WO2008082381A1 - Immune response modifier formulations containing oleic acid and methods - Google Patents
Immune response modifier formulations containing oleic acid and methods Download PDFInfo
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- WO2008082381A1 WO2008082381A1 PCT/US2006/049517 US2006049517W WO2008082381A1 WO 2008082381 A1 WO2008082381 A1 WO 2008082381A1 US 2006049517 W US2006049517 W US 2006049517W WO 2008082381 A1 WO2008082381 A1 WO 2008082381A1
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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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Definitions
- the present invention relates to pharmaceutical formulations for the topical or transdermal delivery of immun ⁇ modifying drugs.
- IRMs immune response modifiers
- certain IRMs may be useftil for treating viral diseases (e.g., human papilloma virus, hepatitis, herpes), neoplasias (e.g., basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma), and TH2- mediated diseases (e.g., asthma, allergic rhinitis, atopic dermatitis), and are also useful as vaccine adjuvants.
- viral diseases e.g., human papilloma virus, hepatitis, herpes
- neoplasias e.g., basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma
- TH2- mediated diseases e.g., asthma, allergic rhinitis, atopic dermatitis
- IRM compounds are small organic molecule imidazoquinoli ⁇ e amine derivatives (see, e.g., U-S. Pat. No. 4,689,338), but a number of other compound classes are known as well (see, e.g., U.S. Pat. Nos. 5,446,153, 6,194,425, and 6,110,929) and more are still being discovered.
- One of these IRM compounds, known as imiquimod has been commercialized in a topical formulation, ALDARA, forthe treatment of actinic keratosis, basal cell carcinoma, or anogenital warts associated with human papillomavirus.
- IRM compounds are disclosed in U.S. Patent Nos.5,238,944; 5,939 ⁇ 090; and 6,425,776; European Patent 0 394 026; and U.S. Patent Publication 2003/0199538.
- the ability to provide therapeutic benefit via topical application of an IRM compound for treatment of a particular condition at a particular location may be hindered by a variety of factors. These factors include: irritation of the skin to which the formulation is applied; formulation wash away; insolubility of the IRM compound in the formulation; chemical degradation of the IRM compound and/or other ingredients, physical instability of the formulation (e.g., separation of components, thickening, precipitation/agglomerization of active ingredient, and the like); poor permeation; and u ⁇ desired systemic delivery of topical IRM formulations if not intended to be transdermal.
- factors include: irritation of the skin to which the formulation is applied; formulation wash away; insolubility of the IRM compound in the formulation; chemical degradation of the IRM compound and/or other ingredients, physical instability of the formulation (e.g., separation of components, thickening, precipitation/agglomerization of active ingredient, and the like); poor permeation; and u ⁇ desired systemic delivery of topical IRM formulations
- the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of an immune response modifier (IRM) compound 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
- IRM immune response modifier
- the present invention provides a pharmaceutical formulation comprising: a therapeutically effective amount of an IRM compound and a pharmaceutically acceptable vehicle including an oleic acid component wherein the oleic acid component has a peroxide value no greater than 5.
- the present invention provides a pharmaceutical formulation comprising: a therapeutically effective amount of an IRM compound and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component is at least 80% oleic acid.
- the present invention also provides methods.
- the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an immune response modifier (IRM) compound and oleic acid by using an oleic acid component that is substantially free of polar impurities.
- IRM immune response modifier
- the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM compound and oleic acid by using an oleic acid component with a peroxide value no greater than 5.
- the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM compound and oleic acid by using an oleic acid component that is at least 80% oleic acid.
- the present invention provides methods for treating disease, including but not limited to the group comprising actinic keratosis, basal cell carcinoma, genital warts, peri-anal warts, malignant melanoma, and molloscum contag ⁇ osum.
- the present invention provides methods to induce cytokine biosynthesis.
- the present invention provides methods to induce interferon biosynthesis.
