Injectable compositions of ursodeoxycholic acid

Abstract

The present invention relates to an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid and (b) sulfobutyl ether-β-cyclodextrin. Such a composition allows the administration of ursodeoxycholic acid at a therapeutic dose without using a high content of a strong base, exhibiting unexpected solubility and stability of ursodeoxycholic acid, wherein the high content of the strong base is present in an amount stoichiometrically equivalent to ursodeoxycholic acid.

Description

Technical Field

[0001] This invention relates to injectable pharmaceutical compositions comprising ursodeoxycholic acid (UDCA) and sulfobutyl ether-β-cyclodextrin, and methods of preparation and use thereof, for example for treating conditions and diseases that respond to ursodeoxycholic acid. Background Technology

[0002] Ursodeoxycholic acid (UDCA) is widely used as a gallstone dissolving agent (for both dissolution and prevention) and for treating various liver pathologies such as hepatobiliary cholestasis and primary biliary cirrhosis. It has also been reported to treat nonalcoholic steatohepatitis (NASH). Furthermore, UDCA has been found to be particularly effective in treating liver pathologies in patients for whom oral administration is impossible or difficult. Ursodeoxycholic acid is marketed in the United States under the brand name... (300mg oral capsules) are sold as a treatment for gallstone dissolution and gallstone prevention, administered in 2 or 3 divided doses of 8-10 mg / kg / day and in 600 mg / day (2 divided doses), respectively. Ursodeoxycholic acid is also marketed by Allergan under the brand name [Brand Name - missing in original text]. It is sold in 250mg and 500mg oral tablets, and the recommended dose for the treatment of primary biliary cirrhosis is 13-15mg / kg / day in 2 to 4 divided doses with food.

[0003] Currently, there are no commercially available injectable drug formulations based on ursodeoxycholic acid because their preparation presents challenges due to their physicochemical properties and the high doses required for administration.

[0004] Ursodeoxycholic acid is a weak acid and is almost insoluble in water; its solubility increases dramatically in the presence of strong bases (such as sodium hydroxide and potassium hydroxide). However, aqueous solutions consisting solely of ursodeoxycholic acid and strong bases are unsuitable for intravenous administration because even minute changes in the amount of strong base during preparation can alter the pH of the injectable solution, which is generally incompatible with intravenous administration.

[0005] In addition, ursodeoxycholic acid is a detergent compound that can cause foaming when added to aqueous solutions used for intravenous infusion.

[0006] To develop a stable, well-buffered intravenous solution suitable for intravenous administration, the inventors of U.S. Patent No. 5,955,456 have developed an injectable formulation of ursodeoxycholic acid comprising a strong base compatible with intravenous administration and aminobutanetriol. Further, US'456 discloses the preferred use of sodium hydroxide or potassium hydroxide as the strong base, and that such a base is used in an amount stoichiometric to that of the acid used (ursodeoxycholic acid), more preferably about 1% w / v of sodium hydroxide. Based on an equistoichiometric proportion of ursodeoxycholic acid, US'456 uses a high concentration of strong base, which has the disadvantage of being unsuitable for intravenous administration, resulting in pH changes.

[0007] European Patent No. EP1147779B1 discloses a method for providing soluble ursodeoxycholic acid, and in particular, Example 4 discloses the preparation of an injectable formulation of ursodeoxycholic acid and β-cyclodextrin in a 1:2 ratio in water to prepare an intravenous solution of 2 mg / mL ursodeoxycholic acid. An injectable solution containing 2 mg / mL ursodeoxycholic acid and β-cyclodextrin for intravenous administration requires a relatively large volume of fluid for intravenous administration (approximately 300 mL for prevention of gallstones).

