WO2010057117A2 - Topical transdermal drug delivery compositions - Google Patents

Abstract

The present invention relates to topical drug compositions and methods for topical drug delivery which promote stability of a drug component and facilitate the penetration of the drug component into the skin of the host. Provided are topical drug compositions containing a suitable pharmaceutical agent agent, such as a vasoactive agent, and/or anti-inflammatory agents, NSAIDs, and/or non-NSAIDs. Also provided are methods for effectively utilizing the compositions for delivering said active agent to the host. These compositions and methods are useful for the transdermal drug delivery and treatment of a number of diseases and disorders in mammals. The invention also relates to methods for formulating or preparing the compositions of the present invention. To minimize irritation, the composition is water based, and preferably does not contain alcohol and/or alkyl hydroxybenzoate preservatives.

Description

TOPICAL TRANSDERMAL DRUG DELIVERY COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority of US 61/114,616 (filed November 14, 2008), US 61/114,836 (filed November 14, 2008), and US 61/114,816 (filed November 14, 2008), the contents of which applications are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to topical transdermal delivery compositions for delivery of drugs. Of particular relevance are topical transdermal delivery systems for many medical conditions and symptoms, such as the treatment of pain, inflammation, poor circulation, and various sexual dysfunctions.

BACKGROUND

[0003] Topical compositions are known for delivery of pharmaceutically active chemicals (hereinafter "drugs") across the skin of mammals. For example, topical cream products (such as Aspercreme® brand sports creme by Chattem, Inc.) contain trolamine salicylate, a chemical similar to aspirin. The FDA lists trolamine salicilate as safe for such topical uses, and many topical trolamine salicylate creams are available over-the-counter. The makers of those creams claim salicylates penetrate into the skin to help relieve arthritis pain. However, the reported effectiveness of those creams varies greatly among consumers. Indeed, the scientific community questions whether those creams can facilitate transdermal absorption of enough of the active ingredient (whether trolamine salicylate, methyl salicilate, ibuprofen, menthol, or other active ingredients) to reach the source of the pain (such as an inflamed muscles, deep dermal tissues, pain receptors, or other targets).

[0004] Known "arthritis cremes" and "sports cremes" utilize known ingredients. For example, Aspercreme® uses 10% trolamine salicilate as the active ingredient, while other cremes use active ingredients such as methyl salicilate, menthol, capsaicin, and camphor, for example. Common inactive ingredients for such topical creme compositions include aloe vera, cetyl alcohol, glycerin, methylparaben, mineral oil, potassium phosphate, propylparaben, stearic acid, triethanolamine, and water, for example. The use of methylparaben and propyl paraben as inactive ingredients is known for non-prescription topical cremes, as well as for other personal and cosmetic products such as skin lotions, moisturizers, and personal lubricants. Similarly, the use of alcohols such as cetyl alcohol, for example, is known for such topically applied nonprescription topical products. Similarly, the use of preservatives, such as alkyl hydroxybenzoates, including methylparaben and propylparaben is known for use in topical compositions. However, the use of methylparaben, propyl paraben, alcohols, and alkyl hydroxybenzoate preservatives in such products poses potential adverse affects to mammals, and their use is increasingly undesirable to consumers.

[0005] In addition to pain relief, topical compositions have been promoted for use in the treatment and management of sexual dysfunction in men and women. For example, as described in U.S. Patent Application 11/010,154 (US Pub. 20060127483), hereby incorporated by reference, the American Foundation for Urologic Disease (AFUD) has developed a classification system to be used by professionals treating female sexual dysfunction. Under this system, female sexual dysfunction includes: hypoactive sexual desire disorder, sexual aversion disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorders. The cause of female sexual dysfunction is not well understood but likely involves vascular, neurological, hormonal and psychogenic factors. Any condition that results in reduced blood flow to the vagina or clitoris can result in sexual dysfunction. Engorgement of these tissues with blood is necessary for producing sexual sensations and for the production of the necessary lubrication.

[0006] Neurological disorders can also cause reduced sensation in the vagina and clitoris resulting in sexual dysfunction. As women approach menopause, changes in hormone levels, particularly estrogen and testosterone, can lead to changes in sexual function. Estrogen is needed to help maintain adequate blood flow, muscle tone and lubrication as well as an adequate level of desire. While levels of testosterone are much lower in females than males, adequate levels still are needed in the female to maintain normal desire and libido. Psychological conditions such as anxiety, depression and obsessive compulsive disorder can all be associated with female sexual dysfunction. In addition, some medications used to treat these conditions, such as serotonin reuptake inhibitors, are associated with reduced desire and libido in women.

