Long-acting parenteral formulations of tofacitinib and tofacitinib salts

Abstract

The present invention relates to long-acting parenteral formulations of tofacitinib comprising of tofacitinib or its fatty acid salts along with pharmaceutically acceptable excipients.

Description

[0001]LONG-ACTING PARENTERAL FORMULATIONS OF TOFACITINIB AND TOFACITINIB SALTS FIELD OF INVENTION The present invention relates to long-acting parenteral formulations of tofacitinib comprising of tofacitinib or its fatty acid salts along with pharmaceutically acceptable excipients. These formulations are used for the treatment of rheumatoid arthritis and other related conditions. BACKGROUND OF THE INVENTION Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the unresolved synovial inflammation. This remains one of the significant causes of disability and labour loss, affecting the population globally. It is characterized by the persistent uncontrollable synovitis, as well as pannus and bone erosion. Tofacitinib, a JAK inhibitor, is approved for the treatment of moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PA), ankylosing spondylitis (AS), ulcerative colitis (UC), and polyarticular course juvenile idiopathic arthritis (pcJIA). Tofacitinib (XELJANZ) is marketed as oral tablets of 5 mg and 10 mg; extended-release oral tablets of 11 mg and 22 mg and oral solution of 1mg / mL. The absolute oral bioavailability of Tofacitinib is 74%. Rapid peak plasma concentrations are reached within 0.5-1 hour. Due to its short elimination half-life of about 3 hours, regular dosing is required to maintain consistent therapeutic levels. US Patent application No. US20140357557 (A1) to Cerulean Pharma INC, discloses a novel compositions of therapeutic cyclodextrin-containing polymers (CDPs) conjugated to a JAK inhibitor and methods of use thereof. US Patent Application No. US20200281857 (A1) to Dauntless Inc., discloses single emulsion microspheres comprising a JAK inhibitor and one or more polymers. Wherein the polymers are selected from poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolide, poly(glycolide- co- lactide) (PLG), polyhydroxybutyrate, poly(sebacic acid), polyphosphazene, PLA- polyethyleneglycol (PEG)-PLA triblock copolymer, or PLG-PEG-PLG triblock copolymer. PCT Publication No. WO2020236950 (A1) to Dauntless Inc., discloses single emulsion microspheres comprising a therapeutic compound or pharmaceutically acceptable salt thereof, is a JAK inhibitor and a poly (lactic-co-glycolic acid) (PLGA) polymer comprising at least one hydrophilic terminus. US Patent Application No. US20180085452 (A1) to Reinhard et al., describes tofacitinib parenteral compositions and methods using hydrogel-embedded tolerance-promoting adjuvants for allergen- or autoantigen-specific immunotherapy. PCT Publication No. WO2017119936 (A1) to Abon Pharmaceuticals LLC, discloses non-aqueous long acting injectable formulations containing a poorly water- soluble active pharmaceutical ingredient; and (ii) a non-aqueous liquid vehicle and (iii) an amphiphilic agent. The prior arts disclose various formulations for JAK inhibitors aimed at enhancing their solubility and stability. These include the use of cyclodextrin-containing polymer conjugates and polymeric microsphere systems incorporating multiple polymers or use of poly (lactic-co-glycolic acid) (PLGA). However these present several challenges and involve complex multi-step synthesis, stringent processing conditions, and the use of organic solvents. Such methods can exhibit variable encapsulation efficiency, batch-to-batch inconsistency, and require specialized manufacturing equipment. Alternative hydrogel-based and non-aqueous liquid vehicles similarly face limitations in scalability, reproducibility, and regulatory acceptance. A particular concern with PLGA-based systems is the risk of polymer accumulation at the injection site and unpredictable biodegradation kinetics, which may lead to local irritation or inconsistent drug release profiles. Furthermore, conjugation strategies involving cyclodextrin polymers can introduce additional chemical steps and purification