveniently be film coated using any film coating material conventional in the pharmaceutical art but preferably an aqueous film coating is used.

[0093] Alternatively, the composition as per this invention may comprise a normal release matrix having a slow release coating. Preferably the combination comprises film coated spheroids containing the active ingredient and a spheronising agent. The spheronising agent may be any suitable pharmaceutically acceptable material which may be spheronised together with the active ingredient to form spheroids. A preferred spheronising agent as per this invention is microcrystalline cellulose. The microcrystalline cellulose used may suitably be, for example, Avicel PH 101 or Avicel PH 102 (Trade Marks, FMC Corporation). The spheroids may optionally contain other pharmaceutically acceptable ingredients conventional in the pharmaceutical art such as binders, bulking agents and colorants. Suitable binders may include water soluble polymers, water soluble hydroxyalkyl celluloses such as

hydroxypropylcellulose or water insoluble polymers (which may also contribute controlled release properties) such as acrylic polymers or copolymers for example ethylcellulose. Suitable bulking agents include lactose.

[0094] Slow release form according to this invention includes osmotic dosage forms with or without passageway or a pore.

[0095] The spheroids are coated with a material which permits release of the active ingredient at a slow rate in an aqueous medium. Suitable slow release coating materials that may be used in this invention include water insoluble waxes and polymers such as polymethylacrylates (for example Eudragit polymers) or water insoluble celluloses, particularly ethylcellulose. Optionally, water soluble polymers such as polyvinylpyrrolidone or water soluble celluloses such as hydroxypropylmethylcellulose or hydroxypropylcellulose may be included. Optionally other water soluble agents such as polysorbate 80 may be added.

[0096] Further in an alternative embodiment, a flux-enhancing agent can also be included in the membrane or slow release coating can include one of the above-described polymers. The flux enhancing agent can increase the volume of fluid imbibed into the core to enable the dosage form to dispense substantially all of the axomadol through the passage and/or the porous membrane. The flux-enhancing agent can be a water-soluble material or an enteric material. Examples of the preferred materials that are useful as flux enhancers include but not limited to sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycols (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68, LUTROL F127, LUTROL F108 which are commercially available from BASF) and mixtures thereof. A preferred flux-enhancer used in this invention is PEG 400.

[0097] A commonly known excipient such as a plasticizer may also be used for preparing the membrane or slow release coating Some commonly known plasticizers include but not limited to adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and all those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate,

dioctylphthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, glycerol tributyrate and the like. Though the exact amount used depends on the type of plasticizer used, typically amounts from about 0 to about 25% are used, and preferably about 2% to about 15% of the plasticizer can be used based upon the total weight of the membrane or sustained release coating.

[0098] Generally, the membrane or slow release coating around the core will comprise from about 1% to about 20% and preferably about 2% to about 10% based upon the total weight of the core and coating.

[0099] The slow release pharmaceutical composition according to the instant invention may

conveniently be film coated using any film coating material conventional in the pharmaceutical art such as an aqueous film coating.

[00100] Alternatively, the slow release composition according to the instant invention may comprise a normal release matrix having a slow release coating and preferably the slow release composition comprises film coated spheroids containing the active ingredient and a spheronising agent.

[00101]The release profile can be modified in a number of ways; 1) loading of the drug will be associated with increased release rates; 2) the use of larger proportions of the water soluble fusible material in the particles or surface active agent in the tabletting formulation will also be associated with a higher release rate of the active ingredient and, 3) by controlling the relative amounts of these ingredients it is possible to adjust the release profile of the axomadol or a salt thereof.

[00102] To produce the slow release axomadol composition of varying dissolution profile in accordance with the invention, particles may be produced according to standard procedures known in the art such as using a Y-Cone or bin-blender, using a suitable size tabletting mould and using conventional tabletting machines. [00103] The membrane or sustained release coating surrounding the core can further optionally comprise a passage that will allow for controlled release of the drug from the core in a preferred embodiment. As used herein the term passage includes an aperture, orifice, bore, hole, weakened area or a credible element such as a gelatin plug that erodes to form an osmotic passage for the release of the axomadol from the dosage form. The passage used, in accordance with the subject invention are well known and are described in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607

[00104]In a further embodiment of the present invention, the invention comprises an oral solid dosage form comprising a therapeutically effective amount of a second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, a HT Agonist and a Proton Pump Inhibitor, with an amount of a pharmaceutical preparation containing axomadol or pharmaceutically acceptable salt thereof which augments the effect of the second active agent.

[00105] In many preferred embodiments of the invention, the pharmaceutical compositions comprising at least one form of axomadol and a second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor, set forth herein are administered orally. Such oral dosage forms may contain one or both of the drugs in immediate or sustained release form. For ease of administration, it is preferred that the oral dosage form contains both drugs. The oral dosage forms may be in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, multiparticulate formulations, syrups, elixirs, and the like.

[00106] The pharmaceutical compositions comprising at least one form of axomadol and a second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D- aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor, set forth herein may alternatively be in the form of microparticles (e.g., microcapsules, microspheres and the like), which may be injected or implanted into a human patient, or other implantable dosage forms known to those skilled in the art of pharmaceutical formulation. For ease of administration, it is preferred that such dosage forms contain both drugs. [00107] Additional pharmaceutical compositions contemplated by the invention further include transdermal dosage forms, suppositories, inhalation powders or sprays, and buccal tablets.

[00108] The combination of at least one form of axomadol and a second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an

Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor can be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.

[00109] Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, penta erythritol fatty acid esters, hydroxymethylcellulose,

polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They can also be combined where desired with other active agents, e.g., other analgesic agents. For parenteral application, particularly suitable are oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages. For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gel caps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay release of the active ingredients.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[00110] Aqueous suspensions contain the above-identified combination of drugs and that mixture has one or more excipients suitable as suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums. Oily suspensions may be formulated by suspending the above-identified combination of drugs in a vegetable oil or mineral oil. The oily suspensions may contain a thickening agent such as beeswax or cetyl alcohol, syrup, elixir, or the like can be used wherein a sweetened vehicle is employed. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. It is also possible to freeze-dry the active compounds and use the obtained lyophilized compounds, for example, for the preparation of products for injection.

[0011 l]The combination of at least one form of axomadol and a second active agent, wherein the second active agent is selected from a group consisting acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo- oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor can be formulated as a controlled or sustained release oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art. The sustained release dosage form may optionally include a sustained released carrier which is incorporated into a matrix along with axomadol, or which is applied as a sustained release coating.

[00112] The sustained release dosage form may include the second active agent in sustained release form and at least one form of axomadol in sustained release form or in immediate release form. At least one form of axomadol may be incorporated into the sustained release matrix along with the second active agent; incorporated into the sustained release coating; incorporated as a separated sustained release layer or immediate release layer; or may be incorporated as a powder, granulation, etc., in a gelatin capsule with the substrates of the present invention. Alternatively, the sustained release dosage form may have at least one form of axomadol in sustained release form and the second active agent in sustained release form or immediate release form.

[00113] The dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid. A pH-dependent coating serves to release the axomadol in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least about twelve hour and preferably up to twenty-four hour analgesia to a patient. When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine. [001 14] Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH-dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.

[00115]Cellulosic materials and polymers, including alkyl celluloses, provide hydrophobic materials well suited for coating the beads according to the invention. Simply by way of example, one preferred alkyl cellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkyl cellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention.

