ORAL MODIFIED RELEASE DOSAGE FORMS

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to oral modified release (MR) compositions comprising 6-(difluoromethyl)-8-[(1 F?,2F?)-2-hydroxy-2-methyl-cyclopentyl]-2-{[1 -

(methylsulfonyl)piperidin-4-yl]amino}-pyrido[2,3-c/]pyrim idin-7(8/-/)-one (hereinafter PF- 06873600) or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient.

Description of Related Art

The compound PF-06873600 is a potent inhibitor of CDK2, CDK4 and CDK6 having the formula (I):

Preparation of PF-06873600 is described in International Patent Publication No. WO2018/033815 and U.S. Patent No. 10,233,188. An anhydrous crystalline form of PF- 06873600 free base (Form 1 ) is described in U.S. Serial No. 62/793516. The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

Modified release (MR) compositions typically provide prolonged blood plasma levels of the formulated drug as compared to immediate release (IR) formulations of the same active pharmaceutical ingredient (API). The MR compositions and dosage forms described herein may provide desirable pharmacokinetic characteristics, such as AUC, half-life (ti/2), Cmax, Cmin, dose-adjusted AUC, dose-adjusted Cmax, fed/fasted AUC, fed/fasted Cmax ratios or fed/fasted Cmin ratios .

BRIEF SUMMARY OF THE INVENTION

The present invention relates to oral modified release (MR) compositions and unit dosage forms comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The modified release of PF-06873600 or a pharmaceutically acceptable salt thereof may be accomplished by any means known in the pharmaceutical arts, including but not limited to the use of an osmotic dosage form, a matrix dosage form, a multiparticulate dosage form, a gastric retentive dosage form, and a pulsatile dosage form. Such MR compositions and unit dosage forms may be useful for the treatment of abnormal cell growth, such as cancer, in a subject in need thereof.

In a first aspect, the invention provides a modified release (MR) composition comprising 6-(difluoromethyl)-8-[(1 F?,2F?)-2-hydroxy-2-methylcyclopentyl]-2-{[1 -

(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-c/]pyrimi din-7(8/-/)-one (PF-06873600), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the invention provides a modified release (MR) composition comprising PF-06873600 free base and a pharmaceutically acceptable carrier. In some embodiments of this aspect, the pharmaceutically acceptable carrier comprises an entraining agent.

In some embodiments of this aspect, the invention provides the modified release (MR) composition further comprising a semipermeable membrane coating. In some such embodiments, the semipermeable membrane coating comprises a a water-insoluble polymer, such as a cellulose derivative, preferably cellulose acetate.

In further embodiments of this aspect, the invention provides the modified release (MR) composition comprising a delivery system selected from the group consisting of a swellable core system, an extrudable core system, and an asymmetric membrane system.

In other embodiments of this aspect, the invention provides the modified release (MR) composition comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in the form of a unit dosage form. In some such embodiments, the unit dosage form is selected from the group consisting of an osmotic dosage form, a matrix dosage form, a multiparticulate dosage form, a gastric retentive dosage form, and a pulsatile dosage form.

In some such embodiments, the unit dosage form is a bilayer tablet comprising: (i) an active layer comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and (ii) a sweller layer comprising a water- swellable polymer and/or an osmotically active agent. Such water-swellable polymers and osmotically active agents may sometimes be referred to as swelling agents herein. In some such embodiments, the unit dosage form is a bilayer tablet comprising: (i) an active layer comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier comprising an entraining agent, and (ii) a sweller layer comprising a water-swellable polymer and/or an osmotically active agent. In some such embodiments, the sweller layer further comprises an osmogent. In some embodiments, the bilayer tablet is coated with a semipermeable membrane coating.

In a second aspect, the invention provides a unit dosage form comprising PF- 06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the unit dosage form is a modified release (MR) dosage form. In some embodiments, the invention provides a unit dosage form comprising PF- 06873600 free base and a pharmaceutically acceptable carrier, wherein the unit dosage form is a modified release (MR) dosage form. In some embodiments of this aspect, the pharmaceutically acceptable carrier comprises an entraining agent.

In a third aspect, the invention provides a unit dosage form, wherein the unit dosage form is a bilayer tablet comprising: (i) an active layer comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and (ii) a sweller layer comprising a water-swellable polymer and/or an osmotically active agent the invention provides a unit dosage form, wherein the unit dosage form is a bilayer tablet comprising: (i) an active layer comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and (ii) a sweller layer comprising a water-swellable polymer and/or an osmotically active agent. In some such embodiments, the unit dosage form is a bilayer tablet comprising: (i) an active layer comprising PF-06873600 free base and a pharmaceutically acceptable carrier, and (ii) a sweller layer comprising a water-swellable polymer and/or an osmotically active agent. In some embodiments of this aspect, the pharmaceutically acceptable carrier comprises an entraining agent. In some embodiments of this aspect, the bilayer tablet is a modified release (MR) unit dosage form that delivers PF-06873600, or a pharmaceutically acceptable salt thereof, primarily by osmotic pressure. In some embodiments of each of the compositions and unit dosage forms, including the bilayer tablets described herein, the pharmaceutically acceptable carrier comprises an entraining agent, wherein the entraining agent is selected from the group consisting of polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methylcellulose (MC), hydroxyethyl cellulose (HEC) and polyvinyl pyrrolidone (PVP), or mixtures thereof. In some embodiments, the entraining agent is polyethylene oxide (PEO) having an average molecular weight of from about 100,000 to about 300,000 daltons. In some such embodiments, the entraining agent is polyethylene oxide (PEO) (WSR N80 grade) having an average molecular weight of about 200,000.

In another aspect, the invention provides a bilayer tablet comprising: (i) an active layer comprising PF-06873600 free base and an entraining agent, and (ii) a sweller layer comprising a water-swellable polymer and an osmogent. In some embodiments of this aspect, the entraining agent is polyethylene oxide (PEO) having an average molecular weight of from about 100,000 to about 300,000 daltons. In some such embodiments, the entraining agent is polyethylene oxide (PEO) having an average molecular weight of about 200,000. In some embodiments of this aspect, the active layer further comprises a lubricant. In some such embodiments, the lubricant is magnesium stearate. In some embodiments of this aspect, the water-swellable polymer is polyethylene oxide (PEO) having an average molecular weight of from about 3,000,000 to about 8,000,000 daltons. In some such embodiments, the water-swellable polymer is polyethylene oxide (PEO) having an average molecular weight of about 5,000,000 daltons. In some embodiments of this aspect, the osmogent is sodium chloride. In some embodiments of this aspect, the sweller layer further comprises a tableting aid and a lubricant. In some such embodiments, the tableting aid is microcrystalline cellulose and a lubricant is magnesium stearate. In some embodiments of this aspect, the bilayer tablet is coated with a semipermeable membrane coating comprising cellulose acetate.

In some embodiments of each of the unit dosage forms described herein, including the bilayer tablets, the unit dosage form comprises from about 5 mg to about 250 mg of PF-06873600, or an equivalent amount of PF-06873600 in the form of a pharmaceutically acceptable salt thereof. In some such embodiments the unit dosage form comprises from about 5 mg to about 100 mg of PF-06873600, or an equivalent amount of PF-06873600 in the form of a pharmaceutically acceptable salt thereof. In some such embodiments, the unit dosage form comprises from about 10 mg to about 50 mg of PF-06873600, or an equivalent amount of PF-06873600 in the form of a pharmaceutically acceptable salt thereof. In other embodiments, the unit dosage form comprises from about 10 mg to about 25 mg of PF-06873600, or an equivalent amount of PF-06873600 in the form of a pharmaceutically acceptable salt thereof.

In some embodiments of each of the unit dosage forms described herein, the unit dosage form comprises about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg of PF-06873600, or an equivalent amount of PF-06873600 in the form of a pharmaceutically acceptable salt thereof. In some embodiments of each of the foregoing, the unit dosage form comprises PF-06873600 free base.

In some embodiments of each of the unit dosage forms described herein, the unit dosage form is a once daily dosage form (QD). In other embodiments of each of the unit dosage forms described herein, the unit dosage form is a twice daily dosage form (BID).

In another aspect, the invention provides a once daily modified release (MR) unit dosage form comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the invention provides a twice daily modified release (MR) unit dosage form comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In some embodiments of each of the unit dosage forms herein, the modified release (MR) unit dosage form delivers PF-06873600 or a pharmaceutically acceptable salt thereof primarily by osmotic pressure.

In other embodiments, the MR unit dosage forms of the present invention comprise a delivery system selected from the group consisting of an extrudable core system, a swellable core system, and an asymmetric membrane technology.

In some embodiments of each of the unit dosage forms described herein, the unit dosage form further comprises a semipermeable membrane coating. In some such embodiments, the semipermeable membrane coating comprises a water-insoluble polymer. In some such embodiments, the semipermeable membrane coating substantially comprises a water-insoluble polymer. In some such embodiments, the water-insoluble polymer comprises a cellulose derivative, preferably a water-insoluble cellulose acetate (e.g., cellulose triacetate).

In some embodiments of each of the unit dosage forms described herein, the semipermeable membrane coating further comprises a water-soluble polymer having an average molecular weight between 2,000 and 100,000 daltons, and sometimes between 2,000 and 50,000 daltons. In some such embodiments, the water-soluble polymer is selected from the group consisting of water-soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, and polyvinyl alcohols. In some such embodiments, the water-soluble cellulose derivative is selected from the group consisting of hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC) and hydroxyethyl-cellulose (HEC).

In another aspect, the invention provides a modified release (MR) unit dosage form comprising: (i) a core comprising PF-06873600, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (ii) a semipermeable membrane coating.

In some embodiments of each of the unit dosage forms, including the bilayer tablets described herein, the unit dosage form is a modified release (MR) dosage form and when administered orally to a subject, PF-06873600 is released in a controlled fashion over a period of from about 6 hours to about 12 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. In some such embodiments, PF-06873600 is released in a controlled fashion over of from about 7 hours to about 1 1 hours. In some such embodiments, PF-06873600 is released in a controlled fashion over of from about 8 hours to about 10 hours, In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 6 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. . In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 7 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 8 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. . In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 9 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 10 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 1 1 hours, so that at least 80% of the PF-06873600 has been released at the end of this period. . In some such embodiments, PF-06873600 is released in a controlled fashion over a period of about 12 hours, so that at least 80% of the PF-06873600 has been released at the end of this period.

In another aspect, the invention provides a modified release (MR) unit dosage form comprising PF-06873600, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the PF-06873600 is embedded in a matrix which releases PF-06873600 by diffusion. In one embodiment, a portion of the outside surface of the matrix is covered with an impermeable coating and the remainder of the outside surface is uncovered.

In some embodiments of the present invention, the unit dosage form is in the form of a tablet, including a bilayer tablet, coated with an impermeable or semipermeable coating. In some such embodiments, the unit dosage form is in the form of a tablet and the uncovered surface is in the form of an opening through the impermeable coating. In other such embodiments, the unit dosage form is in the form of a tablet and the uncovered surface is in the form of a passageway which penetrates through the entire tablet. In still other such embodiments, the unit dosage form is in the form of a tablet and the uncovered surface is in the form of one or more slits through said impermeable coating or in the form of one or more strips removed therefrom.

In some embodiments of any of the unit dosage forms described herein, the unit dosage form is a modified release (MR) dosage form and when administered orally to a subject provides: (i) an AUC in the range of 70% to 125% of the AUC of an amount of PF-06873600 administered as an immediate release (IR) oral formulation BID; and/or (ii) a mean plasma Cmax in the range of 70% to 125% of the mean plasma Cmax of PF- 06873600 administered as an immediate release (IR) oral formulation BID at steady state. In some embodiments of any of the unit dosage forms described herein, the unit dosage form is a modified release (MR) dosage form and when administered orally to a subject provides: (i) an AUC in the range of 70% to 125% of the AUC of an amount of PF-06873600 administered as an immediate release (IR) oral formulation BID; (ii) a mean plasma Cmax in the range of 70% to 125% of the mean plasma Cmax of PF-06873600 administered as an immediate release (IR) oral formulation BID at steady state; and/or (iii) a mean plasma Cmin in the range of 70% to 125% of the mean plasma Cmin of PF- 06873600 administered as an immediate release (IR) oral formulation BID at steady state.

In one embodiment of this aspect, the MR unit dosage form comprises from about 5 mg to about 50 mg of PF-06873600 and the equivalent amount of PF-06873600 administered as an immediate release (IR) formulation is 50 mg BID. In another embodiment of this aspect, the MR unit dosage form comprises from about 5 mg to about 50 mg of PF-06873600 and the equivalent amount of PF-06873600 administered as an immediate release (IR) formulation is 25 mg BID. In another embodiment of this aspect, the MR unit dosage form comprises from about 5 mg to about 50 mg of PF-06873600 and the equivalent amount of PF-06873600 administered as an immediate release (IR) formulation is 10 mg BID.

In another aspect, the invention provides a method of treating abnormal cell growth, such as cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of PF-06873600, or a pharmaceutically acceptable salt, according to any of the modified release compositions or unit dosage forms described herein.

In frequent embodiments of this aspect, the abnormal cell growth is cancer. In one embodiment, the abnormal cell growth is cancer mediated by CDK2, CDK4 and/or CDK6. In some such embodiments, the abnormal cell growth is cancer mediated by CDK2. In other such embodiments, the abnormal cell growth is cancer mediated by CDK4 and/or CDK6. In other embodiments, the abnormal cell growth is cancer mediated by CDK2 and CDK4/6. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2. In other embodiments, the abnormal cell growth is cancer characterized as retinoblastoma (RB)-negative. In some embodiments of this aspect, the abnormal cell growth is cancer, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer and thyroid cancer. In further embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2. In other embodiments, the cancer is characterized as retinoblastoma (RB)-negative.

In other embodiments, the cancer is breast cancer, including, e.g., ER-positive/HR- positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine resistant breast cancer, HER2 receptor antagonist (e.g., trastuzumab) resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/6 inhibition. In some embodiments of each of the foregoing, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2. In other embodiments, the cancer is lung cancer, including SCLC, characterized as retinoblastoma (RB)-negative.

