WO2023044024A1

WO2023044024A1 - Novel ph dependent coating drug delivery system

Info

Publication number: WO2023044024A1
Application number: PCT/US2022/043830
Authority: WO
Inventors: Fang Zhou; Shao FU
Original assignee: Novelstar Pharmaceuticals Inc.
Priority date: 2021-09-17
Filing date: 2022-09-16
Publication date: 2023-03-23

Abstract

Described are pharmaceutically acceptable compositions containing at least one active pharmaceutical ingredient having a pH-dependent solubility in a compressed core tablet and wherein the tablet is coated with a coating composition containing a pH independent, water insoluble polymer, a pH independent, water insoluble polymer, and a pH dependent polymer. Coating compositions for coating compressed tablets are also described.

Description

NOVEL PH DEPENDENT COATING DRUG DELIVERY SYSTEM

FIELD

[0001] The present disclosure relates to drug delivery systems involving pH- dependent coatings for pharmaceutical dosage forms and pharmaceutical compositions coated therewith.

BACKGROUND

[0002] To achieve or extend the therapeutic effect of a pharmaceutical composition, the active ingredient or ingredients contained in a dosage form can be released continuously over an extended period of time.

[0003] Some oral drug delivery systems can provide active pharmaceutical ingredients via sustained release, prolonged release, modified release (MR) or extended release (ER) formulations.

[0004] However, there are challenges associated with developing ER formulations, including the pH dependent solubilities of active pharmaceutical ingredients.

[0005] Weakly basic drugs and salts thereof exhibit a decrease in aqueous solubility at higher pH. A pharmaceutical active ingredient's solubility can be described in terms of the active ingredient's pKa, which is the pH at which a drug exists in equal amounts ionized (i.e., dissolved) and unionized states. That is, when a drug is present in solution having a pH equal to the drug's pKa, half of the drug is dissolved and half of the drug is intact.

[0006] Understanding of how changes in pH alter the ionization of pharmaceutical compositions allows for the determination of where a drug will primarily dissolve, i.e., in the stomach or in the blood.

[0007] Using the Hederson-Hasselbalch equation, one can determine the proportion of dissolved drug to undissolved drug at a given pH.

[0008] For example, Aspirin has a pKa of 3.5. The pH of the stomach and blood are approximately, respectively, 1.6 and about 7.4. At the stomach's pH of 1.4, about one percent of Aspirin is dissolved in the stomach. In the blood, however, the ratio of dissolved Aspirin to undissolved Aspirin is about 10,000 to 1.

[0009] A number of active pharmaceutical ingredients exhibit pH dependent solubility. Unless variations in pH are accounted for in the formulation of a dosage form, an extended release matrices of a pH dependent drug will not adequately introduce active ingredient in vivo over a desired period of time. pH dependent solubility is particularly a problem in the gastrointestinal tract, in which different segments have different pHs. As a drug moves through the gastrointestinal tract, the drug is subjected to environments of different pH. Thus, when the drug reaches a segment having a solubilizing pH, too much of the drug will dissolve, leaving an insufficient amount undissolved to achieve the desired extended release profile.

[0010] For example, due to their substantial drop in solubility at different pHs, pH- dependent active pharmaceutical ingredients will not dissolve sufficiently, leading to a much slower and incomplete release at, for example, pH 4.5 and above.

[0011] Thus, there is a need for drug delivery systems to deliver pharmaceuticals in these differing environments.

BRIEF SUMMARY

[0012] The present disclosure provides an effective, efficient, affordable, and flexible drug delivery system. In particular, the disclosed extended release delivery systems can achieve extended release in both low and high pH environments, thereby providing maximum in vivo bioavailability for active ingredients having pH-dependent solubilities. [0013] Described herein are embodiments of a pharmaceutical coating composition comprising at least one pH-independent, water insoluble polymer, at least one pH- independent, water soluble polymer and at least one pH-dependent polymer.

[0014] Also described herein are embodiments of compositions in which one or more active pharmaceutical ingredients having pH-dependent solubilities are compressed into one or more core tablets, which are subsequently coated with a coat comprising at least one pH- independent, water insoluble polymer, at least one pH-independent, water soluble polymer and at least one pH-dependent polymer.

[0015] The present inventors have surprisingly found that the disclosed ER coating, comprising a combination of a pH-independent, water insoluble polymer, a pH-independent, water soluble polymer, and a pH-dependent polymer over a core tablet can provide sustained release profiles for active pharmaceutical ingredients with decreased solubilities at pH higher than 5 allows for more than 90% release in pH 4.5 and 6.8 media.

[0016] In certain embodiments, the present disclosure is directed to a pharmaceutical coating composition comprising: at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, at least one pH-dependent polymer, and at least one water insoluble plasticizer, or at least one water soluble plasticizer.

[0017] In certain embodiments, the at least one pH-independent, water insoluble polymer comprises ethylcellulose. In certain embodiments, the at least one pH-independent, water soluble polymer comprises povidone. In certain embodiments, the at least one pH- dependent polymer comprises HPMCP, HPMCAS, or sodium alginate. In certain embodiments, the at least one pH-dependent polymer is a water insoluble polymer that comprises Hypromellose Phthalate 55 and/or Hypromellose Phthalate 50. In certain embodiments, the pH-independent, water insoluble polymer is ethylcellulose. In certain embodiments, the pH-independent, water soluble polymer is Povidone K90. In certain embodiments, the pH-dependent, polymer is hypromellose phthalate.

