Pharmaceutical composition of Nor-UDCA

Abstract

The present invention relates to a pharmaceutical composition comprising no-UDCA or a pharmaceutically acceptable salt or ester thereof, and a method for preparing the same. The invention preferably discloses a solid oral dosage form of the non-UDCA, and the solid oral dosage form is preferably in the form of a tablet, a capsule, a disintegrating tablet and an effervescent tablet.

Description

Technical Field

[0001] 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 preparation process thereof. The present invention more specifically relates to a pharmaceutical composition comprising at least about 30% w / w nor-UDCA or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient. Background Art

[0002] 24-Norursodeoxycholic acid (nor-UDCA) is an ursodeoxycholic acid analog (bile acid derivative) used for the treatment and / or prevention of liver disease (preferably chronic liver disease). Nor-UDCA has the following structural formula

[0003]

[0004] EP Patent No. 0624595B1 ("EP'595 Patent") discloses nor-UDCA, its preparation method and its use, especially for lowering cholesterol, with a daily dosage ranging from 3 mg to 5000 mg, preferably ranging from 10 mg to 1000 mg, depending on the patient's weight and constitution. In addition, the EP'595 Patent discloses various dosage forms, preferably oral dosage forms in the form of tablets, capsules or liquids.

[0005] U.S. Patent No. 8,951,995 ("the US'995 patent") discloses a method of treating an inflammatory cholestatic liver disease in a subject, the method comprising 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 type 1, type 2 and type 3), cystic fibrosis, drug-induced cholestasis or non-cholestatic liver disease (e.g., chronic viral hepatitis (B, C, D)), alcoholic and non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease and alpha-1-antitrypsin deficiency. In addition, US'995 patent discloses solid dosage forms for oral administration, including tablets, preferably effervescent tablets or chewable tablets, capsules, pills, powders and granules, in which 24-norursodeoxycholic acid can be mixed with conventionally used substances (such as sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, lubricants (such as magnesium stearate), disintegrants and buffers). Tablets and pills can also be prepared with enteric coatings to prevent 24-norursodeoxycholic acid from being affected by gastric acid and enzymes. As immediate release tablets, these compositions can also contain microcrystalline cellulose and / or dicalcium phosphate.

[0006] US 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 of <10 μm, and wherein the polymorph is substantially free of detectable amorphous nor-UDCA. In addition, US'167 patent discloses solid dosage forms for oral administration, including tablets, preferably effervescent tablets or chewable tablets, capsules, pills, powders, and granules.

[0007] The above prior art discloses a pharmaceutical composition for oral administration, which includes a tablet dosage form containing nor-UDCA. Pharmaceutical tablets containing nor-UDCA have certain disadvantages, and the problems arising therefrom are the dissolution rate, and the disintegration of the tablets varies from batch to batch, with some batches having unacceptably low rates.

[0008] In view of the above disadvantages, there is a need to develop a pharmaceutical composition, most preferably a tablet dosage form comprising nor-UDCA or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, which provides consistent disintegration and dissolution from batch to batch of tablet dosage forms. Summary of the invention

[0009] The present invention relates to a pharmaceutical composition comprising 24-norursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[0010] In an embodiment of the present invention, the present invention provides a tablet dosage form (immediate release tablet) comprising 24-norursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[0011] In a preferred embodiment of the present invention, nor-UDCA is used in crystalline form.

[0012] In a particularly preferred embodiment of the invention, crystalline nor-UDCA is used in micronized form. In this case, the nor-UDCA preferably has an average particle size D of less than 50 μm (in particular from 1 μm to 20 μm). 50 .

[0013] In another embodiment of the present invention, the present invention provides a tablet dosage form comprising at least about 30% w / w nor-UDCA or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[0014] In other embodiments of the present invention, the present invention provides a pharmaceutical composition, preferably a tablet dosage form, comprising (a) 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.

[0015] In another embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0016] Based on the total weight of the tablet,

[0017] (a) from about 30% w / w to about 90% w / w nor-UDCA,

[0018] (b) from about 5% w / w to about 30% w / w of a diluent,

[0019] (c) from about 5% w / w to about 10% w / w of a binder,

[0020] (d) from about 1% w / w to about 10% w / w of a disintegrant,

[0021] (e) from about 0.2% w / w to about 2% w / w of a lubricant, and

[0022] (f) Optionally, the tablet is coated with a film coating composition.