- a pharmaceutical formulation comprising:
- an immune response modifier (IRM) compound selected from the group consisting of imidazoqumoline amines, tetrahydroimidazoqu ⁇ noline amines, ⁇ midazopyridfaie amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2- bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloqu ⁇ noline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, l ⁇ T-imidazo dimers fused to pyridine amines, qui ⁇ oline amines, tetrahydroqu ⁇ noline amines,
- a pharmaceutical 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, lif-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or
- a pharmaceutical 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
- an IRM compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2- bridge
- amines thiazolonaphthyridine amines, liWmidazo 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 is at least 80% oleic acid.
- IJRM compound is selected from the group consisting of amide substituted imidazoquinol ⁇ ne 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 tetrahydro
- formulation as in any one of the preceding embodiments wherein the formulation further comprises an antioxidant.
- a formulation as in any one of the preceding embodiments further comprising an antioxidant, wherein the antioxidant is butylated hydroxyl toluene or butylated hydroxyanisole.
- a formulation of any one of the preceding embodiments further comprising water.
- a formulation of any one of the preceding embodiments further comprising an emulsifier.
- a method of stabilizing a pharmaceutical 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 cycloalkyltmidazopyridme amines, 1,2- bridged imidazoquinoline amines, ⁇ m ⁇ dazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinol ⁇ ne amines; th ⁇ azoloqu ⁇ noline amines, oxazolopyr ⁇ dine amines, thiazolopyrid ⁇ ne amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines; lfWrnidazo dimers fused to pyridine amines, l
- a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM compound selected from the group consisting of imidazoqu ⁇ noJine amines, tetrahydroimidazoquinoli ⁇ e amines, imidazopyridine amines, 6,7-fiised cycloalkylimidazopyridine amines, 1,2- bridged imidazoquinoline amines, imidazonaphthyridine amines, tefrahydroimidazonaphthyridi ⁇ e amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, l/f-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydr
- a method of stabilizing a pharmaceutical 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 cycloalkylimidazopyrid ⁇ ne amines, 1,2- bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyrid ⁇ ne amines, oxazoloquinoline amines, thiazoloqu ⁇ noline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, lJY-im ⁇ dazo dimers fused to pyridine amines, quinoline amines, tetrahydroimi
- the IRM compound is selected from the group consisting of: amide substituted imidazoquinoline amines, sulfonamide substituted ⁇ midazoqurnol ⁇ ne 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
- a method of treating actinic keratosis comprising applying a formulation of any one of embodiments 1 through 21 to the skin of a subject.
- a method of treating basal cell carcinoma comprising applying a formulation of any one of embodiments 1 through 21 to the skin of a subject,-
- a method of treating genital warts comprising applying a ' formulation of any one of embodiments 1 through 21 to the skin or mucosal surface of a subject.
- a method of treating peri-anal warts comprising applying a formulation of any one of embodiments 1 through 21 to the skin or mucosal surface of a subject.
- a method of treating molloscum contagiosum comprising applying a formulation of any one of embodiments 1 through 21 to the skin of a subject.
- a method of inducing cytokine biosynthesis comprising applying a formulation of any one of embodiments 1 through 21 to the skin or mucosal surface of a subject.
- a method of inducing interferon biosynthesis comprising applying a formulation of any one of embodiments 1 through 21 to the skin or mucosal surface of a subject.
- a method of treating malignant melanoma comprising applying a formulation of any one of the preceding embodiments 1 through 21 to the skin of a subject.
- substantially free is used to indicate that the amount present in the composition or formulation is below the level that causes degradation of the active pharmaceutical agent, such that the formulation is unsuitable for pharmaceutical usage, after storage for 4 months at 40 0 C at 75% relative humidity.
- the term can also be used to describe a composition containing less than 10%, less than 5%, less than 1%, or less than 0.1% by weight of agiven substance.
- polar impurities includes, but is not limited to peroxides, aldehydes, ketones, alcohols, metal ions, and/or substances that cause degradation of the active pharmaceutical agent.
