MODULATOR FORMULATIONS OF POSSIBLE IMMUNE MODULATOR CONTAINING OLEIC ACID AND METHODS DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical formulations for the topical or transdermal delivery of immunomodification drugs. In recent years, great efforts have been made, with significant success, to discover new drug compounds that act by stimulating certain key aspects of the immune system, as well as by suppressing certain other aspects. These compounds, which are referred to herein as immune-response modifiers (IRMs), appear to act through immune system mechanisms known as toll-like receptors to induce the biosynthesis of the selected cytokine. They can be useful for the treatment of a wide variety of diseases and conditions. For example, certain MRIs may be useful for the treatment of viral diseases (e.g., human papilloma virus, hepatitis, herpes), neoplasms (e.g., basal cell carcinoma, squamous cell carcinoma, actinic keratosis, melanoma), and diseases TH2-mediated (eg, asthma, allergic rhinitis, atopic dermatitis), and are also useful as vaccine adjuvants. Many of the IRM compounds are derivatives of
imidazoquinoline amine of small organic molecule (see, for example, US Pat. No. 4, 689, 338) but a number of other classes of compounds are also known (see, for example, US Patent Nos. 5, 446, 153, 6,194). , 425 and 6,110,929) and more are still being discovered. One of these IMR compounds, known as imiquimod, has been commercialized in a topical formulation, ALDABA, for the treatment of actinic keratosis, basal cell carcinoma or anogenital warts associated with the human papillomavirus. US Patents Nos. 5,238,944, 5,939,090, and 6,425,776, European Patent 0 394026, and US Patent Publication 2003/0199538 disclose pharmaceutical formulations containing IRM compounds, although some of the beneficial effects of the
IRMs are known, the ability to provide therapeutic benefits via the topical application of an MRI compound for the treatment of a particular condition at a particular site can be hampered by a variety of factors. These factors include: irritation of the skin to which the formulation is applied; the formulation is washed and leaves; insolubility of the IRM compound in the formulation; chemical degradation of the MRI compound and / or other ingredients, physical instability of the formulation (e.g., component separation, thickening,
precipitation / agglomeration of the active ingredient, and the like); poor impregnation; and undesired systemic delivery of topical MRI formulations if they are not intended to be transdermal. Accordingly, there is a permanent need for new and / or improved IRM formulations. It has now been found that, while oleic acid can be used to solubilize IRMs, even highly insoluble IRMs that are difficult to formulate, formulations that comprise an IRM compound in combination with oleic acid can suffer from impaired stability. Surprisingly, the addition Increasing amounts of antioxidants to the formulation does not solve the problem. However, it has been found that using an oleic acid component having reduced amounts of polar impurities, for example peroxides, aldehydes, alcohols, and ketones in a formulation containing an MRI can reduce the formation of impurities and thereby provide the improved stability of the formulation. Instability is an important issue for pharmaceutical formulations and can reduce the shelf life of a product or compromise the possibility of legal approval. It has been found that the stability of a formulation containing an IRM and oleic acid compound can be improved by using an oleic acid component
which is free of or contains low amounts of polar impurities, such as for example peroxides, aldehydes, alcohols, and ketones. Although - it is not intended to be limited to a particular theory or mechanism, it is presumed that the highest amounts of polar impurities present in the oleic acid component can react with the IRM compound, thereby destabilizing the formulation and increasing the rate of formation of impurities derived from the IRM compound. In one aspect, the present invention provides a pharmaceutical formulation that encompasses a therapeutically effective amount of an immune-modifying compound (IRM) and a pharmaceutically acceptable carrier including an oleic acid component, wherein the formulation is substantially free of polar impurities. introduced by the oleic acid component. In another aspect, the present invention provides a pharmaceutical formulation comprising: a therapeutically effective amount of an IRM compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component has a peroxide value not greater than 5. In another aspect, the present invention provides a pharmaceutical formulation comprising: a therapeutically effective amount of an IRM compound and a pharmaceutically acceptable carrier including an acid component
oleic, wherein the oleic acid component is at least 80% oleic acid. The present invention also provides methods. In one aspect, the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an immune-response modifying compound (MRI) and oleic acid using an oleic acid component that is substantially free of polar impurities. In one aspect, the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM compound and oleic acid using an oleic acid component with a peroxide value not greater than 5. In one aspect, the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM compound and oleic acid using an oleic acid component that is at least 80% oleic acid. In another aspect, the present invention provides methods for treating the disease, including but not limited to, the group comprising actinic keratosis, basal cell carcinoma, genital warts, perianal warts, malignant melanoma, and molloscurrr contagiosum. In another aspect, the present invention provides methods for inducing
biosynthesis of the cytokine. In another aspect, the present invention provides methods for inducing the biosynthesis of interferon. A number of additional inclusions can be described as follows: 1. A pharmaceutical formulation comprising: a therapeutically effective amount of an immune-response modifying compound (MRI) selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines , 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazpnaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, amines thiazolonaphthyridine '. ltf-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable carrier including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component.
