Method of controlling formation of imiquimod impurities

• US 7,919,501 B2
• Filed: 01/30/2010
• Issued: 04/05/2011
• Est. Priority Date: 12/17/2004
• Status: Expired due to Fees

• Current Assignee: Medicis Pharmaceutical Corporation (Bausch Health Cos., Inc.)
• Original Assignee: 3M Innovative Properties Company (3M Company)
• Inventors: Statham, Alexis S., Nelson, Robert J.
• Primary Examiner(s): Padmanabhan; Sreeni
• Assistant Examiner(s): CLAYTOR, DEIRDRE RENEE
• Application Number:
  US12/697,244
• Publication Number:
  US 20100120822A1
• Time in Patent Office: 430 Days
• Field of Search: 514/290, 514/393
• US Class Current: 514/290
• 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) related impurities in a pharmaceutical cream formulated with imiquimod and an oleic acid component during storage of the pharmaceutical cream prior to application of the pharmaceutical cream to a dermal or mucosal surface, said method comprising:

formulating the pharmaceutical cream with imiquimod and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the 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 prior to use of the pharmaceutical cream; and

forming a reduced amount of imiquimod-related impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod-related 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 for up to about 6 months after formulation.

2. The method of claim 1, wherein imiquimod-related impurities contained in said pharmaceutical cream are in an amount of about 0.07% wt./wt. less than imiquimod-related impurities contained in said identical pharmaceutical imiquimod cream after storage for about six months after formulation 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.

3. The method of claim 1, wherein imiquimod-related impurities contained in said pharmaceutical cream are in an amount of about 0.03% wt./wt. less than imiquimod-related impurities contained in said identical pharmaceutical imiquimod cream after storage for about six months after formulation 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 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 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 25% by weight based on the total weight of said pharmaceutical cream.

18. The method of claim 1, wherein said oleic acid component is Super Refined oleic acid NF.

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

formulating the pharmaceutical cream with imiquimod and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the 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 prior to use of the pharmaceutical cream; and

forming a reduced amount of imiquimod-related impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod-related 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 for about four months after formulation.

6. The method of claim 5, wherein the level of imiquimod-related impurities formed in said pharmaceutical cream is less than a level of imiquimod-related impurities formed in said identical pharmaceutical imiquimod cream but further formulated with butylated hydroxyanisole (BHA) when said pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions between from about two months after formulation to about six months after formulation.

7. The method of claim 6 wherein imiquimod-related impurities contained in said pharmaceutical cream are in an amount of about 0.25% wt./wt. less than imiquimod-related impurities contained in said identical pharmaceutical imiquimod cream after storage for about four months after formulation 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.

8. The method of claim 6 wherein imiquimod-related impurities contained in said pharmaceutical cream are in an amount of about 0.11% wt./wt. less than imiquimod-related impurities contained in said identical pharmaceutical imiquimod cream after storage for about four months after formulation 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.

9. The method of claim 6, 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.

15. The method of claim 5, 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 25% by weight based on the total weight of said pharmaceutical cream.

19. The method of claim 5, wherein said oleic acid component is Super Refined oleic acid NF.

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

formulating the pharmaceutical cream with imiquimod and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the 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 prior to use of the pharmaceutical cream; and

forming a reduced amount of imiquimod-related impurities in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to an amount of imiquimod-related 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 for about an equal period of time after formulation.

11. The method of claim 10, wherein the level of imiquimod-related impurities formed in said pharmaceutical cream is less than a level of imiquimod-related impurities formed in said identical pharmaceutical imiquimod cream but further formulated with butylated hydroxyanisole (BHA) when said pharmaceutical cream and said identical pharmaceutical imiquimod cream are each stored under identical storage conditions from about two months after formulation to about six months after formulation.

12. The method of claim 10, wherein imiquimod-related impurities contained in said pharmaceutical cream are in an amount of about 0.11% wt./wt. less than imiquimod-related impurities contained in said identical pharmaceutical imiquimod cream after storage for about two months after formulation 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 10, 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.

16. The method of claim 10, 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 25% by weight based on the total weight of said pharmaceutical cream.

17. The method of claim 10, wherein imiquimod-related impurities contained in said pharmaceutical cream are in an amount of about 0.08% wt./wt. less than imiquimod-related impurities contained in said identical pharmaceutical imiquimod cream after storage for about two months after formulation 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.

20. The method of claim 10, wherein said oleic acid component is Super Refined oleic acid NF.