Pharmaceutical composition of nor-UDCA

Abstract

The present invention relates to a pharmaceutical composition comprising nor-UDCA or a pharmaceutically acceptable salt or ester thereof and a process for its preparation. The present invention most preferably discloses a solid oral dosage form of nor-UDCA, preferably in the form of tablets, capsules, disintegrating tablets and effervescent tablets.

Description

Technical Field

[0001] Field of the Invention

[0002] The present invention relates to a pharmaceutical composition comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof, and a process for its preparation. More specifically, the present invention relates to a pharmaceutical composition comprising at least about 30% w / w of nor-UDCA or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

Background Art

[0003] Background of the Invention

[0004] 24-Nor-ursodeoxycholic acid (nor-UDCA) is an ursodeoxycholic acid analogue (bile acid derivative) used for the treatment and / or prevention of liver diseases, preferably chronic liver diseases. Nor-UDCA has the following structural formula.

Chemical Formula

[0005] European Patent No. 0624595 B1 (hereinafter "European Patent '595") discloses nor-UDCA, a method for its preparation, and its use for reducing cholesterol in a daily dose in the range of 3 mg to 5000 mg, preferably in the dose range of 10 to 1000 mg, depending on the patient's body weight and constitution. Further, the EP '595 patent discloses various dosage forms, preferably oral dosage forms in the form of tablets, capsules or liquids.

[0006] U.S. Patent No. 8,951,995 (the "U.S. '995 Patent") discloses a method of treating inflammatory cholestatic liver diseases in a subject by administering to the subject a pharmaceutical composition comprising nor-UDCA and / or a pharmaceutically acceptable salt or ester thereof; wherein the inflammatory cholestatic liver disease is primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or progressive familial intrahepatic cholestasis, particularly progressive familial intrahepatic cholestasis types 1, 2 and 3, cystic fibrosis, drug-induced cholestasis, or noncholestatic cholestatic liver diseases such as chronic viral hepatitis (B, C, D), alcoholic and nonalcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease and alpha-1-antitrypsin deficiency. Further, the "U.S. '995 Patent discloses solid dosage forms for oral administration including tablets, preferably effervescent or chewable tablets, capsules, pills, powders and granules, and 24-nor-ursodeoxycholic acid can be mixed with regularly used substances such as sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, lubricants (e.g., magnesium stearate), disintegrants and buffering agents. Tablets and pills can also be prepared with an enteric coating to prevent 24-nor-ursodeoxycholic acid from being affected by gastric acid and enzymes. As immediate release tablets, these compositions may further contain microcrystalline cellulose and / or dicalcium phosphate.

[0007] U.S. Patent No. 9,512,167 discloses a chemically pure polymorph of nor-UDCA or a pharmaceutically acceptable salt thereof, wherein the total amount of chemical impurities is less than 0.5%, at least 60% of the polymorph particles have a size <10 μm, and wherein the polymorph substantially does not contain detectable amorphous nor-UDCA. Further, the U.S. '167 Patent discloses solid dosage forms for oral administration including tablets, preferably effervescent or chewable tablets, capsules, pills, powders and granules.

[0008] The above prior art discloses a pharmaceutical composition for oral administration comprising a tablet dosage form containing nor-UDCA. Pharmaceutical tablets containing nor-UDCA present certain drawbacks, the problem being the dissolution rate, and the disintegration of the tablets varies between batches, with some batches having unacceptably low rates.

[0009] Considering the above disadvantages, it is necessary to develop a pharmaceutical composition, most preferably a tablet dosage form containing nor-UDCA or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, which provides consistent disintegration and dissolution between batches of the tablet dosage form.

[0010] Summary of the Invention

[0011] The present invention relates to a pharmaceutical composition comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

[0012] In an aspect of the present invention, the present invention provides a tablet dosage form (immediate release tablet) comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

[0013] In a preferred aspect of the present invention, nor-UDCA is used in crystalline form.

[0014] In a particularly preferred aspect of the present invention, crystalline nor-UDCA is used in micronized form. In this case, nor-UDCA has an average particle size D 50 of less than 50 μm, especially 1 - 20 μm.

[0015] In another aspect of the present invention, the present invention provides a tablet dosage form comprising at least about 30% w / w of nor-UDCA or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

[0016] In a further aspect of the present invention, the present invention provides a pharmaceutical composition, preferably in tablet form, comprising (a) from about 30% w / w to about 90% w / w of nor-UDCA, based on the total weight of the tablet, and (b) at least one pharmaceutically acceptable excipient.

[0017] In another aspect of the present invention, the present invention (a) from about 30% w / w to about 90% w / w of nor-UDCA, (b) from about 5% w / w to about 30% w / w of a diluent, (c) from about 5% w / w to about 10% w / w of a binder, (d) from about 1% w / w to about 10% w / w of a disintegrant, (e) from about 0.2% w / w to about 2% w / w of a lubricant, based on the total weight of the tablet, and (f) optionally, the tablet is coated with a film coating composition and provides a tablet form comprising the same.

