BRPI0621407A2 - oleic acid-containing immune response modifying pharmaceutical formulations, stabilization processes thereof and use of a sister immune response modifying compound - Google Patents

Abstract

PHARMACEUTICAL FORMULATIONS OF IMMUNE RESPONSE CONTAINING OLEIC ACID, PROCESSES FOR STABILIZING THE SAME AND USING A COMPOUND IMMUNE IRM RESPONSE MODIFIER. The present invention relates to pharmaceutical formulations and processes including IRM immune response modifying compound and an oleic acid component are provided where stability is improved through the use of oleic acid having low polar impurities such as peroxides.

Description

Report of the Invention Patent for "IMMUNE RESPONSE MODIFYING PHARMACEUTICAL FORMULATIONS CONTAINING OLEIC ACID, PROCESSES OF STABILIZATION OF THE SAME AND USING A COMPOUND IMMUNE RESPONSE MODIFIER"

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional patent application US 60/636916, filed December 17, 2004, and 11/303659 filed December 16, 2005, the contents of which are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to pharmaceutical formulations for the topical or transdermal delivery of immunomodifying drugs.

BACKGROUND

There has been a greater effort in recent years, 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, referred to herein as immune response modifiers (MRIs), appear to act through immune system mechanisms known as toll-like receptors to induce selected cytokine biosynthesis. They can be useful for treating a variety of diseases and conditions. For example, certain MRIs may be useful for treating viral diseases (eg, human papillomavirus, hepatitis, herpes), neoplasms (eg, 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.

Many of the MRI compounds are derivatives of small organic molecule imidazoquoline amine (see, for example, US Patent 4,689,338), but a number of other classes of compounds are also known (see, for example, US Patent 5,446,153. , 6,194,425, and 6,110,929) and more are still being discovered.

One of these MRI compounds, known as imiquimod, has been marketed in a topical formulation, ALDARA, for the treatment of actinic keratosis, basal cell carcinoma, or anogenital wart associated with human papilloma virus.

Pharmaceutical formulations containing MRI compounds are shown in U.S. Patent Nos. 5,238,944; 5,939,090; and 6,425,776; EP patent 0,394,026; and U.S. Patent 2003/0199538.

While some of the beneficial effects of MRIs are known, the ability to provide therapeutic benefit via topical application of an MRI compound to treat a particular condition in a particular location may be hampered by a variety of factors. These factors include: irritation of the skin to which the formulation is applied; washing of the formulation; insolubility of the IRM compound in the formulation; chemical degradation of the IRM compound and / or other ingredients, physical instability of the formulation (eg, component separation, thickening, precipitation / agglomeration of active ingredient, and the like); poor permeation; and unwanted systemic release of topical MRI formulations if not intended to be transdermal.

Similarly there is a continuing need for new and / or improved MRI formulations.

SUMMARY

It has now been found that while oleic acid can be used to solubilize MRIs, highly insoluble, even difficult to formulate MRI formulations comprising an MRI compound in combination with oleic acid may suffer from impaired stability. A little surprisingly, adding larger amounts of antioxidants to the formulation does not solve the problem. However, it has been found that use of an oleic acid component having reduced amounts of polar impurities such as peroxides, aldehydes, alcohols, and ketones in an MRI-containing formulation can reduce the formation of impurities and thereby provide improved stability. of formulation. Instability is an important issue for pharmaceutical formulations and may reduce the shelf life of a product or threaten regulatory approval. It has been found that the stability of a formulation containing an IRM compound and an oleic acid can be improved by using an oleic acid component that is free of or contains low amounts of polar impurities such as peroxides, aldehydes, alcohols and ketones. While not wishing to be bound by any particular theory or mechanism, it is hypothesized that the higher amounts of polar impurities present in the oleic acid component may 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 comprising a therapeutically effective amount of an IRM immune response modifying compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the formulation is substantially free of polar impurities introduced by the acid component. oleic.

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 of 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 oleic acid component, wherein the oleic acid component is at least 80% oleic acid.

The present invention also provides processes.

In one aspect, the present invention provides a method of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM and oleic acid immune response modifying compound by use of an oleic acid component that is substantially free of impurities. polar.

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 by use of an oleic acid component with a peroxide value of 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 MRI compound and oleic acid by use of an oleic acid component which is at least 80% oleic acid.

In another aspect, the present invention provides methods for treating disease, including but not limited to the group comprising actinic keratosis, basal cell carcinoma, genital warts, perianal warts, malignant melanoma, and molloscum contagiosum. In another aspect, the present invention provides processes for inducing cytokine biosynthesis. In another aspect, the present invention provides processes for inducing interferon biosynthesis.