[0023] In one embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0024] (a) from about 30% w / w to about 90% w / w nor-UDCA, and

[0025] (b) Croscarmellose sodium as a disintegrant.

[0026] In one embodiment of the present invention, the present invention provides a tablet dosage form comprising as active ingredients nor-UDCA, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate; wherein about 10% w / w to about 20% w / w of the microcrystalline cellulose based on the total amount of microcrystalline cellulose in the tablet is present in the intragranular portion, about 80% w / w to about 90% w / w of the microcrystalline cellulose based on the total amount of microcrystalline cellulose in the tablet is present in the extragranular portion, and wherein the entire amount of croscarmellose sodium is present in the extragranular portion.

[0027] In a specific embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0028] Based on the total weight of the tablet,

[0029] (a) from about 30% w / w to about 90% w / w nor-UDCA,

[0030] (b) about 5% w / w to about 30% w / w microcrystalline cellulose,

[0031] (c) from about 5% w / w to about 10% w / w polyvinylpyrrolidone,

[0032] (d) from about 1% w / w to about 10% w / w croscarmellose sodium, and

[0033] (e) from about 0.2% w / w to about 2% w / w magnesium stearate.

[0034] In a more specific embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0035] Based on the total weight of the tablet,

[0036] (a) from about 30% w / w to about 90% w / w nor-UDCA,

[0037] (b) about 5% w / w to about 30% w / w microcrystalline cellulose,

[0038] (c) from about 5% w / w to about 10% w / w polyvinylpyrrolidone,

[0039] (d) from about 1% w / w to about 10% w / w croscarmellose sodium,

[0040] (e) from about 0.2% w / w to about 2% w / w magnesium stearate,

[0041] 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 microcrystalline cellulose, based on the total amount of microcrystalline cellulose, is present in the extragranular portion, and wherein the entire amount of croscarmellose sodium is present in the extragranular portion.

[0042] definition

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit any subject matter claimed. In this application, unless otherwise specified, the use of the singular includes the plural. It must be noted that, unless the context clearly specifies otherwise, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural indicators. In this application, unless otherwise specified, the use of "or" means "and / or". In addition, the use of the term "including" and other forms, such as "include", "includes" and "included" is not restrictive.

[0044] The section headings used herein are for organizational purposes only and should not 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 treatises, are hereby expressly incorporated by reference for any purpose.

[0045] The term "about" when used before a numerical value indicates that the value may vary within a reasonable range, for example, within ±10%, ±5%, or ±1% of the stated value.

[0046] As used herein, the term "comprising" or grammatical variations thereof is intended to indicate that compositions, methods, etc. include the recited elements, but not excluding other elements.

[0047] As used herein, the term "comprising" or grammatical variations thereof is intended to indicate that compositions, methods, etc. include the recited elements, but not excluding other elements.

[0048] When used to define compositions and methods, "consisting essentially of" or grammatical variations thereof means excluding other elements that have any significance to the intended use of the combination, but does not exclude elements that do not materially affect the characteristics of the composition or method.

[0049] "Consisting of" or its grammatical variations exclude elements not specifically listed.

[0050] Embodiments defined by each of these transition terms are within the scope of the present invention. For example, when a formulation is described as comprising ingredients A, B, and C, a formulation consisting essentially of A, B, and C and a formulation consisting of A, B, and C are independently within the scope of the present invention.

[0051] The terms "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0052] As used herein, the term "wet granulation" or "wet granulation" refers to the use of a granulating liquid (water, an organic solvent or a solution) to form granules.

[0053] As used herein, the term "dry granulation" refers to the formation of granules without the use of a granulating liquid (water, organic solvent or solution).

[0054] As used herein, the term "high-load solid tablet formulation" refers to a solid tablet comprising at least 30% w / w nor-UDCA per tablet. DETAILED DESCRIPTION

[0055] The present invention provides a pharmaceutical composition comprising 24-norursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[0056] In one embodiment of the invention, the pharmaceutical composition is a solid dosage form for oral administration, including tablets (immediate release tablets), effervescent tablets 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).