2. 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-imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines, amines of thiazolopyridine, oxazolonaphthyridine amines, thiazolonaphthyridine amines, dimethyl imidazoles fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component has a peroxide value not greater than 5. 3. A pharmaceutical formulation comprising: a therapeutically effective amount of an IRM compound selected from the group consisting of of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines,
tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, lH-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines , or tetrahydronaphthyridine amines, and combinations thereof; and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component is at least 80% oleic acid. . A formulation as in any of the above inclusions wherein the IRM component is selected from the group consisting of substituted imidazoquinoline amide amines, substituted imidazoquinoline sulfamide amines, substituted imidazoquinoline urea amines, substituted aryl imidazoquinoline amines ether, imidazoquinoline ether amines substituted heterocyclics, imidazoquinoline amines ether substituted amides, substituted imidazoquinoline ether sulfonamide amines, substituted imidazoquinoline urea ethers, substituted thioether imidazoquinoline amines, imidazoquinoline amines 6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy or substituted arylalkylaxy, imidazoquinoline diamines,
substituted substituted tetrahydroimidazoquinoline amines, substituted tetrahydroimidazoquinoline sulphonamide amines, substituted tetrahydroimidazoquinoline urea amines, substituted aryl tetrahydroimidazoquinoline amines, substituted heterocyclic ether tetrahydroimidazoquinoline amines, substituted tetrahydroimidazoquinoline ether amide substituted amines, substituted tetrahydroimidazoquinoline ether sulfonamide amines, tetrahydroimidazoquinoline ethers urea substituted, substituted tetrahydroimidazoquinoline thioether amines, tetrahydroimidazoquinoline diamines, substituted imidazopyridine amide amines, substituted imidazopyridine sulfonamide amines, substituted imidazopyridine urea amines, substituted aryl ether imidazopyridine amines, substituted heterocyclic ether imidazopyridine amines, imidazopyridine amines substituted amide ether , substituted imidazopyridine ether sulphonamide amines, imidazopyridine urea ethers substitutes uidos, substituted thioether imidazopyridine amines, and combinations thereof. 5. A formulation as in any of the inclusions 1 through 3 wherein the IRM component is an imidazonaphthyridine amine. 6. A formulation as in any of the inclusions from 1 to 3 and 5 where the IRM component is 2-
methyl-1- (2-methylpropyl) -lfi-imidazo [4, 5-c] [1,5] naphthyridin-4-amine. 7. A formulation as in any of the inclusions 1 to 3 wherein the IR component is l- (2-methylpropyl) -lfi-imidazo [4,5-c] quinolin-4-amine. 8 A formulation as in any of the above inclusions wherein the IRM compound is present in an amount of at least 3% by weight, according to the total weight of the formulation. 9 A formulation as in any of the above inclusions wherein the IRM compound is present in an amount of at least 5% by weight, according to the total weight of the formulation. 10. A formulation as in any of the above inclusions wherein the oleic acid component is present in an amount of at least 15% by weight according to the total weight of the formulation. 11. A formulation as in any of the above inclusions wherein the oleic acid component is present in an amount of at least 20% by weight according to the total weight of the formulation. 12. A formulation as in any of the above inclusions wherein the oleic acid component is present in an amount of at least 25% by weight according to the total weight of the formulation.