A number of additional embodiments may be described as follows:

1. A pharmaceutical formulation comprising:

a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazole naphthyridine amines, thiazolonaphyridine amines, pyridine amines, quinoline amine thyridines, quinoline aminesyrinines combinations; 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 immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolo naphthyridine amines, thiazolonaphyridine amines, pyridine amines, quinoline amine tetrahydrin, amine tetrahydrin amines combinations; and

a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5.

3. A pharmaceutical formulation comprising:

a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazole naphthyridine amines, thiazolonaphyridine amines, 1 H-imidazole dimers amine tetrahydrin amines, quinoline amine tetrahydrin amines their combinations; 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 preceding embodiments wherein the MRI compound is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, imidazoquinoline amines substituted, imidazoquinoline amines heterocyclic ether substituted imidazoquinoline ether starch substituted amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline thioether substituted imidazoquinoline, 6- or 9-, 6-, 8-, imidazoquinoline substituted amines aryl, heteroaryl, aryloxy or aryl alkylenoxy, imidazoquinoline diamines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, tetrahydroimidazoquinoline amines aryl ether oxides, tetrahydroimidazoquinoline heterocyclic ether substituted amines, ether starch substituted tetrahydroimidazoquinoline amines, ether sulphonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amine diamine amines substituted with tetrahydroimidazoline ether , imidazopyridine sulfonamide substituted amines, imidazopyridine urea substituted amines, imidazopyridine aryl ether substituted amines, imidazopyridine heterocyclic ether substituted amines, imidazopyridine ether starch substituted amidazopyridine ether amidazopyridine ether , thioether substituted imidazopyridine amines, and combinations thereof.

A formulation as in any one of embodiments 1 to 3 wherein the IRM compound is an amine imidazonaphthyridine.

A formulation as in any of embodiments 1 through 3 and 5 wherein the MRI compound is 2-methyl-1- (2-methyl propyl) -1H-imidazo [4,5-c] [1,5] naphthyridin-2-one. 4-amine.

A formulation as in any of embodiments 1 to 3 wherein the IRM compound is 1- (2-methyl propyl) -1H-imidazo [4,5-c] quinolin-4-amine.

A formulation according to any of the preceding embodiments wherein the MRI compound is present in an amount of at least 3% by weight based on the total weight of the formulation.

A formulation according to any of the preceding embodiments wherein the MRI compound is present in an amount of at least 5% by weight based on the total weight of the formulation.

A formulation as in any of the foregoing embodiments wherein the oleic acid component is present in an amount of at least 15% by weight based on the total weight of the formulation.

A formulation as in any of the foregoing embodiments wherein the oleic acid component is present in an amount of at least 20% by weight based on the total weight of the formulation.

A formulation as in any of the foregoing embodiments wherein the oleic acid component is present in an amount of at least 25% by weight based on the total weight of the formulation.

A formulation as in any of the foregoing embodiments wherein the oleic acid component has been purified by chromatography prior to use in the formulation.

A formulation as in any of the foregoing embodiments wherein the oleic acid component is plant derived.

A formulation as in any preceding embodiment wherein the formulation includes at least one fatty acid other than oleic or isostearic acid.

A formulation as in any of the foregoing embodiments wherein the formulation includes less than 3 wt% isostearic acid based on the total weight of the formulation.

A formulation as in any of the above embodiments wherein the formulation further comprises an antioxidant.

A formulation as in any of the foregoing embodiments further comprising an antioxidant, wherein the antioxidant is butylated hydroxyl toluene or butylated hydroxyanisole.

A formulation as in any of the above embodiments further comprising water.

A formulation as in any of the foregoing embodiments further comprising a preservative system.

A formulation as in any of the above embodiments further comprising an emulsifier.

22. A process for stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, fused -6,7 amines , 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, thiazolonaphthyridines aminines, thiazolinesin aminesoline, aminesazoline naphthyridine amines, or tetrahydronaphthyrine amines, and combinations thereof; and oleic acid by use of an oleic acid component that is substantially free of polar impurities.

23. A process of stabilizing a pharmaceutical formulation comprising a therapeutically effective amount of an MRI compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, fused -6,7 cycloalkylimidazopyridine amines with ponte-1,2, imidaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, thiazolonaphthyridine amines, 1H-imidazoline amides quinoline dimers, thiazole aminimidines amines naphthyridine amines, or tetrahydronaphthyrine amines, and combinations thereof; and oleic acid through the use of an oleic acid component with a peroxide value not greater than 5.

24. A process 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, fused -6,7 cycloalkylimidazoline pyridine amines with ponte-1,2, imidaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, thiazolonaphthyridine amines, 1H-imidazoline amides quinoline dimers, thiazole aminimidines amines naphthyridine amines, or tetrahydronaphthyrine amines, and combinations thereof; and oleic acid through the use of an oleic acid component which is at least 80% oleic acid.