[0057] In an embodiment of the present invention, the present invention provides a tablet dosage form (immediate release tablet) comprising 24-norursodeoxycholic acid (nor-UDCA) or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[0058] In one embodiment of the present invention, the present invention provides a tablet dosage form (immediate release tablet) comprising nor-UDCA and a method for preparing the same, wherein the immediate release tablet has high bioavailability by improved dissolution. The present invention particularly relates to an immediate release tablet administered by oral route, which contains nor-UDCA which is poorly soluble in water.

[0059] The disadvantage of nor-UDCA is that it has poor solubility in aqueous media, so after oral administration, the dissolution profile in the body is insufficient and the bioavailability is low. Therefore, in order to eliminate this disadvantage, the therapeutic dose required for administration must be increased.

[0060] In order to improve the dissolution profile of nor-UDCA and its bioavailability, it would be useful to increase its dissolution to a level close to 100%.

[0061] In a preferred embodiment of the present invention, nor-UDCA is used in crystalline form.

[0062] In a particularly preferred embodiment of the invention, crystalline nor-UDCA is used in micronized form. In this case, the nor-UDCA preferably has an average particle size D of less than 50 μm (in particular from 1 μm to 20 μm). 50 .

[0063] In an embodiment of the present invention, the present invention provides a tablet dosage form comprising at least about 30% w / w nor-UDCA or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable excipient.

[0064] 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 based on the total weight of the tablet dosage form, preferably an amount of about 30% w / w to about 90% w / w of nor-UDCA based on the total weight of the tablet dosage form, 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.

[0065] In embodiments of the present invention, tablets according to the present invention allow for higher drug loadings than prior art tablets, which only exemplify tablets having a nor-UDCA (active ingredient) loading of at least or greater than about 30% w / w. Such higher nor-UDCA loadings allow for the preparation of smaller and lighter tablets, which may be easier to swallow. Furthermore, higher nor-UDCA loadings allow for higher doses in a single tablet, such as 500 mg, 750 mg, 1000 mg, and 1500 mg. This reduces the pill burden on the patient, thereby increasing patient compliance.

[0066] Furthermore, in another embodiment, the high-load solid immediate release tablet of the present invention comprising at least or greater than about 30% w / w nor-UDCA has low brittleness and good tensile strength.

[0067] In some embodiments, the pharmaceutical compositions described herein are prepared by a process comprising wet granulation.

[0068] In another embodiment is a solid tablet formulation comprising nor-UDCA, wherein the solid tablet formulation comprises at least about 30% w / w or greater than 30% w / w nor-UDCA.

[0069] In another embodiment is a solid tablet formulation comprising nor-UDCA, wherein the solid tablet formulation comprises about 30% w / w to about 90% w / w nor-UDCA.

[0070] In another embodiment is a high-load solid tablet formulation comprising at least 30% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0071] In another embodiment is a high-load solid tablet formulation comprising at least 40% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0072] In another embodiment is a high-load solid tablet formulation comprising at least 50% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0073] In another embodiment is a high-load solid tablet formulation comprising about 30% w / w to about 90% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0074] In another embodiment is a high-load solid tablet formulation comprising about 40% w / w to about 90% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0075] In another embodiment is a high-load solid tablet formulation comprising about 50% w / w to about 90% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0076] In another embodiment is a high-load solid tablet formulation comprising about 40% w / w to about 80% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0077] In another embodiment is a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0078] In another embodiment is a high-load solid tablet formulation comprising about 60% w / w to about 80% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0079] In another embodiment is a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0080] In another embodiment is a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the high-load solid tablet comprises about 500 mg to about 1000 mg of nor-UDCA.

[0081] In another embodiment is a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0082] In another embodiment is a high-load solid tablet formulation comprising about 75% w / w to about 90% w / w nor-UDCA and one or more pharmaceutically acceptable excipients.

[0083] In another embodiment is a high-load solid tablet formulation comprising about 75% w / w to about 90% w / w nor-UDCA, wherein the high-load solid tablet comprises greater than about 1000 mg to about 1500 mg of nor-UDCA.

[0084] In another embodiment is a high-load solid tablet formulation comprising at least 30% w / w nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 10% w / w to about 70% w / w.

[0085] In another embodiment is a high-load solid tablet formulation comprising about 30% w / w to about 90% w / w nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 10% w / w to about 70% w / w.

[0086] In another embodiment is a high-load solid tablet formulation comprising about 50% w / w to about 80% w / w nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 20% w / w to about 50% w / w.

