PHARMACEUTICAL COMPOSITIONS FOR TREATING PAIN

Related Applications

This application claims priority under 35 U.S. C. § 119 to U.S. Provisional Application No.:

61/551,376, filed on October 25, 2011, U.S. Provisional Application No.: 61/660,765, filed on June 17, 2012, U.S. Provisional Application No.: 61/619,405, filed on April 2, 2012, and U.S. Provisional Application No.: 61/665,296, filed on June 27, 2012 the disclosures of which are incorporated by reference herein in their entirety.

Field of the Invention

[0001] The present invention provides pharmaceutical compositions, useful treating pain and pain related disorders. The invention further provides, methods for treating pain and pain related disorders using a therapeutically effective amount of the compounds and pharmaceutical compositions disclosed herein.

Background of the Invention

[0002] There are several types of pain. Various pain types include chronic pain, e.g., nociceptive, neuropathic, psychogenic pain, and mixed nociceptive and neuropathic pain.

Examples of these types of pain include, but are not limited to, diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, inflammatory bowel disease (IBD) pain, multiple sclerosis pain, post-operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain and cystitis and vulvar vestibulitis and orchialgia, irritable bowel syndrome, premenstrual syndrome pain, pain resulting from burns or chemical injury or sunburn, and bone injury pain.

[0003] Fibromyalgia (FM) is a chronic pain illness. Symptoms of the disease include muscle aches, pain and stiffness of joints and muscles, soft tissue tenderness, general fatigue, and sleep disturbances. Common sites of this widespread pain include: neck, shoulders, back, pelvic girdle, and hands. The disease and its progression can affect any part of the body. The difficulty with fibromyalgia and pain levels the patient experiences can change over time. Sometime a patient will feel better and sometime a patient can feel worse since the pain waxes and wanes over time.

[0004] Effective treatment options for fibromyalgia, particularly ones that are suitable for long-term use, are very limited. Non-limiting examples of drugs that have been used include, for example, alpha2delta agonists, such as Pregabalin, or gabapentin. However all these medications have reported side effects.

[0005] Another disorder, Irritable bowel disease (IBD) is typically characterized by cramping, abdominal pain, bloating, constipation, and diarrhea. IBD may cause a great deal of discomfort and distress, but it is not believed to cause permanently harm to the intestines or lead to a serious disease, such as cancer. Many patients can control their symptoms with diet, stress management, and prescribed medications. For some patients, however, IBD can be disabling. They may be unable to work, attend social events, or even travel short distances. As many as 20 percent of the adult population, or one in five Americans, have symptoms of IBD, making it one of the most common disorders diagnosed by doctors.

[0006] Treatment options for irritable bowel disease (IBD) are limited. One medication available specifically to treat IBD is alosetron hydrochloride (Lotronex). Lotronex has been re- approved with significant restrictions by the U.S. Food and Drug Administration (FDA) for women with severe IBD who have not responded to conventional therapy and whose primary symptom is diarrhea. However, it is recommended that Lotronex should be used with great caution because it can cause serious side effects such as severe constipation or decreased blood flow to the colon.

[0007] Another type pain is neuropathic pain. It is caused by a primary lesion or dysfunction in the nervous system. Neuropathic pains are divided into peripheral neuropathic pain due to lesion of the peripheral nervous system and central pain following lesions of the central nervous system. Neuropathic pain commonly is described as hot burning, throbbing, shooting, lancinating, stabbing, sharp, cramping, gnawing, aching, heavy, tender, splitting, tiring, exhausting, sickening, fearful, punishing, cruel, icy cold, tingling, pins and needles, intense and itch like. Medical descriptors are allodynia (pain due to a stimulus which does not normally provoke pain), hyperalgesia (an increased response to a stimulus which is normally painful), hyperaesthesia (increased sensitivity to stimulation, excluding the special senses), dysaesthesia (an unpleasant abnormal sensation, whether spontaneous or evoked), hyperpathia (a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold) and neuralgia (pain in the distribution of a nerve or nerves not necessarily of paroxysmal quality). Neuropathic pain may be associated with mood changes, sleep disturbance, fatigue and may have an impact on physical and social functioning. The prevalence of neuropathic pain is estimated to be about 1%.

[0008] The treatment options for neuropathic pain include alpha2delta agonists such as pregabalin, gabapentin, opioids such as morphine, dextromethorphan, and tapentadol etc.

[0009] Compounds of formula I, for example Agomelatine, A, a melatonergic agonist (MTi and MT ₂ receptors) and 5-HT ₂ c antagonist are known for their antidepressant like properties.