In some embodiments of the methods provided herein, the method further comprises administration of one or more additional therapeutic agents in addition to the MR release composition or unit dosage form of the present invention. The additional therapeutic agent(s) may be administered simultaneously, sequentially or concurrently with the MR compositions and unit dosage forms of PF-06873600 described herein. Each of the aspects and embodiments of the present invention described herein may be combined with one or more other embodiments of the present invention described herein that are not inconsistent with the embodiment(s) with which it is combined.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to the following detailed description of the aspects and embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

The term "about" means having a value falling within an accepted standard of error of the mean, when considered by one of ordinary skill in the art. In some embodiments, the term "about" means within ± 10% of the indicated value, and preferably within ± 5% of the indicated value.

PF-06873600 free base or its pharmaceutically acceptable salts may be present in a crystalline or amorphous form, or a mixture of amorphous and crystalline forms, and may be anhydrous or solvated.

The invention described herein may be suitably practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms.

Sustained-release dosage forms are typically designed to provide the longest possible duration of release, to minimize: 1 ) the fluctuations in blood plasma concentration during the dosing interval (i.e. the ratio of the maximum blood plasma concentration, Cmax,ss, to the minimum blood plasma concentration, Cmin,ss, during the dosing interval), and 2) the amount of drug required to achieve the desired therapeutic effect, for the purpose of improving the safety and tolerability profile.

Modified release dosage forms may permit the active ingredient to be gradually released over a relatively long period of time at a uniform concentration, which results in little blood level fluctuation in the subject. Such modified release dosage forms may permit a reduction in the number of dosings required to once daily (QD) or twice daily (BID) while maintaining a consistent therapeutic effect, thus enhancing convenience and potentially improving compliance. To minimize the total dose of drug administered to a subject while providing efficacious blood levels, dosage forms with shorter durations of modified release may be preferred in some cases.

The present invention relates to MR compositions and unit dosage forms comprising PF-06873600, or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API). Such compositions and dosage forms are designed to provide specific pharmacokinetic properties to: (1 ) minimize the amount of PF-06873600 in the unit dosage form required to achieve efficacious blood levels in a subject; and/or (2) optimize the extent of PF-06873600 binding to CDK2, CDK4 and/or CDK6 (e.g., as measured by ICso), to provide the desired level of efficacy (based on the mean Cave or Cmin) over a 24-hour dosing interval. The MR compositions and unit dosage forms of the present invention may provide desired pharmacokinetic properties. Preferably, the MR compositions and unit dosage forms of the invention do not significantly alter the pharmacokinetic profile of PF-06873600 when administered in the fed state versus a fasted stage (i.e. exhibits a lack of food effect), to minimize deviation from the optimal coverage of CDKs.

By“immediate release” or“IR” is meant broadly an oral dosage form formulated to release an API immediately after oral administration. In IR formulations, no deliberate effort is made to modify the drug release rate.

An IR capsule or tablet formulation of PF-06873600, or a pharmaceutically acceptable salt thereof, may be referenced herein as a control for comparison to the modified release (MR) compositions of the invention.

By“modified release” or“MR” is meant broadly that the API is released from an oral dosage form at a rate that is slower than immediate release (IR). Such dosage forms may require less frequent dosing intervals than immediate-release (IR) formulations of the same API. Modified release compositions include oral compositions that consist of one or more of the following:

(a) a controlled release component alone;

(b) a delayed release component and a controlled release component;

(c) a delayed release component and an 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 PF-06873600 may be prepared in a conventional manner by treating a solution or suspension of the free base with about one or two chemical equivalents of a pharmaceutically acceptable acid. The free base form may be regenerated under standard conditions to permit interconversion of salt forms. Conventional concentration and recrystallization techniques may be employed in isolating the salts. Illustrative examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, mesylic, tosylic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, methanesulfonic, benzenesulfonic, and related acids. For example, see Berge et al., J. Pharm. Sci. (1977) 66(1 ):1 -19. In some embodiments, the MR compositions and unit dosage forms of the invention comprise PF-06873600 free base.

The terms“subject”,“patient” and“individual” may be used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human.

As used herein, an“oral dosage form”, including an oral MR or IR dosage form, is a pharmaceutically acceptable oral dosage form, meaning that the dosage form is safe for administration to humans, where all excipients in the dosage form are pharmaceutically acceptable, in other words safe for human ingestion. Oral dosage forms are intended to embrace tablets, capsules, multiparticulates or beads.

As used herein, the term "unit dose" or "unit dosage form" refers to a physically discrete unit that contains a predetermined quantity of API calculated to produce a desired therapeutic effect. The unit dosage form may be in the form of a tablet, capsule, sachet, etc. In some embodiments, the unit dosage form is a tablet. In some such embodiments, the unit dosage form is a bilayer tablet. The term“fasted” as used herein is defined as follows: the dosing state which is defined following an overnight fast (wherein 0 caloric intake has occurred) of at least 10 hours. Subjects may administer the dosage form with 240 ml_ of water. No food should be allowed for at least 4 hours post-dose. Water may be allowed as desired except for one hour before and after drug administration.

The term“fed” as used herein is defined as follows: the dosing state which is defined following an overnight fast (wherein 0 caloric intake has occurred) of at least 10 hours, subjects then begin the recommended high fat meal 30 minutes prior to administration of the drug product. Subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after the start of the meal. The drug product may be administered with 240 ml_ of water. No food should be allowed for at least 4 hours post-dose. Water may be allowed as desired except for one hour before and after drug administration.

To assess the fed/fasted ratio, a single oral dose of API may be administered: 30 minutes after a high-fat, high-calorie meal (approximately 800-1000 calories, with 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; 30 minutes after a low-fat, low-calorie meal (approximately 400-500 calories with 120, 250, and 28- 35 calories from protein, carbohydrate, and fat, respectively); or between meals (1 hour after/2 hours before) a moderate fat and calorie content meal (approximately 500-700 calories consisting of 15% protein, 50% carbohydrate, and 35% fat). An example test high fat meal would be two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk.

The calculation of the mean area under the serum concentration versus time curve (AUC) is a well-known procedure in the pharmaceutical arts and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986). AUC as used herein includes area under the concentration-time curve from time zero extrapolated to infinite time following single dose or the area under the concentration-time curve from time zero to time of the end of dosing interval following steady state/multiple doses. In addition, the calculations for Cmax, Cmin,ss, Tmax, and elimination half-life (t½), are also known to this of ordinary skill in the art and is described, for example, in Shargel, Wu-Pong, and Yu, Applied Biopharmaceutics and Pharmacokinetics (2005).

To determine the mean fed/fasted ratio, the individual ratio of the mean area under the plasma concentration versus time curve of API (e.g. AUCo-inf) in the fed state to the mean area under the plasma concentration versus time curve of API (e.g. AUCo-inf) in the fasted state is first calculated, and then the corresponding individual ratios are averaged together. In this way, it is the average of each corresponding individual’s ratio which is determined.

Drug dissolution represents a critical factor affecting the rate of systemic absorption. A variety of in vitro methods have been developed for assessing the dissolution properties of pharmaceutical formulations, and dissolution testing is sometimes used as a surrogate for the direct evaluation of drug bioavailability. See, e.g., Emmanuel et al., Pharmaceutics (2010), 2:351 -363, and references cited therein. Dissolution testing measures the percentage of the API that has been released from the drug product (i.e., tablet or capsule) and dissolved in the dissolution medium under controlled testing conditions over a defined period of time. To maintain sink conditions, the saturation solubility of the drug in the dissolution media should be at least three times the drug concentration. For low solubility compounds, dissolution may sometimes be determined under non-sink conditions. Dissolution is affected by the properties of the API {e.g., particle size, crystal form, bulk density), the composition of the drug product {e.g., drug loading, excipients), the manufacturing process {e.g., compression forces) and the stability under storage conditions {e.g., temperature, humidity).

Dissolution testing of dosage forms is frequently conducted in a standard USP rotating paddle apparatus in a suitable test medium, as disclosed in the United States Pharmacopoeia (USP) Dissolution Test Chapter 71 1 , Apparatus 2. Representative conditions include addition of the dosage form to a test medium comprising: (i) 500 ml_ of 10 mM pH 5.5 acetate buffer at 37°C in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm; (ii) 500 ml_ of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCI at 37°C in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm; or (iii) 900 ml_ of 0.05M pH 6.8 potassium phosphate buffer at 37 ^Q C in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm. At appropriate times following test initiation (e.g., insertion of the dosage form into the apparatus), filtered aliquots (typically 1 .5 ml_) from the test medium are analyzed for API by high performance liquid chromatography (HPLC). Dissolution results are reported as the percent of the total dose of API tested dissolved versus time.

Methods for assessing the chemical storage stability of solid dosage forms under accelerated aging conditions have been described in the literature. See, e.g., S. T. Colgan, T. J. Watson, R. D. Whipple, R. Nosal, J. V. Beaman, D. De Antonis, “The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies” J. Pharm. Innov. 7:205-2013 (2012); Waterman KC, Carella AJ, Gumkowski MJ, et al. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm Res 2007; 24(4):780-90; and S. T. Colgan, R. J. Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K. Fields, G. Scrivens,“Opportunities for Lean Stability Strategies” J. Pharm. Innov. 9:259-271 (2014).

Modified Release - Osmotic Systems

Swellable-core technology (SCT) systems rely on osmotic pressure and polymer swelling to deliver drugs to the Gl tract in a reliable and reproducible manner. SCT compositions consist of a core tablet containing the drug and a water-swellable component, plus one or more delivery ports. In general, drug-release rates are slower with increasing coating thickness and decreasing coating permeability. Release rates are relatively independent of the drug loading and the number and size of the delivery ports.

In some aspects the invention provides modified release (MR) compositions comprising PF-06873600, or a pharmaceutically acceptable salt thereof, incorporated into an osmotic delivery device, sometimes referred to as an "osmotic pump." Osmotic pumps comprise a core containing an osmotically effective composition of the API surrounded by a semipermeable membrane. The term "semipermeable" in this context means that water can readily diffuse through the membrane, but solutes dissolved in water typically cannot readily diffuse through the membrane relative to the rate of water diffusion through the membrane. In use, when placed in an aqueous environment, the osmotic delivery device imbibes water due to the osmotic activity of the core composition. Owing to the semipermeable nature of the surrounding membrane, the contents of the device (including, e.g., PF-06873600 and any excipients) cannot pass through the non- porous regions of the membrane and are driven by osmotic pressure to leave the device through an opening or passageway pre-manufactured into the dosage form or, alternatively, formed in situ in the Gl tract as by the bursting of intentionally-incorporated weak points in the coating under the influence of osmotic pressure.

Osmotically effective drug compositions include water-soluble species, which generate a colloidal osmotic pressure, and water-swellable polymers. Examples of such dosage forms are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21 ^st Edition, 2006 Chapter 47; page 950-1 and Thombre et al., Osmotic drug delivery using swellable-core technology, J. Controlled Release (2004) 94:75-89, herein incorporated as reference. Water-swellable polymers are hydrophilic polymers which take up water and swell, Examples include polyethylene oxides (PEO), polyacrylic acid derivatives such as polymethyl methacrylate, polyacrylamides, polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, carboxymethylcellulose, starches, and the like. In some embodiments, the water-swellable polymer is selected from the group consisting of polyethylene oxides (PEO), carboxymethylcellulose and croscarmellose sodium. In some embodiments, the water-swellable polymer is PEO with a molecular weight of from about 3,000,000 to about 8,000,000 daltons. In some embodiments, the water-swellable polymer is PEO (POLYOX™ WSR Coagulant grade), having an average molecular weight of about 5,000,00 daltons.

The invention provides a modified release (MR) composition comprising PF- 06873600 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier incorporated into a bilayer osmotic delivery device (e.g., a bilayer tablet or capsule) wherein the pharmaceutically acceptable carrier comprises an entraining agent. In frequent embodiments, the bilayer formulation comprises an active layer comprising the API and an entraining agent, and a sweller layer comprising a water- swellable polymer and/or osmotically active agents that does not contain any API. Both the active layer and the sweller layer may further comprise additional excipients. The bilayer tablet or capsule may be surrounded by a semipermeable membrane which contains one or more openings that are manufactured into the dosage form through such techniques as laser drilling. The entraining agent may be a water-soluble polymer or mixture of water-soluble polymers which wet and hydrate to the appropriate viscosity range to suspend the API particles and flow through the delivery port. Examples of entraining agents include polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methylcellulose (MC), hydroxyethyl cellulose (HEC) and polyvinyl pyrrolidone (PVP), or mixtures thereof. Non-crosslinked polyethylene oxide (PEO), such as PEO (WSR N80 grade), may be used as the entraining agent. The amount of the entraining agent present in the PF-06873600-containing composition (active layer) may range from about 20 wt% to about 95 wt%. In some embodiments, the entraining agent comprises from about 50 wt% to about 95 wt% of the active layer. In some embodiments, the entraining agent comprises from about 70 wt% to about 95 wt% of the active layer. The choice of the molecular weight for the PEO used as the entraining agent depends in part on whether the PEO makes up the bulk of the non-PF-06873600 portion of the active layer, or whether significant amounts of other low-molecular weight water-soluble excipients are included (i.e., the PEO molecular weight choice depends on the fraction of the PF-06873600-containing composition that is PEO). Should the PF-06873600- containing composition in the active layer not become fluid rapidly, the dosage form can swell and rupture the coating that surrounds the core, potentially causing failure of the dosage form. Where the excipients of the PF-06873600-containing composition are primarily PEO (e.g., PEO makes up about 60 wt% or more of the non-PF-06873600 components of the PF-06873600-containing composition), it is generally preferred that the PEO have an average molecular weight of from about 100,000 to about 300,000 daltons. (As used herein, reference to molecular weights of polymers should be taken to mean average molecular weights.) In some embodiments, the PEO is PEO (WSR N80 grade) having an average molecular weight of from about 200,000 daltons.

Alternatively, higher molecular weight PEO, e.g., having an average molecular weight of from about 500,000 to about 800,000 daltons may be used as the entraining agent in the active layer where the PEO is included at a lower fraction of the non-PF- 06873600 excipients, with a portion of the PEO being replaced by a fluidizing agent. Ordinarily, when PEO makes up about 60 wt% or more of the non-PF-06873600 components of the PF-06873600-containing composition, PEO having a molecular weight of 500,000 daltons or more may make the composition too viscous, which can result in a rupture of the coating or at least in a delay of the release of PF-06873600. However, such higher molecular weight PEO may be preferred when the non-PF- 06873600 components of the PF-06873600-containing composition comprise less than about 60 wt% PEO and the composition also comprises a fluidizing agent. When using a higher molecular weight PEO, the amount of fluidizing agent present in the composition may range from about 5 wt% to about 50 wt%, preferably about 10 wt% to about 30 wt% of the PF-06873600-containing composition.