[0018] In a particular aspect of the present invention, the present invention (a) from about 30% w / w to about 90% w / w of nor-UDCA and (b) croscarmellose sodium as a disintegrant and provides a tablet form comprising the same.

[0019] In one aspect of the present invention, the present invention provides a tablet form comprising nor-UDCA, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate as active ingredients; wherein about 10% w / w to about 20% w / w of the microcrystalline cellulose in the tablet is present in the intragranular portion, and about 80% w / w to about 90% w / w of the microcrystalline cellulose in the tablet is present in the extragranular portion, based on the total amount of microcrystalline cellulose in the tablet, and wherein the total amount of croscarmellose sodium is present in the extragranular portion.

[0020] In a particular aspect of the present invention, the present invention (a) from about 30% w / w to about 90% w / w of nor-UDCA, (b) About 5% w / w to about 30% w / w of microcrystalline cellulose, (c) About 5% w / w to about 10% w / w of polyvinylpyrrolidone, (d) About 1% w / w to about 10% w / w of croscarmellose sodium and (e) Based on the total weight of the tablet, about 0.2% w / w to about 2% w / w of magnesium stearate to provide a tablet dosage form.

[0021] In a more specific embodiment of the present invention, the present invention relates to (a) About 30% w / w to about 90% w / w of nor-UDCA, (b) About 5% w / w to about 30% w / w of microcrystalline cellulose, (c) About 5% w / w to about 10% w / w of polyvinylpyrrolidone, (d) About 1% w / w to about 10% w / w of croscarmellose sodium, (e) Based on the total weight of the tablet, about 0.2% w / w to about 2% w / w of magnesium stearate, wherein, based on the total amount of the microcrystalline cellulose, about 10% w / w to about 20% w / w of the microcrystalline cellulose is present in the intragranular portion, and based on the total amount of the microcrystalline cellulose, about 80% w / w to about 90% w / w of the microcrystalline cellulose is present in the extragranular portion, and wherein all of the croscarmellose sodium is present in the extragranular portion to provide a tablet dosage form.

[0022] Definitions

[0023] Unless otherwise defined, 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 claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in the specification and the appended claims, the singular forms "a", "an", and "the" include the plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Further, the use of the terms "including", and other forms such as "include", "includes", and "included" is not limited.

[0024] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are expressly incorporated by reference in their entirety for all purposes.

[0025] The term "about", when used before a numerical value, indicates that the value may vary within a reasonable range, such as within ±10%, ±5%, or ±1 of the stated value.

[0026] As used herein, the term "comprising" or grammatical variations thereof is intended to mean that compositions and methods, etc., include the recited elements but do not exclude others.

[0027] As used herein, the term "comprising" or grammatical variations thereof is intended to mean that compositions and methods, etc., include the recited elements but do not exclude others.

[0028] When the phrase "consisting essentially of" or its grammatical variations are used to define a composition or method, it is intended to mean excluding any other elements that have any essential meaning to the combination for the intended use, but not excluding elements that do not substantially affect the characteristics of the composition or method.

[0029] The phrase "consisting of" or its grammatical variations is intended to mean excluding elements not specifically recited.

[0030] Aspects defined by each of these transitional terms are within the scope of the present invention. For example, if a formulation is described as containing components A, B, and C, formulations consisting essentially of A, B, and C, as well as formulations consisting of A, B, and C, are independent within the scope of the present invention.

[0031] With respect to a formulation, composition, or component as used herein, the term "acceptable" or "pharmaceutically acceptable" means not having a continuous adverse effect on the general health of the subject being treated, or not inactivating the biological activity or properties of the compound and being relatively non-toxic.

[0032] As used herein, the term "wet granulation" or "moist granulation" refers to the formation of granules using a granulating liquid (water, organic solvent, or solution).

[0033] As used herein, the term "dry granulation" refers to the formation of granules without using a granulating liquid (water, organic solvent, or solution).

[0034] As used herein, the term "high-load solid tablet formulation" refers to a solid tablet formulation containing at least 30% w / w of nor-UDCA per tablet.

[0035] Detailed Description of the Invention

[0036] The present invention provides a pharmaceutical composition comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

[0037] In one aspect of the present invention, the pharmaceutical composition is a solid dosage form for oral administration comprising tablets (immediate release tablets), effervescent or chewable tablets, orally disintegrating tablets, sustained release tablets, capsules, sustained release capsules, delayed release tablets, delayed release capsules, pills, powders and granules. Most preferably, the solid dosage form used in the present invention is a tablet dosage form (immediate release tablet).

[0038] In an aspect of the present invention, the present invention provides a tablet dosage form (immediate release tablet) comprising 24-nor-ursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

[0039] In one aspect of the present invention, the present invention provides a tablet dosage form (immediate release tablet) comprising nor-UDCA, wherein the immediate release tablet is a tablet dosage form (immediate release tablet) having high bioavailability through improved dissolution, and provides a method for preparing the same. More specifically, the present invention relates to an immediate release tablet for oral administration containing nor-UDCA having poor water solubility.