[00116] In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl

methacrylates, cyan ethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkyl amide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, amino alkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

[00117] In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former.

Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.

[00118] Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention. [00119] The release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating. The ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.

[00120] The release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.

The pore-formers may comprise one or more hydrophilic materials such as

hydroxypropylmethylcellulose.

[00121] The sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums.

[00122] The sustained release coatings of the present invention can also include materials useful for making micro porous 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.

[00123] The release-modifying agent may also comprise a semi-permeable polymer.

[00124] In other embodiments of the present invention, the controlled release formulation is achieved via a matrix having a controlled release coating as set forth above. The present invention may also utilize a controlled release matrix that affords in-vitro dissolution rates of the opioid within the preferred ranges and that releases the opioid in a pH-dependent or pH-independent manner. The materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix. For example, a matrix in addition to the second active agent and at least one form of axomadol may include:

[00125] Hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.

[00126] In certain preferred embodiments, the invention is directed in part to synergistic combinations of at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a second active agent, such that the therapeutic effect is attained which is greater than that obtained with the dose of second active agent alone.

[00127] In certain embodiments, the combination is administered in a single dosage form. In other embodiments, the combination is administered separately, preferably concomitantly. [00128] In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of a second active agent.

[00129] In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of an opioid analgesic selected from the group consisting of morphine, dihydrocodeine, hydromorphone, oxycodone, oxymorphone, salts thereof, and mixtures of any of the foregoing.

[0013O]In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of a 5-HT agonist.

[0013I]In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of a proton Pump Inhibitor.

[00132] In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of an Antiepileptic.

[00133] In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of second active agent selected from the group consisting of Amantadine, Dextromethorphan, Dextrorphan, Dizocilpine (MK-801, Eticyclidine,

Ibogaine, Ketamine, Memantine, and Nitrous oxide, Phencyclidine, Rolicyclidine and Tenocyclidine.

[00134] In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of a second active agent selected from the group consisting of Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran, Levomilnacipran (F2695),

Sibutramine, Bicifadine and SEP-227162.

[00135] In certain preferred embodiments, the invention is directed to pharmaceutical formulations comprising at least one form of axomadol in an amount sufficient to render a therapeutic effect together with a therapeutically effective or sub-therapeutic amount of a second active agent selected from the group consisting of Atomoxetine/Tomoxetine, Mazindol, Reboxetine, and Viloxazine (Vivalan).

[00136] In certain embodiments, the synergistic combination provides a therapeutic effect which is up to about 30-40 times greater than that obtained with the dose of second active agent alone. [00137] In certain preferred embodiments, the doses of at least one form of axomadol and the second active agent are co-administered orally.

[00138] In further preferred embodiments, the doses of at least one form of axomadol and the second active agent are administered in a single oral dosage form.

[00139] In further preferred embodiments, the doses of at least one form of axomadol and the second active agent are administered in a single oral dosage form, at least one of the active agent is in slow release form.

[0014O]In certain preferred embodiments, the dose of the second active agent would be sub-therapeutic if administered without the dose of at least one form of axomadol.

[00141] The following examples are shown for illustrating the invention related slow release dosage forms comprising at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once or twice daily oral administration. They also exemplify a dosage form comprising at least one form of axomadol, at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake

Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor. These examples in no' way limit the scope of the invention. The person skilled in the art will know how the combination may be modified using other formulations and excipients;

EXAMPLES 1-7;

[00142] The following examples 1-7 are prepared according the formulas provided in Tables 1, 2 and 3 respectively as per the manufacturing process described below.

TABLE l

* Removed during the process

TABLE 2

TABLE 3

MANUFACTURING PROCESS;

[00143] Core Preparation; Axomadol and colloidal silicon dioxide were mixed and passed through a 1.0 mm screen. Polyvinyl alcohol was dissolved in purified water. The mixed axomadol and colloidal silicon dioxide powder was granulated with the aqueous solution of polyvinyl alcohol in a fluidized bed granulator, Glatt GPCGl and then dried. After granulation, the granules were blended with sodium stearyl fumarate and then passed through a 1.0 mm screen. The blend was then compressed into tablet cores using a Manesty Betapress.

[00144] Coating Preparation; The ethyl alcohol and isopropyl alcohol in appropriate quantity were weighed and mixed together. Dibutyl sebacate and ethylcellulose were added to and dissolved in the ethyl alcohol and isopropyl alcohol midst of constant stirring with a propeller stirrer, Coframo RZRl and polyvinylpyrrolidone was added. The solution was stirred until all components were dissolved. The solution was passed through a high pressure homogenizer.

[00145] The tablet cores were coated using the coating solution in a perforated coating pan, O'Hara Labcoat Il 1 36" Pan, Vector LCDS as per the coating parameters are listed in Table 4;

TABLE 4

EXAMPLE 8;

[00146] In yet another example, the invention discloses a slow release dosage form which can effectively be used in the treatment of pain and pain related diseases wherein the dosage forms comprise a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient. The tablet was prepared as a bilayer tablet as per formula in Table 9;

TABLE 9

MANUFACTURING PROCESS;

[00147] Preparation of Layer 1: Axomadol, microcrystalline cellulose and colloidal silicon dioxide were granulated with polyvinyl alcohol and dried. The dried granules are mixed with Ethylcellulose and Hydroxyethylcellulose and lubricated with Sodium stearyl fumarate. [00148] Preparation of Layer 2: Axomadol is mixed with microcrystalline cellulose was granulated with povidone. Granules are dried and mixed with Croscarmellose sodium and finally lubricated with Magnesium stearate.

[00149] Compression: Layer 1 and Layer 2 are loaded into the hopper of bi layer rotary compression machine and compressed with a desired hardness.

EXAMPLE 9;

[00150] In another example, a slow release dosage form comprising at least one form of axomadol tablets were manufactured as per Table 10;

TABLE 10

MANUFACTURING PROCESS;

[00151] The tablets of Example 9, a slow release dosage form comprising at least one form of axomadol tablets, were manufactured in two phases using standard coating processes. In phase I, the axomadol was formulated into a core. In Phase II, the above prepared core was further coated with slow release coat to get a slow release axomadol core as per details are given below;

[00152] Phase I, Core preparation: Axomadol is mixed with microcrystalline cellulose and colloidal silicone dioxide and one or mixture of filler and granulated using suitable method known in the art using a binder solution comprising Polyvinylpyrrolidone or polyvinyl alcohol. The granulated axomadol was dried and screened. This is further lubricated using hydrogenated vegetable oil with or without glidant. The lubricated blend is compressed into tablets using a compression machine.

[00153] Coating Solution and Coating: The coating solution is prepared using aqueous dispersion of water insoluble water permeable polymer of Ethylcellulose with water soluble polymer of

Polyvinylpyrrolidone or 29 hydroxylpropylmethyl cellulose. Polyethylene glycol mixture prepared using propeller stirrer and the same is homogenized using suitable homogenizer. The core tablets are coated using coating solution using standard coater like O' Hara pan coater tip set at 4" at a spray rate of 25 mL/gun/min, exhaust temperature of around 45'C, an atom izat ion pressure from 10-35 psi at a pan speed of 5-8 rpm, using airflow 350 CFM.