Preferred fluidizing agents are low molecular weight, water-soluble solutes such as non-reducing sugars and organic acids with aqueous solubilities of 30 mg/mL or greater. Suitable sugars include xylitol, mannitol, sorbitol, sucrose, lactose, dextrose, trehalose and maltitol. Salts useful as a fluidizing agent include sodium chloride, sodium lactate and sodium acetate. Organic acids useful as a fluidizing agent include adipic acid, citric acid, malic acid, fumaric acid, succinic acid and tartaric acid.

The presence of the fluidizing agent, along with a relatively low level of higher molecular weight PEO (e.g., about 500,000 to about 800,000 daltons) may allow the composition to rapidly reach a low viscosity upon imbibition of water. Such compositions may be useful to deliver relatively high amounts of PF-06873600.

The PF-06873600-containing MR compositions and unit dosage forms may also contain other water-swellable polymers. For example, the PF-06873600-containing MR composition may contain relatively small amounts of water-swellable polymers that greatly expand 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 amounts ranging from 0 wt% to 10 wt% of the PF-06873600-containing composition.

The PF-06873600-containing MR compositions and unit dosage forms may optionally include osmotically effective solutes, often referred to as "osmogens" or "osmogents." The amount of osmogent present in the composition or unit dosage form may range from about 0 wt% to about 50 wt%, and sometimes from about 10 wt% to about 40 wt%. In some embodiments, the osmogent comprises from about 10 wt% to about 50 wt% of the sweller layer. In some such embodiments, the osmogent comprises from about 25 wt% to about 40 wt% of the sweller layer. Typical classes of suitable osmogents are water-soluble salts, sugars, organic acids, and other low-molecule-weight organic compounds that are capable of imbibing water to thereby establish an osmotic pressure gradient across the barrier of the surrounding coating. Typical useful 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 utilized as osmogents. The osmogents can be used alone or as a combination of two or more osmogents.

The PF-06873600-containing MR compositions and unit dosage forms may further include solubility-enhancing agents or solubilizers that promote the aqueous solubility of the drug, present in an amount ranging from about 0 wt% to about 30 wt% of the MR composition or unit dosage forms. Solubilizers include organic acids and organic acid salts, partial glycerides, e.g., less than fully esterified derivatives of glycerin, including glycerides, monoglycerides, diglycerides, glyceride derivatives, polyethylene glycol (PEG) esters, polypropylene glycol esters, polyhydric alcohol esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitan esters, and carbonate salts.

A preferred class of solubilizers is organic acids. For drug products containing a base which are solubilized by protonation, solubility in an aqueous environment of pH 5 or higher may sometimes be reduced. Addition of an organic acid to such formulations may assist in solubilization and hence absorption of the basic drug. Even a slight decrease in the pH of the aqueous solution at high pH can sometimes result in dramatic increases in the solubility of the drug. Organic acids can also promote stability during storage prior to introduction to a use environment due to their tendency to maintain the drug product in a protonated state.

There are a variety of factors to consider when choosing an appropriate organic acid for use as a solubilizer in an osmotic dosage form. The acid should not interact adversely with the drug, should have appropriate water solubility, and should provide good manufacturing properties. Accordingly, a preferred subset of organic acids for use as solubilizers includes citric acid, succinic acid, fumaric acid, adipic acid, malic acid and tartaric acid. Citric acid, malic acid, and tartaric acid have the advantage of high water solubility and high osmotic pressure. Succinic acid and fumaric acid offer a combination of both moderate solubility and moderate osmotic pressure. Other organic acids include ascorbic acid, 2-benzene carboxylic acid, benzoic acid, maleic acid, serbacic acid, sorbic acid, edipic acid, editic acid, glutamic acid and toluenesulfonic acid.

The water-swellable composition may also optionally contain a colorant. The purpose of the colorant is to allow identification of the drug-containing side of the tablet face for purposes of providing the delivery port, such as by laser drilling through the coating. Acceptable colorants include, but are not limited to, FD&C Red Lake No. 40, FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6.

The active layer and/or the sweller layer and/or the semipemermeable (functional rate controlling) membrane may optionally contain an antioxidant, such as but not limited to BHT, BHA, sodium metabisulfite, propyl galate, glycerin, vitamin E, Citric Acid or ascorbyl palmitate. The antioxidant may be present in an amount ranging from 0 wt% to 10 wt% of the drug-containing composition layer and/or the water-swellable composition layer and/or the functional rate controlling membrane. For additional examples of antioxidants, see C.-M. Andersson, A. Hallberg, and T. Floegberg. Advances in the development of pharmaceutical antioxidants. Advances in Drug Research. 28:65-180, 1996.

Both the active layer and the sweller layer may also include other conventional pharmaceutically useful excipients such as binders, including FIPC, FIPMC, FIEC, MC, and PVP, tableting aids, such as microcrystalline cellulose (e.g., Avicel PH-200), and lubricants, such as magnesium stearate,, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, or mixtures of two or more of these. Such excipients may be included in the active layer, the sweller layer or both the active and sweller layers, and may be included in the intra-granular portion, the extra-granular portion, or both portions of the composition.

In some embodiments, the active layer comprises from about 1 wt% to about 20 wt% of a lubricant. In some embodiments, the active layer comprises from about 5 wt% to about 15 wt% of a lubricant. In some embodiments, the active layer comprises about 10 wt% of a lubricant. In some embodiments, the sweller layer comprises from about 1 wt% to about 20 wt% of a lubricant. In some embodiments, the sweller layer comprises from about 1 wt% to about 10 wt% of a lubricant. In some embodiments, the sweller layer comprises about 5 wt% of a lubricant. In some such embodiments, the lubricant is magnesium stearate. In some embodiments, the sweller layer comprises from about 20 wt% to about 75 wt% of a water-swellable polymer. In some such embodiments, the water-swellable polymer is polyethylene oxide (PEO) having an average molecular weight of from about 3,000,000 to about 8,000,000 daltons. In some such embodiments, the sweller layer comprises from about 20 wt% to about 75 wt% polyethylene oxide (PEO) having an average molecular weight of from about 3,000,000 to about 8,000,000 daltons. In some such embodiments, the sweller layer comprises from about 20 wt% to about 75 wt% polyethylene oxide (PEO) having an average molecular weight of about 5,000,000 daltons.

The sweller layer is typically prepared by mixing the water-swellable polymer and the other excipients to form a uniform blend. To obtain a uniform blend, it is desirable to either wet or dry granulate or dry blend ingredients that have similar particle sizes using the types of processes known to those skilled in the art.

Tableting

The PF-06873600-containing composition (active layer) is prepared by mixing an entraining agent and the other excipients to form a uniform blend. To obtain a uniform blend, it is desirable to either wet or dry granulate or dry blend the components using the types of processes known to those skilled in the art.

The tablet core may be prepared by first placing a mixture of the active layer into a tablet press and then leveling the mixture by gentle compression. The sweller layer (i.e., water-swellable composition) is then placed on top of the PF-06873600-containing composition and compressed to complete formation of the bilayer tablet core. Alternatively, the water-swellable composition can be placed into the tablet press first, followed by the PF-06873600-containing composition. Tablet shapes may include any tablet shape known to those skilled in the art. Preferable tablet shapes include SRC (standard round concave), oval, modified oval, capsule, caplet, and almond. The respective amounts of PF-06873600-containing composition (active layer) and water- swellable composition (sweller layer) are chosen to provide satisfactory PF-06873600 release. When it is desired to provide a large PF-06873600 dose in a relatively small dosage size, it is desired to maximize the amount of the active layer comprising PF- 06873600 in the unit dosage form and minimize the amount of the sweller layer, while still obtaining good release performance. In the dosage forms of the present invention, when the water-swellable polymer in the sweller layer is only PEO, the PF-06873600- containing active layer of the composition may comprise from about 50 wt% to about 95 wt% of the tablet core (excluding the membrane coating), and preferably from about 60 wt% to about 80 wt% of the tablet core. In some embodiments, the active layer comprises about 66.7 wt% of the tablet core and the sweller layer comprises about 33.3 wt% of the tablet core.

The absolute value of the diameter and height of the tablets of the present invention can vary over a wide range.

The Coating

Following formation of the core, the semipermeable coating is applied. The coating should have high water permeability and a high strength, while at the same time be easily fabricated and applied. High water permeability is required to permit water to enter the core in sufficient volume. High strength is required to ensure the coating does not burst when the core swells as it imbibes water, leading to an uncontrolled delivery of the core contents. Finally, the coating must have high reproducibility and yield.

It is essential that the coating have at least one delivery port in communication with the interior and exterior of the coating for delivery of the PF-06873600-containing composition. Furthermore, the coating must be non-dissolving and non-eroding during release of the PF-06873600-containing composition, generally meaning that it be water- insoluble, such that PF-06873600 is substantially entirely delivered through the delivery port(s), in contrast to delivery via permeation through the coating.

Coatings with these characteristics can be obtained using hydrophilic polymers such as plasticized and unplasticized cellulose esters, ethers, and ester-ethers. Particularly suitable polymers include cellulose acetate (CA), cellulose acetate butyrate (CAB), and ethyl cellulose (EC). One set of polymers are cellulose acetates having acetyl contents of 25% to 42%. One typical polymer is CA having an acetyl content of about 40%. For example, CA 398-10 (Eastman Fine Chemicals, Kingsport, Tenn.) is reported to have an acetyl content of 39.8% and an average molecular weight of about 40,000 daltons. Another typical CA having an acetyl content of 39.8% is high molecular weight CA having an average molecular weight greater than about 45,000, and specifically, CA 398-30 (Eastman Fine Chemical) which is reported to have an average molecular weight of 50,000 daltons.

The process of coating is conducted in conventional fashion by first forming a coating solution and then coating by spraying, dipping, fluidized bed coating, or by pan coating. To accomplish this, a coating solution is formed comprising the polymer and a solvent. Typical solvents useful with the cellulosic polymers above 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% to 15 wt% of the polymer. The coating solution may further comprise a plasticizer. In some embodiments, the plasticizer is polyethylene glycol 3350 powder (with 100 ppm BHT), i.e., PEG 3350.

The coating solution may also include pore-formers or non-solvents in any amount as long as the polymer remains soluble at the conditions used to form the coating and as long as the coating remains water permeable and has sufficient strength. Pore-formers and their use in fabricating coatings are described in U.S. Pat. Nos. 5,698,220 and 5,612,059, the pertinent disclosures of which are incorporated herein by reference. The term "pore former," as used herein, refers to a material added to the coating solution that has low or no volatility relative to the solvent such that it remains as part of the coating following the coating process but that is sufficiently water swellable or water-soluble such that, in the aqueous use environment it provides a water-filled or water-swollen channel or "pore" to allow the passage of water, thereby enhancing the water permeability of the coating. Suitable pore formers include but are not limited to hydroxypropylcellulose (HPC), polyethylene glycol ("PEG"), PVP, and PEO. To obtain a combination of high water permeability and high strength when PEG or HPC are used as a pore former, the weight ratio of CA:PEG or CA:HPC should range from about 1 :1 to about 10:1 .

The addition of a non-solvent such as water to the coating solution may improve performance. 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 coating polymer or polymers in the solvent. In general, the function of the non-solvent is to impart porosity to the resulting coating. As described below, porous coatings have higher water permeability than an equivalent weight of a coating of the same composition that is not porous, and this porosity is indicated by a reduction in the density of the coating (mass/volume). Although not wishing to be bound by any particular mechanism of pore formation, it is generally believed that addition of a non-solvent imparts porosity to the coating during evaporation of solvent by causing the coating solution to undergo liquid and liquid phase separation prior to solidification. The suitability and amount of a particular candidate material can be evaluated for use as a non-solvent by progressively adding the candidate non-solvent to the coating solution until it becomes cloudy. If this does not occur at any addition level up to about 50 wt% of the coating solution, it generally is not appropriate for use as a non-solvent. When clouding is observed, termed the "cloud point," an appropriate level of non-solvent for maximum porosity is the amount just below the cloud point. For acetone solutions comprising 7 wt% CA and 3 wt% PEG, the cloud point is at about 23 wt% water. When lower porosities are desired, the amount of non solvent can be reduced as low as desired.

Suitable non-solvents are any materials that have appreciable solubility in the solvent and that lower the coating polymer solubility in the solvent. The preferred non solvent depends on the solvent and the coating polymer chosen. In the case of using a volatile polar coating solvent such as acetone, suitable non-solvents include water, glycerol, alcohols such as methanol or ethanol.

When incorporating antioxidants into the coating solution, a third solvent, such as an alcohol, may be required to ensure good dispersion of the antioxidant into the coating. Coatings formed from these coating solutions are generally porous. By "porous" is meant that the coating in the dry state has a density less than the density of the same material in a nonporous form. By "nonporous form" is meant a coating material formed by using a coating solution containing no non-solvent, or the minimal amount of non-solvent required to produce a homogeneous coating solution. The dry-state density of the coating can be calculated by dividing the coating weight (determined from the weight gain of the tablets before and after coating) by the coating volume (calculated by multiplying the coating thickness, as determined by optical or scanning electron microscopy, by the tablet surface area). The porosity of the coating is one of the factors that leads 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 generally should be present in an amount ranging from about 3 wt% to about 30 wt%, and frequently from about 5 wt% to about 10 wt% based on the weight of the uncoated core. A coating weight of at least about 5 wt%, is typically preferred for sufficient strength for reliable performance, although lower coating weights can be used to achieve higher water imbibing rates and, subsequently, higher release rates of the drug from the dosage form.

While porous coatings based on CA, PEG or HPC, and water described above translate to excellent results, other pharmaceutically acceptable materials could be used in the coating so long as the coating has the requisite combination of high water permeability, high strength, and ease of fabrication and application. Further, such coatings may be dense, porous, or "asymmetric," having one or more dense layers and one or more porous layers such as those disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220, the pertinent disclosures of which are incorporated herein by reference.

