Pharmaceutical compositions for treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis

Description

[0001] PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OF RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS, ANKYLOSING SPONDYLITIS, POLYARTICULAR COURSE JUVENILE IDIOPATHIC ARTHRITIS, AND ULCERATIVE COLITIS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a method of treating Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis by administering therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof for the treatment Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis.

[0004] BACKGROUND OF THE INVENTION

[0005] Tofacitinib citrate which is sold under the brand name Xeljanz® has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Tofacitinib has also been studied in clinical trials for the prevention of organ transplant rejection and is currently under investigation for the treatment of psoriasis, atopic dermatitis.

[0006] The drug Tofacitinib is chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2, 3-d] pyrimidin-4-ylamino)-B-oxo-l- piperidine propane nitrile, 2-hydroxy- 1,2, 3 -propane tricarboxylate (1: 1). Tofacitinib is indicated for the treatment rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. Its structure is depicted as follows: Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression.

[0007] Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1 / JAK3, JAK1 / JAK2, JAKl / TyK2, JAK2 / JAK2). Tofacitinib inhibited the in vitro activities of JAK1 / JAK2, JAK1 / JAK3, and JAK2 / JAK2 combinations with IC50 of 406, 56, and 1377 nM respectively.

[0008] Indomethacin is a nonsteroidal anti-inflammatory drug, used to treat severe rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, acute gouty arthritis, bursitis, and tendinitis. The brand name Indocin® is no longer available in the U.S. but may be available as a generic termed indomethacin. The chemical name is -(4-chlorobenzoyl)-5-methoxy-2- methyl-lHindole- 3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16CINO4, and it has the following chemical structure.

[0009] Indocin® is available in capsules in strengths of 25 and 50 mg, in suspension strength of 25 mg / 5 ml and as a suppository in strength of 50 mg per suppository. Initial doses usually start at 25 mg three times daily. Indocin® IV (Indomethacin) for Injection sterile vial contains 1 mg Indomethacin and is used by specialists in infants to close a patent ductus arteriosus in the heart and is not commonly prescribed. Indocin (indomethacin) ordinarily should not be prescribed for pediatric patients under 15 years old. In late pregnancy, Indocin® (Indomethacin and other NS AIDs) should be avoided because it may cause premature closure of the ductus arteriosus. Serious side effects of Indocin® may include heart attack, stroke, skin changes (paleness, blisters, rash, and hives), weight gain, swelling, shortness of breath, tachycardia, unusual bleeding (including GI bleeding), jaundice, stomach pain and pain with urination, bloody urine, blurry vision, and back pain. Patients with asthma that are aspirin-sensitive should avoid use of this drug.

[0010] Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Indocin®, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

[0011] Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation, sine Indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

[0012] OBJECTIVE OF THE INVENTION

[0013] The present invention relates to a method of treating Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis by administering therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof.

[0014] The present invention also relates to a pharmaceutical composition comprising therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof for the treatment Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis.

[0015] In all the embodiments provided herein are a pharmaceutical composition comprising therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof by preparing suitable and stable dosage forms for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, And Ulcerative Colitis or a pharmaceutically acceptable salt thereof.

[0016] The present invention also provides a pharmaceutical dosage form comprising combination of tofacitinib and indomethacin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said dosage from is immediate release or sustained release dosage form.

[0017] SUMMARY OF THE INVENTION

[0018] The present invention relates to a method of treating Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis by administering therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof.

[0019] The present invention also relates to a pharmaceutical composition comprising therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof for the treatment Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis.

[0020] According to the one embodiment the inventors surprisingly found that the combination of tofacitinib and indomethacin produces a synergistic anti-inflammatory effect, such that the therapeutic efficacy of the combination is comparable to, or greater than, that achieved by administering approximately threefold higher doses of each agent as monotherapy. This synergistic interaction permits the use of significantly lower doses of both tofacitinib and indomethacin, thereby reducing the incidence and severity of dose-dependent adverse effects such gastro intestinal toxicity and improving the overall safety profile of the treatment, while maintaining or enhancing therapeutic efficacy.

[0021] According to one embodiment of the invention, there is provided a pharmaceutical composition comprising therapeutically effective amounts of Tofacitinib or pharmaceutical salt thereof.

