DESC:It is difficult to formulate an extended release formulation of a having highly soluble active such as Upadacitinib in a controlled predetermined rate. The selection of suitable excipients and the amount of the excipients to be used is the critical parameter for the formulation to achieve the optimal release rate.

Thus, the present invention provides an extended release formulation of Upadacitinib which is comprising of at least 20-30% by weight of Upadacitinib, release controlling agents and optionally coated with non-functional coating membrane. Tablets according to the invention surprisingly provide for the administration of Upadacitinib in a smaller unit dose of Upadacitinib. The tablets of the invention are, despite the high drug loading, small, and, therefore, convenient to administer.

The present inventors provide extended release formulations of Upadacitinib that not only release the active agent continuously in a predetermined manner and lessen the frequency of dosing but also reduce peak-trough fluctuations thereby maintaining desired therapeutic concentrations for longer duration of time and minimizing side effects otherwise associated immediate release tablets. The formulations of the present invention are stable, easy or convenient to prepare, and provide the desired in vitro release and bioavailability.

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.

The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "controlled release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Upadacitinib is released at a predetermined rate that is slower than the immediate release formulation. AUC, as used herein, refers to the area under the curve that represents changes in blood concentrations of Upadacitinib over time. Cmax, as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of Upadacitinib over time. T-max, as used herein, refers to the time that it takes for Upadacitinib blood concentration to reach the maximum value. T 1/2, as used in this disclosure, refers to the time that it takes for Upadacitinib blood concentration to decline to one-half of the maximum level. Collectively AUC, Cmax, T-max, and T1/2 are the principle pharmacokinetic parameters that characterize the pharmacokinetic responses of a particular drug product such as Upadacitinib in an animal or human subject.

The term Upadacitinib as employed herein refers is used in broad sense to include not only “Upadacitinib free base” per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term "salt" as used herein, refers to salts derived from inorganic or organic acids. Examples of suitable salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, fumarate, hydrochloride, carbonates, bicarbonates, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, nitrates, tartrate, sulfonates, thiocyanate, tosylate, mesylate, and undecanoate.
“Complexing agent” are substances which form a complex with drugs but week bonding without changing the chemical and biological properties of drug molecules. Cyclodextrins are cyclic oligosaccharides, consisting of (a-1,4)-linked a-d-glucopyranose units, with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic poorly soluble compounds, a-cyclodextrin (aCD), ß-cyclodextrin (ßCD), and ?-cyclodextrin (?CD), containing six, seven, and eight glucopyranose units, respectively. They are highly versatile oligosaccharides which possess multifunctional characteristics, and are mainly used to improve the physicochemical stability, solubility, dissolution rate, and bioavailability of drugs. Stability constant, factors affecting complexation, techniques to enhance complexation efficiency.

Pharmaceutically effective amount of Upadacitinib is employed in the composition of the present invention. The term "effective amount" refers to an amount effective to achieve desired preventive, therapeutic and/or beneficial effect. In one embodiment the amount of Upadacitinib in the composition can vary from about 1 weight % to about 90 weight %, based on the total weight of the composition. In another embodiment the amount of Upadacitinib in the composition can vary from about 5 weight % to about 85 weight %, based on the total weight of the composition.

In one embodiment, the Upadacitinib employed for present invention is in the form of free acid or free base or pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of prodrugs, active metabolites, polymorphs, co-crystals, solvates, hydrates, enantiomers, optical isomers, tautomer’s or racemic mixtures thereof.

The extended release compositions of the present invention comprise along with Upadacitinib comprises of at least one release controlling agent. The term "release controlling agent" as used herein means any excipient that can retard the release of active agent and includes, but is not limited to, polymeric release controlling agent, nonpolymeric release controlling agent or combinations thereof.

Suitable polymeric release controlling agent may be employed in the compositions of the present invention. In an embodiment, the polymeric release controlling agent employed in the compositions of the present invention may be swelling or non-swelling. The release controlling agent can be incorporated as polymer matrix or as a rate controlling polymer coating. In a further embodiment, polymeric release controlling agents that may be employed in the compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives or the like or any combinations thereof. Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carb oxy methyl ethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.

Saccharides or polysaccharides include, but are not limited to, guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion (Kollicoat® SR 30D , copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol, mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon® SR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Polyalkylene oxides and derivatives thereof include, but are not limited to, polyethylene oxide and the like or any combinations thereof. The term "polyethylene oxide polymer" or "PEO" as used herein includes all forms and MWs of PEO polymers. Sources of PEO polymers include, e.g., Polyox WSR-303™.