13. A formulation as in any of the above inclusions where the oleic acid component has been purified by chromatography before use in the formulation. 14. A formulation as in any of the above inclusions wherein the oleic acid component is derived from the plant. 15. A formulation as in any of the above inclusions wherein the formulation includes at least one fatty acid other than oleic acid or isostearic acid. 16. A formulation as in any of the above inclusions wherein the formulation includes less than 3% isostearic acid by weight according to the total weight of the formulation. 17. A formulation as in any of the above inclusions wherein the formulation further comprises an antioxidant. 18. A formulation as in any of the above inclusions that also comprises an antioxidant, wherein the antioxidant is butylated hydroxyl toluene or butylated hydroxyanisole. 19. A formulation as in any of the above inclusions which also comprises water. 20. A formulation as in any of the
previous inclusions that also includes a preservative system. 21. A formulation as in any of the above inclusions further comprising an emulsifier. 22. A method for stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an immune-modifier compound (IRM) selected from the group consisting of aminimidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, cycloalkylimidazopyridine amines 6, 7 melts, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, fused iminozo pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and oleic acid using an oleic acid component that is substantially free of polar impurities. 23. A method for stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM compound selected from the group
consists of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines,. imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, dimethyl imidazoles fused to pyridine amines, quinoline amines, tetrahydroquinoline amines , naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and oleic acid using an oleic acid component with a peroxide value not greater than 5. A method for 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 cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines, thiazolopyridine amines, amines oxazolonaphthyridine, thiazolonaphthyridine amines, lH-imidazo dimers fused to the pyridine amines, amines of
quinoline, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; and oleic acid using an oleic acid component which is at least 80% oleic acid. 25. The method as in any of the inclusions 22 to 24 wherein the IR compound is selected from the group consisting of: substituted imidazoquinoline amide amines, substituted imidazoquinoline sulfamide amines, substituted imidazoquinoline urea amines, imidazoquinoline amines substituted aryl ether, substituted heterocyclic ether imidazoquinoline amines, substituted imidazoquinoline ether amido substituted amines, substituted imidazoquinoline ether sulfonamide amines, substituted imidazoquinoline urea ethers, substituted thioether imidazoquinoline amines, imidazoquinoline amines 6-, 7-, 8-, or 9-aryl, heteroaryl, substituted aryloxy or arylalkyloxy, imidazoquinoline diamines, substituted tetrahydroimidazoquinoline amine amines, substituted tetrahydroimidazoquinoline sulphonamide amines, substituted tetrahydroimidazoquinoline urea amines, substituted aryl tetrahydroimidazoquinoline amines, tetrahydroimidazole amines quinoline substituted heterocyclic ether, substituted tetrahydroimidazoquinoline amines ether amide, substituted tetrahydroimidazoquinoline ether sulfonamide amines,
substituted tetrahydroimidazoquinoline urea amines, substituted tetrahydroimidazoquinoline thioether amines, tetrahydroimidazoquinoline diamines, substituted imidazopyridine amide amines, substituted imidazopyridine sulfonamide amines, substituted imidazopyridine urea amines, substituted aryl imidazopyridine amines, substituted heterocyclic ether imidazopyridine amines, amines imidazopyridine substituted amide ether, substituted imidazopyridine ether sulfonamide amines, substituted imidazopyridine urea ethers, substituted thioether imidazopyridine amines, and combinations thereof. 26. The method as in any of the inclusions of 22 to 24 wherein the IRM compound is an imidazonaphthyridine amine. 27. The method as in any of the inclusions of 22 to 24 and 26 wherein the IRM compound is 2-methyl-1- (2-methylpropyl) -lH-imidazo [4, 5-c] [1, 5 ] naphthyridin-4-amine. 28. The method as in any of the inclusions of 22 to 24 wherein the IRM compound is l- (2-methylpropyl) -lH-imidazo [4, 5-c] quinolin-4-amine. 29. A method of treating actinic keratosis, the method comprising applying a formulation of some of the inclusions 1 through 21 to the skin of a subject.
