RU2790166C2 - Oral dosage forms of tofacitinib with continuous release - Google Patents

Abstract

FIELD: oral compositions.

SUBSTANCE: present invention relates to sustained release oral compositions of tofacitinib and its pharmaceutically acceptable salts.

EFFECT: compositions described herein have the desired pharmacokinetic characteristics.

25 cl, 49 tab, 18 ex

Description

INDUSTRY OF INVENTION

This invention relates to oral compositions of 3-((3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl )-3-oxopropionitrile (hereinafter referred to as tofacitinib) with a sustained release, which is an inhibitor of protein kinases such as the enzyme Janus kinase (JAK), and thus is used in therapy as immunosuppressive agents in the following diseases: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, Alzheimer's disease, leukemia, and others indications where suppression of the immune response is desirable. The invention relates to sustained release compositions containing tofacitinib or pharmaceutically acceptable salts thereof. The compositions described herein have the desired pharmacokinetic characteristics. Examples include the ratios of AUC, C _max , dose-corrected AUC, dose-corrected C _max , and the ratio of AUC and C _max after a meal/fasting.

BACKGROUND OF THE INVENTION

Tofacitinib, 3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3- oxopropionitrile has the chemical formula C ₁₆ H ₂₀ N ₆ O and the following structural formula:

The term "tofacitinib" is to be understood, unless otherwise indicated, to include any pharmaceutically acceptable form and salt of the compound. Tofacitinib can exist in crystalline or amorphous forms. Tofacitinib, tofacitinib salts, methods for synthesizing tofacitinib, certain polymorphs of tofacitinib, and uses for tofacitinib are described in WO01/42246, WO02/096909 and WO03/048162.

Tofacitinib is widely known as an inhibitor of protein kinases such as the Janus kinase (JAK) enzyme and thus is useful as immunosuppressive agents in the following conditions: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, diabetes type I and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications where immune suppression is desired.

Tofacitinib was developed as an immediate release tablet form with doses ranging from 5 mg to 10 mg administered twice daily. Tofacitinib, as tofacitinib citrate salt, is approved in the US under the brand name XELJANZ™. Pharmaceutical dosage forms of tofacitinib are known and are described in WO01/42246, WO02/096909 and WO03/048162. In addition, WO2012/100949 describes a modified release formulation of tofacitinib. Although WO2012/100949 mentions that tofacitinib can be formulated into a modified release formulation, the desired pharmacokinetic characteristics have not been described.

Although the commercial instant-release tablet dosage form provides effective levels of tofacitinib in patients (dictated by the average plasma tofacitinib concentration, C _ave , over 24 hours), it is possible to reduce the number of doses to once a day due to the sustained-release dosage form of tofacitinib, while maintaining the same therapeutic effect, thus improving comfort and potentially improving treatment compliance.

Sustained release dosage forms are generally designed to provide the longest possible release period, to minimize: 1) plasma concentration fluctuations over the dosing interval (i.e., the ratio of maximum plasma concentration, C _max,ss , to minimum plasma concentration , C _min,ss , over the dosing interval), and 2) the amount of drug needed to achieve the desired therapeutic effect in order to improve the safety and tolerance profile. For example, WO2012/100949 describes a modified release formulation of tofacitinib with the advantage that tofacitinib is released gradually over a relatively long period at a constant concentration resulting in little fluctuation in the patient's blood.

Surprisingly, however, the bioavailability of tofacitinib was found to decrease with increasing release time, thus requiring an increase in the amount of tofacitinib required in a sustained release dosage form to provide effective levels in the patient's blood.

In addition, the PK profile of twice-daily instant-release tablets contains periods of 24 hours below the IC ₅₀ for the JAK1/3 heterodimer (“drug rest”) due to the combination of all adsorbed drugs and the peak plasma concentration ratio, C _max,ss , to the minimum plasma concentration, C _min,ss , during dosing intervals. Tofacitinib is a selective inhibitor of the Janus kinase (JAK) family, which has a high level of selectivity over other kinases in the human genome. In kinase studies, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent tyrosine kinase (TyK2). In sets of cells where JAK kinases signal in pairs, tofacitinib preferentially inhibits cytokines that signal through JAK3 and/or JAK1, including interleukin (IL)-2, -4, -6, -7, -9, -15, -21 , and type I and II interferons. These cytokines are pro-inflammatory and essential for lymphocyte function. Inhibition of their signaling can lead to the modulation of numerous aspects of the immune response. Inhibition of signaling through JAK3 and/or JAK1 can impair the body's immune system.

Surprisingly, tofacitinib drug rest time relative to IC ₅₀ for JAK1/3 signaling over 24 hours was found to increase with the duration of release from the sustained release dosage form. As such, sustained-release dosage forms as described in the prior art containing tofacitinib do not provide a drug-off period comparable to the PK profile of twice-daily instant-release tablets due to the reduced plasma concentration of tofacitinib provided by sustained-release dosage forms. release as described in the prior art. Accordingly, it has surprisingly been found that to ensure an optimal PK profile (i.e., optimal exposure and optimal C _max,ss /C _min,ss ratio, while avoiding an elevated maximum plasma concentration) for tofacitinib once daily administration, the preferred are dosage forms with a shorter sustained release period. Surprisingly, it has also been found that in order to minimize the total dose of tofacitinib administered to patients, and at the same time to ensure effective blood levels in patients, dosage forms with a shorter sustained release period are preferred.

Brief summary of the invention

This invention relates to sustained release oral formulations of tofacitinib for the treatment of anti-inflammatory and autoimmune diseases, and especially rheumatoid arthritis (RA). Sustained release of tofacitinib can be accomplished by methods known in the art, including, but not limited to, osmotic dosage forms, matrix dosage forms, multiparticulate dosage forms, gastric-sealed dosage forms, and pulsatile dosage forms.

The present invention relates to a once daily pharmaceutical dosage form which contains tofacitinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form is a sustained release dosage form and which, when administered to a subject, has a mean area under the concentration curve in plasma versus time after administration, from about 27 ng-hour/ml per mg of tofacitinib administered to about 42 ng-hour/ml per mg of tofacitinib administered, and an average C _max - C _min ratio in plasma from about 10 to about 100, preferably the average plasma C _max - C _min ratio is from about 20 to about 40, and more preferably from about 20 to about 30. A pharmaceutical dosage form may contain from about 10 mg to about 12 mg of tofacitinib, preferably 11 mg of tofacitinib. In another embodiment, the pharmaceutical dosage form may contain from about 20 to about 24 mg of tofacitinib, preferably 22 mg of tofacitinib. The pharmaceutical dosage form of the invention also provides the subject with a single prolonged time above about 17 ng/ml in the range of about 6 to about 15 hours, and a single prolonged time below about 17 ng/ml in the range of about 9 to about 18 hours. at a dosing interval of 24 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration above about 17 ng/ml in the range from about 6 to about 9 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration below about 17 ng/ml in the range from about 15 to about 18 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration above about 17 ng/ml in the range from about 11 to about 15 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration below about 17 ng/ml in the range from about 9 to about 13 hours. In another embodiment, the pharmaceutical dosage form of the present invention provides the patient with a maximum plasma concentration (C _max ) value of from about 3 ng/mL per mg to about 6 ng/mL per mg of tofacitinib administered.

The present invention also provides a pharmaceutical dosage form for once daily administration which contains tofacitinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form is a sustained release dosage form and which, when administered to a subject, has a mean area under the curve plasma concentrations versus time after administration from about 17 ng-hour/ml per mg of tofacitinib administered to about 42 ng-hour/ml per mg of tofacitinib administered, and an average plasma C _max - C _min ratio of about 10 to about 100, preferably the average plasma C _max - C _min ratio is from about 20 to 40, and more preferably about 20 to 30. A pharmaceutical dosage form may contain from about 10 mg to about 12 mg of tofacitinib, preferably 11 mg of tofacitinib. In another embodiment, the pharmaceutical dosage form may contain from about 20 to about 24 mg of tofacitinib, preferably 22 mg of tofacitinib. The pharmaceutical dosage form of the invention also provides a single prolonged time above about 17 ng/ml in the range of about 6 to about 15 hours, and a single prolonged time below about 17 ng/ml in the range of about 9 to about 18 hours per over a dosing interval of 24 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration above about 17 ng/ml in the range from about 6 to about 9 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration below about 17 ng/ml in the range from about 15 to about 18 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration above about 17 ng/ml in the range from about 11 to about 15 hours. In another embodiment of the invention, the patient has a single prolonged time with a concentration below about 17 ng/ml in the range from about 9 to about 13 hours. In another embodiment, the pharmaceutical dosage form of the present invention may provide a maximum plasma concentration (C _max ) value of about 3 ng/mL per mg to about 6 ng/mL per mg of tofacitinib administered to the patient.

The invention also provides a pharmaceutical dosage form for once daily administration which contains tofacitinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form is a sustained release dosage form and when administered orally to a subject has a constant minimum concentration value (C _min ) in plasma is less than about 0.3 ng/ml per mg of administered tofacitinib.

In another embodiment, the invention provides a pharmaceutical dosage form for once daily administration which contains tofacitinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form is a sustained release dosage form and when administered orally to a subject has an average a postprandial/fasting ratio of plasma concentration versus time under the curve of about 0.7 to about 1.4, and an average postprandial/fasting ratio of maximum plasma concentration (C _max ) of about 0.7 to about 1 .4, preferably from about 0.8 to about 1.25.

In another embodiment, this invention provides a pharmaceutical dosage form which contains tofacitinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein said dosage form is a sustained release dosage form and when added to a test medium containing 900 ml of 0.05M pH 6.8 of potassium phosphate buffer at 37°C in a standard USP rotary paddle mixer, paddle speed 50 rpm, dissolves no more than 30% drug per hour, and no less than 35% and no more than 75 % of the drug in 2.5 hours, and not less than 75% of tofacitinib in 5 hours; preferably not more than 25% drug per hour, and not less than 40% and not more than 70% drug in 2.5 hours.

In another embodiment, this invention provides a pharmaceutical dosage form which contains tofacitinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the dosage form is a sustained release dosage form and when administered orally to a subject provides an AUC in the range of 80% to 125% on the AUC of the amount of tofacitinib administered in the instant release formulation twice daily, and wherein the sustained release dosage form provides an average plasma C _max - C _min ratio of about 10 to about 100, desirably the AUC is in the range of 90% to 110% and the average plasma C _max - C _min ratio is from about 20 to about 40, and more preferably from about 20 to about 30.

In another embodiment, the pharmaceutical dosage form of the present invention may also provide a mean plasma _Cmax in the range of 70% to 125% of the mean plasma _Cmax of tofacitinib formulated in instant release twice daily at steady state, at steady state, oral administration to a patient. In another embodiment, the pharmaceutical dosage form of the present invention provides a drug rest in the range of 80% to 110% drug rest of tofacitinib administered in instant release formulations twice daily over a 24 hour period, when administered orally to a patient. The pharmaceutical dosage form of the present invention may contain from about 10 mg to about 12 mg of tofacitinib and the equivalent amount of tofacitinib formulated in instant release twice daily formulations is 5 mg, preferably the pharmaceutical dosage form contains 11 mg of tofacitinib. A pharmaceutical dosage form of the present invention may contain from about 20 mg to about 24 mg of tofacitinib and the equivalent amount of tofacitinib formulated in twice daily instant release formulations is 10 mg, desirably the pharmaceutical dosage form may contain 22 mg of tofacitinib. In another embodiment, the pharmaceutical dosage form of the present invention provides a drug rest of about 15 to about 18 hours over a 24 th period. In another embodiment, the pharmaceutical dosage form of the present invention provides a drug rest of about 9 to about 13 hours over a 24 th period.

This invention also provides pharmaceutical compositions for the preparation of said sustained release compositions. In one embodiment, the sustained release pharmaceutical dosage form of the present invention comprises a core that contains tofacitinib or a pharmaceutically acceptable salt thereof, and a semi-permeable membrane coating, wherein said coating essentially consists of a water-insoluble polymer. The sustained release dosage form of the present invention can deliver tofacitinib primarily by osmotic pressure. In another embodiment of the present invention, the sustained release dosage form of the present invention may comprise a delivery system selected from the group consisting of the following: extrudable core system, swellable core system, or asymmetric membrane technology.

In another embodiment, the water-insoluble polymer comprises a cellulose derivative, preferably cellulose acetate. In another embodiment of the present invention, the coating further comprises a water-soluble polymer having an average molecular weight of 2000-100,000 daltons. In another embodiment of the present invention, the water-soluble polymer is selected from the group consisting of the following: water-soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates and polyvinyl alcohols. In another embodiment of the invention, the water-soluble cellulose derivatives include hydroxypropylcellulose, hydroxypropylmethylcellulose, or hydroxyethylcellulose.

In another embodiment of the present invention, the core contains a sugar, preferably sorbitol.

In another embodiment, the sustained release pharmaceutical dosage form of the present invention comprises tofacitinib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein said tofacitinib is immersed in a matrix that releases tofacitinib by diffusion. In one embodiment, part of the outer surface of the matrix is covered with an impermeable coating, and the remainder of the outer surface is left uncoated.

In another embodiment of the present invention, the dosage form is in the form of a tablet and the uncoated surface is a hole through an impermeable coating.

In another embodiment of the present invention, the dosage form is in the form of a tablet and the uncoated surface is a passage through the entire tablet.

In another embodiment of the present invention, the dosage form is in the form of a tablet and the uncoated surface is one or more cuts through said impermeable coating, or one or more stripes spaced therefrom.

In another embodiment of the present invention, the dosage form matrix remains substantially intact throughout the release of tofacitinib.

In another embodiment of the present invention, the pharmaceutically acceptable carrier containing the matrix material is selected from the group consisting of the following: waxes, long chain alcohols, fatty acid esters, glycosylated fatty acid esters, phosphoglycerides, polyoxyethylene alkyl esters, carboxylic acids with long chain, sugar alcohols, and mixtures thereof.

In another embodiment of the present invention, the outer surface of said matrix is coated with an enteric coating. The matrix can be formed in the form of a molten-frozen core.

In another embodiment of the present invention, the dosage form matrix contains hydroxypropyl methylcellulose.

In another embodiment of the present invention, tofacitinib is immersed in a matrix that releases tofacitinib by erosion.

In another embodiment of the present invention, the dosage form matrix contains hydroxypropyl methylcellulose.

In another embodiment of the present invention, the dosage form matrix contains poly(ethylene oxide).

In another embodiment of the present invention, the dosage form matrix contains polyacrylic acid.

In another embodiment of the present invention, the reservoir of tofacitinib is enclosed in a membrane that limits the rate of release of tofacitinib by diffusion.

In another embodiment, the sustained release pharmaceutical dosage form of the present invention provides a membrane coated tablet dosage form.

In another embodiment, the sustained release pharmaceutical dosage form of the present invention provides a multiparticulate dosage form comprising particles independently coated with a membrane that limits the rate of release of tofacitinib by diffusion.

The present invention also relates to a method of treating immunological disorders in a subject, comprising administering to a subject in need thereof a sustained release pharmaceutical dosage form of the present invention in an amount effective to treat such disorders. The immunological disorder is selected from the group consisting of the following: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, psoriatic arthritis, Alzheimer's disease, and leukemia, preferably an immunological disorder selected from the group consisting of the following: organ transplant, rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, juvenile idiopathic arthritis, and Crohn's disease . In another embodiment of the present invention, the method further comprises one or more additional agents that modulate the mammalian immune system or anti-inflammatory agents. The additional agent may be selected from the group consisting of the following: non-biological DMARDs, methotrexate, glucocorticoid, glucocorticoid receptor agonist, leflunomide, non-steroidal anti-inflammatory drugs, 6-mecraptopurine, azathioprine, sulfasalazine, and 5-aminosalicylates, preferably, the additional agent is selected from the group consisting of a non-biological DMARD and a glucocorticoid receptor agonist, more desirably, the additional agent is methotrexate.

The present invention also relates to a method for treating atherosclerosis in a subject, comprising administering to a subject in need thereof a sustained release pharmaceutical form of the present invention in an amount effective to treat atherosclerosis. In another embodiment of the present invention, the method also comprises administering an HMG-CoA reductase inhibitor, preferably the HMG-CoA reductase inhibitor is atorvastatin or a pharmaceutically acceptable salt thereof.

The term "tofacitinib" is to be understood, unless otherwise indicated, to include any pharmaceutically acceptable form and salts of the compound. Tofacitinib may be in crystalline or amorphous form. This invention relates to a sustained release dosage form of tofacitinib to provide once daily administration and certain PK characteristics to: 1) minimize the amount of tofacitinib in a sustained release dosage form required to obtain an effective level in the patient's blood, 2) optimize the amount of binding tofacitinib with JAK 1/3 heterodimers (determined by IC ₅₀ , what happens in humans with plasma drug concentrations of approximately 17 ng/mL or 56 nM as described in Meyer DM, Jesson MI, Xiong L, et al. Anti-inflammatory activity and neutrophil reduction mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis J. of Inflammation 2010;7:41 , incorporated herein by reference), which regulates the immune response, for providing the desired level of effectiveness (based on the average C _ave ) over a dosing interval of 24 hours. The sustained release dosage form of the present invention provides the above desired PK characteristics, and especially properties for a once daily dosage form. Desirably, the sustained release dosage form of the invention does not significantly alter the PK profile of tofacitinib when administered after a meal (i.e., has no nutritional effect), as this minimizes deviation from optimal coverage of JAK 1/3 heterodimers.

By "sustained release" is meant that tofacitinib is released from the oral dosage form at a slower rate than immediate release. The oral dosage form includes tablets, capsules, multiparticulates or granules. "Delayed release" includes an oral composition consisting of one or a combination of the following:

a) only the controlled release component;

b) a controlled or delayed release component;

c) delayed and immediate release component.

By "pharmaceutically acceptable form" is meant any pharmaceutically acceptable form, including solvates, hydrates, isomorphs, polymorphs, co-crystals, pseudomorphs, neutral forms, acid addition salt forms, and prodrugs. Pharmaceutically acceptable acid addition salts of tofacitinib are prepared in the usual way by treating a solution or suspension of the free base with one or two chemical equivalents of a pharmaceutically acceptable acid. Salts were isolated using standard concentration and recrystallization techniques. Examples of acceptable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, mesyl, tosyl, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic, such as methanesulfonic, benzenesulfonic and similar acids. Some preferred forms of tofacitinib include tofacitinib free base and tofacitinib citrate.

The terms “subject”, “patient”, and “individual” are used interchangeably to refer to vertebrates, preferably mammals, more preferably humans.

"Solid oral dosage form" of this invention means a pharmaceutically acceptable solid oral dosage form, which means that the dosage form is safe for administration to humans and all excipients in the dosage form are pharmaceutically acceptable, in other words, safe for human consumption.

The term "fasting", as used herein, means the following: a dosing state that occurs after a night without food (where 0 calories are taken) for at least 10 hours. Patients are given a dosage form with 240 ml of water. Eating is not allowed for at least 4 hours after a dose. If necessary, you can drink water, except for a period of 1 hour before and after taking the medicine.

The term "after a meal" as used herein means the following: a dosing state that occurs after a night without food (where 0 calories are taken) for at least 10 hours, after which the patient is prescribed a high-calorie meal for 30 minutes. before taking the medicine. The patient must eat this meal in 30 minutes or less; however, the drug must be administered 30 minutes later. after the start of the meal. The medicine is taken with 240 ml of water. Eating is not allowed for at least 4 hours after a dose. If necessary, you can drink water, except for a period of 1 hour before and after taking the medicine. A high-fat meal (approximately 50% of all food calories come from fat) and a high-calorie meal (approximately 800-1000 calories) should be used as a test meal, in a post-meal medication setting. In this test food, approximately 150, 250, and 500-600 calories come from protein, carbohydrate, and fat, respectively. An example of a test food is two butter-fried eggs, two slices of bacon, two slices of buttered bread, 4 ounces of hash browns, and 8 ounces of whole milk.

), так же известны специалистам в отрасли, и описаны, например, в Shargel, Wu-Pong, and Yu, Applied Biopharmaceutics and Pharmacokinetics (2005). Для определения среднего соотношения после еды/натощак, сначала рассчитывали индивидуальное соотношение средней площади под кривой концентрация-время для тофацитиниба (то есть AUC_0-inf) в состоянии после еды, к средней площади под кривой концентрация-время для тофацитиниба (например, AUC_0-inf) в состоянии натощак, а потом соответствующие индивидуальные соотношения усредняли. Таким образом, определяют среднее для соотношений каждого индивидуума.The calculation of the mean area under the serum concentration versus time (AUC) curve is a known procedure in the pharmaceutical industry, and is described, for example, inWelling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986). AUC as used herein includes the area under the concentration-time curve starting at time zero and extrapolating to infinity for a single dose, or the area under the concentration-time curve from time zero to the end of the dosing interval for a sustained multiple dose . In addition, calculations for C_max, C_min,ss, T_max, and selection of the half-life (t

) are also known to those skilled in the art and are described, for example, inShargel, Wu-Pong, and Yu, Applied Biopharmaceutics and Pharmacokinetics (2005). To determine the mean postprandial/fasting ratio, the individual mean area under the concentration-time curve for tofacitinib was first calculated (i.e., AUC_0-inf) in the postprandial state, to the mean area under the concentration-time curve for tofacitinib (e.g., AUC_0-inf) on an empty stomach, and then the corresponding individual ratios were averaged. Thus, an average is determined for the ratios of each individual.

“Dissolution Test 1” refers to the following testing of tofacitinib dosage forms. The dissolution test was performed in a standard USP rotary paddle mixer as described in USP Dissolution Test, Section 711, Apparatus 2. The paddles were rotated at 50 rpm and the dosage form was added to 900 ml of 0.05M pH 6.8 potassium phosphate buffer at 37°C. At an appropriate time after the start of the test (eg, injection of the dosage form into the apparatus), filtered aliquots (typically 1.5 ml) from the test medium were analyzed for tofacitinib by high performance liquid chromatography (HPLC). Dissolution results are presented as the percentage of the total dose of tested tofacitinib dissolved over time.

detailed description of the invention

This invention relates to sustained release oral formulations of tofacitinib for the treatment of anti-inflammatory and autoimmune diseases, and especially rheumatoid arthritis (RA). Sustained release of tofacitinib may be administered by methods known in the art, including, but not limited to, osmotic dosage forms, matrix dosage forms, multiparticulate dosage forms, gastric-sealed dosage forms, and pulsatile dosage forms.

Sustained release matrix systems (tablets)

In one embodiment, tofacitinib is included in a tablet with an erodible or non-erodible polymer matrix. An erodible matrix is understood to mean a water-erodible or water-swellable or water-soluble matrix, meaning eroded, swellable, or soluble in pure water, or requiring the presence of an acid or base to ionize the polymer matrix in an amount sufficient to cause erosion or dissolution. Upon contact with an aqueous environment, the erodible polymer matrix absorbs water and forms a water-swollen gel or "matrix" that traps tofacitinib. The water-swollen gel matrix gradually erodes, swells, disintegrates, disperses or dissolves in the used medium, thus controlling the release of tofacitinib into the used medium. Examples of such dosage forms are widely known in the industry. See, for example, Remington: The Science and Practice of Pharmacy, 20th ^Edition , 2000 .

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

Celluloses for the erodible matrix include water-soluble and water-erodible celluloses such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate ( CAP), cellulose acetate trimellitate (ACT), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC).

A particularly preferred class of such pulps includes HPMC with varying degrees of low viscosity (MW less than or equal to 50,000 Daltons) and high viscosity (MW greater than 50,000 Daltons). Commercially available low viscosity HPMC polymers include Dow METHOCEL™ E3, E5, E15LV, E50LV and K100LV series, while high viscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M; especially preferred within this group are METHOCEL™ K series. Other commercially available HPMCs include Shin Etsu METOLOSE™ 90SH series. In one embodiment, the HPMC has a low viscosity, which means that the viscosity of a 2% (w/v) solution of HPMC in water is less than about 120 centipoise. The preferred HPMC is HPMC with a viscosity of 2% (w/v) solution of HPMC in water in the range of 80 to 120 cps (eg METHOCEL™ K100LV).

Other materials suitable as an eroded matrix material include, but are not limited to: pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, ethacrylic acid or methacrylic acid copolymers (EUDRAGIT®, Rohm America, Inc. ., Piscataway, New Jersey) and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

The eroded matrix polymer material may also contain additives and excipients known in the pharmaceutical art, including osmopolymers, osmagenes, agents that improve or retard solubility, and excipients that promote stability or processability of the dosage form.

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

Sustained Release Matrix Systems (Multiple Particles)

In another embodiment, the multiparticulate matrix comprises a plurality of particles containing tofacitinib, wherein each particle containing a mixture of tofacitinib with one or more excipients is selected to form a matrix capable of limiting the rate of dissolution of tofacitinib in an aqueous medium. Matrix materials suitable for this embodiment are typically water-insoluble, such as waxes, cellulose, or other water-insoluble polymers. Optionally, the matrix materials may optionally be formulated with water-soluble materials that can be used as binders or permeability modifying agents. Matrix materials suitable for making these dosage forms include microcrystalline cellulose such as Avicel (trademark of FMC Corp., Philadelphia, Pa.), including classes of microcrystalline cellulose to which binders such as hydroxypropyl methylcellulose are added, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, etc., as well as artificial polymers such as poly(vinyl chloride), poly(vinyl acetate), vinyl acetate-ethylene copolymers, polystyrene, etc. Water-soluble binders or penetration modifying agents that are optionally included in the matrix include water-soluble polymers such as hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, poly(N-vinyl-2-pyrrolidinone) (PVP), poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, and other such natural and synthetic materials. In addition, materials that function as release-modifying agents include water-soluble materials such as sugars or salts. Desirable water-soluble materials are lactose, sucrose, glucose, and mannitol, as well as HPC, HPMC, and PVP.

The method of obtaining a matrix of multiple particles includes the process of extrusion/pelletization. For this process, wet tofacitinib is combined with a binder, extruded through a perforated plate or die, and placed on a rotating disk. The extrudate ideally breaks up into particles that are rounded into spheres, spheroids or rounded bars on a rotating plate. Another process and composition for this method involves using water to wet a mixture containing about 20-75% microcrystalline cellulose mixed with, respectively, about 80-25% tofacitinib.

The method of obtaining a matrix of multiple particles includes obtaining wax granules. In this process, the desired amount of tofacitinib is mixed with liquid wax to form a homogeneous mixture, cooled and then passed through a sieve to form granules. Desirable matrix materials are waxy materials. Some waxy substances include hydrogenated castor oil and carnauba wax and stearyl alcohol.