25. The process of any of embodiments 22 to 24 wherein the IRM compound is selected from the group consisting of: amide substituted amidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, imidazoquinoline ether substituted heterocyclic amines, imidazoquinoline ether substituted amines, imidazoquinoline ether substituted sulfonamide amines, imidazquinoline ethers substituted with thioether, imidazoquinoline amine substituted, imidazoquinoline 7-, 8-imine substituted imines -, or 9-aryl, heteroaryl, aryloxy or aryl alkylenoxy, imidazoquinoline diamines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines substituted with urea, tetrahydroimidazoquinoline amines substituted amines ether, tetrahydroimidazoquinoline ether substituted with amine heterocyclic amines, tetrahydroimidazoquinoline ether substituted with starch ether, tetrahydroimidazoquinoline ether substituted with ammonium sulfate, tetrahydroimidazoquinoline ether substituted with urea, tetrahydroimidazoquinoline substituted with amine dihydroimidazole imidazopyridine sulfonamide substituted amines, imidazopyridine urea substituted amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, ether starch substituted imidazopyridine amines ether substituted amidazide pyridine amines imidazopyridine thioether substituted amines, and combinations thereof.

The process as in any of embodiments 22 to 24 wherein the IRM compound is an imidazonaphthyridine amine.

27. The process as in any of embodiments 22 to -24 and 26 wherein the IRM compound is 2-methyl-1- (2-methyl propyl) -1 H -imidazo [4,5-c] [1,5] naphthyridin-4-amine.

The process as in any of embodiments 22 to 24 wherein the IRM compound is 1- (2-methyl propyl) -1 H -imidazo [4,5-c] quinolin-4-amine.

29. A process for treating actinic keratosis, the process comprising applying a formulation of any one of a mode 1 to 21 to the skin of a subject.

30. A method of treating basal cell carcinoma, the process comprising applying a formulation of any one of embodiments 1 to 21 to the skin of a subject.

31. A process of treating genital warts, the process comprising applying a formulation of any one of embodiments 1 to 21 to the mucosal surface or skin of a subject.

32. A method of treating perianal warts, the process comprising applying a formulation of any one of modes 1 to 21 to the mucosal surface or skin of a subject.

33. A process for treating molloscum contagiosum, the process comprising applying a formulation of any one of embodiments 1 to 21 to the skin of a subject.

34. A process of inducing cytokine biosynthesis, the process comprising applying a formulation of any one of embodiments 1 to 21 to the mucosal or skin surface of a subject.

An interferon biosynthesis induction process, the process comprising applying a formulation of any one of claims 1 to 21 to the mucosal or skin surface of a subject.

36. A process of treating malignant melanoma, the process comprising applying a formulation of any of the foregoing embodiments 1 to 21 to the skin of a subject.

The term "substantially free" is used to indicate that the amount present in the composition or formulation is below the level causing degradation of the active pharmaceutical agent, so that the formulation is unsuitable for pharmaceutical use after storage for 4 months at 40 ° C. at 75% 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 limited to, 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 oleic acid-containing matter, 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, stearic acid, linoleic acid, linolenic acid, and other fatty acids, or combinations thereof.

The peroxide value is the number expressed in milliequivalents of active oxygen, the amount of peroxide contained in 1000 g of the substance as determined by the processes described in the 5th edition of European Pharmacopoeia, Section 2.5.5.

Unless otherwise indicated, all numbers expressing quantities, ratios, and numerical properties of ingredients, reaction conditions, and so forth used in the descriptive report and claims are to be construed as being modified in their entirety. all examples by the term "fence".

All parts, percentages, ratios, etc. herein are by weight unless otherwise indicated.

As used herein, "one" or "one" or "o" is used interchangeably with "at least one" to mean "one or more" of the listed element.

The above summary of the present invention is not intended to describe each embodiment shown or each implementation of the present invention. The following description exemplifies more particularly illustrative embodiments. In various parts throughout the patent application, guidance is provided through lists of examples, examples of which may be used in various combinations. In each example, the recited list serves only as a representative group and should not be interpreted as a unique list.

Detailed Description

The present invention provides pharmaceutical formulations including a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines-6,7, imidazoquinoline amines with bridging-1,2, imidazonaphthyridine amines, tetrahydroimidazonaphyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazole naphthyridine amines, thiazolonaphyridines amines quinoline amines quinolines amines amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyrine amines, and combinations thereof; and oleic acid, where the oleic acid component contains a low amount of polar impurities, especially peroxides. Surprisingly, the stability of such formulations is substantially greater than that of similar formulations containing an IRM compound and conventional oleic acid-containing oleic acid with higher amounts of polar impurities as peroxides, even when the oleic acid component is of a compendial grade. In addition, the instability problem of these formulations is not eliminated by additional antioxidants.