30. A method of treatment of basal cell carcinoma, the method comprises applying a formulation of some of the inclusions from 1 to 21 to the skin of a subject. 31. A method of treating genital warts, the method comprising applying a formulation of some of the inclusions 1 through 21 to the skin or mucosal surface of a subject. 32. A method of treating perianal warts, the method comprising applying a formulation of some of the inclusions 1 through 21 to the skin or mucosal surface of a subject. 33. A method of treatment of molloscum contagiosum, the method comprises applying a formulation of some of the inclusions from 1 to 21 to the skin of a suj eto. 34. A method for inducing cytosine biosynthesis The method comprises applying a formulation of some of the inclusions 1 through 21 to the skin or mucosal surface of a subject. 35. A method for inducing interferon biosynthesis, the method comprises applying a formulation of some of the inclusions 1 through 21 to the skin or mucosal surface of a subject. 36. A method of treating malignant melanoma,
the method comprises applying a formulation of some of the above inclusions 1 through 21 to the skin of a subject. The term "substantially released" is used
"5 to indicate that the amount present in the composition or formulation is below the level causing the degradation of the active pharmaceutical agent, such that the formulation is unsuitable for pharmaceutical use, after storage for 4 months at 40 ° C to 75% of
10 relative humidity. The term may 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 a given substance. The term "polar impurities" includes, but is not
15 limits peroxides, aldehydes, ketones, alcohols, metal ions, and / or substances that cause degradation of the active pharmaceutical agent. The term "oleic acid component" is used
.- to describe a source of preformulation or composition of
20 material containing oleic acid, and may include other fatty acids in addition to oleic acid, including but not limited to: myristic acid, palmitic acid, palmitoleic acid, margaric acid, isostearic acid, acid
- stearic acid, linoleic acid, linolenic acid, and other acids
25 fatty, or combinations of that.
The value of the peroxide is the number that expresses in milliequivalents of active oxygen the amount 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. Unless otherwise indicated, all numbers that express quantities, quotients and numerical characteristics of the ingredients, reaction conditions, and so on used in the specification and claims must be understood as being modified in all cases by the term "near". All the parts, percentages, quotients, etc., are here by weight unless otherwise indicated. As used herein, "a" or "the" is alternately used with "at least one" to mean "one or more of the aforementioned element." The above summary of this invention is not intended to describe each of the disclosed inclusions or each implementation of the present invention The description that follows more particularly exemplifies illustrative inclusions.In several places throughout the application, guidance is provided through lists of examples, which In each case, the list recited serves only as a representative group and should not be interpreted as a list.
Exclusive The present invention provides pharmaceutical formulations that include a therapeutically effective amount of an immune-modifying compound (IRM) selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, amines of 1,2-bridged imidazoquinoline, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazolequinoline amines, oxazolopyridine amines. thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, dimethyl imidazoles fused to the pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and oleic acid, where the oleic acid component It contains a low amount of polar impurities, especially peroxides. Surprisingly, the stability of said formulations is substantially greater than that of similar formulations containing an IRM and oleic acid containing conventional oleic acid with higher amounts of polar impurities such as peroxides, even when the oleic acid component is of compendial. In addition, the problem of the instability of these formulations is not
eliminated by the additional antioxidants. With the use of an oleic acid component containing a very low amount of polar impurities, the subsequent formation of impurities in MRI formulations is significantly reduced with respect to other MRI formulations comprising compendial grades of oleic acid after the initial measurement of both (for example, their measurement when initially formulated) and under accelerated conditions (when stored for at least 4 months at 40 ° C and 75% relative humidity), resulting in an increased shelf life of the formulation. For certain inclusions, the formulation encompasses an IRM compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the oleic acid component. For certain inclusions, the formulation encompasses an IRM compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component has a peroxide value not greater than 5. For certain inclusions, the formulation encompasses an IRM compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component is at least 80% oleic acid. In certain inclusions, the formulations here