[0040] nor-UDCA is poorly soluble in aqueous media, thus having an insufficient dissolution profile, and as a result, suffers from the drawback of poor bioavailability in vivo after oral administration. Therefore, in order to avoid this drawback, the therapeutic dose that needs to be administered has to be increased.

[0041] In order to improve the dissolution profile and bioavailability of nor-UDCA, it is useful to increase its dissolution to reach a level close to 100%.

[0042] In a preferred embodiment of the present invention, nor-UDCA is used in crystalline form.

[0043] In a particularly preferred embodiment of the present invention, crystalline nor-UDCA is used in micronized form. In this case, nor-UDCA preferably has an average particle size D of less than 50 μm, especially 1 - 20 μm. 50 and has.

[0044] In an embodiment of the present invention, the present invention provides a tablet dosage form comprising at least about 30% w / w of nor-UDCA or a pharmaceutically acceptable salt or ester thereof, and at least one pharmaceutically acceptable excipient.

[0045] In an embodiment of the present invention, based on the total weight of the tablet dosage form, the present invention provides a tablet dosage form containing at least about 30% w / w of nor-UDCA or a pharmaceutically acceptable salt or ester thereof, preferably about 30% w / w to about 90% w / w of nor-UDCA, more preferably about 45% w / w to about 85% w / w of nor-UDCA, and most preferably about 50% w / w to about 80% w / w of nor-UDCA, based on the total weight of the tablet dosage form.

[0046] In an embodiment of the present invention, the tablets according to the present invention allow a higher drug load than those of the prior art, which is exemplified by tablets having a nor-UDCA (active ingredient) load of at least about 30% w / w or more. This high nor-UDCA load enables the preparation of smaller and lighter tablets that are easier to swallow. Furthermore, the higher the nor-UDCA load, the higher the dosage, such as 500 mg, 750 mg, 1000 mg, 1500 mg, etc., can be achieved with one tablet. The pill burden on the patient is reduced, thereby improving patient compliance.

[0047] In yet another embodiment, the high-load solid immediate-release tablets of the present invention containing at least about 30% w / w or more of nor-UDCA have low friability and good tensile strength.

[0048] In some embodiments, the pharmaceutical compositions described herein are prepared by a process that includes a wet granulation method.

[0049] Another embodiment is a solid tablet formulation comprising nor-UDCA, wherein the solid tablet formulation comprises at least about 30% w / w or more of nor-UDCA.

[0050] Another embodiment is a solid tablet formulation comprising nor-UDCA, wherein the solid tablet formulation comprises from about 30% w / w to about 90% w / w of nor-UDCA.

[0051] Another embodiment is a high-load solid tablet formulation comprising at least 30% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0052] Another embodiment is a high-load solid tablet formulation comprising at least 40% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0053] Another embodiment is a high-load solid tablet formulation comprising at least 50% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0054] Another embodiment is a high-load solid tablet formulation comprising from about 30% w / w to about 90% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0055] Another embodiment is a high-load solid tablet formulation comprising from about 40% w / w to about 90% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0056] Another embodiment is a high-load solid tablet formulation comprising from about 50% w / w to about 90% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0057] Another embodiment is a high-load solid tablet formulation comprising from about 40% w / w to about 80% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0058] Another aspect is a high-load solid tablet formulation comprising from about 50% w / w to about 80% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0059] Another aspect is a high-load solid tablet formulation comprising from about 60% w / w to about 80% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0060] Another aspect is a high-load solid tablet formulation comprising from about 50% w / w to about 80% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0061] Another aspect is a high-load solid tablet formulation comprising from about 50% w / w to about 80% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the high-load solid tablet contains from about 500 mg to about 1000 mg of nor-UDCA.

[0062] Another aspect is a high-load solid tablet formulation comprising from about 60% w / w to about 75% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0063] Another aspect is a high-load solid tablet formulation comprising from about 75% w / w to about 90% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients.

[0064] A further aspect is a high-load solid tablet formulation comprising from about 75% w / w to about 90% w / w of nor-UDCA, wherein the high-load solid tablet contains from about 1000 mg to greater than about 1500 mg of nor-UDCA.

[0065] Another aspect is a high-load solid tablet formulation comprising at least 30% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount from about 10% w / w to about 70% w / w.

[0066] Another aspect is a high-load solid tablet formulation comprising from about 30% w / w to about 90% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of from about 10% w / w to about 70% w / w.

[0067] Another aspect is a high-load solid tablet formulation comprising from about 50% w / w to about 80% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of from about 20% w / w to about 50% w / w.

[0068] Another aspect is a high-load solid tablet formulation comprising from about 60% w / w to about 75% w / w of nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of from about 25% w / w to about 40% w / w.

[0069] In a further aspect of the present invention, the present invention provides a tablet dosage form comprising at least one pharmaceutically acceptable excipient selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and optionally a coating agent for coating the tablet dosage form.

