Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation

• US 6,407,079 B1
• Filed: 10/31/1988
• Issued: 06/18/2002
• Est. Priority Date: 07/03/1985
• Status: Expired due to Term

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Brauns, Ulrich, Müller, Bernd W.
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US07/264,726
• Time in Patent Office: 4,978 Days
• Field of Search: 514/58, 536/46, 536/103
• US Class Current: 514/58
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Pharmaceutical compositions comprising inclusion compounds of sparingly water-soluble or water-instable drugs with β-cyclodextrin ethers or β-cyclodextrin esters and process for the preparation thereof.

Claims

1. Pharmaceutical composition comprising an inclusion compound of (i) a drug capable of fitting into the cavity of the cyclodextrin ring system which is instable or only sparingly soluble in water with (ii) a partially etherified β

-cyclodextrin of the formula;

2. Composition according to claim 1 wherein said residues R are hydroxyethyl, hydroxypropyl, dihydroxypropyl, methyl or ethyl groups.

3. Composition according to claim 2, wherein said partially etherified β

-cyclodextrin of formula I has a molar substitution by hydroxyalkyl groups of 0.05 to 10 and a degree of substitution by alkyl groups of 0 to 2.0.

4. Composition according to claim 1, wherein said drug and said β

-cyclodextrin ether are in a molar ratio of 1;

6 to 4;

1.

5. Composition according to claim 1, wherein said drug is a non-steroid anti-rheumatic agent, a steroid, a cardiac glycoside or derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole or triazole.

6. Composition according to claim 1, wherein said drug is etomidate.

7. Composition according to claim 1, wherein said drug is ketoconazole.

8. Composition according to claim 1, wherein said drug is itraconazole.

9. Composition according to claim 1, wherein said drug is levocabastine.

10. Composition according to claim 1, wherein said drug is flunarizine.

11. Composition according to claim 1, wherein said drug is tubulazole.

12. Pharmaceutical composition comprising an inclusion compound of (i) a drug which is instable or only sparingly soluble in water and which is capable of fitting into the cavity of the β

-cyclodextrin ring system and

(ii) a β

-cyclodextrin derivative of the formula;

13. The composition of claim 12 wherein said molar substitution is from 0.2 to 2.

14. The composition of claim 12 wherein said molar substitution is from about 0.25 to about 1.

15. The composition of claim 12 wherein said molar ratio is from 0.2 to 2.

16. The composition of claim 12 wherein said molar ratio is from about 0.5 to about 1.2.

17. The composition of claim 12 wherein said drug is selected from etomidate, ketoconazole, tubulazole, itraconazole, levacabastine, and flunarizine.

25. The composition of claim 12 wherein the residue R is selected from hydroxyethyl with a molar substitution of from 0.2 to 2, and methyl and ethyl with a degree of substitution of 0 to 2.0.

26. The composition of claim 12 wherein the residue R is selected from hydroxypropyl with a molar substitution of from 0.2 to 2, and methyl and ethyl with a degree of substitution of 0 to 2.0.

18. A method of producing a stabilizing amorphous complex of a drug and mixture of beta-cyclodextrin derivatives comprising the steps of:

(1) dissolving the intrinsically amorphous mixture of beta-cyclodextrin derivatives which are water soluble and capable of forming inclusion complexes with drugs in water, and

(2) solubilizing sparingly water-soluble drugs into the aqueous media to form a solution and form a solubilized drug/cyclodextrin complex.

19. A method of claim 18 wherein the cyclodextrins used are substituted by the following substituents:

hydroxyalkyl.

20. A method of claim 18 wherein the drug is progesterone.

23. A composition of matter for use in the process of claim 18 containing a mixture of substituted beta-cyclodextrin ethers in amorphous form.

21. A composition of matter which contains a water-soluble amorphous complex of beta-cyclodextrin derivatives and a drug.

22. A composition of claim 21 wherein the drug is progesterone.

24. A composition of matter in solid form comprising progesterone as an inclusion complex with hydroxypropyl-beta-cyclodextrin adapted for administration by the oral route.

27. Pharmaceutical composition comprising an inclusion compound of (i) a drug capable of fitting into the cavity of the β

-cyclodextrin ring system which is instable or only sparingly soluble in water and (ii) a partially etherified β

-cyclodextrin derivative of the formula;

28. Composition according to claim 27 wherein the hydroxyalkyl group is selected from hydroxyethyl, hydroxypropyl and dihydroxypropyl.

29. Composition according to claim 27 wherein the hydroxyalkyl group is hydroxyethyl and the molar ratio of said drug to said β

-cyclodextrin derivative is from about 1;

6 to 4;

1.

30. Composition according to claim 27 wherein the hydroxypropyl group is hydroxyethyl and the molar ratio of said drug to said β

-cyclodextrin derivative is from about 1;

6 to 4;

1.

31. Pharmaceutical composition comprising an inclusion compound of (i) a drug capable of fitting into the cavity of the β

-cyclodextrin ring system which is instable or only sparingly soluble in water and (ii) a partially etherified β

-cyclodextrin derivative of the formula;

32. Composition according to claim 31 wherein the alkyl groups hydroxyalkyl groups are selected from hydroxyethyl, hydroxypropyl and dihydroxypropyl having a molar substitution of about 0.2 to 2, and the alkyl groups are methyl or ethyl being present up to a degree of substitution between about 0.5 and 1.2.

33. Composition according to claim 32 wherein the hydroxyalkyl group is hydroxyethyl having a molar substitution of about 0.25 to about 1.

34. Composition according to claim 32 wherein the hydroxyalkyl group is hydroxpropyl having a molar substitution of about 0.25 to about 1.

35. Composition according to claim 32 wherein the ratio of said drug to said β

-cyclodextrin derivative is from about 1;

6 to 4;

1.