described may be in the form of an oil-petticoat emulsion such as a cream or 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 solubilize the IRM compound. Optionally, a lotion or cream of the invention may contain emollients, antioxidants, emulsifiers, viscosity enhancing agents, and / or preservatives. Such components, as well as all other of the formulations described herein, are preferably Modifying Compounds of the
Pharmaceutically acceptable immunoresponse. The formulations of the invention include an IRM compound. Such compounds include, for example, imidazoquinoline amines including, but not limited to, substituted imidazoquinoline amide amines, substituted imidazoquinoline sulfamide amines, substituted imidazoquinoline urea amines, substituted aryl imidazoquinoline amines ether, substituted heterocyclic ether imidazoquinoline amines, amido substituted imidazoquinoline amines ether, substituted imidazoquinoline ether sulfonamide amines, substituted imidazoquinoline urea ethers, substituted thioether imidazoquinoline amines, 6-, 7-, 8-, or 9-axyl, heteroaryl, aryloxy or arylalkyloxy substituted imidazoquinoline amines and imidazoquinoline diamines;
tetrahydroimidazoquinoline amines including, inter alia, substituted tetrahydroimidazoquinoline amine amines, substituted tetrahydroimidazoquinoline sulphonamide amines, substituted tetrahydroimidazoquinoline urea amines, substituted aryl tetrahydroimidazoquinoline amines, substituted heterocyclic ether tetrahydroimidazoquinoline amines, substituted tetrahydroimidazoquinoline ether amide substituted amines, tetrahydroimidazoquinoline amines substituted sulfonamide ether, substituted tetrahydroimidazoquinoline urea ethers, substituted tetrahydroimidazoquinoline thioether amines and tetrahydroimidazoquinoline diamines; imidazopyridine amines including, but not limited to, substituted imidazopyridine amide amines, substituted imidazopyridine sulfonamide amines, substituted imidazopyridine urea amines, substituted aryl ether imidazopyridine amines, substituted heterocyclic ether imidazopyridine amines, imidazopyridine substituted amide amines, amines imidazopyridine substituted sulfonamide ether, substituted imidazopyridine urea ethers and substituted thioether imidazopyridine amines; 1,2-bridged imidazoquinoline amines; 6, 7-fused cycloalkylimidazopyridine amines; imidazonaphthyridine amines; amines of tetrahydroimidazonaphthyridine; oxazoloquinoline amines; thiazolequinoline amines;
oxazolopyridine amines; thiazolopyridine amines; oxazolonaphthyridine amines; thiazolonaphthyridine amines; and 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines. These immune-response modifier compounds are disclosed in, for example, Patents
U.S. Nos. 4, 689, 338; 4, 929, 624; 5, 266, 575; 5, 268, 376;
5, 346, 905; 5, 352, 784; 5, 389, 640; 5,446, 153; 5,482, 936;
5,756,747; 6, 110,929; 6, 194, 425; 6, 331, 539; 6, 376, 669;
6, 451, 810; 6, 525, 064; 6, 541, 485; 6, 545, 016; 6, 545, 017;
6, 573, 273; 6, 656, 938; 6, 660,735; 6, 660,747; 6, 664, 260;
6, 664, 264; 6,664,265; 6, 667, 312; 6, 670,372; 6, 677, 347;
6, 677, 348; 6, 677, 349; 6, 683, 088; 6, 756,382; U.S. Patent Publication Nos. 2004/0091491; 2004/0132766; 2004/0147543; and 2004/0176367; and International Patent Application No. PCT / US04 / 28021 filed on August 27, 2004. For some of these inclusions, the IRM compound is an imidazonaphthyridine amine. For some of these inclusions, the IRM compound is 2-methyl-1- (2-methylpropyl) -lfi-imidazo [4,5-c] [1,5] naphthyridin-4-amine. For some of these inclusions, the IRM compound is an imidazoquinoline amine. For some of these inclusions, the IRM compound is 1- (2-methylpropyl) -1H-imidazo [4, 5-c] quinolin-4-amine (imiquimod). For some inclusions, the
IRM may have low solubility in water, for example less than about 1 ug / mL (example, 0.79 ug / mL in the case of imiquimod), making it 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 dosage regimen, dosage, the site of application, the particular formulation and the condition being treated. As such, it is generally not practical to identify specific amounts of this administration; however, those skilled in the art will be able to determine the appropriate therapeutically effective amounts based on the guidance provided herein, information available in the art pertaining to IRM compounds, and routine testing. The term "a therapeutically effective amount" means an amount of the MRI compound sufficient to induce a therapeutic or prophylactic effect, such as for example the induction of the cytokine, inhibition of the TH2 immune response, anti-tumor or anti-tumor activity, reduction or elimination of the postoperative scar, reduction or resolution of actinic keratosis or lesions of pre-actinic keratosis, reduction in the recurrence of actinic keratosis, treatment of basal cell carcinoma, genital warts,
peri-anal warts, molloscum contagiosum, or protection against epidermal neoplasia induced by uv. In general, the amount of the IRM compound present in a topical formulation of the invention will be an amount effective to treat a certain condition, to prevent recurrence of the condition, or to promote immunity against the condition. In certain inclusions, the amount or concentration of the IRM compound is at least 3% by weight, such as, for example, at least 5%, and at least 10%, by weight according to the total weight of the formulation. In other inclusions, the amount of IRM compound is at most 10% by weight, such as, for example, maximum 5%, maximum 3%, by weight according to the total weight of the formulation. In certain inclusions, the concentration amount of the 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 according to weight total of the formulation. Fatty Acids Topical formulations of the invention include fatty acids. In particular, the topical formulations of the invention contain an oleic acid component. As used herein, the term "fatty acid" means a carboxylic acid, saturated with carbon. Fatty acids, including the component of