[0087] In another embodiment is a high-load solid tablet formulation comprising about 60% w / w to about 75% w / w nor-UDCA and one or more pharmaceutically acceptable excipients, wherein the one or more excipients are present in an amount of about 25% w / w to about 40% w / w.

[0088] In other embodiments 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 an optional coating agent for coating the tablet dosage form.

[0089] In one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising

[0090] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0091] (b) one or more pharmaceutically acceptable excipients.

[0092] In another embodiment of the present invention, the present invention provides a pharmaceutical composition consisting essentially of:

[0093] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0094] (b) one or more pharmaceutically acceptable excipients.

[0095] In other embodiments of the present invention, the present invention provides a pharmaceutical composition consisting of

[0096] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0097] (b) one or more pharmaceutically acceptable excipients.

[0098] In another embodiment of the present invention, the present invention provides a high-load solid tablet comprising

[0099] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0100] (b) one or more pharmaceutically acceptable excipients.

[0101] In other embodiments of the present invention, the present invention provides a high-load solid tablet consisting essentially of:

[0102] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0103] (b) one or more pharmaceutically acceptable excipients.

[0104] In an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising

[0105] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0106] (b) one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants and film coating agents.

[0107] In an embodiment of the present invention, the present invention provides a pharmaceutical composition consisting essentially of:

[0108] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0109] (b) one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants and film coating agents.

[0110] In another embodiment of the present invention, the present invention provides a pharmaceutical composition consisting of

[0111] (a) from about 30% w / w to about 90% w / w of nor-UDCA or a pharmaceutically acceptable salt thereof, and

[0112] (b) one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, lubricants and film coating agents.

[0113] In one embodiment of the present invention, the immediate-release tablet contains 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, and more preferably contains about 500 mg, 750 mg, 1000 mg and 1500 mg of nor-UDCA.

[0114] In an embodiment of the present invention, the diluent used in the present invention is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, starch, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, such as a monohydrate), dextrose, maltose, sucrose, glucose, fructose or maltodextrin. In a preferred embodiment, the diluent is present in an amount of about 1% w / w to about 50% w / w, preferably about 2% w / w to about 45% w / w, more preferably about 3% w / w to about 40% w / w, and most preferably 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 the tablet dosage form of the present invention is microcrystalline cellulose.

[0115] In an embodiment 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 about 2% w / w to about 45% w / w, more preferably about 3% w / w to about 40% w / w, and most preferably about 5% w / w to about 30% w / w, based on the total weight of the tablet dosage form.

[0116] In other specific embodiments of the present invention, the tablet dosage form of the present invention contains about 10% w / w to about 20% w / w of microcrystalline cellulose based on the total amount of microcrystalline cellulose in the tablet of the intragranular portion, and about 80% w / w to about 90% w / w of microcrystalline cellulose based on the total amount of microcrystalline cellulose in the tablet of the extragranular portion.

[0117] In other embodiments of the present invention, the tablet dosage form of the present invention contains a binder selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and 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.

[0118] In a preferred embodiment of the present invention, the tablet dosage form of the present invention contains polyvinylpyrrolidone as a binder, and most preferably used in an amount of about 5% w / w to about 10% w / w based on the total weight of the tablet dosage form.

[0119] In an embodiment 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 comprises about 0.2% w / w to about 20% w / w of disintegrant based on the total weight of the tablet dosage form, most preferably about 1% w / w to about 10% w / w of disintegrant based on the total weight of the tablet dosage form.

[0120] In one embodiment of the present invention, the disintegration time of the high-load solid immediate-release tablet 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.

[0121] The inventors of the present invention surprisingly discovered that high-load immediate release tablets containing greater than about 30% w / w to about 90% w / w nor-UDCA have a disintegration time of less than about 20 minutes, wherein the tablet dosage forms contain about 500 mg, 750 mg, 1000 mg, 1500 mg and 2000 mg of nor-UDCA.

[0122] The inventors of the present invention surprisingly discovered that the dissolution or release of nor-UDCA from a high-load immediate release tablet containing greater than about 30% w / w to about 90% w / w of nor-UDCA has greater than 75% dissolution or release in about 30 minutes, wherein the tablet dosage form contains about 500 mg, 750 mg, 1000 mg, 1500 mg and 2000 mg of nor-UDCA.

