Pharmaceutical preparations containing cyclodextrin derivatives

• US 4,727,064 A
• Filed: 05/29/1985
• Issued: 02/23/1988
• Est. Priority Date: 04/25/1984
• Status: Expired due to Term

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Pitha, Josef
• Primary Examiner(s): Griffin, Ronald W.
• Application Number:
  US06/738,749
• Time in Patent Office: 1,000 Days
• Field of Search: 536/103, 106/210, 514/58, 514/971, 514/965
• US Class Current: 514/58
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Abstract

The invention comprises pharmaceutical preparations consisting generally of a drug with a substantially low water solubility and an amorphous, water-soluble cyclodextrin-based mixtures. In these preparations a stable amorphous state can be achieved. This improves the dissolution properties of the drug and hence its absorption by the body. The required cyclodextrin-based mixtures were prepared from α-, β-, or γ-cyclodextrin which were rendered amorphous through non-selective alkylation. The alkylation agents suitable for that purposes are exemplified by propylene oxide, glycidol, iodoacetamide, chloroacetate, or 2-diethylaminoethylchloride; their reactions with cyclodextrins were performed in a manner to yield mixtures containing many components, a circumstance which effectively prevents crystallization processes within the above pharmaceutical preparation.

Claims

1. A method of producing a stablizing amorphous complex of a drug and a mixture of cyclodextrins which comprises the steps of:

1. Dissolving an intrinsically amorphous mixture of cyclodextrin deratives which are water soluble and capable of forming inclusion complexes with drugs in water; and

2. Solublizing lipophilic drugs into the aqueous media to form a solution and form a solublized drug/cyclodextrin complex.

2. A method of claim 1 wherein the solubilized complex is subjected to freeze-dried or evaporation to provide a solid cyclodextrin/drug complex in powder form.

3. A method of claim 1 wherein cyclodextrins used are substituted by at least one of the following substituents:

hydroalkyl, carboxamide, diethylaminoethyl, carboxymethyl, and carboxyamidomethyl.

4. A method of claim 1 wherein the drug is a hormone.

5. A method of claim 4 wherein the drug is testosterone, an estrogen, or a progesterone.

12. A composition of matter for use in the process of claim 1 containing a mixture of substituted cyclodextrin derivatives in amorphous form.

6. A composition of matter which contains an amorphous complex of cylodextrin and a drug.

7. A omposition of matter of claim 6 wherein the drug is a hormone.

8. A composition of claim 6 wherein the drug is at least one of testosterone, progesterone, and an estrogenic drug.

9. A composition of matter of claim 6 in solid form.

10. A composition of matter of claim 9 which is a tablet.

11. A composition of matter of claim 6 which is in a liquid or semi-liquid form.

13. A composition of matter of claim 6 wherein the drug is a vitamin.

14. A composition of matter of claim 6 wherein the drug is a salt of retinoic acid.

15. A composition of matter of claim 6 wherein the drug is a steroid.

16. A composition of matter of claim 6 wherein the drug is a spironolactone.

17. A composition of matter of claim 6 wherein the drug is an antiviral agent.

18. A composition of matter of claim 17 wherein the antiviral agent is acylovir.

19. A composition of matter of claim 6 wherein the drug is a diuretic.

20. A composition of matter of claim 19 wherein the diuretic is chlorthalidone.

21. A composition of matter of claim 6 wherein the drug is an anticoagulant.

22. A composition of matter of claim 21 wherein the anticoagulant is dicumerol.

23. A composition of matter of claim 6 wherein the drug is an anticonvulsant

24. A composition of matter of claim 23 wherein the drug is diphenylhydantoin.

25. A composition of matter of claim 6 wherein the drug is an antiinflammatory agent.

26. A composition of matter of claim 25 wherein the antiinflammatory agent is iproniazid.

27. A composition of matter of claim 16 wherein the drug is oxyprenolol.

28. A composition of matter in solid or semi-solid form comprising at least one of testosterone, progesterone, and estradiol as an inclusion complex with poly-β

-cylodextin and/or hydroxypropyl-β

-cyclodextrin adapted for administration by buccal route.