TREATMENT OF LOCAL PAIN

PRIORITY

[0001 J The present application claims the benefit of Indian Provisional Patent Application. No. 2056 CHE/2012 filed on 23-May-2012, the entire disclosure of which is relied on for ali purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

10002) This disclosure generally relates to compounds and compositions for the treatment of focal pain. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, polymorphs, esters, salts, stereoisomers, enantiooiers, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

10003} Pain is a subjective experience, influenced by physical, psychological, social, and spiritual factors. The concept of total pain, acknowledges the importance of ail these dimensions and that good pain relief is unlikely without attention to each aspect. Pain and diseases such as cancer are not synonymous: at least two thirds of patienis experience pain at some time during the course of their ill ness, and most will need potent analgesics.

[000 J Severe Pain such as pain, depression, fibromyalgia, rheumatoid arthritis, restless leg syndrome, bipolar disorder are a heterogeneous group of diseases of the nervous system, including the brain, spinal cord, and peripheral nerves that have much different aetiology. Many are hereditary; some are secondary to toxic or metabolic processes. Free arachtdonie 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 injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, .migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain. fOOOS] 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 local pain .

SUMMARY OF THE INVENTION

0006] 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 local pain.

J0007] The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of local pain and its associated complications.

in certain embodiments, the present invention relates to the compounds and composiiions of fomrula I, or pharmaceutically acceptable salts, hydrate, solvate, prodrug, enantiomer or stereoisomer thereof,

0009] Wherein,

R independently represents D, -(¾, ~OC¾, B, -OCDj,

a is independently 2,3 or 7;

each b i s independently 3 , 5 or 6;

e is independent! y 1. 2 or 6;

c and d are each independently H, D, -OH, ~OD, CrQ-aJkyl, -N¾ or ~€0O¾;

n is independently 1, 2, 3, 4 or 5. fOOlOj In the illustrative embodiments, examples of compounds of formula 1 are as set forth below:

(1-2)

Ϊ001..11 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 local pain or its related complications,

[001.21 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 [0013] Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of local pain or its related complications.

[0014] The compositions described herein have several uses The present application provides, for example, methods of treating a patient suffering from local pain or its related complications manifested from metabolic conditions, severe diseases or disorders; Hepatology, Cancer.. Hematological, Orthopedic, Cardiovascular, Renal, Skin, Neurological or Ocular complications.

[H I A M I I ⁾ DESCRI PTION OF TH E IN VENTION

Definitions

[001.5] 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,

[0016] The compounds of the present invention can be present in the form of pharmacetiiicaiiy acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutical ly acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1 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).

[0017] 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

"isomer* " Isomers Hi at ilrft in ihf arranerptnprit nf tfipir stntv in «nar¾» an* ti»rm«ri more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers tha are non- supeiimposable 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-sequeiicing rules of Calm, Ingokl and Pre!og, or by 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" ,

[0Q18J As used herein, the term "metabolic condition ¹¹ 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, 001 > J The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0020) The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal , subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasteraal injection and infusion.

|0021] 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. [0022] The phrase "pharmaceutically acceptable ^' ' is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage fonns which are, within the scope of sound .medical judgment, suitable for use in 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

|0023] The phrase "pharmaceutically acceptable carrier" 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 he '"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 acceptabie carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptabie 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 tragacaiith; (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, mannitol 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) alginte acid; (16) pyrogen-free water, (17) isotonic saline; (18) Ringer's solution, (19) ethyl alcohol; (20) phosphaie buffer solutions, and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations. 0024] The term "prodrug" is intended to encompass compounds that, moieties that are hydroiyzetl under physiological conditions to reveal the desired molecule, in oilier embodiments, the prodrug is converted by an enzymatic activity of the host animal .

[0025] 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).

[0026] The term "predicting" as used herein refers to assessing the probability related diseases patient 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.

[0027] 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 operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain of a subject by administration of an agent even though such agent does not treat the cause of the condition. The terra "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adj nct and palliative treatment.

{0028] 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 efiective 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.

{0029) 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, inactivation, 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 ma also vary with the severity of the condition to be alleviated. It is to be further understood thai for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person admini tering or supervising the administration of the compositions. Typically, dosing |0030] 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 disease or condition.

|0031 ] In certain embodiments, the dosage of the subject compositions 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 ( max) and the area under the plasma concentration-time curve from time 0 to infinity may be used. 0032] 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 salt and/or composiiioii, for a sustained or extended period (as compared to the release from a bolus). This release ma result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.

|0033] The phrases "systemic administration," "administered systemicaSly," "peripheral administration" and "administered peripherally' ¹ are art-recognized, and include the ad mini strati on of a subject composition, therapeutic or other material at a site remote "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.