EXAMPLE 10;

In another example, a slow release dosage form comprising at least one form of axomadol and at least one pharmaceutical excipient were manufactured as per Table 11;

TABLE 11

* Removed in processing

MANUFACTURNG PROCESS: [00154] Core: The slow release axomadol was manufactured by preparing a core and coating with a slow release coat. Core was prepared by granulating 250 mg of axomadol and 167 mg of lactose using a standard granulator. The granulated mix was transferred to a fluid bed granulator and sprayed with 38.75 mg of ethylcellulose and suitable quantity (35 ml) of distilled water. The granules were then dried at 60'C and passed through a 1 mm screen. 103.75 mg of cetostearyl alcohol melt was added to axomadol granules was added and the resulting mixture was mixed thoroughly. The granules were allowed to cool and sieved through a 1.6 mm screen. Purified talc and magnesium stearate were added and mixed with the granules which were then compressed into tablets.

[00155] Coat: The compressed tablets were coated with slow release coating solution prepared according to the Table 13 using standard coating techniques.

EXAMPLES 11-12;

[00156] In slightly modified formulations, Examples 11 and 12 of slow release axomadol were prepared according to the manufacturing methods described under Example 10. In addition varying the excipients, a different polymer was used in Example 12. The formulations had the composition according to Table 12 and 13;

TABLE 12

Total Coat 41.805

Total Weight 649.18

* Removed in processing

TABLE 13

EXAMPLES 13-15:

[00157] In order to demonstrate the effect of particle sizes on the dissolution profiles of the instant invention, additional examples slow release dosage form comprising at least one form axomadol (Examples 13 to 15) were prepared according to the Tables 14-16.

Final Coated Tablet of Example 13 TABLE 14

Final Coated Tablet of Example 14

TABLE 15

Final Coated Tablet of Example 15

MANUFACTURING METHOD: [00158] The slow release dosage form particle comprising at least one form of axomadol was prepared by missing equal quantity of axomadol and Hydrogenated Vegetable oil in a mixer at a rotation speed of around 500 RPM. The mechanical action was continued by heating till the contents were fused together and formed into a mass. The slow release seeds were obtained by using a granulator. The granulator sizes dry granulation to the optimum particle size distribution for efficient tabletting. The resulting seeds were subjected warming and mixing for about 5-15 minutes till pre-determined particle sizes are obtained. The resultant particles, alter cooling, are suitably sieved to give particles having a size range from 0.1 to 3.0 mm, preferably 0.25 to 2.0 mm. The resulting particles may be sieved to form the desired dosage units.

[00159] The resulting particles may be further mixed with Ethyl Cellulose and Cetostearyl alcohol and compressed into tablets. The compressed tablets were coated with coating solution prepared according to the formula in Table 17.

[00160] In order to further analyze the impact of particle sizes on the dissolution profile the slow release composition comprising at least one form of axomadol, additional Examples of 16 -18, were manufactured using the same manufacturing method as described for Examples 13-15. The composition consisted of the formula in Table 17 below;

TABLE 17

REFERENCE EXAMPLES 1, 2 and 3

[00161] A delayed release tablet comprising 50 mg, 100 mg and 150 mg immediate release axomadol tablets was prepared as per the formula in Table 18 using standard manufacturing methods reported in the art.

TABLE 18

EXAMPLE 19;

[00162] Another slow release axomadol tablet dosage was prepared for according to the formula of Table 19 as below

TABLE 19

MANUFACTURING PROCESS;

[00163] The axomadol is delumped by passing it through a 40 mesh screen and collecting it in a clean, polyethylene-lined container and was granulated with Polyvinyl Alcohol and Colloidal Silicon Dioxide in a granulator. The granulated mix was mixed with D-mannitol and sodium stearyl fumarate in a blender. The blended granulated axomadol mix was compressed into tablets. The cellulose acetate, hydroxypropyl cellulose was dissolved in organic solvents and mixed with sodium chloride. The compressed axomadol tablets were coated using standard coating techniques.

EXAMPLE 20;

[00164] Yet another slow release dosage form comprising at least one form axomadol was prepared using multiparticulate osmotic technology using CEFORM according to the formula in Table 20.

TABLE 20

Multiparticulate Osmotic Systems

Tablet Core Ingredients Percent of Tablet

Axomadol 100

Compritol ATO 888 12

Sodium Chloride 10

Gelucire 50/13 8

Slow Release Coating Percent of Coating

Ethyl Cellulose 60.9

Hydroxypropyl Cellulose 26.1

Talc Micronized 13

Organic Solvents Q.S

MANUFACTURBVG PROCESS; [00165] The dosage form of Example 20 was prepared using Ceform microsphere technology (Fuisz Technology Ltd., USA). This technology allows the production of uniformly sized and shaped microspheres of pharmaceutical compounds. These microspheres are almost perfectly spherical, having a diameter that is typically 150 to 180 mm, and allow for high drug content. The microspheres can be used in a wide variety of dosage forms, including tablets, capsules, suspensions, effervescent tablets, and sachets. The microspheres can be formulated for enhanced absorption (Ceform EA) or taste isolation (Ceform TI) and may be coated for controlled release (Ceform CR), provided with an enteric coating (Ceform EC), or combined into a fast/slow release combination (Ceform EA/CR). The microspheres comprising axomadol was coated with a slow release coating release solution prepared using Ethyl Cellulose, Hydroxypropyl cellulose, micronized talc in acetone/I-propyl alcohol solvents.

EXAMPLE 21;

[00166] In another invention, Example 21 prepared according to Table 21 using a lipid hydrophobic system, is yet another slow release axomadol dosage form.

TABLE 21

MANUFACTURING PROCESS;

[00167] Axomadol, hydroxypropyl cellulose, and hydrogenated vegetable oil are agglomerated by means of a molten binder and processed into spherical or nearly spherical granules of homogeneous size using melt granulation at about 85-90'C process. The homogenized mix was solidified, screened in a suitable screener, milled and sized. The lubricant was added and tablets were compressed. The osmotic coating solution comprising Opadry solution was used to coat the compressed axomadol tablets in a coater.

EXAMPLE 22;

[00168] In another invention, Example 22 prepared according to Table 22 using a wax hydrophobic system, is yet another slow release axomadol dosage form.

TABLE 22

[00169] The manufacturing process for preparing release axomadol dosage form according to Table 22 is similar to that of Example 21 with minor modifications easily discerned by a person skilled in art.