[0070] In one aspect of the present invention, the present invention is (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients and provides a pharmaceutical composition.

[0071] In another aspect of the present invention, the present invention is (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients and provides a pharmaceutical composition consisting essentially of.

[0072] In a further aspect of the present invention, the present invention is (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b)One or more pharmaceutically acceptable excipients to provide a pharmaceutical composition comprising the same.

[0073] In another aspect of the present invention, the present invention relates to (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients to provide a high-load solid tablet.

[0074] In a further aspect of the present invention, the present invention relates to (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients to provide a high-load solid tablet consisting essentially of the foregoing.

[0075] In an aspect of the present invention, the present invention relates to (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, and film coating agents to provide a pharmaceutical composition comprising the same.

[0076] In an aspect of the present invention, the present invention relates to (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, and film coating agents to provide a pharmaceutical composition consisting essentially of the foregoing.

[0077] In another aspect of the present invention, the present invention relates to (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and a film coating agent to provide a pharmaceutical composition comprising the same.

[0078] In one aspect of the present invention, the immediate release tablets contain from about 100 mg to about 2000 mg of nor-UDCA, preferably each immediate release tablet contains 100 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 1750 mg and 2000 mg of nor-UDCA, more preferably from about 500 mg, 750 mg, 1000 mg and 1500 mg of nor-UDCA.

[0079] In an aspect of the present invention, the diluents used in the present invention are selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, starch, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (as anhydrous or hydrate, for example as monohydrate), dextrose, maltose, sucrose, glucose, fructose, or maltodextrin. In a preferred aspect, the diluent is present in an amount of from about 1% w / w to about 50% w / w, preferably from about 2% w / w to about 45% w / w, more preferably from about 3% w / w to about 40% w / w, and most preferably from about 5% w / w to about 30% w / w, based on the total weight of the tablet dosage form. The most preferred diluent used in this tablet dosage form is microcrystalline cellulose.

[0080] In an aspect of the present invention, the tablet dosage form of the present invention contains microcrystalline cellulose as a diluent in an amount of 1% w / w to about 50% w / w, preferably from about 2% w / w to about 45% w / w, more preferably from about 3% w / w to about 40% w / w, and most preferably from about 5% w / w to about 30% w / w, based on the total weight of the tablet dosage form.

[0081] In a further specific embodiment of the present invention, the tablet dosage form of the present invention contains microcrystalline cellulose in the intragranular portion in an amount of about 10% w / w to about 20% w / w based on the total amount of microcrystalline cellulose in the tablet, and contains about 80% w / w to about 90% w / w of microcrystalline cellulose in the extragranular portion based on the total amount of microcrystalline cellulose in the tablet.

[0082] In a further aspect of the present invention, the tablet dosage form of the present invention contains a binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose, including any mixture thereof. In a preferred embodiment, the binder is present in an amount of about 1% w / w to about 25% w / w, preferably about 2% w / w to about 20% w / w, more preferably about 3% w / w to about 15% w / w, and most preferably about 5% w / w to about 10% w / w based on the total weight of the tablet dosage form.

[0083] In a preferred embodiment of the present invention, the tablet dosage form of the present invention contains polyvinylpyrrolidone as a binder, and most preferably is used in an amount of about 5% w / w to about 10% w / w based on the total weight of the tablet dosage form.

[0084] In an aspect of the present invention, the tablet dosage form of the present invention contains a disintegrant selected from the group consisting of sodium starch glycolate, crospovidone, and croscarmellose sodium. In a preferred embodiment, the tablet dosage form of the present invention contains a disintegrant in an amount of about 0.2% w / w to about 20% w / w, and most preferably contains a disintegrant in an amount of about 1% w / w to about 10% w / w based on the total weight of the tablet dosage form.

[0085] In one aspect of the present invention, the disintegration time of the high-load solid immediate-release tablets of the present invention is less than about 20 minutes, preferably less than about 15 minutes, more preferably less than about 10 minutes, even more preferably less than about 7.5 minutes, and most preferably less than 5 minutes.

[0086] The inventors of the present invention surprisingly found that the disintegration time of high-load immediate-release tablets containing from about 30% w / w to more than about 90% w / w of nor-UDCA is a disintegration time of less than about 20 minutes, where the tablet dosage forms contain about 500 mg, 750 mg, 1000 mg, 1500 mg, and 2000 mg of nor-UDCA.

[0087] The inventors of the present invention surprisingly found that the dissolution or release of nor-UDCA from high-load immediate-release tablets containing from about 30% w / w to more than about 90% w / w of nor-UDCA has a dissolution or release of more than 75% in about 30 minutes, where the tablet dosage forms contain about 500 mg, 750 mg, 1000 mg, 1500 mg, and 2000 mg of nor-UDCA.

[0088] In another aspect of the present invention, the dissolution or release of nor-UDCA from the high-load solid immediate-release tablets of the present invention has a dissolution or release of more than 75% in about 30 minutes.