Another way to prepare the matrix from multiple particles involves the use of an organic solvent to improve mixing of tofacitinib with the matrix material. This technique can be used when it is desired to use a matrix material with an unsuitably high melting point which, if used in a molten state, will cause degradation of the drug or matrix material, or result in an unacceptable melt viscosity, thus preventing mixing of tofacitinib with the matrix material. Tofacitinib and matrix material can be combined with a small amount of solvent to form a paste and then passed through a sieve to form granules from which the solvent is then removed. Alternatively, tofacitinib and the matrix material may be combined with sufficient solvent to complete the dissolution of the matrix material and the resulting solution (which may contain solid drug particles) spray dried to form a particulate dosage form. This technique is preferred when the matrix material is a high molecular weight synthetic polymer such as a cellulose ether or cellulose ester. Solvents commonly used for this process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more.

In one embodiment, the multiple matrix particles are formed by melt spraying and solidification. The molten-solidified core contains the matrix material. The matrix material has two functions. First, the matrix material allows the formation of relatively smooth round cores susceptible to coating. Second, the matrix material binds optional excipients and/or drugs that may be included in the core. The matrix material has the following physical properties: low enough viscosity in the molten state to form multiple particles, as described below; and rapidly solidify into solids when cooled below their melting point. For multiparticulates incorporating a drug into a core, the matrix desirably has a melting point lower than the melting point or decomposition temperature of the drug and does not substantially dissolve the drug.

The molten-solidified core consists essentially of a continuous phase of matrix material and optionally other excipients, with optional drug particles and optional swelling agent particles encapsulated therein. As a consequence, sufficient matrix material must be present to form smooth cores large enough to be coated. In the case of cores containing solid particles such as drug or swelling agent, the core must contain sufficient matrix material to encapsulate the drug and swelling agent to form relatively smooth and spherical cores that are easier to coat with standard spray than kernels with a non-standard shape. The matrix material may be present in the core in an amount of at least about 30 wt.%, at least about 50 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 90 wt.%, and up to 100 wt.% of the mass of the core without coating.

In order to form small, smooth, round cores, the matrix material must be capable of being melted and then pulverized. The matrix material or mixture of materials is solid at 25°C. However, the matrix material melts, or is capable of melting with the addition of an optional auxiliary, at a temperature lower than 200° C., for suitability for use in the melt-solidification process described below. Desirably, the matrix material has a melting point of 50°C-150°C. Although the term "melting" generally refers to the transition of a crystalline material from a crystalline to a liquid state, which occurs when its melting point is reached, and the term "molten" generally refers to such a crystalline material in the liquid state as used herein, these terms are used in in a broader sense. In the case of "melting", the term is used to heat any material or mixture of materials until they reach a liquid state, in the sense that it can be pumped or sprayed like a crystalline material in a liquid state. Likewise, "molten" refers to any material or mixture of materials that is in a liquid state.

The matrix material is selected from the group consisting of the following: waxes, long chain alcohols (Ci ₂ or greater), fatty acid esters, glycosylated fatty acid esters, phosphoglycerides, polyoxyethylene alkyl esters, long chain carboxylic acids (Ci ₂ or greater ), sugar alcohols, and mixtures thereof. Examples of matrix material include highly refined forms of waxes such as carnauba wax, white and yellow beeswax, ceresin wax, microcrystalline wax, and paraffin wax; long chain alcohols such as stearyl alcohol, cetyl alcohol and polyethylene glycol; fatty acid esters (also known as fats or glycerides) such as isopropyl palmitate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, mixtures of mono-, di- and trialkyl glycerides, including mixtures of glyceryl mono-mono-, di- and tribehenate, glyceryl tristearate, glyceryl tripalmitate, and hydrogenated vegetable oils, including hydrogenated cottonseed oil; glycosylated fatty acid esters such as polyethylene glycol stearate and polyethylene glycol distearate; polyoxyethylene alkyl ethers; polyethoxylated derivatives of castor oil; long chain carboxylic acids such as stearic acid; and sugar alcohols such as mannitol and erythritol. The matrix material may contain mixtures of materials, such as mixtures of any of those listed.

The core may also contain various fillers present in the core in an amount of 0 to 40% by weight, based on the uncoated weight of the core. One desirable excipient is a dissolution enhancer used to increase the rate of water uptake by the core and consequent expansion of the swelling agent. The dissolution enhancer has a different material than the matrix material. The dissolution enhancer may be in a separate or co-phase with the matrix material. Desirably, at least a portion of the dissolution enhancer is phase separated from the matrix material. As water enters the core, the dissolution enhancer dissolves, leaving channels that allow water to enter the core more quickly. In general, dissolution enhancers are amphiphilic compounds, and are generally more hydrophilic than matrix materials. Examples of dissolution enhancers include: surfactants such as poloxamers, docusate salts, polyoxyethylene castor oil derivatives, polysorbates, sodium lauryl sulfate, and sorbitan monoesters; sugars such as glucose, xylitol, sorbitol and maltitol; salts such as sodium chloride, potassium chloride, lithium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate and potassium phosphate; and amino acids such as alanine and glycine; and their mixtures. One surfactant-type dissolution enhancer is poloxambetar (commercially available as LUTROL or PLURONIC from BASF Corp.).

The core may also contain other optional excipients such as agents that inhibit or delay drug release from the multiparticulate. Such dissolution inhibitors are typically hydrophobic and include dialkyl phthalates such as dibutyl phthalate and hydrocarbon waxes such as microcrystalline wax and paraffin wax. Another acceptable class of fillers contains materials that can be used to adjust the viscosity of the molten material to form cores. Such viscosity adjusting agents typically comprise from 0 to 25% by weight of the core. The viscosity of the molten material is a key variable in obtaining nuclei with approximately the same particle size. For example, when using a rotary disc atomizer, it is desirable that the viscosity of the molten mixture be at least about 1 centipoise and less than about 10,000 centipoise, preferably at least 50 centipoise and less than about 1000 centipoise. If the molten mixture has a viscosity outside these ranges, a viscosity adjusting agent may be added to produce a molten mixture in the specified viscosity range. Examples of viscosity reducing excipients include stearyl alcohol, cetyl alcohol, low molecular weight polyethylene glycol (ie, less than about 1000 daltons), isopropyl alcohol, and water. Examples of viscosity enhancers include microcrystalline wax, paraffin wax, artificial wax, high molecular weight polyethylene glycols (i.e. greater than about 5000 daltons), ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, silica, microcrystalline cellulose, magnesium silicate, sugars, and salts.

For those embodiments where the drug is contained in the core, other excipients can be added to adjust the release characteristics of the drug from the cores. For example, a base or acid may be included in the composition to modify the rate at which the drug is released into the aqueous medium. Examples of acids or bases that may be included in the composition include the following: citric acid, adipic acid, malic acid, fumaric acid, succinic acid, tartaric acid, di- and tribasic sodium phosphate, di- and tribasic calcium phosphate, mono-, di- and triethanolamine, sodium bicarbonate and sodium dihydrocitrate. Such fillers may comprise from 0 to 25% by weight of the core, based on the total weight of the core.

Other fillers are added to improve processing, such as fillers that reduce static charge on the cores, or reduce the melting point of the matrix material. Examples of such antistatic agents include talc and silica. Flavorings, colorants and other excipients are also added in normal amounts for normal purposes. Such fillers may comprise from 0 to 25% by weight of the core, based on the total weight of the core.

Multiple particles are produced by a melt-solidification process comprising the steps of: (a) forming a molten mixture containing drug, glyceride (or other waxes), and any release-modifying agent; (b) delivering the molten mixture of step (a) to the atomizer to form droplets of the molten mixture; and (c) solidifying the droplets from step (b) to form multiple particles.

Processing conditions are chosen to maintain the crystallinity of the drug. The temperature of the molten mixture is kept below the melting point of the drug. Desirably, at least 70% by weight of the drug remains crystalline in the molten mixture, more desirably at least 80% by weight, and most desirably at least 90% by weight.

The term "melt mixture" as used herein refers to a mixture of drug, glyceride (or other waxes), and other release-modifying agents that needs significant heating to become essentially liquid so that drops can be formed. or spray. The spraying of the molten mixture can be carried out using any of the spraying methods described below. Typically, the mixture is molten in the sense that it will flow when subjected to one or more forces such as pressure, shear, and centrifugal force, such as occurs in a centrifuge or spinning disc atomizer. Thus, a drug/glyceride/release-modifying agent mixture can be considered "molten" when any part of the drug/glyceride/release-modifying agent mixture becomes liquid enough that the mixture as a whole can be sprayed. Typically, the mixture is fluid enough to spray when the viscosity of the molten mixture is less than about 20,000 cps. Often, the mixture melts when the mixture is heated above the melting point of the glyceride/release-modifying agent mixture, in cases where the glyceride/release-modifying agent mixture is sufficiently crystalline to have a relatively high melting point; or, when the glyceride/release-modifying agent mixture is amorphous, above the softening point of the glyceride/release-modifying agent mixture. The molten mixture is thus often a suspension of solid particles in a liquid matrix. In one preferred embodiment, the melt mixture comprises a mixture of essentially crystalline drug particles suspended in a substantially liquid glyceride/release-modifying agent mixture. In such cases, part of the drug may be dissolved in the glyceride/release-modifying agent mixture, and part of the glyceride/release-modifying agent mixture may remain solid.

Virtually any process can be used to form a molten mixture. One method involves heating the glyceride/release-modifying agent mixture in a reservoir until it liquefies, and then adding the drug to the molten glyceride/release-modifying agent mixture. Typically, the glyceride/release-modifying agent mixture is heated to a temperature of about 10° C., or above the liquefaction temperature. When one or more components of the glyceride/release-modifying agent mixture is crystalline, the temperature is about 10° C. or higher than the melting point of the lowest melting point of the mixture material. The process is carried out so that at least part of the mixture remains liquid before spraying. Once the glyceride/release-modifying agent mixture becomes liquid, the drug substance can be added to the liquid carrier or "melt." Although the term "melt" usually specifically refers to the transition of a crystalline material from a crystalline to a liquid state, which occurs at the melting point, and the term "molten" usually refers to such a crystalline material in its liquid state, as used herein, these terms are used more broadly referring to the case of "melting" the heating of any material or mixture of materials until it reaches a liquid state, that is, it can be pumped or sprayed like a crystalline material in a liquid state. Similarly, "molten" refers to any material or mixture of materials in such a liquid state. Alternatively, the drug, glyceride (or other wax) and release-modifying agent may be added to the reservoir and the mixture heated until the mixture is in a liquid state.

Once the glyceride/release-modifying agent mixture has become liquid and the drug substance has been added, the molten mixture is mixed to ensure even distribution of the drug substance therein. Mixing is usually carried out using mechanical means such as overhead mixers, magnetic mixers and magnetic stirrers, orbital mixers and homogenizers. Optionally, the contents of the reservoir may be pumped out of it and passed through an in-line static mixer or extruder, and then returned back to the reservoir. The shear used to agitate the molten mixture must be high enough to ensure even distribution of the drug in the molten carrier. The shear force is kept low enough not to change the shape of the drug, ie so as to cause an increase in the amount of amorphous drug, or changes in the crystalline form of the drug. It is also preferred that the shear force is not so high as to reduce the particle size of the drug crystals. The molten mixture may be stirred for a period of several minutes to several hours, the stirring time depending on the viscosity of the mixture and the solubility of the drug and any optional excipient in the carrier.

An alternative method of making a melt blend is to use two tanks, melting the glyceride (or other waxes) or release-modifying agent in one tank and the other component in the second tank. The drug substance is added to one of these tanks and mixed as described above. The two melts are then passed through an in-line static mixer or extruder to form a single melt mixture which is sent for spraying as described below.

Another way to obtain a molten mixture is to use a tank system with continuous mixing. In this system, the drug, glyceride (or other waxes), and release-modifying agent are continuously added to a heated tank equipped with continuous mixing facilities while the molten mixture is continuously removed from the tank. The contents of the reservoir are heated so that the temperature of the contents is about 10° C. or greater than the melting point of the carrier. The drug, glyceride (or other waxes) and release-modifying agent are added in such proportions that the molten mixture that is removed from the reservoir has the desired composition. The drug substance is usually added in solid form and may be preheated before being added to the tank. The glyceride (or other waxes) and release-modifying agent may also be pre-heated or even pre-melted before being added to the continuously stirred tank system.

Another way to obtain a molten mixture is to use an extruder. By "extruder" is meant a device or set of devices that forms a molten extrudate by heating and/or shearing and/or forming a uniformly mixed extrudate from a solid and/or liquid (eg molten) mixture. Such devices include, but are not limited to: single screw extruders; twin screw extruders, including co-rotating, counter-rotating, cross-rotating, and non-cross-rotating extruders; multi-screw extruders; piston extruders, consisting of a heated barrel and a piston for extrusion of the molten mixture; gear-pump extruders, consisting of a heated gear-type pump, usually counter-rotating, which simultaneously heats and pumps the molten mixture; and conveyor extruders. Conveyor extruders comprise a solid and/or powder mixture conveyor, such as a screw or pneumatic conveyor, and a pump.

At least a portion of the conveyor is heated to a temperature high enough to form a molten mixture. The molten mixture may optionally be sent to a storage tank before being sent to a pump which directs the molten mixture to a spray gun. Optionally, an in-line mixer may be used before or after the pump to ensure homogeneity of the molten mixture. In each of these extruders, the molten mixture is mixed to form a uniformly mixed extrudate. Such agitation can be accomplished by various mechanical and technological means, including agitation elements, rubbing elements, and countercurrent shear agitation. Thus, in such devices, the composition is fed into an extruder producing a molten mixture, which is then sent to a spray gun.

In one embodiment, the composition is fed to the extruder as a solid powder. The powder mixture is obtained using methods known in the industry for obtaining powder mixtures with high uniformity. It is generally preferred that the particle sizes of drug, glyceride (or other waxes) and release-modifying agent be the same to obtain a homogeneous mixture. However, this is not essential for the successful implementation of the present invention.

The following examples of methods for obtaining a substantially homogeneous mixture are given. First, the glyceride (or other waxes) and the release-modifying agent are milled so that the particle size is approximately the same as the particle size of the drug; then the drug substance, glyceride (or other waxes), and the release-modifying agent are mixed in a V-blender for 20 minutes; the resulting mixture is then rubbed to remove large particles; the resulting mixture was finally stirred for an additional 4 minutes. in some cases, it is difficult to grind the glyceride (or other waxes) and the release-modifying agent to the desired particle size, since many of these materials are waxy and the heat generated during grinding can stick the grinding equipment together. In such cases, small particles of glyceride (or other waxes) and a release-modifying agent can be formed using a melt-or spray-curing process as described below. The resulting solidified particles of glyceride (or other waxes) and release-modifying agent can then be mixed with the drug to form an extruder blend.

Another method of preparing a mixture for an extruder involves melting the glyceride (or other waxes) and the release-modifying agent in a tank, mixing with the drug as described above for the tank system, and then cooling the molten mixture to form a solidified mixture of drug and carrier. This solidified mixture can then be ground to a uniform particle size and sent to an extruder.

A dual feed extruder system can also be used to produce a molten mixture. In this system, the drug, glyceride (or other waxes) and release-modifying agent, all in powder form, are fed into the extruder through one or different mixture feed channels. In this case, there is no need to mix the components.

Alternatively, the glyceride (or other waxes) and the release-modifying agent, in powder form, are fed into the extruder at one point, allowing the extruder to melt the glyceride (or other waxes) and the release-modifying agent. The drug is then added to the molten glyceride (or other waxes) and the release-modifying agent through a second feed port down the length of the extruder, thus minimizing the contact time of the drug with the molten glyceride (or other waxes) and the release-modifying agent. . The closer the second feed channel is to the exit from the extruder, the less time the drug spends in the extruder. Multiple feed extruders can be used when optional fillers are included in multiple particles.

In another method, the composition is in the form of a large particle size or solid mass rather than a powder when fed into an extruder. For example, a solidified mixture can be prepared as described above and then melted to enter a piston extruder barrel and used directly without grinding.

In another method, the glyceride (or other waxes) and the release-modifying agent may first be melted in, for example, a reservoir, and fed into the extruder in molten form. The drug, usually in powder form, can then be introduced into the extruder through the same or a different delivery channel that was used to deliver the glyceride (or other waxes) and release-modifying agent into the extruder. This system has the advantage of separating the melting step for the glyceride (or other waxes) and release-modifying agent from the mixing step, minimizing the contact time of the drug with the melted glyceride (or other waxes) and release-modifying agent.

In each of the above methods, the extruder must be designed to produce a molten mixture with drug crystals uniformly dispersed in the glyceride/release-modifying agent mixture. Typically, the temperature of the extrudate should be about 10° C. or more above the temperature at which the drug and carrier mixture become liquid. The various zones in the extruder must be heated to the appropriate temperature to obtain the desired extrudate temperature as well as the desired degree of mixing or deformation, using means known in the art. As described above for mechanical mixing, minimum shear should be applied to obtain a uniformly molten mixture so that the crystalline form of the drug remains unchanged and dissolution or formation of amorphous drug substance is minimized.

The mixture is desirably melted prior to solidification for at least 5 seconds, more preferably at least 10 seconds, and most preferably at least 15 seconds, to ensure adequate melt homogeneity of the drug/glyceride/release-modifying agent. It is also desirable that the molten mixture remains molten for no more than 20 minutes to limit drug exposure to the molten mixture. As described above, depending on the activity of the selected glyceride/release-modifying agent mixture, it may be desirable to further reduce the time the mixture is in the molten state to less than 20 minutes to limit degradation of the drug to an acceptable level. In such cases, such mixtures are kept molten for less than 15 minutes, and in some cases even less than 10 minutes. When an extruder is used to produce a molten mixture, the above time means the average time from the introduction of the material into the extruder to the solidification of the molten mixture. This average time can be determined using known procedures. In one method, a small amount of dye or other similar compound was added to the mixture while the extruder was operating at nominal conditions. The cured multiparticles were then collected over time and analyzed for dye from which the average time was obtained.

Once the molten mixture has formed, it is delivered to an atomizer which breaks the molten mixture into small droplets. Virtually any method can be used to deliver the molten mixture to the nebulizer, including the use of pumps and various types of pneumatic devices (eg, pressurized containers, pump containers). When an extruder is used to form a molten mixture, the extruder itself may be used to deliver the molten mixture to a spray gun. Typically, the molten mixture is maintained at an elevated temperature during delivery of the mixture to the atomizer to prevent solidification of the mixture and to maintain the fluidity of the molten mixture.

Typically, spraying is done in one of several ways, including (1) "pressure" or single fluid spray guns; (2) two-fluid spray guns; (3) centrifugal or rotary disc atomizers; (4) ultrasonic atomizers; and (5) mechanical vibrating atomizers. A detailed description of spray processes can be found in Lefebvre, Atomization and Sprays (1989) or in Perry's Chemical Engineers' Handbook (7 ^th Ed., 1997) . Preferably, centrifugal or rotary disc atomizers are used, such as the 100 mm FX1 rotary atomizer manufactured by Niro A/S (Seborg, Denmark).

After spraying the molten mixture, the droplets solidify, usually upon contact with a gas or liquid at a temperature below the droplet solidification temperature. It is generally desirable for the droplets to solidify in less than about 60 seconds, desirably less than about 10 seconds, more desirably less than about 1 second. Often, curing at ambient temperature results in fairly rapid hardening of the droplets. However, the solidification step often takes place in a closed space to facilitate the collection of multiple particles. In such cases, the pour point of the medium (gas or liquid) will increase with the time the droplets enter the enclosed space, potentially affecting the formation of multiple particles or the chemical stability of the drug. Thus, the refrigerant gas or liquid is often circulated in an enclosed space to maintain a constant pour point. If it is desired to minimize the time the drug is exposed to high temperatures, for example to prevent degradation, the cooling gas or liquid may be cooled to a temperature below ambient temperature to promote rapid solidification, thus minimizing the formation of decomposed substances.

After the formation of the multiparticulates, it is desirable to subject the multiparticles to a treatment to improve the crystallinity of the drug substance and/or the stability of the multiparticulates.

The multiple particles may also be mixed or blended with one or more pharmaceutically acceptable materials to form an acceptable dosage form. Acceptable dosage forms include tablets, capsules, sachets, oral powders for dilution, etc.

After the formation of the plural particles by spray crystallization, the plural particles may optionally be coated with an additional outer coating. The outer coating may be any conventional coating such as a protective film coating, delayed or sustained drug release coating, or taste masking.

In one embodiment, the coating is an enteric coating that provides a delayed release of the drug. By "enteric coating" is meant an acid resistant coating that remains intact and does not dissolve at pH less than about 4. The enteric coating surrounds numerous particles such that the solid amorphous dispersion layer does not dissolve or erode in the stomach. The enteric coating may include enteric polymers. Enteric polymers include polyacids with a pK _a of about 3-5. Examples of enteric polymers include: cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl acetate cellulose succinate, cellulose acetate succinate, carboxymethyl ethyl cellulose, methyl cellulose phthalate and ethyl hydroxy cellulose phthalate; vinyl polymers such as polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymer; polyacrylates; and polymethacrylates such as methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octylacrylate copolymer; and a styrene-maleic monoester copolymer. These compounds may be used singly or in combination or together with other polymers not described above.

One class of enteric coating materials is pharmaceutically acceptable methacrylic acid copolymers, which are anionic copolymers based on methacrylic acid and methyl methacrylate. Some of these polymers are known and sold as enteric polymers, for example, with aqueous solubility at pH 5.5 and above, such as commercially available EUDRAGIT enteric polymers, for example, Eudragit L 30, a polymer synthesized from dimethylaminoethyl methacrylate, and Eudragit S and Eudragit F.S.

Top coats may include standard plasticizers including dibutyl phthalate; dibutyl sebacate; diethyl phthalate; dimethyl phthalate; triethyl citrate; benzyl benzoate; butyl and glycol esters of fatty acids; mineral oil; oleic acid; stearic acid; cetyl alcohol; stearyl alcohol; Castor oil; corn oil; Coconut oil; and camphor oil; and other excipients such as release agents, glidants, etc. For plasticizers, triethyl citrate, coconut oil and dibutyl sebacate are particularly preferred.

Outer coatings can be formed using solvent-based and hot-melt methods. In solvent-based coating processes, the coating is first formed by forming a solution or slurry containing the solvent, the coating material, and optional coating additives. Coating materials may be completely soluble in the coating solvent, or only dispersed in the solvent as an emulsion or suspension, or a combination thereof. Latex dispersions are an example of an emulsion or suspension suitable for solvent based coating processes. In one aspect, the solvent is liquid at room temperature.

Coating can be done using conventional techniques such as pan coaters, rotary granulators and fluidized bed coaters such as top sprinklers, tangential sprinklers or bottom sprinklers (Wurster coating). The top spray method is also used for coating applications. In this method, the coating solution is sprayed down onto the fluidized cores. The solvent evaporates from the coated cores and the coated cores are refluidized in the apparatus. Application is continued until the desired thickness is achieved. Compositions and methods for preparing multiparticulates of this embodiment are described in detail in US patent applications, US 2005-0181062, US 2005-0181062, US 2008-0199527, US 2005-0186285A1, incorporated herein by reference.

The multiple particles of the invention typically have an average diameter of from about 40 to about 3,000 microns, with a desirable range of 50-1,000 microns, and most preferably from about 100 to 300 microns. While the multiple particles may be of any shape and texture, they are desirably spherical with a smooth surface. These physical characteristics of the multiple particles improve their flow properties, allowing them to be uniformly coated (if necessary). As used herein, the term "approximately" means ±10% of the value.

The multiparticulates of this invention are particularly suitable for controlled release or delayed release, or any combination of these release profiles, when introduced into an environment of use. As used herein, the "environment of use" may be the in vivo gastrointestinal (GI) environment, or the in vitro dissolution test described herein. Information about in vivo release rates can be obtained from the PK profile using standard deconvolution or Wagner-Nelson data processing well known to those in the industry.

After forming the tofacitinib multiparticulate matrix using the above methods, they are mixed with compressible excipients such as lactose, microcrystalline cellulose, calcium diphosphate, etc., and the mixture is compressed to form a tablet or capsule. Disintegrants such as sodium starch glycolate or cross-linked poly(vinylpyrrolidone) are also used. Tablets or capsules prepared by this method disintegrate upon entering an aqueous medium (such as the GI tract), thus affecting the tofacitinib releasing multiple particle matrix.

Other standard formulation excipients are used in the controlled release of the invention, including those known in the industry, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ^edition (2000) . Typically, excipients such as surfactants, pH modifiers, fillers, matrix materials, complexing agents, solubilizers, pigments, lubricants, glidants, flavoring agents, etc. can be used for normal needs and in typical quantities, while not adversely affecting the properties of the compositions.

Examples of matrix materials, fillers or diluents include the following: lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressed sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, poloxamers, polyethylene oxide, hydroxypropyl methylcellulose, and mixtures thereof.

Osmotic systems with sustained release

In another embodiment, tofacitinib is included in osmotic delivery devices or "osmotic pumps" as they are known in the industry. Osmotic pumps contain a core that contains an osmotically effective composition surrounded by a semi-permeable membrane. The term "semipermeable" in this context means that water can easily diffuse through the membrane, but substances dissolved in water usually cannot easily diffuse through the membrane, compared to the rate of diffusion of water through the membrane. In use, when placed in an aqueous environment, the device absorbs water due to the osmotic activity of the composition core. Due to the semi-permeable nature of the surrounding membrane, the contents of the device (including tofacitinib and any excipients) cannot pass through non-porous portions of the membrane, but are directed by osmotic pressure to leave the device through holes or channels pre-engineered in the dosage form, or alternatively formed in situ in the FA tract as a result of rupture of deliberately included weak points in the coating under the influence of osmotic pressure. An osmotically effective composition includes water-soluble species that form colloidal osmotic pressure and water-swellable polymers. Examples of such dosage forms are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21st ^Edition , 2006 Chapter 47; page 950-1, incorporated by reference.