[0007] In men, sexual dysfunction is usually referred to as erectile dysfunction. Erectile dysfunction is defined as the repeated inability to maintain an erection sufficient for satisfactory intercourse. The are a number of potential causes of erectile dysfunction that involve vascular, neurological, hormonal and psychogenic factors. Vascular function is particularly important since an erection is the result of the penis becoming engorged with blood. In addition to organic causes, erectile dysfunction can be the result of certain medications, in particular certain medications used to treat hypertension.

[0008] Treatment options for sexual dysfunction are currently more limited for women than for men. In women, estrogen replacement therapy can relieve many of the symptoms of sexual dysfunction such as vaginal dryness as well as reduce or eliminate symptoms associated with menopause. However, recent studies showing an increase in cardiovascular disease and stroke in women with hormone replacement therapy have raised concerns about the safety of this approach. Treatment with testosterone can increase libido but can also result in weight gain and increased facial hair.

[0009] Several orally administered drug products have been developed for treatment of men's erectile dysfunction, including such phosphodiesterase inhibitors as VIAGRA® brand sildenafil citrate, LEVITRA® brand vardenafil HCl, and CIALIS® brand tadalafϊl. These active ingredients are widely used in oral dosage forms to treat male sexual dysfunction. However, there is no topical transdermal dosage form available for those drugs.

[0010] Additionally, Prostaglandin El (such as Alprostadil® brand prostaglandin El) has been used in the treatment of sexual dysfunction in both men and women. Prostaglandin El is administered as an injectable or as a suppository to function as a smooth muscle relaxant and a vasodilator. In the penis and clitoris, prostaglandin El acts to relax the trabecular smooth muscle and to dilate the arteries. The significant disadvantage of products containing prostaglandin El is the method of their administration. The products for men containing prostaglandin El are CAVERJECT® brand by Pfizer and MUSE® brand by Vivus Inc. In the case of CAVERJECT®, the prostaglandin El is injected directly into the penis. While generally effective, the injectable method for administering CAVERJECT® is painful and unpleasant. MUSE® is a small suppository containing Prostaglandin El that is inserted into a man's urethra. Again, the method of administration is unpleasant.

[0011] Vivus Inc. is developing the product branded as ALISTA® containing prostaglandin El for the treatment of female sexual dysfunction. U.S. Pat. Nos. 5,877,216, 6,593,313 and 6,593,369, assigned to Vivus Inc., relate to use of prostaglandin El in the treatment of female dysfunction, topical application of prostaglandins, optionally including the addition of an androgen, application to the clitoris and/or vulva of a female suffering from sexual dysfunction.

[0012] The product FEMPROX developed by NexMed Inc. of Robbinsville, N.J. contains prostaglandin El as the primary active ingredient and is currently in clinical trials for the treatment of female sexual dysfunction. U.S. Pat. No. 6,486,207 assigned to NexMed Inc. describes compositions containing prostaglandin El and N,N-disubstituted amino alkonates which act as penetration enhancers for the prostaglandin.

[0013] Lastly, patent-pending topical transdermal compositions such as those described in published US patent application serial number 11/010,154 require the undesirable ingredients of alkyl hydroxybenzoate preservatives (including, for example, p-hydroxybenzoic acid methyl ester, methyl paraben, propyl paraben, and other benzoic acid derivative preservatives). As previously described, those particular preservative ingredients are increasingly considered by consumers to be undesirable for topical compositions for application to human skin and other tissues.

[0014] For all these reasons, there is a continuing and unmet need for topical transdermal drug delivery compositions, and methods for topical transdermal drug delivery, which promote stability of at least one active ingredient and facilitate transdermal delivery of at least one active ingredient into the host, without the use of undesirable inactive ingredients such as alkyl hydroxybenzoate preservatives such as methyl paraben, and/or propyl paraben. SUMMARY OF THE INVENTION

[0015] The present invention relates to topical transdermal drug delivery compositions, and methods for topical transdermal drug delivery, which promote stability of at least one active ingredient and facilitate the transdermal delivery of at least one active ingredient into the host, without the use of undesirable active ingredients such as such as alkyl hydroxybenzoate preservatives such as methylparaben, and/or proylparaben. Preferably, the compositions are also essentially free of lower (C1-C6) alkanols.

[0016] The invention also relates to topical drug compositions containing any suitable pharmaceutical agent (also referred to herein as a "drug", "active ingredient", or "active agent"), such as but not limited to: anaesthetics, fungicides, drugs used to treat cancer, analgesics, vasoactive agents (including but not limited to niacin, L-arginine, prostaglandins, and/or agents that produce a prostaglandin response), phosphodiesterase inhibitors, and the like.