- oleic acid component is used to describe a preformulation source or composition of matter containing oleic acid, and may include other fatty acids in
- oleic acid including but not limited to: myristic acid, palmitic acid, palmitoleic acid, margaric acid, isostearic acid, stearic acid, linoleic acid, l ⁇ nolenic acid, and other fatty acids, or combinations thereof.
- the peroxide value is-the number that expresses in milliequivalents of active oxygen the quantity of peroxide contained in 1000 g of the substance as determined • by the methods described in the 5th edition of the European Pharmacopoeia, Section 2.5.5.
- the present invention provides pharmaceutical formulations that include 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 cycloalkyl ⁇ midazopyridine amines, 1 ,2- bridged imidazoquinoline amines, imidazonaphthyridine amines.'-tetrahydroirnidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridi ⁇ e amines, tbiazolonaphthyridine amines, and l ⁇ f-imidazo dimers fused to pyridine amines, quinoline amines,
- IRM immune response modifier
- the stability of such formulations is substantially greater than that of similar formulations containing an IRM compound and oleic acid containing conventional oleic acid with higher 5 amounts of polar impurities such as peroxides, even when the oleic acid component is of compendial grade. Furthermore, the instability problem of these formulations is not eliminated by additional antioxidants.
- the formulation comprises an IRM compound 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.
- the formulation comprises an IRM compound and a pharmaceutically acceptable vehicle including an oleic acid component,0 wherein the oleic acid component has a peroxide value no greater than 5.
- the formulation comprises an IRM compound and a pharmaceutically acceptable vehicle including an oleic acid component, wherein the oleic acid component is at least 80% oleic acid.
- formulations described herein can be in the form of an oil-in-water emulsion such as a cream or a lotion.
- the oil component of the formulation includes an IRM compound and one or more fatty acids, including oleic acid in an amount sufficient to solub ⁇ lize the IRM compound.
- a cream or lotion of the invention can contain emollients, antioxidants, emulsifiers, viscosity enhancing agents, and/or preservatives.
- Such components, as well as all others of ⁇ the formulations described herein,- are preferably pharmaceutically acceptable.
- Formulations of the invention include an IRM compound.
- Such compounds include, for example, imidazoquinoline amines including, but not limited to, substituted imidazoquinoline amines such as, for example, amide substituted
- the IRM compound is an imidazonaphthyridine amine.
- the IRM compound is 2-methyl-l-(2-methyI ⁇ ropyl)- liMmidazo[4,5-c][l,5]naphthyridin-4-amine.
- the IRM compound is an imidazoqui ⁇ oline amine.
- the IRM compound is l-(2-methylpropyt)-l ⁇ f- imidazo[4,5-c]quinoIin-4-am ⁇ ne (imiquimod).
- the IRM may have low solubility in water, for example less than about 1 ug/mL (e.g., 0.79 ug/mL in the case of imiquimod), making them difficult to solubilize in aqueous formulations, and potentially using relatively large amounts of oleic acid in the formulation.
- the amount of IRM compound that will be therapeutically effective in a specific situation will depend on such things as the activity of the particular compound, the dosing regimen, the application site, the particular formulation and the condition being treated. As such, it is generally not practical to identify specific administration amounts herein; however, those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, information available in the aft pertaining to ERM compounds, and routine testing.
- a therapeutically effective amount means an amount of the IRM compound sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, inhibition of TH2 immune response, antiviral or antitumor activity, reduction or elimination of postsurgical scarring, reduction or resolution of actinic keratosis or pre-actinic keratosis lesions, reduction in the recurrence of actinic keratosis, treatment of basal cell carcinoma, genital warts, peri-anal warts, molloscum contagiosum, or protection against uv-induced epidermal neoplasia.
- the amount of IRM compound present in a topical formulation of the invention will be an amount effective to treat a targeted condition, to prevent recurrence of the condition, or to promote immunity against the condition.
- the amount or concentration of IRM compound is at least 3% by weight, such as, for example, at least 5%, and at least 10%, by weight based on the total weight of the formulation.