ADDITIONAL EXAMPLES;

[00170] In other inventions, Examples 23-32 prepared according to the formulas in Tables 23 to 34 are a set of other slow release axomadol dosage examples for illustrative purposes. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the disclosed compositions. The following working examples therefore, are provided for the purpose of illustration only and specifically point out the preferred embodiments, and are not to be construed as limiting in any way the remainder of the disclosure. Therefore, the examples should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. EXAMPLE 23;

TABLE 23

Enteric Coat Hydrophobic Core System

Tablet Core Ingredients Percent of Tablet

Axomadol 100

Colloidal Silicon Dioxide 2.9

Polyvinyl Alcohol 4.5

Ethyl Cellulose 125

Ludipress 14.2

Sodium Stearyl Fumarate 2.8

Tablet Coating Percent of Coating

Eudragit L100-55 44.2

Acetyl Triethyl Citrate 8

Talc 400 97

EXAMPLE 24;

TABLE 24

Hydrophobic Lipid Coat System

Mini-Tablet Core Ingredients Percent of Tablet

Axomadol 100

Colloidal Silicon Dioxide 3.2 Polyvinyl Alcohol 7.3 Sodium Stearyl Fumarate 4.3

Mini-Tablet Coating Percent of Coating

Glyceryl Monostearate 78.3 PEG 8000 3.8

EXAMPLE 25;

TABLE 25

EXAMPLE 26;

TABLE 26

EXAMPLE 27;

TABLE 27

Hydrophilic Swellable Coat System

Tablet Core Ingredients Percent of Tablet

Axomadol 100

Colloidal Silicon Dioxide 2.64

Polyvinyl Alcohol 3

Eudragit RI Powder 110

Sodium Stearyl Fumarate 2.5

Tablet Coating Percent of Coating

EXAMPLE 28;

TABLE 28

Hydrophilic Soluble Polymeric Coat System

Tablet Core Ingredients Percent of Tablet

Axomadol 100

Colloidal Silicon Dioxide 0.66

Polyvinyl Alcohol 1

Hydroxypropyl Methyl Cellulose 28.3

Sodium Stearyl Fumarate 0.96

Percent of

Tablet Coating Coating

Opadry (Clear ) 5% solution 77

Water Q.S

EXAMPLE 29;

TABLE 29

Talc 11

Solvents (Evaporated) Q.S

EXAMPLE 30;

TABLE 30

EXAMPLE 31;

TABLE 31

EXAMPLE 32;

TABLE 32

EXAMPLE 33;

TABLE 33

Axomadol Granules

Axomadol 100

Polyvinylpyrrolidone 7.6 Isopropyl Alcohol* 77 Total Axomadol Granules Weight 184.6

EXAMPLE 34:

TABLE 34

Axomadol Granules

Axomadol 100

Polyvinylpyrrolidone 11.1 Isopropyl Alcohol* 90

Total Axomadol Granule Weight 111.1

Axomadol Tablets MG/Tablet

Axomadol Beads: 66 Axomadol Granules 33

Microcrystalline Cellulose 65

Crospovidone 11.4

PVPK30 12.2

Magnesium Stearate 2.1

Axomadol Tablets 189.7

EXAMPLES-AXOMADOL COMBINATIONS;

[00171]The Examples and their manufacturing processes are representative and for illustration purposes. It is possible for a personal skilled in the art to modify the process or change in active agent to accommodate other similar products and the invention encompasses such changes.

EXAMPLE 35: AXOMADOL-SUMTRIPTAN COMBINATION

[00172] This Example discloses a pharmaceutical composition which can effectively be used in the treatment of pain and pain related diseases wherein the compositions comprise a therapeutically effective amount of axomadol and at least one pharmaceutically acceptable excipient and Sumatriptan Succinate The tablet was prepared as per formula in Table 35;

MANUFACTURING PROCESS: [00173] Preparation of Layer 1 : Sumatriptan Succinate, microcrystalline cellulose and colloidal silicon dioxide were granulated with polyvinyl alcohol and dried. The dried granules are mixed with Ethyl

Cellulose and Hydroxyethylcellulose and lubricated with Sodium stearyl fumarate.

[00174] Preparation of Layer 2: Axomadol mixed with microcrystalline cellulose was granulated with povidone. Granules are dried and mixed with Croscarmellose sodium and finally lubricated with

Magnesium stearate.

[00175] Compression: Layer 1 and Layer 2 are loaded into the hopper of Bilayer rotary compression machine and compressed with a desired hardness.

EXAMPLE 36;

* Removed during the process

EXAMPLE 37; AXOMADOL-MEMANTINE COMBINATION;

TABLE 37

* Removed during the process

MANUFACTURING PROCESS:

[00176] Core Preparation; Memantine HCl and colloidal silicon dioxide were mixed and passed through a 1.0 mm screen. Polyvinyl alcohol was dissolved in purified water. The mixed memantine HCl and colloidal silicon dioxide powder was granulated with the aqueous solution of polyvinyl alcohol in a fluidized bed granulator, Glatt GPCGl and then dried. After granulation, the granules were blended with sodium stearyl fiimarate and then passed through a 1.0 mm screen. The blend was then compressed into tablet cores using a Manesty Betapress.

[00177] Coating Preparation; The ethyl alcohol and isopropanol were weighed and mixed. Dibutyl sebacate and ethylcellulose were added to and dissolved in the ethyl alcohol and isopropyl alcohol while stirring using a propeller stirrer, Coframo RZRl . The ethylcellulose and dibutyl sebacate were allowed to dissolve completely. The polyvinylpyrrolidone was added. The solution was stirred until all components were dissolved. The solution was passed through a high pressure homogenizer, Mini DeBee 2000 with #7 nozzles, Bee International. The tablet cores were coated using the coating solution in a perforated coating pan, O'Hara Labcoat Il 1 36" Pan, Vector LCDS. The coating parameters are listed in Table 38;

Axomadol was coated over the coated tablets cores using standard manufacturing process known in the art. Table 38

[00178] Example 38-42 of this invention disclose a pharmaceutical composition which can effectively be used in the treatment of pain and pain related diseases wherein the compositions comprise a

therapeutically effective amount of Axomadol and at least one pharmaceutically acceptable excipient and either Pregabalin or Gabapentin or Famotidine or Pentaprazole or Esomeprazole or Omeprazole according the formulas disclosed in the Tables 39-44. These combinations can be manufacturing according standard manufacturing methods known in art.

EXAMPLE 38: AXOMADOL-PREGABALBV COMBINATION;

TABLE 39

EXAMPLE 38 B: AXOMADOL-PREGABALEV COMBINATION;

TABLE 39B

Opadry Clear (YS 1-7006)

EXAMPLE 39-AXOMADOL-GABAPENTBV COMBINATION;

Table 40

MANUFACTURING PROCESS:

[00179] The slow -release tablet comprising Axomadol and Pregabalin is prepared using a three step process: 1) Granulation, 2) Tabletting and 3) Membrane coating process. An optional Seal Coating may be done on the core tablet. These are described below [00180] Granulation: The Povidone, K-30, and sodium tribasic phosphate are dissolved in purified water. Axomadol is collected in a clean, polyethylene-lined container after it is delumped by passing it through a 40 mesh screen. The delumped Axomadol is then added to a top-spray fluidized bed granulator and granulated by spraying the binding solution of Povidone and sodium tribasic phosphate at an inlet air temperature of 50-70' C, an atom izat ion air pressure of 1-3 bars and a spray rate of 10-100 ml/min. Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 2% and are passed through a comil equipped with the equivalent of an 18 mesh screen.

[00181]Tabletting: The magnesium stearate and Axomadol are thoroughly blended together, after passing magnesium stearate through a 40 mesh stainless steel screen, for approximately five (5) minutes.

Following this, the granules are compressed on a rotary press fitted with {fraction (15/32)" round standard concave punches. As stated, the orifice may be formed by any means commonly employed in the pharmaceutical industry.

[00182] Seal Coating (Optional): Optionally the seal coating of the tablet can be done by first dissolving the Opadry material, preferably Opadry Clear, in purified water and spraying the Opadry solution onto the core tablet using a pan coater at an exhaust air temperature of 38-42' C degree, an atomization pressure of 28-40 psi and a spay rate of 10-15 ml/min. The core tablet is coated with the sealing solution until a theoretical coating level of approximately 2-4% is obtained.