[0018] In certain embodiments, the present disclosure is directed to a pharmaceutical dosage form comprising a compressed core comprising at least one active ingredient, the compressed core being coated with a coating composition comprising at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, at least one pH-dependent polymer, at least one water insoluble plasticizer, or at least one water soluble plasticizer.

[0019] In certain embodiments, when added to a test medium comprising 900 ml of 0.1 N hydrochloric acid and a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, not less than 10% of a dosage form of this invention is dissolved in one hour, and not less than 30% of the dosage form of this invention is dissolved after two hours, and not less than 70% of the dosage form of this invention is dissolved after four hours, and not less than 80% of the dosage form of this invention is dissolved after eight hours.

[0020] In certain embodiments, at least one active ingredient of the composition has a pKa of 5.0-12.0. In certain embodiments, at least one active ingredient of the composition has a pKa of 7.0-11.9. In certain embodiments, at least one active ingredient of the composition has a pKa of 3.0-11.0. In certain embodiments, at least one active ingredient of the composition has a pKa of 4.5-8.0. In certain embodiments of this invention, at least one water insoluble plasticizer comprises Dibutyl Sebacate (DBS). In certain embodiments of this invention, at least one water soluble plasticizer comprises PEG 1450.

[0021] In certain embodiments, the present disclosure is directed to a pharmaceutical dosage form comprising a compressed core comprising tofacitinib citrate, the compressed core being coated with a coating composition comprising at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, at least one pH- dependent polymer, and optionally at least one water insoluble plasticizer, or at least one water soluble plasticizer.

[0022] In certain embodiments, the tofacitinib citrate is present in an amount of from 1 mg to 22 mg. In certain embodiments, the tofacitinib citrate is present in an amount of from 1 mg, 5 mg, 10 mg, 11 mg, or 22 mg.

[0023] In certain embodiments, the present disclosure is directed to a method of treating rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, or active polyarticular juvenile idiopathic arthritis a subject, comprising administering to a subject in need thereof, a pharmaceutical dosage form according to any disclosure herein.

[0024] Other aspects and advantages of the disclosure will be apparent from the following description and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. As the color drawings are being filed electronically via EFS-Web, only one set of the drawings is submitted.

[0025] FIG. 1 depicts Dissolution Profiles of Tofacitinib Core (uncoated) Tablets, 11 mg, Paddles, 50rpm 0.1N HCl 900 mL.

[0026] FIG. 2 depicts Dissolution Profiles of Tofacitinib Core (uncoated) Tablets 11 mg Paddles, 50rpm 0.1N HCl/pH4.5 acetate buffer /pH6.8 phosphate buffer, 900 mL.

[0027] FIG. 3 depicts Dissolution Profiles of Tofacitinib Core (uncoated) Tablets 11 mg Paddles, 50rpm, 0.1N HCl/pH4.5 acetate buffer /pH6.8 phosphate buffer, 900 mL.

[0028] FIG. 4 depicts Dissolution Profiles of Xeljanz XR*(XR/ER is short for extended-release which means the pill is formulated so that the drug is released slowly over time). Tofacitinib ER coated Tablets 11 mg Paddles, 50rpm 0.1N HCl/pH4.5 acetate buffer /pH6.8 phosphate buffer 900 mL.

[0029] FIG. 5 depicts Dissolution Profiles of Tofacitinib ER Tablets, 11 mg Paddles, 50rpm 0.1N HCl/pH4.5 acetate buffer /pH6.8 phosphate buffer 900 mL.

[0030] FIG. 6 depicts Dissolution Profiles of Tofacitinib ER Tablets, 11 mg Paddles, 50rpm 0.1N HCl/pH4.5 acetate buffer /pH6.8 phosphate buffer 900ml.

[0031] FIG. 7 depicts Dissolution Profiles of Tofacitinib ER Tablets 11 mg Paddles, 50rpm pH6.8 phosphate buffer 900ml.

[0032] FIG. 8 depicts Dissolution Profiles of Tofacitinib ER Tablets in pH 6.8 buffer, Paddles 50rpm, 900mL.

[0033] FIG. 9 depicts Dissolution Profiles of Tofacitinib ER Tablets in 0.1N HCl, Paddles 50rpm, 900mL, 75rpm, 900mL.

DETAILED DESCRIPTION

[0034] While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the subject matter disclosed herein.

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter disclosed herein belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are described herein.

[0036] Various examples and embodiments of the subject matter disclosed are possible and will be apparent to a person of ordinary skill in the art, given the benefit of this disclosure. In this disclosure reference to "some embodiments," "certain embodiments," "certain exemplary embodiments" and similar phrases each means that those embodiments are non-limiting examples of the inventive subject matter, and there can be alternative embodiments which are not excluded.

