CA2643679C - Immune response modifier formulations containing oleic acid and methods - Google Patents

Immune response modifier formulations containing oleic acid and methods Download PDF

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CA2643679C
CA2643679C CA2643679A CA2643679A CA2643679C CA 2643679 C CA2643679 C CA 2643679C CA 2643679 A CA2643679 A CA 2643679A CA 2643679 A CA2643679 A CA 2643679A CA 2643679 C CA2643679 C CA 2643679C
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oleic acid
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imidazoquinoline
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Alexis S. Statham
Robert J. Nelson
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Medicis Pharmaceutical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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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.

Description

What is claimed is:
I. A pharmaceutical formulation for treatment of actinic keratosis, the formulation comprising:
a therapeutically effective amount of an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component.
2. A pharmaceutical formulation for treatment of actinic keratosis, the formulation comprising:
a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines; oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof;
and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5.
3. A pharmaceutical formulation for treatment of actinic keratosis, the formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein 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 preparation of said pharmaceutical formulation.
4. A pharmaceutical formulation for treatment of external genital warts, the formulation comprising:
a therapeutically effective amount of an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline arnines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component.
5. A pharmaceutical formulation for treatment of external genital warts, the formulation comprising:

a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines; oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof;
and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5.
6. A pharmaceutical formulation for treatment of external genital warts, the formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amities, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein 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 preparation of said pharmaceutical formulation.
7. A pharmaceutical formulation for treatment of basal cell carcinoma, the formulation comprising:
a therapeutically effective amount of an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component.
8. A pharmaceutical formulation for treatment of basal cell carcinoma, the formulation comprising:
a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines; oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof;
and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5.
9. A pharmaceutical formulation for treatment of basal cell carcinoma, the formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, I,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyricline amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein 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 preparation of said pharmaceutical formulation.
10. A
formulation as in any one of claims 1-9 wherein the IRM compound is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, 6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy or arylalkyleneoxy substituted imidazoquinoline amines, imidazoquinoline diamines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines; heterocyclic ether substituted tetrahydroimidazoquinoline amines, amido ether substituted tetrahydroimidazoquinoline amines, sulfonamido ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, thioether substituted tetrahydroimidazoquinoline amines, tetrahydroimidazoquinoline diamines, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, amido ether substituted imidazopyridine amines, sulfonamido ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers; thioether substituted imidazopyridine amines, and combinations thereof.
11. A formulation as in any one of claims 1-9 wherein the IRM compound is an imidazonaphthyridine amine.
12. A formulation as in any one of claims 1-9 wherein the IRM compound is 2-methyl-1-(2- methylpropy1)-1H-imidazo [4,5-c] [1,5] naphthyridin-4-amine.
13. A formulation as in any one of claims 1-9 wherein the IRM compound is 1-(2-methylpropy1)-1H-imidazo [4,5-c] quinolin-4- amine.
14. A formulation as in any one of claims 1-12 wherein the IRM compound is present in an amount of at least 5% by weight, based on the total weight of the formulation.
15. The formulation of claim 13, wherein the 1-(2-methylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine is present in an amount of 5% by weight of the formulation.
16. A formulation as in any one of claims 1-15 wherein the oleic acid component is present in an amount of at least 15% by weight based on the total weight of the formulation.
17. A formulation as in any one of claims 1-15 wherein the oleic acid component is present in an amount of at least 20% by weight based on the total weight of the formulation.
18. A formulation as in any one of claims 1-15 wherein the oleic acid component is present in an amount of at least 25% by weight based on the total weight of the formulation.
19. A formulation as in any one of claims 1-18 wherein the oleic acid component has been purified by chromatography prior to use in the formulation.
20. A formulation as in any one of claims 1-18 wherein the oleic acid component is plant-derived.
21. A formulation as in any one of claims 1-20 wherein the formulation includes at least one fatty acid other than oleic acid or isostearic acid.
22. A formulation as in any one of claims 1-21 wherein the formulation includes less than 3% isostearic acid by weight based on the total weight of the formulation.
23. A formulation as in any one of claims 1-22 wherein the formulation further comprises an antioxidant.
24. A formulation as in claim 23 wherein the antioxidant is butylated hydroxyl toluene or butylated hydroxyanisole.
25. A formulation of any one of claims 1-24 further comprising water.
26. A formulation of any one of claims 1-25 further comprising a preservative system.
27. A formulation of any one of claims 1-26 further comprising an emulsifier.
28. A method of stabilizing a pharmaceutical formulation comprising at least 5% by weight 1-(2-methylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine; and at least 15%
by weight oleic acid by using an oleic acid component that is substantially free of polar impurities.
29. A method of stabilizing a pharmaceutical formulation comprising at least 5% by weight 1-(2-methylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine; and at least 15%
by weight oleic acid by using an oleic acid component with a peroxide value no greater than 5.
30. A method of stabilizing a pharmaceutical formulation comprising at least 5% by weight 1-(2-methylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine; and at least 15%
by weight oleic acid by using an oleic acid component that is at least 80% oleic acid.
31. Use of the formulation of any one of claims 1-3 and 10-27 for treatment of actinic keratosis comprising using the formulation on the skin of a subject.
32. Use of the formulation of any one of claims 4-6 and 10-27 for treatment of external genital warts comprising using the formulation on the skin or mucosal surface of a subject.
33. Use of the formulation of any one of claims 7-9 and 10-27 for treatment of basal cell carcinoma comprising using the formulation on the skin of a subject.
34. Use of the formulation of any one of claims 1-27 for inducing interferon biosynthesis comprising using the formulation on the skin or mucosal of a subject.
TOR_LAW\ 8333195\1