[0034] The phrase 'therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to art 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 vaty 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.

[0035] The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodmgs.

[0036] This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdermal administration, or transdermal administration. The pharmaceutical composition may further comprise at least one o a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

[0037] 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 therapeutically effective amount of a compound absorption, inactivation, and excretion rates of the drug as well as the delivers' rate of the salts and compositions from the subject compositions. It is to he noted that dosage values may also vary with the severity of the condition to be ai!eviated. 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 i the art.

|0038] 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 type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

100391 The concentration and/or amount of any compound of formula i 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 flo before and after admini tration of therapeutic formulations disclosed herein. One such method is microdialysis, as reviewed by T. E. Robinson et al., 1991 , microdialysis in the neurosclences, Techniques, volume 7, Chapter 5 . 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 I 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. |004fi| in certain embodiments, the dosage of the subject compounds of formula I provided herein may be determined by reference to the piasrna 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.

|0041 ] Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas I 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 I may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg kg day, 1.0 rag/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 1 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, lit certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I required for the same therapeutic benefit.

|00 2] An effective amount of the compounds of formula I described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

|0 43 ^' } An effective amount may be 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 demyelization and/or elevated reactive oxidative- 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 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 p tient-io-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.

(004 ^' | The compositions provided by this application may be administered to subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenteral ly, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasally, as a rectal suppository, or using a ''flash" 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 daig deliver}-', patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles. 0045] 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 like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium siearate, sodium laur l 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 filled 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 1 ma also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.

[0046] 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 suitably 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 b standard techniques known to those skilled in the art.

[0047] 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, 1.00, 300, 500, 700, 800 mg of the compounds of formula I disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula I.

[0048] Generally, a composition as described herein may be administered orally, or parenteral! y (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical 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.

[0049) The dosage administered will be dependent upon the identity of the metaboli 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.

[0050] illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg kg; intramuscular, .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 1 00 mg/kg of host body wei ht.

[0051] Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasai!y, phar ngol aryngeaily, bronciiially, intra vaginally, rectal! y, or oculariy in a concentrati n of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentratio of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

[0052] 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 forms can be prepared.

[0053] As discussed above, the tablet core contains one or more hydrophilic polymers. hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of suitable water swell able cellulose derivatives include, but are not limited to, sodium caxboxymethylcellu!ose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcel!ulose, hydroxybutylcellulose, hydroxypheny lcell u!ose, hydroxyethylcelluiose (HEC), hydroxypentylcel ose, hydroxypropyiethylceilu!ose, hydj'oxypropylbutylcellulose, and hydroxypropylethylceUulose, and mixtures thereof. Examples of suitable polyalkylene glycols include, but axe not limited to, polyethylene glycol . Examples of suitable thermoplastic polyalkylene oxides include., but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic acid homopolymers and copolymers such as those commerciall available from Noveon Chemicals under the tradename CARBOPOL ^m Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragacanth, pectin, xanthan gum, gel! an gum, maltodextrin, galactomannan, pusstulati, lammarin, sclerog!ucan, gum arabic, inulin, pectin, gelatin, helan, rhamsan, zooglan, methylan, chitin, cyciodextnn, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium tri silicate; 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 poly vinyl pyrrolidone. cross-linked agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof

[0054] The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, filters, adsorbents. |0 5Sj Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcelluSose; wet hinders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethyicellulose, tara, gum arable, tragacanth. pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laniinarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chiiosan, polyvinyl pyrrolidone, celiulosics, sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch glycol ate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyicellulose, starches, microcrystalHne cellulose, and mixtures thereof.

|0056] 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.

|0057] Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water- insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acryiates, methacryiates, 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 to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, esters, mono-., dt~, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoW ^' ax- 932, laurayl macrogol-32 giycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphatidyl choline, phosphatidyl serene, phosphatidyl enositol, phosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not Limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystaiiine wax; and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmeilose sodium, sodium starch glycolate and cross- linked povidone (crospovidone). in one embodiment the tablet core contains up to about 5 percent by weight of such super dismtegrant. j 00581 Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosu!fite, butylhydroxytoluene, butylated hydroxy anisole, edetic 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.

|0059J 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 coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer.

{00601 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 coniaci each other at a center axis of the tablet. In one embodiment the first portion includes the first pharmaceutically active |0061] 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 0062| In one erabodimeirt, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.