[0089] In another aspect of the present invention, the dissolution or release of nor-UDCA from the high-load solid immediate-release tablets is close to 100% (or, in any case, better than the following limits: 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes, and 75% in 30 minutes in a medium consisting of 900 ml of water with 4% β-cyclodextrin buffer added at a blade rotation speed of a USP Type-II apparatus at 75 rpm).

[0090] In the most preferred embodiment, the tablet dosage form of the present invention most preferably contains croscarmellose sodium as a disintegrant. Surprisingly, the inventors have found that when compared with tablet dosage forms containing sodium starch glycolate and crospovidone as disintegrants, the tablet dosage form containing croscarmellose sodium has a significantly shorter disintegration time, and thus croscarmellose sodium is the most preferred disintegrant. Further, the inventors have surprisingly found that when all of the croscarmellose sodium is used in the extra-granular portion of the tablet, the disintegration time of the tablet is extremely short compared to tablets containing all of the croscarmellose sodium in the intra-granular portion and tablets containing croscarmellose sodium in both the intra-granular and extra-granular portions. In the most preferred embodiment, the tablet dosage form of the present invention contains about 0.2% w / w to about 20% w / w of croscarmellose sodium as a disintegrant, based on the total weight of the tablet dosage form, and most preferably about 1% w / w to about 10% w / w of croscarmellose sodium as a disintegrant, based on the total weight of the tablet dosage form.

[0091] In an embodiment of the present invention, the present invention provides (a) about 30% w / w to about 90% w / w of nor-UDCA and (b) croscarmellose sodium as a disintegrant in a tablet dosage form.

[0092] In an embodiment of the present invention, the tablet dosage form of the present invention contains a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate. The most preferably used lubricant in the present invention is magnesium stearate, which is used in an amount of about 0.2% w / w to about 2% w / w based on the total weight of the tablet dosage form in the present invention.

[0093] In an embodiment of the present invention, the tablet dosage form is film-coated with the coating material Opadry. A typical composition of the coating material Opadry can be a combination of polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

[0094] In an embodiment of the present invention, the tablet dosage form of the present invention does not contain a surfactant, and is preferably selected from sodium lauryl sulfate, polysorbate 80, and poloxamer.

[0095] In another embodiment of the present invention, the present invention provides (a) about 30% w / w to about 90% w / w of nor-UDCA, (b) about 5% w / w to about 30% w / w of a diluent, (c) about 5% w / w to about 10% w / w of a binder, (d) about 1% w / w to about 10% w / w of a disintegrant, (e) based on the total weight of the tablet, about 0.2% w / w to about 2% w / w of a lubricant and (f) optionally, the tablet is coated with a film coating composition and provides a tablet dosage form containing the same.

[0096] In the most preferred embodiment, the inventors have surprisingly found that the disintegration time of the tablet dosage form containing a combination of microcrystalline cellulose as a diluent and croscarmellose sodium as a disintegrant is significantly shorter than about 5 minutes, more preferably about 1 minute and 50 seconds, where about 10% w / w to about 20% w / w of microcrystalline cellulose based on the total amount of microcrystalline cellulose in the tablet is present in the intragranular portion, and about 80% w / w to about 90% w / w of microcrystalline cellulose based on the total amount of microcrystalline cellulose is present in the extragranular portion, and where the total amount of croscarmellose sodium is present in the extragranular portion.

[0097] In an aspect of the present invention, the present invention provides a tablet dosage form comprising nor-UDCA, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate as active ingredients, wherein the total amount of croscarmellose sodium is present in the extragranular portion of the tablet.

[0098] In one aspect of the present invention, the present invention provides a tablet dosage form comprising nor-UDCA, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate as active ingredients; wherein based on the total amount of microcrystalline cellulose, about 10% w / w to about 20% w / w of microcrystalline cellulose is present in the intragranular portion, and about 80% w / w to about 90% w / w of microcrystalline cellulose is present in the extragranular portion based on the total amount of microcrystalline cellulose, and wherein the total amount of croscarmellose sodium is present in the extragranular portion.

[0099] In a particular aspect of the present invention, the present invention provides (a) about 30% w / w to about 90% w / w of nor-UDCA, (b) about 5% w / w to about 30% w / w of microcrystalline cellulose, (c) about 5% w / w to about 10% w / w of polyvinylpyrrolidone, (d) about 1% w / w to about 10% w / w of croscarmellose sodium and (e) about 0.2% w / w to about 2% w / w of magnesium stearate based on the total weight of the tablet and provides a tablet dosage form.