requirements, increasing production cost and complexity. Current microsphere and matrix approaches may also suffer from initial burst release or incomplete drug recovery over the intended dosing interval. As a result, there remains a need for parenteral delivery platforms that avoid reliance on PLGA polymers, reduce manufacturing complexity, and deliver controlled, long-acting release of tofacitinib. SUMMARY OF THE INVENTION One aspect of the present invention is to formulate a long acting parenteral formulations comprising of tofacitinib or its fatty acid salts. Another aspect of the invention is to provide a long acting parenteral formulation of tofacitinib or its fatty acid salts free of PLGA polymers. Another aspect of the invention is to formulate a long acting parenteral formulation comprising tofacitinib or its fatty acid salt form as suspension, lyophilized powder or dry powder to be reconstituted as suspension for delayed release of drug. Another aspect of the present invention is to formulate a parenteral formulation having release over prolong period of time, preferably one week to up to six months time period. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: In vitro% drug release of 1C formulation Figure 2: In vitro% drug release of 3B formulation DETAILED DESCRIPTION OF THE INVENTION The term “long acting” in the present invention refers release over a long period of time, preferably one week to up to 6 months time period. The term “tofacitinib” in the context of the present invention relates to tofacitinib as free base or laurate, stearate, decanoate, undecanoate and pentadecanoate salts thereof. As used herein, “lyophilized formulation” refers to a drug substance or formulation that is manufactured by freeze-drying, wherein water / solvent(s) is removed from the product by sublimation, resulting in a dry powder or cake that can be reconstituted with a suitable diluent prior to administration. “Dry powder” refers to a drug substance or formulation that is obtained by removal of solvent from solution or suspension resulting in powder form prepared by using spray drying, tray drying, supercritical fluid process, fluidized drying process, powder layering, vacuum drying and similar processes known in the art. As used herein, “diluent” shall mean solution or vehicle used to reconstitute the drug substance or formulated product, or vehicle used in manufacturing to suspend the drug substance. The diluent can be aqueous or non-aqueous or mixture of aqueous and non-aqueous components and where necessary shall comprise of pharmaceutically acceptable excipients. Rheumatoid arthritis and related autoimmune conditions present significant challenges in treatment due to the need for consistent therapeutic drug levels over extended periods. Current formulations of tofacitinib require frequent dosing due to the drug's short half-life, leading to patient compliance issues and fluctuating plasma concentrations. The present invention addresses these limitations by providing long-acting parenteral formulations of tofacitinib or fatty acid salts thereof, to deliver controlled and sustained drug release over a period ranging from one week to six months. These formulations eliminate reliance on PLGA polymers, which are associated with adverse effects, complex manufacturing processes, and inconsistent drug release profiles. The formulation is designed as either a ready-to-use suspension or a lyophilized powder or dry powder that can be reconstituted prior to administration using a diluent. The suspension or reconstituted product contains a particle size distribution, typically in the range of about 0.5 µm to 100 µm, and more preferably from about 1.5 µm to 30 µm. This ensures optimal depot formation and sustained release at the injection site. The formulation is designed as a ready to use suspension where in lyophilized powder or dry powder is formulated as a stable suspension using diluent and filled into unit dose containers. The formulations of the present invention comprise tofacitinib or the fatty acid salt and other pharmaceutically acceptable excipients. The content of