A

Agomelatine and similar compounds were disclosed in U.S. Patent No. 5, 194,614 and U.S. Patent No. 5,224,442. The patents disclose several compounds of naphthalene structure including agomelatine, their pharmaceutical compositions and methods for treating a living animal afflicted with treatable disorder of the melatoninergic system. Agomelatine has been reported to re-synchronize circadian rhythms, based on animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It has also been reported to increase noradrenaline and dopamine release specifically in the frontal cortex and has no known influence on the extracellular levels of serotonin and to provide an antidepressant-like effect in animal depression models (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm de-synchronization and in models related to stress and anxiety. In humans, agomelatine has been reported to provide positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Thus, it has been marketed for the treatment of major depressive disorders and reported to have a reduced level of sexual side effects, as well as discontinuation effects, compared to other antidepressants.

Agomelatine can also have beneficial effects on sleep associated with a number of disorders.

[0010] Published reports also indicate that compounds of formula I, for example, agomelatine do not alter daytime vigilance and/or memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without significant modification of Rapid Eye Movement (REM) sleep amount or REM latency. Agomelatine is also reported to induce an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients. Agomelatine has no reported abuse potential as measured in healthy volunteer studies.

[0011] There are no reports of pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, and a therapeutically acceptable amount of one or more of the disclosed compounds, useful for preventing or treating pain and pain related disorders, in a patient need of such treatment. Further, methods for preventing or treating pain and pain related disorders, comprising administering a pharmaceutical composition comprising therapeutically effective amount of two or more of the disclosed compounds have not been reported. A composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically acceptable amount of one or more of the disclosed compounds that provides surprisingly useful clinical benefits is disclosed herein. The instant invention provides a composition having one or more of the disclosed compounds that provides clinical benefits when used to treat patients with pain and pain related disorders.

[0012] Thus, there is a need for high efficacy medications that provide relief for patients with pain and pain related disorders, where the medication has reduced undesirable side effects. Further, there is an unmet medical need for compositions and/or dosage forms for the treatment of pain and pain related disorders that are free from or have limited side effects associated with other pain drugs. Finally, there is a need for clinically superior drugs for the treatment of pain and pain related disorders.

Summary of the Invention

[0013] The present invention provides a method for treating pain or pain related disorders in a mammal in need thereof, comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a naphthalene compound having formula I:

I

wherein R ¹ is substituted or unsubstituted (Ci-Ce)alkyl; R ² is hydrogen or substituted or unsubstituted (Ci-C ₆ )alkyl; and R ³ is hydrogen, substituted or unsubstituted (Ci-C ₆ )alkyl, or substituted or unsubstituted (C3-Cio)cycloalkyl, substituted or unsubstituted (C ₆ -Cio)aryl, substituted or unsubstituted (C7-Ci6)arylalkyl, substituted or unsubstituted (Cs-C^heteroaryl, substituted or unsubstituted (C6-C2i)heteroarylalkyl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted (C6-Ci5)heterocycloalkyl group;

wherein the substituents for the alkyl, aryl, cycloalkyl, or heterocyclic groups include (Ci-C ₆ )alkyl, fluoro, chloro, or bromo; or

pharmaceutically acceptable salts, isomers, or polymorphs thereof, and optionally at least one pharmaceutically acceptable carrier.

[0014] In another aspect, the invention provides a method for treating pain or pain related disorders in a mammal in need thereof, comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising naphthalene compounds having formula I- A,

I-A

wherein, R ¹ is methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl), and R ³ is methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, n-pentyl, t-butyl (1,1- dimethylethyl), or phenyl, or pharmaceutically acceptable salts, isomers, or polymorphs thereof.

[0015] In another aspect, the invention provides a method for treating pain or pain related disorders in a mammal in need thereof, comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising naphthalene compounds having formula I, or I-A, wherein R ¹ is methyl and R ³ is methyl, ethyl, isopropyl, isobutyl or phenyl, or pharmaceutically acceptable salts, isomers, or polymorphs thereof.

[0016] In another aspect, the invention provides a method for preventing or treating pain or pain related disorders in a mammal, comprising administering to said mammal a pharmaceutical composition comprising therapeutically effective amount of a compound of formula I, or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a

pharmaceutically acceptable carrier. Preferably, the mammal is a human.

[0017] In another aspect, the present invention provides a method for the prevention or treatment of pain or pain related disorders, wherein the method comprises administration of a therapeutically effective amount of a compound of formula I, or pharmaceutically acceptable salts, isomers, or polymorphs thereof, to a patient in need thereof. Non-limiting examples of pain that can be prevented or treated include neuropathic pain, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, post-operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain, cystitis, vulvar vestibulitis, orchialgia, irritable bowel syndrome, pre -menstrual syndrome pain, pain resulting from burns, e.g., sunburn, or chemical injury, bone injury pain, and the like. Preferably, the pain can be from neuropathic pain, fibromyalgia, diabetic and peripheral neuropathic pain, rheumatoid arthritis, irritable bowel syndrome, osteoarthritis and the like.