[0100] In a more particular aspect of the present invention, the present invention provides (a) about 30% w / w to about 90% w / w of nor-UDCA, (b) about 5% w / w to about 30% w / w of microcrystalline cellulose, (c) about 5% w / w to about 10% w / w of polyvinylpyrrolidone, (d) about 1% w / w to about 10% w / w of croscarmellose sodium, (e) Magnesium stearate in an amount of about 0.2% w / w to about 2% w / w based on the total weight of the tablets, wherein about 10% w / w to about 20% w / w of the microcrystalline cellulose based on the total amount of microcrystalline cellulose is present in the intragranular portion, and about 80% w / w to about 90% w / w of the total microcrystalline cellulose based on the total amount of microcrystalline cellulose is present in the extragranular portion, and wherein the total amount of croscarmellose sodium is present in the extragranular portion to provide a tablet dosage form containing the same.

[0101] In an aspect of the present invention, the present invention relates to a process for the preparation of tablets by a wet / wetting granulation method, preferably by a rapid mixing granulation method or a fluidized bed granulation method.

[0102] In another aspect of the present invention, the present invention relates to a process for the preparation of tablets by a dry granulation method, more preferably by a roller compression method.

[0103] In an aspect of the present invention, the present invention (a) a first granule containing nor-UDCA is prepared by wet granulation, and (b) the granule is then converted into a tablet dosage form by addition of the total amount of croscarmellose sodium and other pharmaceutically acceptable excipients, to provide a process for the preparation of tablets containing nor-UDCA.

[0104] In an aspect of the present invention, the present invention (a) a first granule containing nor-UDCA, about 10% w / w to about 20% w / w of microcrystalline cellulose based on the total amount of microcrystalline cellulose, and polyvinylpyrrolidone is prepared by wet granulation; and (b) the granule is then converted into a tablet dosage form by addition of about 80% w / w to about 90% w / w of the total microcrystalline cellulose based on the total amount of microcrystalline cellulose and the total amount of croscarmellose sodium and magnesium stearate, to provide a process for the preparation of tablets containing nor-UDCA.

[0105] In aspects of the present invention, the present invention relates to tablets comprising nor-UDCA for the treatment of inflammatory cholestatic liver diseases in a subject, where the inflammatory cholestatic liver disease is primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or progressive familial intrahepatic cholestasis, in particular progressive familial intrahepatic cholestasis types 1, 2 and 3, cystic fibrosis, drug-induced cholestasis, or non-cholestatic liver diseases such as chronic viral hepatitis (B, C, D), alcoholic and non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency.

[0106] To illustrate the present invention, the following examples are provided. However, it is understood that the present invention is not limited to the specific conditions or details described in the following examples. The examples only provide specific methodologies useful for understanding and implementing the invention and its various aspects, and thus the examples should not be construed as limiting the invention. Specific preferred and alternative aspects of the present invention are described for the purpose of disclosing the present invention, but modifications to the disclosed aspects may occur to those skilled in the art.

[0107] Example - 1: nor-UDCA tablets prepared by direct compression without granulation

[0108] Tablet composition

Table A

[0109] Process for preparation 1. Sieving nor-UDCA, microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and sodium starch glycolate, and mixing to form a pre-lubricated blend. 2. Mixing the pre-lubricated blend with magnesium stearate to form a lubricated blend. 3. Directly compressing the lubricated blend with a suitable punch to form a tablet dosage form.

[0110] Example - 2: nor - UDCA tablets prepared by the wet granulation process

[0111] Tablet composition [Table B]

[0112] Process for preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. nor - UDCA and microcrystalline cellulose were admixed and mixed, and the further admixed mixture was wet granulated with the binder solution in a high - speed mixer - granulator to form wet granules. 3. The wet granules from Step 2 were dried in a fluid - bed processor to form dry granules. 4. The dry granules from Step 3 were admixed and mixed with sodium starch glycolate to form a pre - lubricated mixture. 5. The pre - lubricated mixture from Step 4 was admixed and mixed with magnesium stearate to form a lubricated blend. 6. The lubricated blend from Step 5 was compressed with suitable punches to form a tablet dosage form.

[0113] Example - 3: nor - UDCA tablets prepared by the wet granulation process

[0114] Tablet composition [Table C]

[0115] Process for preparation 1. Polyvinylpyrrolidone and sodium lauryl sulfate were slowly added and dissolved in pure water to form a binder solution. 2. nor - UDCA, microcrystalline cellulose, and some sodium starch glycolate were admixed and mixed, and the further admixed mixture was wet granulated with the binder solution in a high - speed mixer - granulator to form wet granules 3. Dry the wet granules from Step 2 in a fluid bed processor to form dry granules. 4. Mix and blend the dry granules from Step 3 with the remaining portion of sodium starch glycolate to form a pre-lubricated mixture. 5. Mix and blend the pre-lubricated mixture from Step 4 with magnesium stearate to form a lubricated blend. 6. Compress the lubricated blend from Step 5 with a suitable punch to form a tablet dosage form.