In one embodiment of the present invention, tofacitinib is included in a two-layer osmotic delivery device such that the composition containing tofacitinib must contain a capturing agent in the form of a water-swellable polymer, and a second repellent layer or water-swellable layer containing water-swellable polymers and /or osmotically active agents, but not containing any active agent. The bilayer tablet or capsule is surrounded by a semi-permeable membrane containing one or more holes made in the dosage form by a technique such as laser drilling. Such water-swellable polymers are often referred to in the pharmaceutical industry as "osmopolymers" or "hydrogels". The capturing agent suspends or entraps the drug to facilitate delivery of the drug through the delivery channels. Without being bound by a particular theory, it is believed that during absorption of water into the dosage form, the entrapping agent has sufficient viscosity to suspend or entrap the drug while remaining fluid enough to pass through the delivery channel along with the drug. The amount of capturing agent in a composition containing tofacitinib ranges from about 20% to about 95% by weight. The capturing agent may be a single material or a mixture of materials. Non-cross-linked polyethylene oxide (PEO) can be used as a capture agent. Other suitable capture agents include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), and polyvinylpyrrolidone (PVP), as well as mixtures of these polymers with PEO.

The choice of molecular weight for PEO depends on whether PEO constitutes the bulk of the tofacitinib-free portion of the tofacitinib-containing composition, or whether a significant amount of other low molecular weight, water-soluble excipients is included; that is, the choice of PEO molecular weight depends on the PEO fraction of the tofacitinib-containing composition. The composition containing tofacitinib should not rapidly become liquid, the dosage form may swell or break the coating surrounding the core, potentially causing damage to the dosage form. When the excipients of the tofacitinib composition are predominantly PEO (e.g., PEO is approximately 60 wt.% or more of the non-tofacitinib components of the tofacitinib composition), it is generally desirable that the PEO has an average molecular weight of from about 100,000 to 300,000 daltons (as indicated in this document, reference to the molecular weights of the polymers is to be understood as the average molecular weight).

Alternatively, another embodiment of this invention uses high molecular weight PEO from about 500,000 to 800,000 daltons in the bottom fraction of non-tofacitinib excipients, part of the PEO is replaced by a plasticizer. Typically, when PEO is approximately 60 wt.% or more of the non-tofacitinib components of a tofacitinib-containing composition, PEO with a molecular weight of 500,000 daltons or more makes the tofacitinib-containing composition too viscous, and can lead to coating failure or at least delayed release of tofacitinib . However, such a high molecular weight PEO has been found to be preferred when the non-tofacitinib components of the tofacitinib-containing composition comprise less than about 60% by weight PEO and also include a plasticizer. Using high molecular weight PEO, the amount of plasticizer present in the composition containing tofacitinib is in the range from about 5 to about 50 wt.%, preferably 10-30 wt.% of the composition containing tofacitinib. Desirable plasticizers are low molecular weight, water-soluble solutes such as non-reducible sugars and organic acids with a water solubility of 30 mg/ml or more. Acceptable sugars include xylitol, mannitol, sorbitol, and maltitol. Salts suitable as a plasticizer include sodium chloride, sodium lactate and sodium acetate. Organic acids suitable as a plasticizer include the following: adipic acid, citric acid, malic acid, fumaric acid, succinic acid and tartaric acid.

The presence of a plasticizer, along with a relatively low level of high molecular weight PEO (eg, about 500,000 to about 800,000 daltons), allows the tofacitinib-containing composition to quickly achieve a low viscosity upon absorption of water. In addition, it has been found that such an embodiment is able to deliver a relatively high amount of tofacitinib.

The composition containing tofacitinib may also contain other water-swellable polymers. For example, a composition containing tofacitinib may contain a relatively small amount of water-swellable polymers that expand significantly in the presence of water. Such water-swellable polymers include sodium starch glycolate sold under the trade name EXPLOTAB and croscarmellose sodium sold under the trade name AC-DI-SOL. Such polymers may be present in an amount of from 0 wt.% to 10 wt.% of the composition containing tofacitinib.

The composition containing tofacitinib may optionally include osmotically effective solutes, which are referred to as "osmogens" or "osmagents." The amount of osmagent in the composition containing tofacitinib is in the range from about 0 wt.% to about 50 wt.%, preferably 10 wt.% - 30 wt.% of the composition containing tofacitinib. Typical classes of acceptable osmagents include water-soluble salts, sugars, organic acids, and other low molecular weight organic compounds capable of absorbing water, thus establishing an osmotic pressure gradient across the barrier of the surrounding coating. Typical acceptable salts include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate. Conventionally, chloride salts such as sodium chloride are used as osmagents.

The tofacitinib-containing composition may also include solubility-improving agents or solubilizers that promote dissolution of the drug in water, in an amount of from about 0% to about 30% by weight of the tofacitinib-containing composition. Solubilizers used with tofacitinib include organic acids and organic acid salts, partial glycerides, e.g., partially esterified glycerol derivatives, including glycerides, monoglycerides, diglycerides, glyceride derivatives, polyethylene glycol esters, polypropylene glycol esters, polyhydric alcohol esters, polyoxyethylene ethers, esters of sorbitan, esters of polyoxyethylene and sorbitan, and carbonate salts.

A preferred class of solubilizers are organic acids. In view of the fact that tofacitinib is a base that is solubilized by protonation, and that its solubility in an aqueous environment of pH 5 or higher is reduced, it is believed that the addition of an organic acid to a composition containing tofacitinib will aid in solubilization and, as a consequence, absorption of tofacitinib. Even a slight decrease in the pH of an aqueous solution at high pH will dramatically increase the solubility of tofacitinib. Organic acids can also promote stability during storage prior to introduction into the application environment due to their tendency to maintain the protonated state of tofacitinib.

Numerous factors are taken into account in selecting the appropriate organic acid for use as a solubilizer with tofacitinib in osmotic dosage form. The acid must not adversely interact with tofacitinib, must have acceptable aqueous solubility, and must provide good processing characteristics.

Accordingly, a preferred subclass of organic acids meeting such criteria has been found to include citric, succinic, fumaric, adipic, malic and tartaric acids. Citric, malic and tartaric acids have the advantage of high water solubility and high osmotic pressure. Succinic and fumaric acid give both moderate solubility and moderate osmotic pressure.

The water-swellable composition may also optionally contain a colorant. The purpose of the dye is to provide identification of the surface side of the tablet containing the drug in order to provide a delivery channel, for example by laser drilling through the coating. Acceptable dyes include, but are not limited to: Red No. 40, FD C blue 2 and FD C yellow 6.

The tofacitinib-containing layer and/or the water-swellable layer and/or functional rate-controlling membrane may optionally contain an antioxidant, including but not limited to: BHT, BHA, sodium metabisulfite, propyl gallate, glycerin, vitamin E, citric acid, or ascorbyl palmitate. The antioxidant may be present in an amount in the range from 0 to 10 wt.% of the composition containing tofacitinib, layer and/or layer, swelling in water and/or membrane that controls the functional rate. Additional examples of antioxidants are given in C.-M. Andersson, A. Hallberg, and T. Hoegberg. Advances in the development of pharmaceutical antioxidants. Advances in Drug Research. 28:65-180, 1996 .

The water-swellable composition may also contain other conventional pharmaceutically acceptable excipients such as a binder including HPC, HPMC, HEC, MC and PVP, a tabletting aid such as microcrystalline cellulose, and a lubricant such as magnesium stearate.

The water-swellable composition is obtained by mixing the water-swellable polymer and other fillers to form a homogeneous mixture. To obtain a homogeneous mixture, it is desirable that the dry or wet granulate or mixture of dry ingredients have the same particle size, using methods known in the industry.

tableting

The core is obtained by first placing the mixture of the composition containing tofacitinib in a tablet press and then flattening the mixture by gentle pressing. The water-swellable composition was then placed on top of the tofacitinib-containing composition and compressed to complete core formation. Alternatively, the water-swellable composition could be placed in the tablet press first, followed by the tofacitinib-containing composition.

The appropriate amount of the tofacitinib-containing composition and the water-swellable composition is chosen to provide satisfactory release of tofacitinib. When it is desired to provide a significant dose of tofacitinib in a relatively small dosage form, it is desirable to maximize the amount of the tofacitinib-containing composition and minimize the amount of water-swellable composition while still maintaining good release. In the dosage forms of the present invention, when the water-swellable polymer in the water-swellable composition is PEO only, the tofacitinib-containing composition may comprise from about 50 to about 85 wt.% core, and preferably from about 60 to about 70 wt. %. These values correspond to a weight ratio of the tofacitinib-containing composition to the water-swellable composition from 1 to about 5.7. When all or part of the water-swellable polymer in the water-swellable composition contains sodium starch glycolate or sodium croscarmellose, the tofacitinib-containing composition may comprise from 50 to 90% by weight of the core, and preferably from about 75 to about 85% by weight. These values correspond to the weight ratio of the composition containing tofacitinib and the water-swellable composition from 1 to 9. The absolute value of the diameter and height of the tablet of the present invention can vary over a wide range.

Coating

After the core is formed, a semi-permeable coating is applied. The coating must have high water permeability and considerable strength, and at the same time it must be easy to obtain and apply. A high water permeability is required for sufficient water penetration into the core. Significant strength is required to ensure that the coating does not disintegrate as the core swells during absorption of water, resulting in uncontrolled delivery of the core contents. Ultimately, the coating must have high reproducibility and yield.

It is essential that the coating has at least one delivery channel in communication with the inner and outer surfaces of the coating for delivery of the composition containing tofacitinib. Moreover, the coating must not dissolve or erode during the release of the tofacitinib containing composition, which generally means that the coating must be water insoluble so that tofacitinib is essentially completely delivered through the delivery channels, as opposed to being delivered by penetrating the coating.

Coatings with these characteristics can be obtained using hydrophilic polymers such as plasticized and non-plasticized esters, ethers and cellulose ethers. Particularly suitable polymers include cellulose acetate (AC), cellulose acetate butyrate (ACB), and ethyl cellulose (EC). One set of polymers includes cellulose acetates having an acetyl content of 25-42%. One exemplary polymer is AC having an acetyl content of 39.8%, namely AC 398-10 (Eastman Fine Chemicals, Kingsport, Tenn.). AC 398-10 has an average molecular weight of approximately 40,000 daltons. Another typical AC with an acetyl content of 39.8% is a high molecular weight AC with an average molecular weight of more than about 45,000, namely, AC 398-30 (Eastman Fine Chemical) with an average molecular weight of 50,000 daltons.

Coating is carried out in the usual manner, first by forming a coating solution and then by dip coating, fluidized bed coating, or mold lubrication. To implement this, the coating solution is formed containing a polymer and a solvent. Typical solvents suitable for cellulosic polymers include acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, nitroethane, nitropropane, tetrachloroethane, 1,4-dioxane, tetrahydrofuran, diglyme, and mixtures thereof. The coating solution typically contains 2-15 wt.% polymer.

The coating solution may also contain any amount of blowing agents or non-solvents, as long as the polymer remains soluble under the conditions used to form the coating, and as long as the coating remains permeable to water and has sufficient strength. Blowing agents and their use in coatings are described in US Pat. Nos. 5,698,220 and 5,612,059, the disclosure of which is incorporated herein by reference. The term "blooming agent," as used herein, refers to a material added to a coating solution that is non-volatile, compared to the solvent, so that it remains part of the coating after coating, but it swells significantly in water or dissolves in water, so that in an aqueous environment it forms a water-filled or swollen water channel or "pore" for the passage of water, thereby improving the water permeability of the coating. Suitable blowing agents include, but are not limited to, hydroxypropyl cellulose (HPC), polyethylene glycol ("PEG"), PVP, and PEO. To obtain a combination of high water permeability and high strength when using PEG or HPC as a blowing agent, the weight ratio of AC:PEG or AC:HPC should be in the range from about 6:4 to about 9:1.

The addition of a non-solvent, such as water, to the coating solution leads to an exceptional result. By "non-solvent" is meant any material added to the coating solution that substantially dissolves in the coating solution and reduces the solubility of the polymer coating or polymers in the solvent. In general, the function of the non-solvent is to impart porosity to the resulting material. As described below, porous coatings have a higher water permeability than an equivalent coating weight of the same composition but without pores, and this porosity is indicative of a decrease in coating density (weight/volume). Although investigators do not wish to be bound to any particular mechanism of pore formation, it is generally believed that the addition of a non-solvent imparts porosity to the coating during the evaporation of the solvent, causing separation of the liquid phase of the coating solution prior to curing. The suitability and amount of a particular candidate material for use as a non-solvent can be determined by gradually adding the candidate non-solvent to the coating solution until haze appears. If this does not happen when adding an amount of up to about 50 wt.% of the coating solution, it is considered that this candidate is not suitable as a non-solvent. When cloudiness is observed, referred to as "cloud point", the acceptable level of non-solvent for maximum porosity is the amount below the cloud point. For acetone solutions containing 7 wt.% AC and 3 wt.% PEG, the cloud point is approximately 23 wt.% water. If low porosity is desired, the amount of non-solvent can be reduced to the desired level.

Acceptable non-solvents are any materials with acceptable solubility in the solvent, and this solubility is less than the solubility of the polymer coating in the solvent. The preferred non-solvent depends on the solvent and the coating polymer. When using a volatile polar coating solvent such as acetone, suitable non-solvents include water, glycerin, alcohols such as methanol or ethanol.

Using AC 398-10, the weight ratios of AC:PEG3350:water coating solution are 2.4:1.6:5, 2.8:1.2:5, 3.2:0.8:5 and 3.6: 0.4:5, with the remainder of the solution containing a solvent such as acetone. Thus, for example, in a solution with a mass ratio of AC:PEG3350:water equal to 2.8:1.2:5, AC is 2.8 wt.% of the solution, PEG 3350 is 1.2 wt.% of the solution, water is 5 wt.% solution, and acetone makes up the remaining 91 wt.%. Also, a coating solution with a mass ratio of AC:HPC:water equal to 1.2:0.8:9.8, 2.4:1.6:19.6, 1.6:0.4:4.9 and 3 ,2:0.8:9.8, with the remainder of the solution containing a solvent such as acetone. Thus, for example, in a solution with a mass ratio of AC:HPC:water equal to 1.2:0.8:10, AC is 1.2 wt.% solution, HPC is 0.8 wt.% solution, water is 10 wt. .% solution, and acetone makes up the remaining 88 wt.%. Also, a coating solution with a mass ratio of AC:HPC:methanol equal to 1.8:1.2:19.6, 2.4:1.6:19.6, 1.6:0.4:4.9 and 3 ,2:0.8:9.8, with the remainder of the solution containing a solvent such as acetone. Thus, for example, in a solution with a mass ratio of AC:HPC:methanol at the level of 1.8:1.2:19.6, AC is 1.8 wt.% of the solution, HPC is 1.2 wt.% of the solution, methanol makes up 19.6 wt.% of the solution, and acetone makes up the remaining 77.4 wt.%.

When antioxidants are included in the coating solution, a third solvent may be needed to ensure good dispersion of the antioxidant in the coating. For example, an AC:PEG:water composition in a ratio of 2.4:1.6:5 containing 0.05 wt.% antioxidant solution requires 5 wt.% methanol and 86% acetone.

Coatings formed from such coating solutions are usually porous. By "porous" is meant that the dry coating has a density less than that of the same material in a non-porous form. By "non-porous form" is meant a coating material formed using a coating solution containing no non-solvent, or containing the minimum amount of non-solvent necessary to produce a homogeneous coating solution. The dry density of a coating can be calculated by dividing the coating weight (determined from the weight gain of the tablet before and after coating) by the coating volume (calculated by multiplying the coating thickness determined by optical or scanning electron microscopy by the surface area of the tablet). The porosity of the coating is one of the factors leading to the combination of high water permeability and high strength of the coating.

The weight of the coating around the core depends on the composition and porosity of the coating, but is typically in the range of 3 to 30% by weight of the uncoated core. A coating weight of at least about 8 wt.% is generally preferred for sufficient strength, although a lower coating weight can be used to obtain a high level of water absorption and, as a result, a high release rate of tofacitinib from the dosage form.

Although the porous AC, PEG or HPC and water based coatings described above show excellent results, other pharmaceutically acceptable coating materials can be used as long as the desired combination of high water permeability, high strength and ease of manufacture and application is achieved. Also, such coatings can be dense, porous, or "asymmetric," having one or more dense layers, and one or more porous layers, such as described in US Pat. Nos. 5,612,059 and 5,698,220, incorporated herein by reference.

The coating must contain at least one delivery channel in communication with the inner and outer surfaces of the coating to release the drug-containing composition from the dosage form. The size of the inlet can vary from approximately the size of the drug particles, thus being as small as 1-100 microns in diameter and referred to as a pore, to about 5000 microns in diameter. The shape of the channel may be substantially circular, slot-shaped, or other suitable shape for ease of manufacture and processing. The channels may be formed after coating by mechanical or thermal treatment or by a light beam (eg laser), particle beam or other high energy source, or may be formed in situ by breaking a small portion of the coating. Such a gap can be controlled by intentionally introducing a relatively small portion into the coating. The delivery channels can also be formed in situ by eroding a plug of water-soluble material or by destroying a portion of the coating solvent above a cavity in the core. Delivery channels may be formed by coating the core in such a way that one or more small areas are left uncoated. In addition, the delivery channel can be represented by a large number of holes or pores formed during coating, as is the case for the asymmetric membrane coatings detailed herein and the coatings described in US Pat. Nos. 5,612,059 and 5,698,220 incorporated herein. using links. When the delivery channels are pores, there may be multiple pores ranging in size from 1 micron to more than 100 microns. During use, one or more of these pores may enlarge under the influence of the hydrostatic pressure generated during use. At least one delivery channel must be formed on the side of the coating adjacent to the tofacitinib-containing composition so that the tofacitinib-containing composition will be extruded from the delivery channel due to the swelling of the water-swellable composition. It has been found that during the formation of the delivery channels, holes or pores may also be formed in the coating adjacent to the water-swellable composition.

The cover may optionally comprise a channel in communication with the water-swellable composition. Such a delivery route typically does not change the characteristics of the tofacitinib dosage form, and may provide manufacturing advantages. It is believed that water-swellable compositions, such as compositions containing PEO with a molecular weight of 3,000,000-8,000,000 daltons, are too viscous to significantly exit the channel. In dosage forms where the delivery channels are mechanically or laser-drilled, the tablet must be oriented so that at least one delivery channel is formed in the coating adjacent to the tofacitinib-containing composition. The dye in the water-swellable composition is used to orient the core of the dosage form during the drilling step of manufacturing. By providing a delivery channel on both sides of the dosage form, the need for orientation of the dosage form is eliminated and the dye can be removed from the water-swellable composition.

In another embodiment, tofacitinib is included in variations of the osmotic delivery devices described above, asymmetric membrane technology (AMT). These devices are described in Herbig, et al., J. Controlled Release, 35, 1995, 127-136 , and US Pat. Nos. 5,612,059 and 5,698,220 as coatings in osmotic drug delivery systems. These AMT systems provide the main advantage of controlled release osmotic devices (reliable drug delivery regardless of location in the GI tract) and also do not require the hole-drilling step in the coating that many other osmotic systems require. In forming such porous coatings, a water-insoluble polymer is combined with a water-soluble pore-forming material. The mixture is applied to the core of an osmotic tablet from a combination of water and a solvent. After the coating dries, the phase inversion is carried out through the formation of a porous asymmetric membrane. The use of AMT controlled drug release systems with similar physicochemical characteristics is described in US Patent Application Publication No. US2007/0248671 and incorporated herein by reference.

Although many materials have been described for use as pore formers in the manufacture of asymmetric membranes, all of the materials described above provide chemical or physical stability to the system. Namely, many of the prior art materials are liquids that can potentially migrate to the coating surface during storage. Among solid materials, both polymeric and inorganic materials are described. Inorganic materials can be difficult to consume for several reasons. Namely, they often tend to crystallize and/or adsorb moisture during storage. Specific polymeric materials include polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) derivatives. Both of these materials have a strong tendency to form peroxides and/or formaldehyde during storage (see e.g. Waterman, et al., "Impurities in Drug Products" in Handbook of Isolation and Characterization of Impurities in Pharmaceuticals, S. Ajira and KM Alsante , Eds. 2003, pp. 75-85 ). Many drugs interact with such polymer degradation products due to their intrinsic reactivity as well as their tendency to migrate during storage. However, this range of compositions is rather narrow. US Pat. No. 4,519,801 describes a wide range of water-soluble polymeric components suitable for coatings in osmotic systems, but does not disclose how to properly select water-soluble components for AMT systems. Thus, there remains a need for new blowing materials for AMT systems where the blowing materials do not generate reactive by-products, crystallize or migrate out of the coating during storage.

One aspect of this invention relates to a dosage form that contains (a) a core that contains at least one pharmaceutically active ingredient and (b) at least one coating in the form of an asymmetric membrane, where the specified coating includes:

a. one or more substantially water-insoluble polymer, and

b. one or more solid, water-soluble polymeric materials that do not contain hydrogen peroxide or formaldehyde in an amount of more than about 0.01% m:m after storage at 40°C/75% RH for 12 weeks.

One aspect of the present invention also relates to a dosage form, where the dosage form delivers the drug substance mainly due to osmotic pressure. In specific embodiments, this invention provides a dosage form wherein the pharmaceutically active ingredient is tofacitinib or a pharmaceutically acceptable salt thereof. The water-insoluble polymer as used in the present invention desirably contains a cellulose derivative, more desirably cellulose acetate. The solid, water-soluble polymeric material as used in the present invention contains a polymer having a weight average molecular weight of 2,000 to 50,000 daltons. In desirable embodiments, the solid water-soluble polymeric material is selected from the group consisting of the following: water-soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, polyvinyl alcohols, and zein. In specific embodiments, water-soluble cellulose derivatives include hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose. In certain embodiments, the solid water-soluble polymeric material has a viscosity of a 5% m:m aqueous solution of less than 400 mPa s. In certain embodiments, the solid water-soluble polymeric material has a viscosity of a 5% m:m aqueous solution of less than 300 mPa s. In other embodiments, the solid water-soluble polymeric material has a softening point greater than 55°C.

The dosage form of this invention may be in the form of a tablet or multiple particles. In certain embodiments, the core of this invention contains sugar. More desirably, the sugar is sorbitol. In certain embodiments, the water-insoluble polymer is cellulose acetate and said solid water-soluble polymer material is hydroxypropyl cellulose. In certain desirable embodiments, the dosage form of the invention comprises tofacitinib, or a pharmaceutically acceptable salt thereof, as the pharmaceutically active ingredient, while the water-insoluble polymer is cellulose acetate and the solid water-soluble polymer material is hydroxypropyl cellulose.

The method of the present invention encompasses a method where the coating is applied from a mixture of acetone and water using panning. The method of this invention also encompasses a method wherein the asymmetric membrane comprises cellulose acetate and hydroxypropyl cellulose, which is applied from a mixture of acetone and water in a ratio of about 9:1 - 6:4, m:m, and more preferably about 7:3 - 6:4, m:m, using a coating pan. Namely, the method of the present invention encompasses a method wherein the core comprises tofacitinib or a pharmaceutically acceptable salt thereof.

In preparing the asymmetric membrane coating of the present invention, the water-insoluble component of the asymmetric membrane is preferably derived from cellulose derivatives. Namely, these derivatives include cellulose esters and ethers, specifically, mono-, di- and triacyl esters, where the acyl group consists of 2-4 carbon atoms, and cellulose lower alkyl ethers, where the alkyl contains 1-4 carbon atoms. . Cellulose esters can also be mixed with esters such as cellulose acetate butyrate, or a mixture of cellulose esters. The same combinations are suitable for cellulose ethers, and include mixtures of cellulose esters and cellulose ethers. Other cellulose derivatives that can be used to prepare the asymmetric membranes of this invention include cellulose nitrate, dimethylcellulose acetaldehyde, cellulose acetate ethylcarbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetate dimethaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate dimethaminoacetate, cellulose ethyl carbonate acetate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methylsulfonate, cellulose acetate butylsulfonate, cellulose acetate p-toluenesulfonate, cellulose cyanoacetates, cellulose acetate trimellitate, cellulose methacrylates, and hydroxypropyl methyl acetate cellulose succinate. A particularly desirable water-insoluble component is cellulose acetate. Particularly desirable cellulose acetates include compounds with an acetyl content of about 40% and a hydroxyl content of about 3.5%. Other materials can also be used to form asymmetric membranes, providing materials that are inherently water-insoluble, film-forming, and safe for pharmaceutical use.

In preparing the asymmetric membranes of this invention, the water-soluble polymeric component of this invention contains solid polymeric materials that do not form hydrogen peroxide or formaldehyde during storage for 12 weeks at 40°C./75% relative humidity, in an amount of more than about 0.01 % mm. (100 ppm, ppm). Regarding water solubility, the solid polymeric water-soluble material preferably has a water solubility of more than 0.5 mg/ml; more desirably, more than 2 mg/ml; and even more desirably, more than 5 mg/ml.

The solid polymeric water-soluble material has a melting or softening point above room temperature. Preferably, the solid material has a melting or softening point above 30°C; more preferably above 40°C; and most preferably above 50°C. The melting or softening point can be determined visually using a melting point apparatus, or alternatively can be measured using differential scanning calorimetry (DSC) known in the art. The polymer may be a homopolymer or a copolymer. Such polymers may be natural polymers, or derivatives of natural products, or wholly synthetic. The molecular weight of such materials is preferably high enough to prevent migration and aid in film formation, yet low enough to allow coating (as described below). The preferred molecular weight range of this invention is from 2000 to 50,000 daltons (average weight). Preferred polymers suitable as water-soluble components of the asymmetric membrane of this invention include substituted, water-soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, polyvinyl alcohols, and zein. Particularly preferred water-soluble polymers include hydroxyethyl cellulose, hydroxypropyl cellulose and polyvinyl alcohol.

It is difficult to obtain asymmetric membranes if the viscosity of the coating solution is too high, so one approach to solving this problem is to use more dilute polymer solutions. As a result of the phase behavior of the coating solution, which contains both water-soluble and organic-soluble components, there is a minimum concentration limit for water-soluble polymers to ensure a commercialized process. For this reason, it is desirable that the water-soluble polymers do not have too high a viscosity. Viscosity is determined at 25° C. using a Brookfield LVF viscometer (manufactured by Brookfield Engineering Corp., Middleboro, Mass. ) with combinations of axis and speed, depending on the viscosity level of 5% (m:m) aqueous solutions. Preferred water-soluble polymers have a viscosity of 5% (m:m) solutions of less than 400 mPa s; more desirable, less than 300 mPa s.

Using the above criteria, particularly preferred water soluble polymers include hydroxypropyl cellulose and hydroxyethyl cellulose with 5% (w:m) viscosities lower than 300 mPa s, commercially available examples of such polymers include Klucel EF.TM. and Natrasol LR.TM., both from Aqualon Division of Hercules Corp., Hopewell, Virginia.