[0123] In another embodiment of the present invention, the dissolution or release of nor-UDCA from the high-load solid immediate release tablet of the present invention is greater than 75% within about 30 minutes.

[0124] In another embodiment of the invention, the dissolution or release of nor-UDCA from the high-load solid immediate-release tablet 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 to which 4% β-cyclodextrin buffer has been added, at a blade speed of 75 rpm in a USP Type-II apparatus).

[0125] In a 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 croscarmellose sodium is the most preferred disintegrant because the tablet dosage form containing croscarmellose sodium has a significantly shorter disintegration time compared to the tablet dosage form containing sodium starch glycolate and crospovidone as disintegrants. In addition, the inventors have surprisingly found that the disintegration time of the tablet is very short when the entire amount of croscarmellose sodium is used in the extragranular portion of the tablet compared to tablets containing the entire amount of croscarmellose sodium in the intragranular portion and tablets containing croscarmellose sodium in both the intragranular portion and the extragranular portion. In a 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.

[0126] In an embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0127] (a) from about 30% w / w to about 90% w / w nor-UDCA, and

[0128] (b) Croscarmellose sodium as a disintegrant.

[0129] 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 lubricant most preferably used in the present invention is magnesium stearate, which is used in the present invention in an amount of about 0.2% w / w to about 2% w / w based on the total weight of the tablet dosage form.

[0130] 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 may be a combination of polyvinyl alcohol, polyethylene glycol, talc and titanium dioxide.

[0131] In an embodiment of the present invention, the tablet dosage form of the present invention does not contain a surfactant, preferably selected from the group consisting of sodium lauryl sulfate, polysorbate 80 and poloxamers.

[0132] In another embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0133] Based on the total weight of the tablet,

[0134] (a) from about 30% w / w to about 90% w / w nor-UDCA,

[0135] (b) from about 5% w / w to about 30% w / w of a diluent,

[0136] (c) from about 5% w / w to about 10% w / w of a binder,

[0137] (d) from about 1% w / w to about 10% w / w of a disintegrant,

[0138] (e) from about 0.2% w / w to about 2% w / w of a lubricant, and

[0139] (f) Optionally, the tablet is coated with a film coating composition.

[0140] In a most preferred embodiment, the inventors surprisingly discovered that a tablet dosage form comprising a combination of microcrystalline cellulose as a diluent and croscarmellose sodium as a disintegrant has a disintegration time that is significantly less than about 5 minutes, more preferably about 1 minute 50 seconds, wherein about 10% w / w to about 20% w / w of the microcrystalline cellulose based on the total amount of microcrystalline cellulose in the tablet is present in the intragranular portion, about 80% w / w to about 90% w / w of the microcrystalline cellulose based on the total amount of microcrystalline cellulose is present in the extragranular portion, and wherein the entire amount of croscarmellose sodium is present in the extragranular portion.

[0141] In an embodiment of the present invention, the present invention provides a tablet dosage form comprising as active ingredients nor-UDCA, microcrystalline cellulose, polyvinyl pyrrolidone, croscarmellose sodium and magnesium stearate, wherein the entire amount of croscarmellose sodium is present in the extragranular portion of the tablet.

[0142] In one embodiment of the present invention, the present invention provides a tablet dosage form comprising as active ingredients nor-UDCA, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate; 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, about 80% w / w to about 90% w / w of the microcrystalline cellulose, based on the total amount of microcrystalline cellulose, is present in the extragranular portion, and wherein the entire amount of croscarmellose sodium is present in the extragranular portion.

[0143] In a specific embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0144] Based on the total weight of the tablet,

[0145] (a) from about 30% w / w to about 90% w / w nor-UDCA,

[0146] (b) about 5% w / w to about 30% w / w microcrystalline cellulose,

[0147] (c) from about 5% w / w to about 10% w / w polyvinylpyrrolidone,

[0148] (d) from about 1% w / w to about 10% w / w croscarmellose sodium, and

[0149] (e) from about 0.2% w / w to about 2% w / w magnesium stearate.