[0018] In another aspect, the invention provides a method for treating of preventing pain or a pain related disorder comprising administering a pharmaceutical composition having a therapeutically effective amount of a compound of formula I, or pharmaceutically acceptable salts thereof. The pain can be from any cause, e.g., neuropathic pain, fibromyalgia, diabetic and peripheral neuropathic pain, rheumatoid arthritis, irritable bowel syndrome, inflammatory bowel disease, osteoarthritis, and the like. [0019] In another aspect, the invention provides a method for management of pain, or pain related disorders, comprising administering to a subject in need thereof, a pharmaceutical composition comprising a compound of formula I, and optionally a pharmaceutically acceptable carrier.

[0020] In another aspect, the invention provides a method for the manufacture of a medicament for the treatment of chronic pain in which the active agent is a pharmacologically acceptable salt of a compound of formula I, or I- A, and optionally a pharmaceutically acceptable carrier. A preferred indication is irritable bowel syndrome. Another preferred indication is fibromyalgia.

[0021] In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of serotonin reuptake inhibitor, or pharmaceutically acceptable salts thereof, for use in medical treatment (for example, treatment of pain, e.g., neuropathic pain or fibromyalgia).

[0022] In another aspect, the invention provides a pharmaceutical composition for use in a method for prevention or treatment of pain or pain related disorders in a mammal; comprising administering to said mammal an effective amount of a comprising a compound having formula I, I- A, or pharmaceutically acceptable salt or ester thereof.

[0023] In another aspect, the invention provides a method for the use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or pharmaceutically acceptable salts, isomers, or polymorphs thereof for the preparation of a medicament for treatment of pain and pain related disorders in a mammalian species (for example, a human).

[0024] In another aspect, the invention provides for the manufacture of a medicament for the treatment of chronic pain comprising a compound of formula I, or a pharmacologically acceptable salt, isomer, or polymorph thereof, for treating pain.

[0025] In another aspect, the invention provides a method for treating or preventing pain or a pain related disorder comprising administering a pharmaceutical composition comprising a compound of formula I, or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier. The pharmaceutical composition is suitable for administration by oral, intravenous, intraarterial, intraperitoneal, intradermal, buccal, transdermal, intrathekal (intrathecal), intramuscular, intranasal, transmucosal, subcutaneous, or rectal routes.

[0026] In another aspect, the invention provides a method for the use of a therapeutically effective amount of a compound of formula I, or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, for the preparation of a medicament for the prevention or treatment of pain or pain related disorders.

[0027] In another aspect, the invention provides a compound having formula I, or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a

pharmaceutically acceptable carrier, for use in a method for the prevention or treatment of pain or pain related disorders in a mammal, and wherein the medicament optionally comprises a solid or liquid carrier, comprising administering to said mammal an effective amount of a said compound or said pharmaceutically acceptable salt or ester thereof. Preferably, the mammal is a human.

[0028] In another aspect, the present invention provides the use of a pharmaceutical composition, as disclosed herein, for the prevention or treatment of pain and pain related disorders.

[0029] In another aspect, the invention provides a titration-dosing regimen for the administration of a compound of formula I, or I- A, to patients. The titration-dosing regimen provides a significant reduction in the occurrence of adverse effects from the introduction of an active agent in a slow release dosing, thus increasing patient compliance and medication tolerability.

[0030] The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0031] Figure 1 illustrates the change on NRS pain score comparing the effect of a compound of formula I (agomelatine), in fibromyalgia patients, with the control group.

[0032] Figure 2 illustrates the weekly trend in change in mean sleep quality score comparing a compound of formula I (agomelatine), in fibromyalgia patients, with the control group. [0033] Figure 3 illustrates the change on NRS pain score comparing the effect of a compound of formula I (agomelatine), in diabetic neuropathic pain patients, with the control group.

[0034] Figure 4 illustrates the weekly trend in change in mean sleep quality score comparing a compound of formula I (agomelatine), in neuropathic pain patients, with the control group.

DETAILED DESCRIPTION

DEFINITIONS

[0035] In describing and claiming the invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred materials and methods are described herein. Each of the following terms has meaning associated with it in this section. Exemplary and preferred values listed below for radicals, substituents, and ranges are for illustrations only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

[0036] The terms "a," "an," "the," "at least one," and "one or more" are used

interchangeably. Thus, for example, a composition that comprises "an" element means one element or more than one element.