The coating must also contain at least one delivery port in communication with the interior and exterior of the coating to allow for release of the drug-containing composition to the exterior of the dosage form. The delivery port can range in size from about the size of the drug particles, and thus could be as small as 1 to 100 microns in diameter and may be termed pores, up to about 5000 microns in diameter. The shape of the port may be substantially circular, in the form of a slit, or other convenient shape to ease manufacturing and processing. The port(s) may be formed by post-coating mechanical or thermal means or with a beam of light (e.g., a laser), a beam of particles, or other high- energy source, or may be formed in situ by rupture of a small portion of the coating. Such rupture may be controlled by intentionally incorporating a relatively small weak portion into the coating. Delivery ports may also be formed in situ by erosion of a plug of water- soluble material or by rupture of a thinner portion of the coating over an indentation in the core. Delivery ports may be formed by coating the core such that one or more small regions remain uncoated. In addition, the delivery port can be a large number of holes or pores that may be formed during coating, as in the case of asymmetric membrane coatings, and of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220, the disclosures of which are incorporated by reference. When the delivery pathways are pores there can be a multitude of such pores that range in size from 1 micron to greater than 100 microns, or one or several larger pores, e.g. about 1000 microns. During operation, one or more of such pores may enlarge under the influence of the hydrostatic pressure generated during operation.

Preferred locations of the delivery port(s) include the face of the tablet and the tablet band. A more preferred location includes approximately the center of the tablet band for round, SRC-shaped 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 capsule, caplet, oval, or modified oval shaped tablets. A most preferred location of the delivery port(s) is the approximate center of the tablet band along the major axis of the tablet band for capsule, caplet, oval, or modified oval shaped tablets.

At least one delivery port should be formed on the side of coating that is adjacent to the active layer, so that the PF-06873600-containing composition will be extruded out of the delivery port by the swelling action of the water-swellable composition. It is recognized that some processes for forming delivery ports may also form holes or pores in the coating adjacent to the water-swellable composition. In some embodiments, the delivery port is a single hole with a diameter of 1000 ± 200 micron (0.8-1 .2 mm) drilled on the active layer side of the tablet face. The delivery port may be drilled to completely penetrate the coating across the delivery port diameter (depth of approximately 200 micron).

The coating may optionally include a port in communication with the water- swellable composition (sweller layer). Such a delivery port does not typically alter the PF- 06873600 release characteristics of the dosage form but may provide manufacturing advantages. In dosage forms where the delivery ports are drilled either mechanically or by laser, the tablet must be oriented so that at least one delivery port is formed in the coating adjacent to the PF-06873600-containing composition (i.e., the active layer). A colorant within the water-swellable composition may be used to orient the core dosage form during the drilling step in manufacture. By providing a delivery port on both faces of the dosage form, the need to orient the dosage form may be eliminated and the colorant may be removed from the water-swellable composition.

In another aspect, the API may be incorporated into a variation of the above disclosed osmotic delivery device, an asymmetric membrane technology (AMT). These devices have been disclosed in Herbig, et al., J. Controlled Release, 35, 1995, 127-136, and U.S. Pat. Nos. 5,612,059 and 5,698,220 as coatings in osmotic drug delivery systems. These AMT systems provide the general advantages of osmotic controlled release devices (reliable drug delivery independent of position in gastrointestinal tract), yet do not require the added manufacturing step of drilling a hole in the coating, as seen with a number of other osmotic systems. In the formation of these porous coatings, a water-insoluble polymer is combined with a water-soluble, pore-forming material. The mixture is coated onto an osmotic tablet core from a combination of water and solvent. As the coating dries, a phase inversion process occurs whereby a porous, asymmetric membrane is produced. The use of an AMT system for controlled release of a drug with similar physiochemical properties is described in US Patent Application Publication US2007/0248671 and herein incorporated as reference.

One aspect of the present invention provides a dosage form which comprises (a) a core containing PF-06873600 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and (b) at least one asymmetric membrane technology (AMT) coating wherein said coating comprises:

(i) one or more substantially water-insoluble polymers, and

(ii) one or more solid, water-soluble polymeric materials that do not contain amounts of hydrogen peroxide or formaldehyde greater than about 0.01 percent w:w after storage at 40 degrees C./75 percent RH for 12 weeks.

Water-insoluble polymers useful as AMT coatings are frequently formed from cellulose derivatives. A preferred water-insoluble component for use in AMT is cellulose acetate (CA). Particularly preferred cellulose acetates include those having an acetyl content of about 40 percent and a hydroxyl content of about 3.5 percent. Other cellulose derivatives include cellulose esters and ethers, namely the mono-, di- and triacyl esters wherein the acyl group consists of two to four carbon atoms and lower alkyl ethers of cellulose wherein the alkyl group has one to four carbon atoms. The cellulose esters can also be mixed esters, such as cellulose acetate butyrate, or a blend of cellulose esters. The same variations can be found in ethers of cellulose and include blends of cellulose esters and cellulose ethers. Other cellulose derivatives which can be used include cellulose nitrate, acetaldehyde dimethyl cellulose, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate dimethaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose acetate p-toluene sulfonate, cellulose cyanoacetates, cellulose acetate trimellitate, cellulose methacrylates and hydroxypropylmethylcellulose acetate succinate. Other materials also can be used, provided such materials are substantially water-insoluble, film-forming and safe to use in pharmaceutical applications.

Water-soluble polymers described herein as components of the semipermeable membranes include polymers having an average molecular weight between 2,000 and 100,000 daltons, and sometimes between 2,000 and 50,000 daltons. In some such embodiments, the water-soluble polymer is selected from the group consisting of water- soluble cellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch, polyacrylates, and polyvinyl alcohols. In some such embodiments, the water- soluble cellulose derivative is selected from the group consisting of hydroxypropylcellulose, hydroxy-propylmethylcellulose and hydroxyethyl-cellulose. In some embodiments, the water-soluble polymer comprises hydroxyethylcellulose, hydroxypropyl-cellulose or polyvinylalcohol.

In certain embodiments, the water-soluble polymeric material has a viscosity for a 5 percent w:w aqueous solution of less than 400 mPa s (millipascal second). In certain other embodiments, the solid, water-soluble, polymeric material has a viscosity for a 5 percent w:w aqueous solution of less than 300 mPa s. In other embodiments, the water- soluble, polymeric material has a softening temperature greater than 55 degrees C.

The water-soluble polymeric component of the present invention frequently comprises solid, polymeric materials that do not form hydrogen peroxide or formaldehyde upon storage for 12 weeks at 40 degrees C./75 percent relative humidity, in an amount greater than about 0.01 percent w/w (100 parts per million, ppm). In terms of water solubility, the solid polymeric water-soluble material preferentially has a water-solubility of greater than 0.5 mg/mL; more preferably, greater than 2 mg/mL; and still more preferably, greater than 5 mg/mL.

The solid polymeric water-soluble material has a melting or softening temperature above room temperature. Preferentially, the solid material has a melting or softening temperature above 30 degrees C.; more preferentially, above 40 degrees C.; and most preferentially, above 50 degrees C. Melting and softening points can be determined visually using a melting point apparatus, or alternatively, can be measured using differential scanning calorimetry (DSC), as is known in the art. The polymer can be either a homopolymer or a copolymer. Such polymers can be natural polymers, or be derivatives of natural products, or be entirely synthetic. The molecular weight of such materials is preferentially high enough to prevent migration and aid in film-forming, yet low enough to allow coating (as discussed below). The preferred molecular weight range for the present invention is therefore between 2000 and 50,000 daltons (weight average).

The tablet cores for the present invention can also employ solubilizing additives in the active layer and/or the sweller layer. Such additives may include pH-buffering additives to maintain the core at a pH wherein the active pharmaceutical ingredient has a sufficiently high solubility to be pumped out of the dosage form in solution. The active pharmaceutical ingredient can be present in the core at levels ranging from about 0.1 wt% to about 75 wt%. The core can contain osmotic agents which help to provide the driving force for drug delivery. Such osmotic agents include water-soluble sugars and salts. A particularly preferred osmotic agent is mannitol or sodium chloride.

The tablet core can also contain other additives in the active layer and/or the sweller layer to provide for such benefits as stability, manufacturability and system performance. Stabilizing excipients include pH-modifying ingredients, antioxidants, lubricants, tableting agents, chelating agents, and other such additives as is known in the art. Excipients that improve manufacturability include agents to help in flow, compression or extrusion. Flow can be helped by such additives as talc, stearates and silica. Flow is also improved by granulation of the drug and excipients, as is known in the art. Such granulations often benefit from the addition of binders such as hydroxypropylcellulose, starch and polyvinylpyrrolidone (povidone). Compression can be improved by the addition of diluents to the formulation that function as tableting agents. Examples of diluents include lactose, mannitol, microcrystalline cellulose and the like, as is known in the art. For cores produced by extrusion, the melt properties of the excipients can be important. Generally, it is preferable that such excipients have melting temperatures below about 100 degrees C. Examples of appropriate excipients for melt processes include esterified glycerins and stearyl alcohol. For compressed dosage forms, manufacturability can be improved by addition of lubricants. A particularly preferred lubricant is magnesium stearate.

Cores can be produced using standard tablet compression processes, as is known in the art. Such processes involve powders filling dies followed by compression using appropriate punches. Cores can also be produced by an extrusion process. Extrusion processes are especially well-suited to making small cores (multiparticulates). A preferred extrusion process is a melt-spray-congeal process as described in W02005/053653A1 , incorporated by reference. Cores can also be prepared by layering drug onto seed cores. Such seed cores are preferentially made of sugar or microcrystalline cellulose. Drug can be applied onto the cores by spraying, preferentially in a fluid bed operation, as is known in the art.

The PF-06873600 containing composition may further include solubility-enhancing agents or solubilizers that promote the aqueous solubility of the drug, present in an amount ranging from about 0 wt% to about 30 wt% of the MR composition. Solubilizers include organic acids and organic acid salts, partial glycerides, e.g., less than fully esterified derivatives of glycerin, including glycerides, monoglycerides, diglycerides, glyceride derivatives, polyethylene glycol esters, polypropylene glycol esters, polyhydric alcohol esters, polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitan esters, and carbonate salts.

Sustained Release - Matrix Systems (Tablets)

In another aspect, PF-06873600 or a pharmaceutically acceptable salt thereof may be incorporated into an erodible or non-erodible polymeric matrix tablet. By an erodible matrix is meant aqueous-erodible or water-swellable or aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution. When contacted with the aqueous use environment, the erodible polymeric matrix imbibes water and forms an aqueous-swollen gel or "matrix" that entraps the API. The aqueous-swollen matrix gradually erodes, swells, disintegrates, disperses or dissolves in the environment of use, thereby controlling the release of the drug to the environment of use. Examples of such dosage forms are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20 ^th Edition, 2000.

A key ingredient of the water-swollen matrix is the water-swellable polymer, erodible polymer, or soluble polymer, which may generally be described as an osmopolymer, hydrogel or water-swellable polymer. Such polymers may be linear, branched, or crosslinked. They may be homopolymers or copolymers. Exemplary polymers include naturally occurring polysaccharides such as chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, 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 cellulosics. By“cellulosics” is meant a cellulose polymer that has been modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form an ester-linked or an ether-linked substituent. For example, the cellulosic ethyl cellulose has an ether linked ethyl substituent attached to the saccharide repeat unit, while the cellulosic cellulose acetate has an ester linked acetate substituent.

Cellulosics for the erodible matrix comprise aqueous-soluble and aqueous- erodible cellulosics such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethylcellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC). A preferred class of cellulosics comprises various grades of low viscosity (MW less than or equal to 50,000 daltons) and high viscosity (MW greater than 50,000 daltons) HPMC. Commercially available low viscosity HPMC polymers include the Dow METHOCEL™ series E3, E5, E15LV, E50LV and K100LV, while high viscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M; especially preferred in this group are the METHOCEL™ K series. Other commercially available types of HPMC include the Shin Etsu METOLOSE™ 90SH series. In some embodiments, the HPMC has a low viscosity, meaning that the viscosity of a 2% (w/v) solution of the HPMC in water is less than about 120 cp. A preferred HPMC is one in which the viscosity of a 2% (w/v) solution of the HPMC in water ranges from 80 to 120 cp (such as METHOCEL™ K100LV).

Other materials useful as the erodible matrix material include, but are not limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, New Jersey) and other acrylic acid derivatives such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)- methacrylate, and (trimethylaminoethyl) methacrylate chloride.

The erodible matrix polymer may also contain additives and excipients known in the pharmaceutical arts, including osmopolymers, osmogents, solubility-enhancing or - retarding agents and excipients that promote stability or processing of the dosage form.

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

In some embodiments, the matrix of the dosage form remains substantially intact during the period of drug release. In some embodiments, the pharmaceutically acceptable carrier comprising the matrix material is selected from the group consisting of waxes, long chain alcohols, fatty acid esters, glycolized fatty acid esters, phosphoglycerides, polyoxyethylene alkyl ethers, long chain carboxylic acids, sugar alcohols, and mixtures thereof.

In other embodiments, the outside surface of the matrix is covered with an enteric coating. The matrix may be formed as a melt-congealed core.

In other embodiments, the matrix of the dosage form comprises hydroxypropyl methylcellulose, polyethylene oxide) or polyacrylic acid.

In other embodiments, the API is embedded in a matrix which releases the drug substance by eroding.

Sustained Release - Matrix Systems (Multiparticulates)

In another aspect, the modified release unit dosage form may be prepared in the form of a multiparticulate comprising particles, which particles are independently coated with a membrane which limits the release rate of the API by diffusion.

In one embodiment, a matrix multiparticulate comprises a plurality of drug particles, each particle comprising a mixture of the API with one or more excipients selected to form a matrix capable of limiting the dissolution rate of the drug into an aqueous medium.

Matrix materials useful for this embodiment are generally water-insoluble materials such as waxes, cellulose, or other water-insoluble polymers. If needed, the matrix materials may optionally be formulated with water-soluble materials which can be used as binders or as permeability-modifying agents. Matrix materials useful for the manufacture of these dosage forms include microcrystalline cellulose such as Avicel (registered trademark of FMC Corp., Philadelphia, Pa.), including grades of microcrystalline cellulose to which binders such as hydroxypropyl methyl cellulose have been added, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax, and the like, as well as synthetic polymers such as poly(vinyl chloride), poly(vinyl acetate), copolymers of vinyl acetate and ethylene, polystyrene, and the like. Water soluble binders or release modifying agents which can optionally be formulated into the matrix include water-soluble polymers such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, poly (N-vinyl-2-pyrrolidinone) (PVP), polyethylene oxide) (PEO), poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, and other such natural and synthetic materials. In addition, materials which function as release-modifying agents include water-soluble materials such as sugars or salts. Preferred water-soluble materials include lactose, sucrose, glucose, and mannitol, as well as HPC, HPMC, and PVP.