The stability of water-soluble solid polymeric materials to the formation of hydrogen peroxide can be measured by storing the polymer in an oven with a temperature and relative humidity (RH) of 40°C and 75% RH, respectively. The polymer must be stored in the oven under "open" conditions. The polymer should be stored for at least 12 weeks. Hydrogen peroxide levels can be determined as described in G. M. Eisenberg, "Colorimetric determination of hydrogen peroxide" in Ind. Eng. Chem. (Anal. Ed.), 1943, 15, 327-328 . Under such storage conditions, acceptable polymeric materials of this invention have hydrogen peroxide levels below 100 parts per million (ppm); more desirably below 50 ppm; and most desirably below 10 ppm.

Similarly, the stability of water-soluble polymers to formaldehyde formation can be measured by storing the polymer in an oven at 40°C and 75% RH. The resin must be stored in an airtight container to prevent loss of volatile formaldehyde. The polymer should be stored for at least 12 weeks. Formaldehyde levels can be determined as described in M. Ashraf-Khorassani, et al., "Purification of pharmaceutical excipients with supercritical fluid extraction" in Pharm. dev. Tech. 2005, 10, 1-10 . Under such storage conditions, suitable water-soluble polymeric materials of this invention have formaldehyde levels below 100 ppm, more desirably below 50 ppm, and most desirably below 10 ppm.

It will be appreciated by those skilled in the art that the asymmetric membrane composition may contain small amounts of other materials without significantly altering its function or changing the nature of the present invention. Such additives include glidants (eg, talc and silica) and plasticizers (eg, triethyl citrate and triacetin), which are usually added, if necessary, in an amount of less than about 5% (w:w) of the coating.

Those skilled in the art will appreciate that the active pharmaceutical ingredients may be in the form of pharmaceutically acceptable salts. The cores of this invention may also contain solubilizers. Such additives include pH buffering additives to maintain the core at a pH at which the active pharmaceutical ingredient has a high enough solubility to be pumped out of the dosage form into solution. The active pharmaceutical ingredient may be present in the core in an amount of from about 0.1% (m:m) to about 75% (m:m).

The core may contain osmotic agents that help provide the driving force for drug delivery. Such osmotic agents include water-soluble sugars and salts. A particularly preferred osmotic agent includes mannitol or sodium chloride.

The core of the AMT system may contain other additives to provide benefits such as stability, processability, and system performance. Stabilizing excipients include pH modifying ingredients, antioxidants, chelating agents, and other such additives known in the industry. Machinability-improving fillers include flow, compression, or extrusion aids. Fluidity can be improved with agents such as talc, stearates and silica. Flow can also be improved by granulation of the drug and excipients, as is known in the industry. Such granulation often benefits from the addition of binders such as hydroxypropyl cellulose, starch, and polyvinyl pyrolidone (povidone). Compression can be improved by adding diluents to the composition. Examples of diluents include lactose, mannitol, microcrystalline cellulose, etc., as is known in the industry. For extruded cores, the melting characteristics of the fillers are important. Generally, it is desirable that such fillers have a melting point below about 100°C. Examples of suitable excipients for the melting process include esterified glycerols and stearyl alcohol. For compressed dosage forms, workability is improved by the addition of lubricants. A particularly preferred lubricant is magnesium stearate.

Cores can be prepared using standard tabletting techniques as is known in the industry. Such methods include filling the mold with the powder, then pressing it using suitable punches. Cores can also be obtained by extrusion. Extrusion is well suited for producing small cores (multiple particles). The preferred extrusion is melt-spray-curing as described in WO2005/053653A1, incorporated by reference. The cores can also be obtained by depositing layers of drug on the cores. Such cores are preferably made from sugar or microcrystalline cellulose. The drug can be applied to the cores by spraying, preferably in a fluidized bed, as is known in the industry.

In the practice of this invention, the nuclei are coated with an asymmetric membrane using any technique that can provide an asymmetric membrane as a coating over the entire nucleus. Preferred coating methods are panning and fluid bed coating. In both methods, the water-insoluble polymer and the water-soluble polymer, as well as any other additives, are first dissolved or dispersed in a suitable solvent or combination of solvents. To obtain an acceptable porous membrane, the coating solvent must be optimized for productivity. Typically, solvents are chosen such that the more volatile solvent is preferred over the water-insoluble polymer component. As a result, during the coating process, the water-insoluble polymer component precipitates out of solution. Preferred solvents and solvent ratios are determined by examining the multicomponent solubility of the system. The preferred solvent mixture is acetone and water, in a ratio of from about 9:1 to 6:4, m:m.

In a preferred embodiment of the present invention, tofacitinib is incorporated into a monolithic osmotic delivery device known as an extrudable core system such that the composition containing tofacitinib must contain viscosity increasing polymers and osmotically active agents, and may optionally include solubility enhancing agents and/or antioxidants. . The monolithic tablet or capsule is surrounded by a semi-permeable membrane containing one or more holes made in the dosage form by techniques such as laser drilling. Viscosity-enhancing polymers hang or surround the drug to facilitate drug delivery through delivery channels. Without being bound by a particular theory, it is believed that when water is absorbed into the dosage form, the viscosity increasing polymer has sufficient viscosity to hang or envelop the drug while remaining fluid enough to allow the viscosity increasing polymer to pass through the delivery channels along with the drug. The amount of viscosity increasing polymer contained in the composition containing tofacitinib is in the range of from about 2 wt.% to about 20 wt.%, preferably from about 3 to about 15%, and more desirably from about 4 wt.% to about 10 wt. .%. The viscosity-increasing polymer may consist of a single material or a mixture of materials. Non-crosslinked polyethylene oxide (PEO) and hydroxyethyl cellulose (HEC) can be used as the viscosity increasing polymer. HEC is preferred as the viscosity increasing polymer. The molecular weight of the HEC may be from about 300,000 to about 2,000,000, more preferably from about 700,000 to about 1,500,000.

The composition containing tofacitinib also includes osmotically effective solutes, which are referred to as "osmogens" or "osmagents." The amount of osmagent in a composition containing tofacitinib ranges from about 15% to about 95% by weight, desirably from about 40% to about 90% by weight, more preferably from about 60% to about 85%, and most desirably, about 70% to about 85% of the composition containing tofacitinib. Typical classes of acceptable osmagents include water-soluble salts, sugars, organic acids, and other low molecular weight organic compounds capable of absorbing water to form an osmotic pressure gradient across the barrier of the surrounding coating. Typical salts include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate. Preferred salts include both sodium chloride and potassium chloride. Preferred organic acids include the following: ascorbic acid, 2-benzenecarboxylic acid, benzoic acid, fumaric acid, citric acid, maleic acid, serbacic acid, sorbic acid, edipic acid, editic acid, glutamic acid, toluenesulfonic acid, and tartaric acid. Preferred sugars include mannitol, sucrose, sorbitol, xylitol, lactose, dextrose and trehalose. A more preferred sugar is sorbitol. Osmagents can be used alone or in combination with two or more osmagents.

The tofacitinib-containing composition may also include solubility-enhancing agents or solubilizers that promote drug solubility in water, present in the range of from about 0% to about 30% by weight of the tofacitinib-containing composition. Solubilizers acceptable with tofacitinib include organic acids and organic acid salts, partial glycerides, e.g., partially esterified glycerol derivatives, including glycerides, monoglycerides, diglycerides, glyceride derivatives, polyethylene glycol esters, polypropylene glycol esters, polyhydric alcohol esters, polyoxyethylene ethers, esters of sorbitan, polyoxyethylene esters of sorbitan and carbonate salts.

A preferred class of solubilizers are organic acids. In view of the fact that tofacitinib is a base that is solubilized by protonation, and in view of the fact that its solubility in an aqueous environment with a pH of 5 or higher is reduced, it is believed that the addition of an organic acid to a composition containing tofacitinib helps solubilization and improves the absorption of tofacitinib. . Even a small decrease in the pH of the aqueous solution at high pH leads to a significant increase in the solubility of tofacitinib. Organic acids may also promote stability during storage prior to introduction into the use environment due to their ability to maintain tofacitinib in a protonated state.

There are many factors to consider when selecting an appropriate organic acid for use as a solubilizer with tofacitinib in osmotic dosage form. The acid must not interact adversely with tofacitinib, must be suitably water soluble, and must provide good processing characteristics.

Accordingly, it has been found that a preferred subclass of organic acids meeting such criteria includes citric, succinic, fumaric, adipic, malic and tartaric acids. Citric, malic and tartaric acids have the advantage of high water solubility and high osmotic pressure. Succinic and fumaric acid give a combination of moderate solubility and moderate osmotic pressure.

The functional rate control layer and/or membrane of the composition containing tofacitinib may optionally contain an antioxidant such as, but not limited to, BHT, BHA, sodium metabisulfite, propyl gallate, glycerin, vitamin E, citric acid, or ascorbyl palmitate. The antioxidant may be present in the range of 0 to 10% by weight of the layer and/or the water-swellable layer and/or the rate-controlling membrane of the tofacitinib-containing composition. For additional examples of antioxidants, see C.-M. Andersson, A. Hallberg, and T. Hoegberg . Advances in the development of pharmaceutical antioxidants . Advances in Drug Research. 28:65-180, 1996 .

The composition containing tofacitinib is obtained by mixing the viscosity increasing polymer and other excipients to form a homogeneous mixture. To obtain a homogeneous mixture, it is desirable to subject the components to wet or dry granulation, or dry mixing, using methods known in the industry.

tableting

The core is obtained by first placing the composition mixture containing tofacitinib in a tablet press and compressing to form the core. The shape of the tablet may be any shape known in the art. Preferred tablet shapes include SRC (standard round concave), oval, modified oval, capsule, capsule tablet, and almond. More preferred tablet shapes include oval, modified oval, capsule tablet and capsule.

Coating

After nucleation, a semi-permeable coating is applied. The coating should have high water permeability and high strength, and at the same time it should be easy to manufacture and apply. High water permeability is required to allow sufficient water to enter the core. High strength is required to ensure that the coating does not burst when the core swells during water absorption, resulting in uncontrolled delivery of the core contents. Finally, the coating must have high reproducibility and yield.

It is essential that the coating has at least one delivery channel in communication with the outer and inner surfaces of the coating for delivery of the composition containing tofacitinib. Moreover, the coating should not dissolve and erode during the release of the composition containing tofacitinib, it is generally understood that it should be water-insoluble, so that tofacitinib is essentially completely delivered through the delivery channels, as opposed to delivery by penetration through the coating.

Coatings with these characteristics are obtained using hydrophilic polymers such as plasticized and non-plasticized cellulose esters, ethers and ester-ethers. Particularly suitable polymers include cellulose acetate (AC), cellulose acetate butyrate (ACB), and ethyl cellulose (EC). One set of polymers includes cellulose acetates with an acetyl content of 25-42%. One exemplary polymer is AC 39.8% acetyl, namely AC 398-10 (Eastman Fine Chemicals, Kingsport, Tenn.). AC 398-10 has an average molecular weight of approximately 40,000 daltons. Another exemplary 39.8% acetyl AC is a high molecular weight AC with an average molecular weight greater than about 45,000, namely AC 398-30 (Eastman Fine Chemical), which has an average molecular weight of 50,000 daltons.

Coating is carried out in the usual manner, first by forming a coating solution and then by dip coating, fluidized coating, or drag coating. To accomplish this, the coating solution contains a polymer and a solvent. Typical solvents suitable for cellulosic polymers include acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, nitroethane, nitropropane , tetrachloroethane, 1,4-dioxane, tetrahydrofuran, diglyme, and mixtures thereof. The coating solution typically contains 2-15 wt.% polymer.

The coating solution may also contain any amount of blowing agents or non-solvents as long as the polymer remains soluble under the conditions used to form the coating and as long as the coating remains water permeable and has sufficient strength. Blowing agents and their use in coatings are described in US Pat. Nos. 5,698,220 and 5,612,059, incorporated herein by reference. The term "blooming agent" as used herein refers to a material added to a coating solution that is not volatile or slightly volatile, compared to the solvent, so that it remains as part of the coating after coating but preferentially swells or dissolves in water. so that, in an aqueous environment of use, it allows the formation of a water-filled or water-swollen channel or "pore" for the passage of water, thereby improving the water permeability of the coating. Suitable blowing agents include, but are not limited to, hydroxypropyl cellulose (HPC), polyethylene glycol ("PEG"), PVP, and PEO. To obtain a combination of high water permeability and high strength when using PEG or HPC as a blowing agent, the weight ratio of AC:PEG or AC:HPC should be in the range from about 6:4 to about 9:1. AC:HPC is the preferred coating composition. The preferred ratio of AC:HPC is in the range of 6:4 to 7:3. The preferred weight ratio of AC:PEG is in the range of 6:4 to 7:3.

The addition of a non-solvent, such as water, to the coating solution leads to an exceptional result. By "non-solvent" is meant any material added to the coating solution that substantially dissolves in the coating solution and reduces the solubility of the polymer coating or polymers in the solvent. In general, the function of the non-solvent is to impart porosity to the resulting material. As described below, porous coatings have a higher water permeability than an equivalent coating weight of the same composition but without pores, and this porosity is indicative of a decrease in coating density (weight/volume). Although researchers do not wish to be bound by any particular pore formation mechanism, it is generally believed that the addition of a non-solvent imparts porosity to the coating during solvent evaporation, causing separation of the liquid phase of the coating solution prior to curing. The suitability and amount of a particular candidate material for use as a non-solvent can be determined by gradually adding the candidate non-solvent to the coating solution until haze appears. If this does not happen when adding an amount of up to about 50 wt.% of the coating solution, it is considered that this candidate is not suitable as a non-solvent. When cloudiness is observed, referred to as "cloud point", the acceptable level of non-solvent for maximum porosity is the amount below the cloud point. For acetone solutions containing 7 wt.% AC and 3 wt.% PEG, the cloud point is approximately 23 wt.% water. If low porosity is desired, the amount of non-solvent can be reduced to the desired level.

Acceptable non-solvents are any materials with acceptable solubility in the solvent, and a solubility lower than the solubility of the polymer coating in the solvent. The preferred non-solvent depends on the solvent and the coating polymer. When using a volatile polar coating solvent such as acetone, suitable non-solvents include water, glycerin, alcohols such as methanol or ethanol.

Using AC 398-10, the weight ratios of AC:PEG3350:water coating solution are 2.4:1.6:5, 2.8:1.2:5, 3.2:0.8:5 and 3.6: 0.4:5, with the remainder of the solution containing a solvent such as acetone. Thus, for example, in a solution with a mass ratio of AC:PEG3350:water equal to 2.8:1.2:5, AC is 2.8 wt.% of the solution, PEG 3350 is 1.2 wt.% of the solution, water is 5 wt.% solution, and acetone makes up the remaining 91 wt.%. Also, a coating solution with a mass ratio of AC:HPC:water equal to 1.2:0.8:9.8, 2.4:1.6:19.6, 1.6:0.4:4.9 and 3 ,2:0.8:9.8, with the remainder of the solution containing a solvent such as acetone. Thus, for example, in a solution with a mass ratio of AC:HPC:water equal to 1.2:0.8:10, AC is 1.2 wt.% solution, HPC is 0.8 wt.% solution, water is 10 wt. .% solution, and acetone makes up the remaining 88 wt.%. Also a coating solution with a mass ratio of AC:HPC:methanol equal to 1.8:1.2:19.6, 2.4:1.6:19.6, 1.6:0.4:4.9 and 3, 2:0.8:9.8, with the remainder of the solution containing a solvent such as acetone. Thus, for example, in a solution with a mass ratio of AC:HPC:methanol at the level of 1.8:1.2:19.6, AC is 1.8 wt.% of the solution, HPC is 1.2 wt.% of the solution, methanol makes up 19.6 wt.% of the solution, and acetone makes up the remaining 77.4 wt.%.

When antioxidants are included in the coating solution, a third solvent may be needed to ensure good dispersion of the antioxidant in the coating. For example, an AC:PEG:water composition in a ratio of 2.4:1.6:5 containing 0.05 wt.% solution requires 5 wt.% methanol and 86% acetone.

Coatings formed from such coating solutions are usually porous. By "porous" is meant that the dry coating has a density less than that of the same material in a non-porous form. By "non-porous form" is meant a coating material formed using a coating solution containing no non-solvent, or containing the minimum amount of non-solvent necessary to produce a homogeneous coating solution. The dry density of a coating can be calculated by dividing the coating weight (determined from the weight gain of the tablet before and after coating) by the coating volume (calculated by multiplying the coating thickness determined by optical or scanning electron microscopy by the surface area of the tablet). The porosity of the coating is one of the factors leading to the combination of high water permeability and high strength of the coating.

The weight of the coating around the core depends on the composition and porosity of the coating, but is typically in the range of 3 to 30% by weight of the uncoated core. A coating weight of at least about 8 wt.% is generally preferred for sufficient strength, although a lower coating weight can be used to obtain a high level of water absorption and, as a result, a high release rate of tofacitinib from the dosage form. For dosage forms containing tofacitinib, a coating weight gain of 5-10% is preferred to provide the desired release.

Although the porous AC, PEG or HPC and water based coatings described above show excellent results, other pharmaceutically acceptable coating materials can be used as long as the desired combination of high water permeability, high strength and ease of manufacture and application is achieved. Also, such coatings can be dense, porous, or "asymmetrical" having one or more dense layers and one or more porous layers, such as described in US Pat. Nos. 5,612,059 and 5,698,220, incorporated herein by reference.

The coating must contain at least one delivery channel in communication with the inner and outer surfaces of the coating to release the drug-containing composition from the dosage form. The size of the inlet can vary from approximately the size of the drug particles, thus being as small as 1-100 microns in diameter and referred to as a pore, to about 5000 microns in diameter. The shape of the channel may be substantially circular, slot-shaped, or other suitable shape for ease of manufacture and processing. The channels may be formed after coating by mechanical or thermal treatment or by a light beam (eg laser), particle beam or other high energy source, or may be formed in situ by breaking a small portion of the coating. Such a gap can be controlled by intentionally introducing a relatively small portion into the coating. The delivery channels can also be formed in situ by eroding a plug of water-soluble material or by destroying a portion of the coating solvent above a cavity in the core. Delivery channels may be formed by coating the core in such a way that one or more small areas are left uncoated. In addition, the delivery channel can be represented by a large number of holes or pores formed during coating, as is the case for the asymmetric membrane coatings detailed herein and the coatings described in US Pat. Nos. 5,612,059 and 5,698,220 incorporated herein. using links. When the delivery channels are pores, there may be multiple pores ranging in size from 1 micron to more than 100 microns. During use, one or more of these pores may enlarge under the influence of the hydrostatic pressure generated during use. The location of the delivery channels can be anywhere on the surface of the tablet. The preferred arrangement of the delivery channels includes the front surface of the tablet and the tablet tape. A more preferred location includes approximately the center of the tablet band for SRC round tablets, and approximately the center of the tablet band along the major axis and/or approximately the center of the tablet band along the minor axis of the tablet band for a capsule, capsule, oval or modified oval tablet. The most preferred location of the delivery channels includes the approximate center of the tablet strip along the major axis of the tablet strip for a capsule, capsule, oval or modified oval tablet.

Sustained release reservoir system

Another class of sustained release tofacitinib dosage forms of this invention includes membrane-moderated or reservoir systems. In this class, the tofacitinib reservoir is surrounded by a rate-limiting membrane. Tofacitinib moves across the membrane by a well-known mass transfer mechanism, including but not limited to dissolution in the membrane followed by diffusion through the membrane or diffusion through fluid-filled pores within the membrane. These individual reservoir dosage forms can be large, as in the case of a tablet containing one large reservoir, or multiple particles, as in the case of a capsule containing multiple particles, each of which is coated with a membrane. The coating can be non-porous but permeable to tofacitinib (eg, tofacitinib can diffuse directly across the membrane), or porous. In other embodiments of the invention, the specific transport mechanism is not critical.

Sustained release coatings known in the industry can be used to form a membrane, especially polymeric coatings such as cellulose esters or ethers, an acrylic polymer, or a mixture of polymers. Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer may be applied as a solution in an organic solvent, or as an aqueous dispersion or latex. The coating procedure can be carried out on standard equipment such as a fluidized bed coater, a Wurster unit, or a rotary coater.

If necessary, the permeability of the coating can be adjusted by mixing two or more materials. A suitable method of adjusting the porosity of the coating involves adding a predetermined amount of finely divided water-soluble material, such as sugars or salts or water-soluble polymers, to a solution or dispersion (eg, aqueous latex) of the membrane-forming polymer. When the dosage form is introduced into the aqueous environment of the GI tract, these water-soluble additives in the membrane are washed out of the membrane, leaving pores that promote drug release. The membrane coating can also be modified with the addition of known plasticizers in the industry.

A suitable method of applying the membrane coating involves dissolving the coating polymer in a mixture of solvents chosen such that, as the coating dries, the applied coating solution undergoes phase reversal, resulting in the formation of a membrane with a porous structure. Numerous examples of this type of coating system are given in European Patent 0 357 369 B1, published 03/07/1990, incorporated by reference.

The morphology of the membrane is not critical as long as the permeability characteristics described above are maintained. The membrane may be amorphous or crystalline. It may have any category of morphology obtained by any method, and may be, for example, an interfacial polymerized membrane (which contains a thin boundary shell on a porous support), a porous hydrophilic membrane, a porous hydrophobic membrane, a hydrogel membrane, an ionic membrane, and may be composed of from other such materials, characterized by controlled permeability to tofacithinia.

A suitable reservoir system is a capsule having a shell containing a rate-limiting membrane material, including any of the membrane materials previously described, and filled with the tofacitinib composition. A particular advantage of this configuration is that the capsule can be produced independently of the drug composition, thus manufacturing conditions that could adversely affect the drug substance can be used to produce the capsule. One embodiment is a capsule having a shell made from a porous or permeable heat treated polymer. Another embodiment is represented by an asymmetric membrane capsule shell; for example, a membrane having a thin surface layer on one surface and most of its thickness is composed of a permeable porous material. The method for producing an asymmetric membrane capsule includes phase inversion with solvent exchange, where the polymer solution applied to the capsule mold is phase-separated by replacing the solvent with a miscible non-solvent. Examples of asymmetric membranes suitable for this invention are described in the aforementioned European Patent 0 357 369 B1.

Another embodiment of the class of reservoir system includes multiple particles, where each particle is coated with a polymer designed to provide sustained release of tofacitinib. Numerous particles contain tofacitinib and one or more excipients, which is necessary for manufacturing and technical characteristics. The size of the individual particles, as previously stated, is usually about 50 microns - 3 mm, although small deviations from these sizes are also suitable. In general, the particles contain tofacitinib and one or more binders. It is generally desirable to produce dosage forms that are small in size so that they are easy to swallow, particles containing a large fraction of tofacitinib are preferred over the vehicle. Binders suitable for making such particles include microcrystalline cellulose (eg, Avicel.RTM., FMC Corp.), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and similar materials or combinations thereof. In general, binders suitable for granulation and tabletting such as starch, pregelatinized starch and poly(N-vinyl-2-pyrrolidinone) (PVP) can also be used to form multiple particles.

The tofacitinib multiparticulate reservoir system can be prepared using techniques known in the industry including, but not limited to, extrusion and pelletizing, wet granulation, fluidized bed granulation, and rotary granulation. In addition, particles can also be obtained by creating a tofacitinib formulation (drug + excipients) on top of a core (e.g. nonpareil grain) by applying a layer of drug, e.g. powder coating or coating the tofacitinib composition by spraying a solution or dispersion of tofacitinib in a suitable binder solution onto the cores. in a fluidized bed, using a Wurster installation or a rotary device. An example of a suitable composition and method is spraying a dispersion of the tofacitinib/hydroxypropylcellulose composition in water. Advantageously, tofacitinib can be loaded into an aqueous composition beyond its water solubility limit.

The method for producing the multiparticulate cores of this embodiment is extrusion/pelleting, as previously described for the multiparticulate matrix. Another process and composition for this method involves the use of water for a wet mix of about 5-75% microcrystalline cellulose and about 95-25% tofacitinib, respectively. In another embodiment, the method comprises applying water to a wet mixture of about 5-30% microcrystalline cellulose and about 5-70% tofacitinib, respectively.

Sustained release coatings known in the industry, especially polymeric coatings, can be used to produce a membrane, as previously described for reservoir systems. Suitable and preferred polymer coatings, coating equipment and methods also include those previously described.

The release rate of tofacitinib from coated multiparticulates can also be controlled by factors such as composition and binder content in the drug core, coating thickness and permeability, and surface area to volume ratio of the multiparticulates. It will be appreciated by those skilled in the art that increasing the thickness of the coating will decrease the release rate, while increasing the permeability of the coating or the surface area to volume ratio of the multiple particles will increase the release rate. If necessary, the permeability of the coating can be adjusted by mixing two or more materials. Suitable series of coatings include mixtures of water-insoluble and water-soluble polymers, for example, ethylcellulose and hydroxypropylmethylcellulose, respectively. A suitable coating modification includes the addition of finely divided water-soluble material such as sugars or salts. When placed in an aqueous environment, these water-soluble additives are washed out of the membrane, leaving pores that improve drug delivery. The membrane coating can also be modified with the addition of plasticizers known to those skilled in the art. Another suitable membrane option is a mixture of solvents, chosen in such a way that when the coating dries, the applied coating solution undergoes phase reversal, which leads to the formation of a membrane with a porous structure.

Another embodiment is represented by multiple particles containing approximately 5-50% tofacitinib, where the individual particles are coated with an aqueous dispersion of ethyl cellulose which dries to form a continuous film.

Another embodiment is represented by the situation where tofacitinib particles are less than about 400 microns in size and are coated with an ethyl cellulose or cellulose acetate phase inversion membrane.

Another embodiment is represented by the situation where tofacitinib particles are less than about 400 microns in size and are coated with an aqueous dispersion of ethyl cellulose that dries to form a continuous film.

Another embodiment is represented by the situation where the tofacitinib particles are less than about 300 microns in size and are coated with an aqueous dispersion of ethyl cellulose that dries to form a continuous film.

Delayed and controlled release components

Another class of dosage forms includes forms that provide a delay before the start of controlled release of tofacitinib. One embodiment is a tablet containing a core that contains tofacitinib coated with a first coating of a polymeric material suitable for controlled release of tofacitinib and a second coating suitable for delayed release of the drug upon swallowing the dosage form. The first coating is applied over and around the tablet. The second coat over and around the first coat.

The tablet can be prepared by methods known in the art and contains a therapeutically acceptable amount of tofacitinib plus excipients necessary to form the tablet using the chosen technique.