[0037] The term "Analgesic" as used herein, means to include any drug used to relieve pain including paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) for example, the salicylates, narcotic drugs for example, morphine, synthetic drugs with narcotic properties for example, tramadol, tapentadol, asimadoline, antiepileptics (e.g., pregabalin, gabapentin) and various others other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; for example, tricyclic antidepressants and

anticonvulsants.

[0038] A disease or disorder is "alleviated" if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.

[0039] A "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

[0040] The terms "medicament", "drug" or "active agent" are used interchangeably, and as used herein are defined to include at least one form of a compound of formula I or I-A; chosen from their respective salts, their respective optically active enantiomers, racemic mixtures thereof, isomers, polymorphs, prodrugs, active metabolites, pharmaceutically acceptable salts thereof, such as, for example, acid addition or base addition salts of the disclosed compounds salts, optically active enantiomers, racemic mixtures thereof, prodrugs, active metabolites, pharmaceutically acceptable salts thereof, such as, for example, acid addition or base addition salts of the disclosed compounds, which can be used to prepare the disclosed pharmaceutical compositions.

[0041] The term "agomelatine" as used herein is defined to mean at least one form of agomelatine chosen from agomelatine salts, polymorphs, prodrugs, active metabolites, pharmaceutically acceptable salts thereof, such as for example, acid addition or base addition salts of agomelatine.

[0042] The term "band range" as used herein, is defined as the difference in in vitro dissolution measurements of the controlled release formulations when comparing the dissolution profile (curve) obtained by the formulation upon completion of the manufacturing of the coated product (prior to storage) and the dissolution profile obtained after the coated product is exposed to accelerated storage conditions, expressed as the change in percent of the active agent released from the coated product at any dissolution time point along the dissolution curves.

[0043] The term "effective amount" as used herein, means an amount sufficient to produce a selected effect. For example, an effective amount of a compound of formula I, and is an amounts that is sufficient in order to relieve the pain symptoms of the patient to be controlled when compared with no treatment.

[0044] The term "therapeutically effective amount" as used herein, means an amount that elicits a biological response in a mammal, including the effect from a suboptimal amount.

[0045] 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.

[0046] 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 purpose 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.

[0047] The term "pain and pain related disorder" as used herein, includes all types of pain, e.g., chronic pain such as nociceptive, neuropathic, psychogenic pain, and mixed category pain (nociceptive and neuropathic components). This terms, pain or pain related disorder, include in particular, but are not limited to, diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, inflammatory bowel disease (IBD) pain, postoperative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, migraine, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain and cystitis and vulvar vestibulitis and orchialgia, irritable bowel disease (IBD), pre-menstrual syndrome pain, pain resulting from burns or chemical injury or sunburn, and bone injury pain.

[0048] Preferably, pain which can be treated includes but is not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain, cancer pain and the like. Non-limiting examples of chronic pain, to be treated by the disclosed compositions is

nociceptive pain. Preferred indications of nociceptive pain are inflammatory and post-operative pain. In another aspect, it is preferred that the chronic pain to be treated is neuropathic pain. Preferred indications of neuropathic pain are neurogenic pain and facial and oral neuralgias.

[0049] Specific examples of pain that can be treated include but are not limited to

inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain, cancer pain, depression, epilepsy, pain comorbid with depression, pain comorbid with epilepsy, epilepsy comorbid with depression and the like. [0050] The terms "slow-release" or "controlled release" are used interchangeably and as used herein, applies to any release from a 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 such as, extended release, delayed release, sustained release, controlled release, timed release, specific release and targeted release, and the like.

[0051] The term "extended release material" as used herein, in an inner solid particulate phase or an 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. The "extended release material" present in the inner solid particulate phase may be the same as or different from the "extended release material" present in the outer solid continuous phase.

[0052] The term "hydrophilic polymers" as used herein, include, but are not limited, to hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium, carboxymethylcellulose, carboxymethylcellulose calcium, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone, carbomer, potassium pectate, potassium pectinate, and the like.

[0053] The term "hydrophobic polymers" as used herein, 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™), and the like.

[0054] Other hydrophobic materials which may be employed in the inner solid particulate phase and/or outer solid continuous phase include, but are not limited, to waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol myristyl alcohol etc; and fatty acid esters such as glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oil, and the like. [0055] The term "candidate for sustained release" as used herein, 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.

[0056] The term "binding agent" as used herein, refers to any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polymethacrylate, polyvinyl alcohol, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents include water-soluble materials such as, for example, 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.

[0057] The term "pharmaceutically acceptable derivative" as used herein, means various pharmaceutical equivalent isomers, enantiomers, complexes, salts, hydrates, polymorphs, esters, and the like, e.g., of agomelatine.