[00183] Membrane Coating Process: A homogenizer was used for dissolving the cellulose acetate is dissolved in acetone. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear membrane coating solution is then sprayed onto the seal coated tablets using a fluidized bed coater employing the following conditions: product temperature of 16-22'C, atomization pressure of approximately 3 bars and spray rate of 120-150 ml/min. The sealed core tablet is coated until a theoretical coating level of approximately 3% is obtained. Tween 80 and hydroxypropyl methylcellulose are dissolved in purified water. Pregabalin is then dispersed into this solution. The resulting suspension is then sprayed onto the above-membrane-coated tablets.

EXAMPLE 40-AXOMADOL-FAMOTIDINE COMBINATION;

Table 41

mg/tablets

Axomadol 100

Famotidine 20

HPMC 33

Magnesium Stearate 7

EXAMPLE 41-AXOMADOL-PANTAPRAZOLE COMBINATION;

Table 42

EXAMPLE 42- AXOMADOL- ESOMEPRAZOLE COMBINATION;

Table 43

EXAMPLE 43-AXOMADOL-NAPROXCINOID COMBINATION

[00184] In yet another example, the invention discloses a slow release dosage form which can effectively be used in the treatment of pain and pain related diseases wherein the dosage forms comprise a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one form of naproxcinod. The tablet was prepared as exemplified in Table 44;

MANUFACTURING PROCESS:

[00185] Preparation of Layer 1: Axomadol, microcrystalline cellulose and colloidal silicon dioxide were granulated with polyvinyl alcohol and dried. The dried granules are mixed with Ethylcellulose and

Hydroxyethylcellulose and lubricated with Sodium stearyl fiimarate.

[00186] Preparation of Layer 2: Naproxcinod is mixed with microcrystalline cellulose was granulated with povidone. Granules are dried and mixed with Croscarmellose sodium and finally lubricated with

Magnesium stearate.

[00187] Compression: Layer 1 and Layer 2 are loaded into the hopper of bilayer rotary compression machine and compressed into a tablet comprising axomadol and naproxcinod with a desired hardness.

EXAMPLE 44- AXOMADOL-NAPROXEN COMBINATION;

[00188] In yet another example, the invention discloses a slow release dosage form which can effectively be used in the treatment of pain and pain related diseases wherein the dosage forms comprise a therapeutically effective amount of at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one form of naproxen. The tablet was prepared as exemplified in Table 45 and was manufactured according to the process described for Example 43;

Magnesium stearate 0.5 -2%

EXAMPLE 45-AXOMADOL-ATOMOXETBVE COMBINATION;

[00189] The tablet was prepared as exemplified in Table 46 and was manufactured according to the process described for Example 43;

Table 46

EXAMPLE 46-AXOMADOL-RIVASTIGMINE COMBINATION:

DISSOLUTION STUDIES:

[00190] The tablets comprising slow release axomadol and at least one pharmaceutical excipient, formulated according Examples 1-3 were evaluated for dissolution profiles with an apparatus USP basket of 10 mesh as per following conditions Table 48;

[00191] The composition of instant invention exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37.degree. C.) such that after 2 hours, from about 0% up to about 30% (by weight) of axomadol is released, after 4 hours, from about 5% to about 55% (by weight) of axomadol is released, after 12 hours, more than about 50% (by weight) of axomadol is released, and after 24 hours, more than about 80% (by weight) of axomadol is released.

[00192] Still further, the composition of instant invention exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37' C.) such that after 2 hours, from about 0% up to about 30% (by weight) of axomadol is released, after 4 hours, from about 5% to about 22% (by weight) of axomadol is released, after 6 hours, from about 15% to about 38% (by weight) of the axomadol is released, after 8 hours, more than about 40% (by weight) of axomadol is released.

[00193] Further, the composition of instant invention exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37' C.) such that after 2 hours, from about 2% to about 10% of axomadol is released, after 4 hours, from about 12% to about 20% of axomadol is released, after 6 hours, from about 30% to about 38% of axomadol is released, after 8 hours, from about 48% to about 56% of axomadol is released, after 10 hours, from about 64% to about 72% of axomadol is released, and after 12 hours, more than about 76% of axomadol is released.

[00194] Table 49 provides the dissolution data of the three Examples 1, 2 and 3;

Dissolution Profile of Examples 1, 2 and 3 TABLE 49

[00195] FIGURE 2 is the dissolution profile of a slow release Axomadol dosage form according to Examples 6.

[00196] The dissolution studies of Example 10-12 were carried out using Ph. Eur. Paddle Method 100 rpm, in 900 ml 0.1 N hydrochloric acid at 37'C. and using UV detection at 270 nm and the in vitro dissolution of axomadol are in Table 51;

TABLE 51

[00197] The present inventor found that in order to achieve a slow release profile of axomadol over at least a twelve hour period following the administration of drug, the in vitro release rate preferably corresponds to the following rate of axomadol released; between 0 and 50% axomadol released after 1 hour; between 0 and 75% axomadol released after 2 hours; between 3 and 95% axomadol released after 4 hours; between 10 and 100% axomadol released after 8 hours; between 20 and 100% axomadol released after 12 hours; between 30 and 100% axomadol released after 16 hours; between 50 and 100% axomadol released after 24 hours; and greater than 80% axomadol released after 36 hours, by weight. [00198] Another preferred preparation especially suited for twice-a-day dosing has an in vitro release rate corresponding to the following % rate of axomadol released: between 20 and 50% axomadol released after 1 hour; between 40 and 75% axomadol released after 2 hours; between 60 and 95% axomadol released after 4 hours; between 80 and 100% axomadol released after 8 hours; between 90 and 100% axomadol released after 12 hours; by weight

[00199] Yet another preferred preparation particularly suited for once-a-day dosing has an in-vitro release rate corresponding to the following % rate of axomadol released:

between 0 and 50% axomadol released after 1 hour, between 0 and 75% axomadol released after 2 hours; between 10 and 95% axomadol released after 4 hours; between 35 and 100% axomadol released after 8 hours; between 55 and 100% axomadol released after 12 hours; between 70 and 100% axomadol released after 16 hours; greater than 90% axomadol released after 24 hours, by weight

[00200] A still further preferred preparation in accordance with the invention also particularly suited for once-a-day dosing has an in vitro release rate corresponding to the following % rate if; between 0 and

30% axomadol released after 1 hour, between 0 and 40% axomadol released after 2 hours; between 3 and

55% axomadol released after 4 hours; between 10 and 65% axomadol released after 8 hours; between 20 and 75% axomadol released after 12 hours; between 30 and 88% axomadol released after 16 hours; between 50 and 100% axomadol released after 24 hours, greater than 80% axomadol released after 36 hours, by weight

[00201] More preferably a preparation for once-a-day dosing has an in vitro release rate substantially as follows: between 15 and 25% axomadol released after 1 hour; between 25 and 35% axomadol released after 2 hours; between 30 and 45% axomadol released after 4 hours; between 40 and 60% axomadol released after 8 hours; between 55 and 70% axomadol released after 12 hours; between 60 and 75% axomadol released after 16 hours; by weight.

[00202] The release profile can be modified in a number of ways; 1 ) loading of the drug will be associated with increased release rates; 2) the use of larger proportions of the water soluble fusible material in the particles or surface active agent in the tabletting formulation will also be associated with a higher release rate of the active ingredient and, 3) by controlling the relative amounts of these ingredients it is possible to adjust the release profile of the axomadol or a salt thereof.