[0022] According to another embodiment of the invention, there is provided a pharmaceutical composition comprising combination of therapeutically effective amounts of Tofacitinib and Indomethacin or a pharmaceutically acceptable salt thereof.

[0023] The present invention also provides for a pharmaceutical composition comprising combination of Tofacitinib and Indomethacin and at least a pharmaceutically acceptable carrier selected from pH raising agent, antioxidant, transition metal complexing agent, pH lowering agent, tonicity regulating agent, optionally a preservative, and optionally a solvent.

[0024] The present invention is directed to a method for treating Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis in a human in need of such treatment comprising, consisting of, and / or consisting essentially of administering to the human a therapeutically effective amount of tofacitinib in combination with Indomethacin.

[0025] In another embodiment provided a method for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis in a human subject in need thereof. The method comprises administering an effective amount of tofacitinib, preferably in the range of approximately 0.1 mg to 100 mg per day, more preferably from about 1 mg to about 10 mg per day as a once-daily administration. In addition, indomethacin is administered in an effective amount, preferably from about 0.1 mg to about 100 mg per day, more preferably about 1 mg to about 40 mg per day as a once- daily administration. The administration of both tofacitinib and indomethacin may be carried out simultaneously or sequentially, in any order, to achieve the therapeutic benefit of treating the aforementioned autoimmune and inflammatory disorders.

[0026] DETAIUED DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 illustrates the changes in body weight over the treatment period across six experimental groups: disease control (CFA), tofacitinib injection (CFA+TOFA INJ), indomethacin injection (CFA+INDO INJ), a combination of tofacitinib and indomethacin injections (CFA+TOFA+INDO INJ), combined tofacitinib and indomethacin oral administration (CFA+TOFA+INDO ORAL), and a sham group.

[0028] Figure 2 illustrates the changes in paw volume over the treatment period across six experimental groups: disease control (CFA), tofacitinib injection (CFA+TOFA INJ), indomethacin injection (CFA+INDO INJ), a combination of tofacitinib and indomethacin injections (CFA+TOFA+INDO INJ), combined tofacitinib and indomethacin oral administration (CFA+TOFA+INDO ORAL), and a sham group. Figure 3 illustrates the changes in paw volume over the treatment period across six experimental groups: disease control (CFA), tofacitinib injection (CFA+TOFA INJ), indomethacin injection (CFA+INDO INJ), a combination of tofacitinib and indomethacin injections (CFA+TOFA+INDO INJ), combined tofacitinib and indomethacin oral administration (CFA+TOFA+INDO ORAL), and a sham group.

[0029] Figure 4 illustrates the Tumor Necrosis factor -alpha levels over the treatment period across disease control (CFA), a combination of tofacitinib and indomethacin injections (CFA+TOFA+INDO INJ), combined tofacitinib and indomethacin oral administration (CFA+TOFA+INDO ORAL)

[0030] Figure 5 illustrates the Interleukin- 10 (IL- 10) levels over the treatment period across disease control (CFA), a combination of tofacitinib and indomethacin injections (CFA+TOFA+INDO INJ), combined tofacitinib and indomethacin oral administration (CFA+TOFA+INDO ORAL)

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0033] DEFINITIONS

[0034] Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to”.

[0035] “Pharmaceutically acceptable carrier or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0036] A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

[0037] “Effective amount” or “therapeutically effective amount” refers to an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.

[0038] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0039] “Tofacitinib” refers to Tofacitinib or a pharmaceutically acceptable salt thereof. Examples of Tofacitinib salts include, but are not limited to citrate, hydrochloride, formate, acetate, propionate, and hexanoate salts. The preferred Tofacitinib salt is Citrate salt.

[0040] By “pharmaceutically acceptable form” is meant any pharmaceutically acceptable form, including, solvates, hydrates, isomorphs, polymorphs, co-crystals, pseudomorphs, neutral forms, acid addition salt forms, and prodrugs. The pharmaceutically acceptable acid addition salts of tofacitinib are prepared in a conventional manner by treating a solution or suspension of the free base with about one or two chemical equivalents of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, mesylic, tosylic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic such as methanesulfonic, benzene sulfonic, and related acids. Some preferred forms of tofacitinib include the free base and tofacitinib citrate. Dosage forms

[0041] The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), or rectal administration routes.

