Non-inclusion cyclodextrin complexes

• US 20030109492A1
• Filed: 10/18/2002
• Published: 06/12/2003
• Est. Priority Date: 10/18/2001
• Status: Active Grant

• Current Assignee: Decode Genetics Ehf. (Amgen Inc.)
• Original Assignee: Decode Genetics Ehf. (Amgen Inc.)
• Inventors: Loftsson, Thorsteinn
• Granted Patent: US 7,115,586 B2
• Time in Patent Office: Days
• US Class Current: 514/58
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• 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

Abstract

The invention provides a number of methods for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water. In one preferred embodiment, solubilization of the active ingredient is enhanced by combining it with β-cyclodextrin in an aqueous complexation medium comprising β-cyclodextrin and a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with β-cyclodextrin and its inclusion complexes.

Claims

1. A method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising combining said active ingredient with β

-cyclodextrin in an aqueous complexation medium, said medium comprising from about 0.1% to about 80% (weight/volume) of β

-cyclodextrin and from about 0.1% to about 5% (weight/volume) of a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with β

-cyclodextrin and its inclusion complexes, said charged compound being acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

2. A method according to claim 1, wherein the aqueous medium is maintained at a temperature of from about 30°

C. to about 150°

C. for a period of time of from about 0.1 to about 100 hours after the active ingredient is added.

3. A method according to claim 1, wherein said negatively-charged compound is a salt of a monofunctional carboxylic acid which does not form inclusion complexes with β

-cyclodextrin or which does so very poorly, or is a salt of a carboxylic acid having a lipophilic moiety which forms an inclusion complex with β

-cyclodextrin.

4. A method according to claim 3, wherein the salt is an alkali metal, alkaline-earth metal or aluminum salt of acetic acid or of propionic acid.

5. A method according to claim 3, wherein said salt is an alkali metal, alkaline-earth metal or aluminum salt of a carboxylic acid having a lipophilic moiety.

6. A method according to claim 5, wherein said salt is the salt of a nonsteroidal antiinflammatory or analgesic agent.

7. A method according to claim 6, wherein said salt is sodium salicylate, sodium benzoate or sodium gentisate.

8. A method according to claim 6, wherein said salt is amfenac sodium, bromfenac sodium, diclofenac sodium, diflumidone sodium, enolicam sodium, fenoprofen calcium, ibuprofen aluminum, indomethacin sodium, magnesium salicylate, meclofenamate sodium, naproxen sodium, sodium salicylate, tifurac sodium, tolemetin sodium or zomepirac sodium.

9. A method according to claim 1, wherein said active ingredient is a drug.

10. A method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising combining said active ingredient with β

-cyclodextrin in an aqueous complexation medium, said medium comprising from about 0.1% to about 80% (weight/volume) of β

-cyclodextrin;

from about 0.1% to about 10% (weight/volume) of a pharmacologically inactive water-soluble polymer acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition; and

from about 0.1% to about 5% (weight/volume) of a negatively- or positively-charged compound which forms an inclusion or non-inclusion complex with β

-cyclodextrin and its inclusion complexes, said charged compound being acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

11. A method according to claim 10, wherein the pharmacologically inactive water-soluble polymer is a cellulose derivative.

12. A method according to claim 11, wherein said cellulose derivative is hydroxypropyl methyl cellulose.

13. A method according to claim 10, wherein the aqueous medium is maintained at a temperature of from about 30°

C. to about 150°

C. for a period of time of from about 0.1 to about 100 hours after the active ingredient is added.

14. A method according to claim 10, wherein said negatively-charged compound is a salt of a monofunctional carboxylic acid which does not form inclusion complexes with β

-cyclodextrin or which does so very poorly, or is a salt of a carboxylic acid having a lipophilic moiety which forms an inclusion complex with β

-cyclodextrin.

15. A method according to claim 14, wherein the salt is an alkali metal, alkaline-earth metal or aluminum salt of acetic acid or of propionic acid.

16. A method according to claim 14, wherein said salt is an alkali metal, alkaline-earth metal or aluminum salt of a carboxylic acid having a lipophilic moiety.

17. A method according to claim 16, wherein said salt is the salt of a nonsteroidal antiinflammatory or analgesic agent.

18. A method according to claim 17, wherein said salt is sodium salicylate, sodium benzoate or sodium gentisate.

19. A method according to claim 17, wherein said salt is amfenac sodium, bromfenac sodium, diclofenac sodium, diflumidone sodium, enolicam sodium, fenoprofen calcium, ibuprofen aluminum, indomethacin sodium, magnesium salicylate, meclofenamate sodium, naproxen sodium, sodium salicylate, tifurac sodium, tolemetin sodium or zomepirac sodium.

20. A method according to claim 10, wherein said active ingredient is a drug.

21. A method for enhancing the aqueous solubility of an active ingredient which is insoluble or sparingly soluble in water and which does not readily form an inclusion complex with cyclodextrin, said active ingredient being a drug, cosmetic additive, food additive or agrochemical, said method comprising adding said active ingredient to an aqueous complexation medium which comprises from about 0.1% to about 70% (weight/volume) of said cyclodextrin, said complexation medium being saturated, prior to addition of said active ingredient, with a compound which forms an inclusion complex with said cyclodextrin and which is acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

22. A method according to claim 21, wherein said aqueous complexation medium further comprises from about 0.01% to about 10% (weight/volume) of a pharmacologically inactive, water-soluble polymer acceptable for use in a pharmaceutical, cosmetic, food or agricultural composition.

23. A method according to claim 21, wherein said cyclodextrin comprises at least one member selected from the group consisting of α

, β

- and γ

-cyclodextrin, and the hydroxypropyl, hydroxyethyl, sulfobutyl ether, glucosyl, maltosyl and methylated derivatives of α

-, β

- and γ

-cyclodextrin.

24. A method according to claim 21, wherein the compound with which the complexation medium is saturated prior to addition of said active ingredient has a log P value of greater than about 3.5 in its unionized form.

25. A method according to claim 24, wherein the log P value of said compound is greater than about 4.0 in its unionized form.

26. A method according to claim 21, wherein the compound with which the complexation medium is saturated prior to addition of said active ingredient has surface activity when ionized.

27. A method according to claim 26, wherein said compound is sodium diflunisal.

28. A method according to claim 25, wherein said compound is cholesterol.

29. A method according to claim 21, wherein said active ingredient is a drug.

30. A method according to claim 22, wherein the pharmacologically inactive water-soluble polymer is a cellulose derivative.

31. A method according to claim 30, wherein said cellulose derivative is hydroxypropyl methyl cellulose.

32. A method according to claim 21, wherein the aqueous medium is maintained at a temperature of from about 30°

C. to about 150°

C. for a period of time of from about 0.1 to about 100 hours after the active ingredient is added.

33. A method according to claim 22, wherein the aqueous medium is maintained at a temperature of from about 30°

C. to about 150°

C. for a period of time of from about 0.1 to about 100 hours after the active ingredient is added.

34. A method according to claim 21, wherein the active ingredient has a solubility of less than 10 mg/mL in 60% (weight/volume) aqueous hydroxypropyl-β

-cyclodextrin at 20°

C.

35. A method according to claim 34, wherein said solubility is less than 5 mg/mL.