METHOD OF STABILIZING IMIQUIMOD

• US 20100130529A1
• Filed: 01/30/2010
• Published: 05/27/2010
• 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 7,902,242 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 stabilizing 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) in a pharmaceutical cream formulated with the 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 a therapeutically effective amount of 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

maintaining a greater amount of the therapeutically effective amount of imiquimod in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to a reduced amount of imiquimod maintained in an identical pharmaceutical imiquimod cream but formulated with a compendial grade oleic acid component rather than a refined oleic acid component when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the pharmaceutical cream can deliver the greater therapeutically effective amount of imiquimod 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 said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.07% wt./wt. after storage of said pharmaceutical cream for about six months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

3. The method of claim 1, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.14% wt./wt. after storage of said pharmaceutical cream for about six months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

4. The method of claim 1, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.04% wt./wt. after storage of said pharmaceutical cream for about six months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

5. The method of claim 1, wherein said pharmaceutical cream further comprises an antioxidant selected from the group consisting of butylated hydroxyl toluene (BHT) and butylated hydroxyanisole (BHA).

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.

11. The method of claim 1, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.04% wt./wt. after storage of said pharmaceutical cream for about four months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

8. A method of stabilizing 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) in a pharmaceutical cream formulated with the 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 a therapeutically effective amount of 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

maintaining a greater amount of the therapeutically effective amount of imiquimod in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to a reduced amount of imiquimod maintained in an identical pharmaceutical imiquimod cream but formulated with a compendial grade oleic acid component rather than a refined oleic acid component when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the pharmaceutical cream can deliver the greater therapeutically effective amount of imiquimod 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 said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.18% wt./wt. after storage of said pharmaceutical cream for about four months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

10. The method of claim 8, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.29% wt./wt. after storage of said pharmaceutical cream for about four months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

12. The method of claim 8, wherein said pharmaceutical cream further comprises an antioxidant selected from the group consisting of butylated hydroxyl toluene (BHT) and butylated hydroxyanisole (BHA).

13. The method of claim 8, 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 8, 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 stabilizing 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) in a pharmaceutical cream formulated with the 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 a therapeutically effective amount of 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

maintaining a greater amount of the therapeutically effective amount of imiquimod in the pharmaceutical cream during said storing of the pharmaceutical cream, as compared to a reduced amount of imiquimod maintained in an identical pharmaceutical imiquimod cream but formulated with a compendial grade oleic acid component rather than a refined oleic acid component when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions, so that the pharmaceutical cream can deliver the greater therapeutically effective amount of imiquimod 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 said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.07% wt./wt. after storage of said pharmaceutical cream for about two months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

17. The method of claim 15, wherein said pharmaceutical cream contains imiquimod impurities in an amount of no more than about 0.15% wt./wt. after storage of said pharmaceutical cream for about two months, where absorbance of said pharmaceutical cream is analyzed at about 308 nm using a UV detector.

18. The method of claim 15, wherein said pharmaceutical cream further comprises an antioxidant selected from the group consisting of butylated hydroxyl toluene (BHT) and butylated hydroxyanisole (BHA).

19. 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.

20. 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.