[00203] The Examples 13-18 were prepared by preparing different particle sizes and they were subjected to in vitro dissolution test using Ph. Eur. Paddle Method 100 rpm, in 900 ml 0.1 N hydrochloric acid at 37'C, using UV detection at 270 nm. The results are in Tables 53 and 54.

TABLE 52

Table 53

[00204] The Reference Example 1 at least one form of axomadol was evaluated for dissolution profile using a method as per U.S. Pharmacopoeia XXII Paddle Method in phosphate buffer at pH7.4 and at 50 rpm, the dissolution rate for the final tablets was as follows in Table 55

Table 55

Reference Example

1

Percent of

Time Axomadol

0.5 44

1 73

METHOD OF ADMINISTRATION;

[00205] The present inventions further include a method of treating pain and pain related conditions. This was established using four well controlled human clinical trials for one slow release Axomadol dosage form (Example 10) and three different combinations Examples 36, 38 and 43. A typical study determined the efficacy of either a slow release dosage form of Axomadol compared to that of an Immediate Release dosage form (Reference Example 2) or that of a combination in comparison with monotherapy with respective drugs. The fixed dose combination comprising Axomadol and Sumatriptan (Example 36), a combination comprising Axomadol and Pregabalin (Example 38), a combination comprising Axomadol and Naproxen (Example 44). Each of these combinations was compared against monotherapy with the respective drugs for the treatment of pain and pain related conditions in patients.

CLINICAL TRIAL I:

[00206] The study was done to evaluate the pain relief and safety of a slow release dosage form (Example

10) that is suitable for once or twice daily administration in comparison with Reference Example 2. The study compared 2 Axomadol doses with Reference Example 2 in patients with moderate or severe pain following bunionectomy surgery.

[00207] Study Type: Interventional

[00208] Study Design: Allocation: Randomized

[00209] Endpoint Classification: Safety/Efficacy Study

[00210] Intervention Model: Parallel Assignment

[0021 l]Masking: Double Blind (Subject, Investigator)

[00212] Primary Purpose: Treatment

[00213] Primary Outcome Measures:

[00214] Patient's Global Evaluation of Study Medication [ Time Frame: Day 2 and Day 3 ] [ Designated as safety issue: No ]

[00215] Summed Pain Intensity (SPI) (categorical) through 24 hours [Time Frame: Day 2 and Day 3 ] [

Designated as safety issue: No ]

[00216] Inclusion Criteria: [00217] Patients who underwent an uncomplicated primary unilateral first metatarsal bunionectomy surgery (with or without ipsi lateral hammer to repair) who required open manipulation of bone with periosteal evaluation under general anesthesia (Mayo block)

[00218] Patients with a baseline pain intensity (VAS) of greater than or equal to 45 mm

[00219] Patients with a baseline pain intensity (categorical) of moderate or severe

[00220] Exclusion Criteria:

[00221] Patients scheduled to undergo other surgical procedures that would be expected to produce a greater degree of surgical trauma than the orthopedic procedure alone

[00222] Treatment with patient-controlled analgesia (PCA) subsequent to the end of anesthesia

[00223] Long-acting local anesthetics or local anesthetics co-administered with epinephrine injected into the index joint space

[00224] Use of tricyclic antidepressants, tranquilizers, neuroleptics, neuroleptic antiemetics, COX-2 inhibitors, NSAIDs, and corticosteroids

[00225] Use of NSAID or analgesia after midnight the night prior to surgery or unwilling to abstain from

NSAIDs or other analgesics, except as specified in the protocol, during the study

[00226] Arm 1: Active Comparator- Axomadol 100 mg tablet (Example 10) by mouth followed by

Axomadol 100 mg tablet (Example 10) by mouth after 1 to 12 hours of the initial dose on Day 1 then

Axomadol 100 mg tablet (Example 10) by mouth once daily on Days 2 through 5.

[00227] Arm 2: Active Comparator- Axomadol 100 mg tablet (Reference Example 2) by mouth followed by an Axomadol 100 mg tablet (Reference Example 2) by mouth after 1 to 12 hours of the initial dose on

Day 1 then an Axomadol 100 mg tablet (Reference Example 2) by mouth once daily on Days 2 through 5.

Results

[00228] The objectives of the inventions are met for the slow release axomadol (Example 10) produced statistically significant and clinically meaningful reductions, faster compared to the Reference Example 2, for the primary efficacy variable in pain intensity associated with surgery. We considered that a clinically significant benefit of using Slow Release Axomadol (Example 10) would be a reduction in the pain score

(VAS) of at least 15 % less compared to the other treatment. Overall adverse effects for Axomadol 100 mg (Example 10) were not different from those with Reference Example 2.

CLINICAL TRIAL U:

[00229] The study was of double-blind, randomized, placebo-controlled, and two-period cross-over design. After a 2-week run-in period, 44 diabetic patients (22 men, 22 women with type 2 diabetes, age [mean ± SE] 59.3 ± 2.2 years, duration of diabetes 9.1 ± 2.5 years, duration of painful neuropathy 2.8 ± 0.6 years) were randomized to receive either placebo or Axomadol 50 mg (Reference Example 1) mg or pregabalin 250 mg or slow release Axomadol 50 mg + pregabalin 250 mg (Example 38) FDC for 4 weeks Biweekly pain and other sensory symptoms were assessed using a visual analog scale (VAS). The patient characteristics are shown in Table 56.

TABLE 56

*Data are n or means, SE. Age Range; "f HbA Ic Reference Range 4.2-5.9%.

[00230] Each patient had long history of difficult-to treat painful neuropathy and had tried various drugs such as acetaminophen, duloxetine, amitriptyline or gabapentin and had discontinued because the symptoms were unresponsive or due to unacceptable side effects. Eligible subjects included type 1 and type 2 diabetic patients not on any other medications for their neuropathic pain and with stable diabetic control. Exclusion criteria included erratic glycemic control, peripheral vascular disease (PVD) with absent foot pulses, presence of active foot ulceration, treatment with sublingual glyceryl trinitrate, patients on erectile dysfunction drugs, factors affecting the patient's evaluation of pain, and the presence of other causes of peripheral neuropathies. No major changes made for diabetes treatment during the duration of the study.

[00231] Patients were assessed neurological Iy at the beginning of the run in period after which, the patients were randomly allocated to receive the placebo or Axomadol 250 mg or pregabalin 250 mg or Axomadol 250 mg + pregabalin 250 mg FDC for 4 weeks. A 10-cm visual analog scale (VAS) was recorded biweekly by the patients for pain, where 0 means no pain at all and 10 means the most severe pain ever experienced. The treatment effect was defined to be the difference between the final score and the baseline score on the Likert scale for each treatment phase. [00232] The objectives of the inventions are met for the fixed dose combination comprising axomadol and pregabalin produced statistically significant and clinically meaningful reductions, compared to the monotherapy using either axomadol or pregabalin, for the primary efficacy variable in pain intensity associated with diabetic neuropathy. We considered that a clinically significant benefit of using fixed dose axomadol and pregabalin/gabapentin would be a reduction in the pain score (VAS) of at least 15 % compared to the other treatment.

CLINICAL TRIAL IH:

[00233] An adult female migraineur complains of a migraine attack with typical symptoms: headache, nausea and sensitivity to light and sound. She is administered a single oral tablet containing Example 35; Fixed Dose Combination of Axomadol (50 mg) and Sumatriptan (50 mg) Combination. Her symptoms start to diminish within one hour and, by three hours, she is completely symptom free. No relapse over the next 48 hours is reported.