A process for manufacturing matrix multiparticulates is the extrusion/spheronization process. For this process, the drug may be wet-massed with a binder, extruded through a perforated plate or die, and placed on a rotating disk. The extrudate ideally breaks into pieces which are rounded into spheres, spheroids, or rounded rods on the rotating plate. Another process and composition for this method involves using water to wet-mass a blend comprising about 20% to about 75% of microcrystalline cellulose blended with, correspondingly, about 80% to about 25% of the drug.

Another process for manufacturing matrix multiparticulates is the preparation of wax granules. In this process, a desired amount of API is stirred with liquid wax to form a homogeneous mixture, cooled and then forced through a screen to form granules. Preferred matrix materials are waxy substances. Some preferred waxy substances are hydrogenated castor oil and carnauba wax and stearyl alcohol.

A further process for manufacturing matrix multiparticulates involves using an organic solvent to aid mixing of the API with the matrix material. This technique can be used when it is desired to utilize a matrix material with an unsuitably high melting point that, if the material were employed in a molten state, would cause decomposition of the drug or of the matrix material, or would result in an unacceptable melt viscosity, thereby preventing mixing of the drug with the matrix material. The API and matrix material may be combined with a modest amount of solvent to form a paste, and then forced through a screen to form granules from which the solvent is then removed. Alternatively, the API and matrix material may be combined with enough solvent to completely dissolve the matrix material and the resulting solution (which may contain solid drug particles) spray dried to form the 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 typically employed for the process include acetone, ethanol, isopropanol, ethyl acetate, and mixtures of two or more.

In one embodiment, the matrix multiparticulates are formed by the melt spray congeal process. The melt-congeal core comprises a matrix material. The matrix material serves two functions. First, the matrix material allows formation of relatively smooth, round cores that are amenable to coating. Second, the matrix material binds the optional excipients and/or drugs that may be incorporated into the core. The matrix material has the following physical properties: a sufficiently low viscosity in the molten state to form multiparticulates, as detailed below; and rapidly congeals to a solid when cooled below its melting point. For those multiparticulates incorporating drug in the core, the matrix preferably has a melting point below that of the melting point or decomposition point of the drug and does not substantially dissolve the drug.

The melt-congeal cores consist essentially of a continuous phase of matrix material and optionally other excipients, with optional drug particles and optional swelling agent particles encapsulated within. Because of this, a sufficient amount of matrix material must be present to form smooth cores that are large enough to coat. In the case of cores containing solid particles, such as drug or swelling agent, the core must contain a sufficient amount of matrix material to encapsulate the drug and swelling agent to form relatively smooth and spherical cores, which are more easily coated by conventional spray-coating processes than irregularly-shaped ones. The matrix material may be present in the core from at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, and up to about 100 wt% based on the mass of the uncoated core.

To form small, smooth round cores, the matrix material must be capable of being melted and then atomized. The matrix material or mixture of materials is solid at 25 degrees C. Flowever, the matrix material melts, or is capable of melting with the addition of an optional processing aid, at a temperature of less than 200 degrees centigrade so as to be suitable for melt-congeal processing described below. Preferably, the matrix material has a melting point between 50 degrees C and 150 ^c C. Although the term "melt" generally refers to the transition of a crystalline material from its crystalline to its liquid state, which occurs at its melting point, and the term "molten" generally refers to such a crystalline material in its fluid state, as used herein, the terms are used more broadly. In the case of "melt," the term is used to refer to the heating of any material or mixture of materials sufficiently that it becomes fluid in the sense that it may be pumped or atomized in a manner similar to a crystalline material in the fluid state. Likewise, "molten" refers to any material or mixture of materials that is in such a fluid state.

The matrix material is selected from the group consisting of waxes, long chain alcohols (Ci2 or greater), fatty acid esters, glycolized fatty acid esters, phosphoglycerides, polyoxyethylene alkyl ethers, long chain carboxylic acids (C12 or greater), sugar alcohols, and mixtures thereof. Exemplary matrix materials include highly purified forms of waxes, such as Camauba 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-, di-, and tribehenate, glyceryl tristearate, glyceryl tripalmitate and hydrogenated vegetable oils, including hydrogenated cottonseed oil; glycolized fatty acid esters, such as polyethylene glycol stearate and polyethylene glycol distearate; polyoxyethylene alkyl ethers; polyethoxylated castor oil derivatives; long-chain carboxylic acids such as stearic acid; and sugar alcohols such as mannitol and erythritol. The matrix material may comprise mixtures of materials, such as mixtures of any of the foregoing.

The core may also contain a variety of other excipients, present in the core in an amount of from 0 wt% to 40 wt%, based upon the mass of the uncoated core. One preferred excipient is a dissolution enhancer, which may be used to increase the rate of water uptake by the core and consequent expansion of the swelling agent. The dissolution enhancer is a different material than the matrix material. The dissolution enhancer may be in a separate phase or a single phase with the matrix material. Preferably, 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 which allow water to more rapidly enter the core. In general, dissolution enhancers are amphiphilic compounds and are generally more hydrophilic than the 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 mixtures thereof. One surfactant-type dissolution-enhancer is a poloxambetar (commercially available as the LUTROL or PLURONIC series from BASF Corp.).

The core may also contain other optional excipients, such as agents that inhibit or delay the release of drug from the multiparticulates. Such dissolution- inhibiting agents are generally hydrophobic and include dialkylphthalates such as dibutyl phthalate, and hydrocarbon waxes, such as microcrystalline wax and paraffin wax. Another useful class of excipients comprises materials that may be used to adjust the viscosity of the molten feed used to form the cores. Such viscosity- adjusting excipients will generally make up 0 wt% to 25 wt% of the core. The viscosity of the molten feed is a key variable in obtaining cores with a narrow particle size distribution. For example, when a spinning-disk atomizer is employed, it is preferred that the viscosity of the molten mixture be at least about 1 cp and less than about 10,000 cp, preferably at least 50 cp and less than about 1000 cp. If the molten mixture has a viscosity outside these ranges, a viscosity-adjusting agent can be added to obtain a molten mixture within the viscosity range. Examples of viscosity- reducing excipients include stearyl alcohol, cetyl alcohol, low molecular weight polyethylene glycol (i.e., less than about 1000 daltons), isopropyl alcohol, and water. Examples of viscosity-increasing excipients include microcrystalline wax, paraffin wax, synthetic wax, high molecular weight polyethylene glycols (i.e., greater than about 5000 daltons), ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, silicon dioxide, microcrystalline cellulose, magnesium silicate, sugars, and salts.

For those embodiments containing a drug in the core, other excipients may be added to adjust the release characteristics of the drug from the cores. For example, an acid or base may be included in the composition to modify the rate at which drug is released in an aqueous use environment. Examples of acids or bases that can be included in the composition include 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 citrate dihydrate. Such excipients may make up 0 wt% to 25 wt% of the core, based on the total mass of the core.

Still other excipients may be added to improve processing, such as excipients to reduce the static charge on the cores or to reduce the melting temperature of the matrix material. Examples of such anti-static agents include talc and silicon dioxide. Flavorants, colorants, and other excipients may also be added in their usual amounts for their usual purposes. Such excipients typically may make up 0 wt% to 35 wt% of the core, based on the total mass of the core.

The multiparticulates are made via a melt-congeal process comprising the steps: (a) forming a molten mixture comprising the drug, the glyceride (or other waxes), and any release modifying agents; (b) delivering the molten mixture of step (a) to an atomizing means to form droplets from the molten mixture; and (c) congealing the droplets from step (b) to form multiparticulates.

The processing conditions are typically chosen to maintain the crystallinity of the drug. The temperature of the molten mixture is kept below the melting point of the drug. Preferably, at least 70 wt% of the drug remains crystalline within the molten feed, more preferably, at least 80 wt% and most preferably at least 90 wt%.

The term "molten mixture" as used herein refers to a mixture of drug, glyceride (or other waxes), and any release modifying agents required heated sufficiently that the mixture becomes sufficiently fluid that the mixture may be formed into droplets or atomized. Atomization of the molten mixture may be carried out using any of the atomization methods described below. Generally, 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 that exerted by a centrifugal or spinning-disk atomizer. Thus, the drug/glyceride/release-modifying agent mixture may be considered "molten" when any portion of the drug/glyceride/ release-modifying agent mixture becomes sufficiently fluid that the mixture as a whole may be atomized. Generally, a mixture is sufficiently fluid for atomization when the viscosity of the molten mixture is less than about 20,000 cp. Often, the mixture becomes molten 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 sharp 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 therefore often a suspension of solid particles in a fluid matrix. In one preferred embodiment, the molten mixture comprises a mixture of substantially crystalline drug particles suspended in a glyceride/release-modifying agent mixture that is substantially fluid. In such cases, a portion of the drug may be dissolved in the glyceride/release modifying agent mixture and a portion of the glyceride/ release-modifying agent mixture may remain solid.

Virtually any process may be used to form the molten mixture. One method involves heating the glyceride/release-modifying agent mixture in a tank until it is fluid and then adding the drug to the molten glyceride/release-modifying agent mixture. Generally, the glyceride/ release-modifying agent mixture is heated to a temperature of about 10 degrees C. or more above the temperature at which it becomes fluid. When one or more of the glyceride/release-modifying agent components is crystalline, this is generally about 10 degrees C. or more above the melting point of the lowest melting point material of the mixture. The process is carried out so that at least a portion of the feed remains fluid until atomized. Once the glyceride/release-modifying agent mixture has become fluid, the drug may be added to the fluid carrier or "melt." Alternatively, the drug, the glyceride (or other wax), and the release-modifying agent may be added to the tank and the mixture heated until the mixture has become fluid.

Once the glyceride/release-modifying agent mixture has become fluid and the drug has been added, the molten mixture is mixed to ensure the drug is uniformly distributed therein. Mixing is generally done using mechanical means, such as overhead mixers, magnetically driven mixers and stir bars, planetary mixers, and homogenizers. Optionally, the contents of the tank can be pumped out of the tank and through an in-line, static mixer or extruder and then returned to the tank. The amount of shear used to mix the molten feed should be sufficiently high to ensure uniform distribution of the drug in the molten carrier. The amount of shear is kept low enough so the form of the drug does not change, i.e., to minimize an increase in the amount of amorphous drug or a change in the crystalline form of the drug. It is also preferred that the shear not be so high as to reduce the particle size of the drug crystals. The molten mixture can be mixed from a few minutes to several hours, the mixing time being dependent on the viscosity of the feed and the solubility of drug and any optional excipients in the carrier.

An alternative method of preparing the molten mixture is to use two tanks, melting either the glyceride (or other waxes) or the release-modifying agent in one tank and the other component in another tank. The drug is added to one of these tanks and mixed as described above. The two melts are then pumped through an in-line static mixer or extruder to produce a single molten mixture that is directed to the atomization process described below.

Another method that can be used to prepare the molten mixture is to use a continuously stirred tank system. In this system, the drug, glyceride (or other waxes), and release-modifying agent are continuously added to a heated tank equipped with means for continuous stirring, while the molten feed is continuously removed from the tank. The contents of the tank are heated such that the temperature of the contents is about 10 degrees C. or more above 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 removed from the tank has the desired composition. The drug is typically added in solid form and may be pre-heated prior to addition to the tank. The glyceride (or other waxes), and release-modifying agent may also be preheated or even pre-melted prior to addition to the continuously stirred tank system.

In another method for forming the molten mixture is by an extruder. By "extruder" is meant a device or collection of devices that creates a molten extrudate by heat and/or shear forces and/or produces a uniformly mixed extrudate from a solid and/or liquid (e.g., molten) feed. Such devices include, but are not limited to single-screw extruders; twin- screw extruders, including co-rotating, counter-rotating, intermeshing, and non intermeshing extruders; multiple screw extruders; ram extruders, consisting of a heated cylinder and a piston for extruding the molten feed; gear-pump extruders, consisting of a heated gear pump, generally counter-rotating, that simultaneously heats and pumps the molten feed; and conveyer extruders. Conveyer extruders comprise a conveyer means for transporting solid and/or powdered feeds, such, such as a screw conveyer or pneumatic conveyer, and a pump.

At least a portion of the conveyer means is heated to a sufficiently high temperature to produce the molten mixture. The molten mixture may optionally be directed to an accumulation tank, before being directed to a pump, which directs the molten mixture to an atomizer. Optionally, an in-line mixer may be used before or after the pump to ensure the molten mixture is substantially homogeneous. In each of these extruders the molten mixture is mixed to form a uniformly mixed extrudate. Such mixing may be accomplished by various mechanical and processing means, including mixing elements, kneading elements, and shear mixing by backflow. Thus, in such devices, the composition is fed to the extruder, which produces a molten mixture that can be directed to the atomizer.

In one embodiment, the composition is fed to the extruder in the form of a solid powder. The powdered feed can be prepared using methods well known in the art for obtaining powdered mixtures with high content uniformity. Generally, it is desirable that the particle sizes of the drug, glyceride (or other waxes), and release-modifying agent be similar to obtain a substantially uniform blend. However, this is not essential to the successful practice of the invention.

An example of a process for preparing a substantially uniform blend is as follows. First, the glyceride (or other waxes) and release-modifying agent are milled so that their particle sizes are about the same as that of the drug; next, the drug, glyceride (or other waxes), and release-modifying agent are blended in a V-blender for 20 minutes; the resulting blend is then de-lumped to remove large particles; the resulting blend is finally blended for an additional 4 minutes. In some cases, it is difficult to mill the glyceride (or other waxes), and release-modifying agent to the desired particle size since many of these materials tend to be waxy substances and the heat generated during the milling process can gum up the milling equipment. In such cases, small particles of the glyceride (or other waxes), and release-modifying agent can be formed using a melt- or spray- congeal process, as described below. The resulting congealed particles of glyceride (or other waxes), and release-modifying agent can then be blended with the drug to produce the feed for the extruder. Another method for producing the feed to the extruder is to melt the glyceride (or other waxes) and release-modifying agent in a tank, mix in the drug as described above for the tank system, and then cool the molten mixture, producing a solidified mixture of drug and carrier. This solidified mixture can then be milled to a uniform particle size and fed to the extruder.

