The invention relates to an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients. The present invention further provides a process for preparing such compositions and their use thereof to treat inflammatory or autoimmune diseases/disorders.

BACKGROUND OF THE INVENTION

Upadacitinib is described chemically as: (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2- a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1).

Upadacitinib is an oral small molecule inhibitor of the Janus associated kinases (JAK) being proposed for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). Upadacitinib is currently being marketed in United States under the brand name RINVOQ ® as extended release 15mg tablet.

U.S. Patent No. 8,962,629 and U.S. Patent No. RE47221 discloses upadacitinib as product.

U.S. Publication No. 20190322677 discloses method of treating moderately to severely active rheumatoid arthritis in a subject in need thereof comprising orally administering once daily to the subject (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-- trifluoroethyl)pyrrolidine-1-carboxamide.

U.S. Publication No. 20150118229 discloses method of treating in a human an autoimmune disease or disorder, or an inflammatory disease or disorder, the method comprising administering to said human an effective amount of the free (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1carboxamide.

U.S. Patent No. 9,951,080 discloses the crystalline hemihydrate of upadacitinib.

PCT Publication No. WO 2020/063939 A1 discloses crystalline form CSI of upadacitinib with XRD peaks.

PCT Publication No. WO 2020/177645 A1 discloses crystalline form CSII of upadacitinib with XRD peaks.

IN 201741010259 discloses amorphous upadacitinib or a salt thereof, its amorphous solid dispersion and pharmaceutical compositions thereof.

PCT Publication No. WO 2020/115213 A1 discloses solvate comprising upadacitinib and acetic acid.

U.S. Patent No. 9,963,459, U.S. Patent No. 10,519,164, U.S. Patent No. 10,202,393, U.S. Patent No. 10,202,394, and U.S. Patent No. 10,344,036 disclose extended release solid dosage form comprising upadacitinib or a pharmaceutically acceptable salt thereof, an acidic pH modifier; and a release controlling hydrophilic polymer.

Therefore, there exists a need in the art to develop an alternate pharmaceutical composition of upadacitinib which would be bioequivalent to marketed formulation i.e. Rinvoq®.

SUMMARY OF THE INVENTION

According to one aspect, the present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a release controlling agent and optionally one or more pharmaceutically acceptable excipients.

According to second aspect, the present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, wherein the composition does not contain release controlling hydrophilic polymer.

According to third aspect, the present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) optionally a film coating over the extended release core.

According to fourth aspect, the present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) optionally a film coating over the extended release core,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer.

According to fifth aspect, the present invention provides an extended release oral pharmaceutical composition comprising:
a) a core, wherein the core comprises upadacitinib, optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer.

According to sixth aspect, the present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises a homogeneous mixture of upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the extended release core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer.

According to one embodiment, the hydrophobic release controlling agent is selected from the group comprising waxes, fatty acids, fatty alcohols, fatty acids esters, glycerides, oils, silicones, silicates and/or mixtures thereof.

According to another embodiment, the hydrophobic release controlling agent is selected from the group comprising glyceryl monostearate, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax, cetyl alcohol, calcium silicate, stearic acid and/or mixtures thereof.
According to another embodiment, the pharmaceutically acceptable excipient is selected from the group comprising diluent/filler, binder, pH modifier, glidant and lubricant.

According to another embodiment, the pharmaceutical composition as per the present invention is useful for the treatment of autoimmune or inflammatory diseases or disorders.

According to yet another embodiment, the present invention provides a process for preparing an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, wherein said pharmaceutical composition does not contain hydrophilic release controlling polymer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a release controlling agent and optionally one or more pharmaceutically acceptable excipients.

The present invention provides an extended release pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients. It further provides the processes for preparing such compositions and their methods of use.

The present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, wherein the composition does not contain release controlling hydrophilic polymer.

The term “upadacitinib” used herein refers to a pharmaceutically active molecule as well as its pharmaceutically acceptable and therapeutically active salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, analogues, etc. that induce a desired pharmacological or physiological effect. The term also includes all polymorphic forms, whether crystalline or amorphous.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive components that are useful in preparing a dosage form and which are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient.

The term “composition” or “solid oral composition” or “dosage form” or “pharmaceutical composition” or “formulation” as used herein synonymously include tablet, granules in a tablet, pellets, pellets in a tablet, capsules, powder, or any other suitable dosage form meant for oral administration.