The first coating may be a controlled release coating known in the industry, especially a polymer coating, to form a membrane, as previously discussed for reservoir systems. Suitable polymeric coating materials, coating equipment and methods also include those mentioned above.

Materials suitable for obtaining a second coating on a tablet include polymers known in the industry as delayed release enteric coatings. They are mainly pH sensitive materials such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, poly(vinyl acetate phthalate), and acrylic copolymers such as Eudragit L-100 (RohmPharma), Eudragit L 30 D-55, Eudragit S 100, Eudragit FS 30D, and similar materials are described in more detail below in the "delayed release" section. The thickness and type of delayed release coating is adjusted to obtain the desired delay. In general, thinner coatings are more resistant to erosion and, as a result, provide a longer delay, as do coatings that dissolve at pH above 7. Preferred coatings usually have a thickness of from about 10 microns to about 3 mm, and more preferably 10 microns - 500 µm.

When swallowed, the double-coated tablet passes through the stomach, where the second coating prevents the release of tofacitinib under acidic conditions. As the tablet passes from the stomach into the small intestine, where the pH is higher, the second coating erodes or dissolves according to the physicochemical properties of the selected material. Upon erosion or dissolution of the second coating, the first coating prevents immediate or rapid release of tofacitinib and modulates the release so as to avoid high concentrations, thus minimizing side effects.

Another embodiment includes multiple particles, where each particle is double coated, as described above for the tablet, first with a polymer designed for the controlled release of tofacitinib and then coated with a delayed release polymer in the GI environment upon ingestion of the dosage form. The particles contain tofacitinib and may contain one or more excipients necessary for manufacturing and performance. Multiple particles containing a significant fraction of tofacitinib compared to the binder are preferred. The multiple particles may be formulated and prepared as previously described for the multiple particles used to make reservoir systems (including extrusion and pelletizing, wet granulation, fluidized bed granulation, and rotary granulation, grain production, etc.).

Controlled release coatings are known in the industry, especially polymer coatings for membrane formation, as previously discussed for tank systems. Suitable polymeric coating materials, coating equipment and methods also include those mentioned above.

The release rate of tofacitinib from controlled release multiparticulates (eg, multiparticulates prior to delayed release coating) and methods of coating modification are controlled by factors previously described for tofacitinib multiparticulate reservoir systems.

The second double coated multiparticulate membrane or coating is a delayed release coating that is applied over the first controlled release coating as described for the tablet and may be formed from the same materials. It should be noted that the use of so-called "intestinal" materials for the present invention differs significantly from their use for the preparation of conventional enteric dosage forms. For standard enteric forms, the goal is to delay drug release until the dosage form has passed the stomach, and then to deliver the dose shortly after exiting the stomach. Release of tofacitinib directly and completely in the duodenum is undesirable, however, due to local metabolism, which is sought to be minimized or avoided in the present invention. Therefore, if conventional enteric polymers are used in the present invention, it is necessary to apply them in a much thicker layer than usual in order to delay drug release until the dosage form enters the intestine. However, it is desirable to provide controlled delivery of tofacitinib after dissolution or eroding of the delayed release coating, thus the advantage of the present invention is realized by a suitable combination of delayed release with controlled release, and the delayed release portion alone may not necessarily meet the USP enteric criteria. The thickness of the delayed release coating is set to provide the required delay. In general, thicker coatings are more resistant to erosion and, as a result, provide longer respite.

It should also be noted that the sustained release osmotic systems described above may also be categorized as delayed release rather than controlled release. Typical sustained release osmotic systems provide an initial delay of 0.5-6 hours before releasing the drug in a controlled manner. In this manner, typical sustained release monolithic or dual layer osmotic systems embody the definition of a delay followed by a controlled release.

Bursting osmotic granules and nuclei (pulsating delivery)

In another embodiment ("osmotic core bursting device"), tofacitinib is included in an osmotic bursting device containing a tablet core or bead core containing tofacitinib and optionally one or more osmagents. Devices of this type have been described in Baker, US Pat. No. 3,952,741, incorporated herein by reference. Examples of osmagents include sugars such as glucose, sucrose, mannitol, lactose, etc.; and salts such as sodium chloride, potassium chloride, sodium carbonate, etc.; water-soluble acids such as tartaric acid, fumaric acid, etc. The tablet core or bead core containing tofacitinib is coated with a polymer that forms a semi-permeable membrane, i.e. a membrane that is permeable to water but essentially impermeable to tofacitinib. Examples of polymers that provide a semi-permeable membrane include cellulose acetate, cellulose acetate butyrate and ethyl cellulose, preferably cellulose acetate. The semi-permeable membrane may alternatively be composed of one or more waxes such as animal wax and insect wax such as beeswax and vegetable waxes such as carnauba wax and hydrogenated vegetable oils. A molten mixture of polyethylene glycol, such as polyethylene glycol-6000, and a hydrogenated oil, such as hydrogenated castor oil, can be used as coatings as described for the Yoshino ionized tablet (Capsugel Symposia Series; Current Status on Targeted Drug Delivery to the Gastrointestinal Tract; 1993 ;pp.185-190) . Some preferred semipermeable membranes include cellulose esters and ethers, polyacrylic acid derivatives such as polyacrylates and polyacrylate esters, and polyvinyl alcohols and polyalkenes such as ethylene vinyl alcohol. Other semipermeable membranes include cellulose acetate and cellulose acetate butyrate.

When a "bursting osmotic core" tablet or bead coated with this invention is placed in an aqueous environment, water passes through the semi-permeable membrane into the core, dissolving some of the tofacitinib and osmagent, generating colloidal osmotic pressure, which leads to rupture of the semi-permeable membrane and release of tofacitinib into the aqueous environment. . By choosing the size and shape of the bead or tablet core, the type and amount of osmagent, and the thickness of the semi-permeable membrane, the delay time between exposure of the dosage form to the aqueous medium and release of tofacitinib can be chosen. It will be appreciated by those skilled in the art that increasing the surface area to volume ratio of the dosage form and increasing the osmotic activity of the osmagent will decrease the delay time, while increasing the thickness of the coating will increase the delay time. The osmotically bursting devices of the present invention substantially do not release tofacitinib from the dosage form until the dosage form has passed from the stomach and enters the small intestine in about 15 minutes. or more. Some osmotically ruptured devices do not substantially release tofacitinib from the dosage form until the dosage form has passed from the stomach and enters the small intestine approximately 30 minutes or more. Other osmotically ruptured devices do not substantially release tofacitinib from the dosage form until the dosage form has passed from the stomach and enters the small intestine about 90 minutes or more. Other osmotically bursting devices do not substantially release tofacitinib from the dosage form until the dosage form has passed from the stomach and enters the small intestine, preferably approximately 3 hours or more, thus providing minimal release of tofacitinib in the duodenum and upper small intestine. intestines. The bursting core osmotic tablet or bead has a core containing from about 10-95% tofacitinib, about 0-60% osmagent as described above, and about 5-20% other pharmaceutical additives such as binders and lubricants. The semi-permeable membrane on a tablet, for example cellulose acetate, is from about 2% to about 30%, preferably from about 3% to about 10%, by weight of the tablet core. The semi-permeable membrane on the bead, for example cellulose acetate, comprises from about 2% to about 80% by weight of the bead core. In another embodiment, the semi-permeable coating on the bead is 3-30% by weight of the bead core.

The bursting core osmotic device does not have a mechanism to "detect" whether the device has exited the stomach and entered the duodenum. Thus, devices of this type release tofacitinib at a predetermined time after entering the aquatic environment, for example, after ingestion. On an empty stomach, indigestible, non-degradable solids, such as the "bursting core osmotic device" of the invention, exit the stomach during phase III of the gastric migratory myoelectric complex (IMMC), which occurs approximately every 2 hours in humans. Depending on the stage of IMMC during fasting dosing, the bursting core osmotic device may exit the stomach almost immediately after dosing, or 2 after dosing. In the postprandial state, indigestible, non-decomposing solids, <11 mm in diameter, slowly pass from the stomach into the food contents ( Khosla and Davis, Int. J. Pharmaceut. 62 (1990) R9-R11 ). If the indigestible, non-degradable solids are greater than about 11 mm in diameter, such as the size of a conventional tablet, they will remain in the stomach during the digestion of the food, and enter the duodenum during phase III of the IMMC complex, after the food has been completely digested and exited from the stomach. The release of tofacitinib may be delayed up to approximately 15 minutes or more. Release of tofacitinib may be delayed up to 30 minutes or more. The release of tofacitinib may be delayed up to approximately 90 minutes or more. The release of tofacitinib may be delayed up to approximately 3 hours or more after the dosage form has exited the stomach. The bursting core osmotic device begins to release tofacitinib approximately 2.5 hours after exposure to the aquatic environment, such as after ingestion, to be more reliable that the device will release tofacitinib distally from the duodenum when taken on an empty stomach. Another "bursting core osmotic device" begins to release tofacitinib approximately 4 hours after exposure to the aquatic environment. This 4 hour delay allows the dose to be taken in a fed state, and gives approximately 3.5 hours of delay in a full stomach, followed by approximately 30 minutes. delay after the dosage form has passed from the stomach. Thus, the release of tofacitinib in the most sensitive part of the GI tract, the duodenum, is minimized.

In another embodiment, a "bursting coated swellable core", a tablet or granule containing tofacitinib, is prepared such that it also contains 25-70% of a swellable material such as a swellable colloid (e.g. gelatin) as described in Milosovich, US Pat. No. 3,247,066 incorporated by reference. Swellable core materials are hydrogels, for example, hydrophilic polymers that absorb water and swell, such as polyethylene oxides, polyacrylic acid derivatives such as polymethyl methacrylate, polyacrylamides, polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, carboxymethyl cellulose, starches, etc. d. Swellable hydrogels for this embodiment include polyethylene oxides, carboxymethyl cellulose, and croscarmellose sodium. The core of the tablet or granule containing the colloid/hydrogel and tofacitinib is covered, at least in part, by a semi-permeable membrane. Examples of polymers providing a semi-permeable membrane include cellulose acetate and cellulose acetate butyrate, and ethyl cellulose. The semi-permeable membrane may alternatively be composed of one or more waxes such as animal wax and insect wax such as beeswax and vegetable waxes such as carnauba wax and hydrogenated vegetable oils. A molten mixture of polyethylene glycol, such as polyethylene glycol-6000, and a hydrogenated oil, such as hydrogenated castor oil, can be used as a coating, as described for the Yoshino ionized tablet (Capsugel Symposia Series; Current Status on Targeted Drug Delivery to the Gastrointestinal Tract; 1993 ;pp.185-190) . Some semipermeable membranes include cellulose esters and ethers, polyacrylic acid derivatives such as polyacrylates and polyacrylate esters, and polyvinyl alcohols and polyalkenes such as ethylene-vinyl alcohol copolymer, cellulose acetate and cellulose acetate butyrate.

When a coated tablet or bead containing a bursting, swellable coated core is placed in an aqueous environment, water passes through the semi-permeable membrane into the core, the core swells, resulting in rupture of the semi-permeable membrane and release of tofacitinib into the aqueous environment. By choosing the size and shape of the bead or tablet core, the type and amount of the swelling agent, and the thickness of the semi-permeable membrane, the delay time between placing the dosage form in an aqueous environment and releasing tofacitinib can be chosen. Preferred coated bursting swellable core devices of this invention include devices that do not substantially release tofacitinib from the dosage form until the dosage form has passed from the stomach and enters the small intestine after approximately 15 minutes. or more, preferably about 30 minutes or more, thus minimizing the release of tofacitinib in the duodenum.

The coated bursting swellable core tablet or granule contains from about 10-70% tofacitinib; about 15-60% swellable material, eg hydrogel; about 0-15% optional osmagent; and about 5-20% other pharmaceutical additives such as binders and lubricants. The semi-permeable membrane on the tablet, preferably cellulose acetate, is from about 2% to about 30%, preferably 3-10%, by weight of the tablet core. The semi-permeable membrane on the bead, preferably cellulose acetate, is from about 2% to about 80%, preferably 3-30%, by weight of the bead core.

The coated bursting swellable core device does not have a mechanism to "detect" whether the device has exited the stomach and entered the duodenum. Thus, devices of this type release tofacitinib at a predetermined time after exposure to the aquatic environment, for example, after ingestion, as previously described for the ruptured core osmotic device, and the same considerations and advantages apply to coated ruptured swellable core devices. Coated bursting swellable core devices can be combined with instant release devices to provide a dosage form that releases the drug either immediately after administration or at one or more predetermined time intervals after dosing.

In another embodiment, a "pH triggered osmotic bursting device", tofacitinib is included in the device described in US Patent 5,358,502 published 10/25/1994, incorporated by reference. The device contains tofacitinib and optionally one or more osmagents surrounded by at least a partially semi-permeable membrane. The semi-permeable membrane is permeable to water and essentially impermeable to tofacitinib and osmagent. Acceptable osmagents are the same as those described above for the bursting core osmotic device. Acceptable semi-permeable membrane materials are the same as described above for the bursting core osmotic device. The pH triggers are attached to a semi-permeable membrane. The pH-triggering agents are activated by pH levels above 5.0, and trigger unexpected delivery of tofacitinib. In this embodiment, the pH triggers include a membrane or polymeric coating surrounding the semi-permeable coating. The pH-start coating contains a polymer that is essentially impermeable and insoluble in the gastric pH environment, but which becomes permeable and soluble at duodenal pH, approximately pH 6.0.

Examples of pH-sensitive polymers include polyacrylamides, phthalate derivatives such as acid hydrocarbon phthalates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose phthalate, polyvinyl acetate phthalate , polyvinyl acetate hydrophthalate, sodium acetate cellulose phthalate, starch acid phthalate, styrene-maleic acid-dibutyl phthalate copolymer, styrene-maleic acid copolymer polyvinyl acetate phthalate, styrene-maleic acid copolymers, polyacrylic acid derivatives such as acrylic acid-acrylic ester copolymers, polymethacrylic acid and its esters, copolymers of polyacrylic and methacrylic acid, shellac, and copolymers of vinyl acetate and crotonic acid.

Preferred pH sensitive polymers include shellac; phthalate derivatives, especially cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, especially polymethyl methacrylate mixed with acrylic acid, and acrylic ester copolymers; and copolymers of vinyl acetate and crotonic acid. As described above, cellulose acetate phthalate is available as a latex under the trademark Aquateric.RTM. (trademark FMC Corp., Philadelphia), and acrylic copolymers are available under the tradename Eudragit-R.RTM and Eudragit-L.RTM. For proper application in this embodiment, these polymers must be plasticized using the plasticizers described above. The pH triggered coating may also contain a mixture of polymers, such as cellulose acetate and cellulose acetate phthalate. Another suitable mixture contains Eudragit-L.RTM and Eudragit-S.RTM; their ratio and coating thickness determine the "trigger" sensitivity, eg the pH at which the outer pH-triggered coating weakens and dissolves.

A pH controlled osmotic rupture device typically works as follows. After oral ingestion, the pH-adjustable coating surrounding the semi-permeable coating, which in turn surrounds the tofacitinib-containing tablet or granule core, remains undissolved and intact in the stomach. In the stomach, water can begin to permeate through the pH-adjusted coating and the semi-permeable coating, thus starting the hydration of the core containing tofacitinib and an optional osmagent. Once the device has exited the stomach and entered the small intestine, the pH-adjusted coating quickly disintegrates and dissolves, and water passes through the semi-permeable coating, dissolving tofacitinib and the optional osmagent within the core. After the colloidal osmotic pressure across the semi-permeable coating exceeds a certain threshold value, the semi-permeable coating is destroyed and the device ruptures, releasing tofacitinib. Preferably, this gap and release of tofacitinib occurs after approximately 15 minutes. or more, preferably 30 minutes. or more, after the pH-adjusted osmotic bursting device exits the stomach and enters the duodenum, thus minimizing the effect of tofacitinib on the sensitive duodenum.

For a pH controlled osmotic bursting device, the delay period or delay period is controlled by the choice and amount of osmagent in the core, the choice of semi-permeable coating, and the thickness of the semi-permeable coating. The skilled artisan will appreciate that, for example, a thicker semi-permeable coating will provide a longer delay after the device exits the stomach. A preferred pH controlled osmotically bursting device is a tablet or bead core containing tofacitinib with an optional osmagent, coated with a 3-20 wt% cellulose acetate membrane, coated with a 3-20 wt% membrane containing approximately cellulose acetate/cellulose acetate phthalate in the ratio 1:1. Another preferred pH controlled osmotic bursting device is a tablet or bead core containing tofacitinib with an optional osmagent, coated with a 3-20 wt% cellulose acetate membrane, coated with a 3-20 wt% membrane, containing from about 9:1 to about 1: 1 Eudragit-L.RTM./Eudragit-S.RTM.

Advantageously, because the pH-adjusted osmotic bursting device has a mechanism that determines the release of the device from the stomach, individual variability in gastric emptying is not relevant.

In another embodiment, the "pH controlled bursting coated swellable core", the tofacitinib containing tablet or bead core and the swellable material are coated with a semi-permeable coating which is itself coated with a pH sensitive coating. The composition of the core, including the selection of the swellable material, is as described above for the coated bursting swellable core. The choice of semi-permeable coating material and pH sensitive coating material is as described above for the "pH controlled osmotic core". This device is described in detail in US Patent Application 08/023,227, filed Feb. 25, 1993, incorporated by reference.

A pH controlled bursting swelling core typically works as follows. After oral ingestion, the pH-adjustable coating surrounding the semi-permeable coating, which in turn surrounds the tofacitinib-containing tablet or granule core, remains undissolved and intact in the stomach. In the stomach, water can begin to permeate through the pH-adjustable coating and the semi-permeable coating, thus initiating hydration of the core containing tofacitinib and a water-swellable material, preferably a hydrogel. When the pH-adjusted bursting swellable core has exited the stomach and entered the small intestine, the pH-adjusted coating quickly disintegrates and dissolves, and water passes through the semi-permeable coating, dissolving tofacitinib and the water-swellable material inside the core. After the swelling pressure across the semi-permeable coating exceeds a certain threshold, the semi-permeable coating ruptures and the device ruptures, releasing tofacitinib. Preferably, this gap and release of tofacitinib occurs after approximately 15 minutes. or more, preferably 30 minutes. or more after the pH-controlled osmotic bursting device exits the stomach and enters the duodenum, thus minimizing the effect of tofacitinib on the sensitive duodenum.

For "pH-adjustable bursting swelling core", the delay period or delay period is controlled by the choice and amount of swelling material in the core, the selection of the semi-permeable coating, and the thickness of the semi-permeable coating. The skilled artisan will appreciate that, for example, a thicker semi-permeable coating will provide a longer delay after the device exits the stomach. The pH-adjusted bursting swellable core contains a tablet or granule core containing tofacitinib with a synthetic hydrogel, preferably carboxymethyl cellulose, coated with a 3-20 wt% cellulose acetate membrane coated with a 3-20 wt% cellulose acetate/cellulose acetate phthalate membrane in a ratio of 1:1. Another pH-adjusted bursting swellable core comprises a tablet or granule core containing tofacitinib with a synthetic hydrogel, preferably carboxymethyl cellulose, coated with a 3-20 wt% cellulose acetate membrane coated with a 3-20 wt% membrane composed of from about 9:1 up to approximately 1:1 Eudragit-L.RTM./Eudragit-S.RTM.

Advantageously, due to the fact that the pH-controlled bursting swelling core has a mechanism that determines the exit of the device from the stomach, individual variability in gastric emptying is not important. The pH-adjusted bursting swellable cores can be combined with instant release devices to form a dosage form that releases the drug both immediately after administration and at one or more pre-designated locations in the GI tract after dosing.

A current review of such fracturing technology is presented in the Journal of Controlled Release; 134 (2009) 74-80 , which is incorporated by reference.

Delayed release embodiments of the invention are oral solid dosage forms containing tofacitinib and a pharmaceutically acceptable carrier, releasing no more than 10% of incorporated tofacitinib into the mammalian stomach, and releasing no more than 10% more during the first 15 minutes after entry into the duodenum. the intestines of mammals. The timing of release of tofacitinib in the stomach or duodenum can be tested using a variety of approaches including, but not limited to, x-ray, magnetic resonance imaging, gamma scintigraphy, or direct sampling of gastric or duodenal contents by intubation. These tests, while possible, are highly problematic to perform on humans. A more suitable test for the delayed release of the present invention is the two step in vitro dissolution test.

The invention is illustrated by the following non-limiting examples.

Examples

Example 1 Extrudable Core Osmotic Tablet

22 mg tablet core

Half the batch size of sorbitol, 2663.01 g (also see Table 1 below), was added to the 28 L bin. The batch size of Copovidone, 420.00 g, was then added to the 28 L bin. The batch size of Tofacitinib, 623.98 g, was then added to the 28 L bin. Batch Size Hydroxycellulose, 560.00 g, was then added to the 28 L bin. The remaining half batch size of sorbitol, 2663.01 g, was added to the 28 liter bin. All components were mixed in the hopper for 15 min. at 12 +/- 1 rpm

The mixture was passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller running at approximately 950 rpm. The mixture was collected in a second 28 L bin. The contents of the hopper were stirred for 10 min. at 15 +/- 1 rpm.

Magnesium stearate, 70 g, was passed through an 850-micron mesh sieve and added to the hopper and the contents mixed for 5.5 minutes at 12+/- 1 rpm. The final mixture was transferred to the hopper of a Fette rotary tablet press. The tablets were compressed using 0.2620" x 0.5240" modified oval tools to an average target weight of 400 mg +/- 5%, an average target thickness of 5.35 mm +/- 0.05 mm, and a target strength of 13 kPa. The tablets were passed through a dust collector and a metal detector.

Table 1 No. Material Function Composition (%) grams 1 tofacitinib citrate Active ingredient 8.914 623.98 2 Sorbitol Osmagen 76.086 5326.02 3 Hydroxyethylcellulose Viscosifying agent 8,000 560.00 4 Kollidon VA 64 (copovidone) Binder 6,000 420.00 5 magnesium stearate lubricant 1,000 70.00 Tablet core weight - - - 100 7000.00

11 mg tablet core.

Half the batch size of sorbitol, 2819.01 g (also see Table 2 below), was added to the 28 liter hopper. The batch size of Copovidone, 420.00 g, was then added to the 28 L bin. The batch size of Tofacitinib, 311.99 g, was then added to the 28 L bin. Batch Size Hydroxycellulose, 560.00 g, was then added to the 28 L hopper. The remaining half batch size of sorbitol, 2819.0 g, was added to the 28 liter hopper. All components were mixed in the hopper for 15 minutes at 12 +/- 1 rpm.

The mixture was passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller running at approximately 950 rpm. The mixture was collected in a second hopper with a volume of 28 liters. The contents of the hopper were stirred for 10 minutes at 15 +/- 1 rpm.

Magnesium stearate, 70 g, was passed through an 850-micron mesh sieve and added to the hopper and the contents mixed for 5.25 minutes at 12 +/- 1 rpm. The final mixture was transferred to the hopper of a Fette rotary tablet press. The tablets were compressed using 0.2620" x 0.5240" modified oval tools to an average target weight of 400 mg +/- 5%, an average target thickness of 5.35 mm +/- 0.05 mm, and a target strength of 15 kPa. The tablets were passed through a dust collector and a metal detector.

table 2 No. Material Function Composition (%) grams 1 tofacitinib citrate Active ingredient 4.457 311.99 2 Sorbitol Osmagen 80.543 5638.01 3 Hydroxyethylcellulose Viscosifying agent 8,000 560.00 4 Kollidon VA64 (copovidone) Binder 6,000 420.00 5 magnesium stearate lubricant 1,000 70.00 Tablet core weight - - - 100 7000.00

Tablet coating and drilling

A coating solution (4.049 kg) was prepared according to the following steps: first, all 396.0 g of water (also see Table 3 below) and 1464.0 g of acetone were added to a 5 L vessel and stirred for 5 minutes. Hydroxypropylcellulose (32.4 g) was added to the mixture and mixed for 5 minutes. Cellulose acetate (48.6 g) was added to the mixture and mixed for 5 minutes. The remaining 2108 g of acetone was added to the mixture and stirred for 3 hours. This procedure gave a 2% solid solution (w/m).

Table 3 Tablet coating composition 1 % in coverage mg/tablet coating m/m (%) Lot size (grams) 1. Tofacitinib Citrate Tablet core --- 400 ------- -------- 2. Cellulose acetate (398-10) 1.2 14.4 3.6 48.6 3. Hydroxypropylcellulose (Klucel EF) 0.8 9.6 2.4 32.4 4. Acetone 88.2 (1058.4) ------ 3572.0 5. Purified water 9.8 (117.6) ------ 396.0 total weight 100 424 6.0 4049.0

Oval tablets (900 g) weighing 400 mg were coated in a Vector LDCS-5 enrober with a 1.5 L partially perforated tray operating at 20 rpm and an air flow of 30 cu.f./min with an outlet temperature of 40°C. 2% (m./m.). The solid solution was applied until a wet weight level of 6.2% was reached. After that, the tablets were removed from the pan and dried at 40°C for 16 hours.

A single hole (1000 microns) was drilled into the end of the oval tablet strip. The hole can be drilled mechanically or with a laser. The 6% coating provided the following release into pH 6.8 media at 50 rpm paddle speed based on dissolution test 1 (Table 4):

Table 4 Time (h) 11 mg tablet
% drug dissolved 22 mg tablet
% drug dissolved 1 eleven 15 2.5 55 61 5 87 92

Example 2 . Osmotic tablets with an extrudable core with a coating solution Acetone:Methanol (200 mg)

11 mg tablet core

Half the batch size of sorbitol, 38.014 kg (also see Table 5 below), was added to the 300 L hopper. The batch size of Copovidone, 6.00 kg, was then added to the 300 L bin. The batch size of Tofacitinib, 8.914 kg, was then added to the 300 L bin. Batch size Hydroxycellulose, 8.00 kg, was then added to the 300 L bin. The remaining half batch size of sorbitol, 38.014 g, was added to the 300 L hopper. All materials were added using a vacuum transfer system and passed through a Comil rotary mill equipped with a 0.032″ filter and round edge impeller running at approximately 1400 rpm. All components were mixed in the hopper for 20 min. at 12 +/- 1 rpm

The mixture was passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller operating at approximately 1400 rpm. The mixture was collected in a second 300 L bin. The contents of the hopper were stirred for 20 min. at 12 +/- 1 rpm

Magnesium stearate, 1.00 kg, was passed through an 850-micron mesh sieve and added to the hopper and the contents mixed for 5 minutes. at 12 +/- 1 rpm Tablets were compressed using 0.2080" x 0.4160" modified oval tools on a Manesty Mark IV rotary tablet press to an average target weight of 200 mg +/- 5%, an average target thickness of 4.17 mm +/- 0.05 mm , and a target strength of 10 kPa. The tablets were passed through a dust collector and a metal detector.