tofacitinib ranges from 1 % w / v to about 10% w / v. The excipients in the formulation may include surfactants, suspending agents, polymers, buffering agents, osmolality adjusting agents, thickening agents, lipids, fatty acids, fatty acid derivatives, preservatives, solvents, solubilizers and diluents. The formulations may also comprise flavonoids, phenolic compounds, phytosterols, polysaccharides where one or more agents are selected from quercetin dihydrate, betasitosterol, chondroitin sulfate, sinapic acid and its derivatives, pentadecanoic- L- carnitine, N-acetyl glucosamine and hyaluronate or its derivatives, gelatin, which may have synergistic effect. The term surfactant in the present invention relates to anionic, cationic, non-ionic, amphoteric surfactants. The surfactants may be selected from polyethylene glycols, polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40, sorbitan diisostearate, polyoxyethylene fatty acid esters, ethylene oxide / propylene oxide copolymers like Poloxamer P182, Poloxamer P407, Poloxamer P188, Poloxamine 908, sorbitan monolaurate, sorbitan monooleate and sorbitan monopalmitate, glycerol esters of fatty acids such as glyceryl monooleate, glyceryl monostearate, behenic acid and glyceryl behenate, alkali salts of fatty acids such as sodium caprylate, sodium caprate and also other sugar esters of fatty acids such as Ryoto sugar esters having HLB of 1 to 17 are RyotoTMSugar Ester (P-1670), Ryoto Sugar Ester (P-170) also known as sucrose palmitate 1670, sucrose palmitate (P-170) and Ryoto Sugar Ester (O-170) sucrose oleate. Surfactants also include, lecithins, (having HLB value below 10), hydrogenated lecithin, egg lecithin (egg lipoid), soy lecithin (soya phosphatidylcholine hydrogenated (Lipoid SPC-3)), PEGylated phospholipids, lysophosphatidylcholine and pentadecanoyl–L Carnitine. The surfactant quantity ranges from about 0.1 % w / v to 20 % w / v. The term fatty acids in the present invention relates to fat soluble components comprising saturated and unsaturated fatty acids having C4-C24 hydrocarbon chains. These fatty acids may be selected from palmitic acid, stearic acid (also known as octadecanoic acid), myristic acid, lauric acid, dodecanoic acid, decanoic acid, pentadecylic acid, also known as pentadecanoic acid and undecanoic acid. If present, their content may be in the range of 0.1 % w / v to 30 % w / v, more preferably present in the range from about 0.1 % w / v to 10 % w / v. The osmolality adjusting agents or tonicity adjusting agents are selected from but not limited to mannitol, sorbitol, lactose, sodium chloride, potassium chloride, phosphate buffers, dextrose, sugars, and glycerin. The viscosifying agents may be selected from sodium alginate, hyaluronic acid, gelatin, cellulose derivatives including methylcellulose, carboxy methyl cellulose, hydroxypropyl methylcellulose, hydroxy ethyl cellulose, PEG derivatives, Pegylated lipids or phospholipids, polyvinyl derivatives and starch derivatives. Buffers may be used to maintain the pH within a physiologically acceptable range, typically between 4.0 and 8.0. Preferably the pH is in the range of 4.5 to 7.8. These may be selected from acetate, phosphate, tris and citrate, or alkali salts, including, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, sodium acetate, sodium sulfide, sodium bicarbonate, alkaline amino acids and amino acids including, arginine, histidine, glycine, lysine, aspartic acid, glutamic acid, organic amines, mineral acids, carboxylic acids, and amino sugars. The solvents may be selected from N-methyl- 2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), ethanol, ethers, acetone, dimethyl acetamide (DMA), tertiary butyl alcohol (TBA), acetonitrile and dimethyl formamide (DMF), dimethyl isosorbide (DMI), alcohols, ethers, ketones, chlorinated solvents like dichloromethane and chloroform. These solvents may be used in the lyophilization or other drying processes and may be removed in the process. The polymers are used to control the release of tofacitinib over a period of time and may be selected from Polycaprolactone PCL1002, Polycaprolactone