By using an oleic acid component containing a very low amount of polar impurities, the subsequent formation of impurities in IRM formulation is significantly reduced compared to other IRM formulations comprising compendial degrees of oleic acid after both initial measurement (i.e. their measurement). initially formulated) and under accelerated conditions (when stored for at least 4 months at 40 ° C and 75% relative humidity), resulting in increased formulation shelf life.

For certain embodiments, the formulation comprises an MRI 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 embodiments, the formulation comprises an IRM compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component has a peroxide value of no greater than 5. For certain embodiments, the formulation comprises an MRI compound and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component is at least 80% oleic acid.

In certain embodiments, formulations described herein may be in the form of an oil-in-water emulsion such as a cream or lotion. The oil component of the formulation includes an MRI compound and one or more fatty acids, including oleic acid in an amount sufficient to solubilize the MRI compound. Optionally, a cream or lotion of the invention may 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.

Immune Response Modification Compounds

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 imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, ether substituted imidazoquinoline amines aryl, imidazoquinoline ether substituted heterocyclic amines, imidazoquinoline ether substituted starch amines, imidazoquinoline substituted ammonium ether amines, imidazoquinoline urea substituted ethers, imidazoquoline amine substituted thioether, 7- imidazoquine amines 8- or 9-aryl, heteroaryl, aryloxy or aryl alkylenoxy, and imidazoquoline diamines; tetrahydroimidazoquinoline amines including, but not limited to, amide substituted tetrahydroquinazoline amines, tetrahydroquinazoline amines, tetrahydroquinazoline amines substituted with amide, tetrahydroquinazoline amines substituted with amide, tetrahydroquinazoline amines substituted with amide substituted tetrahydroquinoline amines starch ether substituted amines, tetrahydroimidazoquinoline ether sulfonamido substituted amines, urea substituted tetrahydroimidazoquinoline ethers, thioether substituted tetrahydroimidazinoline, and tetrahydroquinoline diamines; imidazopyridine amines including, but not limited to, imidazopyridine amide substituted amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, arid ether substituted imidazopyridine heterocyclic amine substituted imidazopyridine amines imidazopyridine starch substituted amines ether; sulfonamido ether substituted imidazo pyridine amines, urea substituted imidazopyridine ethers, and thioether substituted imidazopyridine amines; 1,2-bridged imidazoline quinoline; fused cycloalkylimidazopyridine amines 6.7; imidazonaphthyridine amines; tetrahydroimidazonaphthyridine amines; oxazole quinoline amines; thiazoloquinoline amines; oxazolopyridine amines; thiazolopyridine amines; oxazole naphthyridine amines; thiazolonaphthyridine amines; and 1 H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyrine amines.

These immune response modifying compounds are shown in, for example, U.S. Patent 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; 6,656,928; 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; Patent Publication No. 2004/0091491; 2004/132766; 2004/0147543; and 2004/0176367; and International Patent Application No. PCT / US04 / 28021 filed August 27, 2004.

For certain of these embodiments, the MRI compound is an amine imyzaphthyridine. For certain of these embodiments, the IRM compound is 2-methyl-1- (2-methyl propyl) -1H-imidazo [4,5-c] [1,5] naphthyridin-4-amine. For certain of these embodiments, the MRI compound is an imidazoquinoline amine. For certain of these embodiments, the IRM compound is 1- (2-methyl propyl) -1 H -imidazo [4,5-c] quinolin-4-amine (imiquimod). For some embodiments, MRI may have low water solubility, for example, less than about 1 µg / ml (eg, 0.79 µg / ml for 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 particular situation will depend on such things as the activity of the particular compound, the dosage regimen, the site of application, the particular formulation and the condition being treated. As such, it is generally not practical to identify specific amounts of administration 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 art pertaining to MRI compounds, and routine testing. The term "therapeutically effective amount" means an amount of the MRI compound sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, TH2 immune response inhibition, antitumor or antiviral activity, reduction or elimination of post-scar formation. -surgery, reduction or resolution of actinic keratosis or pre-actinic keratosis lesions, reduction in recurrence of actinic keratosis, treatment of basal cell carcinoma, genital warts, perianal warts, molioscum contagiosum, or protection against epidermal neoplasia uv-induced.

In general, the amount of MRI 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. In certain embodiments, the amount or concentration of MRI compound is at least 3 wt%, such as, for example, at least 5 wt% and at least 10 wt% based on the total weight of the formulation. In other embodiments, the amount of IRM compound is at most 10 wt%, such as, for example, at most 5 wt%, at most 3 wt% based on the total weight of the formulation. In certain embodiments, the amount or concentration of MRI 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.