[00234] An adult female migraineur complains of a migraine attack with typical symptoms: migraine headache, nausea and sensitivity to light and sound. She is administered a single oral tablet containing Example 35; Fixed Dose Combination of Axomadol (50 mg) and Sumatriptan (50 mg). Her symptoms start to diminish within one hour. By three hours, she is completely symptom free and has no relapse over the next 48 hours.

[00235] The same symptoms as in the patients of above are presented by a male, 25 years of age. Upon oral administration of a single tablet Example 35 Fixed Dose Combination of Axomadol (50 mg) and Sumatriptan (50 mg) and the same result is obtained.

CLINICAL TRAIL IV:

[00236] Trial Type

[00237] The study design determined the efficacy of a fixed dose combination of Axomadol and

Naproxen in comparison against monotherapy with naproxen and Axomadol for the treatment of pain and pain related conditions

[00238] Drugs:

[00239] Fixed Dose Combination of Axomadol 50 mg +Naproxen 250 mg (Example 44), Axomadol 50 mg (Reference Example 1), Naproxen 250 mg

[00240] Treatment Arms [00241] Treatment A; Fixed Dose Combination of Axomadol 50 mg +Naproxen 250 mg (Example 44,

Study Drug)

[00242] Treatment B: Axomadol 50 mg (Reference Example 1, Comparator)

[00243] Treatment C: Naproxen 250 mg

[00244] Patients:

[00245] 35 patients were used in a clinical trial were suffering from Chronic non-cancer pain (CNCP), defined as pain for longer than 6 months, including neuropathic pain, osteoarthritis, rheumatoid arthritis, fibromyalgia, and back and musculoskeletal pain were included in the clinical trial.

[00246] Those patients with migraines, dental pain, abdominal pains (from chronic pancreatitis, kidney stones, etc.) and ischemic pain from vascular disease were excluded because they are usually not classified as CNCP. Patients with history of addiction (alcohol or drugs) were excluded from the trials.

[00247] Randomization:

[00248] Randomization was performed with computer-generated random numbers in blocks of 10.

Randomization codes of the Study Drug or Comparator treatments were placed in sequentially numbered, opaque, sealed envelopes in the biopsy center. When a patient was recruited and consented, the next numbered envelope was opened by the operator, who had no knowledge of the randomization code before the treatment.

[00249] Side Effects:

[00250] There were 6 side effects that occurred significantly more often among those taking axomadol than those in the placebo groups: constipation (RD 16%, 95% CI 10%-22%); nausea (RD 15% (1 1%-

19%); dizziness or vertigo (RD 8% (5%-12%); somnolence or drowsiness (RD 9% (5%-13%); vomiting

(RD 5% (2%-7%); and dry skin, itching or pruritus (RD 4% (l%-6%). Risk differences for the other side effects noted (diarrhea, appetite loss, abdominal pain, dry mouth, headache, fatigue, blurred vision or accommodation disturbance, sleeplessness or insomnia, confusion, and sweating) were all statistically non-significant. There was no difference in the extent of side effects between the Study Drug (Example

44) and Comparator Drug (Reference Example 1).

[00251] Compared with the Study Drug (Example 44) used in the clinical trial, only three side effects occurred significantly more frequently with Comparator Drug (Reference Example 1): the RD for nausea was 14% (95% CI 4%-25%); constipation, 9% (1%-17%); and somnolence or drowsiness, 6% (0-11%).

However one side effect, diarrhea (RD -2%, 95% CI -3% to 0), occurred less often with axomadol than with other drugs. Risk differences for the other 12 side effects (vomiting, dizziness, dry skin, loss of appetite, abdominal pain, dry mouth, headache, fatigue, vision disturbance, insomnia, confusion and sweating) were not statistically significant. [00252] Scale and Measurement:

[00253] Pain was assessed using a visual analogue scale (VAS) graded from 0-100 mm. Pain scoring was performed every three hours after drug administration for a total of 24 hours. The patients were taught with a standard method by the physician how to use a VAS scoring from 0 to 100 mm to grade the intensity of pain experienced during the treatment. On that scale, the left endpoint, 0, was defined as no pain and the right endpoint 100, as the worst pain the patient could imagine. There were no further marks on the line. The intensity of pain was indicated by the distance in millimeters from the left end. Patients were asked to grade the pain intensity immediately after the administration of drugs and every three hour after for 24 hours by drawing a vertical line over each VAS line. The doctors who prescribed the medicines obtained all the VAS forms for that specific patient.

[00254] Statistical Analysis

[00255] Data are expressed as means ± SD. Differences in VAS were analyzed with use of the unpaired Student t test and differences in pain score reductions between the two groups were analyzed with use of the Mann- Whitney U test for the median difference. Similar statistical tests were used for between group comparisons of other outcome variables as appropriate. A two tailed P value of less than. 0.5 was considered to demonstrate statistical significance. SAS software was used for the statistical analysis.

[00256] We considered that a clinically significant benefit of using Reference Example 1 and Axomadol and Naproxen (Example 44) would be a reduction in the pain score (VAS) of at least 15% compared to the Comparator.

VAS PAIN SCORE

Claims

CLAIMS We claim:

1. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once or twice daily oral administration.

2. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once or twice daily oral administration and provides equivalent clinical effect to an immediate release form of same dosage.

3. A slow release dosage form of claim 1 or 2 wherein the slow release is either delayed release or extended release or controlled release or modified released or prolonged release form.

4. A pharmaceutical dosage form for treating a disorder wherein the dosage form comprises a

therapeutically effective amount at least one form of Axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump

Inhibitor.

5. A method of treating a disorder in a human by administering a slow release dosage form

comprising at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form is suitable for once or twice daily oral administration.

6. A method of treating a disorder in a human by administering of a dosage form comprising a

therapeutically effective amount at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor for treating a patient in need thereof.

7. A dosage form of claim 4 wherein the antiepileptic is aminobutyric acid, beclamide,

barbexaclone, brivaracetam, clonazepam, carbamazepine, ethotoin, ethadione, ethosuximide, eslicarbazepine, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, lacosamide, mephenytoin, methylphenobarbital, metharbital, mesuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, paramethadione, phenacemidβ, pheneturide, phensuximide, pregabalin, progabide rufinamide, selectracetam, stiripentol, sultiame, topiramate, trimethadione, tiagabine, valproic acid, amino(diphenylhydantoin) valeric acid, valpromide, vigabatrin and zonisamide.

8. A dosage form of claim 4 wherein the NSAID is Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin, Indomethacin, Sulindac, Etodolac, Diclofenac, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib.

9. A dosage form of claim 4 wherein the opiate is endorphin, enkephalin, dynorphin, and

endomorphin, alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, buprenoφhine, butoφhanol, clonitazene, codeine, desomoφhine, dextromoramide, dezocine, diampromide, diamoφhone, dihydrocodeine, dihydromoφhine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,

ethylmethylthiambutene, ethylmoφhine, etonitazene, faxeladol, fentanyl, heroin, hydrocodone, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levoφhanol,

levophenacylmoφhan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moφhine, myrophine, narceine, nicomoφhine, norlevoφhanol, normethadone, naloφhine, nalbuphene, normoφhine, noφipanone, opium, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomoφhan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tapentadol, and, tramadol, mixtures or salts of any of the foregoing,.