1 0631 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 formulati ns include compressed tablets, gels, films, coatings, liquids and particles that ca be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art. 0064] 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 an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads).

|Q065| Extended release formulations are generally prepared as diffusion or osmotic diffusion system typically c nsists of one of two types of devices, reservoir and matrix, which are well known 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 .

[0066] 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,

[0067] Delayed release dosage formulations axe 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 a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.

[006SJ A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug 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.

[0069] 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 the dosage form is released in 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 ours, and more preferably approximately 5 hours to 12 hours, foil owing administration.

|0O7O] 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 particles that release drug substantially immediately following oral administration 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,

100711 For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or parti ally aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared. 0072] Methods of preparing various pharmaceutical compositions with a certai 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, Easton, Pa., 19th Edition (1 95). j0073| 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 may be divided into a number of smaller doses to be administered at varying intervals of time, depending i n part, on the release rate of the compositions and the desired dosage. [0074) Formulations useful in the methods provicfed 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 mode of administration.

[0075J 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. j0076j The compounds of formula I described herein may be administered in i nhalant or aerosol formulations. ^' The inhalant or aerosoi 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 0.0 i~ 1.0% w/w, of medicament relative to the total weight of the formulation.

J0O77J 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: (!) fillers or extenders, such as starches, lactose, sucrose, glucose, rnannitol, and/or silicic acid; (2) binders, such as, for example, carboxyniethylcellulose, alginates, gelatin, polyvinyl pyrroSidone, sucrose and/or acacia; (3) hum ctants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates., and 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 !auryl 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 fillers in soft and hard-tilled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

|0078 ^' | Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microeniulsions, solutions, suspensions., syrups and elixirs. In addition to the subject compositions, the li uid dosage forms may contai inert diluents commonly used in the art, such as, for example, water or other solvents, sol ubili zing agents and emui sillers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butyl eoe glycol, oils (in particular, cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol polyethylene glycols and fatty acid esters of sorhitan, and mixtures thereof.

|0079J Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxy!ated isostearyl alcohols, polyoxyethylene sorbitol, and sorhitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mi tures thereof.

1008 1 Formulations for rectal or vaginal administrati n 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, hut- liquid at body temperature and, therefore, will melt in the appropriate body cavity and foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0081 ) 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 pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellents that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties. j00S2| 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, tragacanfh, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionally contain customary propellents, such as chlorofluorohydrocarbons and volatile un substituted hydrocarbons, such as butane and propane.

[00831 Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplary patches and methods of patch delivery are described in US Patent Nos. 6,974,588, 6,564,093, 6,3 Ϊ 2,7 i 6, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

|0084| In another embodiment, a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chlonde-poiyurethane composite and 2-10 parts by weight of a composite .film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on t e surface of the polyaikylene terephihalate film; and a second adhesive layer comprising a styrene-dieae-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 terephihalate 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 terephihalate film.

[0085J Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose,

[0086] 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 drugs. 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 (iontophoresis) for large-molecule drugs.

[0087] Iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080.646 to Theeu es. The principal mechanisms by which iontophoresis enhance molecular transport across the skin are (a) preferential passage of counter-ions when an electric fie!d is applied or (c) increase skin permeability due to application of electrical current.

[0088] 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., oral and parenteral)., are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0089] 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.

[0090] Methods and compositions for the treatment of local pain. Among other things, herein is provided a method of treating local pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula l;

Formula I

[009.1 ] Wherein,

R ¹ independently represents D, -<¾, -OCH3, H.-OCD ₃ .

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independentl 1 , 2 or 6;

c and d are each independently H, D, -OH, -OD, C;r€t _> -alkyl, -NH ₂ or -COCH ₃ ; n is independently 1 , 2, 3, 4 or 5,

M ETHODS OF MAKING

2J Exarapies of synthetic pathways useful for making compounds of formuf

0093] Step- I : Synthesis of com pound

|0094] S-raethyl-6-nonynoic acid 3 was prepared by adding anhydrous tetrahydrofuran (15ml) and hexamethylphosphorami.de (3.8mi) to a 5 Oml 3 -necked B flask equipped with a thermometer, a magnetic stirrer and nitrogen in/outlet. The mixture was cooled to about - 78°C to about -75°C. Methyl-batvne 1 Us was then added followed by dropwise about -30°C and stirred at this temperature for about 30 minutes. A solution of 5- bromovaleric acid 2 ( 1.33 g in 3ml of THF) was added dropwise at about -30°C for about 10 to about 1 5 minutes. The mixture was then gradually wanned to room temperature and stirred overnight. The reaction was then warmed up. Approximately 50ml of 3 HCI was added the solution of reaction. The solution was then extracted with ethyl acetate (2x20 .ml) and washed with brine. The extraction yielded about 1 .1 g of crude product.