[0150] In a more specific embodiment of the present invention, the present invention provides a tablet dosage form comprising

[0151] Based on the total weight of the tablet,

[0152] (a) from about 30% w / w to about 90% w / w nor-UDCA,

[0153] (b) about 5% w / w to about 30% w / w microcrystalline cellulose,

[0154] (c) from about 5% w / w to about 10% w / w polyvinylpyrrolidone,

[0155] (d) from about 1% w / w to about 10% w / w croscarmellose sodium,

[0156] (e) from about 0.2% w / w to about 2% w / w magnesium stearate,

[0157] 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, 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 entire amount of croscarmellose sodium is present in the extragranular portion.

[0158] In an embodiment of the present invention, the present invention relates to a process for preparing tablets by wet / wet granulation, preferably rapid mixer granulation or fluidized bed granulation.

[0159] In another embodiment of the present invention, the present invention relates to a process for preparing tablets by dry granulation method, more preferably by roller compaction method.

[0160] In an embodiment of the present invention, the present invention provides a method for preparing a tablet comprising nor-UDCA, wherein:

[0161] (a) preparing first granules containing nor-UDCA by wet granulation; and

[0162] (b) The granules are then converted into tablet dosage form by adding the entire amount of croscarmellose sodium and other pharmaceutically acceptable excipients.

[0163] In an embodiment of the present invention, the present invention provides a process for preparing a tablet comprising nor-UDCA, wherein:

[0164] (a) preparing a first granule comprising nor-UDCA, about 10% w / w to about 20% w / w microcrystalline cellulose based on the total amount of microcrystalline cellulose and polyvinylpyrrolidone by wet granulation; and

[0165] (b) The granules are then converted into tablet dosage forms by adding about 80% w / w to about 90% w / w of total microcrystalline cellulose based on the total amount of microcrystalline cellulose and the entire amount of croscarmellose sodium and magnesium stearate.

[0166] In an embodiment of the invention, the present invention relates to a tablet comprising nor-UDCA for use in treating an inflammatory cholestatic liver disease in a subject, 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 type 1, type 2 and type 3), cystic fibrosis, drug-induced cholestasis or non-cholestatic liver disease (e.g. chronic viral hepatitis (B, C, D)), alcoholic and non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease and alpha-1-antitrypsin deficiency.

[0167] The following examples are provided to illustrate the present invention. However, it should be understood that the present invention is not limited to the specific conditions or details described in the following examples. These examples should not be construed as limiting the present invention, because these examples only provide specific methods that help understand and implement the present invention and its various aspects. Although some preferred and alternative embodiments of the present invention have been described for the purpose of disclosing the present invention, those skilled in the art may modify the disclosed embodiments.

[0168] Example 1: nor-UDCA tablets prepared by direct compression rather than granulation

[0169] Tablet composition

[0170]

[0171]

[0172] Preparation process

[0173] 1. Screen and mix Nor-UDCA, silicified microcrystalline cellulose, polyvinyl pyrrolidone, sodium lauryl sulfate and sodium glycolate starch to form a pre-lubricated blend.

[0174] 2. Blend the pre-lubricated blend with magnesium stearate to form a lubricated blend.

[0175] 3. Directly compress the lubricated blend using a suitable punch to form a tablet dosage form.

[0176] Example 2: Nor-UDCA tablets prepared by wet granulation process

[0177] Tablet composition

[0178]

[0179] Preparation process

[0180] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0181] 2. Nor-UDCA and microcrystalline cellulose were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixer granulator to form wet granules.

[0182] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0183] 4. Blend and mix the dried granules from step 3 with sodium starch glycolate to form a pre-lubricated mixture.

[0184] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0185] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0186] Example 3: Nor-UDCA tablets prepared by wet granulation process

[0187] Tablet composition

[0188]

[0189]

[0190] Preparation process

[0191] 1. Slowly add and dissolve polyvinyl pyrrolidone and sodium lauryl sulfate in purified water to form an adhesive solution.

[0192] 2. Nor-UDCA, microcrystalline cellulose, and a portion of sodium glycolate starch were blended and mixed, and the blended mixture was further wet-granulated with a binder solution in a rapid mixing granulator to form wet granules.

[0193] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0194] 4. Blend and mix the dried granules from step 3 with the remaining portion of sodium starch glycolate to form a pre-lubricated mixture.

[0195] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0196] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0197] Example 4: Nor-UDCA tablets prepared by wet granulation process

[0198] Tablet composition

[0199]

[0200] Preparation process

[0201] 1. Slowly add and dissolve polyvinyl pyrrolidone and sodium lauryl sulfate in purified water to form an adhesive solution.

