Method of preparing a pharmaceutical cream and minimizing imiquimod impurity formation (at least four months storage)

• US 7,902,244 B2
• Filed: 02/01/2010
• Issued: 03/08/2011
• 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): Richter; Johann R.
• Assistant Examiner(s): Carter; Kendra D
• Application Number:
  US12/697,434
• Publication Number:
  US 20100120832A1
• Time in Patent Office: 400 Days
• Field of Search: 514/393, 514/209, 548/302.1
• US Class Current: 514/393
• 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 preparing a pharmaceutical cream formulated with an oleic acid component and 1-(2-methylpropyl)-1H imidazo[4,5-c]quinolin-4-amine (imiquimod) and minimizing formation of imiquimod-related impurities in the prepared pharmaceutical cream during storage of the prepared pharmaceutical cream prior to application of the prepared pharmaceutical cream to a dermal or mucosal surface, said method comprising:

(a) preparing a water phase preparation for formulating the prepared pharmaceutical cream, the water phase preparation comprising pharmaceutically acceptable excipients;

(b) preparing an oil phase preparation for formulating the prepared pharmaceutical cream, the oil phase preparation comprising imiquimod and 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;

(c) adding said water phase preparation to said oil phase preparation to form an emulsion;

(d) homogenizing the emulsion to formulate the prepared pharmaceutical cream;

(e) storing the prepared pharmaceutical cream prior to use of the pharmaceutical cream; and

(f) minimizing the formation 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 formulated with a compendial grade oleic acid component when the pharmaceutical cream and the identical pharmaceutical imiquimod cream are each stored under identical storage conditions for up to about four months after formulation.

2. The method of claim 1, wherein said pharmaceutical cream contains imiquimod-related impurities in an amount of about 0.18% wt./wt. or less after storage of said pharmaceutical cream for about four months after formulation, 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-related impurities in an amount of no more than about 0.29% wt./wt. after storage of said pharmaceutical cream for about four months after formulation, 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-related impurities in an amount of about 0.04% wt./wt. after storage of said pharmaceutical cream for about four months after formulation, 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 25% by weight based on the total weight of said pharmaceutical cream.

8. The method of claim 1, said method including the further step of:

forming a premix comprised of imiquimod and the oleic acid component before said preparing of the oil phase preparation.

9. The method of claim 8, said method including the further step of:

adding petrolatum, cetyl alcohol, stearyl alcohol, polysorbate, sorbitan monostearate to the premix.

10. The method of claim 8, said method including the further step of:

adding BHA to the premix.

11. The method of claim 9, said method including the further steps of:

stirring the premix; and

heating the premix while said stirring to about 55°

C.

12. The method of claim 10, said method including the further steps of:

stirring the premix; and

heating the premix while said stirring to about 55°

C.

13. The method of claim 8, said method including the further step of:

adding benzyl alcohol to the oil phase preparation.

14. The method of claim 9, said method including the further step of:

adding benzyl alcohol to the oil phase preparation.

15. The method of claim 10, said method including the further step of:

adding benzyl alcohol to the oil phase preparation.

16. The method of claim 1, wherein said homogenizing was for about 5 minutes.

17. The method of claim 1, said method including the further steps of:

forming a paraben premix comprised of methyl hydroxybenzoate, propyl hydroxybenzoate and water before said preparing of the water phase preparation;

stirring and heating the paraben premix until the methyl hydroxybenzoate and propyl hydroxybenzoate are dissolved in the water; and

cooling the heated and stirred paraben premix in which the methyl hydroxybenzoate and propyl hydroxybenzoate are dissolved.

18. The method of claim 17, said method including the further steps of:

adding glycerin to the cooled paraben premix; and

heating the cooled paraben premix mixed with glycerin to a temperature of about 55°

C.

19. The method of claim 18, said method including the further steps of:

adding xanthan gum to the heated paraben premix mixed with glycerin; and

mixing and heating the heated paraben premix mixed with glycerin and xanthan gum until the xanthan gum is dispersed in the heated paraben premix mixed with glycerin and xanthan gum.

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