Pharmaceutical cream having similar or less levels of imiquimod impurity formation as cream with BHA (comparator)

• US 7,906,524 B2
• Filed: 02/01/2010
• Issued: 03/15/2011
• 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:
  US12/697,423
• Publication Number:
  US 20100120830A1
• Time in Patent Office: 407 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 pharmaceutical cream formulated with 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) for topical application to a dermal or mucosal surface, said pharmaceutical cream comprising:

a therapeutically effective amount of imiquimod;

a pharmaceutically acceptable vehicle including an oleic acid component, where said 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 said pharmaceutical cream; and

a level of imiquimod impurities formed during storage of said pharmaceutical cream;

wherein the level of imiquimod impurities formed in said pharmaceutical cream is less than a level of imiquimod impurities formed in an 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 for about six months after formulation.

2. The pharmaceutical cream of claim 1, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of 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.

3. The pharmaceutical cream of claim 1, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about 0.10% 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 pharmaceutical cream 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.

5. The pharmaceutical cream 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.

18. The pharmaceutical cream 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.

6. A pharmaceutical cream formulated with 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) for topical application to a dermal or mucosal surface, said pharmaceutical cream comprising:

a therapeutically effective amount of imiquimod;

a pharmaceutically acceptable vehicle including an oleic acid component, where said 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 said pharmaceutical cream; and

a level of imiquimod impurities formed during storage of said pharmaceutical cream;

wherein the level of imiquimod impurities formed in said pharmaceutical cream is less than a level of imiquimod impurities formed in an 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 for about four months after formulation.

7. The pharmaceutical cream of claim 6, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about 0.25% wt./wt. less than imiquimod 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 pharmaceutical cream of claim 6, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about 0.11% wt./wt. less than imiquimod 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 pharmaceutical cream 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.

10. The pharmaceutical cream of claim 6, 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.

11. A pharmaceutical cream formulated with 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) for topical application to a dermal or mucosal surface, said pharmaceutical cream comprising:

a therapeutically effective amount of imiquimod;

a pharmaceutically acceptable vehicle including an oleic acid component, where said 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 said pharmaceutical cream; and

a level of imiquimod impurities formed during storage of said pharmaceutical cream;

wherein the level of imiquimod impurities formed in said pharmaceutical cream is less than a level of imiquimod impurities formed in an 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 for about two months after formulation.

12. The pharmaceutical cream of claim 11, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about 0.11% wt./wt. less than imiquimod 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 pharmaceutical cream of claim 11, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about 0.08% wt./wt. less than imiquimod 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.

14. The pharmaceutical cream of claim 11, wherein imiquimod impurities contained in said pharmaceutical cream are in an amount of about 0.05% wt./wt. less than imiquimod 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.

15. The pharmaceutical cream of claim 11, 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 pharmaceutical cream of claim 11, 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.

17. The pharmaceutical cream of claim 11, 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.