[0058] The term "pharmaceutically-acceptable salt" as used herein, refers to salts that retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesirable. In many cases, the disclosed compounds are capable of forming acid or base salts by virtue of the presence of amino or carboxyl groups or groups similar thereto. The preparation of the salts and suitable acids or bases is known in the art.

[0059] The term "Sleep Disorder" as used herein, means any disorder that affects, or disrupts, sleep. They include any disorder affecting five stages (Stage 1 non-rapid eye movement (NREM) sleep, Stage 2 non-rapid eye movement (NREM) sleep, Stage 3 non-rapid eye movement (NREM) sleep, Stage 4 non-rapid eye movement (NREM) sleep and Rapid Eye Movement (REM) sleep) of sleep.

Pharmaceutical Compositions of the Present Invention

[0060] The present invention provides compositions comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically equivalent salt, isomer, or polymorph thereof, for treating pain and pain related disorders. The disclosed compounds can be formulated for any route of administration (e.g., the formulations described herein) and can be administered in a single dose or multiple doses to a subject in need thereof.

[0061] The active ingredient, for the disclosed method, a compound of formula I, is preferably used in the free amphoteric form. Pharmaceutically acceptable salts that retain the biological effectiveness and properties of the compounds of formula I, and second active agent that are not biologically or otherwise undesirable, can also be used and can show superior bioavailability.

[0062] The pharmaceutical compositions are intended for parenteral, intranasal, topical, oral, buccal, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment. Commonly, the pharmaceutical compositions are administered

parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application at areas affected by pain and pain related disorders.

[0063] In the preparation of pharmaceutical formulations either singly or with an additional therapeutic agent in the form of dosage units for oral administration the agent can be mixed with solid, powdered ingredients, such as lactose, microcrystalline cellulose, maltodextrin, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets such as chewable and oral disintegrating tablets.

[0064] The compounds of formula I, or I-A can be an acid addition salt. 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, fumarate, maleate, butyne-l ,4-dioate, hexyne-l ,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.

[0065] The compounds of formula I, or I-A can be a base addition salt. 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.

[0066] Soft gelatin capsules can be prepared by mixing the active agent and vegetable oil, fat, or other suitable vehicle. Hard gelatin capsules can contain granules of the active agent, alone or in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

[0067] Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, e.g., solutions or suspensions containing about 0.2-20 wt % of the active agent and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations can contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration can also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Methods for Treatment of pain and pain related disorders.

[0068] The present invention provides methods for prevention or treatment of pain and pain related disorders in a patient, by administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or I-A. The disclosed

compositions can be administered to a patient to treat, prevent, ameliorate, inhibit the progression of, or reduce the severity of one or more symptoms of pain and pain related disorders in a human patient.

[0069] Non-limiting examples of pain or pain related disorders that can be treated using the disclosed compositions include: lack of sleep, difficulty in falling asleep, sleep awakenings, disturbed sleep, pain, tingling, numbness, tremors, loss of balance, weakness in one or more limbs, fatigue, muscle spasms, that are associated with pain. The symptoms of pain or pain related disorders, and their resolution during treatment, can be measured by a physician during a physical examination.

[0070] The pharmaceutical compositions, for management of pain and pain related disorders, comprise from about 0.1 mg to about 1500 mg of a compound of formula I (e.g., agomelatine), from about 0.1 mg to about 1500 mg of an antiepileptic and optionally a pharmaceutically acceptable carrier. Preferably, the disclosed pharmaceutical composition comprises from 1 to about 500 mg of a compound of formula I (agomelatine) and from about 5 to about 1000 mg of an antiepileptic. More preferably, the disclosed pharmaceutical composition comprises from 5 to about 100 mg of a compound of formula I (agomelatine) and from about 10 to about 600 mg of an antiepileptic. Most preferably, the disclosed pharmaceutical composition comprises from about 10 to about 50 mg of a compound of formula I (agomelatine) and from about 250 to about 350 mg of pregabalin.

[0071] In another embodiment, the disclosed method comprises administering to a subject in need of relief from pain and pain related disorders, a pharmaceutical composition comprising from about 0.1 mg to about 1500 mg of a compound of formula I (e.g., agomelatine), and optionally a pharmaceutically acceptable carrier. Preferably, the disclosed pharmaceutical composition comprises from about 1 mg to about 500 mg of a compound of formula I

(agomelatine). More preferably, the disclosed pharmaceutical composition comprises from about 5 mg to about 100 mg of a compound of formula I (agomelatine). Most preferably, the disclosed pharmaceutical composition comprises from 10 to about 50 mg of a compound of formula I (agomelatine).