[0037] The articles "a," "an," and "the" are used herein to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0038] As used herein, the term "about" means ±10 % of the noted value. By way of example only, at least "about 50 seconds" could include from at least 45 seconds to and including at least 55 seconds. It is also understood that each unit between two particular units are also disclosed. For example, if 10-15 or 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0039] The word "comprising" is used in a manner consistent with its open-ended meaning, that is, to mean that a given product or process can optionally also have additional features or elements beyond those expressly described. It is understood that wherever embodiments are described with the language "comprising," otherwise analogous embodiments described in terms of "consisting of' and/or "consisting essentially of' are also contemplated and within the scope of this disclosure.

[0040] All references to singular characteristics or limitations of the present disclosure shall include the corresponding plural characteristic(s) or limitation(s) and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0041] The present disclosure relates to dosage forms and compositions for coating dosage forms containing active pharmaceutical ingredients having pH-dependent solubilities.

[0042] In such pharmaceutical compositions, active pharmaceutical ingredients are compressed into core tablets or uncoated tablets, which are subsequently coated with an extended-release (ER) coat comprising one or more pH-independent, water insoluble polymers, one or more pH-independent, water soluble polymers, and one or more pH- dependent polymers.

[0043] The one or more pH-independent, water insoluble polymers act as a retarding agent, whereas the one or more pH-independent, water soluble polymers and the one or more pH-dependent polymers act as pore-formers.

[0044] In certain embodiments, the pH-independent polymer (i.e., the pH- independent, water insoluble polymers and pH-independent, water soluble polymers) can be ethylcellulose (EC), cellulose acetate, polyvinyl acetate, and/or cellulose acetate butyrate. In certain embodiments, the pH-dependent polymer can be polymers useful for gastroresistant film coatings of tables or pellets. In certain embodiments, polymers useful for gastroresistant film coatings of tables or pellets can be cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), and Eudragit L and S. In certain embodiments, the pH-dependent polymer can be AquaSolve™ Hypromellose Acetate Succinate (HPMCAS) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) (an enteric polymer). Hypromellose acetate succinate is soluble in some solvents and insoluble in gastric fluid, but will swell and dissolve rapidly in the upper intestine and release the drug.

[0045] In certain emboidments, the pH-dependent polymer can be one on the following table:

[0046] In certain embodiments, the pH-independent, water insoluble polymer can be ethylcellulose. In certain embodiments, the pH-independent, water insoluble polymer can be Aquaion™ ethylcellulose, including the different grades of Aquaion™ Ethylcellulose. EC has many varieties that differ in grade and viscosity (e.g., Ethocel™ Standard Grade 45/50 Premium, 100 Premium, 200 premium). Each of the different grades and viscosities of ethylcellulose can be suitable for use. In certain embodiments, the viscosity of the ethylcellulose can be EC 40-100.

[0047] In certain embodiments, the pH-independent, water soluble polymer can be a water soluble polymer that can form pores. In certain embodiments, the pH-independent, water soluble polymer can be povidone. In certain embodiments, the pH-independent, water soluble polymer can be Povidone K90. In certain embodiments, the pH-independent, water soluble polymer can be: other grades of povidones (e.g., PVP K30, (PVP K60, PVP K120); methylcellulose and/or hydroxypropyl methylcellulose (e.g., HPMC E3 HPMC E5, HPMC E15, etc., and including those with low viscosity grades); Klucel™ Hydroxypropyl cellulose (HPC) and cellulose derivatives having water solubility and/or organic solubility; Natrosol™ 250 Hydroxy ethylcellulose (HEC); water soluble polyols; water soluble sugars (e.g., mannitol, sorbitol).

[0048] In certain embodiments, the pH-dependent polymer can be hypromellose phthalate, cellulose acetate phthalate, polymethacrylates (e.g., Eudragit L or Eudragit S), polyvinyl acetate phthalate, and shellac. In certain embodiments, the pH-dependent polymer can be hypromellose phthalate, Eudragit L or Eudragit S. In certain embodiments, the pH- dependent polymer can be a biodegradable polymer. In certain embodiments, the biodegradable polymer can be guar gum, pectin, chitosan, inulin, and/or amylose.

[0049] In certain embodiments, the pharmaceutical coating composition comprises a plasticizer. The plasticizer can affect the oral dosage form coating and can significantly influence the quality of the coatings, particularly the drug release. For example, film flexibility and adhesiveness, can reduce Tg (the glass transition temperature) of the polymers, and can affect the release of the drug. The membranes plasticized with suitable additive can reach the optimal parameters of permeability when combined with the drug release profile.

[0050] In certain embodiments, the at least one hydrophobic or water insoluble plasticizer can be dibutyl Sebacate (DBS), triacetin, acetylated monoglyceride, diethyl phthalate, fats and oils such as olive oil, castor oil. The addition of these plasticizers in an amount of 5-10 wt.% (based on total quantity of dry polymers) can be effective to delay crack generation in the film or to improve the simulated gastric fluid resistance of the coating agent. In certain embodiments, the at least one hydrophilic or water soluble plasticizer can be triethyl citrate (slightly soluble in water, 6.5 mg/100 ml water, miscible with alcohol and ether), polyethylene glycols (PEG) with different molecular weights (e.g., weight-average molecular weights of 300, 1450, 2000, 3350, 4000, 6000, and 8000 g/mol), triacetin citrate, acetyltriethyl citrate, Polyethylene Glycol Monomethyl Ether, and Sorbitol Sorbian Solution.