[0008] To overcome the above-mentioned drawbacks, there is a need to develop injectable pharmaceutical compositions for intravenous administration that have a significantly reduced volume (better patient safety, children, patients with fluid restrictions, etc.) and contain ursodeoxycholic acid, which is stable for intravenous administration without pH changes. Summary of the Invention

[0009] This invention relates to ursodeoxycholic acid compositions suitable for intravenous administration, which are stable under environmental and / or freezing conditions, significantly reduce the volume required for intravenous administration, and provide completely dissolved ursodeoxycholic acid without the need for large amounts of strong base. As described herein, compositions suitable for parenteral administration include ursodeoxycholic acid and a cyclodextrin derivative selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0010] This invention relates to injectable pharmaceutical compositions comprising ursodeoxycholic acid, a cyclodextrin derivative, and optionally a buffer, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0011] The present invention further relates to injectable pharmaceutical compositions comprising about 10 mg / mL to about 50 mg / mL of ursodeoxycholic acid, about 100 mg / mL to about 300 mg / mL of a cyclodextrin derivative, and optionally a buffer, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin. Detailed Implementation

[0012] This invention provides an injectable pharmaceutical composition comprising ursodeoxycholic acid and a cyclodextrin derivative selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin. Most preferably, the cyclodextrin derivative used in this invention is sulfobutyl ether-β-cyclodextrin.

[0013] In a preferred embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid and (b) sulfobutyl ethyl ether-β-cyclodextrin.

[0014] In a further embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid and (b) sulfobutyl ethyl ether-β-cyclodextrin, wherein such composition does not contain high amounts of strong bases (preferably sodium hydroxide and potassium hydroxide) present in amounts equivalent to stoichiometric amounts of ursodeoxycholic acid.

[0015] In one embodiment, the present invention provides an intravenous pharmaceutical composition comprising ursodeoxycholic acid, a cyclodextrin derivative, and optionally a buffer, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0016] In another embodiment, the present invention provides a stable injectable pharmaceutical composition comprising ursodeoxycholic acid, a cyclodextrin derivative, and optionally a buffer, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0017] In another embodiment, the present invention provides an injectable pharmaceutical composition comprising about 10 mg / mL to about 50 mg / mL of ursodeoxycholic acid, more preferably about 15 mg / mL to about 40 mg / mL of ursodeoxycholic acid, and most preferably about 25 mg / mL of ursodeoxycholic acid.

[0018] In a further embodiment, the present invention provides an injectable pharmaceutical composition comprising about 100 mg / mL to about 300 mg / mL of sulfobutyl ether-β-cyclodextrin, more preferably about 150 mg / mL to about 250 mg / mL of sulfobutyl ether-β-cyclodextrin.

[0019] In another embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid at about 10 mg / mL to about 50 mg / mL and (b) sulfobutyl ether-β-cyclodextrin at about 150 mg / mL to about 250 mg / mL.

[0020] In a further embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) about 10 mg / mL to about 50 mg / mL of ursodeoxycholic acid and (b) about 150 mg / mL to about 250 mg / mL of sulfobutyl ether-β-cyclodextrin, wherein such composition does not contain high amounts of strong bases (preferably sodium hydroxide and potassium hydroxide) present in amounts equivalent in stoichiometry to ursodeoxycholic acid.

[0021] In embodiments of the invention, the invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid at about 10 mg / mL to about 50 mg / mL, (b) a cyclodextrin derivative at about 150 mg / mL to about 250 mg / mL, and optionally a buffer, said cyclodextrin derivative being selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0022] In a further embodiment of the invention, the invention provides a stable injectable pharmaceutical composition comprising essentially (a) ursodeoxycholic acid at about 10 mg / mL to about 50 mg / mL, (b) a cyclodextrin derivative at about 100 mg / mL to about 300 mg / mL, and optionally a buffer, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0023] In a further embodiment of the invention, the invention provides a stable injectable pharmaceutical composition comprising essentially about 25 mg / mL of ursodeoxycholic acid and about 150 mg / mL to about 250 mg / mL of a cyclodextrin derivative selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0024] In another embodiment of the invention, the invention provides a stable injectable pharmaceutical composition comprising essentially about 25 mg / mL of ursodeoxycholic acid and about 150 mg / mL to about 250 mg / mL of a cyclodextrin derivative selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin, for the treatment of various pathological conditions of the liver, such as hepatic cholestasis, primary biliary cirrhosis, and non-alcoholic steatohepatitis (NASH).