[0072] In the disclosed method, a patient can be administered a dosage form comprising a compound of formula I and optionally an additional therapeutic agents such as, antiepileptic, opioids, NSAIDS, PPAR-alpha agonists to prevent or treat pain or a pain related disorder.

[0073] The disclosed pharmaceutical compositions can be prepared by methods known in the art. Such methods are well known in the art for example in "Remington's Pharmaceutical Sciences", A.R. Gennaro (ed.), 17th edition, Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93. [0074] The active agent (or a portion of active agent) can be present in the disclosed pharmaceutical formulations at least partially in controlled-release form. Moreover, any controlled release/ immediate release combination of the agent can also be present in the disclosed pharmaceutical formulation. For example, a portion of the compound of formula I, can be released from the disclosed formulations with a delay, e.g., if administered orally, rectally or percutaneously. Such formulations are particularly useful for "once-daily" or "twice-daily" preparations, which only have to be taken once a day, or twice a day, respectively. Suitable controlled-release materials are well known to those skilled in the art.

[0075] The disclosed pharmaceutical compositions can be prepared in various forms such as, for example, 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. The compositions can be, for example, a tablet formed from granules, spheroids, pellets, multiparticulates and the like or the granules, spheroids, pellets, multiparticulates can be in pellets

[0076] The disclosed solid pharmaceutical compositions can be tablets, for example, the components of the pharmaceutical composition can be granulated with a pharmaceutical carrier, for example, conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example, water, in order to form a solid composition which can be divided into unit dosage forms such as tablets, or capsules, and the like. The disclosed tablets or capsules prepared can be coated suitably to provide an osmotic delivery system. Non-limiting examples of osmotically driven release systems are, for example, disclosed in U.S. patent no. 4,765,989, U.S. patent no. 4,783,337 and U.S. patent no. 4,612,008.

[0077] The disclosed compositions can be in dosage forms, e.g., coated tablets wherein the coating includes at least one water-insoluble, water permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, and the second active agent. In a preferred form the coating can have at least one water-insoluble, water-permeable film-forming polymer varies from about 20% to about 90% of the coating dry weight, the proportion of the at least one plasticizer varies from about 5% to about 30% of the coating dry weight, and the proportion of the at least one water-soluble polymer varies from about 10% to about 75% of the coat dry weight. [0078] The compound of formula I, or a portion thereof, in the disclosed compositions, can also be incorporated in a matrix. Non- limiting examples of matrices are provided in U.S. patent no. 5,330,761, U.S. Patent No. 5,399,362, U.S. Patent No. 5,472,711 and U.S. Patent No.

5,455,046. The matrix can be any type known to a person skilled the art, that affords slow release active agent over at least about a twelve -hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of an agomelatine or secondary agent within the therapeutically effective ranges. The disclosed composition can preferably use a slow release matrix. Alternatively, normal release matrices having a coating that provides for slow release of the active agents can be used.

[0079] The slow release matrices that can be employed in the disclosed compositions can also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colorants, flavorants, 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 can be used to prepare this composition. Non-limiting examples of lubricants are, e.g., magnesium stearate and sodium stearyl fumarate. Non-limiting examples of binding agents are, e.g., hydroxypropyl methylcellulose, polyvidone and methyl- cellulose. Suitable disintegrating agents include starch, sodium starch glycolate, crospovidone, croscarmellose sodium and the like.

[0080] Alternatively, the composition comprising a compound of formula I, and the second agent, wherein one of the active agents is in slow release form, can 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 can be any suitable pharmaceutically acceptable material that can be combined with the active ingredient to form spheroids.

[0081] The amount of the disclosed pharmaceutical composition to be administered to the patient can vary as is well known to those skilled in the art. Factors such as, for example, the weight of the patient, the route of administration, or the severity of the illness can affect the exact amount administered. Suitable methods of delivering the disclosed composition include, but are not limited to oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal (intrathecal), intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration. [0082] The following Examples are for illustrating the invention related to compositions comprising agomelatine and no intended to limit the scope of the invention. The experimental examples disclose the preparation and use of a composition comprising agomelatine for treating a disorder and are intended to be a way of illustrating but not limiting the invention.

PHARMACOLOGICAL STUDIES

Example 1: Pharmacological Studies for Treatment of Fibromyalgia

[0083] An Exploratory study to test the tolerability and safety of Agomelatine in the treatment of patients with Fibromyalgia was conducted. The study, a double blind design was conducted to assess the efficacy and safety of the disclosed compositions, compared with a placebo for the pain relief and improvements in sleep quality associated with fibromyalgia. The measured change from baseline to end of treatment with respect the single primary endpoint provided a mean pain score from patients' daily pain diaries, as measured by the 11 -point Numerical Rating Scale (NRS). Each day on awakening, patients rated their pain during the previous 24 hours.

[0084] The 3 to 30-day screening phase was followed by a 1-week, single blind, placebo lead-in baseline phase begun at visit 2. Subjects were provided a placebo for 1 week to obtain an evaluation of the baseline variables, including safety measures. At visit 3, the patients were randomized to 1 of 4 treatment groups: 1) agomelatine, 2) placebo, in a 1 : 1 ratio. Assignment to treatment groups was determined by a computer-generated random sequence using an interactive voice response system. The treatment phase was a double blind for 12 weeks. The patients were evaluated Weeks 1, 2, 5, 9, 13 (termination), and 13 (follow up).

[0085] The level of drug(s) administered to the patients was determined by titration. The number of placebo capsules was similarly adjusted to maintain the blinding.

[0086] Sample Size: A total of about 41 patients were enrolled from 48 screened. The design ensured that drugs were administered to at least 15 patients in each arm.

[0087] The patients were both female and male, at least 18 years of age old. All met the

ACR criteria for primary fibromyalgia, had widespread pain for at least 3 months, pain in at least

11 of 18 specific tender point sites, and an average pain score > 4 on an 10-point numeric rating scale (NRS; 0 = "no pain" to 10 = "worst possible pain") during the baseline assessment. All patients reported a score > 40 mm on the 100-mm numeric rating scale (NRS) at visits 1 (screening) and 2 (the placebo lead-in phase).

[0088] The patients were instructed to maintain their normal daily routine and not to alter exercise regimens, and they were allowed to continue stable (e.g., for > 30 days prior to screening) non-pharmacologic therapy, such as physical therapy, massage, chiropractic care, and psychological therapy, through the course of the trial.

[0089] Patients with associated pain from traumatic injury, rheumatic disease or other medical disorders that contributed to the symptoms of fibromyalgia were excluded. In addition, patients who had previously used agomelatine or melatonin unsuccessfully for any reasons were also excluded.

[0090] The patients underwent a one -week of washout period during which all medications were stopped. After the washout period the patients were allowed to continue their original medications and were treated once daily with one of: 1) Agomelatine (25 mg); or 2) a placebo for patients in Control arm.

Measurement Methods

[0091] Primary Measures: The change in pain levels, from baseline to end of treatment, with respect the single primary endpoint was the mean pain score, taken from the patients' daily pain diaries, as measured using the 1 1 -point NRS. Each day on awakening, patients rated their pain during the previous 24 hours. The proportion of responders, defined as patients with a > 30% reduction in mean pain score from baseline to endpoint, was determined as a supplemental measure of the primary efficacy measure, as was weekly mean pain score.

[0092] In addition, the patient's sleep quality and sleep efficacy was measured using actigraph as described under Example 1. The actigraphs and the sleep logs were evaluated in a blinded fashion without prior knowledge of the results of the questionnaires.

[0093] Statistical Analysis: SPSS 10.0 was used for the statistical analysis. A p value of <

0.05 was considered as significant between agomelatine arm and comparator arm.

[0094] Results: Figure 1 is an illustration of the change on NRS pain score comparing the effect of agomelatine, in fibromyalgia patients, with the control groups. [0095] Figure 2 is an illustration of the weekly trend in change in mean sleep quality score comparing the agomelatine in fibromyalgia patients, with the control groups. In summary, agomelatine provides significant benefit in treat fibromyalgia.

Example 2: An Efficacy Study of Agomelatine in Subjects with Neuropathic Pain

Associated with Diabetic Peripheral Neuropathy (DPN).

[0096] Study Design: This was a two-center, interventional, randomized, parallel assignment, double blind design to study the efficacy of agomelatine compared to control with standard first line treatments in patients with neuropathic pain associated with Diabetic

Peripheral Neuropathy (DPN).

[0097] Sample size: 43 patients were screened to achieve a recruitment of 14 patients in each of the two clinical arms. The goal was to ensure at least 10 patients completed the study for the entire duration.

[0098] Patient Selection: A history of pain for at least 24 months and no greater than five years attributed to DPN (Note: this requirement refers to duration of pain, not the duration of polyneuropathy). The patient must have a baseline 24-hour average daily pain intensity score >4.0 as measured on a 10-point pain intensity numerical rating numeric rating scale. The Baseline score is the calculated mean of the daily scores during the 7 days prior to

randomization. (The subject must record at least four assessments of the 24-hour average daily pain intensity score during the seven-day Baseline Period). The patients who used either agomelatine or melatonin for any reason were excluded.

[0099] Primary Efficacy Measures: The first primary efficacy measure was mean Numeric Rating Scale (NRS) from daily pain diaries (11 -point numeric rating scale) from TO until the end of the treatment study.

[00100] The secondary efficacy measure was the mean sleep quality and mean sleep efficacy as measured by actigraph and sleep dairies. Each day on awakening, patients rated their pain during the previous 24 hours. The proportion of responders, defined as patients with a > 30% reduction in mean pain score from baseline to endpoint, was determined as a supplemental measure of the primary efficacy measure, as was weekly mean pain score. The actigraphs and the sleep logs were evaluated in a blinded fashion without prior knowledge of the results of the questionnaires. [00101] The patients underwent a one -week of washout period during which all medications were stopped. After the washout period the patients were allowed to continue their original medications and were treated once daily with one of: 1) Agomelatine (25 mg); 2) a placebo for patients in Control arm.

[00102] Statistical Analysis: SPSS 10.0 was used for the statistical analysis. A p value of < 0.05 was considered as significant between agomelatine arm and comparator arm.

Results:

[00103] Figure 3 illustrates the change on NRS pain score comparing the effect of agomelatine, in fibromyalgia patients, with the control groups. Figure 4 illustrates the weekly trend in change in mean sleep quality score comparing the agomelatine in fibromyalgia patients, with the control groups.

[00104] In summary, agomelatine provides significant benefit in treat neuropathic pain. The compounds of this invention are routinely formulated into dosage forms that could be administered to patients.

Example 3: Injection vials

[00105] A solution of 100 g of a compound of the Formula I (e.g., agomelatine) and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid. The solution is sterile-filtered, filled into injection vials, lyophilized and sterile-sealed. Each injection vial contains about 5 mg of active ingredient.

Example 4: Suppositories

[00106] A mixture of 20 g of a compound of the Formula I (e.g., agomelatine) is melted with 100 g of soya lecithin and 1 ,400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains about 20 mg of the compound of the Formula I.

Example 5: Sterile Solution

[00107] A solution of 1 g of a compound of the Formula I (e.g., agomelatine), 9.38 g of

NaH ₂ P(V2H ₂ 0, 28.48 g of Na ₂ HP0 ₄ "2H ₂ 0 and 0.1 g of benzalkonium chloride is prepared in

940 ml of double-distilled water. The pH is adjusted to 6.8, and the solution is made up 1 :1: 1 with distilled water and sterilized by irradiation. This solution can be used in the form of eye drops. Example 6: Ointment

[00108] A compound of Formula I (e.g., agomelatine), 500 mg, is mixed with 99.5 g of petroleum jelly under aseptic conditions. This provides an ointment with 0.5 % active agent.

Example 7: Tablets

[00109] A mixture of 1 kg of a compound of the Formula I (e.g., agomelatine), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in conventional manner such that each tablet contains about 10 mg of active ingredient.

Example 8: Coated tablets

[00110] Tablets are prepared and formed by compression as described in Example 7 and covered in conventional manner with a coating prepared, e.g., with sucrose, potato starch, talc, tragacanth and colorant.

Example 9: Capsules

[00111] The compound of the Formula I (e.g., agomelatine) 2 kg are filled into hard gelatin capsules in conventional manner so that each capsule contains about 20 mg of the active ingredient. The capsules can also use a composition having optional in active ingredients, such as those used to from the tablets, etc.

Example 10: Ampoules

[00112] A solution of 1 kg of a compound of the Formula I (e.g., agomelatine) in 60 L of double-distilled water is filled into ampoules and lyophilized under aseptic conditions and the ampoules are sealed under sterile conditions. Each ampoule contains about 10 mg of active ingredient.

[00113] It is also noted that compositions including compounds having formula I, disclosed herein, have been shown to be useful in treating pain and pain related disorders in the following applications U.S. Provisional Application No. : 61/551 ,376, filed on October 25, 201 1 ; U.S. Provisional Application No.: 61/660,765, filed on June 17, 2012; U.S. Provisional Application No. : 61/619,405, filed on April 2, 2012; and U.S. Provisional Application No.: 61/665,296, filed on June 27, 2012; and PCT application no.: , filed concurrently herewith, (attorney docket no. 1 1 1-P-026WO01). [00114] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The disclosures of each and every patent, patent application, and publication cited herein are expressly incorporated herein by reference in their entirety into this disclosure. In the case of any inconsistencies, the present disclosure, including any definitions therein will prevail. Illustrative embodiments of this disclosure are discussed and reference has been made to possible variations within the scope of this disclosure. These and other variations and modifications in the disclosure will be apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that this disclosure and the claims shown below are not limited to the illustrative embodiments set forth herein.