[0202] 2. Nor-UDCA and microcrystalline cellulose were blended and mixed, and the blended mixture was further wet-granulated with a binder solution in a rapid mixing granulator to form wet granules.

[0203] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0204] 4. Blend and mix the dried granules from step 3 with the crospovidone to form a pre-lubricated mixture.

[0205] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0206] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0207] Example 5: Nor-UDCA tablets prepared by wet granulation process

[0208] Tablet composition

[0209]

[0210] Preparation process

[0211] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0212] 2. Nor-UDCA, microcrystalline cellulose and a portion of croscarmellose were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixing granulator to form wet granules.

[0213] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0214] 4. Blend and mix the dried granules from step 3 with the remaining portion of the croscarmellose sodium to form a pre-lubricated mixture.

[0215] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0216] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0217] Example 6: Nor-UDCA tablets prepared by wet granulation process

[0218] Tablet composition

[0219]

[0220] Preparation process

[0221] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0222] 2. Nor-UDCA, microcrystalline cellulose and a portion of croscarmellose were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixing granulator to form wet granules.

[0223] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0224] 4. Blend and mix the dried granules from step 3 with the remaining portion of the croscarmellose sodium to form a pre-lubricated mixture.

[0225] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0226] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0227] Example 7: Nor-UDCA tablets prepared by wet granulation process

[0228] Tablet composition

[0229]

[0230] Preparation process

[0231] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0232] 2. Nor-UDCA and a portion of microcrystalline cellulose were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixer granulator to form wet granules.

[0233] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0234] 4. Blend and mix the dried granules from step 3 with the croscarmellose sodium and the remaining portion of the microcrystalline cellulose to form a pre-lubricated mixture.

[0235] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0236] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0237] Example 8: Film coating of Nor-UDCA of Example 7

[0238] Tablet composition

[0239]

[0240]

[0241] Preparation process

[0242] 1. Nor-UDCA core tablets were prepared according to the process described in Example 7.

[0243] 2. The core tablets of Example 7 were coated with Opadry coating dispersion, which was prepared by dispersing Opadry II white material in purified water.

[0244] Example-9: Tablet disintegration time test of Examples 1-8

[0245] The disintegration time test of the tablets in Examples 1 to 8 was carried out by using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 1 below.

[0246] Table 1

[0247] Example No. Disintegration time Example 1 The blend has poor compaction properties and cannot be pressed into tablets Example 2 15 minutes 30 seconds Example 3 17 minutes 30 seconds Example 4 18 minutes 50 seconds Example 5 11 minutes 50 seconds Example 6 6 minutes 10 seconds Example 7 1 minute 50 seconds Example 8 3 minutes 30 seconds

[0248] Example 10: Dissolution profile of the Nor-UDCA tablet of Example 8

[0249] The tablets of Example 8 were dissolved using a USP Type-II (paddle) apparatus in purified water containing 4% β-cyclodextrin buffer / 900 mL at 37±0.5° C. and at a speed of 75 RPM. The dissolution results are shown in Table 2.

[0250] Table 2

[0251]

[0252]

[0253] Example 11: Nor-UDCA tablets prepared by wet granulation

[0254] Tablet composition

[0255]

[0256] Preparation process

[0257] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0258] 2. Nor-UDCA, microcrystalline cellulose and a portion of croscarmellose sodium were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixer granulator to form wet granules.

[0259] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0260] 4. Blend and mix the dried granules from step 3 with a portion of the croscarmellose sodium to form a pre-lubricated mixture.

[0261] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0262] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0263] Example 12: Nor-UDCA tablets prepared by wet granulation

[0264] Tablet composition

[0265]

[0266]

[0267] Preparation process

[0268] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0269] 2. Nor-UDCA and a portion of microcrystalline cellulose were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixing granulator to form wet granules.

[0270] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0271] 4. Blend and mix the dried granules from step 3 with the croscarmellose sodium and the remaining portion of the microcrystalline cellulose to form a pre-lubricated mixture.

[0272] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0273] 6. Compress the lubricated blend from step 5 using suitable punches to form tablet dosage forms.