Table 5 No. Material Function Composition (%) The consignment
100 kg 1 tofacitinib citrate Active ingredient 8.914 8.914 2 Sorbitol Osmagen 76.086 76.086 3 Hydroxyethylcellulose Viscosifying agent 8,000 8.00 4 Copovidone Binder 6,000 6.00 5 magnesium stearate lubricant 1,000 1.00 Tablet core weight - - - 100 100.00

22 mg tablet core

Half the batch size of sorbitol, 33.086 kg (also see Table 6 below), was added to the 300 L bin. The batch size of colloidal silica, 1.00 kg, was then added to the 300 L bin. The batch size of Copovidone, 6.00 kg, was then added to the 300 L bin. The batch size of Tofacitinib, 8.914 kg, was then added to the 300 L bin. Batch size Hydroxycellulose, 8.00 kg, was then added to the 300 L bin. The remaining half batch size of sorbitol, 33.086 g, was added to the 300 L bin. All materials were added using a vacuum transfer system and passed through a Comil rotary mill equipped with a 0.032” filter and a round edge impeller operating at approximately 1400 rpm. All components were mixed in a hopper for 20 min. at 12 +/- 1 rpm

The mixture was passed through a Comil rotary mill equipped with a 0.032” filter and a round rim impeller running at approximately 1400 rpm. The mixture was collected in a second 300 L bin. The contents of the hopper were stirred for 20 min. at 12 +/- 1 rpm

Magnesium stearate, 1.00 kg, was passed through an 850-micron mesh sieve and added to the hopper and the contents mixed for 5 minutes. at 12 +/- 1 rpm Tablets were compressed using 0.2080" x 0.4160" modified oval tools on a Manesty Mark IV rotary tablet press to an average target weight of 200 mg +/- 5%, an average target thickness of 4.17 mm +/- 0.05 mm , and a target strength of 11 kPa. The tablets were passed through a dust collector and a metal detector.

Table 6 No. Material Function Composition (%) Batch 100 kg 1 tofacitinib citrate Active ingredient 17.828 17.828 2 Sorbitol Osmagen 66.172 66.172 3 Hydroxyethylcellulose Viscosifying agent 8,000 8.00 4 Copovidone Binder 6,000 6.00 5 colloidal silicon dioxide Glidant 1,000 1.00 6 magnesium stearate lubricant 1,000 1.00 Tablet core weight - - - 100 100.00

A coating solution (750 kg) was prepared according to the following steps (see also Table 7): first, all 147.0 kg of methanol and 580.5 g of acetone were added to a 250 gallon flask. Cellulose acetate (13.5 kg) was added to the mixture. Hydroxypropylcellulose (9.0 kg) was added to the mixture. The contents of the container were stirred for one hour. This procedure gave a 3% (m./m.) solid solution.

Table 7 Coated tablet composition
200 mg % in coverage mg/tablet coating m/m (%) Lot size (kg) 1. Tofacitinib Citrate Tablet core --- 200 --- --------- 2. Cellulose acetate (398-10) 1.8 7.9 4.0 13.5 3. Hydroxypropylcellulose (Klucel EF) 1.2 5.3 2.6 9.0 4. Methanol 19.6 (86.2) --- 147.0 5. Acetone 77.4 (340.6) --- 580.5 total weight 100 213.2 6.6 750.0

Oval tablets (250 kg) weighing 200 mg were coated in a Vector HC-130 enrober operating at 8 rpm. and an airflow of 1000 cfm. with an outlet temperature of 28°C. A solid solution of 3% (w/w) was applied until a wet weight increase of 6.8% was achieved. The tablets were then removed from the pan and dried at 45° C. for 24 hours.

A single hole (600 microns) was drilled at the end of the oval tablet strip. The hole can be drilled mechanically or with a laser. The 6.6% coating provided the next release into a pH 6.8 medium at a paddle speed of 50 rpm. based on dissolution test 1 (Table 8):

Table 8 Time (h) 11 mg tablet
% drug dissolved 22 mg tablet
% drug dissolved 1 eleven 10 2.5 55 55 5 85 82

Example 3 Osmotic Tablets with Extrudable Core and Coating Membrane of Cellulose Acetate and Polyethylene Glycol (200 mg)

Tofacitinib sustained release 11 mg and 22 mg core tablets were prepared as described in Example 2.

A coating solution of 1200 g was prepared according to the following steps (see also Table 9): first, 60 g of water and 19.2 g of polyethylene glycol were added to a 5 l vessel and stirred until the solution was clear. Methanol (60 g) and 0.504 g BHA were added to the solution and stirred until clear. Acetone (1031.496 g) and 28.8 g of cellulose acetate were added to the mixture. The contents of the container were stirred for 3 hours. This procedure gave a solid solution of 4% (m./m.).

Table 9 No. Material Composition (%) grams 1 Cellulose acetate (398-10) 2,400 28.8 2 Polyethylene glycol (PEG 3350) 1,600 19.2 3 Butylated hydroxyanisole (BHA) 0.042 0.504 4 Purified water 5,000 60.0 5 methanol 5,000 60.0 6 Acetone 85.958 1031.496 100

Oval tablets (240 g) weighing 200 mg were coated in a Vector LDCS-5 enrober operating at 30 rpm and 40 cfm airflow with an outlet temperature of 28°C. A solid solution of 3% (w/w) was applied until a wet weight increase of 9.2% was achieved. The tablets were then removed from the pan and dried at 40° C. for 16 hours.

A single hole (600 microns) was drilled into the end of the oval tablet strip. The hole can be drilled mechanically or with a laser. The 9% coating provides the following release into pH 6.8 media at 50 rpm paddle speed based on dissolution test 1 (Table 10):

Table 10 Time (h) 11 mg tablet
% drug dissolved 22 mg tablet
% drug dissolved 1 28 thirty 2.5 72 70 5 92 90

Example 4 Controlled Release Hydrophilic Matrix Tablet

The metal surfaces of the 10 L hopper were precoated by adding batch size (also see Table 11 below) 1484.85 g of Fast Flo 316 lactose and mixing for 2 minutes at 12 +/- 1 rpm. The batch size of Tofacitinib, 171.15 g, was added to a 10 L bin and loaded onto lactose monohydrate. The Tofacitinib container was flushed with some lactose monohydrate from a 10 L hopper. Batch size Hypromelose, 720 g, was added to a 10 L bin. All components were mixed in the hopper for 10 minutes at 12 +/- 1 rpm.

The mixture was passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller running at approximately 1400 rpm. The mixture was collected in a second 10 L bin. The contents of the hopper were stirred for 10 minutes at 12 +/- 1 rpm.

Intracrystalline magnesium stearate, 6 g, was added to the hopper and mixed for 3 minutes at 12 +/- 1 rpm. The lubricated mixture was passed through a Gerteis roller press equipped with knurled rollers, removable rim flanges and a linear vibrating mill containing a portable rotor and a 1 mm thick pumice plate. The desired layered solids fraction of 0.7 (0.67-0.73) and pellets were collected in the original 10 liter hopper.

Intracrystalline magnesium stearate, 18 g, was added to the hopper and the contents were mixed for 3 minutes at 12 +/- 1 rpm. The final mixture was passed through a Kilian T-100 rotary tablet press. Tablets were compressed using 13/32” SRC tools to an average target weight of 500 mg +/- 5% and a target strength of 15 kPa. The tablets were passed through a dust collector and a metal detector.

Table 11
Composition of a tablet of Tofacitinib (22 mg) with a hydrophilic matrix;
weight of all tablets 500 mg Ingredient Function % in composition grams tofacitinib citrate Active Ingredient 7.1 171.15 Methocel K100LV CR Premium Polymer, controlled release gelling agent thirty 720.00 lactose monohydrate,
FastFlo 316 Filler 61.9 1484.85 Magnesium Stearate, Vegetable Source (IG) lubricant 0.25 6.00 Magnesium Stearate, Vegetable Source (EG) lubricant 0.75 18.00 Total 100 2400.00

Compressed tablets provide the next release in a medium with a pH of 6.8, at a speed of rotation of the blades of 50 rpm based on the dissolution test 1 (Table 12).

Table 12 Time (h) % drug dissolved 1 24 2.5 47 5 76

Example 5 Bilayer Osmotic Tablet (20 mg)

The batch sizes of Tofacitinib and Polyethylene oxide N80 (see also Table 13) were passed through a 30 mesh sieve and added to a 500 cm ³ amber glass bottle. The mixture was stirred for 10 minutes using a Turbula blender. Magnesium stearate (0.2 g) was passed through a 30 mesh sieve and added to the active blend flask and mixed for 3 minutes.

The batch sizes of polyethylene oxide (coagulant class), blue lacquer and sodium chloride were passed through a 20 or 30 mesh sieve and added in that order to a 500 cm ³ flask. The mixture was stirred for 10 minutes. using a Turbula blender. Magnesium stearate (0.5 g) was passed through a 30 mesh sieve and added to the swelling bed flask and mixed for 3 minutes.

The tablets were compressed using 9 mm standard round convex tools to an average target weight of 400 mg +/- 5%, an average target thickness of 7 mm +/- 0.05 mm, and a target strength of 15 kPa.

Table 13 Active layer components: Quality: Quantity
(mg)/unit: % Lot size (g) tofacitinib citrate 33.333 12.5 5.0 Polyethylene oxide grade WSR N80 NF 232 87.0 34.8 magnesium stearate ^e NF/EP 1.333 0.5 0.2 266.667 100.0 40

Intumescent layer components: Quality: Quantity
(mg)/unit: % Lot size (g) Polyethylene oxide Coagulant class ^a NF 86 64.5 64.5 Sodium chloride ^b USP/EP 46.4 34.8 34.8 Laco-dye FD&C blue
No. ^2d food 0.267 0.2 0.2 magnesium stearate ^e NF/EP 0.667 0.5 0.5 133.333 100.0 100.0

The coating solution was prepared according to the following steps (see also Table 14 below): first, all 194.6 g of water and 800 g of acetone were added to a 5 liter tank and mixed for 5 minutes. Hydroxypropylcellulose (24 g) was added to the mixture and mixed for 5 minutes. Cellulose acetate (36 g) was added to the mixture and mixed for 5 minutes. The remaining 946.3 g of acetone was added to the mixture and stirred for 3 hours. This procedure gave a 3% solid solution (W/M).

Table 14 Coated tablet composition % in coverage mg/tablet increase in wt.% coating m/m (%) Lot size (g) 1. Tofacitinib citrate bilayer core-tablet core --- 400 ------- -------- 2. Cellulose acetate (398-10) 1.8 14.4 3.6 36.0 3. Hydroxypropylcellulose (Klucel EF) 1.2 9.6 2.4 24.0 4. Acetone 87.3 (698.4) ------- 1746.3 5. Purified water 9.7 (77.6) ------- 194.6 total weight 100 424 6 2000.9

SRC (250 g) 400 mg tablets were coated using the Vector LDCS-5 Coating System with a 0.5 L semi-perforated tray running at 30 rpm and 30 cfm airflow with an outlet temperature of 40°C . A solid solution of 3% (m./m.) was applied to achieve an increase in wet weight to 6.2%. After that, the tablets were removed from the pan and dried at 40°C for 16 hours.

A single hole (1000 microns) was drilled into the end of the oval tablet strip. The hole can be drilled mechanically or with a laser. The desired 6% coverage provided the following release into pH 6.8 media at 50 rpm paddle speed based on dissolution test 1 (Table 15):

Table 15 Time (h) Gain 6 wt.%
(% drug dissolved) 1 6 2.5 42 5 95

Example 6 Bilayer Osmotic Tablet (11 mg)

The batch size of Polyethylene oxide N80 (active layer) (see also Table 16) was passed through a 30 mesh sieve. Large particles remaining on the sieve were discarded. Polyethylene oxide was added to a 500 cm ³ amber glass bottle and mixed by hand to coat the inside of the bottle. The batch size of Tofacitinib was added and mixed for 10 minutes. using a Turbula blender. Magnesium stearate (1.0 g) was added to the active mixture bottle and mixed for 3 minutes.

The batch size of Polyethylene oxide grade coagulant (swellable layer) and sodium chloride were passed through a 30 mesh sieve. Polyethylene oxide, batch size of microcrystalline cellulose, batch size of blue lacquer, and sodium chloride powder were added in that order to a 950 cm ³ flask. The mixture was stirred for 10 minutes. using a Turbula blender. Magnesium stearate (1.0 g) was added to the swelling bed flask and mixed for 3 minutes.

Bilayer tablets were compressed using standard 9/32 inch round convex tools to an average target weight of 180.0 mg +/- 5% and an average target thickness of 5.0 mm +/- 0.1 mm.

Table 16 Active layer components: Quality: Qty
(mg)/unit: % Lot size (g) tofacitinib citrate 17.76 14.80 14.80 Polyethylene oxide grade WSR N80 ^a NF 101.04 84.20 84.20 magnesium stearate ^e NF/EP 1.20 1.00 1.00 120.00 100.00 100.00

Intumescent layer components: Quality: Qty
(mg)/unit: % Lot size (g) Polyethylene oxide Coagulant class ^a NF 32.52 54.20 108.40 Microcrystalline cellulose PhEur/NF 12.00 20.00 40.00 Sodium chloride ^b USP/EP 15.00 25.00 50.00 Laco-dye FD&C blue
No. ^2d food 0.18 0.30 0.60 magnesium stearate ^e NF/EP 0.30 0.50 1.00 60.00 100.0 200.00

The coating solution was prepared according to the following steps (see also Table 17): First, 180.0 g of water was added to 48.6 g of PEG 3350 in a 4 L mixing flask and mixed or agitated by hand until the PEG was completely dissolved. Then 131.4 g of cellulose acetate was added to a 4 L mixing flask containing the PEG-water solution. AC was scattered as a suspension or wet sediment. Using a 4 L mixing flask equipped with a rotary impeller, 2.640.0 g of acetone was added to the PEG-water-AC mixture. The contents of the mixing flask were shaken until all solids were dissolved.

Table 17 No. Material Composition (%) grams 1 Cellulose acetate 4.38 131.4 2 Polyethylene glycol 3350 with 100 ppm BHT (PEG 3350) 1.62 48.6 3 Acetone ⁽¹⁾ 88.00 2640.0 4 Purified water ⁽¹⁾ 6.00 180.0 Total 100.00 3000.0

Component wt.% coating solution mg/tablet Tofacitinib Citrate Bilayer Tablet-Core Core - 180.00 Coating composition Cellulose acetate 4.38 17.08 Polyethylene glycol 3350 with 100 ppm BHT (PEG 3350) 1.62 6.32 Acetone ⁽¹⁾ 88.00 343.20 Purified water ⁽¹⁾ 6.00 23.40 Total 100.00 203.40 ⁽¹⁾ included for coating purposes, not present in final dosage form.

180 mg bilayer core tablets (250 g) were coated using the Vector LDCS-5 Coating System with a 0.5 L fully perforated pan operating at 30 rpm and 35 cfm airflow with outlet temperature 32°C. A 6% (w/m) solid solution was applied until a wet weight gain during coating of 25.2 mg per tablet was achieved. After that, the tablets were removed from the pan and dried at 40°C for 16 hours.

A single inlet port with a diameter of 1.0 mm was formed through the coating membrane at the center of the outer side of the drug layer of the bilayer tablet. The inlet can be formed mechanically or by laser. Desired coverage of 23.4 mg or 13% by weight of the target bilayer core provided a controlled release showing 80% drug delivery in 3.5 hours in a pH 6.8 environment at a paddle speed of 50 rpm based on dissolution test 1 Additional solubility data are shown in Table 18.

Table 18 Time (h) % release 1.0 13 2.5 55 5.0 96

Example 7 Antioxidant Bilayer Osmotic Tablet (11 mg)

The composition of Example 7 was prepared as follows (see also Table 19): Polyethylene oxide N80 was passed through a 30 mesh sieve. Large particles of polyethylene oxide N80 remaining on the sieve were removed. Separately, the primary particle size of sodium metabisulphite and butylated hydroxyanisole was reduced using a mortar and pestle. A quarter batch size of polyethylene oxide was combined with the batch sizes of sodium metabisulphite and butylated hydroxyanisole, and added to a 950 ^cm3 stained glass bottle and mixed for 5 minutes. in a Turbula blender. The remaining polyethylene oxide N80 and batch size of tofacitinib citrate were added to a 950 ^cc dark glass bottle and mixed in a Turbula blender for 10 minutes. The mixture was passed through a Co-mil mini mill using a 0.8 mm mesh sieve to improve mixing and distribution of the components. The mixture was then blended for an additional 10 minutes in a Turbula blender. The batch size ^of magnesium stearate was then added to the previous blend in a 950 cc dark glass bottle and blended for 3 minutes in a Turbula blender.

Coagulant class polyethylene oxide and sodium chloride were passed through a 30 mesh sieve, and large particles remaining on the sieve were discarded. Separately, the primary particle size of sodium metabisulphite and butylated hydroxyanisole was reduced using a mortar and pestle. Half the batch size of polyethylene oxide was combined with the batch sizes of sodium metabisulphite and butylated hydroxyanisole and added to a 950 cm ³ stained glass bottle and mixed for 5 minutes in a Turbula blender. The remaining coagulant-grade polyethylene oxide, microcrystalline cellulose, blue lacquer and sodium chloride powder were added in this order to a 950 ^cm3 smoked glass bottle and stirred for 10 minutes. using a Turbula blender. The mixture was passed through a Co-mil mini mill using a 0.8 mm mesh sieve to improve mixing and distribution of the components. Magnesium stearate (1.0 g) was added to the flask and stirred for 3 minutes.

Bilayer tablets were compressed using standard 9/32 inch round convex tools to an average target weight of 180.0 mg +/- 5% and an average target thickness of 5.0 mm +/- 0.1 mm.

Table 19 Active Layer Components wt.% Quantity per unit Lot size (mg/tablet) (G) tofacitinib citrate 14.80 17.76 29.61 Polyethylene oxide (Polyox WSR N80) 79.30 95.16 158.59 Sodium Metabisulphite 4.67 5.60 9.33 Butylated hydroxyanisole 0.23 0.28 0.47 magnesium stearate 1.00 1.20 2.00 Total 100.00 120.00 200.00 Intumescent layer components: wt.% Quantity per unit Lot size (mg/tablet) (G) Polyethylene oxide (Polyox WSR coagulant) 51.67 31.00 103.33 Microcrystalline cellulose 20.00 12.00 40.00 Sodium chloride 25.00 15.00 50.00 Sodium Metabisulphite 2.41 1.45 4.82 Butylated hydroxyanisole 0.12 0.07 0.24 Laco-dye FD&C blue
No. 2 0.30 0.18 0.60 magnesium stearate 0.50 0.30 1.00 Total 100.00 60.00 200.00

The coating solution was prepared according to the following steps (see also Table 20): First, 150.0 g of water was added to 40.5 g of PEG 3350 in a 4 L mixing flask and mixed or agitated by hand until the PEG was completely dissolved. Next, cellulose acetate (109.5 g) was added to a 4 L mixing flask containing the PEG-water solution. AC was scattered as a suspension or wet sediment. Using a 4 L mixing flask equipped with a rotary impeller, 2198.1 g of acetone was added to the PEG-water-AC mixture. The contents of the mixing flask were shaken until all solids were dissolved.

Table 20 No. Material Composition (%) grams 1 Cellulose acetate 4.38 109.5 2 Polyethylene glycol 3350 with 100 ppm BHT (PEG 3350) 1.62 40.50 3 Sodium Metabisulphite 0.064 1.60 4 Butylated hydroxyanisole 0.012 0.31 5 Acetone ⁽¹⁾ 87.92 2198.1 6 Purified water ⁽¹⁾ 6.00 150.0 Total 100.00 2500.0

Tofacitinib bilayer tablets (250 g) were coated in a Vector LDCS-5 with a 0.5 L fully perforated pan operating at 30 rpm and 35 cfm airflow with an outlet temperature of 32°C. A 6% (w/w) solid solution was applied to increase the coating weight to 25.2 mg per tablet. After that, the tablets were removed from the pan and dried at 40°C for 16 hours.

A single inlet with a diameter of 1.0 mm was formed through the coating membrane, in the center of the outer drug layer of the bilayer tablet. The inlet was formed mechanically or by laser. The desired coating (23.7 mg or 13% by weight of the bilayer core) provided a controlled drug release that corresponded to 80% of the drug delivered in 2.8 hours in a pH 6.8 environment at a paddle speed of 50 rpm based on dissolution test 1. Additional dissolution data are given in Table 21.

Table 21 Time (h) % release 1.0 17 2.5 73 5.0 98

Example 8 22 mg Bilayer Osmotic Tablet

The composition of Example 8 was prepared as follows (see also Table 22): The batch size of Polyethylene oxide N80 was passed through a 30 mesh sieve. Large particles remaining on the sieve were discarded. Polyethylene oxide N80 was added to a 500 cm ³ amber glass bottle and mixed by hand to coat the inside of the bottle. Batch size Tofacitinib was added and mixed for 10 minutes. using a Turbula blender. Magnesium stearate (1.0 g) was added to the active mixture bottle and mixed for 3 minutes.

The batch size of Polyethylene oxide grade coagulant and sodium chloride were passed through a 30 mesh sieve. Polyethylene oxide, batch size of microcrystalline cellulose, batch size of blue lacquer, and sodium chloride powder were added in that order to a 950 cm ³ flask. The mixture was stirred for 10 minutes using a Turbula blender. Magnesium stearate (1.0 g) was added to the swelling bed flask and mixed for 3 minutes.

The tablets were compressed using standard 5/16 inch round convex tools to an average target weight of 250.0 mg +/- 5% and an average target thickness of 5.6 mm +/- 0.1 mm.

Table 22 Active layer components: Quality: Qty
(mg)/unit: % Lot size (g) tofacitinib citrate 35.53 21.28 21.28 Polyethylene oxide grade WSR N80 ^a NF 129.80 77.72 77.72 magnesium stearate ^e NF/EP 1.67 1.0 1.00 167.00 100.0 100.00

Intumescent layer components: Quality: Qty
(mg)/unit: % Lot size (g) Coagulant Polyethylene oxide Class ^a NF 44.99 54.20 108.40 Microcrystalline cellulose PhEur/NF 16.60 20.00 40.00 Sodium chloride ^b USP/EP 20.75 25.00 50.00 Laco-dye FD&C blue No. 2 ^d food 0.25 0.30 0.60 magnesium stearate ^e NF/EP 0.42 0.50 1.00 83.00 100.0 200.00

The coating solution was prepared according to the following steps (see also Table 23): First, 180.0 g of water was added to 48.6 g of PEG 3350 in a 4 L mixing flask, and mixed or agitated by hand until the PEG was completely dissolved. Next, 131.4 g of cellulose acetate was added to a 4 L mixing flask containing the PEG-water solution. AC was dispersed as a suspension or wet sediment. Using a 4 L mixing flask equipped with a rotary impeller, 2.640.0 g of acetone was added to the PEG-water-AC mixture. The contents of the mixing flask were shaken until all solids were dissolved.

Table 23 No. Material Composition (%) grams 1 Cellulose acetate 4.38 131.4 2 Polyethylene glycol 3350 with 100 ppm BHT (PEG 3350) 1.62 48.6 3 Acetone 88.00 2640.0 4 Purified water 6.00 180.0 Total 100.00 3000.0

Component wt.% coating solution mg/tablet Tofacitinib Citrate Bilayer Tablet-Core Core - 250.00 Cellulose acetate 4.38 20.08 Polyethylene glycol 3350 with 100 ppm BHT (PEG 3350) 1.62 7.43 Acetone ⁽¹⁾ 88.00 403.33 Purified water ⁽¹⁾ 6.00 27.5 Total 100.00 277.50 ⁽¹⁾ included for coating purposes, not present in final dosage form

250 g bilayer core tablets were coated using the Vector LDCS-5 Coating System with a fully perforated pan (0.5 L) or drum running at 30 rpm, 35 cfm airflow with an outlet temperature of 32 °C A 6% (m/m) solid solution was applied to achieve a coating weight of 30.0 mg per tablet. After that, the tablets were removed from the pan and dried at 40°C for 16 hours.

A single entry hole with a diameter of 1.0 mm was formed through the coating membrane at the center of the outer drug layer of the bilayer tablet. The inlet was formed mechanically or by laser. The desired coating (27.5 mg or 11% by weight of the bilayer core) provided a controlled drug release that represented 80% drug delivery in 3.7 hours in a pH 6.8 environment at a paddle speed of 50 rpm based on dissolution test 1. Additional dissolution data are shown in Table 24.

Table 24 Time (h) % release 1.0 eleven 2.5 53 5.0 90

Example 9 Composition AMT 20 mg

The composition of Example 9 was prepared as follows (see also Table 25). Pass the batch sizes of Tofacitinib, Mannitol, Microcrystalline Cellulose and Dibasic Calcium Phosphate through a 30 mesh sieve and add to a 500 cm ³ amber glass bottle. The mixture was stirred for 10 min. using a Turbula blender. Pass 0.3 g of magnesium stearate through a 30 mesh sieve and add to the active blend bottle and mix for 3 minutes.

The mixture was pressed into compacts containing a solid fraction of ~0.70. The compacts were crushed to form a granulate. Pass 0.2 g of magnesium stearate through a 30 mesh sieve, add to the vial of active granulate and mix for 3 minutes.

Tablets were compressed using standard 9 mm round convex tools to an average target weight of 400 mg +/- 5%, an average target thickness of 7 mm +/- 0.05 mm, and a target strength of 15 kPa.

Table 25 Intumescent layer components: Quality: Quantity
(mg)/unit: % Lot size (g) tofacitinib citrate 33.33 8.33 3.33 Mannitol 2080 NF/EP 140.00 35 14 Microcrystalline cellulose NF/EP 60.00 15 6 Dibasic calcium phosphate NF/EP 161.67 40.42 16.17 magnesium stearate ^e NF/EP 3.00 0.75 0.3 magnesium stearate ^e NF/EP 2.00 0.50 0.2 400.00 100.0 40

A coating solution was prepared according to the following steps (see also Table 26): First, 115 g of water and 150 g of acetone were added to a 2 L flask and stirred for 5 minutes. 12 g of hydroxypropyl cellulose was added to the mixture and mixed for 5 minutes. Added 28 g of cellulose acetate to the mixture and stirred for 5 minutes. The remaining 195 g of cellulose acetate was added to the mixture and stirred for 3 hours. This procedure gave a solid solution of 8% (m./m.).