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 saturated or unsaturated carboxylic acid having from 6 to 28 carbon atoms, such as, for example, from 10 to 22 carbon atoms.

Fatty acids, including the oleic acid component, may be present in the formulation in an amount sufficient to solubilize the IRM compound. In certain embodiments, the amount of the oleic acid component is at least 0.05 wt.%, At least 1.0 wt.%, At least 3.0 wt.%, At least 5.0 wt. %, at least 15%, or at least 25%, based on the total weight of the formulation. In certain embodiments, the amount of oleic acid component is a maximum of 40 wt%, a maximum of 30 wt%, a maximum of 15 wt%, or a maximum of 10% based on the total weight of the formulation.

Compendial grade oleic acid typically contains from 65 to 88 percent of (Z) -octa dec-9-enoic acid (oleic acid) along with varying amounts of saturated and unsaturated fatty acids. Fatty acid composition is determined by gas chromatography using the procedure described in European Pharmacopeia monograph 01/2005: 0799.

For certain embodiments, the oleic acid component contains at least 50%, at least 60%, at least 70% or at least 80% oleic acid. For certain embodiments, the oleic acid component contains at least 80% oleic acid.

For certain embodiments, the oleic acid component is substantially free of polar impurities such as peroxides. For certain embodiments, 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 embodiments, the oleic acid component has a peroxide value of less than 10. For certain embodiments, the oleic acid component has a peroxide value of less than 5.

For certain embodiments, the oleic acid component comprises SUPER REFINED Oleic Acid NF, available from Croda Inc., Edison, New Jersey, USA.

For certain embodiments, the topical formulations of the invention may include fatty acids in addition to those included in the oleic acid component. For example, certain embodiments may include isostearic acid. In some embodiments, the total amount of fatty acids, including those in the oleic acid component, is at least 0.05 wt.%, At least 1.0 wt.%, At least 3.0 wt.% 5.0%, at least 10%, at least 15%, or. at least 25% based on the total weight of the formulation. In certain embodiments, the total amount of fatty acids, including those in the oleic acid component, is a maximum of 40% by weight, a maximum of 30% by weight, a maximum of 15% by weight, a maximum of 10% based on total weight. of the formulation.

Antioxidants

For certain embodiments, the topical formulations of the invention may 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 USP NF 2004: The United States Pharmacopeia, 27th Revision 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 enantiomers) L), propyl gallate, sodium formaldehyde sulfoxylate, sodium thiosulphate, and tocopherol.

For certain embodiments, the antioxidant is selected from the group comprising aromatic hydroxy groups capable of donating hydrogen atom. Examples of such antioxidants include BHA, BHT1 propyl gallate, and tocopherol.

For certain embodiments, the antioxidant is selected from the group consisting of BHA1 BHT1 and combinations thereof. In certain embodiments, the antioxidant is BHA.

Preservative System

The formulation will often include a preservative system. The preservative system includes one or more compounds that inhibit microbial growth (eg, fungal and bacterial growth) within the formulation (eg during manufacture and use). The preservative 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 esters and salts. Various combinations of these compounds may be included in the preservative system. In some embodiments of the invention, the preservative system includes methylparaben, propylparaben, and benzyl alcohol.

In some embodiments 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 based on the total weight of the formulation. In other embodiments of the invention 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 Not more than 0,5%, not more than 0,4%, not more than 0,3% and not more than 0,2% by weight based on the total weight of the formulation.

Emollients

The 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; fatty acid esters, for example isopropyl myristate, isopropyl palmitate, diisopropyl dilinoleate dimer; medium chain triglycerides (e.g., 8 to 14 carbon atoms), 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 emollizers may be used if desired.

In certain embodiments, the amount of the emollient is at least 1.0 wt.%, At least 3.0 wt.%, At least 5.0 wt.%, Or at least 10 wt.% Based on weight. total formulation. In certain embodiments, the amount of emollient is at most 30 wt%, at most 15 wt%, or at most 10 wt%, based on the total weight of the formulation.

Formulations intended for dermal or topical use typically have sufficient amounts of an oil phase and an emollient to provide desirable qualities such as spreadability and sensation.

Viscosity Improvement Agent

The formulations of the present invention may also comprise a viscosity enhancing agent. Examples of suitable viscosity enhancing agents include long chain alcohols, for example, cetyl alcohol, stearyl alcohol, cetearyl alcohol; cellulose ethers such as hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose; polysaccharide gums such as xanthan gum; and homopolymers and copolymers of allyl sucrose or allyl pentaerythritol cross-linked acrylic acid 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-1 (USP / NF Monograph; Carbomer 1342), all available from Noveon, Cleveland, Ohio .