Acrylic acid derivatives include, but are not limited to, methacrylic acids, poiymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butylmethacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethyl acrylate methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic acid'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid'ethyl acrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer based polymeric release controlling agent includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In one embodiment, polymers with low viscosity are employed in the compositions of the present invention as release controlling agent such as, but not limited to, Methocel K4M, and the like or combinations.

The term "non-polymeric release controlling agent" as used herein refers to any excipient that can retard the release of an active agent and that does not comprise of repeating units of monomers. Suitable non-polymeric release controlling agents employed in the present invention include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, resins and the like or combinations thereof. Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids that may be employed in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment, the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Suitable long chain monohydric alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol or mixtures thereof.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols. Waxes that may be employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof. Mixtures of these waxes with the fatty acids may also be used. Waxes are also monoglyceryl esters, diglyceryl esters, or tri glyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxy! groups of glycerol is substituted by a fatty acid. Glycerides that may be employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl di stearate,
glyceryl tri stearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyri state, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleyl macrogolglycerides, stearoyl macrogolglycerides, and the like, or mixtures thereof.

Resins employed in the compositions of the present invention include, but are not limited to, shellac and the like or any combinations thereof. In one embodiment the non-polymeric release controlling agent employed includes, but is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean oil), Castorwax® (Hydrogenated castor oil, Croduret® (Hydrogenated castor oil), Carbowax®, Compritol® (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil), Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofine® (Hydrogenated cottonseed oil), Softisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol® diisostearique (Polyglyceryl Diisostearate), Geleol® (Glyceryl Stearate), and mixtures thereof.
In preferred embodiment, the formulation of present invention comprises of combination of hydroxypropyl methyl cellulose and polyethylene oxide as release rate controlling agents.

The amount of release controlling agent used in the extended release formulations of the present invention may vary depending upon the degree of controlled or extended release desired. In an embodiment, release controlling agent is present in the composition in an amount from about 1% to about 50 % by weight of the dosage form. In a preferred embodiment, release controlling agent is present in the formulation in an amount from about 10% to about 30% by weight of the dosage form.

In one embodiment, Upadacitinib is in the form of, but not limited to, powder, granules, pellets, beads, minitablet or the like is treated with at least one release controlling agent. In a further embodiment the active agent may be in micronized form. The active ingredient may be treated by any of the techniques known in the art such as, but not limited to, melt granulation, hot melt extrusion, fluid bed coating, wet granulation, spray drying, extrusion-spheronization, dry granulation or roll compaction. In an embodiment, Upadacitinib is blended or physically mixed with release controlling agent.

In addition to the above discussed excipients, the controlled release compositions of the present invention comprise at least one pharmaceutically acceptable excipients, such as, but not limited to complexing agent, glidants, lubricants, disintegrants, stabilizers, optionally pH modifier, release controlling agent, preservatives, colorants and the like or combinations thereof where in the formulation is free of diluents.

Suitable glidants included in the present formulation can be selected from the group consisting of silica, fumed silica, silicified cellulose, sodium stearate, magnesium aluminum silicate, pyrogenic silica, hydrated sodium silio-aluminate, cellulose, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, Colloidal silicon dioxide and physical or co-processed combinations thereof. The glidant can be silica, and can be a hydrophilic fumed silica (colloidal silicon dioxide).
Examples of suitable lubricants include, but are not limited to, polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and the like. In one embodiment, the lubricant is magnesium stearate.

Examples of suitable pH modifiers include, but are not limited to, organic acids, such as tartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate; magnesium or calcium carbonate or bicarbonate; and combinations thereof. In one embodiment, the pH modifier is tartaric acid.

In one embodiment, the pharmaceutical composition comprises from about 10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof. In other embodiments, the formulation comprises from about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about 30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %, about 15 w/w.%, about 20 w/w %, about 25 w/w % or about 30 w/w % pH modifier. In one embodiment, the pH modifier is tartaric acid.

Suitable disintegrants be employed in the formulations of the present invention include croscarmellose sodium, crospovidone, sodium starch glycolate, starch or combinations thereof.