Oleic acid may be present in the formulation in an amount sufficient to solubilize the IRM compound. In certain inclusions, the amount of the 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% by weight. %, at least 15%, or at least 25%, according to the total weight of the formulation. In certain inclusions, 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%, according to the total weight of the formulation. Compound grade oleic acid typically contains 65 to 88 percent (7) -octadec-9-enoic acid (oleic acid) along 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 the monograph European Pharmacopoeia 01/2005: 0799. For certain inclusions, the oleic acid component contains at least 50%, at least 60%, so minus 70% or at least 80% oleic acid. For certain inclusions, the oleic acid component contains at least 80% oleic acid. For certain inclusions, the oleic acid component is substantially free of polar impurities, such as
for example peroxides. For certain inclusions, the oleic acid component contains less than 10%, less than 5%, less than 1%, or less than 0.1% by weight of polar impurities. For certain inclusions, the oleic acid component has a peroxide value of less than 10. For certain inclusions, the oleic acid component has a peroxide value of less than 5. For certain inclusions, the oleic acid component comprises Oleic Acid NF SUPER REFINED, available from Croda Inc., Edison, New Jersey, USA. For certain inclusions, the topical formulations of the invention may include fatty acids in addition to those included in the oleic acid component. For example, certain inclusions may include isostearic acid. In some inclusions, 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 weight, at least 3.0% by weight, so less 5.0%, at least 10%, at least 15%, or at least 25%, according to the total weight of the formulation. In certain inclusions, 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 least 10%, by weight. according to the total weight of the formulation. Antioxidants
For certain inclusions, the topical formulations of the invention may include an antioxidant. Suitable antioxidants are those that are pharmaceutically acceptable and described in the International Cosmetic Ingredients Dictionary and Manual, Ninth Edition, Volume 4, 2002, and in USP NF 2004: The Pharmacopoeia of the United States of America, 27th Review and the National Formulary 22nd Edition Examples of suitable antioxidants include ascorbic acid (D and / or L enantiomers), ascorbyl palmitate (D and / or L enantiomers), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine (D and / or L enantiomers), propyl gallate, sodium formaldehyde sulfoxylate, sodium thiosulfate, and tocopherol. For certain inclusions, the antioxidant is selected from the group comprising aromatic hydroxy groups capable of the donation of the hydrogen atom. Examples of such antioxidants include BHA, BHT, propyl gallate, and tocopherol. For certain inclusions, the antioxidant is selected from the group consisting of BHA, BHT, and combinations thereof. For certain inclusions, the antioxidant is BHA. Preservative System The formulation will often include a system
preservative. The preservative system includes one or more compounds that inhibit microbial growth (e.g., fungal and bacterial growth) within the formulation (e.g., during manufacture and use). The condom system will generally include at least one preservative compound, such as, for example, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenoxyethanol, and sorbic acid or sorbic acid derivatives such as asters and salts. Several combinations of these compounds can be included in the condom system. In some inclusions of the invention, the preservative system includes methylparaben, propylparaben and benzyl alcohol. In some inclusions of the invention, the preservative compound is present in an amount of at least 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 according to the total weight of the formulation. In other inclusions of the invention, the preservative compound is present in a maximum amount of 3%, such as, for example, maximum 2.5%, maximum 2.0%, maximum 1.0%, maximum 0.5%, maximum 0.4%, at most 0.3%, and at most 0.2%, by weight according to the total weight of the formulation. Emollients
Topical formulations of the invention may also include at least one emollient. Examples of useful emollients include, but are not limited to, long chain alcohols, for example, cetyl alcohol, stearyl alcohol, cetearyl alcohol; esters of severe acid, e.g., isopropyl-macromat. isopropyl palmitate, diisopropyl dilinoleate dimer; medium chain (example, 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. In certain inclusions, the amount of 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, according to the total weight of the formulation. In certain inclusions, the amount of emollient is at most 30% by weight, at most 15% by weight, or at most 10% by weight, according to the total weight of the formulation. Formulations intended for dermal or topical use typically have amounts of an oil phase and a sufficient emollient to provide desirable qualities such as spreadability and sensation. Agent to Enhance Viscosity