A two-feed extruder system can also be used to produce the molten mixture. In this system the drug, glyceride (or other waxes) and release-modifying agent, all in powdered form, are fed to the extruder through the same or different feed ports. In this way, the need for blending the components is eliminated.

Alternatively, the glyceride (or other waxes) and release-modifying agent in powder form may be fed to the extruder at one point, allowing the extruder to melt the glyceride (or other waxes) and release-modifying agent. The drug is then added to the molten glyceride (or other waxes) and release-modifying agent through a second feed delivery port part way along the length of the extruder, thus minimizing the contact time of the drug with the molten glyceride (or other waxes) and release-modifying agent. The closer the second feed delivery port is to the extruder exit, the lower is the residence time of drug in the extruder. Multiple-feed extruders can be used when optional excipients are included in the multiparticulate.

In another method, the composition is in the form of large solid particles or a solid mass, rather than a powder, when fed to the extruder. For example, a solidified mixture can be prepared as described above and then molded to fit into the cylinder of a ram extruder and used directly without milling.

In another method, the glyceride (or other waxes) and release-modifying agent can be first melted in, for example, a tank, and fed to the extruder in molten form. The drug, typically in powdered form, may then be introduced to the extruder through the same or a different delivery port used to feed 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 contact of the drug with the molten glyceride (or other waxes) and release-modifying agent. In each of the above methods, the extruder should be designed such that it produces a molten mixture with the drug crystals uniformly distributed in the glyceride/release-modifying agent mixture. Generally, the temperature of the extrudate should be about 10 degrees C. or more above the temperature at which the drug and carrier mixture becomes fluid. The various zones in the extruder should be heated to appropriate temperatures to obtain the desired extrudate temperature as well as the desired degree of mixing or shear, using procedures well known in the art. As discussed above for mechanical mixing, a minimum shear should be used to produce a uniform molten mixture, such that the crystalline form of the drug is unchanged, and dissolution or formation of amorphous drug is minimized.

The feed is preferably molten prior to congealing for at least 5 seconds, more preferably at least 10 seconds, and most preferably at least 15 seconds, to ensure adequate homogeneity of the drug/glyceride/release-modifying agent melt. It is also preferred that the molten mixture remain molten for no more than about 20 minutes to limit exposure of the drug to the molten mixture. As described above, depending on the reactivity of the chosen glyceride/release-modifying agent mixture, it may be preferable to further reduce the time that the mixture is molten to well below 20 minutes to limit drug degradation to an acceptable level. In such cases, such mixtures may be maintained in the molten state for less than 15 minutes, and in some cases, even less than 10 minutes. When an extruder is used to produce the molten feed, the times above refer to the mean time from when material is introduced to the extruder to when the molten mixture is congealed. Such mean times can be determined by procedures well known in the art. In one exemplary method, a small amount of dye or other similar compound is added to the feed while the extruder is operating under nominal conditions. Congealed multiparticulates are then collected over time and analyzed for the dye, from which the mean time is determined.

Once the molten mixture has been formed, it is delivered to an atomizer that breaks the molten feed into small droplets. Virtually any method can be used to deliver the molten mixture to the atomizer, including the use of pumps and various types of pneumatic devices (e.g., pressurized vessels, piston pots). When an extruder is used to form the molten mixture, the extruder itself can be used to deliver the molten mixture to the atomizer. Typically, the molten mixture is maintained at an elevated temperature while delivering the mixture to the atomizer to prevent solidification of the mixture and to keep the molten mixture flowing.

Generally, atomization occurs in one of several ways, including (1 ) by "pressure" or single-fluid nozzles; (2) by two-fluid nozzles; (3) by centrifugal or spinning-disk atomizers, (4) by ultrasonic nozzles; and (5) by mechanical vibrating nozzles. Detailed descriptions of atomization processes can be found in Lefebvre, Atomization and Sprays (1989) or in Perry's Chemical Engineers' Handbook (7th Ed. 1997). Preferably, a centrifugal or spinning-disk atomizer is used, such as the FX1 100-mm rotary atomizer manufactured by Niro A/S (Soeborg, Denmark).

Once the molten mixture has been atomized, the droplets are congealed, typically by contact with a gas or liquid at a temperature below the solidification temperature of the droplets. Typically, it is desirable that the droplets are congealed in less than about 60 seconds, preferably in less than about 10 seconds, more preferably in less than about 1 second. Often, congealing at ambient temperature results in sufficiently rapid solidification of the droplets. However, the congealing step often occurs in an enclosed space to simplify collection of the multiparticulates. In such cases, the temperature of the congealing media (either gas or liquid) will increase over time as the droplets are introduced into the enclosed space, potentially effecting the formation of the multiparticulates or the chemical stability of the drug. Thus, a cooling gas or liquid is often circulated through the enclosed space to maintain a constant congealing temperature. When it is desirable to minimize the amount of time the drug is exposed to high temperatures, e.g., to prevent degradation, the cooling gas or liquid can be cooled to below ambient temperature to promote rapid congealing, thus minimizing formation of degradants.

Following formation of the multiparticulates, it may be desired to post-treat the multiparticulates to improve drug crystallinity and/or the stability of the multiparticulate.

The multiparticulates may also be mixed or blended with one or more pharmaceutically acceptable materials to form a suitable dosage form. Suitable dosage forms include tablets, capsules, sachets, oral powders for constitution, and the like. Following formation of the melt spray congeal multiparticulates, the multiparticulates may optionally be coated with an additional exterior coating. The exterior coating may be any conventional coating, such as a protective film coating, a coating to provide delayed or modified release of the drug, or to provide taste-masking.

In one embodiment, the coating is an enteric coating to provide delayed release of the drug. By "enteric coating" is meant an acid resistant coating that remains intact and does not dissolve at pH of less than about 4. The enteric coating surrounds the multiparticulate so that the solid amorphous dispersion layer does not dissolve or erode in the stomach. The enteric coating may include an enteric coating polymer. Enteric coating polymers are generally polyacids having a pK _a of about 3 to 5. Examples of enteric coating polymers include: cellulose derivatives, such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate succinate, carboxy methyl ethyl cellulose, methylcellulose phthalate, and ethylhydroxy 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-octyl acrylate copolymer; and styrene-maleic mono-ester copolymer. These may be used either alone or in combination, or together with other polymers than those mentioned above.

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

The exterior coatings may include conventional 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 anti-tack agents, glidants, etc. For plasticizers, triethyl citrate, coconut oil and dibutyl sebacate are particularly preferred.

Exterior coatings can be formed using solvent-based and hot-melt coating processes. In solvent-based processes, the coating is made by first forming a solution or suspension comprising the solvent, the coating material and optional coating additives. The coating materials may be completely dissolved in the coating solvent, or only dispersed in the solvent as an emulsion or suspension or a combination of the two. Latex dispersions are an example of an emulsion or suspension that may be useful as in a solvent-based coating process. In one aspect, the solvent is a liquid at room temperature.

Coating may be conducted by conventional techniques, such as by pan coaters, rotary granulators and fluidized bed coaters such as top-spray, tangential- spray or bottom-spray (Wurster coating). A top-spray method can also be used to apply the coating. In this method, coating solution is sprayed down onto the fluidized cores. The solvent evaporates from the coated cores and the coated cores are re-fluidized in the apparatus. Coating continues until the desired coating thickness is achieved. Compositions and methods for making the multiparticulates of this embodiment are detailed in the following US Patent Applications, US 2005-0181062, US 2005-0181062, US 2008-0199527, US 2005-0186285A1 which are herein incorporated as reference in their entirety.

The multiparticulates of the invention generally are of a mean diameter from about 40 micron to about 3,000 micron, with a preferred range of about 50 micron to about 1 ,000 micron, and most preferably from about 100 micron to about 300 micron. While the multiparticulates can have any shape and texture, it is preferred that they be spherical, with a smooth surface texture. These physical characteristics of the multiparticulates improve their flow properties, permit them to be uniformly coated (if desired). The multiparticulates of the present invention are particularly suitable for controlled release or delayed release or any combination of these two release profiles when introduced to a use environment. As used herein, a "use environment" can be either the in vivo environment of the gastrointestinal (Gl) tract or the in vitro dissolution tests described herein. Information about in vivo release rates can be determined from the pharmacokinetic profile using standard deconvolution or Wagner-Nelson treatment of the data which should be readily known to those skilled in the art.

Once the matrix multiparticulates are formed through methods described above, they may be blended with compressible excipients such as lactose, microcrystalline cellulose, dicalcium phosphate, and the like and the blend compressed to form a tablet or capsule. Disintegrants such as sodium starch glycolate or crosslinked poly(vinyl pyrrolidone) are also usefully employed. Tablets or capsules prepared by this method disintegrate when placed in an aqueous medium (such as the Gl tract), thereby exposing the multiparticulate matrix which releases the drug therefrom.

Other conventional formulation excipients may be employed in the controlled release portion of the invention, including those excipients known in the art, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 ^th edition (2000). Generally, excipients such as surfactants, pH modifiers, fillers, matrix materials, complexing agents, solubilizers, pigments, lubricants, glidants, flavorants, and so forth may be used for customary purposes and in typical amounts without adversely affecting the properties of the compositions.

Example matrix materials, fillers, or diluents include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible 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, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.

Sustained Release - Reservoir Systems

Another class of modified release dosage forms includes membrane-moderated or reservoir systems. In this class, a reservoir of the drug substance is surrounded by a rate-limiting membrane. The drug traverses the membrane by mass transport mechanisms well known in the art, including but not limited to dissolution in the membrane followed by diffusion across the membrane or diffusion through liquid-filled pores within the membrane. These individual reservoir system dosage forms may be large, as in the case of a tablet containing a single large reservoir, or multiparticulate, as in the case of a capsule containing a plurality of reservoir particles, each individually coated with a membrane. The coating can be non-porous, yet permeable to the drug (for example PF-06873600 may diffuse directly through the membrane), or it may be porous. As with other embodiments of this invention, the particular mechanism of transport is not believed to be critical.

In some embodiment, the reservoir of the API is encased in a membrane which limits the release rate of the drug by diffusion.

Sustained release coatings as known in the art may be employed to fabricate the membrane, especially polymer coatings, such as a cellulose ester or ether, 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 operation may be conducted in standard equipment such as a fluid bed coater, a Wurster coater, or a rotary bed coater.

If desired, the permeability of the coating may be adjusted by blending of two or more materials. A useful process for tailoring the porosity of the coating comprises adding a pre-determined amount of a finely-divided water-soluble material, such as sugars or salts or water-soluble polymers to a solution or dispersion (e.g., an aqueous latex) of the membrane-forming polymer to be used. When the dosage form is ingested into the aqueous medium of the Gl tract, these water-soluble membrane additives are leached out of the membrane, leaving pores which facilitate release of the drug. The membrane coating can also be modified by the addition of plasticizers, as known in the art.

A useful variation of the process for applying a membrane coating comprises dissolving the coating polymer in a mixture of solvents chosen such that as the coating dries, a phase inversion takes place in the applied coating solution, resulting in a membrane with a porous structure. Examples of this type of coating system are given in European Patent Specification 0 357 369 B1 , published Mar. 7, 1990, herein incorporated by reference.

The morphology of the membrane is not of critical importance so long as the permeability characteristics enumerated herein are met. The membrane can be amorphous or crystalline. It can have any category of morphology produced by any particular process and can be, for example, an interfacially-polymerized membrane (which comprises a thin rate-limiting skin on a porous support), a porous hydrophilic membrane, a porous hydrophobic membrane, a hydrogel membrane, an ionic membrane, and other such materials which are characterized by controlled permeability to PF-06873600.

A useful reservoir system embodiment is a capsule having a shell comprising the material of the rate-limiting membrane, including any of the membrane materials previously discussed, and filled with a drug composition. A particular advantage of this configuration is that the capsule may be prepared independently of the drug composition, thus process conditions that would adversely affect the drug can be used to prepare the capsule. One embodiment is a capsule having a shell made of a porous or a permeable polymer made by a thermal forming process. Another embodiment is a capsule shell in the form of an asymmetric membrane; e.g., a membrane that has a thin skin on one surface and most of whose thickness is constituted of a highly permeable porous material. A process for preparation of asymmetric membrane capsules comprises a solvent exchange phase inversion, wherein a solution of polymer, coated on a capsule shaped mold, is induced to phase-separate by exchanging the solvent with a-miscible non-solvent. Examples of asymmetric membranes useful in this invention are disclosed in the aforementioned European Patent Specification 0 357 369 B1 .

Another embodiment of the class of reservoir systems comprises a multiparticulate wherein each particle is coated with a polymer designed to yield modified release of the API. The multiparticulate particles each comprise the drug and one or more excipients as needed for fabrication and performance. The size of individual particles, as previously mentioned, is generally between about 50 micron and about 3 mm, preferably between about 100 micron and 400 micron, although beads of a size outside this range may also be useful. In general, the beads comprise the API and one or more binders. As it is generally desirable to produce dosage forms which are small and easy to swallow, beads which contain a high fraction of drug relative to excipients are preferred. Binders useful in fabrication of these beads include microcrystalline cellulose (e.g., Avicel.RTM., FMC Corp.), hydroxypropyl cellulose (FIPC), hydroxypropyl methyl cellulose (FIPMC), and related materials or combinations thereof. In general, binders which are useful in granulation and tableting, such as starch, pregelatinized starch, and poly (N-vinyl-2- pyrrolidinone) (PVP) may also be used to form multiparticulates.

Reservoir system multiparticulates may be prepared using techniques known to those skilled in the art, including, but not limited to, the techniques of extrusion and spheronization, wet granulation, fluid bed granulation, and rotary bed granulation. In addition, the beads may also be prepared by building the API composition (drug plus excipients) up on a seed core (such as a non-pareil seed) by a drug-layering technique such as powder coating or by applying the drug composition by spraying a solution or dispersion of API in an appropriate binder solution onto seed cores in a fluidized bed such as a Wurster coater or a rotary processor. An example of a suitable composition and method is to spray a dispersion of a drug/hydroxypropylcellulose composition in water. Advantageously, the drug can be loaded in the aqueous composition beyond its solubility limit in water.