[0051] In embodiments described herein, the pH-dependent polymer component in the ER coat can dissolve at a pH higher than 5.0, thereby delaying drug release at lower pH and providing a more porous ER coat in a medium with pH above 5.0. Active pharmaceutical ingredients having pH-dependent solubilities will continue to diffuse out of the coated tablets at higher pH despite decreased solubility. [0052] As described below in further detail as an exemplary embodiment, the active pharmaceutical ingredient tofacitinib citrate was used as a non-limiting model drug. As a result of employing coating formulations described herein, the coated tablet provided a drug release profile with a 0.5 hour-1 hour lag time in low pH (e.g., pH 1.2) medium and reach a more than 80% drug release in high pH medium (e.g., pH 6.8).

[0053] Certain embodiments described herein are directed to once-daily pharmaceutical dosage forms. Other embodiments described herein are directed to a twice- daily pharmaceutical dosage forms. For example, once daily ER capsules, which can be filled by different functional coating pellets or tablets. The core pellets or core tablets can be coated by the claimed coating systems to provide modified drug release profiles for 12 hours or 24 hours period.

[0054] In certain embodiments, the dosage form can be a pellet, a tablet, pellets in tablets, pellets in capsules, mini tablets in capsules, and tablets in capsules.

[0055] In certain embodiments, a tablet can be prepared by direct compression of the materials or can be prepared the formulation of microspheres and then compression. In certain embodiments, microspheres can be characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry, and/or dissolution studies to verify that a tablet possesses gastroresistant or controlled-release characteristics.

[0056] As used herein, "controlled release" denotes release of an active - pharmaceutical agent that is not an immediate release. In some embodiments, a controlled release is an extended release. In other embodiments, a controlled release is a delayed release. As used herein, "controlled release" and "modified release" are used interchangeably.

[0057] The terms "controlled release" and "modified release" encompass "extended release" and "delayed release" formulations, as well as formulations having both extended- release and delayed-release characteristics. An "extended-release" formulation can extend the period over which drug is released or targeted to the desired site. A "delayed-release" formulation can be designed to delay the release of the pharmaceutically active compound for a specified period. Such formulations are referred to herein as "delayed-release" or "delayed- onset" formulations or dosage forms. Modified-release formulations of the present disclosure include those that exhibit both a delayed- and extended-release, e.g., formulations that only begin releasing after a fixed period of time or after a physicochemical change has occurred, for example, then continue releasing over an extended period. As used herein, the term "immediate release formulation," is meant to describe those formulations in which disintegrate , rapidly and get dissolved to release the medicaments, the dissolution criterion is Q=80% in 30 minutes

[0058] In general, extended release drug products are dosage forms that allow at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate- release (conventional) dosage form. Examples of extended-release (ER, XR XL) dosage forms include controlled-release, sustained-release, and long-acting drug products.

[0059] In an aspect, compositions described herein comprise active pharmaceutical ingredients in a compressed core.

[0060] In an aspect, any suitable pharmaceutically acceptable binder can be used. In some embodiments the binder is one or more starches, microcrystalline cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and polyvinylpyrrolidone (PVP).

[0061] In an aspect, the one or more active pharmaceutical ingredients can be mixed with one or more extra-granular excipients.

[0062] In certain embodiments, suitable excipients for use in the compositions or dosage forms can be fillers, diluents, glidants, disintegrants, binders, lubricants etc. Other pharmaceutically acceptable excipients can be include acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, , sweetening agents, wetting agents, etc.

[0063] In an aspect, any pharmaceutically acceptable excipients can be included.

[0064] In an aspect, any suitable core structure can be used. The drug core can have one, two, three, or more drug layers with one, two, three or more protective layers around each drug layer. In certain embodiments, the core is an immediate release core wherein the core is a compressed core surrounded by at least an immediate release coating or film.

[0065] In an aspect, a skilled artisan can select a suitable polymer from those commonly known in the art and discussed herein.

[0066] Core tablets containing one or more active pharmaceutical ingredients described herein can be prepared by tablet compression techniques. In certain embodiments, the tablets can be prepared by granules, which produced by different technologies, for example fluid bed top sparing granulation, high shear mixer with solvent granulation, In certain embodiments, the dry granulation comprises dry blending direct compression and roller compaction dry granulation.

[0067] In an aspect, a once daily dosage form can comprise administration or ingestion of one, two, three, four, five or more tablets at once in multiple dosage forms or a single dosage form. For example, one, two or three modified release tablets can be administered in the morning, depending on the amount of active ingredient contained in each tablet or capsule. In an aspect, a once daily dosage form described herein can be administered to a patient in the form of 1, 2, 3, 4, 5, 6 tablets at a time as single dosage form. In certain embodiments, a once-daily dosage form is administered to a patient in the form of 1, 2, 3, or 4 tablets at a time as single dosage form. In certain embodiments, a once daily dosage form is administered to a patient in the form of 1 or 2 tablets at a time as single dosage form. [0068] In an aspect, a twice daily dosage form described herein can comprise administration of one, two, three, four, five or more tablets at once as single dosage form. In certain embodiments for twice daily dosage, a dosage form of one or two tablets is administered at once as single dosage form. For example, one or two tablets can be administered in the morning and one or two tables can be administered in the evening as single dosage form.