[0116] Example - 4: nor-UDCA tablets prepared by the wet granulation process

[0117] Tablet composition

Table D

[0118] Process for preparation 1. Slowly add polyvinylpyrrolidone and sodium lauryl sulfate and dissolve in pure water to form a binder solution. 2. Mix and blend nor-UDCA and microcrystalline cellulose, and further wet granulate the blended mixture with the binder solution in a high-speed mixer granulator to form wet granules. 3. Dry the wet granules from Step 2 in a fluid bed processor to form dry granules. 4. Mix and blend the dry granules from Step 3 with crospovidone to form a pre-lubricated mixture. 5. Mix and blend the pre-lubricated mixture from Step 4 with magnesium stearate to form a lubricated blend. 6. Compress the lubricated blend from Step 5 with a suitable punch to form a tablet dosage form.

[0119] Example - 5: nor-UDCA tablets prepared by the wet granulation process

[0120] Tablet composition

Table E

[0121] Process for preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. nor-UDCA, microcrystalline cellulose, and some croscarmellose were admixed and mixed, and the further admixed mixture was wet granulated with the binder solution in a high-speed mixer granulator to form wet granules. 3. The wet granules from Step 2 were dried in a fluid bed processor to form dry granules. 4. The dry granules from Step 3 were admixed and mixed with the remaining portion of sodium croscarmellose to form a pre-lubricated mixture. 5. The pre-lubricated mixture from Step 4 was admixed and mixed with magnesium stearate to form a lubricated blend. 6. The lubricated blend from Step 5 was compressed with suitable punches to form a tablet dosage form.

[0122] Example - 6: nor-UDCA tablets prepared by the wet granulation process

[0123] Tablet composition

Table F

[0124] Process for preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. nor-UDCA, microcrystalline cellulose, and some croscarmellose were admixed and mixed, and the further admixed mixture was wet granulated with the binder solution in a high-speed mixer granulator to form wet granules. 3. The wet granules from Step 2 were dried in a fluid bed processor to form dry granules. 4. The dry granules from Step 3 were admixed and mixed with the remaining portion of sodium croscarmellose to form a pre-lubricated mixture. 5. The pre-lubricated mixture from Step 4 was admixed and blended with magnesium stearate to form a lubricated blend. 6. The lubricated blend from Step 5 was compressed with suitable punches to form a tablet dosage form.

[0125] Example - 7: nor-UDCA tablets prepared by the wet granulation process

[0126] Tablet composition

Table G

[0127] Process for preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. nor-UDCA, and a portion of microcrystalline cellulose were admixed and blended, and the further admixed mixture was wet granulated with the binder solution in a high shear mixer granulator to form wet granules. 3. The wet granules from Step 2 were dried in a fluid bed processor to form dry granules. 4. The dry granules from Step 3 were admixed and blended with croscarmellose sodium and the remaining portion of microcrystalline cellulose to form a pre-lubricated mixture. 5. The pre-lubricated mixture from Step 4 was admixed and blended with magnesium stearate to form a lubricated blend. 6. The lubricated blend from Step 5 was compressed with suitable punches to form a tablet dosage form.

[0128] Example - 8: Film coating of nor-UDCA of Example - 7

[0129] Tablet composition

Table H

[0130] Process for preparation 1. Prepare the core tablets of nor-UDCA by the process as disclosed in Example-7. 2. Coat the core tablets of Example-7 with an Opadry coating dispersion prepared by dispersing Opadry II white material in pure water.

[0131] Example-9: Disintegration time tablet test of Examples 1 to 8.

[0132] The disintegration time of the tablets of Examples 1 to 8 was determined using the apparatus as disclosed in USP General Chapter 701, and the disintegration time of the tablets is shown in Table-1 below.

Table 1

[0133] Example-10: Dissolution profile of the nor-UDCA tablets of Example-8

[0134] The dissolution of the tablets of Example-8 was carried out using a USP Type-II (paddle) apparatus in 900 mL of pure water containing 4% β-cyclodextrin buffer at 75 RPM at a temperature of 37 ± 0.5°C. The dissolution results are shown in Table-2.

Table 2

[0135] Example-11: nor-UDCA tablets prepared by wet granulation

[0136] Tablet composition

Table I

[0137] Process for preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. Nor-UDCA, microcrystalline cellulose, and some croscarmellose sodium were admixed and mixed, and the further admixed mixture was wet granulated with a binder solution in a high-speed mixer granulator to form wet granules. 3. The wet granules of Step 2 were dried in a fluid bed processor to form dry granules. 4. The dry granules of Step 3 were admixed and mixed with some croscarmellose sodium to form a pre-lubricated mixture. 5. The pre-lubricated mixture of Step 4 was admixed and mixed with magnesium stearate to form a lubricated blend. 6. The lubricated blend of Step 5 was compressed with suitable punches to form a tablet dosage form.

[0138] Example - 12: Nor-UDCA tablets prepared by wet granulation.