In certain embodiments, the amount of viscosity enhancing agent, when used, is at least 0.1 wt%, at least 0.2 wt%, at least 0.5 wt%, at least 0, 6 wt.%, At least 0.7 wt.%, At least 0.9 wt.%, Or at least 1.0 wt.% Based on the total weight of the formulation. In certain embodiments, the amount of viscosity enhancing agent, when used, is at most 10 wt%, at most 5 wt%, at most 3.0 wt%, at most 2.0 wt% , or at most 1.5% by weight, based on the total weight of the formulation.

Emulsifier

The formulations of the invention may additionally comprise an emulsifier. Suitable emulsifiers include nonionic surfactants such as, for example, polysorbate 60, sorbitan monostearate, polyglyceryl 4-oleate, polyoxyethylene lauryl ether (4), etc. In certain embodiments, the emulsifier is chosen 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 (e.g., Uniqema SPAN 85, New Castle, DE).

If included, the emulsifier is generally present in an amount from 0.1% to 10% by weight of total formulation weight, for example 0.5% to 5.0% by weight, and 90.75%. % to 4.0% by weight. In certain embodiments, the amount of emulsifier, if used, is present in an amount of at least 0.1 wt%, at least 0.5 wt%, at least 0.75 wt%, 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 emulsifier, if used, is present in an amount of up to 10% by weight; a maximum of 5.0 wt.% or a maximum of 3.5 wt.% 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.

Optionally, a formulation of the invention may contain additional pharmaceutically acceptable excipients as humectants, such as, for example, glycerin; chelating agents, such as, for example, ethylene diamino tetraacetic acid; and pH adjusting agents, such as, for example, potassium hydroxide or sodium hydroxide.

In some examples, a simple ingredient may perform more than one function in a formulation. For example, cetyl alcohol may serve as both an emollient and a viscosity enhancer.

Illustrative Formulation

In one embodiment of the present invention, a pharmaceutical formulation includes:

5% by weight of 1- (2-methyl propyl) -1H-imidazo [4,5-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 wt% polysorbate 60;

0.6% by weight sorbitan monostearate;

2% by weight glycerin;

0.2% by weight methyl hydroxybenzoate;

0.02 wt% propyl hydroxybenzoate;

0.5% by weight xanthan gum;

2% by weight of benzyl alcohol; and

49.98% by weight of water;

where weight percentages are based on the total weight of the formulation.

Application Processes

Formulations according to the present invention may be applied to any appropriate location, for example, topically to mucosal and / or dermis surfaces. In the case of dermal application, for example, depending on the MRI compound concentration, formulation composition, and dermis surface, the therapeutic effect of the MRI compound may extend only to the superficial layers of the dermis surface or to tissues below the dermis surface. dermis surface. Thus, another aspect of the present invention is directed to a process for treating a condition associated with mucosa and / or dermis comprising applying to the skin of one of the foregoing formulations. As used herein, a "mucosal and / or dermis-associated condition" means an inflammatory, infectious, neoplastic or other condition that surrounds a mucosal and / or dermis surface or that is sufficiently close to a mucosal surface. and / or dermis to be affected by a topically applied therapeutic agent to the surface. Examples of a condition associated with dermis and / or mucosa include warts, atopic dermatitis, postoperative healing, lesions caused by a herpes virus, and epidermal neoplasms such as, for example, actinic keratosis, pre-keratosis lesions. actinic, malignant melanomas, basal cell carcinoma, and squamous cell carcinoma.

In one embodiment, the formulations may be applied to the skin surface for treating actinic keratosis (AK). Actinic keratosis are premalignant lesions considered biologically to be both carcinoma in situ and squamous intraepidermal neoplasia. AK is the most common epidermal tumor and is induced by ultraviolet (UV) radiation, typically from sunlight. Due to its precancerous nature, AK can be considered the most important manifestation of sun-induced skin damage.

In some embodiments, the formulations described above are particularly advantageous for dermal and / or mucosal application for a period of time sufficient to achieve a desired therapeutic effect without unwanted systemic absorption of the MRI compound. Examples

The following examples are provided to further describe various formulations and processes according to the invention. The examples, however, are not intended to limit formulations and processes within the spirit and scope of the invention.

Test Process

A reverse phase high performance liquid chromatography (HPLC) process was used to determine the amount of impurities in oleic acid containing cream formulations.

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 aqueous ammonium phosphate buffer (prepared by combining 5.1 mL orthophosphoric acid with 985 mL water and then adjusting to pH 2.5 with concentrated ammonium hydroxide) and acetonitrile ; Gradient: start running at 10% acetonitrile, zero initial retention time, then linear gradient to 70% acetonitrile for fifteen minutes, zero final retention time; flow rate: 2.0 mL / min; injection volume: 200 μL; Running time: 15 minutes.