[0069] In an aspect, a three times daily dosage form described herein can comprise administration of one, two, three, four, five or more tablets at once as single dosage form. In certain embodiments for three times daily dosage, a dosage form of one or two tablets is administered at once as single dosage form. For example, one tablet can be administered at a time, three different times throughout the day.

[0070] In an aspect, compositions described herein can comprise an active pharmaceutical ingredient in any amount.

[0071] In an aspect, embodiments herein can comprise one or more binders. For example, embodiments described herein can comprise Povidone binders, such as Povidon USP (Kollidon 25; Kollidon 30; Kollidon 40; Kollidon VA64; Kollidon 90), or other commercially available binders. Tablets described herein can comprise one or more binders in an amount (wt%) of 0.5% to 10%, such as 1.0% to 8.0%, such as 2.0% to 6.0% per tablet, based on the total weight of the tablet.

[0072] In an aspect, embodiments herein can comprise one or more wetting agents. For example, embodiments described herein can comprise sodium lauryl sulfate, or other commercially available wetting agents.

[0073] In another aspect, embodiments described herein can contain one or more lubricants. For example, embodiments described herein can comprise Compritol 888 ATO, or other commercially available lubricants. Tablets described herein can comprise one or more lubricants in an amount (wt%) of 0.1% to 10%, such as 1% to 4.0%, such as 2.0% to 8.0% per tablet, based on the total weight of the tablet.

[0074] In an aspect, embodiments herein can comprise one or more superdisintegrants. For example, embodiments described herein can comprise sodium starch glycolate, or other commercially available disintegrants. Tablets described herein can comprise one or more superdisintegrants in an amount (wt%) of 0.5% to 15%, such as 1.0% to 10.0%, such as 2.0% to 6.0% per tablet, based on the total weight of the tablet.

[0075] In an aspect, tablets described herein can have a total weight of between 100 mg and 300 mg, 150 mg and 250 mg, or 180 mg and 200 mg.

[0076] In an aspect, the tablets can be a round shape, and the size of the tablets can be from 1 to 7 mm in diameter. In some embodiments, the tablets can a capsule shape, or an oval shape.

[0077] In some embodiments, a compressed core can comprise two or more different active pharmaceutical ingredients.

[0078] In other embodiments, only a single active pharmaceutical ingredient is present.

[0079] In an aspect, the ER coat comprising at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, and at least one pH- dependent polymer can be used to coat any active pharmaceutical ingredient.

[0080] In certain embodiments of the present disclosure, the active pharmaceutical ingredient can be a single active ingredients or two or more active ingredients.

In certain embodiments, the active pharmaceutical ingredient or ingredients can have any pKa value, such as 0.1-14, or 1-13, or 2-12, or 3-11, or 4-10, or 5-9, or 6- 8, or 0.1-7, or 7-14, or 5-12. In certain embodiments, the active pharmaceutical ingredient can have a pKa in a strong base and a pKa in a strong acid. For example, Guanfacine HCl has a pKa of 11.64 in a strong base and a pKa of 8.65 in a strong acid, and has a basic pKa of 7.69. Tofacitinib citrate has a pKa of 9.15 strong base and a pKa of 6.44 in a strong acid), and has a basic pKa 5.07. Therefore, Guanfacine and Tofacitinib has higher solubility at acidic pH than basic pH conditions. [0081] In certain exemplary embodiments, compositions described herein comprise one or more active pharmaceutical ingredients having pKa of 5.0-12.0 in acid.

[0082] In certain exemplary embodiments, compositions described herein can comprise one or more one or more active pharmaceutical ingredients having pKa of 9.0-11.90 and one or more active pharmaceutical ingredients having pKa of 7.0-11.8.

[0083] In certain exemplary embodiments, compositions described herein comprise one or more active pharmaceutical ingredients having pKa of 4.0-11.0.

[0084] In certain exemplary embodiments, compositions described herein can comprise one or more one or more active pharmaceutical ingredients having pKa of 5.0- 10.0 and one or more active pharmaceutical ingredients having pKa of 4.5-8.0.

[0085] In certain emboidments, the active pharmaceutical ingredient or ingredients can have any pKa as shown in the following table and/or can be any API shown in the following table:

[0086] In an aspect, pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed can also be included. The pharmaceutically acceptable carrier can be a sterile aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt- forming counterions such as sodium; and/or nonionic surfactants.

[0087] Non-limiting examples of the pharmaceutical coating composition of the present disclosure are provided herein.

EXAMPLES

For purposes of illustration, one non-limiting example of an active pharmaceutical ingredient having pH-dependent solubility is tofacitinib citrate. The chemical name of tofacitinib citrate is (3R,4R)-4-methyl-3-(rnethyl-7H-pyrroIo[2,3-d]pyrimidin-4-ylamino)-β-oxo- piperidinepropanenitrile, 2 -hydroxy- 1,2,3 -propanetricarboxylate (1:1) and corresponding to the molecular formula C₁₆H₂₀N₆O•C₆H₈O₇ , with a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base). The chemical structure of tofacitinib citrate is:

Example 1: Preparation of Core Tablets

1) Dry blending and direct compression

[0088] The core tablets contained immediate release cores. In the formulation, sorbitol was selected as filler, hydroxyethyl cellulose and copovidone (Kollidon VA64) as binder, and magnesium stearate as the lubricant. The influence of the ingredients of cores on drug release were investigated. Dry blending/direct compression and fluid bed wet granulation processes were carried out to evaluate the influence of formation and granulation process on the tablet compressibility and dissolution profile.