Table 26 Tablet coating composition 1 % in coverage mg/tablet gain 7.5 wt.% 1. Tofacitinib citrate tablet core --- 400 2. Cellulose acetate (398-10) 5.6% 21.0 3. Hydroxypropylcellulose (Klucel EF) 2.4% 9.0 4. Acetone 69.0% (258.8) 5. Purified water 23.0% (86.2) total weight 100% 430

250 g of 400 mg SRC tablets were coated with a Vector LDCS-5 Coating System with a 0.5 L semi-perforated tray running at 30 rpm and 30 cfm airflow. with an outlet temperature of 40°C. A solid solution of 8% (m./m.) was sprayed to increase the wet weight of 7.5%. The tablets were removed from the coating pan and dried at 40°C for 16 hours.

Example 10 Two-layer osmotic capsule 20 mg

premix

98.94 g of polyethylene oxide (Polyox WSR N80 LEO) and 1.06 g of magnesium stearate were passed through a 30-mesh sieve and added to a 250 ml amber glass bottle. The mixture was stirred using a Turbula mixer (model T2F) operating at 49 cycles/min for 2 minutes.

Active layer - weight 600 mg

283.71 mg of the pre-blend was added to beaker 1 and agitated by hand to pre-coat the inside of the glass bulb. Tofacitinib citrate (32.57 mg) was passed through a 20 or 30 mesh sieve and added to beaker 1. An additional 283.71 mg of premix was then added to beaker 1. The contents of the beaker were mixed using a Turbula mixer (model T2F) with an operating setting of 49 cycles / min for 5 min. The mixture was then transferred to a Natoli hydraulic tablet press with a separate station and compressed to the desired thickness of 15.6 mm using a 5.500” B-type 0.3051” top punch with a modified head and a 4.755” B-type 0.3051” bottom punch with a flat surface and tapered edge.

Swelling layer - weight 300 mg

The swell layer for the composition of Example 10 was prepared as follows (see also Table 27): batch sizes of coagulant class polyethylene oxide, blue lacquer, sodium chloride and microcrystalline cellulose were passed through a 20 or 30 mesh sieve, added in that order to a 10 L bin mixer. The contents of the blender were stirred for 10 minutes at 12 rpm. The mixture was then passed through a Comil 197S sieve with a round impeller and a 0.055″ round sieve at 1000 rpm. The batch size of magnesium stearate was added to the middle of the pureed mixture in the bin blender. The contents of the blender were stirred for 5 minutes at 12 rpm. The mixture was then transferred to a Kilian T-100 rotary tablet press and compressed to a target weight of 300 mg and a target thickness of 6.65 mm using a 5.500” B-type 0.3051” top punch with a modified head and a 4.755” B-type 0 .3051” bottom punch with flat surface and tapered edge.

Table 27 Component: Quality: Quantity
(mg)/unit: % Lot size (g) Polyethylene oxide Coagulant class ^a NF 154.50 51.5 2060.00 Sodium chloride ^b USP/EP 104.40 34.8 1392.00 Microcrystalline cellulose ^c NF/EP 39.00 13.0 520.00 Laco-dye FD&C blue No. 2 ^d food 0.60 0.2 8.00 magnesium stearate ^e NF/EP 1.50 0.5 20.00 300.00 100.0 4000.00

Capsule shell

A precoat solution (2.5 kg) was prepared by combining 25 g of polysorbate 80 with 2475 g of acetone and stirring for 10 minutes or until dissolved to give a 1% (w/w) solution.

A functional coating solution (15 kg) was prepared according to the following steps (see also Table 28): first, all 375 g of water and 120 g of PEG 3350 were added to a suitable flask and mixed. Acetone (14.325 g) was added to the mixture and stirred. Cellulose acetate (180 g) was added to the mixture and stirred until a homogeneous solution was obtained. This procedure gave a solid solution of 2% (m./m.).

Table 28 Capsule shell composition % in coverage mg caps mg in capsule body Lot size (g) 1. Cellulose acetate (398-10) 1.2 58.5 55.5 180 2. Polyethylene glycol 3350 0.8 39.0 37.0 120 3. Acetone 95.5 (4655.6) (4416.9) (14,325) 4. Purified water 2.5 (121.9) (115.6) (375) total weight 100 97.5 92.5 15,000

1 kg of HDPE capsule molds (caps or bodies) were coated using the Vector LDCS-5 Coating System with a 1.5 L semi-perforated pan, operating at 18 rpm and an air flow of 40 cfm. and outlet temperature 40°C. After a quick coating of molds with 1% m./m. precoat solution, 2% (w/w) functional solid coating solution was sprayed at a rate of 20 g/min with a spray pressure of 10 psi and a spray distance of 3 inches to increase wet weight by 12.5%. The capsule molds were then removed from the pan and dried at 40° C. for 24 hours. The capsule shells were removed from the molds and cleaned.

A single hole (2000 microns) was drilled at the end of the capsule body. The hole can be drilled mechanically or with a laser.

Set

The active layer was inserted into the capsule shell half through a pre-drilled hole. The swelling layer was inserted into the same half of the capsule shell, first with the flat side, placed close to the active layer. These components were inserted into the other half of the capsule shell to close the capsule. Received and combined in this way, these components provide the next release in the environment with a pH of 6.8, at a speed of rotation of the blades of 50 rpm, based on the dissolution test 1 (Table 29).

Table 29 Time (h) % drug dissolved 1 4 2.5 25 5 65

80% of tofacitinib dissolved in approximately 6 hours in dissolution test 1.

Example 11 Two Layer Osmotic Capsule 20 mg

premix

Polyethylene oxide (Polyox WSR N80 LEO) (98.94 g) and 1.06 g of magnesium stearate were passed through a 30 mesh sieve and added to a 250 ml amber glass bottle. The mixture was mixed using a Turbula mixer (model T2F) running at 49 cycles/min for 2 minutes.

Active layer - weight 600 mg

The premix (283.71 mg) was added to beaker 1 and agitated by hand to pre-coat the inside of the beaker. Tofacitinib citrate (32.57 mg) was passed through a 20 or 30 mesh sieve and added to beaker 1. The premix (283.71 mg) was then added to beaker 1. The contents of the beaker were then mixed using a Turbula mixer (model T2F) operated with speed 49 cycles / min., for 5 minutes. The mixture was then transferred to a Natoli hydraulic tablet press with a separate station and compressed to the desired thickness of 15.6 mm using a 5.500” B-type 0.3051” top punch with a modified head and a 4.755” B-type 0.3051” bottom punch with a flat surface and tapered edge.

Swelling layer

The swelling layer for the composition of Example 11 was prepared as follows (see also Table 30). The batch sizes of coagulant-grade polyethylene oxide, blue varnish, sodium chloride, and microcrystalline cellulose were passed through a 20 or 30 mesh sieve, added in that order to a 10 L bin mixer. The contents of the blender were stirred for 10 minutes at a speed of 12 rpm. The mixture was then passed through a Comil 197S sieve with a round impeller and a 0.055″ round sieve at 1000 rpm. The batch size of magnesium stearate was added to the middle of the screened mixture in the bin mixer. The contents of the blender were stirred for 5 minutes at a speed of 12 rpm. The mixture was then transferred to a Kilian T-100 rotary tablet press and compressed to a target tablet weight of 300 mg and a thickness of 6.65 mm using a 5.500” B-type 0.3051” top punch with a modified head and a 4.755” B-type 0.3051 ” bottom punch with flat surface and tapered edge.

Table 30 Component: Quality: Qty
(mg)/unit: % Lot size (g) Coagulant Polyethylene oxide Class ^a NF 154.50 51.5 2060.00 Sodium chloride ^b USP/EP 104.40 34.8 1392.00 Microcrystalline cellulose ^c NF/EP 39.00 13.0 520.00 Laco-dye FD&C blue No. 2 ^d food 0.60 0.2 8.00 magnesium stearate ^e NF/EP 1.50 0.5 20.00 300.00 100.0 4000.00

Capsule shell

A precoat solution (2.5 kg) was prepared by combining 25 g of polysorbate 80 with 2475 g of acetone and stirring for 10 minutes or until dissolved to give a 1% (w/w) solution.

A functional coating solution (15 kg) was prepared according to the following steps (see also Table 31): first, 375 g of water and 61.5 g of PEG 3350 were added to a suitable flask and mixed. Acetone (14.325 g) was added to the mixture and stirred. Cellulose acetate (225 g) was added to the mixture and stirred. CHP 13.5 g was added to the mixture and stirred until a homogeneous solution was obtained. This procedure gave a 2% solid solution (w/w).

Table 31 Capsule shell composition % in coverage mg caps mg in capsule body Lot size (g) 1. Cellulose acetate (398-10) 1.50 73.1 69.38 225 2. Polyethylene glycol 3350 0.41 20.0 18.69 61.5 3. Triethyl citrate (CHP) 0.09 4.4 4.16 13.5 4. Acetone 95.5 (4655.6) (4416.9) (14,325) 5. Purified water 2.5 (121.9) (115.6) (375) total weight 100 97.5 92.5 15,000

1 kg of HDPE capsule molds (lids or bodies) were coated using the Vector LDCS-5 Coating System with a 1.5 L semi-perforated pan, 18 RPM operating parameters, 40 cfm airflow with outlet temperature 40°C. After a quick coating of molds with 1% m./m. precoat solution, 2% (m/m) functional solid coating solution was sprayed at a rate of 20 g/min. with a spray pressure of 10 psi and a spray distance of 3 inches for a 12.5% increase in wet weight. The capsule molds were then removed from the pan and dried at 40° C. for 24 hours. The capsule shells were removed from the molds and cleaned.

A single hole (2000 microns) was drilled at the end of the capsule body. The hole can be drilled mechanically or with a laser.

Set

The active layer was inserted into the capsule shell half through a pre-drilled hole. The swelling layer was inserted into the same half of the capsule shell, first with the flat side, positioned close to the active layer. These components were inserted into the other half of the capsule shell to close the capsule. Received and combined in this way, these components provide the following release in the environment with a pH of 6.8, at a speed of rotation of the blades of 50 rpm based on the dissolution test 1 (Table 32).

Table 32 Time (h) % drug dissolved 1 1 2.5 4 5 21

80% of tofacitinib was dissolved in approximately 14 hours in Dissolution Method 1.

Example 12 Controlled Release Hydrophilic Matrix Tablet

The metal surfaces of the 10 L hopper were precoated by adding batch size (also see Table 33 below), 963g of Fast Flo 316 lactose and mixed for 2 minutes at 12 +/- 1 rpm. Batch size Tofacitinib (164g) was added to a 10L hopper and added to lactose monohydrate. The Tofacitinib container was flushed with some lactose monohydrate from a 10 L hopper. The batch size of Hypromellose, 1150 g, was added to a 10 L hopper. All components were mixed in the hopper for 10 min. at 12 +/- 1 rpm.

The mixture was passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller running at approximately 1400 rpm. The mixture was collected in a second 10 L bin. The contents of the hopper were stirred for 10 minutes at 12 +/- 1 rpm.

Intracrystalline magnesium stearate, 5.75 g, was added to the hopper and mixed for 3 minutes. at 12 +/- 1 rpm. The lubricated mixture was passed through a Gerteis roller press equipped with knurled rollers, removable rim flanges, and a linear vibratory mill including a portable rotor and a 1 mm pumice plate. The required sliver of 0.7 solids (0.67-0.73) and pellets were collected in the original 10 L hopper.

Intracrystalline magnesium stearate, 17.25 g, was added to the hopper and the contents were mixed for 3 minutes at 12 +/- 1 rpm. The final mixture was passed through a Kilian T-100 rotary tablet press. Tablets were compressed using 13/32” SRC tools to an average target weight of 500 mg +/- 5% and a target strength of 15 kPa. The tablets were passed through a dust collector and a metal detector.

Table 33
Tofacitinib tablet composition with hydrophilic matrix (22 mg); total weight of tablets 500 mg Ingredient Function % in composition grams tofacitinib citrate Active Ingredient 7.1 164.00 Methocel K100LV CR Premium Polymer, controlled release gelling agent 50 1150.00 lactose monohydrate,
FastFlo 316 Filler 41.9 963 Magnesium Stearate, Vegetable Source (IG) lubricant 0.25 5.75 Magnesium Stearate, Vegetable Source (EG) lubricant 0.75 17.25 Total 100 2300.00

Compressed tablets provide the next release in a medium with a pH of 6.8, at a speed of rotation of the blades of 50 rpm based on the dissolution test 1 (Table 34).

Table 34 Time (h) % drug dissolved 1 16 2.5 32 5 54

Example 13 Instant Tablet release (10 mg)

Table 35: Tablet Composition of Example 13 Component name Quality Tablet composition (mg) 1. Tofacitinib citrate Pharm 16.155 2. Microcrystalline cellulose Ph.Eur/NF 245.23 3. Lactose monohydrate Ph.Eur/NF 122.615 4. Croscarmellose sodium Ph.Eur/NF 12,000 5. Magnesium stearate Ph.Eur/NF 1,000 6. Magnesium stearate Ph.Eur/NF 3,000 WEIGHT OF THE TABLET CORE: 400,000 7. Opadry II white (based on HPMC) Pharm 12,000 8. Purified water Ph.Eur/USP (68,000) Total: 412,000

The tablet composition of Example 13 was prepared according to the following method. Components 1-4 were combined and processed using a mix-mill-mix procedure. Component 5 was then added to the mixture and combined using a mixing procedure. This lubricated mixture was then subjected to dry granulation. Component 6 was then added to the dry granulate and combined using a mixing procedure. The lubricated granulate was compressed into 400 mg tablets using a rotary tablet press. The tablets were then coated using a film coater spraying a solution containing Components 7 and 8 prior to coating the tablets with a weight of 12 mg.

Example 14 Instant Release Tablet (5 mg)

Table 36: Tablet Composition of Example 14 Component name Quality Tablet composition (mg) 1. Tofacitinib citrate Pharm 8.078 2. Microcrystalline cellulose Ph.Eur/NF 314.615 3. Lactose monohydrate Ph.Eur/NF 157.307 4. Croscarmellose sodium Ph.Eur/NF 15,000 5. Magnesium stearate Ph.Eur/NF 2,500 6. Magnesium stearate Ph.Eur/NF 2,500 WEIGHT OF THE TABLET CORE: 500,000 7. Opadry II white (based on HPMC) Pharm 20,000 8. Purified water Ph.Eur/USP (113,333) Total: 520,000

The tablet was obtained according to the following method. Components 1-4 were combined and processed using a mix-mill-mix procedure. Component 5 was then added to the mixture and combined using a mixing procedure. This lubricated mixture was then subjected to dry granulation. Component 6 was then added to the dry granulate and combined using a mixing procedure. The lubricated granulate was compressed into 500 mg tablets using a rotary tablet press. The tablets were then coated using a film coater spraying a solution containing Components 7 and 8 prior to coating the tablets with a weight of 20 mg.

Example 15 Study A

The relative bioavailability of a single dose of 2 different sustained-release tofacitinib (20 mg) oral formulations was determined relative to a single dose of tofacitinib (10 mg) immediate-release (IR) tablets, and the following cut-offs were determined for tofacitinib:C _max ,T _max .AUC_inf, AUC_last. Additional cutoffs were determined for the relative bioavailability (%RBA) of tofacitinib of each sustained release formulation relative to the immediate release formulation. release (MB).

The study was a randomized, open-label, single dose, 3-period, 3-treatment, 6-sequence crossover study in 12 healthy male patients (see Table 37). Patients received two different sustained-release formulations of tofacitinib and an immediate-release tablet with a washout period of 3 days between doses. The sustained release formulations were given as a single dose of 20 mg and the immediate release formulation was given as two tablets with a single dose of 5 mg.

Table 37 Subsequence Period 1 2 3 ABC (n=2) A B C BCA (n=2) B C A CAB (n=2) C A B ACB (n=2) D E C BAC (n=2) E A D BCA (n=2) A E B

A: Instant release tablet, 10 mg;

B: Example 10 two-layer osmotic capsule, 20 mg;

C: Example 11 two-layer osmotic capsule, 20 mg.

Patients were kept fasting overnight for a minimum of 8 hours prior to study drug administration. On the morning of the first day in each period, all patients received a single oral dose of study medication with 240 mL of water. Patients were given a standardized lunch 4 hours after dosing.

Introduced dosage forms:

Tofacitinib tablet (10 mg) with immediate release (reference): obtained in Example 13.

Tofacitinib bilayer osmotic capsule (20 mg): prepared in Example 10.

Tofacitinib bilayer osmotic capsule (20 mg): prepared in Example 11.

Throughout the study periods, blood samples were collected periodically to provide plasma for pharmacokinetic analysis. PK samples were analyzed using standard analytical methods. Dose-normalized natural log-transformed AUC _inf , AUC _last and C _max were analyzed for tofacitinib using a mixed effect model with sequence, period and treatment as fixed effects and subject in sequence as random effect. An estimate of the adjusted standard deviations (Comparison Test) and the corresponding 90% confidence intervals were derived from this model. Adjusted standard deviations and 90% confidence intervals for differences were raised to the power to estimate the ratio of the adjusted geometric means (Test/Comparison) and 90% confidence intervals for coefficients. The control formulation of the immediate release tablet was the Comparative treatment and the sustained release formulations were the Test treatment.

Relative bioavailability tofacitinib was evaluated as the ratio of the dose-normalized adjusted geometric mean values of the Test and Comparative Test for AUC_inf.

PK parameters AUC _inf , AUC _last , C _max , T _max , and t _1/2 were summarized descriptively by processing and analysis (where applicable). For AUC _inf and C _max , individual subject parameters were plotted by treating each analyte separately (where applicable). Concentrations were listed and summarized descriptively by timing of PK sampling, processing, and analyte (where applicable). Individual, mean, and median concentration-time data profiles were plotted through processing and analysis (where applicable). For statistical review, nominal PK sampling times were used for mean and median sampling time plots, and actual PK sampling times were used for individual patient time plots.

Predicted static values were obtained using the superposition method using WinNonLin software (Pharsight Corp). The superposition was used on each individual PK profile to obtain a static PK profile for each patient. The designations and method for determining the PK parameters are given in Table 38. The results of the study are shown in Table 39.

Table 38 Parameter Definition Definition method AUC _last the area under the plasma concentration-time curve in the range from zero to the last time point at which it was possible to quantify the parameter (C _last ) Logarithmic Trapezoidal Method AUC _inf Area under the plasma concentration-time curve from zero to infinity AUC _last + (C _last */k _el ), where C _last * is the predicted plasma concentration at the last time point at which it was possible to quantify the parameter, obtained from logarithmic regression analysis. AUC _inf,dn Area under the plasma concentration-time curve from zero to infinity divided by the administered dose AUC _inf /dose _Cmax Maximum
plasma concentration Derived directly from the data Cmax _,dn Maximum
plasma concentration divided by administered dose C _max /dose

_Tmax Time to reach _Cmax Obtained directly from the data as the time of first occurrence _t½ Elimination half-life in the final phase Loge(2)/k _el where k _el is the terminal phase rate constant calculated by linear regression on a log-linear concentration-time curve. The regression used only those data that described the terminal log-linear slope of the curve. Cmin _,ss Minimum plasma concentration observed during the 24-hour interval between doses Obtained from steady-state pharmacokinetic profile data calculated from single dose data using the superposition method Cmin _,dn,ss Minimum plasma concentration observed during the 24-hour interval between doses C _min,ss /dose _Cmax,ss Maximum plasma concentration observed during the 24-hour interval between doses Obtained from steady-state pharmacokinetic profile data calculated from single dose data using the superposition method _Cmax,ss / Cmin _,ss The ratio of maximum and minimum plasma concentration observed during the 24-hour interval between doses Time with a concentration of 17 ng / ml Period of time during the 24-hour interval between doses when the plasma concentration was 17 ng/mL Obtained from steady-state pharmacokinetic profile data calculated from single dose data using the superposition method

Rest from medication
(time below
17 ng/ml) Period of time during the 24-hour interval between doses when the plasma concentration was below 17 ng/mL Obtained from steady-state pharmacokinetic profile data calculated from single dose data using the superposition method

Table 39 PK parameters of a single dose MV tablet,
10 mg
(Comparative) Example 10 Osmotic capsule, 20 mg
(Test) Example 11 Osmotic capsule, 20 mg
(Test) _Cmax (ng/ml) 121.5 (30%) 41.8 (24%) 18.2 (16%) Cmax _,dn (ng/ml/mg) 12.1 (30%) 2.1 (24%) 0.9 (16%) AUC _inf (ng*h/ml) 339.5 (17%) 543.6 (23%) 390.2 (38%) AUC _inf,dn (ng*h/ml/mg) 34.0 (17%) 27.2 (23%) 18.8 (38%) t½ (h) 3.35 (13%) 5.84 (23%) 6.07 (53%) T _max (h) 0.5 (0.25-2) 5 (4-10) 13 (4-24) Dose-normalized C _max ratio (%) 100% 17% (14-20%) 7.5% (6-9%) Dose-normalized RBA (%) 100% 80% (65-99%) 55% (45-69%)

The above values are given as geometric mean values (% of the coefficient of variation (CV)) for all except: mean (range) for T _max ; arithmetic mean (%CV) for t½. The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Assumed stationary FK parameters 10 mg
MV twice a day
(Comparative) Example 10 Osmotic capsule,
20 mg QD
(Test) Example 10 Osmotic capsule,
25 mg QD*
(Test) Example 11 Osmotic capsule,
20 mg QD
(Test) Example 11 Osmotic capsule,
33 mg QD*
(Test) _Cmax,ss (ng/ml) 125.4
(thirty%) 46.0
(24%) 57.5
(24%) 23.7
(thirty%) 39.1
(thirty%) Cmin _,ss (ng/ml) 3.7
(39%) 6.1
(37%) 7.7
(37%) 9.9
(76%) 16.3
(76%) Cmin _,dn,ss (ng/ml/mg) 0.19
(39%) 0.31
(37%) 0.31
(37%) 0.50
(76%) 0.50
(76%)

Cmin _,ss ratio (%) 100% 166%
(128-215%) 207%
(160-268%) 267%
(123-581%) 441%
(203-958%) _Cmax,ss / Cmin _,ss 34 7.5 7.5 2.4 2.4 Time from conc. 17 ng/ml (h) 12.6
(2 x 6.3 h) 13.1 15.1 16.9 18.6 Rest from medication (time below 17 ng/mL) (h)_ 11.4 10.9 8.9 7.1 5.4

The above values are given as geometric mean values (%CV). The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

* - necessary dose adjustment to achieve 100% RBA with those modified release durations.

The results of this study indicate that sustained release dosage forms that take 6 hours or more to release and dissolve 80% of tofacitinib do not meet the desired PK characteristics for sustained release tofacitinib dosage forms. Namely, a sustained release dosage form that takes 6 hours or more to release and dissolve 80% of tofacitinib, and which contains the required amount of tofacitinib to provide an AUC value equivalent to the immediate release dosage form, provides more time with a concentration of 17 ng/mL ( JAK 1/3 receptor IC ₅₀ values) than time with a concentration of 17 ng/ml instant release dosage form. Also, the sustained release dosage form, which takes 14 hours to release and dissolve 80% of tofacitinib, has a higher dose-normalized C _min , _ss , lower dose-normalized AUC, and lower relative bioavailability compared to the instantaneous dosage form. release, requiring an increase in the concentration of tofacitinib to obtain an AUC equivalent to the AUC of the immediate release dosage form. These results support the requirement for a sustained release dosage form of tofacitinib that release and dissolution of 80% of tofacitinib last less than 6 hours.

Example 16 Study B

The relative bioavailability of 3 different sustained release tofacitinib (22 mg) oral formulations was determined relative to a single dose of tofacitinib (10 mg) immediate release tablets. release (MR), and the following cut-offs were determined for tofacitinib:C _max ,T _max .AUC_inf, AUC_last. Additional cutoffs were determined for the relative bioavailability (%RBA) of tofacitinib of each sustained release formulation relative to the immediate release formulation. release (MB).

The study was a randomized, open, single dose, 4-period, 6-treatment, 6-partially overlapping study in 30 healthy male patients (see Table 40). In the first period, patients received one of two different sustained release formulations of tofacitinib in the postprandial state. In the second and third periods, patients received two of three different sustained release formulations of tofacitinib. In the fourth period, patients received an immediate release tablet. The washout period was 3 days between doses. The three sustained release formulations were given as a single dose of 22 mg and the immediate release formulation was given as two tablets with a single dose of 5 mg.

Table 40 Subsequence Period 1 (after eating) 2 (on an empty stomach) 3 (on an empty stomach) 4 (on an empty stomach) 1 (n=5) A C D F 2 (n=5) A C E F 3 (n=5) B D E F 4 (n=5) B D C F 5 (n=5) A E C F 6 (n=5) B E D F

A: 4-hour, extrudable core tablet, 22 mg, after meals;

B: Example 4, Matrix tablet, 22 mg, after meals;

C: 4-hour, extrudable core tablet, 22 mg, on an empty stomach;

D: Example 4 Matrix tablet, 22 mg, fasting;

E: Example 12 Matrix tablet, 22 mg, fasting;

F: Instant-release tablet, 2×5 mg, on an empty stomach.

In Period 1, after an overnight fast of at least 8 hours, patients were given a standard FDA high-fat breakfast 30 minutes prior to study drug administration. Breakfast was consumed within 30 minutes or less. Patients received either Treatment A or Treatment B 30 minutes (+/-5 minutes) after starting breakfast. No food should be eaten for at least 4 hours after the dose. Water was not to be drunk one hour before and one hour after the dose. Dosing in periods 1, 2 and 3 was performed with a minimum washout time of 72 hours. The next study period (periods 2, 3, and 4) began immediately after completion of the 72-hour break and FA sampling on day 4 of the previous period (periods 1, 2, and 3, respectively). In periods 2, 3, and 4, study drug was administered after an overnight fast of at least 8 hours. Eating was allowed only 4 hours after the dose. No water was allowed to be drunk one hour before and one hour after taking study medication.

Introduced dosage forms:

Tofacitinib tablet with instant release, 5 mg, (comparative): obtained in Example 14 above.

Tofacitinib extrudable core tablet, 22 mg: prepared in Example 1 above.

Tofacitinib Matrix Tablets, 22 mg: Prepared in Example 4 and 12 above.

Throughout the study periods, blood samples were collected periodically to provide plasma for PK analyses. The results of the study are shown in Table 41. PK samples were analyzed using standard analytical methods.