[0274] Example 13: Tablet disintegration time test of Example 11 and Example 12

[0275] The tablet disintegration time test of Example 11 and Example 12 was carried out by using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 3 below.

[0276] Table 3

[0277] Example No. Disintegration time Embodiment 11 15 minutes 16 seconds Example 12 1 minute 30 seconds

[0278] Examples 14 to 17: Nor-UDCA tablets prepared by wet granulation

[0279] Tablet composition

[0280]

[0281] Preparation process

[0282] 1. Slowly add and dissolve polyvinyl pyrrolidone in purified water to form an adhesive solution.

[0283] 2. Nor-UDCA and a portion of microcrystalline cellulose were blended and mixed, and the blended mixture was further wet granulated with a binder solution in a rapid mixing granulator to form wet granules.

[0284] 3. The wet granules from step 2 are dried in a fluid bed processor to form dry granules.

[0285] 4. Blend and mix the dried granules from step 3 with croscarmellose sodium and the remaining portion of microcrystalline cellulose as required to form a pre-lubricated mixture.

[0286] 5. Blend and mix the pre-lubricated mixture from step 4 with the magnesium stearate to form a lubricated blend.

[0287] 6. Compress the lubricated blend from step 5 using a suitable punch to form a tablet dosage form.

[0288] Observation results: The disintegration time test of the tablets in Examples 14 to 17 was carried out by using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 4 below.

[0289] Table 4

[0290] Example No. Disintegration time Embodiment 14 25 minutes 16 seconds Embodiment 15 22 minutes 30 seconds Example 16 1 minute 10 seconds Embodiment 17 1 minute 40 seconds

[0291] Examples 18 to 21: Nor-UDCA tablets prepared by wet granulation

[0292] Tablet composition

[0293]

[0294] The preparation process is similar to the preparation process disclosed in Examples 14-17.

[0295] Tablets with the compositions of Example 20 and Example 21 could not be compressed due to compactibility issues.

[0296] Observation results: The disintegration time test of the tablets in Examples 18 and 19 was carried out using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 5 below.

[0297] Table 5

[0298]

[0299]

[0300] Example 22: Nor-UDCA Tablets Prepared by Direct Compression

[0301] Tablet composition

[0302]

[0303] Observations: When 99% w / w Nor-UDCA and 1.0% w / w magnesium stearate were mixed and compressed by direct compression, the blend had poor compactability and could not be compressed into tablets.

[0304] Examples 23 to 25: Nor-UDCA tablets prepared by wet granulation

[0305] Tablet composition

[0306]

[0307] The preparation process is similar to the preparation process disclosed in Examples 14-17.

[0308] Observation results: The disintegration time test of the tablets in Examples 23 to 25 was carried out by using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 6 below.

[0309] Table 6

[0310] Example No. Disintegration time Embodiment 23 2 minutes 40 seconds Embodiment 24 3 minutes 20 seconds Embodiment 25 3 minutes 10 seconds

[0311] Examples 26 to 28: Nor-UDCA tablets prepared by wet granulation

[0312] Tablet composition

[0313]

[0314] The preparation process is similar to the preparation process disclosed in Examples 14-17.

[0315] Observation results: The disintegration time test of the tablets in Examples 26 to 28 was carried out by using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 7 below.

[0316] Table 7

[0317] Example No. Disintegration time Embodiment 26 1 minute 50 seconds Embodiment 27 4 minutes 30 seconds Embodiment 28 5 minutes 25 seconds

[0318] Examples 29 to 31: Nor-UDCA tablets prepared by wet granulation

[0319] Tablet composition

[0320]

[0321]

[0322] The preparation process is similar to the preparation process disclosed in Examples 14-17.

[0323] Observation results: The disintegration time test of the tablets in Examples 29 to 31 was carried out by using the apparatus disclosed in USP General Chapter 701. The disintegration time of the tablets is shown in Table 8 below.

[0324] Table 8

[0325] Example No. Disintegration time Embodiment 29 2 minutes 20 seconds Embodiment 30 3 minutes 40 seconds Embodiment 31 4 minutes 90 seconds

Claims

1. A pharmaceutical composition comprising (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.

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 of claim 1, wherein the composition comprises about 250 mg to about 2000 mg of nor-UDCA.

4. The pharmaceutical composition according to claim 1, wherein the average particle size (D 50 ) is less than 50μm.

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

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

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