[0089] Four formulations were designed with different grades of Sorbitol as main filler, Hydroxy ethylcellulose (Natrosol™ 250L) and Kollidon VA64 as binder, fumaric acid as buffer agent, Magnesium Stearate as a lubricant. The different grades of water soluble filler Sorbitols were Neosorb XTAB 300S (d50=426 μm), Neosorb P60W (d50=220 μm), and Sorbitol Parteck SI 400 (d50=566 μm). The four formulations had similar dissolution data and all the drug release reached more than 90% in 30 minutes (Table 1). Formulation Lot 178 had faster release at 15 min, which could be attributed to the formulation having less HEC (Natrosol™ 250L Pharm) than formulation Lot 183, hence a faster tablet disintegration (

[0090] Table 1, Table 4and FIG. 1). Formulation Lot 233 had similar formulation to Lot 217, but 5% Fumaric acid was used as a buffer agent to increase the drug solubility in high pH media, e.g., pH 6.8 phosphate buffer. The same amount of Sorbitol Parteck SI 400 or other excipients were removedto achieve the same tablet weight. The dissolution data of Lot 233 suggested that core formulation with 5% fumaric acid had slowed down drug release at 15 min at 0.1N HCl, when comparing the data in pH 4.5 and pH 6.8 buffers, respectively (Table 3). This could have been attributed to the fumaric acid dose not dissolving in 0.1HCl, therefore slow down the drug release rate. The core formulation of Lot 217 was used for the core tablets (Lot PB01) (Table 1) for ER functional coating and the dissolution data for core tablets lot PB01 is summarized in Table 5. The data showed that core tablets had immediate release profiles in different pH media and that the drug release reached to more than 90% in 30 minutes (FIG. 3). The flowability and compressibility of the granules made by dry blending process were acceptable for compression processing.

[0091] Dry blending and direct compression processes for a batch size of 1.2kg

1) Passed the Tofacitinib Citrate and Sorbitol through a # 30 mesh screen into a blender.

2) Mixed the materials for 10 minutes at 25 RPM.

3) Added Natrosol™ 250L and Kollidon VA64 into the blender, mixing for 20 min at 25 RPM.

4) Passed Magnesium Stearate through #30 mesh screen and mix for 3 min at 25 RPM

5) Compressed tablet at 10kP hardness.

2) Fluid bed granulation

[0092] Fluid bed wet granulation was performed to evaluate the influence of the granulation method on tablet characteristics. Based on dry blending and direct compression study of Lot 183, and a similar formulation was used. The lot 197 and Lot 210 (Table 2) had the same composition as Lot 183, but were granulated by fluid bed wet granulation, and 25% water amount of the dry powder weight was added by top spraying. To evaluate the influence of fluid bed granulation on granule flowability for Lot 197, 63.11% Neosorb P60W was used in the wet granulation and 8% Neosorb P60W and 1% glidant colloidal silicon dioxide were used in the dry blending stage. Lot 210 used 63.11% Neosorb P60W and Kollidon VA64 in the wet granulation, and the HEC Natrosol ™ 250L and remaining materials were added in dry blending stage. When compared to the dry blending process of Lot 183, the results suggested that the fluid bed granulation could improve the formulation flowability and compressibility. The dissolution data of Lot 197 and Lot 210 indicated that the core tablets produced by fluid bed granulation process had about 20% slower drug release rate at 15min (Table 4, FIG. 1) than the same formulation (Lot 183) made by dry blending direct compression process.

Table 1. Formulations of Lot 178, Lot 183, Lot 217 and Lot 233

Table 2. Formulation Fluid Bed Wet Granulation

Table 3. Dissolution data of Tofacitinib Citrate IR Core, 11mg Tablets

Paddles, 50rpm 900 mL, 0.1N HCl, pH4.5 acetate buffer and pH 6.8 phosphate buffer

Table 4. Dissolution of Tofacitinib Citrate IR Tablets, 11mg in 900mL of 0.1N HCl, USP-I (basket), 100 rpm

Table 5. Dissolution data of Tofacitinib Citrate IR Core Tablets, 11mg

[0093] Conclusion: Based on experimental data, the Tofacitinib citrate core tablets of formulation Lot 217 made by the direct compression process had good flowability and fastest drug release rate (up to 80%) in 15 minutes when compared to other core tablet formulations, and reduced dissolution variation. The fluid bed granulation process can be used as option to improve the granulation flowability and compressibility as needed.