Claims (34)

What is claimed is:
1. A pharmaceutical formulation for treatment of actinic keratosis, the formulation comprising:
a therapeutically effective amount of an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
2. A pharmaceutical formulation for treatment of actinic keratosis, the formulation comprising:
a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines; oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof;
and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5; and wherein the pharmaceutical formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
3. A pharmaceutical formulation for treatment of actinic keratosis, the formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein 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 preparation of said pharmaceutical formulation, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and metal ion.
4. A pharmaceutical formulation for treatment of external genital warts, the formulation comprising:
a therapeutically effective amount of an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
5. A pharmaceutical formulation for treatment of external genital warts, the formulation comprising:
a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines; oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof;
and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5; and wherein the pharmaceutical formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
6. A pharmaceutical formulation for treatment of external genital warts, the formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein 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 preparation of said pharmaceutical formulation, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and metal ion.
7. A pharmaceutical formulation for treatment of basal cell carcinoma, the formulation comprising:
a therapeutically effective amount of an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
8. A pharmaceutical formulation for treatment of basal cell carcinoma, the formulation comprising:
a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines; oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof;
and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5; and wherein the pharmaceutical formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
9. A pharmaceutical formulation for treatment of basal cell carcinoma, the formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable vehicle including an oleic acid component, wherein 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 preparation of said pharmaceutical formulation, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and metal ion.
10. A formulation as in any one of claims 1-9 wherein the IRM compound is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, 6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy or arylalkyleneoxy substituted imidazoquinoline amines, imidazoquinoline diamines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines; heterocyclic ether substituted tetrahydroimidazoquinoline amines, amido ether substituted tetrahydroimidazoquinoline amines, sulfonamido ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, thioether substituted tetrahydroimidazoquinoline amines, tetrahydroimidazoquinoline diamines, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, amido ether substituted imidazopyridine amines, sulfonamido ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers; thioether substituted imidazopyridine amines, and combinations thereof.
11. A formulation as in any one of claims 1-9 wherein the IRM compound is an imidazonaphthyridine amine.
12. A formulation as in any one of claims 1-9 wherein the IRM compound is 2-methyl-1-(2- methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
13. A formulation as in any one of claims 1-9 wherein the IRM compound is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.
14. A formulation as in any one of claims 1-12 wherein the IRM compound is present in an amount of at least 5% by weight, based on the total weight of the formulation.
15. The formulation of claim 13, wherein the 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine is present in an amount of 5% by weight of the formulation.
16. A formulation as in any one of claims 1-15 wherein the oleic acid component is present in an amount of at least 15% by weight based on the total weight of the formulation.
17. A formulation as in any one of claims 1-15 wherein the oleic acid component is present in an amount of at least 20% by weight based on the total weight of the formulation.
18. A formulation as in any one of claims 1-15 wherein the oleic acid component is present in an amount of at least 25% by weight based on the total weight of the formulation.
19. A formulation as in any one of claims 1-18 wherein the oleic acid component has been purified by chromatography prior to use in the formulation.
20. A formulation as in any one of claims 1-18 wherein the oleic acid component is plant-derived.
21. A formulation as in any one of claims 1-20 wherein the formulation includes at least one fatty acid other than oleic acid or isostearic acid.
22. A formulation as in any one of claims 1-21 wherein the formulation includes less than 3% isostearic acid by weight based on the total weight of the formulation.
23. A formulation as in any one of claims 1-22 wherein the formulation further comprises an antioxidant.
24. A formulation as in claim 23 wherein the antioxidant is butylated hydroxyl toluene or butylated hydroxyanisole.
25. A formulation of any one of claims 1-24 further comprising water.
26. A formulation of any one of claims 1-25 further comprising a preservative system.
27. A formulation of any one of claims 1-26 further comprising an emulsifier.
28. A method of stabilizing a pharmaceutical formulation comprising at least 5% by weight 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; and at least 15%
by weight oleic acid by using an oleic acid component that is substantially free of polar impurities, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
29. A method of stabilizing a pharmaceutical formulation comprising at least 5% by weight 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; and at least 15%
by weight oleic acid by using an oleic acid component with a peroxide value no greater than 5; and wherein the pharmaceutical formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
30. A method of stabilizing a pharmaceutical formulation comprising at least 5% by weight 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; and at least 15%
by weight oleic acid by using an oleic acid component that is at least 80% oleic acid, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component, wherein the polar impurities include one or more of a peroxide, an aldehyde, a ketone, an alcohol and a metal ion.
31. Use of the formulation of any one of claims 1-3 and 10-27 for treatment of actinic keratosis on the skin of a subject.
32. The pharmaceutical formulation of any one of claims 4-6 and 10-27 for use in the treatment of external genital warts on the skin or mucosal surface of a subject.
33. The pharmaceutical formulation of any one of claims 7-9 and 10-27 for use in the treatment of basal cell carcinoma on the skin of a subject.
34. The pharmaceutical formulation of any one of claims 1-27 for use in inducing interferon biosynthesis on the skin or mucosal of a subject.
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