The term “extended release” as used herein refers to designed to slowly release a drug in the body over an extended period of time.

The present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or pharmaceutically acceptable salts, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients wherein the composition comprises about 5 mg to about 100 mg of upadacitinib or its pharmaceutically acceptable salts, ester, solvates, polymorphs thereof. Preferably the composition comprises from about 7.5 mg to about 45 mg of upadacitinib. Most preferably, about 15 mg of upadacitinib.

The present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, wherein the upadacitinib is present in crystalline form or amorphous form.

The present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, wherein the upadacitinib is having the particle size of D90 less than about 200µ (microns).

The present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises a homogeneous mixture of upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) optionally a film coating over the extended release core.

The present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises a homogeneous mixture of upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) optionally a film coating over the extended release core,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer.

The present invention provides an extended release oral pharmaceutical composition comprising:
a) a core, wherein the core comprises upadacitinib, optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating.

The present invention provides an extended release oral pharmaceutical composition comprising:
a) a core, wherein the core comprises upadacitinib, optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer.

The present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises a homogeneous mixture of upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the extended release core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating.
The present invention provides an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises a homogeneous mixture of upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the extended release core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer.

The present invention provides an extended release oral pharmaceutical composition comprising upadacitinib or its pharmaceutically acceptable salts thereof, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, wherein the part of hydrophobic release controlling agent is incorporated in matrix and another part of hydrophobic release controlling agent is incorporated in coating.

Suitable hydrophobic extended release agent includes polymeric as well as non-polymeric agents.
Hydrophobic non-polymeric agents include waxes such as white wax, paraffin, bees wax, carnauba wax and the like; fatty acids such as stearic acid, palmitic acid, lauric acid and the like, fatty alcohols such as cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. glycerylmonostearate, glyceryl behenate, glyceryl monooleate, glyceryl palmitostearate, palmitin, glyceryl distearate, stearin, tristearin, behenic, laurin, myristin, hydrogenated vegetable oil, hydrogenated castor oil, cottonseed oil, silicones, calcium silicate and/or mixtures thereof.
Hydrophobic polymeric agents include but are not limited to polymers, such as polyvinyl chloride, polyvinyl acetate, polyethylene, shellac, zein, poly (vinyl acetate), vinyl acetate/vinyl chloride copolymers, polyvinyl acetate and povidone copolymer, polyacrylate and its copolymers, polymethacrylates and its copolymers including Eudragits, polyamides, polylactic and polyglycolic acids, ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate phthalate, polystyrene and/or mixtures thereof.
The hydrophobic release controlling agent is present in the amount of about 1% w/w to about 85 % w/w by weight of the composition.

The pharmaceutically acceptable excipients as per the present invention are selected from the group comprising diluent/filler, binder, pH modifier, glidant, lubricant and/or combinations thereof.

Suitable diluent/filler includes but is not limited to starch, powdered celluloses, polysaccharides, dibasic calcium phosphate, calcium phosphate, calcium carbonate, calcium citrate, tricalcium citrate, magnesium carbonate, lactose monohydrate, lactose anhydrous, microcrystalline cellulose, mannitol, dextrose, sucrose, sorbitol, xylitol, inositol, dextrates, lactitol, maltodextrin, trehalose, and/or combinations thereof. Further, the amount of diluent is preferably in the range of 10% w/w to 90% w/w by weight of the composition.

Suitable binder includes, but is not limited to acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch and/or combinations thereof. Further, the amount of binder is preferably in the range of 10% w/w to 50% w/w by weight of the composition.

The extended release pharmaceutical composition according to present invention may be formulated in order to obtain dissolution independent of pH. The preferred manner to achieve such dissolution is to add a pharmaceutically acceptable acidic pH modifier into the dosage form according to the methods known to one skilled in the art.

Suitable acidic pH modifier includes, for example, an acidic substance such as tartaric acid, citric acid, lactic acid, fumaric acid, phosphoric acid, malic acid, maleic acid, adipic acid, succinic acid, ascorbic acid, acetic acid, amino acid which includes glutamic acid, aspartic acid and the like. Further, the amount of pH modifiers is preferably in the range of 1% w/w to 50% w/w by weight of composition.