[0139] Tablet Composition

Table J

[0140] Process for Preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. Nor-UDCA and some microcrystalline cellulose were admixed and mixed, and the further admixed mixture was wet granulated with the binder solution in a high-speed mixer granulator to form wet granules. 3. The wet granules of Step 2 were dried in a fluid bed processor to form dry granules. 4. The dry granules of Step 3 were admixed and mixed with croscarmellose sodium and the remaining portion of microcrystalline cellulose to form a pre-lubricated mixture. 5. The pre-lubricated mixture of Step 4 was admixed and mixed with magnesium stearate to form a lubricated blend. 6. The lubricated blend of Step 5 was compressed with suitable punches to form a tablet dosage form.

[0141] Example - 13: Disintegration time tablet test of Examples 11 and 12.

[0142] The disintegration times of the tablets in Examples 11 and 12 were determined using an apparatus as disclosed in USP General Chapter 701, and the disintegration times of the tablets are shown in Table - 3 below. [Table 3]

[0143] Examples 14 - 17: nor - UDCA tablets prepared by wet granulation.

[0144] Tablet composition [Table K]

[0145] Process for preparation 1. Polyvinylpyrrolidone was slowly added and dissolved in pure water to form a binder solution. 2. nor - UDCA and some microcrystalline cellulose were admixed and mixed, and the further admixed mixture was wet - granulated with the binder solution in a high - speed mixer - granulator to form wet granules. 3. The wet granules from Step 2 were dried in a fluid - bed processor to form dry granules. 4. The dry granules from Step 3 were admixed and mixed with croscarmellose sodium and the remaining part of the microcrystalline cellulose to form a pre - lubricated mixture as required. 5. The pre - lubricated mixture from Step 4 was admixed and mixed with magnesium stearate to form a lubricated blend. 6. The lubricated blend from Step 5 was compressed with a suitable punch to form a tablet dosage form.

[0146] Observation: The disintegration times of the tablets in Examples 14 - 17 were determined using an apparatus as disclosed in USP General Chapter 701, and the disintegration times of the tablets are shown in Table - 4 below. [Table 4]

[0147] Examples 18 to 21: nor-UDCA tablets prepared by wet granulation

[0148] Tablet composition

Table L

[0149] Observation: The disintegration times of the tablets in Examples 18 to 19 were determined using an apparatus as disclosed in USP General Chapter 701, and the disintegration times of the tablets are shown in Table - 5 below.

Table 5

[0150] Example 22: nor-UDCA tablets prepared by direct compression

[0151] Tablet composition

Table M

[0152] Examples 23 to 25: nor-UDCA tablets prepared by wet granulation

[0153] Tablet composition

Table N

[0154] Observation: The disintegration times of the tablets in Examples 23 to 25 were determined using an apparatus as disclosed in USP General Chapter 701, and the disintegration times of the tablets are shown in Table-6 below. [Table 6]

[0155] Examples 26 to 28: nor-UDCA tablets prepared by wet granulation.

[0156] Tablet composition [Table O] The process for preparation was the same as the process for preparation disclosed in Examples 14 to 17.

[0157] Observation: The disintegration times of the tablets in Examples 26 to 28 were determined using an apparatus as disclosed in USP General Chapter 701, and the disintegration times of the tablets are shown in Table-7 below. [Table 7]

[0158] Examples 29 to 31: nor-UDCA tablets prepared by wet granulation

[0159] Tablet composition [Table P] The process for preparation was the same as the process for preparation disclosed in Examples 14 to 17.

[0160] Observation: The disintegration times of the tablets in Examples 29 to 31 were determined using an apparatus as disclosed in USP General Chapter 701, and the disintegration times of the tablets are shown in Table-8 below. [Table 8]

Claims

1. (a)About 30% w / w to about 90% w / w of nor - UDCA or a pharmaceutically acceptable salt thereof and (b)One or more pharmaceutically acceptable excipients A pharmaceutical composition comprising.

2. The pharmaceutical composition according to claim 1, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants and film - coating agents.

3. The pharmaceutical composition according to claim 1, wherein the composition consists of about 250 mg to about 2000 mg of nor - UDCA.

4. The average particle size (D ５０ ) of nor-U DCA is less than 50 μm, and the pharmaceutical composition according to claim 1.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from the group consisting of immediate - release tablets, effervescent tablets, chewable tablets, orally disintegrating tablets, chewable tablets, capsules, pills, powders and granules.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a high - load solid immediate - release tablet.

7. The high - load solid immediate - release tablet is (a)About 5% w / w to about 30% w / w of a diluent, (b)About 5% w / w to about 10% w / w of a binder, (c)About 1% w / w to about 10% w / w of a disintegrant, and (d)About 0.2% w / w to about 2% w / w of a lubricant The pharmaceutical composition according to claim 1, consisting of.

8. The high - load solid immediate - release tablet is (a)About 5% w / w to about 30% w / w of microcrystalline cellulose, (b)About 5% w / w to about 10% w / w of polyvinylpyrrolidone, (c)About 1% w / w to about 10% w / w of croscarmellose sodium and (d)Based on the total weight of the tablet, about 0.2% w / w to about 2% w / w of magnesium stearate The pharmaceutical composition according to claim 7, consisting of.

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