Example 2: Development of pH Dependent ER Coating Formulation

[0094] Development of Novel ER Drug Delivery System for Weak Base Drugs: Embodiments of the disclosure can comprise Tofacitinib citrate as model drug, Ethylcellulose (EC), a pH independent, water insoluble polymer to form water insoluble barrier membranes. The viscosity or molecular weight grade of EC can impact drug release rates. The viscosity or molecular weight grade of EC can impact drug release rates. Drug release is reduced with increasing molecular weight (viscosity) of EC, as higher molecular weight grade EC provide higher mechanical strength and less permeability films. Alternately, the addition of hydrophobic plasticizers to coating formulations can provide for slower drug release, due to a decreased residual internal stress within the coating, resulting in more coherent films. In cases, Ethocel 100FP Premium has been selected as pH independent water insoluble polymer. Hypromellose Phthalate HP50 (or HP55 and P55s) as a pH dependent pore former, Povidone (e.g., Kollidon K90F) as a pH independent, water-soluble pore former, and Dibutyl Sebacate NF (DBS) as a hydrophobic plasticizer of coating membranes. The coating dispersions or solutions were prepared by solvent media (e.g., alcohols) with properly mixing in a container. The core tablets (see Example 1 of Core Tablets) were coated in a coating pan within a controlled product temperature range (25°C-50°C) and proper airflows and spray rates with a smooth coating process. When the coated tablet was swallowed and proceeded to the stomach, the partial water-soluble ingredients, Povidone, dissolved and formed pores in the ethylcellulose membrane. Then water or GI tract media moved into the coated tablet and hydrated or dissolved the drug and hydrophilic ingredients in the coated tablets. The drug in the coated tablets was then driven into GI tract media by a pore diffusing process. The pores were fully permeable for the drug and water. The drug release mechanism is different from an osmotic semipermeable membranes, which can allow water molecular moving into the coated tablet, but would not allow drug molecules moving into GI tract media, but by a drug release port made by laser drill. When the coated tablet moved into an area where pH value is around 4.5 or higher than 5.0, the pH dependent ingredient HP50 dissolved, forming more and bigger pores, and enhanced the drug release rate in the pH 5 above GI tract areas and increased the drug absorptance and bioavailability. Drug release was driven by a diffusion process, where the drug moved from a high concentration core area into lower drug concentration areas when in the GI tract or dissolution media. 1) pH dependent formulation without fumaric acid in the cores • Influence of the HPMCP on drug release

[0095] Two functional coating formulations of 1 Img Tofacitinib citrate ER Tablets were developed with the same core tablet formulation (see Table 7) but different ER coatings (Table 8). The coating formulation Lot 188 was pH independent, without Hypromellose Phthalate, while the coating formulation Lot 191 contained 10% of Hypromellose Phthalate (HPMCP HP50) to replace the same amount of Ethylcellulose (Methocel 100FP Premium). The ER coating weight gain was 40mg dry solids per tablet. The product dissolution profiles were investigated by USP-II (Paddle), 50 rpm in 900mL medium, which is 0.1N HCl (pH 1.2), pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. The commercial product Xeljanz XR (Tofacitinib citrate ER Tablet, 11mg) was used as refence for comparison in the three media. The influences of the dissolution medium pH and product formulation on drug release were evaluated. The dissolution data are summarized in Table 9 and plotted in FIG.4 - FIG.7. In general, the formulations displayed different drug release profiles in the three media, and the drug release rates decreased as pH increased. The highest drug release rate of the three formulations was observed in 0.1N HCl (pH 1.2), and slower drug release profiles occurred at pH 4.5 and pH 6.8. This is attributed to Tofacitinib citrate being a weak base with pKa 5.03, therefore drug solubility is reduced at pH 4.5 or above.

[0096] When comparing the drug release profile in 0.1N HCl, Xeljanz XR (Tofacitinib citrate 11mg) ER Tablets provided a slightly slower drug release in pH 4.5 buffer but had a significant slower drug release in pH 6.8 buffer. The drug release reached about 80% at 4 hr and reached 90% at 6 hr (FIG. 4). This could be attributed to the ECS osmatic (laser drill) drug delivery system constantly extruding drug out from the coating shell into the dissolution medium. [0097] For formulation Lot 188, the pH independent product showed that the drug release profiles in pH 4.5 and pH 6.8 were lower than in 0.1 N HCl. For example, the ER tablets of Lot 188 released about 50% and 90% drug at 2hr and 4 hr in 0.1N HCl, respectively. But it took 4 hours and 8 hours to release 50% and 90% in pH 4.5 and pH 6.8 buffers, respectively (FIG.5). This demonstrated that the drug release process was driven by a drug diffusion system compared to Xeljanz XR. Because the drug solubility is low in pH 4.5 and pH 6.8 media, some drug remained in the coated tablets and caused drug release rates to slow down.

[0098] To improve the drug release in high pH value media, Formulation Lot 191 was formulated by adding 10% HPMCP HP50 to replace the same amount of the Ethocel 100FP Premium (Table 8) and with other excipient being the same. FIPMCP HP50 was dissolved in the media of pH 5.0 or above, which increased the porosity of the coating membrane and enhanced the drug release rate and extent. For example, the ER tablets of Lot 191 released about 50% drug at 2 hrs in pH 4.5 and then the drug release rate was faster in pH 6.8 buffer than in pH4.5 buffer. The drug release reached about 100% in both of the media at 8 hours(FIG.6). The results indicated the formulation Lot 191 with HPMCP had a faster drug release than the formulation Lot 188, and slight faster drug release than the commercial product, Xeljanz XR(Tofacitinib citrate 11mg) Tablets in pH6.8 buffer (FIG. 7).