Solution Sample: A portion (about 300 mg) of the cream formulation was precisely weighed into a volumetric flask (100 mL). Diluent (50 to 60 mL, prepared by combining 250 parts acetonitrile, 740 parts water and 10 parts hydrochloric acid, all parts by volume) was added to the flask. The vial was vortexed 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 polypropylene or polytetrafluoroethylene filter to provide the sample solution.

Preparation of Cream Formulations

The cream formulations in Table 1 below were prepared using the following process.

Phase Preparation Water: A paraben premix was prepared by combining methyl hydroxybenzoate (methylparaben), propyl hydroxybenzoate (propylparaben), and water; heating the mixture until the paraben has 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 slowly added with stirring. Mixing with heating was continued until the xanthan gum had dispersed.

Phase Preparation Oil: An imiquimod / oleic acid premix was prepared by combining imiquimod and oleic acid and then stirring at room temperature overnight. Petrolate, 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 ° C. Benzyl alcohol was added to the oil phase just prior to phase combination.

Phase Combination: Both phases have been removed from their heat source. 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 homogenizer rate was reduced and homogenization was continued until the crema temperature was 25 ° C.

Table 1 summarizes A-D creams on a weight-by-weight percentage basis. The formulations were packaged in glass containers.

<table> table see original document page 25 </column> </row> <table> <formula> formula see original document page 26 </formula>

11- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine

2 J.T.Baker, a division of Mallinckrodt Baker, Inc., Phillipsburg, NJ, USA

3 Croda, Inc., Edison, NJ, USA

A set of containers was stored under environmental conditions; The samples used to determine initial values came from these containers. The remaining containers were stored in a constant temperature and humidity chamber at 40 ° C at 75% relative humidity. At selected time points, containers were removed from the chamber and then stored under ambient conditions until analyzed. Samples were analyzed using the test procedure described above for impurities. At the time points of 2, 4 and 6 months samples were taken from both the top and bottom of the containers. Results are shown in Table 2 below where each value is the result of a simple determination. Values are not normalized for weight loss that may have occurred during storage.

Table 2

<formula> formula see original document page 26 </formula> Table 2 <table> table see original document page 27 </column> </row> <table>

1Cremes Α, Β, C and D were analyzed 16 days, 15 days, 14 days, and 15 days respectively after they were prepared.

2All samples were analyzed 10 days after the containers were removed from the constant temperature and humidity chamber.

3All samples were analyzed 12 days after the containers were removed from the constant temperature and humidity chamber. 4All samples were analyzed 7 days after the containers were removed from the constant temperature and humidity chamber.

The full patent descriptions, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. In case of conflict, this descriptive report, including definitions, should control. Various modifications and changes to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. Illustrative embodiments and examples are provided by way of example only and are not intended to limit the scope of the present invention. The scope of the invention is limited only by the claims shown as follows.

Claims (32)

