Pharmaceutical preparation containing cyclosporin(S) for oral administration and process for producing the said preparation

• US 6,136,357 A
• Filed: 09/14/1998
• Issued: 10/24/2000
• Est. Priority Date: 10/04/1995
• Status: Expired due to Term

• Current Assignee: NeuroVive Pharmaceutical AB
• Original Assignee: CicloMulsion AG
• Inventors: Dietl, Hans
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/051,173
• Time in Patent Office: 771 Days
• Field of Search: 424/450, 424/435, 514/9, 514/11, 514/78, 514/885
• US Class Current: 426/435
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

Cyclosporin(s) are formulated as a pharmaceutical preparation that provides good and uniform resorption of the cyclosporin(s) with no nonphysiological pharmaceutical adjuvants, by combining the cyclosporin(s) with (i) monoglycerides, diglycerides, and/or triglycerides of natural fatty acids, (ii) natural fatty acids and/or alkaline salts of natural fatty acids, and (iii) 3-sn-phosphatidyl choline(s), and/or phosphatidyl ethanolamine(s), and optionally also (iv) natural bile acids and/or alkaline salts of natural bile acids, and (v) a natural alcohol. The pharmaceutical preparation does not contain water and is not an emulsion.

Claims

1. A pharmaceutical preparation containing cyclosporin(s) for oral administration, comprising the following components:

(A) a cyclosporin,

(B) a member selected from the group consisting of monoglycerides, diglycerides, and triglycerides of natural fatty acids, and combinations thereof,

(C) a member selected from the group consisting of natural fatty acids, alkaline salts of natural fatty acids, and combinations thereof, and

(D) a substance containing a member selected from the group consisting of

3-sn-phosphatidyl choline(s), phosphatidyl ethanolamine(s), and combinations thereof;

with the proviso that said pharmaceutical preparation does not contain water and is not an emulsion.

2. A pharmaceutical preparation in accordance with claim 1, further comprising as an additional component a member selected from the group consisting of natural bile acids, alkaline salts of natural bile acids, and combinations thereof.

3. A pharmaceutical preparation in accordance with claim 1, further comprising as an additional component a natural alcohol.

4. A pharmaceutical preparation in accordance with claim 1 in which component (B) is a mixture of monoglycerides, diglycerides, and triglycerides of natural fatty acids, in which

said triglycerides constitute 20-60% by weight of said preparation,

said diglycerides constitute 15-50% by weight of said preparation, and

said monoglycerides constitute 3-20% by weight of said preparation.

5. A pharmaceutical preparation in accordance with claim 1, in which component (D) is a lecithin of natural origin.

6. A pharmaceutical preparation in accordance with claim 5 in which said lecithin is a member selected from the group consisting of soybean lecithin, egg lecithin, and combinations thereof.

7. A pharmaceutical preparation in accordance with claim 1 in which said components are contained in an enteric coated capsule soluble in the small intestine.

8. A pharmaceutical preparation in accordance with claim 7 in which said enteric coated capsule is a gelatin capsule.

9. A process for the preparation of a pharmaceutical preparation comprising the following components:

(A) a cyclosporin,

(B) a member selected from the group consisting of monoglycerides, diglycerides, and triglycerides of natural fatty acids, and combinations thereof,

(C) a member selected from the group consisting of natural fatty acids, alkaline salts of natural fatty acids, and combinations thereof, and

(D) a substance containing a member selected from the group consisting of

3-sn-phosphatidyl choline(s), phosphatidyl ethanolamine(s), and combinations thereof,

said process comprising mixing said cyclosporin with components (B), (C), and (D) in a natural alcohol in the absence of water and without forming an emulsion.

12. A process in accordance with claim 9 further comprising mixing said cyclosporin and said components (B), (C), and (D) with a member selected from the group consisting of natural bile acids, alkaline salts of natural bile acids, and combinations thereof, in said natural alcohol.

10. A process for the preparation of a pharmaceutical preparation comprising the following components:

(A) a cyclosporin,

(B) a member selected from the group consisting of monoglycerides, diglycerides, and triglycerides of natural fatty acids, and combinations thereof,

(C) a member selected from the group consisting of natural fatty acids, alkaline salts of natural fatty acids, and combinations thereof, and

(D) a substance containing a member selected from the group consisting of

3-sn-phosphatidyl choline(s), phosphatidyl ethanolamine(s), and combinations thereof,

said process comprising dissolving said cyclosporin in a natural alcohol prior to combining said cyclosporin with components (B), (C), and (D), and doing so in the absence of water and without forming an emulsion.

13. A process in accordance with claim 10 further comprising combining said cyclosporin thus dissolved and said components (B), (C), and (D) with a member selected from the group consisting of natural bile acids, alkaline salts of natural bile acids, and combinations thereof.

11. A method for treating a subject by administration of cyclosporin(s), said method comprising orally administering to said subject a pharmaceutical preparation that does not contain water and is not an emulsion, said pharmaceutical preparation comprising the following components:

(A) a cyclosporin,

(B) a member selected from the group consisting of monoglycerides, diglycerides, and triglycerides of natural fatty acids, and combinations thereof,

(C) a member selected from the group consisting of natural fatty acids, alkaline salts of natural fatty acids, and combinations thereof, and

(D) a substance containing a member selected from the group consisting of

3-sn-phosphatidyl choline(s), phosphatidyl ethanolamine(s), and combinations thereof.

14. A process in accordance with claim 11 in which said pharmaceutical preparation further comprises a member selected from the group consisting of natural bile acids, alkaline salts of natural bile acids, and combinations thereof.

15. A process in accordance with claim 11 in which said pharmaceutical preparation further comprises a natural alcohol.

16. A process in accordance with claim 11 in which said pharmaceutical preparation further comprises:

(E) a member selected from the group consisting of natural bile acids, alkaline salts of natural bile acids, and combinations thereof, and

(F) a natural alcohol.