Table 7. Formulation of Tofacitinib Citrate core tablets, 11mg

Table 8. Coating formulation (with and without HPMCP HP 50)

Table 9. Dissolution of Tofacitinib Citrate ER Tablets, 11mg in 900mL of 0.1N HCl , pH 4.5, and pH 6.8, USP-II (Paddle), 50 rpm.

2) pH dependent formulation with fumaric acid in the cores

[0099] Based on the core formulation Lot 183, a new core formulation of Lot 233 was designed by using 5% buffer agent fumaric acid to replace the same amount of Sorbitol to increase the solubility of Tofacitinib Citrate in the pH 6.8 buffer (Table 10). Core tablets Lot 233 were coated with EC/PVP/HPMCP system to form ER coated tablets Lot 234 (Table 11). The dissolution results indicated that the formulation Lot 234 with 5% Fumaric acid in the cores provided an almost linear dissolution profile and reached to 100% drug release in 8 hours in pH 6.8 buffer (Table 12 and FIG. 8). The results surprisingly indicated that the EC/PVP/HPMCP coating system combined with weak acid agent, for example fumaric acid in the core tablets, could significantly enhance drug release of a weak base drug (e.g., Tofacitinib Citrate) at pH 6.8 (Table 12). The Formulation Lot 234 had similar dissolution profiles to the commercial product Xeljanz XR (Tofacitinib citrate 11mg) ER Tablets in 0.1 N HCl and pH 6.8 buffer (the dissolution similarity factor (f2) values are more than=51 in both of dissolution media). FIG. 9).

Table 10. Core Formulation with Fumaric, Lot 233

Table 11. Coating Formulation with HPMCP, Lot 234

D: Bulk density, TD: Tapped density, PSD: Particle size distribution Table 12. Dissolution data of ER Tablets, Lot 234 (Cores contain 5% Fumaric acid, coating with EC-PVP-HPMCP)

Claims

CLAIMS What is claimed is:

1. A pharmaceutical coating composition comprising: at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, at least one pH-dependent polymer, and optionally at least one water insoluble plasticizer or at least one water soluble plasticizer.

2. The pharmaceutical coating composition according to claim 1, wherein the at least one pH-independent, water insoluble polymer comprises Ethylcellulose.

3. The pharmaceutical coating composition according to claim 1, wherein the at least one pH-independent, water soluble polymer comprises a povidone.

4. The pharmaceutical coating composition according to claim 1, wherein the at least one pH-dependent polymer comprises HPMCP, HPMCAS, or sodium alginate.

5. The pharmaceutical coating composition according to claim 1, wherein the at least one pH-dependent polymer is a water insoluble polymer that comprises Hypromellose Phthalate 50 and Hypromellose Phthalate 55.

6. The pharmaceutical coating composition according to claim 1, wherein the pH- independent, water insoluble polymer is ethylcellulose.

7. The pharmaceutical coating composition according to claim 1, wherein the pH- independent, water soluble polymer is Povidone K90.

8. The pharmaceutical coating composition according to claim 1, wherein the pH- dependent polymer is hypromellose phthalate.

9. A pharmaceutical dosage form comprising a compressed core comprising at least one active ingredient, the compressed core being coated with a coating composition comprising at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, at least one pH-dependent polymer, and optionally at least one water insoluble plasticizer or at least one water soluble plasticizer.

10. The pharmaceutical dosage form according to claim 9, wherein, when added to a test medium comprising 900 ml of 0.1 N hydrochloric acid and a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, not less than 10% of the pharmaceutical dosage form is dissolved in one hour, and not less than 30% of the pharmaceutical dosage form is dissolved after two hours, not less than 70% of the pharmaceutical dosage form is dissolved after four hours, and not less than 80% of the pharmaceutical dosage form is dissolved after eight hours.

11. The pharmaceutical dosage form according to claim 9, wherein the at least one active ingredient has a pKa of 5.0-12.0.

12. The pharmaceutical dosage form according to claim 11, further comprising at least one active ingredient having a pKa of 7.0-11.9.

13. The pharmaceutical dosage form according to claim 9, wherein the at least one active ingredient has a pKa of 3.0- 11.0.

14. The pharmaceutical dosage form according to claim 11, further comprising at least one active ingredient having a pKa of 4.5-8.0.

15. The pharmaceutical coating composition according to claim 1, wherein the at least one water insoluble plasticizer comprises Dibutyl Sebacate (DBS).

16. The pharmaceutical coating composition according to claim 1, wherein the at least one water soluble plasticizer comprises PEG 1450.

17. A pharmaceutical dosage form comprising a compressed core comprising tofacitinib citrate, the compressed core being coated with a coating composition comprising at least one pH-independent, water insoluble polymer, at least one pH-independent, water soluble polymer, at least one pH-dependent polymer, and optionally at least one water insoluble plasticizer or at least one water soluble plasticizer.

18. The pharmaceutical dosage form according to claim 17, wherein the tofacitinib citrate is present in an amount of from 1 mg to 22 mg.

19. The pharmaceutical dosage form according to claim 17, wherein the tofacitinib citrate is present in an amount of from 1 mg, 5 mg, 10 mg, 11 mg, or 22 mg.

20. A method of treating rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, or active polyarticular juvenile idiopathic arthritis a subject, comprising administering to a subject in need thereof, a pharmaceutical dosage form according to any one of claims 9-19.