Suitable glidants may comprise but not limited to talc, colloidal silicon dioxide, aluminum silicate, colloidal silica, starch or mixtures thereof. Further, the amount of glidant is preferably in the range of 0.01% w/w to 20% w/w by weight of the composition.

Suitable lubricants may comprise but not limited to magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate or mixtures thereof. Further, the amount of lubricant is preferably in the range of 0.1% w/w to 20% w/w by weight of the composition.

Other pharmaceutically acceptable excipients which may be included are e.g. surfactants/wetting agent, antioxidants, chelating agents, plasticizers, complexing agents, disintegrants, solvents and the like.

The pharmaceutical compositions as per the present invention may be film coated with various film coating materials known in the art e.g. commercially available Opadry®.

The pharmaceutical compositions as per the present invention can be prepared by any suitable method known in the art such as direct compression, dry or wet granulation (aqueous/non-aqueous or combination), extrusion spheronization, melt extrusion, melt granulation, coating over inert spheres, spray coating, spray drying and solvent evaporation.

Suitable surfactants include but are not limited to anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. Suitable surfactants are poloxamer, polysorbate, cremophore, soluplus, lecithin and sodium lauryl sulfate.

Suitable solvents include but are not limited to purified water, methanol, ethanol, isopropyl alcohol, methylene chloride/ dichloromethane, chloroform, ethylacetate, acetone and/or mixtures thereof.

Suitable plasticizers include but are not limited to, dibutyl sebacate; vegetable oil, e.g., castor oil or glycerol; or a glyceryl ester of a fatty acid, e.g., glyceryl triacetate or glyceryl monoricinoleate, triethyl citrate and/or mixtures thereof.

The pharmaceutical composition as per the present invention may be in the form of tablets, capsules, tablets filled in capsule, mini tablets filled in capsule, sachets containing powder or granules, pellets, and the like. Preferably, the pharmaceutical composition as per the present invention is tablet.

The pharmaceutical composition as per the present invention is a gastro-retentive tablet.

The pharmaceutical composition as per the present invention is in matrix form.

The pharmaceutical composition as per the present invention is in reservoir form.

The pharmaceutical composition as per the present invention is meant for once daily administration.

The pharmaceutical compositions as per the present invention are stable under accelerated conditions (40°C/75% RH) for at least six (06) months and are also stable under normal conditions (25°C/60% RH) for at least twelve (12) months.

The pharmaceutical composition as per the present invention is useful for the treatment for a condition treatable by inhibition of Jak1 activity, and wherein the condition is Rheumatoid Arthritis (RA), Crohn's disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren's Syndrome, alopecia areata, vitiligo, or atopic dermatitis.

The composition can be used for treatment of autoimmune or inflammatory diseases/disorders either alone or in combination with other drugs e.g. DMARD (disease modifying anti-rheumatic drugs), such as methotrexate.

The various embodiments of the present invention can be assembled in several different ways.
The present invention provides a process for preparing an extended release oral pharmaceutical composition comprising:
a) an extended release core, wherein the extended release core comprises a homogeneous mixture of upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
b) optionally a film coating over the extended release core,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer and wherein said process comprises:
1. Sifting together upadacitinib, diluent, pH modifier, a hydrophobic release controlling agent and glidant through suitable sieve and collecting in polybag.
2. Sifting lubricant through suitable sieve and collecting in polybag.
3. Lubricating the blend of step 1 in suitable blender using lubricant.
4. Compressing the lubricated blend of step 3 with suitable punches to form tablets.
5. Optionally, film coating the tablets obtained in step 4.

The present invention provides a process for preparing an extended release oral pharmaceutical composition comprising:
a) a core, wherein the core comprises upadacitinib, optionally one or more pharmaceutically acceptable excipients, and
b) an extended release coating over the core, wherein the extended release coating comprises a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients, and
c) optionally a film coating over the extended release coating,
wherein the pharmaceutical composition does not contain hydrophilic release controlling polymer and wherein said process comprises:
1. Sifting together upadacitinib, diluent and pH modifier, through suitable sieve and collecting in polybag.
2. Preparing granulating solution and granulating the blend of step 1.
3. Blending the granules obtained in step 2 with suitable glidant.
4. Lubricating the granules of step 3.
5. Compressing the lubricated granules of step 4 with suitable punches to form tablet.
6. Preparing the coating solution comprising a hydrophobic release controlling agent, solvent and optionally one or more pharmaceutically acceptable excipients.
7. Coating the tablet of step 5 with coating solution of step 6.
8. Further, film coating the coated tablets of step 7.