- the amount of IRM compound is at most 10% by weight, such as, for example, at most 5%, at most 3%,
- the amount or concentration of IRM compound is at least 0.02% by weight, such as, for example, at least 0.03%, at least 0.10%, and at least 0.30% by weight based on the total weight of the formulation.
- the topical formulations of the invention include fatty acids.
- the topical formulations of the invention contain an oleic acid component.
- fatty acid means a carboxylic acid, either saturated or unsaturated having 6 to 28 carbon atoms, such as, for example, from 10 to 22 carbon atoms.
- the fatty acids, including the oleic acid component may be present in the formulation in an amount sufficient to solubilize the IRM compound-
- the amount of oleic acid component is at least 0.05% by weight, at least 1.0% by weight, at least 3.0% by weight, at least 5.0%, at least 10%, at least 15%, or at least 25%, based on the total weight of the formulation.
- the amount of oleic acid component is at most 40% by weight, at most 30% by weight, at most 15% by weight, or at most 10%, based on the total weight of the formulation.
- Compendial grade oleic acid typically contains from 65 to 88 percent (Z)- octadec-9-enoic acid (oleic acid) together with varying amounts of saturated and other unsaturated fatty acids.
- the composition of fatty acids is determined by gas chromatography using the method described in European Pharmacopeia monograph 01/2005:0799.
- the oleic acid component contains at least 50%, at least 60%, at least 70% or at least 80% oleic acid.
- the oleic acid component contains at least 80% oleic acid.
- the oleic acid component is substantially free of polar impurities, such as peroxides.
- the oleic acid component contains less than 10%, less than 5%, less than 1%, or less than 0.1% by weight of polar impurities.
- the oleic acid component has a peroxide value less than 10.
- the oleic acid component has a peroxide value less than 5.
- the oleic acid component comprises SUPER REFINED Oleic Acid NF, available from Crodalnc, Edison, New Jersey, USA.
- the topical formulations of the invention can include fatty acids in addition to tf j ose included in the oleic acid component.
- fatty acids in addition to tf j ose included in the oleic acid component.
- certain embodiments can-inclt ⁇ e isostearic acid.
- the total amount of fatty acids, including those in the oleic acid component is at least 0.05% by weight, at least 1.0% by weighs at least 3.0% by weight, at least 5.0%, at least 10%, at least 15%, or at least 25%, based on the total weight of the formulation.
- the total amount of fatty acids, including those in the oleic acid component is at most 40% by weight, at most 30% by weight, at most 15% by weight, or at most 10%, based on the total weight of the formulation.
- topical formulations of the invention can include an antioxidant.
- Suitable antioxidants are those that are pharmaceutically acceptable and described in the International Cosmetic Ingredient Dictionary and Handbook, Ninth Edition, Volume 4, 2002, and in the USP NF 2004: The United States Pharmacopeia, 27 th Revision and The National Formulary, 22 nd Edition.
- antioxidants examples include ascorbic acid (D and/or L e ⁇ antiomers), ascorbyl palmitate (D and/or L enantiomers), bufylated hydroxyan ⁇ sole (BHA), butylated hydroxytoluene (BHT), cysteine (D and/or L enantiomers), propyl gallate, sodium formaldehyde sulfoxylate, sodium thiosulfate, and tocopherol.
- ascorbic acid D and/or L e ⁇ antiomers
- ascorbyl palmitate D and/or L enantiomers
- BHA bufylated hydroxyan ⁇ sole
- BHT butylated hydroxytoluene
- cysteine D and/or L enantiomers
- the antioxidant is selected from the group comprising aromatic hydroxy groups capable of hydrogen atom donation.
- antioxidants include BHA, BHT, propyl gallate, and tocopherol.
- the antioxidant is selected from the group consisting of BHA, BHT, and combinations thereof.
- the antioxidant is BHA.
- the formulation often will include a preservative system.
- the preservative system includes one or more compounds that inhibit microbial growth. (e.g., fungal and bacterial growth) within the formulation (for example, during manufacturing and use).