The formulations of the present invention may also encompass an agent for enhancing viscosity. Examples of suitable agents for enhancing viscosity include long chain alcohols, for example, cetyl alcohol, stearyl alcohol, cetearyl alcohol; cellulose ethers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose; polysaccharide gums such as xanthan gum; and homopolymers and copolymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol such as those polymers designated as carbomers in the United States Pharmacopoeia. Suitable carbomers include, for example, those available as CARBOPOL 934P, CARBOPOL '97IP, CARBOPOL 940. CARBOPOL 974P, CARBOPOL 980. and PEMULEN TR-I (Monograph USP / NF: Carbomer 1342), all available from Noveon, Cleveland. Ohio. In certain inclusions, the amount of the viscosity enhancing agent, 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, according to the total weight of the formulation. In certain inclusions, the amount of agent to enhance the "viscosity" when used, is at most 10% by weight, at most 5.0% by weight, at most 3.0% by weight, as
maximum 2.0% by weight, or at most 1.5% by weight, according to the total weight of the formulation. Emulsifier The formulations of the invention may also comprise an emulsifier. Suitable emulsifiers include nonionic surfactants such as, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4-oleate, polyoxyethylene () laureth ether, etc. In certain inclusions, the emulsifier is selected from poloxamers (e.g., PLURONIC F68, also known as POLOXAMER 188, a poly (ethylene glycol) -block-poly (propylene glycol) -block-poly (ethylene glycol), available from BASF, Ludwigshafen, Germany) and sorbitan trioleate (for example, SPAN 85 available from Uniqema, New Castle, DE). If included, the emulsifier is generally present in an amount of 0.1% to 10% by weight of the total weight of the formulation, eg, from 0.5% to 5.0% by weight, and from 0.75% to 4.0% by weight. In certain inclusions, 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, according to the total weight of the formulation. In certain inclusions, the amount of the emulsifier, if used, is
present in a maximum amount of 10% by weight, maximum 5.0% by weight, or maximum 3.5% by weight, according to 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. Optionally, a formulation of the invention may contain additional pharmaceutically acceptable excipients such as for example 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. In some cases, a single ingredient can perform more than one function in a formulation. For example, cetyl alcohol can serve as an emollient and as a viscosity enhancer. Illustrative Formulation In an inclusion of the present invention, a pharmaceutical formulation includes: 5% by weight of 1- (2-methylpropyl) -lfi-imidazo [, 5-c] quinolin-4-amine; 28% by weight of SUPER REFINED oleic acid; 2.2% by weight of cetyl alcohol; 3.1% by weight of stearyl alcohol; 3% by weight of petrolatum;
3.4% by weight of polysorbate 60; 0.6% by weight of sorbitan monostearate; 2% by weight of glycerin; 0.2% by weight of methyl hydroxybenzoate; -5 0.02% by weight of propyl hydroxybenzoate; 0.5% by weight of xanthan gum; 2% by weight of benzyl alcohol; and 49.98% by weight of water; wherein the percentages of weight are based on the total weight of the formulation. Methods of Application The formulations according to the present invention can be applied to any suitable place, for example, topically to dermal and / or mucosal surfaces. In the case of dermal application, for example, depending on the concentration of the IRM compound, the composition of the formulation, and the cutaneous surface, the therapeutic effect of the IRM compound can extend only to the surface layers of the cutaneous surface or to the tissues. thin 0 below the cutaneous surface. Thus, another aspect of the present invention is directed to a method for the treatment of a cutaneous and / or mucosal associated condition comprising applying to the skin one of the preceding formulations. According
Herein is used, a "cutaneous and / or mucosal associated condition" 5 means an inflammatory, infectious, neoplastic condition
or another that involves a cutaneous and / or mucosal surface or that is in sufficient proximity to a cutaneous surface and / or mucosa to be affected by a therapeutic agent applied topically to the surface. Examples of a cutaneous and / or mucosal associated condition include warts, atopic dermatitis, postoperative scars, lesions caused by a herpes virus, and epidermal neoplasms, such as actinic keratosis, actinic pre-keratosis lesions, malignant melanomas, basal cell carcinoma, and carcinoma
10 scaly cell. In an inclusion, the formulations can be applied to the surface of the skin for the treatment of actinic keratosis (AK). Actinic keratosis are premalignant lesions considered biologically as
15 carcinoma in-situ or intra-squamous squamous neoplasia. AK is the most common epidermal tumor and is induced by ultraviolet (UV) radiation, typically solar light. Due to its precancerous nature, AK can be considered the most important manifestation of sun-induced skin damage.In some inclusions, the formulations described above are particularly advantageous for cutaneous and / or mucosal use for a period of time. sufficient time to obtain a desired therapeutic effect without the undesired systemic absorption of the IRM compound.
