Oral cyclosphorin formulations

• US 6,254,885 B1
• Filed: 03/09/1998
• Issued: 07/03/2001
• Est. Priority Date: 08/25/1995
• Status: Expired due to Fees

• Current Assignee: SangStat Medical Corporation (Sanofi ), University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: SangStat Medical Corporation (Sanofi ), University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Levy, Ralph E., Cho, Moo J., Pouletty, Philippe J.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/037,176
• Time in Patent Office: 1,212 Days
• Field of Search: 424/455, 514/885, 514/962, 514/975
• US Class Current: 424/455
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C02F 1/50 by addition or application of a germicide or by oligodynamic treatment C02F1/4606, C02F1/467, C02F1/76 take precedence
• CPC Class Codes: C02F 2103/42 from bathing facilities, e.g. swimming pools
• CPC Class Codes: C02F 2201/008 Mobile apparatus and plants, e.g. mounted on a vehicle
• CPC Class Codes: C02F 2301/046 Recirculation with an external loop

Abstract

Improved oral cyclosporin formulations which have high bioavailability and are capable of admiration in hard capsules are provided. In the subject formations, cyclosporin is delivered in an orally acceptable vehicle comprising at least one alkanol solvent of from 2 to 3 carbon atoms in combination with at least one non-ionic surfactant. The subject formalations may further comprise at least one cosolvent, where cosolvents of interest include fatty acids and diols. The subject formulations find use in immuno-suppressive therapy.

Claims

1. A cyclosporin formulation consisting essentially of:

cyclosporin;

at least one alkanol solvent of from 2 to 3 carbon atoms;

at least one non-ionic polyoxyalkylene surfactant, wherein said surfactant is selected from the group consisting of polyoxyethylene alcohols and fatty acid monoesters of ethoxylated polyols of from 4 to 6 carbon atoms; and

at least one cosolvent, wherein said cosolvent is selected from the group consisting of mono-esters of a lower alkanol and a fatty acid of from 14 to 18 carbon atoms and diols of from 8 to 28 carbon atoms.

2. The formulation according to claim 1, wherein said alkanol solvent is from about 5 to 75% (v/v) of said formulation.

3. The formulation according to claim 1, wherein said at least one non-ionic polyoxyalkylene surfactant is from about 5 to 65% (v/v) of said formulation.

4. The formulation according to claim 2, wherein said at least one cosolvent is from about 20 to 80% (v/v) of said formulation.

9. A hard capsule cyclosporin formulation consisting essentially of:

a hard capsule containing the oral formulation according to claims 1 or 5.

10. A method for achieving immunosuppression in a host, said method comprising:

administering to said host a cyclosporin formulation according to claims 1 or 5;

whereby immunosuppression in said host is achieved.

11. The method according to claim 10, wherein said at least one alkanol solvent is selected from the group consisting of ethanol and propylene glycol and is from about 5 to 75% (v/v) of said formulation.

12. The method according to claim 10, Wherein said at least one non-ionic polyoxyethylene surfactant is selected from the group consisting of polyoxyethylene (4) lauryl ether and polyoxyethylene (20) mono sorbitan mono-oleate.

13. The method according to claim 10, wherein at least one of said at least one cosolvents is a said fatty acid ester selected from the group consisting of isopropyl myristate and ethyl oleate.

14. A method according to claim 10, wherein at least one of said at least one cosolvents is polyethylene glycol 400.

15. A method for prolonging the viability of a donor organ in a host, said method comprising;

orally administering to said host in conjunction with transplantation of said donor organ a cyclosporin formulation according to claim 1.

16. The method according to claim 15, wherein said formulation is administered in a hard capsule.

17. The method according to claim 15, wherein said formulation is administered chronically after said transplantation.

5. A cyclosporin formulation consisting essentially of:

Cyclosporin A;

at least one alkanol solvent selected from the group consisting of ethanol and propylene glycol, wherein said alkanol solvent is from about 5 to 75% (v/v) of said formulation;

at least one non-ionic polyoxyethylene surfactant, wherein said non-ionic polyoxyethylene surfactant is selected from the group consisting of polyoxyethylene alcohols and mono-esters of ethoxylated sorbitans, and is from about 5 to 65% (v/v) of said formulation; and

at least one cosolvent, wherein said at least one cosolvent is selected from the group consisting of a mono-ester of a lower alkanol of from 2 to 4 carbon atoms and a fatty acid of from 14 to 18 carbon atoms, wherein said cosolvent is from about 20 to 80% (v/v) of said formulation.

6. The formulation according to claim 5, wherein said non-ionic surfactant is selected from the group consisting of polyoxyethylene (4) lauryl ether and polyoxyethylene (20) mono sorbitan mono-oleate.

7. The formulation according to claim 5, wherein said formulation comprises two cosolvents, wherein one said cosolvents is a diol of from 8 to 28 carbon atoms.

8. The formulation according to claim 7, wherein said diol is a polyoxyethylene glycol.