PCL1005, Sucrose acetate isobutyrate (SAIB) and sodium alginate. The content of polymers ranges from 0% w / v to 15% w / v. In the present invention parenteral formulations of tofacitinib or its fatty acid salt forms are filled into suitable containers or into prefilled injectable device. The pharmaceutical formulations may be administered parenterally via intravenous, subcutaneous, intracutaneous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial routes. The administration results in the formation of a depot at the injection site which acts as a drug reservoir and maintains therapeutic effects over a prolonged period of time. The formulations may be processed using milling, conventional mixing, high shear homogenization, high pressure homogenization, probe sonication, solvent evaporation, co-precipitation, solvent-anti-solvent method, SPG (Shirasu porous glass membranes), matrix and direct suspension. The vehicle for formulating the suspension may be selected from aqueous vehicle comprising of buffers, solvents, cosolvents, water or combination of these. The lyophilized product may be reconstituted with a suitable diluent before use. The diluents for reconstitution are selected from water for injection (WFI), saline (0.9% NaCl), 5% dextrose solution, Ringer's solution, lactated Ringer's solution, aqueous buffers, aqueous solutions comprising of cosolvents and optionally with buffers. The formulations have excellent stability where samples stored at accelerated conditions (40°C ± 2°C / 75% RH ± 5% RH) for 1 week showed no significant change in physical or chemical parameters. The assay remained almost unchanged and there is no increase in impurities. In one embodiment, the parenteral formulations of tofacitinib comprises of: i. Tofacitinib i. surfactants, ii. one or more pharmaceutically acceptable excipients In another embodiment, the parenteral formulations of tofacitinib comprises of: i. Tofacitinib or its salt ii. surfactants, iii. polymer iv. one or more pharmaceutically acceptable excipients According to the present invention below are few manufacturing procedures to formulate parenteral formulations of tofacitinib and are not intended to limit the scope of the invention. 1. General manufacturing procedure for direct suspension method The solvent phase was prepared by mixing ethanol, Soya phosphatidylcholine hydrogenated (Lipoid SPC-3), and optionally pentadecanoic acid, then heated and stirred at 40^°C and 300^rpm until a uniform solution was obtained. The aqueous phase was prepared by mixing pH 7.4 phosphate buffer, poloxamer P 407 followed by addition of osmolality adjusting agent optionally, then heated and stirred at 30^°C and 300^rpm until a uniform solution was obtained. The prepared solvent and aqueous phases were premixed under stirring at 500^rpm until a homogeneous mixture (“Diluent”) was obtained. To this diluent tofacitinib freebase or tofacitinib pentadecanoate was added and stirred at 300^rpm until a homogeneous solution is obtained. Optionally hyaluronic acid or gelatin solution was prepared by dissolving hyaluronic acid in pH 7.4 phosphate buffer with stirring at 300^rpm uniform. Further reconstitution with hyaluronic acid solution was carried out by dropwise addition to the mixture under stirring at 500^rpm for 10 minutes until uniform. Finally the pH was measured and if required pH was adjusted with histidine, volume was adjusted with phosphate buffer (pH 7.4), and the formulation was stored at room temperature. Example 1 1A 1B S.No Ingredientsmg / mL %w / v mg / mL %w / v 1 Tofacitinib Freebase 61.41 6.141 61.41 6.141 2 Poloxamer P407 7.5 0.75 7.5 0.75 Soya phosphatidylcholine 3 2.5 0.25 2.5 0.25 hydrogenated 4 Ethanol 5 0.5 5 0.5 5 Hyaluronic acid - - 3 0.3 Qs to Qs to Qs to Qs to 6 Phosphate buffer pH 7.4 1mL 100% 1mL 100% Table 1: Initial physical parameters and assay details of formulation 1A at room temperature Description Milky white color suspension Osmolality (mOsm / kg) 235 Viscosity(m.Pass) 3.986 Assay of Tofacitinib (% w / w) 100.2 Example 1.1 1C 1D S.No Ingredientsmg / mL %w / v mg / mL %w / v 1 Tofacitinib Freebase - - 64.33 6.433 