METHOD OF CONTROLLING FORMATION OF IMIQUIMOD IMPURITIES (BHA COMPARATOR)

• US 20100120822A1
• Filed: 01/30/2010
• Published: 05/13/2010
• Est. Priority Date: 12/17/2004
• Status: Active Grant

• Current Assignee: Medicis Pharmaceutical Corporation (Bausch Health Cos., Inc.)
• Original Assignee: 3M Innovative Properties Company (3M Company)
• Inventors: Statham, Alexis S., Nelson, Robert J.
• Granted Patent: US 7,919,501 B2
• Time in Patent Office: Days
• US Class Current: 514/293
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators

Abstract

Pharmaceutical formulations and methods including an immune response modifier (IRM) compound and an oleic acid component are provided where stability is improved by using oleic acid have low polar impurities such as peroxides.

Claims

1. A method of controlling formation of 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) impurities in a pharmaceutical cream formulated with imiquimod during storage of the pharmaceutical cream prior to application of the pharmaceutical cream to a dermal or mucosal surface to treat a dermal or mucosal associated condition, said method comprising:

formulating the pharmaceutical cream with imiquimod and a pharmaceutically acceptable vehicle including a refined oleic acid component, wherein the refined oleic acid component contains at least about 80% oleic acid by weight as a fatty acid and has a peroxide value of no more than about 5 milliequivalents of oxygen per kilogram and contains less than about 1% by weight polar impurities at or prior to formulation of the pharmaceutical cream;

storing the formulated pharmaceutical cream for at least about six months prior to use of the pharmaceutical cream; and

forming a reduced or similar amount of imiquimod impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but further formulated with butylated hydroxyanisole (BHA) when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the formation of imiquimod impurities in the pharmaceutical cream is reduced and a therapeutically effective amount of imiquimod can be delivered from the pharmaceutical cream to treat the dermal or mucosal associated condition when the pharmaceutical cream is applied to a dermal or mucosal surface following said storing of the pharmaceutical cream.

2. The method of claim 1, wherein the level of imiquimod impurities formed in said pharmaceutical cream remains similar to or is less than a level of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but further formulated with hydroxyanisole (BHA) when said pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions between about two and about six months.

3. The method of claim 1, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of no more than about 0.07% wt./wt. less than imiquimod impurities contained in said identical pharmaceutical imiquimod cream after storage for about six months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

4. The method of claim 1, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of no more than about 0.03% wt./wt. less than imiquimod impurities contained in said identical pharmaceutical imiquimod cream after storage for about six months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

5. The method of claim 1, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about the same % wt./wt. as contained in said identical pharmaceutical imiquimod cream after storage for about six months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

6. The method of claim 1, wherein the imiquimod is present in an amount of not more than 10% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of no more than about 40% by weight based on the total weight of said pharmaceutical cream.

7. The method of claim 1, wherein the imiquimod is present in an amount of about 5% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of about 28% by weight based on the total weight of said pharmaceutical cream.

8. A method of controlling formation of 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) impurities in a pharmaceutical cream formulated with imiquimod during storage of the pharmaceutical cream prior to application of the pharmaceutical cream to a dermal or mucosal surface to treat a dermal or mucosal associated condition, said method comprising:

formulating the pharmaceutical cream with imiquimod and a pharmaceutically acceptable vehicle including a refined oleic acid component, wherein the refined oleic acid component contains at least about 80% oleic acid by weight as a fatty acid and has a peroxide value of no more than about 5 milliequivalents of oxygen per kilogram and contains less than about 1% by weight polar impurities at or prior to formulation of the pharmaceutical cream;

storing the formulated pharmaceutical cream for at least about four months prior to use of the pharmaceutical cream; and

forming a reduced or similar amount of imiquimod impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but further formulated with butylated hydroxyanisole (BHA) when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the formation of imiquimod impurities in the pharmaceutical cream is reduced and a therapeutically effective amount of imiquimod can be delivered from the pharmaceutical cream to treat the dermal or mucosal associated condition when the pharmaceutical cream is applied to a dermal or mucosal surface following said storing of the pharmaceutical cream.

9. The method of claim 8, wherein the level of imiquimod impurities formed in said pharmaceutical cream remains similar to or is less than a level of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but further formulated with hydroxyanisole (BHA) when said pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions between about two and about six months.

10. The method of claim 9 wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of no more than about 0.25% wt./wt. less than imiquimod impurities contained in said identical pharmaceutical imiquimod cream after storage for about four months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

11. The method of claim 9 wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of no more than about 0.11% wt./wt. less than imiquimod impurities contained in said identical pharmaceutical imiquimod cream after storage for about four months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

12. The method of claim 9 wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of no more than about 0.03% wt./wt. greater than imiquimod impurities contained in said identical pharmaceutical imiquimod cream after storage for about four months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

13. The method of claim 9, wherein the imiquimod is present in an amount of not more than 10% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of no more than about 40% by weight based on the total weight of said pharmaceutical cream.

14. The method of claim 9, wherein the imiquimod is present in an amount of about 5% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of about 28% by weight based on the total weight of said pharmaceutical cream.

15. A method of controlling formation of 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) impurities in a pharmaceutical cream formulated with imiquimod during storage of the pharmaceutical cream prior to application of the pharmaceutical cream to a dermal or mucosal surface to treat a dermal or mucosal associated condition, said method comprising:

formulating the pharmaceutical cream with imiquimod and a pharmaceutically acceptable vehicle including a refined oleic acid component, wherein the refined oleic acid component contains at least about 80% oleic acid by weight as a fatty acid and has a peroxide value of no more than about 5 milliequivalents of oxygen per kilogram and contains less than about 1% by weight polar impurities at or prior to formulation of the pharmaceutical cream;

storing the formulated pharmaceutical cream for at least about two months prior to use of the pharmaceutical cream; and

forming a reduced or similar amount of imiquimod impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but further formulated with butylated hydroxyanisole (BHA) when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the formation of imiquimod impurities in the pharmaceutical cream is reduced and a therapeutically effective amount of imiquimod can be delivered from the pharmaceutical cream to treat the dermal or mucosal associated condition when the pharmaceutical cream is applied to a dermal or mucosal surface following said storing of the pharmaceutical cream.

16. The method of claim 15, wherein the level of imiquimod impurities formed in said pharmaceutical cream remains similar to or is less than a level of imiquimod impurities formed in an identical pharmaceutical imiquimod cream but further formulated with hydroxyanisole (BHA) when said pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions between about two and about six months.

17. The method of claim 15, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of no more than about 0.11% wt./wt. less than imiquimod impurities contained in said identical pharmaceutical imiquimod cream after storage for about two months of said pharmaceutical cream and said identical pharmaceutical imiquimod cream, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

18. The method of claim 15, wherein the imiquimod is present in an amount of not more than 10% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of no more than about 40% by weight based on the total weight of said pharmaceutical cream.

19. The method of claim 15, wherein the imiquimod is present in an amount of about 5% by weight based on the total weight of said pharmaceutical cream and wherein the oleic acid component is present in an amount of about 28% by weight based on the total weight of said pharmaceutical cream.