DESC:It is difficult to formulate extended release formulation 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 low dose Upadacitinib which is comprising of at least 3-8% by weight of Upadacitinib, release controlling agents and 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.

Channeling agent’s variation both qualitative and quantitative significantly affected drug release kinetics from prepared matrix tablets, higher amount of channeling agent increased drug release rate and extent. Most of the formulations fitted better with first order kinetic model and some with Korsmeyer equation which defined drug release rate and mechanism. With the increase of channeling agent content, maximum formulations deviated to follow zero order release kinetics. Examples of channeling agent’s is sugar, sodium chloride, and polyols.

The present invention relates to extended release layered composition of Upadacitinib or its pharmaceutically acceptable salts thereof, processes for the preparing of formulation comprising Upadacitinib and one or more pharmaceutically acceptable excipients.

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. 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. 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. Tmax, 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, Tmax, 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, camphorsulfonate, 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.

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 retarding polymer. The term " Release retarding polymer " 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 3% 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 Channeling agent, diluents, glidants, lubricants, disintegrants, stabilizers, pH modifier, release controlling agent, preservatives, colorants and the like or combinations thereof.

Diluents are inert ingredients sometimes used as bulking agents in order to decrease the concentration of the active ingredient in the final formulation. Suitable diluents used in the present invention are selected from, not limited to, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethyl cellulose,

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).

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, at least one channeling agent, release retarding polymer and at least one preservative and one or more other pharmaceutically acceptable excipients.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, at least one channeling agent, release retarding polymer and one or more other pharmaceutically acceptable excipients to releasing the active ingredient for a longer period of time.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, at least one preservative and one or more other pharmaceutically acceptable excipients to releasing the active ingredient for a longer period of time.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, at least one channeling agent, release retarding polymer and one or more other pharmaceutically acceptable excipients in such a way as to make the drug bioavailable during a prolonged period of time of at least 12 hours from its administration. Thus anti-inflammatory action of the drug Upadacitinib is optimized.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, where in the formulation is coated with a release controlling polymer coating in order to achieve the extended release of Upadacitinib.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, and one or more Anti-oxidant / Preservative.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, and one are more pharmaceutically acceptable excipients like channeling agent, release retarding polymer, preservative, glidant, lubricant.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib contain intragranular portion and extra granular portion, where in the Intragranular Portion contain Upadacitinib Hemihydrate and one are more pharmaceutically acceptable excipients and extra granular portion contain one are more pharmaceutically acceptable excipients.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib contain Intragranular Portion comprising Upadacitinib with Release retarding polymer, Channeling agent and one are more pharmaceutically acceptable excipients and extra granular portion contain Anti-oxidant / Preservative, Release retarding polymer, Glidant and Lubricant.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib contain intragranular portion comprising Upadacitinib with HPMC, KCL and one are more pharmaceutically acceptable excipients and extra granular portion contain ascorbic acid, Aerosil-200, Magnesium Stearate and HPMC.

In one the embodiment of the present invention relates to extended release composition of Upadacitinib wherein Upadacitinib is present in an amount of about 7.5 mg to about 45 mg equivalent to Upadacitinib base.
In one the embodiment of the present invention relates to extended release composition of Upadacitinib or its pharmaceutically acceptable salts thereof, is prepared by granulation technique; preferably wet granulation method.

In one the embodiment of the present invention is related to a solid fixed dose oral pharmaceutical composition comprising the oral dosage form is more preferably extended release tablet dosage form.

Examples of suitable Channeling agent include, but are not limited to Potassium Chloride, Microcrystalline cellulose, Sodium chloride.

Examples of suitable Preservative Ascorbic acid, benzoic acid, sodium benzoate, methyl paraben, ethyl paraben, propyl paraben, Sorbic acid, ascorbic acid and its salts thereof.

Examples of suitable colorant red ferric oxide, titanium oxide, lead oxide, copper sulfate, and carbon black.

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

In one of the embodiment, the binder be employed in the formulations, the examples of binder for the understanding of this invention include other than microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, and polyvinylpyrrolidone.

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.

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:
S. No. Ingredients Qty/ Tablet (mg) Qty/ Tablet (mg)
Intragranular Portion
1. Upadacitinib Hemihydrate 15.355 46.065
2. Benzoic acid 70.000 70.000
3. HPMC E3 premium LV 20.000 20.000
4. KCL 128.000 97.290
5. Purified water q.s. q.s
Extra granular Portion
6. Ascorbic acid 100.000 100.000
7. HPMC E3 premium LV 78.645 78.645
8. HPMC K 4 M 56.000 56.000
9. Aerosil-200 4.800 4.800
10. Magnesium Stearate 7.200 7.200
Tablet Weight 480.00 480.00
Coating materials
11. Opadry Red (PVA Based) 14.40
12. Opadry Purple (PVA Based) 14.40
13. Purified Water - q. s. q. s.
Coated tablet weight 494.40 494.40

Manufacturing Process:
Brief Manufacturing Procedure (Wet Granulation Process):
Sifting:
1. Co sift the Upadacitinib hemihydrate, Benzoic Acid, HPMC E3 LV, Potassium Chloride through sieve #40 ASTM.
2. Granulate the above material of step 1 purified water.
3. Dry the granules at 60C until LOD reaches below 2.5 % w/w at 105C
4. Sift material of step 3 through sieve no #30 ASTM and collect the material in polybag.
Blending
5. Load the materials of step 3 into octagonal blender add Ascorbic acid, HPMC K4 M, HPMC E3 LV and Aerosil 200 that are pre-sifted through sieve no #40 and blend for 30 minutes.
6. Sift Magnesium stearate through sieve no #60
7. Load the sifted quantity of magnesium stearate of step 6 into step 5 materials into octagonal blender and blend for 05 minutes.
Compression
8. Compress the above blends of Step 7 with suitable tooling with a target tablet weight of 480 mg.
Film Coating
9. Coat the tablets of step 8 with film coating material with build-up 3.0 ± 1%w/w.
Coating composition: PVA based composition.
,CLAIMS:1) An Extended release pharmaceutical composition comprising Upadacitinib or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients comprising at least one channeling agent, release retarding polymer and one or more other pharmaceutically acceptable excipients.

2) The Extended release pharmaceutical composition as claimed in claim 1, where in the channeling agent used in the composition is potassium chloride or one or more pharmaceutically acceptable excipients.

3) The Extended release pharmaceutical composition as claimed in claim 1, where in the release retarding polymer used in the composition is hydroxypropylmethylcellulose.

4) The Extended release pharmaceutical composition as claimed in claim 1, where in the pharmaceutically acceptable excipients used in this composition not limited to channelling agent, release retarding polymer, preservative, glidant, lubricant.

5) The Extended release pharmaceutical composition as claimed in claim 1, where in the pharmaceutically acceptable excipients of this composition are benzoic acid, HPMC, KCL, ascorbic acid, aerosil, magnesium Stearate.

6) The Extended release pharmaceutical composition as claimed in claim 1, where in intragranular portion contain Upadacitinib and one or more acceptable excipients and extra granular portion contain one or more pharmaceutically acceptable excipients.

7) The process for the preparation of extended release pharmaceutical composition as claimed in claim 1, involving co sift the Upadacitinib hemihydrate, benzoic acid, HPMC, potassium chloride, granulate the above sift, dry it load the above content into blender add Ascorbic acid, HPMC, aerosil, sift the magnesium stearate and blend the total content and press with suitable parameters.

8) The Extended release pharmaceutical composition as claimed in claim 1, indicated for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis and ankylosing spondylitis.