TREATMENT OF SEVERE FAIN

PRIORITY jOtiOI ^' l The present application claims the benefit of Indian Provisional Patent Application No. 1854/CHE 2012 filed on j.O-May-2012, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

[0002] This disclosure generally relates to compounds and compositions for the treatment of severe pain. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, esters, stereoisomers, enantiomers, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE I VENTION

[0003] Pain is a subjective experience, influenced by physical, psychological, social, and spiritual factors. The concept of total pain acknowledges the importance of all these dimensions and that good pain rel ief is unlikely without attention to each aspect. Pain and diseases such as cancer are not synonymous: at least two thirds of patients experience pain at some time during the course of their illness, and most will need potent analgesics.

[0004] Opioids are a cornerstone of the management of cancer pain and postoperative pain and are used increasingl for the management of chronic non-cancer pain. Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vital safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity. Chronic pain, such as lower back pain, also occurs in younger persons and is the leading cause of disability in younger than 45 years. In younger patients, physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels.

[0005] Severe pain is associated with pain, injury, inflammation, burning of seasonal allergies, eye pain, itchiness, depression, bipolar disorder are a heterogeneous group of diseases of the nervous system, including the brain, spinal cord, and peripheral nerves that have much different aettology. Many are hereditary; some are secondary ⁷ to toxic or metabolic processes. Free radicals are highly reactive molecules or chemical species capable of independent existence.

[0006] Generation of highly Reactive Oxygen Species (ROS) is an integral feature of normal cellular function like mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. The release of oxygen free radicals has also been reported during the recovery phases from many pathological noxious stimuli to the cerebral tissues. Some of the pain associated neurological disorders include injur} ¹ , post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, depression, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain.

|0007] Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of severe pain.

SUMMARY OF THE INVENTION

{0008 J The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as severe pain. 100091 The invention herein provides compositions comprising of formula 1 or pharmaceutical acceptable salt hydrate, solvate, polymorphs, prodrug, enantiomer, or stereoisomer thereof. The invention also provides pharmaceutica! compositions comprising one or more compounds of formula Ϊ or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of severe pain and its associated complications.

Formul i

[0010] in certain embodiments., the present invention relates to the compounds and compositions of formula 1, or pharmaceutically acceptable salts, hydrate, solvate, prodrug, polymorphs, enantiomer, or stereoisomer thereof.

Formula 1

Wherein, 



o

a is independently 2,3 or 7;

each h is independently 3, 5 or 6;

e is independently L 2 or 6;

c and d are each independently H, D, -OH, -OD, Ci-CValkyl, -NH ₂ or -COCi¾;

n is independently 1, 2, 3, 4 or 5.

iOOl l J In the illustrative embodi ments, examples of compounds of formula 1 are as set forth below:

(1-1 )

(1-2)

[0012J Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of severe pain or its related complications.

[001.3 J The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.

{0014J Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of severe pain or i ts related complications.

[0015] The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from severe pain or its related complications manifested from metabolic conditions, severe diseases or disorders; Hepatol ogy. Cancer, Hematol gical, Orthopedic, Cardiovascular, Renal, Skin, Neurological or Ocular complications. DETAILED DESCRIPTION OF THE INVENTION

Definitions

(0016| As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

J0017 j The compounds of the present invention can foe present in the form of pharmaceutically acceptabie saits. The compounds of the present invention can also he present in the form of pharmaceutically acceptabie esters (i.e., the meihyi and ethyi esters of the acids of formula I to be used as prodrugs). The compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).

(001.8 J Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereorners are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequeneing roles of Cahn, Ingold and Prelog, or b the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively), A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture" {0019] As used herein, the term "metabolic condition" refers to an inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent.

[0020] In some embodiments, a moiecular conjugate comprises of compounds selected from the group consisting of R-lipoic acid (CAS No. 1200-22-2), salsa! ate (CAS No. 552-94-3), acetylcysteine (CAS No. 61 -9! -1), Eicosapentaeiiofc acid (CAS No. 10417- 94-4), Docosahexaenoic acid (CAS No. 6217-54-5).

[0021] The term "polymorph* as used herein is art-recognized and refers to one crystal structure of a given compound.

[0022] The phrases "parenteral administration" and "administered parenterally" as used herei refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intraperi cardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradennai, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

{0023] A "patient," "subject/' or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

{0024] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use i contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. {0025| The phrase "pharmaceutically acceptable carrier ¹ ' is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a. pharmaceutically acceptable carrier is non-pyrogenic Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (1.1) polyols, such as glycerin, sorbitol, nannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyroge -free water; ( 17) isotonic saline; (18) Ringer's solution; ( 1 ) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. 0026] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydroiyzed under physiological conditions to reveal the desired molecule, in other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

10027] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

|002S] The term "predicting" as used herein refers to assessing the probability related diseases patiem will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i .e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention.

|0029] The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as severe pain, such as postoperative, cancer, kidney stones , fractures., nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia, of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment. 100301 The phrase "therapeutically effective amount" is an ait-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, in certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being admini stered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art ma empirically determine the effective amount of a particular composition without necessitating undue experi mentation.