- the preservative system will generally include at least one preservative compound, such as, for example, methylparaben, ethylparaben, propylparaben,
- the preservative system includes methylparaben, propylparaben and benzyl alcohol.
- the preservative compound is present in an amount of atleast 0.01% by weight, such as for example, at least 0.02%, at least 0.03%, at least 0.04%, and at least 0.05%, by weight based on the total weight of the formulation.
- the preservative compound is present in an amount of at most 3 %, such as for example, at most 2.5%, at most 2.0%, at most 1.0%, at most 0.5%, at most 0.4%, at most 0.3%, and at most 0.2%, by weight based on the total weight of the formulation.
- Emollients such as for example, at most 2.5%, at most 2.0%, at most 1.0%, at most 0.5%, at most 0.4%, at most 0.3%, and at most 0.2%, by weight based on the total weight of the formulation.
- the topical formulations of the invention may also include at least one emollient.
- emollients include but are not limited to long chain alcohols, for example, cetyl alcohol, stearyl alcohol, cetearyl alcohol; fatty acid esters, for example, isopropyl mysristate, isopropyl palmitate, diisopropyl dimer dilmoleate; medium-chain (e.g., 8 to 14 carbon atoms) triglycerides, for example, caprylic/capric triglyceride; cetyl esters; hydrocarbons of 8 or more carbon atoms, for example, light mineral oil, white petrolatum; and waxes, for example, beeswax.
- Various combinations of such emollients can be used if desired.
- the amount of the emollient is at least 1.0% by weight, at least 3.0% by weight, at least 5.0% by weight, or at least 10% by weight, based on the total weight of the formulation. In certain embodiments, the amount of emollient is at most 30% by weight, at most 15% by weight, or at most 10% by weight, based'on the total weight of the formulation.
- Formulations intended for dermal or topical use typically have amounts of an oil phase and an emollient sufficient to provide desirable qualities such as spreadabilhy and feel.
- Viscosity Enhancing Agent The formulations of the present invention can also comprise a viscosity- enhancing agent
- suitable viscosity enhancing agents include long chain alcohols, for example, cetyl alcohol, stearyl alcohol, cetearyl alcohol; cellulose ethers such as hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose; polysaccharide gums such as
- xanthan gum and homopolymers and copolymers of acrylic acid crossli ⁇ ked with allyl sucrose ⁇ allyl pe ⁇ taerythrioJ such as those polymers designated as carbomers in the United States Pharmacopoeia.
- Suitable carbomers include, for example, those available as CARBOPOL 934P, CARBOPOL 971P, CARBOPOL 940, CARBOPOL.974P, CARBOPOL 980, and PEMULEN TR-I (USP/NF Monograph; Carbomer 1342), all available from Noveon, Cleveland, Ohio.
- the amount of the viscosity enhancing agent s when used is at least 0.1% by weight, at least 0.2% by weight, at least 0.5% by weight, at least 0.6% by weight, at least 0.7% by weight, at least 0.9% by weight, or at least 1.0% by weight, based on the total weight of the formulation. In certain embodiments, the amount of the viscosity-enhancing agent, when used, is at most 10% by weight, at most 5.0% by weight, at most 3.0% by weight, at most 2.0% by weight, or at most 1.5% by weight, based on the total weight of the.formulation.
- Emulsif ⁇ er The formulations of the invention can additionally comprise an emulsifier.
- Suitable er ⁇ ulsif ⁇ ers include non-ionic surfactants such as, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4 oleate, polyoxyethyle ⁇ e(4) Iauryl ether, etc.
- the emulsifier is chosen from poloxamers (e.g., PLURONIC F68, also known as POLOXAMER 188, a poly(ethylene glycol)-block- poly(propylene glycol)-bloclc-poly(ethylene glycol), available from BASF,
- sorbitan trioleate e.g., SPAN 85 available from Un ⁇ qema, New Castle, DE.