Dose-normalized natural log-transformed AUC _inf , AUC _last and C _max were analyzed for tofacitinib using a mixed effect model with sequence, period and treatment as fixed effects and subject in sequence as random effect. An estimate of the adjusted standard deviations (Comparison Test) and the corresponding 90% confidence intervals were derived from this model. Adjusted standard deviations and 90% confidence intervals for differences were raised to the power to estimate the ratio of the adjusted geometric means (Test/Comparison) and 90% confidence intervals for coefficients. The control formulation of the immediate release tablet was the Comparative treatment and the sustained release formulations were the Test treatment.

Relative bioavailability tofacitinib was evaluated as the ratio of the dose-normalized adjusted geometric mean values of the Test and Comparative Test for AUC_inf.

PK parameters AUC _inf , AUC _last , C _max , T _max , and t _1/2 were summarized descriptively by processing and analysis (where applicable). For AUC _inf and C _max , individual subject parameters were plotted by treating each analyte separately (where applicable). Concentrations were listed and summarized descriptively by timing of PK sampling, processing, and analyte (where applicable). Mean and median individual patient concentration-time profiles were plotted on a processing and analysis chart (where applicable). For statistical review, nominal PK sampling times were used for mean and median sampling time plots, and actual PK sampling times were used for individual patient time plots.

Predicted static values were obtained using the superposition method using WinNonLin software (Pharsight Corp). The superposition was used on each individual PK profile to obtain a static PK profile for each patient.

Table 41 Single dose, bioavailability assessment 10 mg MB tablet (Comp.) 22 mg ECS
(Test) 22 mg matrix (Example 4)
(Test) 22 mg matrix
(Example 12)
(Test) _Cmax (ng/ml) 108 (28%) 101 (28%) 89 (29%) 59 (29%) Cmax _,dn (ng/ml/mg) 10.8 (28%) 4.6 (28%) 4.0 (29%) 2.7 (29%) AUC _inf (ng*h/ml) 367 (24%) 757 (23%) 781 (27%) 702 (23%) AUC _inf,dn (ng*h/ml/mg) 36.7 (24%) 34.4 (23%) 35.5 (27%) 31.9(23%) T _max (h) 0.5 (0.5-4.0) 4.0 (2.0-6.0) 2.5 (1.0-6.0) 3.0 (2.0-4.0)

(ч)t

(h) 3.7 (13%) 5.6 (60%) 5.3 (51%) 6.0 (46%) C _max ratio (%) 100% 92%
(82%-104%) 84%
(75%-94%) 56%
(50%-62%) Dose-normalized RBA (%) 100% 91%
(87%-96%) 97%
(92%-101%) 89%
(85%-94%)

. Вышеприведенные соотношения представлены как соотношения среднегеометрических значений (90% доверительные интервалы).The above values are given as geometric mean values (% of the coefficient of variation (CV)) for all except: mean (range) for T _max ; arithmetic mean (%CV) for t

. The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Single dose, effect of food 22 mg ECS 22 mg matrix (Example 4) Grade on an empty stomach
(Comparative) After meal
(Test) on an empty stomach
(Comparative) After meal
(Test) _Cmax (ng/ml) 101 (28%) 113 (20%) 89 (29%) 136 (25%) AUC _inf (ng*h/ml) 757 (23%) 732 (21%) 781 (27%) 823 (24%) T _max (h) 4.0 (2.0-6.0) 4.0 (3.0-6.0) 2.5 (1.0-6.0) 3.0 (2.0-6.0)

(ч)t

(h) 5.6 (60%) 4.9 (31%) 5.3 (51%) 4.8 (56%) C _max ratio (%) 100% 113% (100-128%) 100% 153% (135-174%) RBA (%) 100% 100% (95-106%) 100% 105% (99-110%)

. Вышеприведенные соотношения представлены как соотношения среднегеометрических значений (90% доверительные интервалы).The above values are given as geometric mean values (% of the coefficient of variation (CV)) for all except: mean (range) for T _max ; arithmetic mean (%CV) for t

. The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Predicted FC parameters 10 mg
MV twice a day 22 mg
ECS QD 22 mg matrix QD
(Example 4) 22 mg matrix QD
(Example 12) After meal
(Comparative) After meal
(Test) After meal
(Test) After meal
(Test) _Cmax,ss
(ng/ml) 112.7
(thirty%) 104.5
(thirty%) 92.6
(32%) 66.2
(27%) Cmin _,ss
(ng/ml) 5.0
(66%) 3.80
(92%) 3.31
(89%) 7.36
(60%) Cmin _,dn,ss
(ng/ml/mg) 0.25
(66%) 0.17
(92%) 0.15
(89%) 0.33
(60%) Cmin _,ss
ratio (%) 100% 74%
(59-92%) 64%
(51-81%) 159%
(134-190%) _Cmax,ss / Cmin _,ss 23 28 28 9 Time from conc. 17 ng/ml (h) 13.4
(2 x 6.7 h) 13.2 14.1 17.6 Rest from medication (time below 17 ng/mL) (h) 10.6 10.8 9.9 6.4

The above values are given as geometric mean values (%CV). The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Sustained-release dosage forms containing 22 mg of tofacitinib, which release and dissolve 80% of tofacitinib in 4-5 hours, provide dose-proportional PK characteristics and meet the desired PK requirements when taken on an empty stomach. Sustained release dosage forms containing 22 mg of tofacitinib, which release and dissolve 80% of tofacitinib by osmotic pressure in 4 hours, provide similar PK characteristics when taken on an empty stomach and after a meal. Sustained release dosage forms containing 22 mg of tofacitinib, which release and dissolve 80% of tofacitinib by diffusion and erosion through the matrix in 5 hours, do not provide similar C _max characteristics when taken on an empty stomach or after a meal.

Example 17 Study C

The relative bioavailability of a single dose of sustained release tofacitinib (11 mg) oral formulation was determined relative to a single dose of sustained release tofacitinib (22 mg) tablets, and the following cut-offs were determined for tofacitinib:C _max ,T _max .AUC_inf, AUC_last. An additional cutoff was determined for the relative bioavailability (%RBA) of tofacitinib in the sustained release formulation (11 mg) relative to the sustained release formulation (22 mg).

The study was a randomized, open-label, single dose, 2-period, 2-treatment, 2-sequence crossover study in 20 healthy male patients (see Table 42). Patients received two different sustained release formulations of tofacitinib with a washout period of 3 days between doses. The sustained release formulations were given as a single dose of 11 or 22 mg.

Table 42 Subsequence Period 1 2 AB (n=10) A B BA (n=10) B A

A: 11 mg extrudable core tablet prepared in Example 1 above.

B: Tablet with extrudable core, 22 m, obtained in Example 1 above.

Patients were kept on an empty stomach overnight for at least 8 hours before taking study medication. On the morning of day 1 of each period, all patients received a single oral dose of study medication with 240 mL of water. Patients were given a standard lunch 4 hours after dosing.

Introduced dosage forms:

Tofacitinib sustained release dosage forms, 22 mg: prepared in Example 1 above.

Tofacitinib sustained release dosage forms, 11 mg: prepared in Example 1 above.

Throughout the study periods, blood samples were collected periodically to provide plasma for PK analyses. The results of the study are shown in Table 43. PK samples were analyzed using standard analytical methods.

Dose-normalized natural log-transformed AUC _inf , AUC _last and C _max were analyzed for tofacitinib using a mixed effect model with sequence, period and treatment as fixed effects and subject in sequence as random effect. An estimate of the adjusted standard deviations (Comparison Test) and the corresponding 90% confidence intervals were derived from this model. Adjusted standard deviations and 90% confidence intervals for differences were raised to the power to estimate the ratio of the adjusted geometric means (Test/Comparison) and 90% confidence intervals for coefficients. The 22 mg immediate release tablet formulation was the Comparative Treatment and the 11 mg sustained release formulation was the Test Treatment.

Relative bioavailability tofacitinib was evaluated as the ratio of the dose-normalized adjusted geometric mean values of the Test and Comparative Test for AUC_inf.

суммировали описательно путем обработки и анализа (где применимо). Для AUC_inf и C_max, индивидуальные параметры субъекта были нанесены на график путем обработки каждого анализируемого вещества по отдельности (где применимо). Концентрации включали в перечень и суммировали описательно указанием времени взятия ФК образцов, обработки и анализируемого вещества (где применимо). Данные среднего и медиана профилей отдельного пациента концентрация-время были нанесены на график обработки и анализа (где применимо). Для обзора статистики, для средних и медианных графиков по времени отбора проб использовали номинальное время отбора ФК образцов, для графиков времени отдельных пациентов использовали фактическое время отбора ФК образцов.PK parameters AUC _inf , AUC _last , C _max , T _max , and t

summarized descriptively by processing and analysis (where applicable). For AUC _inf and C _max , individual subject parameters were plotted by treating each analyte separately (where applicable). Concentrations were listed and summarized descriptively by timing of PK sampling, processing, and analyte (where applicable). Mean and median individual patient concentration-time profiles were plotted on a processing and analysis chart (where applicable). For statistical review, nominal PK sampling times were used for mean and median sampling time plots, and actual PK sampling times were used for individual patient time plots.

Predicted static values were obtained using the superposition method using WinNonLin software (Pharsight Corp). The superposition was used on each individual PK profile to obtain a static PK profile for each patient.

Table 43 Single dose
FK parameters 11 mg
(Test) 22 mg
(Comparative) _Cmax (ng/ml) 42.2 (32%) 84.4 (22%) Cmax _,dn (ng/ml/mg) 3.84 (32%) 3.84 (22%) AUC _inf (ng*h/ml) 315.6 (21%) 645.8 (23%) AUC _inf,dn (ng*h/ml/mg) 28.7 (21%) 29.4 (23%) T _max (h) 3.0 (2.0-4.0) 3.0 (2.0-4.0)

(ч)t

(h) 6.25 (36%) 7.3 (46%) Cmax _,dn ratio (%) 100% (91-110%) 100% AUC _inf,dn ratio (%) 98% (95-101%) 100%

. Вышеприведенные соотношения представлены как соотношения среднегеометрических значений (90% доверительные интервалы).The above values are given as geometric mean values (%CV) for all except: mean (range) for T _max ; arithmetic mean (%CV) for t

. The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Predicted FC parameters 11 mg QD
(Test) 22 mg QD
(Comparative) _Cmax,ss (ng/ml) 43.6 (35%) 87.6 (25%) Cmin _,ss (ng/ml) 1.7 (53%) 3.5 (75%) Cmin _,dn,ss (ng/ml/mg) 0.15 (53%) 0.16 (75%) C _min,dn,ss ratio (%) 95% (72-125%) 100% _Cmax,ss / Cmin _,ss 26 25 Time from conc. 17 ng/ml (h) 6.6 11.1 Rest from medication (Time below 17 ng/mL) (h) 17.4 12.9

The above values are given as geometric mean values (%CV). The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Sustained release dosage forms containing 11 mg and 22 mg of tofacitinib that release and dissolve tofacitinib according to the formula (based on dissolution test 1) provide dose-proportional PK characteristics and meet the desired PK requirements.

Example 18 Study D

The relative bioavailability of 11 mg sustained release tofacitinib tablets was determined relative to a single dose of two 5 mg immediate release tofacitinib tablets (MW) and determined the following cut-offs for tofacitinib:C _max ,T _max .AUC_inf, AUC_last. An additional cutoff was determined for the relative bioavailability (%RBA) of tofacitinib for each sustained release formulation relative to the MB formulation.

The study was a randomized, open-label, single dose, 2-period, 2-treatment, 2-sequence crossover study in 26 healthy male patients (see Table 44). Patients received sustained release formulations of tofacitinib citrate (11 mg) or two immediate release formulations of tofacitinib citrate (5 mg), with a washout period of 3 days between doses.

Table 44 Subsequence Period 1 2 AB (n=13) A B BA (n=13) B A

A: 11 mg extrudable core tablet prepared as follows:

Table 45 No. Material Function Composition (%) The consignment
300 kg 1 tofacitinib citrate active agent 8.885 26.656 2 Sorbitol Osmagen 76.115 228.344 3 Hydroxyethylcellulose viscosifying agent 8,000 24,000 4 Copovidone Binder 6,000 18,000 5 magnesium stearate lubricant 1,000 3,000 Tablet core weight - - - 100% 300,000

Half the batch size of sorbitol, 114.172 kg, was added to the 800 L hopper. The batch size of Copovidone, 18,000 kg, was then added to the 800 L hopper. The batch size of Tofacitinib, 26.656 kg, was then added to the 800 L hopper. The batch size of Hydroxycellulose, 24,000 kg, was then added to the 800 L hopper. The remaining half of the batch size of sorbitol, 114.172 g, was added to the 800 L bin. All materials were added using a vacuum transfer system and passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller running at approximately 1400 rpm. All components were mixed in the hopper for 20 minutes at 12 +/- 1 rpm.

The mixture was passed through a Comil rotary mill equipped with a 0.032″ filter and a round edge impeller running at approximately 1400 rpm. The mixture was collected in a second 800 L bin. The contents of the hopper were stirred for 20 minutes at 12 +/- 1 rpm.

Magnesium stearate, 3,000 kg, was passed through a sieve with a mesh size of 850 microns and added to the hopper and the contents were mixed for 5 minutes at 12 +/- 1 rpm. Tablets were compressed using 0.2080" x 0.4160" modified oval tools on a Manesty Mark IV rotary tablet press to an average target weight of 200 mg +/- 5%, an average target thickness of 4.17 mm +/- 0.05 mm , and a target strength of 11 kPa. The tablets were passed through a dust collector and a metal detector.

Table 46 Coated tablet composition
200 mg % in coverage mg/tablet Coating m./m. (%) Lot size (kg) 1. Tofacitinib citrate, tablet core --- 200 --- --------- 2. Cellulose acetate (398-10) 1.8 8.4 4.2 13.5 3. Hydroxypropylcellulose (Klucel EF) 1.2 5.6 2.8 9.0 4. Methanol 19.6 (91.5) --- 147.0 5. Acetone 77.4 (361.2) --- 580.5 total weight 100 214.0 7.0 750.0

A coating solution of 750 kg was prepared according to the following steps. First, all 147.0 kg of methanol and 580.5 g of acetone were added to a 250 gallon tank. Cellulose acetate (13.5 kg) was added to the mixture. Hydroxypropylcellulose (9.0 kg) was added to the mixture. The contents of the container were stirred for one hour. This procedure gave a 3% solid solution (W/M).

Oval tablets (250 kg) of 200 mg were coated in a Vector HC-130 coater at 8 rpm and 1500 cfm airflow. with an outlet temperature of 28°C. A 3% solid solution (w/w) was applied until a 7% wet weight increase was achieved. The tablets were then removed from the pan and dried at 45° C. for 24 hours.

A single hole (600 microns) was drilled at the end of the oval tablet strip. The hole can be drilled mechanically or with a laser. A 7% coating provided the following release into a pH 6.8 environment at a paddle speed of 50 rpm based on dissolution test 1 (Table 47):

Table 47 Time (h) Tablet 11 mg
% drug dissolved 1 8 2.5 49 6 89

B: Tofacitinib 2×5 mg

tablet with instant release (comp.) was prepared as follows:

Table 48: Composition Tablets with immediate release (5 mg) Component name Quality Composition (mg) 1. Tofacitinib citrate Pharm 8.078 2. Microcrystalline cellulose Ph.Eur/NF/JP 122.615 3. Lactose monohydrate Ph.Eur/NF/JP 61.307 4. Croscarmellose sodium Ph.Eur/NF/JP 6,000 5. Magnesium stearate Ph.Eur/NF/JP 0.500 6. Magnesium stearate Ph.Eur/NF/JP 1,500

WEIGHT OF THE TABLET CORE: 200,000 7. Opadry II white (HPMC based) Pharm 6,000 8. Purified water Ph.Eur/USP/JP (34,000) Total: 206,000

The tablet was obtained according to the following method. Components 1-4 were combined and processed using a mix-crush-mix procedure. Component 5 was then added to the mixture and combined using a mixing procedure. This lubricated mixture was then subjected to dry granulation. Component 6 was then added to the dry granulate and combined using a mixing procedure. The lubricated granulate was compressed into 200 mg tablets using a rotary tablet press. The tablets were then coated using a film coater spraying a solution containing Components 7 and 8 to coat the tablets with 6 mg.

Patients were kept on an empty stomach overnight for at least 8 hours before taking study medication. On the morning of day 1 of each period, all patients received a single dose of study medication with 240 mL of water. Patients were given a standardized lunch 4 hours after dosing.

Introduced dosage forms:

Tofacitinib 5 mg immediate release tablet (comp.): Prepared as described above.

Sustained release dosage forms of Tofacitinib (11 mg): Prepared as described above.

Throughout the study periods, blood samples were collected periodically to provide plasma for PK analyses. The results of the study are shown in Table 49. PK samples were analyzed using standard analytical methods. Dose-normalized natural log-transformed AUC _inf , AUC _last and C _max were analyzed for tofacitinib using a mixed effect model with sequence, period and treatment as fixed effects and subject in sequence as random effect. An estimate of the adjusted standard deviations (Comparison Test) and the corresponding 90% confidence intervals were derived from this model. Adjusted standard deviations and 90% confidence intervals for differences were raised to the power to estimate the ratio of the adjusted geometric means (Test/Comparison) and 90% confidence intervals for coefficients. The 2×5 mg instant release formulation was the comparative treatment and the 11 mg sustained release formulation was the test treatment.

Relative bioavailability tofacitinib was evaluated as the ratio of the dose-normalized adjusted geometric mean values of the Test and Comparative Test for AUC_inf.

PK parameters AUC _inf , AUC _last , C _max , T _max , and t _1/2 were summarized descriptively by processing and analysis (where applicable). For AUC _inf and C _max , individual subject parameters were plotted by treating each analyte separately (where applicable). Concentrations were listed and summarized descriptively by timing of PK sampling, processing, and analyte (where applicable). Mean and median individual patient concentration-time profiles were plotted on a processing and analysis chart (where applicable). For statistical review, nominal PK sampling times were used for mean and median sampling time plots, and actual PK sampling times were used for individual patient time plots.

Predicted static values were obtained using the superposition method using WinNonLin software (Pharsight Corp). The superposition was used on each individual PK profile to obtain a static PK profile for each patient.

Table 49 Single dose
FK parameters 11 mg modified release
(Test) 2 × 5 mg instant release
(compar.) _Cmax (ng/ml) 40.8 (29%) 88.2 (29%) Cmax _,dn (ng/ml/mg) 3.70 (29%) 8.82 (29%) AUC _inf (ng*h/ml) 297.5 (23%) 286.3 (20%) AUC _inf,dn (ng*h/ml/mg) 27.0 (23%) 28.6 (20%) T _max (h) 3.54 (3.00-6.00) 0.50 (0.50-2.00)

(ч)t

(h) 5,705 (41%) 3,413 (18%) C _max(adj) ratio (%) 92% (85-100%) 100% AUC _inf ratio (%) 104%
(100%-107%) 100%

. Вышеприведенные соотношения представлены как соотношения среднегеометрических значений (90% доверительные интервалы).The above values are given as geometric mean values (%CV) for all except: mean (range) for T _max ; arithmetic mean (%CV) for t

. The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Predicted Stationary FC 11 mg modified release QD
(Test) 2×5 mg instant release twice daily
(compar.) _Cmax,ss (ng/ml) 41.6 (31%) 45.0 (28%) Cmin _,ss (ng/ml) 1.3 (60%) 1.5 (53%) Cmin _,dn,ss (ng/ml/mg) 0.12 (60%) 0.15 (53%) _Cmin,dn,ss Ratio (%) 88% (73%-106%) 100% _Cmax,ss / Cmin _,ss 32 thirty Time from conc. above 17 ng/ml (h) 6.3 5.6 Rest from medication (time below 17 ng/mL) (h) 17.7 18.4

The above values are given as geometric mean values (%CV). The above ratios are presented as ratios of geometric mean values (90% confidence intervals).

Sustained-release dosage forms containing 11 mg of tofacitinib, which release and dissolve 80% of tofacitinib in 4-5 hours, provide similar PK parameters to the instant-release dosage form containing 10 mg of tofacitinib and meet the desired PK requirements when taken on an empty stomach.

Claims (31)

1. A single-use pharmaceutical dosage form that contains a core containing 22 mg of tofacitinib or an equivalent amount of tofacitinib in the form of its pharmaceutically acceptable salt and osmogen, and a semi-permeable membrane coating surrounding the core, where said coating contains a water-insoluble polymer, wherein said dosage form is a sustained release dosage form and when added to test medium containing 900 ml of 0.05 M potassium phosphate buffer pH 6.8 at 37° C. in a standard USP rotating paddle apparatus where the paddles rotate at a speed of 50 rpm, dissolves not more than 30% of tofacitinib or its pharmaceutically acceptable salt in 1 hour, and not less than 35% and not more than 75% of tofacitinib or its pharmaceutically acceptable salt in 2.5 hours, and not less than 75% of tofacitinib or a pharmaceutically acceptable salt thereof in 5 hours, and wherein said dosage form delivers tofacitinib or a pharmaceutically acceptable salt thereof to a subject by osmotic pressure, and wherein the water-insoluble polymer is a cellulose derivative that supports the release of tofacitinib or a pharmaceutically acceptable salt thereof salt. 2. A single-use pharmaceutical dosage form that contains a core containing 22 mg of tofacitinib or an equivalent amount of tofacitinib in the form of its pharmaceutically acceptable salt and osmogen, and a semi-permeable membrane coating surrounding the core, where said coating contains a water-insoluble polymer, wherein the dosage form is a sustained release dosage form and when administered orally to a subject provides an AUC in the range of 80 to 125% of the AUC of 10 mg tofacitinib or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, administered as an instant release formulation twice daily (BID), and provides a geometric mean ratio of C _max to C _min in plasma from 10 to 100, and where the dosage form delivers tofacitinib or its pharmaceutically acceptable salt to the subject due to osmotic pressure, and where the water-insoluble polymer is a cellulose derivative, which supports the release of tofacitinib or a pharmaceutically acceptable salt thereof. 3. Pharmaceutical dosage form according to claim 2, where the AUC range is 90-110% and the geometric mean concentration from C _max to C _min in plasma is from 20 to 40. 4. Pharmaceutical dosage form according to claim 3, where the geometric mean concentration from C _max to C _min in plasma is from 20 to 30. 5. The pharmaceutical dosage form of claim 2, wherein the dosage form is orally provided to the subject with a mean plasma _Cmax in the range of 70% to 125% of the mean plasma _Cmax of tofacitinib administered in instant release formulations twice daily at stationary state. 6. The pharmaceutical dosage form of claim 2, wherein the dosage form is administered to the subject orally to provide drug rest in the range of 80% to 110% of the drug rest of tofacitinib administered in instant release formulations twice daily over a 24 hour period. . 7. The pharmaceutical dosage form of claim 2 wherein the rest from the drug is 15 to 18 hours over a 24 hour period. 8. A single-use pharmaceutical dosage form that contains a core containing 22 mg of tofacitinib or an equivalent amount of tofacitinib in the form of its pharmaceutically acceptable salt and osmogen, and a semi-permeable membrane coating surrounding the core, where said coating contains a water-insoluble polymer, wherein said dosage form is a sustained release dosage form, and which, when administered to a subject, has a mean plasma concentration-versus-time curve after administration from 17 ng-hour/mL per mg tofacitinib to 42 ng-hour/mL per mg tofacitinib , and the geometric mean ratio of C _max to C _min in plasma is from 10 to 100, and at the same time, the dosage form releases tofacitinib, or a pharmaceutically acceptable salt thereof, in the subject due to osmotic pressure, and the water-insoluble polymer is a cellulose derivative , which supports the release of tofacitinib, or a pharmaceutically acceptable salt thereof. 9. Pharmaceutical dosage form according to claim 8, where the geometric mean ratio of C _max to C _min in plasma is from 20 to 40. 10. Pharmaceutical dosage form according to claim 9, where the geometric mean ratio of C _max to C _min in plasma is from 20 to 30. 11. The pharmaceutical dosage form of claim 8, wherein the subject has a single prolonged time at a dose above 17 ng/mL of 6 to 15 hours, and a single prolonged time at a dose below 17 ng/mL of 9 to 18 hours over a 24 hour interval dosing. 12. The pharmaceutical dosage form of claim 11 wherein the subject has a single prolonged time at a dose above 17 ng/mL of 6 to 9 hours. 13. The pharmaceutical dosage form of claim 11, wherein the subject has a single prolonged time at a dose below 17 ng/mL between 15 and 18 hours. 14. The pharmaceutical dosage form of claim 11 wherein the subject has a single prolonged time at a dose above 17 ng/mL between 11 and 15 hours. 15. The pharmaceutical dosage form of claim 11 wherein the subject has a single prolonged time at a dose below 17 ng/mL between 9 and 13 hours. 16. The pharmaceutical dosage form of claim 8, wherein the subject has a mean maximum plasma concentration (C _max ) of 3 to 6 ng/mL per mg of dosed tofacitinib. 17. The pharmaceutical dosage form of claim 8, wherein said dosage form delivers tofacitinib or a pharmaceutically acceptable salt thereof using a system selected from the group consisting of an extrudable core system, a swellable core system, and asymmetric membrane technology. 18. The pharmaceutical dosage form of claim 8, wherein said cellulose derivative is cellulose acetate. 19. The pharmaceutical dosage form of claim 8, wherein said coating further comprises a water-soluble polymer that has an average molecular weight of 2,000 to 100,000 daltons. 20. The pharmaceutical dosage form of claim 19, wherein said water-soluble polymer is selected from the group consisting of: water-soluble cellulose derivatives, gum arabic, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, and polyvinyl alcohols. 21. The pharmaceutical dosage form of claim 20, wherein said water-soluble cellulose derivatives are hydroxypropylcellulose, hydroxypropylmethylcellulose, or hydroxyethylcellulose. 22. The pharmaceutical dosage form of claim 8, wherein the osmogen contains sugar. 23. The pharmaceutical dosage form of claim 22, wherein the sugar is sorbitol. 24. The pharmaceutical dosage form of claim 8, wherein the subject has a mean trough plasma concentration (C _min ) of less than 0.3 ng/mL per mg of dosed tofacitinib. 25. The once-daily pharmaceutical dosage form of claim 8, wherein when administered orally to a subject, the dosage form has a mean postprandial/fasting plasma concentration-versus-time ratio of 0.7 to 1.4 and a mean peak concentrations (C _max ) in plasma after meals / on an empty stomach from 0.7 to 1.4.