[0031] in certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that, said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivaiion, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

{0032J Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the di sease or condition. 100331 In certain embodiments, the dosage of the subject compositions provided herein may be detemiined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Craax) and the area under the plasma concentration-time cun'e from time 0 to infinity may be used,

[003 J When used with respect to a pharmaceutical composition or other material, the term "'sustained release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active sail and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.

[0035] The phrases "systemic administration," "administered systemically," "peripheral administration" aid "admini tered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administratio of an agent for the disease being treated, even if the agent is subsequently distributed systemicaiiy, may be termed "local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient' s system and, thus, is subject to metabolism and other like processes.

[0036] The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

[0037] The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.

[0038 J This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I ma be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdennal administration, or transdermal administration. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

[0039] in many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula I) to be delivered in an amount sufficient to deliver to a patient a therapeutical y effective amount of a compound of formul I or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula 1 or its pharmaceutical acceptable salts will depend on absorption, ioactivatlon, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions, it is to be noted that dosage values may also vary with the severity of the condition to be alleviated, it Is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art. j004ti] Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula I may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the ty e of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition. 0041] The concentration and/or amount of any compound of formula 1 may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is microdialysis, as reviewed by T. E. Robinso et aL, 1991 , microdialysis in the neuroscie ces. Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula Ϊ such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the salts or compositions may be determined thereby with suitable calibration, procedures using known concentrations of salts or compositions.

|0042] in certain embodiments, the dosage of the subject compounds of formula I provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used. |0043j Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas 1 is in the range of about 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses, for instance 0.01 mg kg day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas 1 may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg kg day, 1..0 mg/kg/day, 5 mg kg/day, 10 mg kg day, 20 mg/kg/day, 30 mg kg/day, or 40 mg kg/day. Compounds of Formula I may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1,0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is iess than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula 1 required for the same therapeutic benefit.

[0044) An effective amount of the compounds of formula Ϊ described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

|0O45] An effective amount may he sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or demyelkation and/or elevated reactive oxidaiive- nitrosative species and/or abnormalities in physiological homeostasis' s, in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment, that the physician considers appropriate for the patient, in considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.

[0046] The compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenteraliy, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasal!}', as a rectal suppository, or using a "flash' ¹ formulation, i.e., allowing the medication, to dissolve in the mouth without the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug deliver}', by stereotactic injection, or in oanoparticSes.

[0047] The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the li ke. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginioe, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium iauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard tilled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof. The compounds of formula I may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.

|004S] For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitabl buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration, in this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art

|0049] The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula 1 disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula ] .

|005G] (Jenerally, a composition as described herein ma be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary ) Topical admi istration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional manner. J0 511 The dosage administered will be dependent upon the identity of the metabolic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment if any; the frequency of treatment and therapeutic ratio.

[0052] Illustratively, dosage levels of the administered active ingredients are: intravenous, 0. 1 to about 200 rag/kg; intramuscul r, 1 to about 500 rag/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg kg of host body weight. 0053] Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasaily, pharyngolaryngeaily, bronchi ally, intravaginally, rectaliy, or ocularly in a concentration of from about 0.01 to about 50% wAv of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

[0054] The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient. For oral administration either solid or fluid unit dosage form can be prepared.

[0055] As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, hut are not limited to, water swellabie cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocol ^' loids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of suitable water swellabie cellulose derivatives include, but are not limited to, sodium carboxymethylcellitlose, cross-linked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellu!ose (HPMC), hydroxyisopropylcellulose, hydroxy butyl cellulose, hydroxyphenylcelluJose, hydroxyethylcellulose (HEC), hydroxypentylceliulose, hydroxy propylethylceflulose, hydroxy propy!butylcellulose, and hydroxy-propyl ethylcel lulose, and mixtures thereof. Examples of suitable polyaikylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyaikylene oxides include, but are not limited to, polyethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high -molecular weight crosslinked acrylic acid horaopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL ^iM . Examples of suitable bydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragacanth, pectin, xanthan gum. gellan gum, maltodextrin, galactomannau, pusstulan, laminarin, scleroglucan, gum arabic, hmlin. pectin, gelatin, whelan, rhamsan, zooglan, methyl an, cbitm, cyclodextrin, chitosan, and mixtures thereof. Examples of suitabie clays include, but are not limited to, smectites such as beritonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof. Examples of suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-Hnked carboxy methyl cellulose sodium, and mixtures thereof. j 0056 J The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, g!idants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof. jOOSTj Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellu!ose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carhoxymethylcelluiose, tara, gum arabic, tragacanth, pectin, xanthan. gellan, gelatin, maltodextrin, galaetoroannan, pusstulan, laminarin, scieroglucan, ίηυίϊη, whelan, rhamsan, zooglan, methylan, chitin, cyelodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof Suitable disiiitegrants include, but are not limited to, sodium starch glycol ate, cross-linked polyvinylpyrrolidone, cross-linked carboxymet ylcellulose, starches, microcrystaliine cellulose, and mixtures thereof. j ^' 0058) Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.