0095J The crude product was purified by column chromatography using about 50g of silica gel and eluted with a 2: 1 mixture of hexane/ethyl acetate. The col lections were combined. Solvents were removed under vacuum to give compound 3 as light yellow oil.

100961 Step-2: Synthesis of compound 4:

rt, over night

[00 7J Compound 3, anhydrous tetrahydrofuran (!20m!) and t-BuOM (2 8ml) were added to a IL 3 -necked RB flask equipped with a condenser, a thermometer and a magnetic stirrer under Argon in/outlet. The mixture was cooled to about -S5°C to about - 45°C. H3 (approx. 150-200ml) was condensed to the flask, lithium (0.1-0.1 Sg/ea.) was added piece wise at -60°C to about -45X and the mixture was stirred until a dark biue color disappeared before adding the next piece of lithium. A TLC after addition of 0.4g lithium revealed approximately 40% to about 50% conversion. Additional lithium (0.75 g) was then added and the completion was observed by TLC. The reaction mixture was stirred for a additional hour (temperature -45°C to -42°C). MH C (2g) was added portion-wise at approximately -45°C to about -42°C. The mixture was gradually warmed to room temoerature ovemiuht. A TLC of the reaction mixture revealed a clean oroduct. 6N HCJ (approx. 50ml added portion wise at 25°C) to a pH of about 2 to about 3. The mixture was then extracted with ethyl acetate (2 X 300ml). The ethyl acetate layers were combined, washed with brine (200ml) dried over anhydrous Na ₂ SO and filtered. The dried mixture was concentrated under vacuum at about 30°C to yielded light yellow oil as compound 4.

[0099] Step-3 : Synthesis of compound 5;

|00100| Compound 4 (200g) was treated with thionyl chloride (419 g). The reaction mixture was then heated at about 70°C for about 1 hr. Excess thionyl chloride was removed under vacuum to produce 249 g of a crude product. The caide acid chloride 5 was then used in a fourth synthesis step without further purification.

[00101] Step-4: Synthesis of compound 7:

over night

7

[00102] 4-Hy droxy-3 -methoxy benzyiamine HCI salt 6 (3.35g) and dimethyl fonna ide ( lOmi) were added io a 100ml 3-necked RB flask equipped with an additional funnel, a thermometer and a maenetic stirrer under nitroaen. 5N aOH (7 ml ) was added nortion- was added drop vise at about. 0°C to about 5 ^C C or 10°C for about 20 minutes. An additional 5ml of anhydrous dim ethyl fonmimide was added. The mixture was gradually warmed to room temperature and stirred under nitrogen overnight. Water (ISOmi) was added. The mixture was extracted with ethyl acetate (i X 100ml and 1 x 50rol). The ethyl acetate extract was washed with ΪΝ HQ (2 X 60m!) followed by saturated aHCQj (2 x 100m!) and brine.

|00103| The extract was then dried over anhydrous ajSO* and filtered. Solvents were removed under vacuum at about 35°C to about 40°C to give a thick light orange/pink residue (wt. ^:::: 3.4g). The crude product was purified by column chromatography using from about .150 to about 160s of silica ael e!uted with a 1.1 mixture of eifivl acetate/hexane. Collections from the colum purification were combined, concentrated under vacuum at about 40*C and dried under vacuum to produce 3.1 g of the desired product as a white solid compound 7.

|00104] Step-5: Synthesis of compound 9: e

{0 105} Sodium bicarbonate (13.6 mmol) was dried under vacuum by heat gun The apparatus was vented with dry Argon, CH2CI2 (6 mh) and triphosgene (6.8 mmol ) were added and the reaction mixture was cooled to 5-10 °C via an ice bath. Compound 8 (6.8 mmol). After stirring for 3 !i, the formed sodium chloride as well as remaining sodium bicarbonate was removed via filtration and the remaining filtrate was concentrated under reduced pressure and dried under high vacuum to yield the final compound 9. Μ.Έ: C _2J ¾ ₂ N ₂ CX, ; MoL Wt: 424.24 ; Elemental Analysis: C, 70.73; H, 7.60; N, 6.60; O, 15.07.

EQUIVALENTS

(00106| The present disclosure provides among other things compositions and methods for treating local pain and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

INCORPORATION BY REFERENCE

[00107] All publications and patents mentioned herein, including those items listed above, are hereb incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.