Stabilized oral prostaglandin formulation and the process for the preparation thereof

• US 4,113,882 A
• Filed: 05/13/1976
• Issued: 09/12/1978
• Est. Priority Date: 10/21/1974
• Status: Expired due to Term

• Current Assignee: Yamanouchi Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Original Assignee: Yamanouchi Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Murakami, Masuo, Kawada, Hiroitsu, Okazaki, Kiyoshi, Sekino, Jun, Shimizu, Hidemi, Kawahara, Shigemi
• Primary Examiner(s): Rosen, Sam
• Application Number:
  US05/686,154
• Time in Patent Office: 852 Days
• Field of Search: 424/305, 424/317
• US Class Current: 514/573
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Abstract

There is disclosed a dry, stabilized oral pharmaceutical formulation containing a prostaglandin E group prepared from a lyophilized composition comprising a prostaglandin E group and at least a member selected from the group consisting of a thiol compound, dextrin, dextran, a lower alkyl cellulose, and a water-soluble salt of deoxycholic acid.

Claims

1. A stabilized oral prostaglandin composition comprising a therapeutically effective amount of a lyophilized composition which comprises (A) a prostaglandin E group compound and (B) an effective amount of at least one member selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, a lower alkyl cellulose, a dextran, and dextrin;

and a pharmaceutically acceptable carrier for oral administration.

2. The stabilized oral prostaglandin composition as claimed in claim 1 wherein said prostaglandin E group compound is a member selected from the group consisting of 4(R),16(R)-dimethyl-prostaglandin E₂, 4(S),16(R)-dimethyl-prostaglandin E₂, 4(S),16(S)-dimethyl-prostaglandin E₂, 4(R),16(S)-dimethyl-prostaglandin E₂, 16(R,S)-methyl-20-methoxy-prostaglandin E₂, 16(S)-methyl-20-methoxy-prostaglandin E₂, and 16(R)-methyl-20-methoxy-prostaglandin E₂.

3. The stabilized oral prostaglandin composition as claimed in claim 2 wherein said prostaglandin E group compound is 16(S)-methyl-20-methoxy-prostaglandin E₂.

4. The stabilized oral prostaglandin composition as claimed in claim 1 wherein said lower alkylcellulose or ethylcellulose is methylcellulose.

5. The stabilized oral prostaglandin composition as claimed in claim 1 wherein said lyophilized composition comprises 16(S)-methyl-20-methoxy-prostaglandin E₂ and dextran.

6. The stabilized oral prostaglandin composition as claimed in claim 1 in which said lyophilized composition comprises from 5 to 250 mg of said member per 2-150γ

of said prostaglandin E group compound.

7. The stabilized oral prostaglandin composition as claimed in claim 1 wherein said carrier is selected from the group consisting of mannitol, lactose, starch, magnesium stearate, talc, and mixtures thereof.

8. The stabilized oral prostaglandin composition as claimed in claim 1 wherein said dextran has a mean molecular weight of between 5,000 and 5,000,000.

9. A process of preparing a stable oral prostaglandin composition which comprises preparing an aqueous solution of a prostaglandin E group compound and an effective amount of at least one member selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, a lower alkyl cellulose, a dextran, and a dextrin;

lyophilizing said solution to provide a lyophilized composition; and

mixing a therapeutically effective amount of said lyophilized composition with a pharmaceutically acceptable carrier for oral administration.

10. The process as claimed in claim 9 wherein said prostaglandin E group is a member selected from the group consisting of 4(R),16(R)-dimethyl-prostaglandin E₂, 4(S),16(R)-dimethyl-prostaglandin E₂, 4(S),16(S)-dimethyl-prostaglandin E₂, 4(R),16(S)-dimethyl-prostaglandin E₂, 16(R,S)-methyl-20-methoxy-prostaglandin E₂, 16(S)-methyl-20-methoxy-prostaglandin E₂, and 16(R)-methyl-20-methoxy-prostaglandin E₂.

11. The process as claimed in claim 10 wherein said prostaglandin E group is 16(S)-methyl-20-methoxy-prostaglandin E₂.

12. The process as claimed in claim 9 wherein said lower alkylcellulose is methylcellulose or ethylcellulose.

13. The process as claimed in claim 9 wherein said lyophilized composition comprises 16(S)-methyl-20-methoxy-prostaglandin E₂ and dextran.

14. The process as claimed in claim 9 wherein said lyophilized composition comprises from 5 to 250 mg. of said member per 2-150γ

of said prostaglandin E group compound.

15. The process as claimed in claim 9 wherein said carrier is selected from the group consisting of mannitol, lactose, starch, magnesium stearate, talc, and mixtures thereof.

16. The process as claimed in claim 9 wherein said dextran has a mean molecular weight of between 5,000 and 5,000,000.

17. A lyophilized pharmaceutical composition comprising as the active ingredient a therapeutically effective amount of a prostaglandin E group compound selected from the group consisting of 4(R),16(R)-dimethyl-prostaglandin E₂, 4(S),16(R)-dimethyl-prostaglandin E₂, 4(S),16(S)-dimethyl-prostaglandin E₂, 4(R),16(S)-dimethyl-prostaglandin E₂, 16(R,S)-methyl-20-methoxy-prostaglandin E₂, 16(S)-methyl-20-methoxy-prostaglandin E₂, and 16(R)-methyl-20-methoxy-prostaglandin E₂, and an effective amount of at least one member selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, a lower alkyl cellulose, a dextran, and dextrin.

18. The lyophilized pharmaceutical composition as claimed in claim 17, wherein said prostaglandin E group compound is 16(S)-methyl-20-methoxy-prostaglandin E₂.