A method for manufacturing the multiparticulate cores of this embodiment is the extrusion/spheronization process, as previously discussed for matrix multiparticulates. A representative process and composition for this method involves using water to wet-mass blend about 5% to about 75% of microcrystalline cellulose with correspondingly about 95% to about 25% of drug. In another embodiment, the process involves the use of water to wet-mass blend of about 5% to about 30% of microcrystalline cellulose with correspondingly about 5% to about 70% PF-06873600.

A modified release coating as known in the art, especially polymer coatings, may be employed to fabricate the membrane, as previously discussed for reservoir systems. Suitable and preferred polymer coating materials, equipment, and coating methods also include those previously discussed.

The rate of drug release from the coated multiparticulates can also be controlled by factors such as the composition and binder content of the drug-containing core, the thickness and permeability of the coating, and the surface-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, whereas increasing the permeability of the coating or the surface-to-volume ratio of the multiparticulates will increase the release rate. If desired, the permeability of the coating may be adjusted by blending of two or more materials. A useful series of coatings comprises mixtures of water-insoluble and water-soluble polymers, for example, ethylcellulose and hydroxypropyl methylcellulose, respectively. A useful modification to the coating is the addition of finely-divided water-soluble material, such as sugars or salts. When placed in an aqueous medium, these water-soluble membrane additives are leached out of the membrane, leaving pores which facilitate delivery of the drug. The membrane coating may also be modified by the addition of plasticizers, as is known to those skilled in the art. Another useful variation of the membrane coating utilizes a mixture of solvents chosen such that as the coating dries, a phase inversion takes place in the applied coating solution, resulting in a membrane with a porous structure.

Bursting Osmotic Beads and Cores (Pulsatile Delivery)

In a further embodiment ("bursting osmotic core device"), the drug is incorporated in an osmotic bursting device which comprises a tablet core or bead core containing the API and, optionally, one or more osmogents. Devices of this type have been generally disclosed in Baker, U.S. Pat. No. 3,952,741 , which is incorporated herein by reference. Examples of osmogents are sugars such as glucose, sucrose, mannitol, lactose, and the like; and salts such as sodium chloride, potassium chloride, sodium carbonate, and the like; water-soluble acids such as tartaric acid, fumaric acid, and the like. The API- containing tablet core or bead core is coated with a polymer which forms a semipermeable membrane, that is, a membrane which is permeable to water but is substantially impermeable to the drug. Examples of polymers which provide a semipermeable membrane are cellulose acetate, cellulose acetate butyrate, and ethylcellulose, preferably cellulose acetate. The semipermeable coating membrane may alternatively be composed of one or more waxes, such as insect and animal waxes such as beeswax, and vegetable waxes such as carnauba wax and hydrogenated vegetable oils. A melt mixture of a polyethylene glycol, e.g., polyethylene glycol-6000, and a hydrogenated oil, e.g., hydrogenated castor oil, may be used as a coating, as described for isoniazid tablets by Yoshino (Capsugel Symposia Series; Current Status on Targeted Drug Delivery to the Gastrointestinal Tract; 1993; pp.185-190). Some preferred semipermeable coating materials are cellulose esters and cellulose ethers, polyacrylic acid derivatives such as polyacrylates and polyacrylate esters, and polyvinyl alcohols and polyalkenes such as ethylene vinyl alcohol copolymer. Other semipermeable coating materials are cellulose acetate and cellulose acetate butyrate.

When a coated tablet or bead of the "bursting osmotic core" embodiment of this invention is placed in an aqueous environment of use, water passes through the semipermeable membrane into the core, dissolving a portion of the drug and osmogent, generating a colloidal osmotic pressure which results in bursting of the semipermeable membrane and release of PF-06873600 into the aqueous environment. By choice of bead or tablet core size and geometry, identity and quantity of osmogent, and thickness of the semipermeable membrane, the time lag between placement of the dosage form into the aqueous environment of use and release of the enclosed PF-06873600 may be chosen. It will be appreciated by those skilled in the art that increasing the surface-to-volume ratio of the dosage form and increasing the osmotic activity of the osmogent serve to decrease the time lag, whereas increasing the thickness of the coating will increase the time lag. Some osmotic-bursting devices exhibit substantially no release of the drug from the dosage form until the dosage form has exited the stomach and has resided in the small intestine for about 15 minutes or about 30 minutes or greater. Other osmotic-bursting devices exhibit substantially no release of the drug from the dosage form until the dosage form has exited the stomach and has resided in the small intestine for about 90 minutes or greater. Still other osmotic-bursting devices exhibit substantially no release of the drug from the dosage form until the dosage form has exited the stomach and has resided in the small intestine for and most preferably 3 hours or greater, thus assuring that minimal PF-06873600 is released in the duodenum and upper small intestine. A bursting osmotic core tablet or bead has a tablet or bead core which may contain from about 10-95% of API, about 0-60% osmogent, as described above, and about 5-30% other pharmaceutical aids such as binders and lubricants. The semipermeable membrane coating on a tablet, such as a cellulose acetate coating, is present at a weight corresponding to from about 2% to about 30%, preferably from about 3% to about 10%, of the weight of the tablet core. The semipermeable membrane coating on a bead, such as a cellulose acetate coating, is present at a weight corresponding to from about 2% to about 80% of the weight of the bead core. In another embodiment, the semipermeable coating on a bead is present at a weight corresponding to from 3% to 30% of the weight of the bead core. A bursting osmotic core device possesses no mechanism for "sensing" that the device has exited the stomach and entered the duodenum. Thus, devices of this type release the API at a predetermined time after entering an aqueous environment, e.g., after being swallowed. In the fasted state, indigestible non-disintegrating solids, such as the "bursting osmotic core devices" of this invention, are emptied from the stomach during phase III of the Interdigestive Migrating Myoelectric Complex (IMMC), which occurs approximately every 2 hours in the human. Depending on the stage of the IMMC at the time of dosing in the fasted state, a bursting osmotic core device may exit the stomach almost immediately after dosing, or as long as 2 hours after dosing. In the fed state, indigestible non-disintegrating solids, which are <1 1 mm in diameter, will empty slowly from the stomach with the contents of the meal (Khosla and Davis, Int. J. Pharmaceut. 62 (1990) R9-R1 1 ). If the indigestible non-disintegrating solid is greater than about 1 1 mm in diameter, e.g., about the size of a typical tablet, it will be retained in the stomach for the duration of the digestion of the meal, and will exit into the duodenum during phase III of an IMMC, after the entire meal has been digested and has exited the stomach. The release of the drug can be delayed until about 15 min or more. The release of the drug can be delayed until 30 minutes or more. The release of the drug can be delayed until about 90 minutes or greater. The release of the drug can be delayed until about 3 hours or greater after the dosage form has exited the stomach. A bursting osmotic core device starts to release the drug at about 2.5 hours after entering an aqueous environment, e.g., after ingestion, to more reliably assure that the device releases the API distal to the duodenum, when dosed in the fasted state. Another "bursting osmotic core device" will start to release the drug at about 4 hours after entering an aqueous environment. This 4 hour delay permits dosing in the fed state and allows for an about 3.5 hour retention in the fed stomach, followed by an approximately 30 minute delay after the dosage form has exited from the stomach. In this way, the release of the drug into the most sensitive portion of the gastrointestinal tract, the duodenum, is minimized.

In a further embodiment, a "bursting coated swelling core", a PF-06873600- containing tablet or bead is prepared which also comprises 25-70% of a swellable material, such as a swellable colloid (e.g., gelatin), as described in Milosovich, U.S. Pat. No. 3,247,066, incorporated herein by reference. Swelling core materials are hydrogels, e.g., hydrophilic polymers which take up water and swell, such as polyethylene oxides, polyacrylic acid derivatives such as polymethyl methacrylate, polyacrylamides, polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, carboxymethylcellulose, starches, and the like. Swelling hydrogels for this embodiment include polyethylene oxides, carboxymethylcellulose and croscarmellose sodium. The colloid/hydrogel-containing PF- 06873600-containing core tablet or bead is coated, at least in part, by a semipermeable membrane. Examples of polymers which provide a semipermeable membrane are cellulose acetate and cellulose acetate butyrate, and ethylcellulose. The semipermeable coating membrane may alternatively be composed of one or more waxes, such as insect and animal waxes such as beeswax, and vegetable waxes such as carnauba wax and hydrogenated vegetable oils. A melt mixture of a polyethylene glycol, e.g., polyethylene glycol-6000, and a hydrogenated oil, e.g., hydrogenated castor oil, may be used as a coating, as described for isoniazid tablets by Yoshino (Capsugel Symposia Series; Current Status on Targeted Drug Delivery to the Gastrointestinal Tract; 1993; pp.185- 190). Some semipermeable coating materials are cellulose esters and cellulose ethers, polyacrylic acid derivatives such as polyacrylates and polyacrylate esters, polyvinyl alcohols and polyalkenes such as ethylene vinyl alcohol copolymer, cellulose acetate and cellulose acetate butyrate.

When a coated tablet or bead having a bursting coated swelling core is placed in an aqueous environment of use, water passes through the semipermeable membrane into the core, swelling the core and resulting in bursting of the semipermeable membrane and release of the drug into the aqueous environment. By choice of bead or tablet core size and geometry, identity and quantity of swelling agent, and thickness of the semipermeable membrane, the time lag between placement of the dosage form into the aqueous environment of use and release of the enclosed drug may be chosen. Preferred bursting coated swelling core devices of this invention are those which exhibit substantially no release of the drug from the dosage form until the dosage form has exited the stomach and has resided in the small intestine for about 15 minutes or greater, preferably about 30 minutes or greater, thus assuring that minimal drug is released in the duodenum. A bursting coated swelling core tablet or bead has a tablet or bead core which may contain from about 10-70% PF-06873600; about 15-60% swelling material, e.g., hydrogel; about 0-15% optional osmogent; and about 5-30% other pharmaceutical aids such as binders and lubricants. The semipermeable membrane coating on a tablet, preferably a cellulose acetate coating, is present at a weight corresponding to from about 2% to about 30%, preferably from 3% to 10%, of the weight of the tablet core. The semipermeable membrane coating on a bead, preferably a cellulose acetate coating, is present at a weight corresponding to from about 2% to about 80%, preferably from 3% to 30%, of the weight of the bead core.

A bursting coated swelling core device possesses no mechanism for sensing that the device has exited the stomach and entered the duodenum. Thus, devices of this type release their drug contents at a predetermined time after entering an aqueous environment, e.g., after being swallowed, as previously discussed for bursting osmotic core devices, and the same consideration and preferences apply to making bursting coated swelling core devices. Bursting coated swelling core devices may be combined with immediate release devices to create a dosage form that will release drug both immediately after administration and at one or more additional predetermined times after dosing.

In a further embodiment, a "pH-triggered osmotic bursting device", PF-06873600 may be incorporated into a device of the type described in allowed commonly assigned co-pending U.S. Pat. No. 5,358,502, issued Oct. 25, 1994, incorporated herein by reference. The device comprises the API and optionally one or more osmogents, surrounded at least in part by a semipermeable membrane. The semipermeable membrane is permeable to water and substantially impermeable to the drug and osmogent. Useful osmogents are the same as those described above for bursting osmotic core devices. Useful semipermeable membrane materials are the same as those described above for bursting osmotic core devices. A pH-trigger means is attached to the semipermeable membrane. The pH-trigger means is activated by a pH above 5.0 and triggers the sudden delivery of the drug. In this embodiment, the pH-trigger means comprises a membrane or polymer coating which surrounds the semipermeable coating. The pH-trigger coating contains a polymer which is substantially impermeable and insoluble in the pH range of the stomach but becomes permeable and soluble at about the pH of the duodenum, about pH 6.0.

Exemplary pH-sensitive polymers are polyacrylamides, phthalate derivatives such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

Preferred pH-sensitive polymers include shellac; phthalate derivatives, particularly cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate; polyacrylic acid derivatives, particularly polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers; and vinyl acetate and crotonic acid copolymers. As described above cellulose acetate phthalate is available as a latex under the tradename Aquateric.RTM. (registered trademark of FMC Corp., Philadelphia, Pa.), and acrylic copolymers are available under the tradenames Eudragit-R.RTM. and Eudragit-L.RTM.. For appropriate application in this embodiment, these polymers should be plasticized utilizing plasticizers described above. The pH- trigger coating may also comprise a mixture of polymers, for example cellulose acetate and cellulose acetate phthalate. Another suitable mixture comprises Eudragit-L.RTM. and Eudragit-S.RTM.; the ratio of the two, and the coating thickness, defining the sensitivity of the "trigger", e.g., the pH at which the outer pH-trigger coating weakens or dissolves.

A pH-triggered osmotic bursting device generally operates as follows. After oral ingestion, the pH-trigger coating, which surrounds the semipermeable coating, which in turn surrounds the drug-containing core tablet or bead, remains undissolved and intact in the stomach. In the stomach, water may or may not commence penetration through the pH-trigger coating and the semipermeable coating, thus starting hydration of the core, which contains the drug and optional osmogent. After the device has exited the stomach and has entered the small intestine, the pH-trigger coating rapidly disintegrates and dissolves, and water passes through the semipermeable coating, dissolving the drug and optional osmogent within the core. As the colloidal osmotic pressure across the semipermeable coating exceeds some threshold value, the semipermeable coating fails, and the device bursts, releasing the API. It is preferred that this bursting and release of the drug occur at about 15 minutes or more, preferably 30 minutes or more, after the pH- triggered osmotic bursting device exits the stomach and enters the duodenum, thus minimizing exposure of the sensitive duodenum to the drug.

For a pH-triggered osmotic bursting device, the lag-time or delay-time is controlled by the choice and amount of osmogent in the core, by the choice of semipermeable coating, and by the thickness of the semipermeable coating. It will be appreciated by those skilled in the art, for example, that a thicker semipermeable coating will result in a longer delay after the device has exited the stomach. A preferred pH-triggered osmotic bursting device is a bead or tablet core of PF-06873600 with optional osmogent, coated with a 3-20% by weight cellulose acetate membrane, coated with a 3-20% by weight membrane composed of about 1 :1 cellulose acetate/cellulose acetate phthalate. Another preferred pH-triggered osmotic bursting device is a bead or tablet core of PF-06873600 with optional osmogent, coated with a 3-20% by weight cellulose acetate membrane, coated with a 3-20% by weight membrane comprising from about 9:1 to about 1 :1 Eudragit-L.RTM./Eudragit-S.RTM.