[0042] The Composition according to the invention may contains tofacitinib from about 0.1 mg to about 50 mg, more preferably about 1 mg to about 25 mg, and most preferably about 1 mg to 10 mg and indomethacin from about 0. 1 mg to about 100 mg, more preferably 50 mg to about 100 mg, and most preferably about Img to 40 mg per day.

[0043] Moreover, the pharmaceutical compositions described herein, which include the active agents can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0044] In one embodiment the present invention provides a pharmaceutical composition comprising Tofacitinib in the form of Injection, Powder for Oral Solution or Suspension, Soft gelatine capsule, cream. The compositions are useful for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis.

[0045] In another embodiment present invention provides a pharmaceutical composition comprising tofacitinib and indomethacin in the form of injection, Immediate release tablets and sustained or extended-release tablets.

[0046] In another embodiment the sustained release pharmaceutical dosage form of the present invention, comprising tofacitinib and indomethacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier wherein said tofacitinib and indomethacin is embedded in a matrix which releases tofacitinib and indomethacin by diffusion.

[0047] Sustained Release — Matrix Systems (Tablets) In one embodiment, Tofacitinib & Indomethacin is incorporated into an erodible or non- erodible polymeric matrix tablet. By an erodible matrix is meant aqueous-erodible or water- swellable or aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution. When contacted with the aqueous use environment, the erodible polymeric matrix imbibes water and forms an aqueous-swollen gel or “matrix” that entraps the tofacitinib and indomethacin. The aqueous-swollen matrix gradually erodes, swells, disintegrates, disperses or dissolves in the environment of use, thereby controlling the release of tofacitinib and indomethacin to the environment of use. Examples of such dosage forms are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000.

[0048] A key ingredient of the water-swollen matrix is the water-swellable, erodible, or soluble polymer, which may generally be described as an osmopolymer, hydrogel or water-swellable polymer. Such polymers may be linear, branched, or crosslinked. They may be homopolymers or copolymers. Exemplary polymers include naturally occurring polysaccharides such as chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; alginates such as ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate; gelatin; collagen; and cellulosics. By “cellulosics” is meant a cellulose polymer that has been modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form an ester-linked or an ether-linked substituent. For example, the cellulosic ethyl cellulose has an ether linked ethyl substituent attached to the saccharide repeat unit, while the cellulosic cellulose acetate has an ester linked acetate substituent.

[0049] Cellulosics for the erodible matrix comprise aqueous-soluble and aqueous-erodible cellulosics such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethylcellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). A particularly preferred class of such cellulosics comprises various grades of low viscosity (MW less than or equal to 50,000 daltons) and high viscosity (MW greater than 50,000 daltons) HPMC. Commercially available low viscosity HPMC polymers include the Dow METHOCEL™ series E3, E5, E15LV, E50LV and K100LV, while high viscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M; especially preferred in this group are the METHOCEL™ K series. Other commercially available types of HPMC include the Shin Etsu METOLOSE™ 90SH series. In one embodiment, the HPMC has a low viscosity, meaning that the viscosity of a 2% (w / v) solution of the HPMC in water is less than about 120 cp. A preferred HPMC is one in which the viscosity of a 2% (w / v) solution of the HPMC in water ranges from 80 to 120 cp (such as METHOCEL™ K100LV).

[0050] Other materials useful as the erodible matrix material include, but are not limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acid derivatives such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0051] The erodible matrix polymer may also contain additives and excipients known in the pharmaceutical arts, including osmopolymers, osmagens, solubility-enhancing or — retarding agents and excipients that promote stability or processing of the dosage form.

[0052] In a non-erodible matrix system, tofacitinib and indomethacin are distributed in an inert matrix. The drug is released by diffusion through the inert matrix. Examples of materials suitable for the inert matrix include insoluble plastics, such as copolymers of ethylene and vinyl acetate, methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride, and polyethylene; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, and crosslinked polyvinylpyrrolidone (also known as crospovidone); and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides. Such dosage forms are described further in Remington: The Science and Practice of Pharmacy, 20th edition (2000).

[0053] In another embodiment of the present invention, the pharmaceutically acceptable carrier comprising the matrix material is selected from the group consisting of waxes, long chain alcohols, fatty acid esters, glycolized fatty acid esters, phosphoglycerides, polyoxyethylene alkyl ethers, long chain carboxylic acids, sugar alcohols, and mixtures thereof.

[0054] In another embodiment of the present invention, the matrix of the dosage form comprises hydroxypropyl methylcellulose in an amount from 1% to 60% total weight of the tablet, preferably 10% to 50% total weight of the tablet, and more preferably 20% to 40% total weight of the tablet and most preferably 30% of the total weight of the tablet.

[0055] In another embodiment of the present invention, tofacitinib and indomethacin is embedded in a matrix which releases tofacitinib and indomethacin by eroding.

[0056] In other embodiment of the present invention, the pharmaceutically acceptable carrier comprising fillers, or diluents include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof. The fdlers, or diluents may be present in an amount from 1% to 60% total weight of the tablet, preferably 10% to 50% total weight of the tablet, and more preferably 20% to 40% total weight of the tablet and most preferably 40% of the total weight of the tablet.

[0057] In another embodiment of the present invention, the matrix of the dosage may also include other conventional pharmaceutically useful excipients such as a binder, including HPC, HPMC, HEC, MC, and PVP, a tableting aid, such as microcrystalline cellulose, and a lubricant such as magnesium stearate. The binder may be present in an amount from 1% to 10% total weight of the tablet, preferably 1% to 5% total weight of the tablet, and most preferably 4% of the total weight of the tablet.

[0058] In some embodiments of the present invention, the matrix of the dosage may also include lubricants selected from the group consisting of stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate. In preferred embodiments the lubricant is selected from Magnesium stearate, Sodium stearyl fumarate, Stearic acid. The lubricant may be present in an amount from 0.1% to 5% total weight of the tablet, preferably 1% to 5% total weight of the tablet, and most preferably 1% of the total weight of the tablet.

[0059] Immediate Release Tablets:

[0060] In Some of the embodiments the present invention provides an immediate release dosage forms comprising Tofacitinib and indomethacin for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis, and Ulcerative Colitis or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments the immediate release dosage form according to the invention may contains pharmaceutically acceptable carrier or excipient includes without limitation any adjuvant, carrier, binder, lubricant, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0062] The diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments the diluent is microcrystalline cellulose and lactose monohydrate. The diluent may be present as intragranular and extragranular. The composition may comprise diluent in an amount from about 1% to about 80% total weight of the tablet, preferably about 50% to about 75% total weight of the tablet, and more preferably about 75% of the total weight of the tablet.

[0063] In some embodiments, the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum. In some embodiments, the disintegrating agent is croscarmellose sodium. The disintegrating agent may be present as intragranular and extragranular. The composition may comprise disintegrating agent in an amount from about 1% to about 5% total weight of the tablet, preferably about 2% to about 3% total weight of the tablet, and more preferably about 3% of the total weight of the tablet.

[0064] In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate. The composition may comprise lubricant in an amount from about 1% to about 5% total weight of the tablet, preferably about 1% to about 2% total weight of the tablet, and more preferably about 1.5% of the total weight of the tablet.

[0065] In some embodiments the binder is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), povidone (PVP) K29 / 32, hydroxypropylcellulose (HPC), ethylcellulose (EC), com starch, pregelatinized starch, gelatin, and sugar. The composition may comprise binder in an amount from about 1% to about 5% total weight of the tablet, preferably about 1% to about 2% total weight of the tablet, and more preferably about 12% of the total weight of the tablet.

[0066] In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate. The composition may comprise lubricant in an amount from about 1% to about 5% total weight of the tablet, preferably about 1% to about 2% total weight of the tablet, and more preferably about 1.5% of the total weight of the tablet.

[0067] The liquid pharmaceutical composition according to the invention comprises combination of Tofacitinib or a pharmaceutically acceptable salt thereof, a suitable buffer, a suitable tonicity agent, a suitable solubilizing agent, a suitable preservative, a suitable antioxidant, pH adjuster, water and a pharmaceutically acceptable excipient.

[0068] The present invention provides for a composition that may comprise at least one pH raising agent in an amount that raises the pH of the composition. In some embodiments, the pH raising agent comprises a buffer system. The term “buffer system” refers to a component present in a composition or solution which may provide a resistance to significant change in pH caused by a strong acid or base. A buffer system may comprise a single agent or more than one agent, such as a weak acid and its conjugate base. A buffer system may provide a resistance to a significant pH change by interacting with a strong acid or strong base in a composition or solution, thereby at least partially preventing the pH of the composition or solution from changing significantly.

[0069] Generally, a buffer system has one or more buffer ranges wherein the buffer system has the ability to provide resistance to significant pH change. When a composition or solution comprising the buffer system has a pH inside the buffer system's buffer range, the pH of the composition or solution will not change significantly with the addition of equimolar amounts of a strong acid or strong base. The suitable buffers include, but are not limited to, phosphate buffers, acetate buffer.

[0070] In some embodiments, the pH raising agent may have a buffer range from a pH of about 4 to 8, preferably from a pH of about 6 to 8.

[0071] The present invention provides for a composition that can optionally comprise one or more solvents. In some embodiments, the solvent may be acceptable for pharmaceutical administration. Examples of methods of pharmaceutical administration include, but are not limited to, subcutaneous, intracameral, intravenous, and intramuscular injection, infusion, intra-arterial administration, intracardiac injection, endotracheal administration, intraosseous administration, oral inhalation, topical administration, and as ophthalmic irrigation.

[0072] Preferably, the solvent comprises one or more of acetic acid, acetone, acetonitrile, animal oil, aqueous buffer, benzene, bisabolol, butanol, carbon tetrachloride, chlorobenzene, chloroform, dimethylformamide, dioxane, essential oil, ethanol, ethyl acetate, ethyl oleate, ethylene chloride, fatty acid esters, glycerin, glycofurol, hexane, hydrogenated vegetable oil, isopropanol, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, methanol, methylene chloride, mineral oil, polyethylene glycol, polyol, propylene glycol, silicone fluid glyceride, squalane, terpene, tetrahydrofuran, toluene, triacetin, tributyl citrate, triethyl citrate, vegetable oil, and / or water. Preferably the solvent comprises ethanol.

[0073] The following examples further describe and demonstrate embodiments within the scope of the present Invention. The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the Invention.

[0074] Example 1:

[0075] Table 1: Injectable Formulation containing Tofacitinib

[0076] Example 2

[0077] Tablet 2: Tofacitinib + Indomethacin Extended-Release Tablets

[0078] Example 3:

[0079] Table 3: Injectable Formulation with Tofacitinib + Indomethacin

[0080] Example 4:

[0081] Effect of Orally Administered Tofacitinib in combination with Indomethacin in Rat Model of Inflammatory Pain

[0082] Method

[0083] The effect of orally and intravenously administered Tofacitinib in combination with Indomethacin on Rheumatoid Arthritis were examined using the rat complete Freund's adjuvant (CFA) model. Rheumatoid Arthritis was induced by injection of 100% CFA in a 75 pL volume into the left hind paws of Wistar rats in two doses. Initial prime dose on Day 1 and followed by booster dose on day 7. On 14thday all Rheumatoid Arthritis induced animals were checked for induction by physical parameters like increased paw volume, ankle diameter, redness and swelling at the ankle joint with pain sensitivity and tenderness to touch reflex. The Paw volumes, ankle diameter and photographs of paws were recorded.

[0084] The arthritis induced animals were grouped under six different groups which includes Group 1 : Disease control (no treatment)

[0085] Group 2: Tofacitinib alone (injection)

[0086] Group 3: Indomethacin alone (injection)

[0087] Group 4: Combination of Tofacitinib and Indomethacin (oral)

[0088] Group 5: Combination of Tofacitinib and Indomethacin (injection)

[0089] Group 6: Sham

[0090] The Group 2 is administered with Composition 1 disclosed in Example 1. The Group 3 is administered with Indomethacin solution. The Group 4 is administered with Composition 3 disclosed in Example 2. The Group 5 is administered with Composition 4 disclosed in Example 3. Treatment doses were administered daily for 14 consecutive days. Doses were selected based on pharmacologically relevant levels known to be effective in rodent models. The dosing schedule is provided in the Table 4.

[0091] Table 4: Dose schedule for Disease control group, Tofacitinib Injection Group, Indomethacin injection group, Tofacitinib + Indomethacin injection group, Tofacitinib + Indomethacin oral group and Sham group. Results:

[0092] The combination of Tofacitinib and Indomethacin significantly reduced arthritic pain and swelling compared when compared to Tofacitinib and Indomethacin administered alone. A 14- day treatment regimen, administered either orally or via injection, demonstrated efficacy in alleviating these symptoms. As illustrated in Figure 1, animals receiving the combination therapy demonstrated a significant improvement in body weight retention relative to the disease control group and both monotherapy groups. Figure 2 and Figure 3 show the reduction in paw thickness and paw volume, respectively. The combination-treated groups exhibited statistically significant improvements in both parameters when compared to animals receiving Tofacitinib alone, Indomethacin alone, and the disease control. To further evaluate the anti-inflammatory potential of the combination therapy, serum cytokine levels were measured at the end of the study period. Samples from the disease control group and the combination treatment group were analyzed. As shown in Figure 4, animals treated with the combination of Tofacitinib and Indomethacin exhibited a marked reduction in tumour necrosis factor-alpha (TNF-a) levels relative to the disease control group. Additionally, as illustrated in Figure 5, treatment with the combination therapy resulted in a significant increase in interleukin- 10 (IL- 10) levels, a cytokine associated with anti-inflammatory activity. The findings indicate that the combination therapy of Tofacitinib and Indomethacin, administered either orally or by injection, offers enhanced therapeutic efficacy in the treatment of inflammatory arthritis compared to treatment with either agent alone.

Claims

Claims:

1. A method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis in a mammal in need thereof, comprising administering a therapeutically effective amount of tofacitinib and indomethacin, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the mammal is a human being that receives a total daily dose of Tofacitinib citrate that is about 1 mg to about 10 mg.

3. The method of claim 1, wherein the mammal is a human being that receives a total daily dose of Indomethacin that is about 1 mg to about 40 mg.

4. The method of claim 1 to 3, wherein the total dose is administered as once daily or twice daily.

5. A method of treating Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis and Ulcerative Colitis in an individual in need thereof, comprising administering an oral solid dosage form comprising Tofacitinib and indomethacin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. The method of claim 5, wherein the oral solid dosage form is a tablet or capsule.

7. The method of claim 5, wherein the Tofacitinib is present in an amount ranging from about 1 mg to about 10 mg.

8. The method of claim 5, wherein the Tofacitinib is in the form of tofacitinib citrate.

9. The method of claim 5, wherein the oral solid dosage form provides modified release of one or both of Tofacitinib and indomethacin.

10. The method of claim 5, wherein the oral solid dosage form is administered once daily.

11. The method of claim 5, wherein the pharmaceutically acceptable carrier comprises a diluent, binder, disintegrant, and lubricant.

12. A method of treating Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Polyarticular Course Juvenile Idiopathic Arthritis and Ulcerative Colitis in an individual in need thereof, comprising administering an injectable liquid dosage form comprising Tofacitinib and indomethacin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. The method of claim 12, wherein the injectable liquid dosage form is administered via subcutaneous injection.

14. The method of claim 12, wherein the injectable liquid dosage form is administered via intravenous injection.

15. The method of claim 12, wherein the Tofacitinib citrate is present in a concentration ranging from about 0. 1 mg / mL to about 10 mg / mL.

16. The method of claim 12, wherein the indomethacin is present in a concentration ranging from about 2 mg / mL to about 50 mg / mL.

17. The method of claim 12, wherein the wherein the pharmaceutically acceptable carrier comprises buffering agent, preservatives and solvents.

18. The method of claim 17, wherein the injectable liquid dosage form comprises a buffering agent selected from citrate, phosphate, or acetate buffers.

19. The method of claim 17, wherein the injectable liquid dosage form comprises a solvent selected from aqueous and non-aqueous.

20. The method of claim 12, wherein the injectable liquid dosage form has a pH in the range of about 4.0 to about 8.0.

Images