- the emulsifier is generally present in an amount of 0.1% to 10% by Weight of total formulation weight, for example, from 0.5% to 5.0% by weight, and from 0.75% to 4.0% by weight. In certain embodiments, the amount of the emulsifier, if used, is present in an amount of at least 0.1% by weight, at least 0.5% by weight, at least 0.75% by weight, at least 1.0% by weight, at least 2.5% by weight, at least 3.5% by weight, at least 4.0% by weight, or at least 5.0% by weight, based on the total weight of the formulation. In certain embodiments, the amount of the emulsifier, if used; is present in an amount of at most 10% by weighty at most 5.0% by weight, or at most 3.5% by weight, based on the total weight of the formulation.
- Some formulations of the invention are oil-in-water emulsions.
- the water used in these formulations is typically purified water
- a formulation of the invention can contain additional pharmaceutically acceptable excipients such as humectants, such as for example, • glycerin; chelating agents, such as for example, ethylenediaminetetraacetic acid] and pH adjusting agents, ' such as for example, potassium hydroxide or sodium hydroxide.
- humectants such as for example, • glycerin
- chelating agents such as for example, ethylenediaminetetraacetic acid]
- pH adjusting agents such as for example, potassium hydroxide or sodium hydroxide.
- a single ingredient can perform more than one function in a formulation.
- cetyl alcohol can serve as both an emollient and a viscosity enhancer.
- Illustrative Formulation in one embodiment of the present invention, includes:
- Formulations according to the present invention can be applied to any suitable location, for example topically to dermal and/or mucosal surfaces.
- the therapeutic effect of the IRM compound may extend only to the superficial layers of the dermal surface or to tissues below the dermal surface.
- another aspect of the present invention is directed to a method for the treatment of a dermal and/or mucosal associated
- a "dermal and/or mucosal associated condition” means an inflammatory, infectious, neoplastic or other condition that involves a dermal and/or mucosal surface or that is in sufficient proximity to a dermal and/or mucosal surface to be affected by a therapeutic agent topically applied to the surface.
- Examples of a dermal and/or mucosal associated condition include warts, atopic dermatitis, postsurgical scars, lesions caused by a herpes virus, and epidermal neoplasias, such as for example actinic keratosis, pre-actinic keratosis lesions, malignant melanomas, basal cell carcinoma, and squamous cell carcinoma.
- the formulations can be applied to the surface of skin for treatment of actinic keratosis (AK).
- Actinic keratosis are premal ⁇ gnant lesions considered biologically to be either carcinoma in-s ⁇ tu or squamous intraepi dermal neoplasia.
- AK is the most frequent epidermal tumor and is induced by ultraviolet (UV) radiation, typically from sunlight. Because of its precancerous nature, AK may be considered the most important manifestation of sun-induced skin damage.
- the above-described formulations are particularly advantageous for dermal and/or mucosal application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic absorption of the IRM compound.
- HPLC reversed phase high performance liquid chromatography
- HPLC parameters Analytical column: ZORBAX RX C8, 5 micron particle, 15.0 x 0.46 cm, (available from Agilent Technologies, Wilmington, Delaware, USA); Detector: UV at 308 run; Mobile phase: gradient mixture of aqueous
- Sample solution A portion (about 300 mg) of the cream formulation was accurately weighed into a volumetric flask (100 mL). Diluent (50 to 60 mL, prepared by combining 250 parts of acetonitrile, 740 parts of water and 10 parts of hydrochloric acid, all parts by volume) was added to the flask. The flask was vortexed until the cream was completely dispersed and then sonicated for a minimum of 5 minutes. The solution was allowed to cool to ambient temperature and then diluted to volume with diluent and mixed. A portion of the solution was filtered using a syringe equipped with a 0.45 micron polypropylene or polytetralfluoroethylene filter to provide the sample solution.
- the cream formulations in Table 1 below were prepared using the following method.
- Water phase preparation A paraben premix was prepared by combining methyl hydroxybenzoate (methylparaben), propyl hydroxybenzoate (propylparaben), and water; heating the mixture with stirring until the parabens were dissolved; and then allowing the resulting solution to cool to ambient temperature.