Advantageously, because a pH-triggered osmotic bursting device possesses a mechanism for sensing that the device has exited the stomach, intersubject variability in gastric emptying is not significant.

In a further embodiment, a "pFI-triggered bursting coated swelling core", a tablet core or bead containing the drug and a swelling material is coated with a semipermeable coating which is further coated with a pH-sensitive coating. The core composition, including choice of swelling material is as described above for the bursting coated swelling core embodiment. The choice of semipermeable coating material and pH- sensitive coating material are as described above for the "pH-triggered osmotic core" embodiment.

A pH-triggered bursting swelling core embodiment generally operates as follows. After oral ingestion, the pH-trigger coating, which surrounds the semipermeable coating, which in turn surrounds the drug-containing core tablet or bead, remains undissolved and intact in the stomach. In the stomach, water may or may not commence penetration through the pH-trigger coating and the semipermeable coating, thus starting hydration of the core, which contains the drug and water-swellable material, preferably a hydrogel. When the pH-triggered bursting swelling core device exits the stomach and enters the small intestine, the pH-trigger coating rapidly disintegrates and dissolves, and water passes through the semipermeable coating, dissolving the drug and swelling the water- swellable material within the core. As the swelling pressure across the semipermeable coating exceeds some threshold value, the semipermeable coating fails, and the device bursts, releasing the API. This bursting and release occurs at about 15 minutes or more, around about 30 minutes, after the pH-triggered bursting swelling core device exits the stomach and enters the duodenum, thus minimizing exposure of the sensitive duodenum to the drug.

For the "pH-triggered bursting swelling core" device, the lag-time or delay-time can be controlled by the choice and amount of swelling material in the core, by the choice of semipermeable coating, and by the thickness of the semipermeable coating. It will be appreciated by those skilled in the art, for example, that a thicker semipermeable coating will result in a longer delay after the device has exited the stomach. A pH-triggered bursting swelling core device contains a bead or tablet core of the drug with synthetic hydrogel, preferably carboxymethylcellulose, coated with a 3-20% by weight cellulose acetate membrane, coated with a 3-20% by weight membrane composed of about 1 :1 cellulose acetate/cellulose acetate phthalate. Another pH-triggered bursting swelling core device contains a bead or tablet core of the drug with synthetic hydrogel, preferably carboxymethylcellulose, coated with a 3-20% by weight cellulose acetate membrane, coated with a 3-20% by weight membrane composed of from about 9:1 to about 1 :1 Eudragit-L.RTM./Eudragit-S.RTM. Advantageously, because a pH-triggered bursting swelling core device possesses a mechanism for sensing that the device has exited the stomach, intersubject variability in gastric emptying is not significant. pH-triggered bursting swelling core devices may be combined with immediate release devices to create a dosage form that will release drug both immediately after administration and at one or more additional predetermined locations in the Gl tract after dosing. A review of this bursting technology is Journal of Controlled Release; 134 (2009) 74-80 and herein incorporated as reference in its entirety.

The invention will be illustrated in the following non-limiting examples. Examples

Example 1. General Process for Preparation of PF-06873600 SCT Active Laver

Granulation

The PF-06873600 (100 mg/g) SCT active layer granulation was prepared according to the following procedure.

Table 1

The polyethylene oxide (“PEO”) (POLYOX™ WSR N80; average MW 200,000) was passed through a 500-micron sieving screen and subdivided into three equal parts. The first portion of PEO was added to an intermediate bulk container (IBC-A), using a default bin size of 0.4 kg/L of working blend capacity. PF-06873600 (prepared as described in US 10,233,188) was added to IBC-A, followed by a second portion of PEO. The mixture was blended for 15 minutes at 15 rpm.

The blend was passed through a Comil rotary milling system equipped with a 1 .4 mm (0.055”, 055R) screen and a rounded edge impeller (1601 or equivalent) running at approximately 1000 (800-1200) rpm. The blend was collected in a second bin, IBC-B, of equivalent size.

The third portion of PEO was added to IBC-A along with the intra-granular portion of magnesium stearate and the bin contents were blended for 3 minutes at 15 rpm. The contents were passed through the same Comil rotary milling system running at approximately 800 (600-1000) rpm and collected in IBC-B. The contents of IBC-B were blended for 8 minutes at 12 rpm.

The prepared blend was processed through a Gerteis roller compactor (Mini- Pactor 250/25 or equivalent) equipped with knurled rollers, side rims, and an inline oscillating mill containing a die-pocket rotor and an 0.8 mm mill screen with a gap setting corresponding to a 2.0 mm screen. The granulation was collected in the initial bin, IBC- A, and the contents were blended for 5 minutes at 12 rpm. The extra-granular portion of magnesium stearate was added, and the contents were blended for an additional 5 minutes at 12 rpm.

The batch quantities of polyethylene oxide (POLYOX™ WSR Coagulant grade, average MW 5,000,000), sodium chloride, microcrystalline cellulose and blue dye were passed through a 20- or 30-mesh screen and added to a 500 cc bottle. The blend was mixed for 10 minutes with a Turbula bottle blender. Magnesium stearate was passed through a 30-mesh screen and added to the bottle of sweller layer and mixed for 3 minutes. Table 2.

Example 3. PF-06873600 10 mg MR SCT Bilaver Tablet Cores

The PF-06873600 (100 mg/g) SCT active layer granulation was prepared according to Example 1. The sweller layer blend was prepared according to Example 2.

PF-06873600 10 mg MR SCT bilayer tablet cores were compressed using an SCT specific 7-mm round convcave tooling to achieve the following targets: average active layer weight of 100.0 mg ± 3% (97.0-103.0 mg); average bilayer core weight of 150.0 mg ± 3% (145.5-154.5 mg); average bilayer core thickness of 4.2 mm ± 0.1 mm (4.1 -4.3 mm); and a bilayer core hardness of >3 kP.

Table 3

Example 4. PF-06873600 10 mg MR Tablet (Duration 1 )

The PF-06873600 10 mg MR SCT tablet cores were prepared according to Example 3.

The coating solution was prepared on a gravimetric basis. The purified water was added to an appropriate mixing vessel. Polyethylene glycol 3350 powder (inhibited with 100 ppm BHT) (“PEG 3350”) was added to the mixing vessel and completely dissolved with appropriate mixing. The acetone was added to the mixing vessel, using a portion to rinse the PEG 3350 solution container if necessary. Cellulose acetate was gradually added to the solution while mixing to avoid formation of large agglomerates. Following addition of the cellulose acetate, the vessel was sealed to minimize solvent evaporation and mixing was continued until all solids were dissolved. The coating solution was used within 24-hours of preparation.

Table 4

Tablet Coating and Drilling

Bilayer tablet cores were coated using a Vector LCDS-5 with a 1 .5-Liter semi- perforated pan operating at 25 rpm and a process airflow of 40 ± 5 CFM having an exhaust temperature of 36 ± 4 ^Q C. Tablet cores were preheated for >30 minutes in the pan with a pan rotation of 3 rpm. The coating solution was applied at a spray rate of 20 ± 3 g/minute, until the wet weight gain reached a level of 8.3% (12.5 mg/tablet). The coated tablets were then removed from the coating pan for final drying at 40 ^Q C for 20-36 hours. A single hole with a diameter of 1000 ± 200 micron (0.8-1.2 mm) was drilled on the active layer side of the tablet face. The delivery port was drilled to completely penetrate the coating across the delivery port diameter (depth of approximately 200 micron). The delivery port hole can be drilled either by mechanical means or via laser ablation.

Example 5. Representative Batch of 10 mg MR Tablet (Duration 1 )

The components used in the preparation of a representative batch of 5,000 units of the 10 mg MR tablets (Duration 1 ), prepared according to Example 4, is provided in Table 5 below.

Table 5

Example 6. PF-06873600 10 mg MR Tablet (Duration 2)

The PF-06873600 10 mg MR SCT tablet cores were prepared according to Example 3. The coating solution composition was prepared on a gravimetric basis. The purified water was added to an appropriate mixing vessel. PEG 3350 was added to the mixing vessel and completely dissolved with appropriate mixing. The acetone was added to the mixing vessel, using a portion to rinse the PEG 3350 solution container if necessary. Cellulose acetate was gradually added to the solution while mixing to avoid formation of large agglomerates.

Following addition of the cellulose acetate, the vessel was sealed to minimize solvent evaporation and mixing was continued until all solids were dissolved. The coating solution was used within 24-hours of preparation.

Table 6

Tablet Coating and Drilling

Bilayer tablet cores were coated using a Vector LCDS-5 with a 1.5-Liter semi- perforated pan operating at 25 rpm and a process airflow of 40 ± 5 CFM having an exhaust temperature of 36 ± 4 °C. Tablet cores were preheated for >30 minutes in the pan with a pan rotation of 3 rpm. The coating solution was applied at a spray rate of 20 ± 3 g/minute, until the wet weight gain reached a level of 12.7% (19.0 mg/tablet). The tablets were subjected to in-process drying in the coater for >15 minutes at a pan speed of 3 rpm, airflow of 60 ± 5 CFM and exhaust temperature of about 40 ^Q C (35-43 ^Q C). The coated tablets were then removed from the coating pan for final drying at 40 ^Q C for 20-36 hours.

A single hole with a diameter of 1000 ± 200 micron (0.8-1.2 mm) was drilled on the active layer side of the tablet face. The delivery port was drilled to completely penetrate the coating across the delivery port diameter (depth of approximately 200 micron). The delivery port hole can be drilled either by mechanical means or via laser ablation.

Example 7. Representative Batch of 10 mg MR Tablet (Duration 2)

Components for a representative batch of 5,000 units of the 10 mg MR tablets (Duration 2), prepared according to Examples 6, is provided in the table below.

Table 7

Example 8. PF-06873600 40 mg MR SCT Bilaver Tablet Cores

The PF-06873600 100 mg/g SCT active layer granulation was prepared according to Example 1. The sweller layer blend was prepared according to Example 2.

PF-06873600 10 mg MR SCT bilayer tablet cores were compressed using an SCT specific 1 1 -mm round convcave tooling to achieve the following targets: average active layer weight of 400.0 mg ± 3% (388.0-412.0 mg); average bilayer core weight of 600.0 mg ± 3% (582.0-618.0 mg); average bilayer core thickness of 6.8 mm ± 0.1 mm (6.7-6.9 mm); and a bilayer core hardness of >8 kP.

Table 8

Example 9. PF-06873600 40 mg MR Tablet (Duration 1 )

The PF-06873600 40 mg MR SCT tablet cores were prepared according to Example 8. The coating solution composition was prepared on a gravimetric basis. The purified water was added to an appropriate mixing vessel. PEG 3350 was added to the mixing vessel and completely dissolved with appropriate mixing. The acetone was added to the mixing vessel, using a portion to rinse the PEG 3350 solution container if necessary. Cellulose acetate was gradually added to the solution while mixing to avoid formation of large agglomerates. Following addition of the cellulose acetate, the vessel was sealed to minimize solvent evaporation and mixing was continued until all solids were dissolved. The coating solution was used within 24-hours of preparation.

Table 9

Tablet Coating and Drilling

Bilayer tablet cores were coated using a Vector LCDS-5 with a 1.5-Liter semi- perforated pan operating at 25 rpm and a process airflow of 40 ± 5 CFM having an exhaust temperature of 36 ± 4 °C. Tablet cores were preheated for >30 minutes in the pan with a pan rotation of 3 rpm. The coating solution was applied at a spray rate of 20 ± 3 g/minute, until the wet weight gain reached a level of 5.2% (31.0 mg/tablet). The tablets were subjected to in-process drying in the coater for >15 minutes at a pan speed of 3 rpm, airflow of 60 ± 5 CFM and exhaust temperature of about 40 ^Q C (35-43 ^Q C). The coated tablets were then removed from the coating pan for final drying at 40 ^Q C for 20-36 hours.

A single hole with a diameter of 1000 ± 200 micron (0.8-1.2 mm) was drilled on the active layer side of the tablet face. The delivery port was drilled to completely penetrate the coating across the delivery port diameter (depth of approximately 200 micron). The delivery port hole can be drilled either by mechanical means or via laser ablation.

Example 10. Representative Batch of 40 mg MR Tablet (Duration 1 )

Components for a representative batch of 1 ,250 units of the 40 mg MR tablets (Duration 1 ), prepared according to Example 9, is provided in the table below.

Table 10

Example 1 1. PF-06873600 40 mg MR Tablet (Duration 2)

The PF-06873600 40 mg MR SCT tablet cores were prepared according to Example 8.

The coating solution composition was prepared on a gravimetric basis. The purified water was added to an appropriate mixing vessel. PEG 3350 was added to the mixing vessel and completely dissolved with appropriate mixing. The acetone was added to the mixing vessel, using a portion to rinse the PEG 3350 solution container if necessary. Cellulose acetate was gradually added to the solution while mixing to avoid formation of large agglomerates. Following addition of the cellulose acetate, the vessel was sealed to minimize solvent evaporation and mixing was continued until all solids were dissolved. The coating solution was used within 24-hours of preparation.

Table 1 1

Tablet Coating and Drilling

Bilayer tablet cores were coated using a Vector LCDS-5 with a 1.5-Liter semi- perforated pan operating at 25 rpm and a process airflow of 40 ± 5 CFM having an exhaust temperature of 36 ± 4 °C. Tablet cores were preheated for >30 minutes in the pan with a pan rotation of 3 rpm. The coating solution was applied at a spray rate of 20 ± 3 g/minute, until the wet weight gain reached a level of 5.2% (31.0 mg/tablet). The tablets were subjected to in-process drying in the coater for >15 minutes at a pan speed of 3 rpm, airflow of 60 ± 5 CFM and exhaust temperature of about 40 ^Q C (35-43 ^Q C). The coated tablets were then removed from the coating pan for final drying at 40 ^Q C for 20-36 hours.

A single hole with a diameter of 1000 ± 200 micron (0.8-1.2 mm) was drilled on the active layer side of the tablet face. The delivery port was drilled to completely penetrate the coating across the delivery port diameter (depth of approximately 200 micron). The delivery port hole can be drilled either by mechanical means or via laser ablation.

Example 12. Representative Batch of 40 mg MR Tablet (Duration 2)

Components for a representative batch of 1 ,250 units of the 40 mg MR tablets (Duration 1 ), prepared according to Example 1 1 , is provided in the table below. Table 12