[0025] In another embodiment, the present invention provides a stable injectable pharmaceutical composition comprising ursodeoxycholic acid, a cyclodextrin derivative, an optional pH adjuster, and water, wherein the cyclodextrin derivative is selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0026] The injectable pharmaceutical composition described herein optionally further comprises a pH adjuster. The pH adjuster used in this invention is selected from the group consisting of sodium hydroxide and hydrochloric acid. The pH of the injectable pharmaceutical composition of this invention is from about 2.0 to about 8.0. The pH of the injectable pharmaceutical composition used in this invention is from about 2.0 to about 4.0.

[0027] In a further embodiment, the present invention provides an injectable pharmaceutical composition comprising ursodeoxycholic acid, a cyclodextrin derivative (the cyclodextrin derivative being selected from the group consisting of hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin), an optional pH adjuster, and water, wherein the pH of the composition is from about 2.0 to about 8.0.

[0028] In another embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid, (b) sulfobutyl ether-β-cyclodextrin, (c) water and (d) optionally a pH adjuster.

[0029] In a further embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid at about 10 mg / mL to about 50 mg / mL, (b) sulfobutyl ether-β-cyclodextrin at about 150 mg / mL to 250 mg / mL, (c) water, and (d) optionally a pH adjuster.

[0030] In another embodiment, the present invention provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid at about 10 mg / mL to about 50 mg / mL, (b) sulfobutyl ether β-cyclodextrin at about 150 mg / mL to about 250 mg / mL, and (c) water, wherein the pH of the composition is about 2.0 to about 4.0.

[0031] The osmolality of the composition can be determined by a freezing point depression method, but any other suitable method may also be used. According to one embodiment, the osmolality of the compositions of the present invention ranges from about 180 mOs / kg to about 900 mOs / kg, preferably from about 600 mOs / kg to about 800 mOs / kg.

[0032] The present invention further provides an injectable pharmaceutical composition comprising (a) ursodeoxycholic acid at about 10 mg / mL to about 50 mg / mL, (b) sulfobutyl ether-β-cyclodextrin at about 150 mg / mL to about 250 mg / mL, and (c) water, wherein the pH of the composition is about 2.0 to about 4.0, and wherein the weight molar osmotic pressure concentration of the composition is about 600 mOs / kg to about 800 mOs / kg.

[0033] According to another aspect of the invention, the present invention relates to the use of ursodeoxycholic acid in the preparation of injectable formulations suitable for treating pathological conditions of the liver, such as hepatic cholestasis, primary biliary cirrhosis, and non-alcoholic steatohepatitis (NASH).

[0034] In embodiments of the invention, the present invention relates to injectable formulations of ursodeoxycholic acid for intravenous administration (particularly by slow infusion). In a further embodiment of the invention, the injectable formulation of ursodeoxycholic acid is diluted in a solution for intravenous infusion to facilitate administration by slow infusion. A particularly advantageous solution for intravenous infusion is a conventional isotonic solution (containing 0.9% sodium chloride).

[0035] The duration of treatment comprises slow intravenous infusion of ursodeoxycholic acid, preferably administered via a formulation forming the subject matter of this invention, and varies depending on the pathological condition to be treated. Typically, the duration varies between 1 and 30 days, advantageously between 3 and 10 days, and preferably between 5 and 7 days. Several treatment cycles may be performed if necessary.

[0036] Typically, the daily dose of ursodeoxycholic acid administered according to the invention is between 2 and 30 mg / kg of body weight, advantageously between 4 and 20 mg / kg, and preferably between 8 and 15 mg / kg. For adults of normal physical condition, the daily dose is between 500 and 2000 mg.

[0037] Therefore, a unit dose may contain 100 to 2000 mg of ursodeoxycholic acid. According to a preferred aspect, a unit dose contains 250 mg, 500 mg, or 625 mg of ursodeoxycholic acid in volumes of 10 mL, 20 mL, and 25 mL, respectively.

[0038] The following embodiments are provided to illustrate the present invention. However, it should be understood that the present invention is not limited to the specific situations or details described in the following embodiments. The embodiments should not be construed as limiting the present invention, as these embodiments only provide specific methodologies that help in understanding and practicing the present invention and its various aspects. Although certain preferred and alternative embodiments of the invention have been set forth for the purposes of disclosing the invention, modifications can be made to the disclosed embodiments by those skilled in the art.

[0039] Example 1: Injectable composition of ursodeoxycholic acid

[0040]

[0041] Preparation process:

[0042] Sulfobutyl ethyl ether-β-cyclodextrin was dissolved in a necessary amount of water for injection, ursodeoxycholic acid was further dissolved and the pH was adjusted to between 7.3 and 7.5 with sodium hydroxide to form a final solution, which was then filtered and sterilized by aseptic filtration and / or autoclaving.

[0043] The injectable pharmaceutical composition formulated in Example 1 was stored at 40°C / 75%RH for approximately 6 months, and the pH, weight molar osmotic pressure concentration, analysis and related substances are presented in Table 1.

[0044] Table 1

[0045]

[0046] Example 2: Injectable Composition of Ursodeoxycholic Acid

[0047]

[0048]

[0049] Preparation process:

[0050] Hydroxypropyl-β-cyclodextrin was dissolved in a necessary amount of water for injection, ursodeoxycholic acid was further dissolved, and the pH was adjusted to between 7.3 and 7.5 with sodium hydroxide to form a final solution. The final solution was filtered and sterilized by aseptic filtration and / or autoclaving.

[0051] Example 3: Solubility of ursodeoxycholic acid in sulfobutyl ether-β-cyclodextrin (SBECD).

[0052] Ursodeoxycholic acid was mixed with sulfobutyl ether-β-cyclodextrin in water, and the resulting solution was filtered through a 0.22 μm filter. The clarified filtered solution was analyzed by HPLC. The analysis results of ursodeoxycholic acid are presented in Table 2.

[0053] Table 2

[0054]

[0055] Example 4: Injectable Compositions of Ursodeoxycholic Acid

[0056]

[0057] Preparation process:

[0058] Sulfobutyl ether-β-cyclodextrin was dissolved in a necessary amount of water for injection, ursodeoxycholic acid was further dissolved, and the pH was adjusted to between 2.5 and 4.0 with sodium hydroxide to form the final solution. The final solution was then filtered and sterilized in glass vials using aseptic filtration and / or autoclaving, each vial containing 25 mL of the final solution (containing 625 mg of UDCA).

[0059] The injectable pharmaceutical composition formulated in Example 4 was stored at 40°C / 75%RH for approximately 3 months, and the pH, weight molar osmotic pressure concentration, analysis and related substances are presented in Table 3.

[0060] Table 3

[0061]

Claims

1. An injectable pharmaceutical composition comprising: (a) 10 mg / mL to 50 mg / mL ursodeoxycholic acid, (b) 150 mg / mL to 250 mg / mL of sulfobutyl ether-β-cyclodextrin, and (c) water; The pH of the composition is between 2.0 and 4.

0.

2. The composition of claim 1, wherein the composition does not contain a high level of a strong base present in an amount stoichiometrically equivalent to ursodeoxycholic acid.

3. The composition of claim 1, wherein the composition is in the form of an aqueous solution suitable for intravenous injection or infusion.

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