10. A dosage form of claim 4 wherein the 5-HT agonist is sumatriptan, rizatriptan, naratriptan,

zolmitriptan, eletriptan, almotriptan, and frovatriptan.

11. A dosage form of claim 4 wherein the proton pump inhibitor is Omeprazole, Lansoprazole,

Esomeprazole, Pantoprazole and Rabeprazole

12. A dosage form of claim 4 wherein the antiepileptic agent is selected from the group consisting of phenytoin, fosphenytoin, carbamazepine, valproic acid, felbamate, lamotrigine, topiramate, ethosuximide, clonazepam, diazepam, phenobarbital, mephobarbital, metharbital, primidone, levetiracetam, zonisamide, vigabatrin, gabapentin, tiagabine, clobazam, clorazepate, nitrazepam, lorazepam, methsuximide, phensuximide, ethotoin, mephenytoin, valproate, ethadione, paramethadione, trimethadione, oxcarbazepine, acetazolamide, igmesine, phenacemide, pheneturide, pregabalin, progabalin, ralitoline, remacemide hydrochloride, and rufϊnamide, or is an isomer, a pharmaceutical acceptable salt, ester, or prodrug thereof.

13. A dosage form of claim 4 wherein the NMDA receptor antagonist Amantadine,

Dextromethorphan, Dextrorphan, Ketamine, Ketobemidone, Memantine, Methadone, Nitrous oxide, Phencyclidine and Rilutek.

14. A dosage form of claim 4 wherein the said Serotonin Reuptake Inhibitor is venlafaxine,

duloxetine, milnacipran and desvenlafaxine.

15. A dosage form of claim 4 wherein the acetylcholinesterase inhibitor is Metrifonate,

Physostigmine, Neostigmine, Pyridostigmine, Ambenonium, Demarcarium, Rivastigmine, Galantamine, Donepezil, Tacrine, Edrophonium, Huperzine A, Ladostigil and Ungeremine

16. A dosage forms of claim 4 wherein the Norepinephrine Reuptake Inhibitor is atomoxetine,

mazindol, viloxazine and reboxetine.

17. A pharmaceutical kit comprising at least one form of axomadol and a second active agent,

wherein the second active agent is selected from a group consisting acetaminophen, an NSAID, an Opioid, an Antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N- methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor.

18. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released when measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37' C, such that after 2 hours, from about 0% up to about 30% (by weight) of axomadol is released, after 4 hours, from about 5% to about 55% (by weight) of axomadol is released, after 12 hours, more than about 50% (by weight) of axomadol is released, and after 24 hours, more than about 80% (by weight) of axomadol is released.

19. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released when measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37' C, such that after 2 hours, from about 0% up to about 30% (by weight) of axomadol is released, after 4 hours; from about 5% to about 22% (by weight) of axomadol is released, after 6 hours, from about 15% to about 38% (by weight) of the axomadol is released, after 8 hours, more than about 40% (by weight) of axomadol is released.

20. A slow release dosage form comprising at least one form of axomadol and at least one pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released when measured using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCI at 37' C.) such that after 2 hours, from about 2% to about 10% of axomadol is released, after 4 hours, from about 12% to about 20% of axomadol is released, after 6 hours, from about 30% to about 38% of axomadol is released, after 8 hours, from about 48% to about 56% of axomadol is released, after 10 hours, from about 64% to about 72% of axomadol is released, and after 12 hours, more than about 76% of axomadol is released.

21. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released when measured in vitro in a type 1 dissolution basket apparatus according to U.S. Pharmacopoeia XXI in phosphate buffer at pH 7.2 and at 75 rpm: from 0 to 50% of the total naproxen is released after 1 hour of measurement in said apparatus; from 20 to 70% of the total axomadol is released after 2 hours of measurement in said apparatus; and not less than 50% of the total axomadol is released after a total of 4 hours of measurement in said apparatus.

22. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released; between 0 and 50% axomadol released after 1 hour; between 0 and 75% axomadol released after 2 hours; between 3 and 95% axomadol released after 4 hours; between 10 and 100% axomadol released after 8 hours; between 20 and 100% axomadol released after 12 hours; between 30 and 100% axomadol released after 16 hours; between 50 and 100% axomadol released after 24 hours; and greater than 80% axomadol released after 36 hours, by weight.

23. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released: between 20 and 50% axomadol released after 1 hour; between 40 and 75% axomadol released after 2 hours; between 60 and 95% axomadol released after 4 hours; between 80 and 100% axomadol released after 8 hours; between 90 and 100% axomadol released after 12 hours; by weight.

24. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released: between 0 and 50% axomadol released after 1 hour; between 0 and 75% axomadol released after 2 hours; between 10 and 95% axomadol released after 4 hours; between 35 and 100% axomadol released after 8 hours; between 55 and 100% axomadol released after 12 hours; between 70 and 100% axomadol released after 16 hours; greater than 90% axomadol released after 24 hours, by weight.

25. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released;; between 0 and 30% axomadol released after 1 hour; between 0 and 40% axomadol released after 2 hours; between 3 and 55% axomadol released after 4 hours; between 10 and 65% axomadol released after 8 hours; between 20 and 75% axomadol released after 12 hours; between 30 and 88% axomadol released after 16 hours; between 50 and 100% axomadol released after 24 hours, greater than 80% axomadol released after 36 hours, by weight.

26. A slow release dosage form comprising at least one form of axomadol and at least one

pharmaceutically acceptable excipient, wherein the said dosage form exhibits the following rate of axomadol released: between 15 and 25% axomadol released after 1 hour; between 25 and 35% axomadol released after 2 hours; between 30 and 45% axomadol released after 4 hours; between 40 and 60% axomadol released after 8 hours; between 55 and 70% axomadol released after 12 hours; between 60 and 75% axomadol released after 16 hours; by weight.

27. A dosage form of claim 4, wherein the axomadol is used in sub-optimal amount.

28. A dosage form of claim 4, wherein the said second active agent is used in sub-optimal amount.

29. A dosage form of claim 4, wherein axomadol and the said second active agent are used in sub- optimal amount.

30. A pharmaceutical dosage form for treating a disorder wherein the dosage form comprises a

therapeutically effective amount at least one form of Axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting of acetaminophen, an NSAID, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor, wherein at least one of active agents is in slow release form.

31. Use of a pharmaceutical dosage form comprising a therapeutically effective amount at least one form of axomadol and at least one pharmaceutically acceptable excipient and at least one second active agent, wherein the second active agent is selected from a group consisting of

acetaminophen, an NSAED, an Opioid, an antiepileptic, a Norepinephrine Reuptake Inhibitor, a Serotonin Norepinephrine reuptake inhibitor (SNRl), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, NMDA (N-methyl-D-aspartic acid) Receptor antagonist, an Acetylcholinesterase inhibitor, a HT Agonist and a Proton Pump Inhibitor.

32. A method of claim 6 wherein the disorder is pain and pain related conditions, down's syndrome, beta-amyloidal angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, mild cognitive impairment, Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, depression, schizophrenia, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration, gastritis, peptic ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), acid reflux, eosinophilic esophagitis, inflammatory bowel disease including Crohn's disease, irritable bowel syndrome, infection or trauma to the gastrointestinal tract.