- Glycerin was added to the premix and the mixture was heated to 55 ⁇ S 0 C.
- Xanthan gum was slowly added with mixing. Mixing with heating was continued until the xanthan gum was dispersed.
- Oil phase preparation An imiquimod/oleic acid premix was prepared by combining imiquimod and the oleic acid and then stirring at ambient temperature overnight Petrolatum, cetyl alcohol, stearyl alcohol, polysorbate 60, sorbitan monostearate; and butylated hydroxyanisole (BHA),- if included; were added to the premix. The oil phase was then heated with stirring to 55 ⁇ 5 0 C. Benzyl-alcohol was added to the oil phase just prior to phase combination.
- BHA butylated hydroxyanisole
- Phase combination 1 Both phases were removed from their heat source. The aqueous phase was added to the oil phase and the emulsion was homogenized at •
- the cream was placed in an ice/water bath while homogenizing and homogenization was continued until the temperature of the cream was 35 0 C.
- the homogenizer speed was reduced and homogenization was continued until the temperature of the cream was 25°C.
- Table 1 summarizes creams A-D in percentage weight-by-weight basis. The formulations were packaged in glass containers.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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BRPI0621407-0A BRPI0621407A2 (en) | 2006-12-29 | 2006-12-29 | oleic acid-containing immune response modifying pharmaceutical formulations, stabilization processes thereof and use of a sister immune response modifying compound |
MX2008010860A MX2008010860A (en) | 2006-12-29 | 2006-12-29 | Immune response modifier formulations containing oleic acid and methods. |
CA2643679A CA2643679C (en) | 2006-12-29 | 2006-12-29 | Immune response modifier formulations containing oleic acid and methods |
PCT/US2006/049517 WO2008082381A1 (en) | 2006-12-29 | 2006-12-29 | Immune response modifier formulations containing oleic acid and methods |
CR10209A CR10209A (en) | 2006-12-29 | 2008-08-14 | FORMULATIONS OF THE IMMUNORESPUEST MODIFIER CONTAINING OLEIC ACID AND METHODS |
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PCT/US2006/049517 WO2008082381A1 (en) | 2006-12-29 | 2006-12-29 | Immune response modifier formulations containing oleic acid and methods |
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BR (1) | BRPI0621407A2 (en) |
CA (1) | CA2643679C (en) |
CR (1) | CR10209A (en) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2011008324A1 (en) | 2009-07-13 | 2011-01-20 | Graceway Pharmaceuticals, Llc | Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030199538A1 (en) * | 2001-11-29 | 2003-10-23 | 3M Innovative Properties Company | Pharmaceutical formulation comprising an immune response modifier |
US20040089855A1 (en) * | 1996-06-18 | 2004-05-13 | Abb Technology Ag | High oleic acid oil compositions and methods of making and electrical insulation fluids and devices comprising the same |
-
2006
- 2006-12-29 WO PCT/US2006/049517 patent/WO2008082381A1/en active Application Filing
- 2006-12-29 CA CA2643679A patent/CA2643679C/en not_active Expired - Fee Related
- 2006-12-29 MX MX2008010860A patent/MX2008010860A/en active IP Right Grant
- 2006-12-29 BR BRPI0621407-0A patent/BRPI0621407A2/en not_active IP Right Cessation
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2008
- 2008-08-14 CR CR10209A patent/CR10209A/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040089855A1 (en) * | 1996-06-18 | 2004-05-13 | Abb Technology Ag | High oleic acid oil compositions and methods of making and electrical insulation fluids and devices comprising the same |
US20030199538A1 (en) * | 2001-11-29 | 2003-10-23 | 3M Innovative Properties Company | Pharmaceutical formulation comprising an immune response modifier |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011008324A1 (en) | 2009-07-13 | 2011-01-20 | Graceway Pharmaceuticals, Llc | Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts |
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CA2643679A1 (en) | 2008-07-10 |
CA2643679C (en) | 2017-09-12 |
MX2008010860A (en) | 2009-02-25 |
CR10209A (en) | 2008-11-26 |
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