EXAMPLES The following Examples are provided to further describe the various formulations and methods according to the invention. The examples, however, are not intended to limit formulations and methods within the spirit and scope of the invention. Test Method A reverse high-performance liquid chromatography (HPLC) method was used to determine the amount of impurities in cream formulations containing oleic acid. 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 nm; Mobile phase: gradient mixture of the aqueous ammonium phosphate compensatory reagent (prepared by combining 5.1 mL of orlo-phosphoric acid with 985 mL of water and then adjusting to pH 2.5 with concentrated ammonium hydroxide) and acetonitrile; Gradient: start the operation 10% acetonitrile, zero initial waiting time, then linear gradient to 70% acetonitrile for 15 minutes, zero final waiting time; Flow rate: 2.0 mL / minute; Injection volume: 200 L; Operating time: 15 minutes. Sample solution: A portion (about 300 mg) of the cream formulation was weighed exactly in one
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 diluent bottle. The bottle was swirled until the cream was completely dispersed and then sonicated for a minimum of 5 minutes. The solution was allowed to cool to room 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 filter of polypropylene or polytetrafluoroethylene to provide the sample solution. Preparation of Cream Formulations The cream formulations in Table 1 below were prepared using the following method: Preparation of the water phase: A paraben premix was prepared by combining methyl hydroxybenzoate (methylparaben), propyl hydroxybenzoate (propylparaben), and water; heating the mixture and stirring until the parabens were dissolved; and then allowing the resulting solution to cool to room temperature. Glycerin was added to the premix and the mixture was heated to 55 ± 5 ° C. Xanthan gum was added slowly mixing. The mixing and heating continued until the xanthan gum dispersed. Preparation of the oil phase: One was prepared
premix of imiquimod / oleic acid combining imiquimod and oleic acid and then stirring at room temperature overnight. The 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 by stirring at 55 ± 5 ° C. Benzyl alcohol was added to the oil phase just before the phase combination. Phase combination: Both phases were removed from their source hot. The aqueous phase was added to the oil phase and the emulsion was homogenized at high speed for at least 5 minutes. The cream was placed in an ice / water bath while homogenizing and homogenization was continued until the temperature of the cream was 35 ° C. The speed of the homogenizer was reduced and the homogenization was continued until the temperature of the cream was 25 ° C. Table 1 summarizes the A-D creams based on the weight-for-weight percentage. The formulations were packaged in glass containers.
• 5
11- (2-methylpropyl) -lH-imidazo [4, 5-c] quinolin-4-amine 2J.T. Baker, a division of Mallinckrodt Baker, Inc,
Phillipsburg, NJ, USA 15 3Croda, Inc, Edison, NJ, USA A group of containers was stored under ambient conditions; the samples used to determine the. Initial values came from these containers. The remaining containers were stored in a compartment with temperature ^ and
20 constant humidity at 40 ° C to 75% relative humidity. At selected points in time, the containers were removed from the compartment and then stored under ambient conditions until analyzed. The samples were analyzed using
'.' The test method described above for impurities. In
25 the time points of month 2, 4, and 6 the samples were
taken from both the top and bottom of the containers. The results are shown in Table 2 below where each value is the result of a single determination. The values are not normalized by weight loss which may have occurred during storage.
1 Creams A, B, C and D were analyzed 16 days, 15 days, 14 days and 15 days respectively, after having been prepared. 2 All samples were analyzed 10 days after the containers were removed from the compartment with constant temperature and humidity. 3 All samples were analyzed 12 days after the containers were removed from the compartment with constant temperature and humidity. All samples were analyzed 7 days after the containers were removed from the compartment with constant temperature and humidity. The full disclosures of patents,
Patent documents and publications cited herein are incorporated by reference in their entirety as if each had been individually incorporated. In case of conflict, this specification, including definitions, will control. Some modifications and alterations of this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. Inclusions and illustrative examples are provided as examples only and are not intended to limit the scope of the present invention. The scope of the invention is limited only by the claims indicated below.