A pharmaceutical formulation comprising: a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, fused cycloalkylimidazopyridine amines-6, 7, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphyridine amines, oxazolo quinoline amines, thiazoloquinoline amines, thiazolopyridine amines, oxazole naphthyridine amines, thiazolonaphthyridines aminesimidines aminesazoline aminesazole - quinoline amines, naphthyridine amines, or tetrahydronaphthyrine 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. A pharmaceutical formulation comprising: a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, fused cycloalkylimidazopyridine amines-6, 7, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphyridine amines, oxazolo quinoline amines, thiazoloquinoline amines, thiazolopyridine amines, oxazole naphthyridine amines, thiazolonaphthyridines aminesimidines aminesazoline aminesazole - quinoline amines, naphthyridine amines, or tetrahydronaphthyrine amines, and combinations thereof; and a pharmaceutically acceptable carrier including an oleic acid component, wherein the oleic acid component has a peroxide value no greater than 5. A pharmaceutical formulation comprising: a therapeutically effective amount of an IRM immune response modifying compound selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, fused cycloalkylimidazopyridine amines-6, 7, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphyridine amines, oxazolo quinoline amines, thiazoloquinoline amines, thiazolopyridine amines, oxazole naphthyridine amines, thiazolonaphthyridines aminesimidines aminesazoline aminesazole - quinoline amines, naphthyridine amines, or tetrahydronaphthyrine 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. Formulation according to Claim 1, characterized in that the MRI compound is selected from the group consisting of amid-substituted imidazoquinoline amines, sulfonamide-substituted imidazoquinoline, urea-substituted imidazoquinoline, aryl ether-substituted imidazoquinoline, imidazoquinoline - in heterocyclic ether substituted amines, ether starch substituted imidazoquinoline, sulfonamide ether substituted imidazoquinoline amines, urea substituted imidazoquinoline thioether substituted imines, imidazoquinoline, 6-, 7- substituted 6- amine imidazoquinoline amines , or 9-aryl, heteroaryl, aryloxy or aryl alkylenoxy, imidazoquinoline diamines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazquinoline amines, tetrahydroimidazoquinoline amines ether-substituted tetrahydroimidazoquinoline heterocyclic ether-substituted tetrahydroimidazoquinoline, starch ether substituted tetrahydroimidazoquinoline, sulfonamide ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline-amine dihydroimidazoline amines , imidazopyridine sulfonamide substituted amines, imidazopyridine urea substituted amines, imidazopyridine aryl ether substituted amines, imidazopyridine heterocyclic ether substituted amines, imidazopyridine ether starch substituted amidazopyridine ether amidazopyridine ether , thioether substituted imidazopyridine amines, and combinations thereof. Formulation according to Claim 1, characterized in that the IRM compound is an amine imidazonaphthyridine. Formulation according to Claim 1, characterized in that the IRM compound is 2-methyl-1- (2-methyl propyl) -1H-imidazo [4,5-c] naphthyridin-4-amine. Formulation according to claim 1, characterized in that the IRM compound is 1- (2-methyl propyl) -1H-imidazo [4,5-c] quinolin-4-amine. Formulation according to Claim 1, characterized in that the IRM compound is present in an amount of at least 5% by weight based on the total weight of the formulation. Formulation according to claim 7, characterized in that 1- (2-methyl propyl) -1H-imidazo [4,5-c] quinolin-4-amine is present in an amount of 5% by weight. of the formulation. Formulation according to Claim 1, characterized in that the oleic acid component is present in an amount of at least 15% by weight based on the total weight of the formulation. Formulation according to Claim 1, characterized in that the oleic acid component is present in an amount of at least 20% by weight based on the total weight of the formulation. Formulation according to Claim 1, characterized in that the oleic acid component is present in an amount of at least 25% by weight based on the total weight of the formulation. Formulation according to claim 1, characterized in that the oleic acid component was purified by chromatography prior to use in the formulation. Formulation according to Claim 1, characterized in that the oleic acid component is derived from plants. Formulation according to claim 1, characterized in that the formulation includes at least one fatty acid other than oleic acid or isostearic acid. Formulation according to Claim 1, characterized in that the formulation includes less than 3% iswestearic acid by weight based on the total weight of the formulation. Formulation according to claim 1, characterized in that the formulation further comprises an antioxidant. Formulation according to claim 1, characterized in that it further comprises an antioxidant, wherein the antioxidant is butylated hydroxytoluene or butylated hydroxyanisole. Formulation according to claim 1, characterized in that it further comprises water. Formulation according to claim 1, characterized in that it further comprises a preservative system. Formulation according to claim 1, characterized in that it further comprises an emulsifier. A process for stabilizing a pharmaceutical formulation comprising at least 5% by weight of 1- (2-methyl propyl) -1H-imidazo [4,5-c] quinolin-4-amine; and at least 15% by weight of oleic acid, characterized in that it is by use of an oleic acid component that is substantially free of polar impurities. A process for stabilizing a pharmaceutical formulation comprising at least 5% by weight of 1- (2-methyl propyl) -1H-imidazo [4,5-c] quinolin-4-amine; and at least 15% by weight of oleic acid, characterized in that it is by use of an oleic acid component with a peroxide value not greater than 5. A process for stabilizing a pharmaceutical formulation comprising at least 5% by weight of 1- (2-methyl propyl) -1H-imidazo [4,5-c] quinolin-4-amine; and at least 15% by weight of oleic acid, characterized in that it is by use of an oleic acid component which is at least 80% oleic acid. Process for treating actinic keratosis, characterized in that it comprises applying a formulation as defined in claim 1 to the skin of a subject. A method of treating basal cell carcinoma, characterized in that it comprises applying a formulation as defined in claim 1 to the skin of a subject. Process for treating genital warts, characterized in that it comprises applying a formulation as defined in claim 1 to the mucosal surface or skin of a subject. Interferon biosynthesis induction process, characterized in that it comprises the application of a formulation of claim 1 to the mucosal or skin surface of a subject. Use of an IRM immune response modifying compound as defined in claim 1, characterized in that it is for the manufacture of a formulation for the treatment of actinic keratosis. Use of an IRM immune response modifying compound as defined in claim 1, characterized in that it is for the manufacture of formulations for the treatment of basal cell carcinoma. Use of an IRM immune response modifying compound as defined in claim 1, characterized in that it is for the manufacture of formulation for the treatment of genital warts. Use of an IRM immune response modifying compound as defined in claim 1, characterized in that it is for the manufacture of formulation for the induction of interferon biosynthesis.