The pharmaceutical compositions as per the present invention can be prepared by
applying pressure to a powder blend to form a compact, and milling the compact to form granules which are finally compressed to tablet; wherein the powder blend comprises upadacitinib, a hydrophobic release controlling agent and optionally one or more pharmaceutically acceptable excipients.

The following examples will illustrate in more detail the various aspects of the present invention.

Example 1:
Ingredient 15 mg %W/W

Pre - Lubrication material
Upadacitinib 15.00 3.53
Microcrystalline Cellulose 164.95 38.81
Mannitol 100.40 23.62
Tartaric Acid 56.00 13.18
Glyceryl behenate 71.00 16.70
Colloidal Silicon Dioxide 2.40 0.57
Lubrication material
Magnesium Stearate 4.25 1.00
Average weight of Core tablets 414.00 ---
Film Coating material
Opadry 11.00 2.59
Average weight of Coated Tablets 425.00 100

Process:
1. Sift together upadacitinib, microcrystalline cellulose, mannitol, tartaric acid, glyceryl behenate and colloidal silicon dioxide through suitable sieve and collect in polybag.
2. Further, sift magnesium stearate through suitable sieve and collect in polybag.
3. Prelubricate the blend of step 1 in suitable blender.
4. Lubricate the pre-lubricated blend of step 3 in suitable blender with sifted magnesium stearate.
5. Compress the lubricated blend with suitable punches.
6. Film coating the compressed tablets of step 5 using Opadry.
7. Pack the tablets as per requirement.
Example 2:
Ingredient 15 mg %w/w

Pre - Lubrication material
Upadacitinib 15.00 3.53
Microcrystalline Cellulose 85.95 20.22
Mannitol 100.40 23.62
Fumaric Acid 56.00 13.18
Glyceryl monostearate 150.00 35.29
Colloidal Silicon Dioxide 2.40 0.57
Lubrication material
Magnesium Stearate 4.25 1.00
Average weight of Core tablets 414.00 ---
Film Coating material
Opadry 11.00 2.59
Average weight of Coated Tablets 425.00 100

Process:
1. Sift together upadacitinib, microcrystalline cellulose, mannitol, fumaric acid, glyceryl monostearate and colloidal silicon dioxide through suitable sieve and collect in polybag.
2. Sift magnesium stearate through suitable sieve and collect in polybag.
3. Pre-lubricate blend of step 1 in suitable blender.
4. Lubricate the pre-lubricated blend of step 3 in suitable blender with sifted magnesium stearate.
5. Compress the lubricated blend with suitable punches.
6. Film coating the compressed tablets of step 5 using Opadry.
7. Pack the tablets as per requirement.
Example 3:

Ingredient
15 mg %w/w
Upadacitinib 15.00 3.53
Microcrystalline Cellulose 193.45 45.52
Mannitol 100.40 23.62
Fumaric Acid 56.00 13.18
Purified water qs qs
Pre-lubrication material
Colloidal Silicon Dioxide 2.40 0.56
Lubrication material
Magnesium Stearate 4.25 1.00
Average weight of core tablets 371.50 ---
Control release coating
Hydrogenated vegetable oil 42.50 10.00
Ethanol qs ---
Film Coating material
Opadry 11.00 2.59
Average weight of Coated Tablets 425 100.00

Process:
1. Sift together upadacitinib, microcrystalline cellulose, mannitol, fumaric acid, through suitable sieve and collect in polybag.
2. Prepare granulating solution and granulate the blend of step 1.
3. Blend the granules after drying with suitable glidant.
4. Lubricate the granules of step 3.
5. Compress the granules with suitable punches to form tablet.
6. Prepare the coating solution by melting hydrogenated vegetable oil.
7. Coat the tablet of step 5 with coating solution of step 6.
8. Further, film coating the coated tablets of step 7 with Opadry.

According to another embodiment of the present invention, there is provided a pharmaceutical composition which is useful for the treatment of autoimmune or inflammatory diseases or disorders.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Dated 1st Day of October, 2020 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer