Gastroresistant pharmaceutical formulations for oral administration containing salts of bile acids

• US 5,302,398 A
• Filed: 04/01/1992
• Issued: 04/12/1994
• Est. Priority Date: 04/12/1991
• Status: Expired due to Fees

• Current Assignee: ALFA Wassermann BV (Alfasigma S.p.A.)
• Original Assignee: ALFA Wassermann BV (Alfasigma S.p.A.)
• Inventors: Egidio, Marchi, Gabriele, Rotini L., Gianfranco, Tamagnone
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Bawa, Raj
• Application Number:
  US07/861,461
• Time in Patent Office: 741 Days
• Field of Search: 424/456, 424/451, 424/457, 424/458, 424/459, 424/463, 424/464, 424/471, 424/472, 424/474, 424/475
• US Class Current: 424/474
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Abstract

Pharmaceutical formulations for oral administration coated by an enterosoluble gastroresistant film, preferably selected from gastroresistant granulates, gastroresistant tablets, gastroresistant hard gelatine capsules containing powders or granulates or two or more tablets or oily suspensions, gastroresistant soft gelatine capsules containing oily suspensions and hard gelatine capsules containing gastroresistant granulates or two or more gastroresistant tablets, containing therapeutically effective amounts of salts of bile acids with alkali metals or organic bases, process for their preparation and therapeutic use thereof in the treatment of biliary calculoses, biliary dyspepsias, biliary cirrhosis and chronic and cholestatic hepatopathies.

Claims

1. A pharmaceutical formulation for oral use consisting of a core and an outer coating, said core containing a salt of a bile acid, said bile acid being a member selected from the group consisting of cholic, deoxycholic, chenodeoxycholic, iocholic, iodeoxycholic and ursodeoxycholic acids, said bile acid salt being a member selected from the group consisting of the salt with sodium, lithium, potassium, triethylamine, triethanolamine, trimethanolamine, N-methylmorpholine, 1-(2-hydroxyethyl)-pyrrolidine, L-arginine, L-lysine, L-ornithine, D-glucamine, N-methyl-D-glucamine, glucosamine and choline, the amount of said bile acid salt being 158-582 mgs, said outer coating is insoluble in the acidic gastric juice but is soluble at a pH higher than 5, said formulation containing between said core and said outer coating a non-protective coating in the amount of 1-5% by weight with respect to said non-coated portion, said non-protective coating consisting of hydroxypropylmethylcellulose, polyethylene glycol 6000, titanium dioxide and talc.

2. The formulation according to claim 1 wherein said outer coating is made by coating said core with at least one substance which is a member selected from the group consisting of cellulose acetate, copolymers of methacrylic acid and of methacrylic esters in different ratios, polyvinylacetophthalate and hydroxypropylmethyl-cellulose phthalate and a plasticizer which is at least one member selected from the group consisting of diethylphthalate, dibutylphthalate, triacetin, polyethylene glycols and acetylated monoglycerides, said outer coating being in amount between 2% and 10% of the weight of said core.

4. The formulation according to claim 1 which is a member selected from the group consisting of gastroresistant granulates, gastroresistant tablets, gastroresistant hard gelatine capsules containing powders or granulates or two or more tablets or oily suspensions, gastroresistant soft gelatine capsules containing oily suspensions and hard gelatine capsules containing gastroresistant granulates or two or more gastroresistant tablets.

3. A pharmaceutical formulation for oral use consisting of a core and an outer coating said core containing a salt of a bile acid, said bile acid being a member selected from the group consisting of cholic, deoxycholic, chenodeoxycholic, iocholic, iodeoxycholic and ursodeoxycholic acids, said bile acid salt being a member selected from the group consisting of the salt with sodium, lithium, potassium, triethylamine, triethanolamine, trimethanolamine, N-methylmorpholine, 1-(2-hydroxyethyl)-pyrrolidine, L-arginine, L-lysine, L-ornithine, D-glucamine, N-methyl-D-glucamine, glucosamine and choline, the amount of said bile acid salt being 158-582 mgs, said outer coating is insoluble in the acidic gastric juice but is soluble at a pH higher than 5, said formulation containing between said core and said outer coating a non-protective coating in the amount of 1-5% by weight with respect to said non-coated portion, said non-protective coating consisting of at least one member selected from the group consisting of hydroxypropylmethyl-cellulose, polyethylene glycol 6000, titanium dioxide and talc wherein said non-protective coating additionally contains a pharmaceutically acceptable dye.

5. The method of treatment of a living subject affected by biliary calculoses, biliary dyspepsias, biliary cirrhosis, chronic and cholestatic hepatopaties, which consists of orally administering to said subject a formulation for oral use consisting of a core and an outer coating, said core containing a bile acid salt, said bile acid being a member selected from the group consisting of cholic, deoxycholic, chenodeoxycholic, iocholic, iodexycholic and ursodeoxycholic acids and mixtures thereof, said salt of said bile acid being with an alkali metal or an organic base, the amount of said bile acid salt being 158-582 mgs and said outer coating is insoluble in the acidic gastric juice but is soluble at a pH higher than 5, said formulation having a non-protective coating between said core and said outer coating.