|0059 ^' J Suitable insoluble edible materials far use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereo Examples of suitable water- insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof Examples of suitable fats include, but are not limited io, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphatidyl choline, phosphofidyl serene, phosphatidyl enositoi, pliosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to. carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarraellose sodium, sodium starch glycolate and cross- linked povidone (crospovidone). n one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant.

[0060) Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetk acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid., benzoic acid, and sorbic acid, and mixtures thereof.

[0061 J In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns. In embodiment, the immediate release coatine is typical ly compressed at a density of more than about 0.9 g/cc, as measured by the weight and vol ume of that specific layer.

[0062] In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet. In one embodiment, the first portion includes the first pharaiaceiitically active agent and the second portion includes the second pharmaceutically active agent, j0063| in one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent, in one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core. |0064] In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core, hi another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.

|0065] Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form. Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art

|0066J The immediate release dosage, unit, of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in art encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing grannies or beads).

|0067] Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington—The Science and Practice of Pharmacy", 20th. Ed„ Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are wellknown and described in die art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. {00681 An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads. 069] Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule

|O07O] A pulsed release dosage form is one that mimics multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the dr g presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release.

J0071 j Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt % to 70 wt %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. ¾, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is released i the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 1.4 hours, and more preferably approximately 5 hours to .12 hours, following administration. {0072 j Another dosage form contains a compressed tablet or a capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads, granules panicles that release drug substantially immediately following oral adraiiiistratton to provide an initial dose. The delayed release dosage unit, contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.

[0073] For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.

[0074] Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula I or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences. Mack Publishing Company Eastoii, Pa., 19th Edition (1 95), 0075] In addition, in certain embodiments, subject compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray drying. The subject compositions may be administered once, or ma be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.

{00761 Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular m de of administration.

{0077] Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. 0078] The compounds of formula 1 described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.

[0079] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following; (T) fillers or extenders, such as starches, lactose, sucrose, glucose, rnannitoL and/or silicic acid; (2) binders, such as, for example, carlx xymethyl cellulose, alginates, gelatin, polyvinyl pyrroiidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginie acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternar ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as tillers in soft and hard-filled gelatin capsules using lactose or ras!k sugars, as well as high molecular weight polyethylene glycols and the like.

[0080] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, mieroemulsions, solutions, suspensions, syrups and elixirs, in addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyi alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mi tures thereof.

[0081 ) Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxyiated isostearyl alcohols, polyoxyetliyiene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, beotonlte, agar- agar and tragacanth, and mixtures thereof.

[0082] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will, melt in the appropriate body cavity and release the encapsulated compound(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0083] Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition may be mixed under sterile conditions with a phannaceirticaily acceptable carrier, and with any preservatives, buffers, or propellents that may be required. For transdermal administration, the complexes may i clude lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

(0084) The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacaiith, cellulose derivatives, polyethylene glycols, silicones, bentonit.es, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipienis such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionally contain customary propellants, such as chiorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. f0085| Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplary patches and methods of patch deli very are described in US Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

[0086] ^' in another embodiment, a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resi composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a sty reiie-ethylene-butylene- sty rent* copolymer, a first adhesive layer on the one side of the composite film, and a polyalkykne terephthaiate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthaiate film; and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer, A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyaikylene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyaikylene terephthalate film.

| 0S7J Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive a d laminating the drug-containing adliesive onto a suitable backing member, e.g. a polyester backing membrane. The darg should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.

[00S8] Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule dnigs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresi ) for large-molecule drugs.

{0 89 J Iontophoresis is a technique employed for enhancing the flu of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is give in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent, that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.

[0090] In some cases, it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., orai and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combinatioti is desired by the prescribing physician.

[0091] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit, dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent.

[0092] Methods and compositions for the treatment of severe pain Among other things, herei n is provided a method of treating severe pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula I:

Wherein.

R each independently represents H, D ₅ O, Ct¾ ₅ null

32

33

a is independently 2.3 or 7;

each b is i ndependently 3, 5 or 6;

e is independently L 2 or 6;

c and d are each independently H, D, -OH, -OD, Ci-Cc-alky!, - H _Z or -COCO ¾ n is independently 1, 2, 3, 4 or 5.