As discussed herein, sustained peak plasma concentrations can theoretically be achieved by means of sustained release matrix systems. However, when such systems are made of hydrophilic polymers, such as HPMC, they seldom provide pH independent drug release of pH-dependent soluble drugs, and they are normally incapable of attaining zero-order release except for practically insoluble drugs. Unexpectedly, is has now been discovered that when a pH modifier, such as tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof, is used in a hydrophilic sustained release matrix system, it allows Compound 1 or a pharmaceutically acceptable salt or solid state form thereof to be released at a steady rate regardless of the pH of the environment. In an unexpected finding, it was discovered that as a tablet containing the hydrophilic polymer matrix system erodes.

In one of the embodiments of the present invention is to manufacturing an extended release pharmaceutical formulation comprising Upadacitinib, cyclodextrin and one or more other pharmaceutically acceptable excipients where in the formulation is free of diluent and pH modifying agent.
The present invention also provides a use of the pharmaceutical composition in the manufacture of a medicament for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Atopic Dermatitis, Ulcerative Colitis, and Ankylosing Spondylitis.

Examples
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1: Composition of Upadacitinib extended release tablets.
S. No. Ingredients Category Qty/
Tablet
(mg) Qty/ Tablet
(mg) Qty/ Tablet
(mg)
Intra granular Material
1. Upadacitinib API 15.00 30.00 45.00
2. Cyclodextrin Solubilizing agent 45.00 90.00 135.00
3. Purified water Solvent q. s. q. s. q. s.
Extra granular Material
4. Cyclodextrin Solubilizing agent 32.00 64.00 96.00
5. HPMC E5 LV Release retarding polymer 32.80 65.60 98.40
6. HPMC K 4M / K100M Release retarding polymer 32.00 64.00 96.00
7. Colloidal silicon dioxide Glidant 0.80 1.60 2.40
8. Magnesium Stearate Lubricant 2.40 4.80 7.20
Total core tablet weight 160.00 320.00 480.00
Coating materials
9. Opadry Purple (PVA Based) - 4.80 - -
10. Opadry Red (PVA Based) - - 9.60 -
11. Opadry Yellow (PVA Based) - - - 14.40
12. Purified Water (PVA Based) q. s. q. s. q. s.
Coated tablet weight 164.80 329.60 494.40

Brief Manufacturing Procedure:
1. Sift the Upadacitinib, Cyclodextrin, load into blender and mix for suitable time period.
2. Granulate blended mix with water in RMG
3. Dry the wet mass of using Fluid Bed drier until the LOD reacts below 3.00 % w/w
4. Sift the granules of step 3.0 through suitable sieve
5. Ensure all the material pass through sieve #30 ASTM
6. Sift extra granular quantities of Hypromellose and Colloidal silicon dioxide through sieve # 40 ASTM.
7. Sift magnesium stearate through # 60 ASTM and collect the material in polybag.
8. Load the materials of step 7 and 8 into octagonal blender and blend for 15 minutes.
9. Load the sifted quantity of magnesium stearate of step 9 into step 10 into octagonal blender and blend for 05 minutes.
10. Compress the above blend with suitable tooling.
11. Coat the tablets of step 13 with film coating material with build-up 3.0 ± 1%w/w.
Coating composition: PVA based composition.
,CLAIMS:1. The extended release pharmaceutical composition comprising Upadacitinib or its pharmaceutically acceptable salts thereof, at least one release retarding polymer, complexing agent and one or more pharmaceutically acceptable excipients, where in the composition is free of diluent and pH modifying agent.

2. The extended release pharmaceutical composition as claimed in claim 1, where in the release retarding polymer is used in the composition is HPMC.

3. The extended release pharmaceutical composition as claimed in claim 1, where in the complexing agent is used in this composition is cyclodextrin.

4. The extended release pharmaceutical composition as claimed in claim 1, where in pharmaceutically acceptable excipients are release controlling polymer, complexing agent, glidant, lubricant and optionally pH modifying agent.

5. The extended release pharmaceutical composition as claimed in claim 1, where in the pharmaceutically acceptable excipients are HPMC, colloidal silicon dioxide, magnesium stearate optionally tartaric acid.

6. The extended release pharmaceutical composition as claimed in claim 1, where in the composition is prepared by wet-granulation method.

7. The process for the preparation of the pharmaceutical composition as claimed in claim 1, involving the steps of sift the Upadacitinib and cyclodextrin, granulate the blend with RMG, dry the wet mass using fluid bed, sift the extra granular quantities of excipients, perform the lubrication using magnesium stearate, compress the lubricated blend with suitable tooling.

8. The extended release pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, crohn’s disease, ankylosing spondylitis, non-radiographic axial spondyloarthritis.