Tofacitinib Pentadecanoic 2 60 6 - - acid salt 3 Poloxamer P407 7.5 0.75 3 0.3 4 Gelatin - - 3 0.3 Soya phosphatidylcholine 5 5 0.5 2.5 0.25 hydrogenated 6 Ethanol 20 2 7.5 0.75 7 Histidine 30 3 - - Qs to Qs to Qs to Qs to 8 Phosphate buffer pH 7.4 1mL 100% 1mL 100% Table 2: Initial Physical parameters and assay details of formulation 1C at room temperature Description Milky white color suspension Osmolality (mOsm / kg) 839 Viscosity(m.Pass) 12.202 Assay of Tofacitinib (% w / w) 99.6 Table 3: Initial and 1 week physical parameters, assay and related substances details of formulation 1D ParametersInitial 1W-40°CDescription Milky white color Milky white color suspension suspension pH7.27 6.87Osmolality (mOsm / kg)293 336Viscosity ( m.Pass)6.3967 7.6083Assay of Tofacitinib (% w / w)101.7 101.3Related Substances (% w / w)0.06 0.06In vitro Dissolution conditions and % Drug release of 1C formulation Table No.4: In vitro Dissolution conditions of IC formulation Dissolution Apparatus USP-II Dissolution Media pH 7.4 Phosphate Buffer (USP) Temperature 37°C RPM 50 Media volume 2000 mL Membrane 12-14 kd Spectrum Spectra / Por 4 Dialysis membrane Table No.5: In vitro % Drug release of 1C formulation Cumulative Amount of drug Amount of drug released Days released (mg) per day (mg) Day-18 66.69 2.34 Day-19 66.15 -0.54 Day-20 67.68 1.53 Day-21 68.85 1.17 Day-22 70.20 1.35 Day-23 72.45 2.25 Day-24 74.70 2.25 Day-25 74.70 0.00 Day-26 76.95 2.25 Day-27 79.92 2.97 Average amount (mg) released per day in last 10 days (day 18 to 27): 1.56 mg2. Method for preparation of ready to use suspension using solvent evaporationOrganic phase was prepared by dissolving tofacitinib freebase in acetonitrile, tert- butyl alcohol, SAIB, decanoic acid, and optionally PCL1005 / PCL1002. The mixture was stirred at 500 rpm for 5 minutes at 50^°C until fully dissolved. Aqueous phase was prepared by dissolving Poloxamer P188 and mannitol in pH 7.4 phosphate buffer by stirring at 500 rpm for 5 minutes at 50^°C. The organic phase was evaporated using a rotary evaporator at 50^°C, 100 rpm, under 145 mbar (acetonitrile) and 340 mbar (tertiary butyl alcohol) vacuum. The residue was reconstituted with the aqueous phase and probe-sonicated at 40^°C, 40% amplitude, for 5 minutes (1 min on / 20 sec off pulse). Final volume was adjusted with pH 7.4 buffer and stored at room temperature. Example 2 2A 2B S.No Ingredientsmg / mL %w / v mg / mL %w / v 1 Tofacitinib Freebase 68.83 6.883 68.83 6.883 2 Sucrose Acetate Isobutyrate 30 3 30 3 3 Acetonitrile 50 5 50 5 4 Tertiary butyl alcohol 30 3 30 3 5 Decanoic acid 30 3 30 3 6 Poloxamer P188 10 1 10 1 7 Polycaprolactone (PCL1005) - - 5 0.5 8 Polycaprolactone (PCL1002) 5 0.5 - - 9 Mannitol 40 4 40 4 Qs to Qs to Qs to Qs to 10 Phosphate buffer pH 7.4 1mL 100% 1mL 100%3. Manufacturing procedure of ready to use suspension using SPG membranes(Shirasu porous glass membranes) Aqueous phase was prepared by addition of pH 7.4 phosphate buffer and poloxamer P 407 to a manufacturing vessel, followed by stirring at 500rpm for 5 minutes at 50^°C until dissolved. Organic phase was prepared by adding Tofacitinib freebase or Tofacitinib Pentadecanoic acid salt in DMSO or NMP or DMA or DMF or DMI and Soya phosphatidylcholine hydrogenated (Lipoid SPC-3), (with / without pentadecanoic acid) in ethanol, stirred for 500 rpm for 5 minutes at 50^°C, until dissolved in a manufacturing vessel. The prepared aqueous and organic phases were processed using SPG (Shirasu Porous Glass) under the following conditions: 1-hour process time, 0.2 mbar pressure, and a 0.5^µm, 1.1^µm, or 2^µm hydrophobic membrane. The above prepared suspension (formulation) was subjected for filtration and residue was washed with water to remove solvent by filtration. Further in preparing redisperse phase surfactant (Poloxamer P407 or P188) and osmolality adjusting agent were dissolved in pH 7.4 phosphate buffer with stirring at 500 rpm for 5 minutes. The residue was then stirred for 20 minutes until homogeneous. Finally the pH was measured, volume adjusted with pH 7.4 phosphate buffer, and the formulation was stored at room temperature. Example 3 3A 3B S.No Ingredientsmg / mL %w / v mg / mL %w / v 1 Tofacitinib Freebase 61.412 6.1412 61 6.1 2 Dimethyl sulfoxide 300 30 300 30 3 Ethanol 10 1 10 1 4 Pentadecanoic acid - - 46.5 4.65 5 Poloxamer P 407 5 0.5 5 0.5 6 Soya phosphatidylcholine 5 0.5 2.5 0.25 hydrogenated Qs to Qs to Qs to Qs to 7 Phosphate buffer pH 7.4 1mL 100 1mL 100 Table 6: Initial physical parameters and assay details of formulation 3B at room temperature Description Milky white colour suspension Osmolality (mOsm / kg) 293 Viscosity(m.Pass) 9.8385 Assay of Tofacitinib (% w / w) 99.6 In vitro Dissolution conditions and % Drug release of 3B formulation Table No.7: In vitro Dissolution conditions of 3B formulation Dissolution Apparatus USP-II Dissolution Media pH 7.4 Phosphate Buffer (USP) Temperature 37°C RPM 50 Media volume 2000 mL Membrane 12-14 kd Spectrum Spectra / Por 4 Dialysis membrane Table No.8: In vitro % Drug release of 3B formulation Cumulative Amount of drug Amount of drug released per Days released (mg) day (mg) Day-18 99 3.24 Day-19 101.34 2.34 Day-20 103.5 2.16 Day-21 107.28 3.78 Day-22 111.78 4.5 Day-23 110.88 -0.9 Day-24 115.38 4.5 Day-25 115.2 -0.18 Day-26 119.34 4.14 Day-27 121.5 2.16 Average amount (mg) released per day in last 10 days ( day 18 to 27): 2.574 mg 4. Manufacturing process of ready to use suspension with high shear homogenization procedure and probe sonication Suspension was prepared by dissolving poloxamer P188, mannitol, and sodium caprylate in pH 7.4 phosphate buffer and followed by dispersing the tofacitinib freebase or tofacitinib pentadecanoate, with stirring at 500 rpm for 5 minutes. The above suspension was homogenized at 6000 rpm for 30 minutes, followed by probe sonication at 35^°C, 60% amplitude, for 20 minutes (1 min on / 20 sec off). The sonicated suspension was mixed with the sodium alginate solution at 500 rpm. The volume was adjusted with pH 7.4 buffer and stored at room temperature. Example 4 4A 4B S.No Ingredients mg / ml %w / v mg / ml %w / v 1 Tofacitinib Freebase 10.48 1.048 - - 2Tofacitinib Pentadecanoic acid salt- - 18.12 1.8123 Mannitol 30 3 30 3 4 Sodium alginate 8 0.8 8 0.8 5 Polaxamer P188 5 0.5 5 0.5 6 Sodium caprylate 1 0.1 0.5 0.05 Qs to Qs to Qs to Qs to 7 Phosphate buffer pH 7.4 1 mL 100% 1 mL 100% 5. Manufacturing process for Lyophilized product by freeze drying method The compositions in the present invention may be manufactured by solvent evaporation followed by emulsification using high shear homogenization and probe sonication or high pressure homogenization. Solvent evaporation is achieved by reduced pressure or vacuum evaporation or lyophilization. Preparation of organic phase: Dissolve API in acetonitrile and tertiary butyl alcohol in a beaker and dissolve egg lecithin in ethanol in another beaker, both the solutions are premixed followed by cyclomixing and evaporation or removal of solvent either by evaporation or lyophilization. Reconstitution process: The powder residue obtained from the above process was added to required quantity of diluent containing buffer, poloxamer, viscosifying agent and osmolality adjusting agent so as to get the target concentration of the final product. Example 5 S. No. Ingredients mg / ml ¾w / vOrganic phase 1. Acetonitrile 340 34 2. Tertiary butyl alcohol 680 68 3. Tof'acitinib Freebase 10.55 1.055 4. Tofacitinib Pentadecanoic acid 18.12 1.812 5. Ethanol 40 4 6. Egg lecithin 25 0.25 Reconstitution solution 7.Sodium chloride 40.48. Gelatin 10 l 9. Poloxamer Pl 88 10 1 10. Phosphate buffer pH 7.4 Qs to 1 ml Qs to 100%

Claims

or the fatty acid salt of tofacitinib in the composition is from about 0.5 µm to about 100 µm.

8. The composition of claim l, wherein the composition is administered via a routeselected from intravenous, subcutaneous, intracutaneous, intramuscular, intra­ articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial.

9. The composition ofclaim l, wherein the composition is used for the treatment ofrheumatoid arthritis or a related autoimmune condition by parenteraladministration to a subject in need thereof.

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