Methods for using compounds of formula I:

[0093J The invention also includes methods for treating severe pain, such as postoperative, cancer, kidney stones, fractures, locai pain including infiltration, nerve biock, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia and neuralgia. METHODS OF MAKING

|0094| Examples of synthetic pathways useful for making compounds of formula 1 are set forth in example below and generalized in scheme I :

Scheme - t:

7 8

|0095] Step-1 : Sy nthesis of compound 2:

f chloroform f _{

rt- refiux. 2h

1 2

[0096] A solution of 0.065 mole of N-methyl diethanolamtiie 1 in 6 ml of chlorotonn was added drop wise, at room temperature over a period of 45 minutes to 0.143 mole of SOCIj in 8 ml of chloroform. The mixture was reftuxed for I h and chilled. The crystalline material was isolated by suction filtration, washed with diethyl ether and dried. The salt which was filtered is hygroscopic. j0097| Step-2: Synthesis of compound 5:

10098 J Into a three necked 100 ml round bottom fl sk equipped with a mechanical stirrer and reflux condenser was placed 3.0 g of{0.020 mole) of compound 3 0,020 mole of compound 2, 0.001 mole of hexadecyltri butyl phosphonium bromide 4 and 30 ml of 50% aqueous NaOH. The mixture was stirred vigorously at 100 ^l C for 1. hr. The cooled reaction mixture was transferred to a separating funnel diluted with 100 ml water and extracted with 3x50 mi of diethyl ether. The ether extracts were washed with water 2x50 ml; and extracted with three 50 ml portions of 1 :1 mixture of HC1 and water. The acid extracts were neutralized with solid NaHCOa and extracted with 3x50 mi ether. The ether extracts were dried over and evaporated. The residue was vacuum distilled to yield 3.41 g of desired product 5. B P 142 ^,! C, 0.3 mm of Hg.

|0099J Step-3: Synthesi s of compound 6:

5 6

jOO!OOj A 500ml distillation apparatus, equipped with a dropping funnel, condenser, stirrer, and drying tubes, was charged with a solution of ethyl magnesium bromide (prepared from 8.21g of magnesium and 35.57g of ethyl bromide) in 130ml of dry ether. A solution of 42g of compound 5 in 80ml of hot anhydrous xylene was added over a period of 15 mm. Solvent was distilled from the reaction vessel until the temperature of the reaction mixture rose to 70-80°C, and the mixture heated under reflux for an additional 4.25 h. The condenser was then arranged for distillation, and a solution consisting of 65ml of concentrated (37.5%) hydrochloric acid and 65ml of water was added to the hot reaction mixture over a period of 10 min, all of the remaining solvent distilling during this addition. The hot suspension was drawn off and the vessel rinsed with 20ml of 18% HCI. The product hydrochloride, which crystallized upon cooling the combined acid solutions, was collected, dissolved in 240ml of boiling water containing 2g of activated charcoal, the solution heated to boiling, filtered while hot, and the charcoal residue washed with 10ml boiling water. A solution of 6.5g of sodium hydroxide in 10ml water was added to the combined filtrates. The aqueous layer was extracted with ethyl acetate, dried over Na2S04, evaporated to get the residue which was purified through column to get compound 6.

{00101] Step-4: Synthesis of compound 7.

001021 Compound 6 (1 mmol) was dissoived in dry DCM (5 mi) and added boron tribromide (BBr ₃ ) (1.0 M, 2mmol) at 0 °C and stirred the reaction mixture at rt for 5h. After completion of reaction the mixture was cooled to 0 °C and added saturated aqueos NaHCO? dropwise to neutralize the reaction mixture. The two layers were separated and the organic layer was dried over and evaporated to get the crude material which o purification through column to obtain compound 7,

7 8 {0010 j Stirring a mixture of a solution of compound 7 (18.0 mmol; 1.0 eq) and acid 8 (18.0 mmol; 1 ,0 eq) in Dichlorom ethane {DCM) (200 mL; LR grade); l -etliyl-3-{3 '- dimethyiaminopropyi)carbodiimide.HCi (EDC1HC1) (527.0 mmol; L5 eq) and 4- Dimethyiaminopyridine(D AF) (18.0 mmo!; 1.0 eq) at room temperature (RT) for 24 hours. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was diluted with DCM (200 mL), washed with water (2x300 mL) followed by brine solution (300 mL) and dried over anhydrous Ι% ₂ $(> ₄ and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel by using ethyl acetate-pet ether to obtain the final product 9. Moi. Wi: 435.19; Elemental Analysis: C, 63 41 ; H, 7.64; N, 3.22; O, 1 1.02; S, 14.72.

1001051 The term "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ . Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum.

EQUIVALENTS

The present disclosure provides among other things compositions and methods for treating severe pain and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive.

INCORPORATION BY REFERENCE

{00106J All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. n case of conflict, the present application, including any definitions herein, will control .