[0017] The topically applied formulations of the present invention are transdermally active for incorporating at least one drug and delivering pharmacologically effective amounts of the drug to a targeted area of the host or patient. The topical composition is an aqueous formulation that includes at least one pharmaceutical agent, such as a vasoactive agent, at least one humectant, at least one viscosity increasing agent, and an emulsifying agent. The compositions may optionally include one or more preservatives or solvents, with the provisio that any preservative is not selected from the group consisting of alkyl hydroxybenzoates. Preferably, the composition is also essentially free of alcohol. If the composition includes alcohol, the alcohol is preferably not a lower (C1-C6) alkanol. For example, one or more alkoxalated alcohols, such as methoxypolyethylene glycol (aka PEG-6 methyl ether) may optionally be provided as a humectant. Viscosity increasing agents include but are not limited to hydrophilic colloids, in particular high molecular weight colloids. Emulsifying agents include but are not limited to fatty cid esters and polyols, such as polyvinyl alcohol (aka PVA). Additional or optional ingredients, as shown in the example, can include propylene glycol, glycerin, alcohols, alkyl hydroxybenzoate preservatives, for example. [0018] Vasoactive pharmaceutical agents are those agents that affect either the constriction or relaxation of blood vessels. Suitable vasoactive agents include, but are not limited to, prostaglandins such as prostaglandin El, as well as niacin, L-arginine, and others.

[0019] In some embodiments of the invention, the vasoactive agent is a prostaglandin present from about 0.05% to about 0.15% by weight of the composition. In this embodiment, the composition further includes an aqueous solution of hydroxyethylcellulose, carboxymethylcellulose, methoxypoly ethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin. In a further embodiment of the invention the composition also includes niacin.

[0020] In some other vasoactive embodiments, niacin is provided as a vasoactive agent, and is present at less than about 5% of the composition by weight. In one vasoactive embodiment of the invention, in addition niacin as an active ingredient, the composition includes an aqueous solution of hydroxyethylcellulose, carboxymethylcellulose, methoxypolyethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin. In a further embodiment of the invention the composition includes, in addition to niacin, another active ingredient.

[0021] In still other vasoactive embodiments, L-arginine is provided as a vasoactive agent, and is present at less than about 10% of the composition by weight. In this embodiment, the composition further includes an aqueous solution of hydroxyethylcellulose, carboxymethylcellulose, methoxypolyethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin. In a further embodiment of the invention the composition also includes niacin.

[0022] In some other embodiments, the composition includes an aqueous solution of niacin, hydroxyethylcellulose, carboxymethylcellulose, methoxypolyethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin. In a further embodiment of the invention the composition includes, in addition to niacin, another active ingredient selected from: analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs; anticancer agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti- infective agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; calcium channel blockers; beta- blockers; antiarrhythmic agents; central nervous system stimulants; decongestants; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; ophthalmic drugs; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics; tranquilizers; vasodilators; and combinations thereof.

[0023] The invention is further directed to methods for transdermally delivering at least one active ingredient to the host. These compositions and methods are useful for the treatment of, among other things, pain, inflammation, poor circulation, and sexual dysfunction, in both men and women, as well as for other conditions wherein transdermal delivery of any active ingredient is desirable.

[0024] The invention also includes a method for treating a mammal in need thereof by applying the above described topical transdermal composition to a desired region of the skin of the host mammal. In a particular embodiment, the method involves treating a mammal in need of vasodilation by applying the composition including at least one vasodilator in an amount sufficient to alleviate the sensation of cold.

[0025] In another embodiment, the method involves treating a mammal suffering from sexual dysfunction by applying the composition to the genitals and/or genital region. The composition is preferably applied at least about five minutes prior to sexual activity.

[0026] The invention also includes a method for treating sexual dysfunction by topically applying the above described composition to a desired region of the skin of the host. In a particular embodiment, a female desiring treatment for sexual dysfunction applies said composition to the vagina and/or clitoral regions. The composition is preferably applied about ten minutes prior to sexual activity. [0027] Another embodiment of the invention is a method for treating erectile dysfunction in males by applying to the skin of the penis the above described composition to deliver the vasoactive agent, such as a prostaglandin, directly to the penis. In a preferred embodiment the composition is applied to the penis within about ten minutes prior to sexual activity. In a further embodiment, when the composition is intended for use by males, the number and concentration of viscosity increasing agents and emulsifying agents is increased.

[0028] The invention also relates to methods for formulating or preparing the compositions of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 is a profile of day 1 plasma pharmacokinetic values for oral and topical treatments with ibuprofen in miniature swine.

[0030] FIG.2 is a profile of day 5 plasma pharmacokinetic values for oral and topical treatments with ibuprofen in miniature swine.

[0031] FIG. 3 is a five day profile of plasma pharmacokinetic values for oral and topical treatments with ibuprofen in miniature swine.

DETAILED DESCRIPTION OF THE INVENTION

[0032] The topically applied formulations of the present invention are transdermally active for incorporating at least one pharmaceutically active ingredient ("drug") and delivering pharmacologically effective amounts of the at least one drug to a targeted area of the host or patient. In some embodiments, more than one drug is included in the composition. In each embodiment, the topical composition is an aqueous formulation that includes at least one drug, at least one viscosity increasing agent, at least one humectant, and at least one emulsifying agent. In further embodiments, the composition includes niacin and at least one other drug. In still other embodiments, the composition further includes at least one of propylene glycol, glycerin, and only one of either an alcohol and an alkyl hydroxybenzoate preservative. [0033] Exemplary viscosity increasing agents include but are not limited to hydrophilic colloids, such as high molecular weight colloids including hydroxyethylcellulose and/or carboxymethylcellulose. Suitable hydrophilic colloids are of high molecular weight and include carboxymethylcellulose and hydroxyethylcellulose. Suitable carboxymethylcelluloses that can be used in the invention have a viscosity from about 2,000 cps to about 5,000 cps in a 1% solution. Preferred hydroxyethylcelluloses suitable for use in the invention have a viscosity from about 1,000 cps to about 3,000 cps in a 1% solution. Preferably, the hydrophilic colloid component has a high average molecular weight, e.g. in the order of 10,000-15,000 daltons. Suitable materials are available from Hercules Inc. of Wilmington Del. For example the carboxymethylcellulose product AQUALON® CMC 7H3SXF and the hydroxyethylcellulose product NATRO SOL® 250H NF grade are suitable materials.

[0034] Exemplary humectants include, but are not limited to alkoxylated alcohol humectants, such as methoxypolyethylene glycol, methoxypolypropylene glycol and methoxypolyvinyl glycol. When present, any alkoxylated alcohol preferably has an average molecular weight of from about 300 to about 750 daltons, preferably about 350 daltons. Such materials are readily available from commercial sources.

[0035] Exemplary emulsifying agents include but are not limited to polyols and/or fatty acid esters. For example, suitable fatty acid esters include polysorbates. Preferably, the fatty acid esters preferably have a molecular weight greater than 1 ,000 daltons. By way of further example, suitable polyols include polyvinyl alcohol, for example.

[0036] Exemplary optional viscosity-increasing ingredients include glycerin and propylene glycol.

[0037] Optionally, the composition may include one or more preservatives, with the provisio that any preservative is preferably not selected from the group consisting of alkyl hydroxybenzoates. One feature common among the preferred embodiments herein is the absence of an alkyl hydroxybenzoate preservative such as p-hydroxybenzoic acid methyl ester, also known as methyl 4-hydroxybenzoate and as methyl paraben. Methyl paraben and propylparaben have recently become the focus of consumer concern as an undesirable ingredient in cosmetics and other personal products. Therefore, even when such a alkyl hydroxybenzoate preservative present in the compositions of the present invention, such ingredient comprises less than 5% of the composition by weight.

[0038] Another preferable common feature among the compositions herein is the absence of an alkanol solvent, such as ethanol, as an ingredient in the composition. Alkanaols include C1-C6 lower alkanols such as ethanol, methanol, butanol, propanol, pentanol and hexanol. However, the composition may optionally include a solvent, but preferably the solvent is essentially free of alcohol. If the composition includes any alcohol, the alcohol is preferably not an alkanol. For example, as previously mentioned, one or more alkoxalated alcohols may optionally be provided, whether as a solvent or as a humectant.

Vasoactive Ingredients

[0039] Vasoactive agents are those drugs that affect either the constriction or relaxation of blood vessels. Suitable vasoactive agents include, but are not limited to, prostaglandins such as prostaglandin El, as well as niacin, L-arginine, phosphodiesterase inhibitors, alpha-adrenergic receptor antagonists, prostaglandins, dopamine agonists, potassium channel openers and endothelin antagonists, for example.

[0040] In some embodiments of the invention, the vasoactive agent is a prostaglandin present from about 0.05% to about 0.15% by weight of the composition. In one embodiment, the composition further includes an aqueous solution of hydroxyethylcellulose, carboxymethylcellulose, methoxypoly ethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin. One preferred vasoactive agent is prostaglandin El, which has the generic drug name of alprostadil. It is preferred that the prostaglandin El be highly pure. In a further embodiment, when prostaglandin El is present, prostaglandins other than prostaglandin El comprise less than 1.5% of the total prostaglandins in the composition. A suitable prostaglandin El is available from Chinoin Pharmaceutical and Chemical Works Co. Ltd. of Budapest, Hungary. In a further embodiment, the composition further includes niacin.

[0041] In other embodiments, niacin is provided as the vasoactive agent, and is present at less than about 5% of the composition by weight. In one vasoactive embodiment of the invention, in addition to niacin as an active ingredient, the composition includes an aqueous solution of hydroxyethylcellulose, carboxymethylcellulose, methoxypolyethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin.

Other Active Ingredients

[0042] In a further embodiment of the invention the composition includes, in addition to niacin, another active ingredient selected from: analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs; anticancer agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; calcium channel blockers; beta-blockers; antiarrhythmic agents; central nervous system stimulants; decongestants; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; ophthalmic drugs; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics; tranquilizers; vasodilators; and combinations thereof.

[0043] In still other embodiments, L-arginine is provided as a vasoactive agent, and is present at less than about 10% of the composition by weight. In this embodiment, the composition further includes an aqueous solution of hydroxyethylcellulose, carboxymethylcellulose, methoxypolyethylene glycol, and optionally one or more of propylene glycol, polyvinyl alcohol and glycerin. In a further embodiment of the invention the composition further includes niacin.

EXAMPLES

Example 1

[0044] In one example, the composition is a composition comprising purified water, carboxymethylcelulose, hydroxyethylcellulose, methoxypolyethylene glycol (aka PEG-6 methyl ether), polyvinyl alcohol (aka PVA), propylene glycol, and glycerin. In this embodiment, the active agent in the composition is niacin, which is known to produce a prostaglandin response that results in vasodilation and associated flushing of the skin in mammals. When this embodiment is applied topically to human skin, including the skin of extremities such as arms, writs, hands feet, legs, knees, ankles, feet, necks, ears, noses, and other skin, tissues of the human genitalia such as the clitoris, labia, penis, for example, as well as mucous membranes, the niacin produces a prostaglandin response in the localized tissues. The prostaglandin response results in a feeling of warmth, as well as increased localized blood flow that may desirably engorge localized tissues. Application of the niacin-only composition of this example to female genital tissues such as the clitoris and/or labia has been shown to stimulate local blood flow, as well as to facilitate a reflexive production of natural vaginal moisture and lubrication. In a preferred embodiment, the composition is applied to the clitoris within about five to about twenty minutes prior to sexual activity. The composition can further be used as a vaginal moisturizer to alleviate vaginal dryness in female mammals resulting from any number of causes, including but not limited to menopause, diet, exercise, sexual disorders, for example.

[0045] In still a further embodiment of this example, where niacin is included as an active ingredient, the composition of the above Example 1 may be applied to skin of the extremities of mammals to improve localized blood flow. For example, topical application of the composition to the fingers, hands, and lower arms, and/or to the toes, feet, and lower legs of humans suffering from poor blood circulation can be therapeutic. In the particular example of Renois disease, localized and topical application of the composition of the composition containing niacin has been shown to relieve the feeling of cold in a patient's hands and fingers. Additionally, use of the composition has been shown to provide relief to arthritis pain in the hands, feet and extremities. In view of the transdermal characteristics of the formulation including niacin, it is expected that the composition will be effective in delivering additional active ingredients through skin, mucosa, and other exposed tissues of mammals. For example, it is expected that other active ingredients that are compatible with niacin can provided in the composition and delivered by topical application to mammal tissues. Exemplary ingredients include analgesic agents and ; anesthetic agents and antiarthritic agents, such as NSAIDS, for example. In another example, the composition can deliver non-NSAID additional active ingredients including: respiratory drugs; anticancer agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; calcium channel blockers; beta- blockers; antiarrhythmic agents; central nervous system stimulants; decongestants; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; ophthalmic drugs; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics; tranquilizers; vasodilators; and combinations thereof.

[0046] By way of non- limiting example, suitable formulations for topical compositions consistent with this example, and other embodiment examples, are described in Table 1.

Table 1.

[0047] When niacin is provided as an active agent, the composition can be utilized as a topical drug delivery system for treatment of any condition in a mammal that benefits from localized vasodilatation and associated improved local blood flow. That desirable result may be supplemented by the presence of a second active ingredient, such as another vasodilator, NSAID, and/or non-NSAID therapeutic agent as described herein.

[0048] In a further embodiment, when the composition is intended for use by male mammals, the number and concentration of viscosity increasing agents and emulsifying agents is preferably increased. It is believed that application of the composition, especially when the active agent includes niacin and/or another erectile-affecting active ingredient may be useful in treating erectile dysfunction in males. For example, by applying to the skin of the penis the above described composition to deliver a vasoactive agent, such as niacin and/or a prostaglandin, and optionally an erectile dysfunctions drug directly to the penis and/or the surrounding male genitalia, such as the scrotum and peritineum. In a preferred embodiment the composition is applied to the penis within about ten minutes prior to sexual activity. In a further embodiment, when the composition is intended for use as a personal lubricant, the number and concentration of viscosity increasing agents and emulsifying agents can be adjusted so as to reduce friction during intercourse.

Example 2

[0049] Importantly, while the composition listed in Table 1 included niacin as the active ingredient, other agents may be provided in addition to niacin. For example, additional vasoactive agents including , but not limited to prostaglandins, L-arginine, methol, camphor, and prostaglandins such as prostaglandin El, as well as niacin, L-arginine, phosphodiesterase inhibitors, alpha-adrenergic receptor antagonists, prostaglandins, dopamine agonists, potassium channel openers and endothelin antagonists may be included.

[0050] By way of further example, other active ingredients that may be added in addition to, or in lieu of, niacin include antiinflammatories. For example, the anti-inflammatory may include a non-steroidal anti-inflammatory (NSAID"). Exemplary NSAID active ingredients include, but are not limited to non-steroidal anti inflammatory drug (NSAID) selected from the group consisting of ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate(N-[4-(2,4diamino 6- pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid); aspirin(acetylsalicylic acid); salicylic acid; diphenhydramine(2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen(2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (-)); phenylbutazone(4- butyl-l,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-fuoro-2-methyl-l-[[p- (methylsulfϊnyl)phenyl]methylene-]-lH- -indene-3 -acetic acid; diflunisal(2',4',-difluoro-4- hydroxy-3-biphenylcarboxylic acid; piroxicam(4-hydroxy-2-methyl-N-2-pyridinyl-2H- 1 ,2- benzothiazine-2-carboxa- mide 1,1 -dioxide, an oxicam; indomethacin(l-(4-chlorobenzoyl)-5- methoxy-2-methyl-H-indole-3-acetic acid); meclofenamate sodium(N-(2,6-dichloro-m- tolyl)anthranilic acid, sodium salt, monohydrate); ketoprofen(2-(3-benzoylphenyl)-propionic acid; tolmetin sodium(sodium l-methyl-5-(4-methylbenzoyl-lH-pyrrole-2-acetate dihydrate); diclofenac sodium(2-[(2,6-dichlorophenyl)amino]benzeneatic acid, monosodium salt); hydroxychloroquine sulphate(2-{[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino}ethanol sulfate(l :l); penicillamine(3-mercapto-D-valine); flurbiprofen([l,l-biphenyl]-4-acetic acid, 2- fluoro-alphamethyl-, (+-)); cetodolac(l-8-diethyl-13,4,9, terra hydropyrano-[3-4-13]indole-l- acetic acid; mefenamic acid(N-(2,3-xylyl)anthranilic acid; and diphenhydramine hydrochloride(2-diphenyl methoxy-N,N-di-methylethamine hydrochloride) .

Example 3

[0051] Importantly, while the composition listed in Table 1 included niacin as the active ingredient, other agents may be provided in lieu of niacin. For example, additional vasoactive agents including , but not limited to prostaglandins, L-arginine, methol, camphor, and prostaglandins such as prostaglandin El, as well as niacin, L-arginine, phosphodiesterase inhibitors, alpha-adrenergic receptor antagonists, prostaglandins, dopamine agonists, potassium channel openers and endothelin antagonists, may be included.

Composition Uses

[0052] In embodiments where NSAIDS are provided as an active ingredient, whether in combination with niacin or in lieu of niacin, the composition is a viscous aqueous composition. The viscous, gel-like nature of the composition is maintained even if the composition is frozen and thawed, such as to preserve the composition from degradation prior to use. When used for the treatment of female sexual dysfunction the composition is preferably applied to the perineal area of the female host, in particular the vagina and clitoris. This allows the niacin to increase the blood flow to these tissues resulting in the increased production of lubrication and increased tactile sensitivity, thereby improving the sexual function of the host. A single dose of the composition is about 2-3 ml and should be applied shortly before sexual activity, preferably not more than an hour before sexual activity. The effect of the niacin lasts for about one hour. After the one hour period the composition may be reapplied if necessary.

[0053] In the case of the treatment of erectile dysfunction, the composition, whether containing niacin and an erectile drug, such as but not limited to sildenafil citrate, is preferably applied directly to the penis so that blood flow can be increased leading to an improved erection. The usual dose is preferably about 2-3 ml and is applied shortly before sexual activity, preferably not more than ten minutes before sexual activity.

[0054] Improvement in sexual function can be evaluated by the use of questionnaires or diaries where the patient records the quality of their sexual experiences. Data collection should include a pretreatment baseline period of 4-8 weeks. Specific endpoints of the sexual experience include satisfactory sexual intercourse, sexual intercourse resulting in orgasm, oral sex resulting in orgasm and partner-initiated or self masturbation resulting in orgasm. A statistically significant change in the frequency of successful and satisfactory sexual experiences over time provides a measure of the effectiveness of the treatment for sexual function. The determination of what is a successful and satisfactory sexual experience is made by the patient not the patients partner. Physical changes such as increased blood flow to the genitals, engorgement of the penis or clitoris or changes in vaginal lubrication can also be measured but should be considered as secondary supportive information and not a primary indication of the success or failure of the treatment.

[0055] Questionnaires which can be used to evaluate sexual function include the Female Sexual Distress Scale described by Derogatis et. al. (J. Sex Marital Ther. 28(4):317-30, 2002) and the Female Sexual Function Index described by Rosen et. al. (J. Sex Marital Ther. 26(2): 191-208, 2000). And for males the International Index of Erectile Function (IIEF) described by Rosen et. al. (Int. J. Impotence Res. 11 :319-326, 1999) can be used.

Manufacturing Methods

[0056] In one embodiment, the invention involves a process of formulating the compositions described above. The method of preparation comprises the sequential addition of the following ingredients to water at one or more elevated temperatures in the range of about 55 ° C to about 90 ⁰ C during stirring said ingredients comprising p-hydroxybenzoic acid methylester, hydroxyethylcellulose, carboxymethylcellulose and methoxypolyethylene glycol; and when the composition is at a temperature below about 60° C adding an aqueous solution of niacin, and optionally an alcohol. In a further embodiment of the process, the process optionally comprises heating water to about 90° C and adding p-hydroxybenzoic acid methyl ester to the water at the heated temperature. After the addition the water is allowed to cool while stirring at about 450 rpm. When the temperature of the aqueous composition is about 75° C to about 80° C, hydroxyethylcellulose and carboxymethylcellulose are added and stirring of the aqueous composition at about 450 rpm is continued. When the temperature of the water is about 55° C to about 60° C methoxypolyethylene glycol is added and stirring is continued at 450 rpm. A naturally occurring or synthetic active ingredient is dissolved in an aqueous or organic solvent, and the resulting solution is added to the aqueous composition with stirring at about 300 rpm. While stirring, propylene glycol is added to the aqueous composition. After addition of the propylene glycol stirring is reduced to a speed of about 90 rpm. In one embodiment, the composition is packaged in a suitable container. In a further embodiment a single dosage amount of the composition is packaged in a disposable container.

[0057] In another embodiment, water is heated to about 90° C and the heat is turned off. Methyl paraben (free base) is added to the heated water for 2 hours while stirring at about 450 rpm. Hydroxyethylcellulose and carboxymethylcellulose are mixed together in equal proportions by weight. When the temperature of the aqueous composition is about 70-80° C, a roughly equal proportional mixture of hydroxyethylcellulose and carboxymethylcellulose is added while stirring at 450 rpm for about 30-35 minutes. When the temperature of the aqueous composition cools to about 55-60° C, optionally methoxypolyethylene glycol is added while stirring at about 450 rpm for 6 hours. In a separate stirrer, the niacin and any other active ingredient is dissolved in an aqueous or organic solvent while stirring at slow speed for 5 minutes. The niacin/active solution is added to the aqueous composition while stirring at about 300 rpm for 1 hour. Propylene glycol is added to the aqueous composition while stirring at about 300 rpm for 1 hour. After the 1 hour, the stirring speed is reduced to about 90 rpm and the stirring of the aqueous composition continues overnight. The completed composition is packaged in suitable containers. It has been found that tubes made of polypropylene provide optimal stability. To maintain stability during long term storage, the composition is desirably stored at -between about 15° C to about 30° C Nonetheless, the composition is stable at room temperature for up to about 120 days, and can be frozen if storage for a longer period of time is desired.

[0058] For the stirring steps of the above procedures, stirrers that are capable of maintaining a constant stirring speed even when the viscosity of the solution is increased are preferred. Such stirrers are referred to as fixed torque stirrers. Suitable stirrers include model BDC303 produced by Caframo Limited of Wiarton, Canada.

Further Examples of Compositions and Methods

[0059] In yet another example, the composition is a composition comprising purified water, carboxymethylcelulose, hydroxyethylcellulose, methoxypolyethylene glycol (aka PEG-6 methyl ether), polyvinyl alcohol (aka PVA), propylene glycol, and glycerin. The active agent in the composition is niacin, which is known to produce a prostaglandin response that results in vasodilation and associated flushing of the skin in mammals. When applied topically to human skin, including tissues of the human genitalia such as the clitoris, labia, penis, for example, as well as mucous membranes, the niacin produces a prostaglandin response in the localized tissues.

[0060] By way of non- limiting example, suitable topical compositions consistent with this embodiment are described in Table 2. Importantly, while the compositions listed in Table 2 include niacin as the pharmaceutically active agent, other agents may be provided in addition to, or in lieu of, niacin. Table 2.

[0061] When niacin is provided as the agent, the embodiment of this example can be utilized as a topical drug delivery system for treatment of any condition in a mammal that benefits from localized vasodilation and associated improved local bloodflow.

[0062] Improving genital blood flow and sensation in females. For example, application of the composition of this example to female genital tissues such as the clitoris and/or labia has been shown to stimulate local bloodflow, as well as to facilitate a reflexive production of natural vaginal moisture and lubrication. In a preferred embodiment the composition is applied to the clitoris within about ten to about twenty minutes prior to sexual activity.

[0063] Improving genital blood flow and sensation in male genitalia. In a further embodiment, when the composition is intended for use by males, the number and concentration of viscosity increasing agents and emulsifying agents is increased.

[0064] It is believed that application of the composition of this example may be useful in treating erectile dysfunction in males by applying to the skin of the penis the above described composition to deliver a vasoactive agent, such as niacin and/or a prostaglandin, directly to the penis, as well as to surrounding male genitalia, such as the scrotum and peritineum. In a preferred embodiment the composition is applied to the penis within about ten minutes prior to sexual activity. In a further embodiment, when the composition is intended for use by males, the number and concentration of viscosity increasing agents and emulsifying agents is increased.

[0065] Improving Localized Blood Flow. In still a further embodiment, the composition of the above example may be applied to skin oft he extremities of mammals to improve localized blood flow. For example, topical application of the composition to the fingers, hands, and lower arms, and/or to the toes, feet, and lower legs of humans suffering from poor blood circulation can be therapeutic. In the particular example of Reynaud's phenomenon disease, localized and topical application of the compositions herein niacin has been shown to relieve the feeling of cold in a patient's hand sand fingers. In particular, the following composition is exemplary of appropriate compositions useful in condition such as Rayhauld's phenomenon, dermal circulatory diseases, and the like.

Table 3 (a). Exemplary Ray nauld Pain Gel - 1.00% Formulation (3 Litres) (e.g., wt/vol).

Table 3(b).

Step l Water 86.00% - Measure 2580 ml water. Start to heat water to 65c.

Step 2 Potassium Sorbate 0.20% - 6.0Og add to water while water is heating. Stir for 1 hour or until water temp reaches 65 c.

[0066] NSAID Examples - Ibuprofen Gel Formulations. In yet another embodiment, the composition provide for transdermal delivery of delivering an active ingredient such as an NSAID, or other active pharmaceutical ingredients that are compatible with the composition and appropriate for transdermal delivery. The following illustrate non-limiting examples of gel formulations and methods of making them.

Table 4. Exemplary ibuprofen Gel 4% 4% (1000ml) No overage (e.g., wt/vol).

[0067] Note: The inventors contemplate adding in Phenoxyethanol at about 2.00% after some additional testing.

Table 5. Exemplary ibuprofen Gel 4% 12th Batch (1000ml) - Batch for Trials, (e.g., wt/vol).

Animal Studies

[0068] Pig Studies. Applicant commissioned an animal study "Oral and Dermal Dose Tolerance and Pharmacokinetic Study of Ibuprofen in Miniature Swine (Pilot, Non-GLP)." The study was performed by an independent research center. As of the time of filing this patent application, the in life portion of this study has been completed and research center is in the process of writing a draft final report of the findings. However, a preliminary data review is provided herein and summarizes preliminary data and analytical results that represent, to date, the best information possible with respect to the outcome of this study.

[0069] Study Objectives: This study was designed to evaluate the dermal absorption characteristics of a novel ibuprofen gel at two concentration levels of the active pharmaceutical ingredient (4% and 10% Ibuprofen) and to compare and contrast ibuprofen absorption and elimination kinetics following dermal administration of the gel formulations with oral administration absorption and elimination kinetics for Motrin® (ibuprofen), an approved pharmaceutical for the relief and treatment of joint pain. The following formulation was used in this animal study, and was prepared by the methods previously described herein: Table 6.

[0070] There were no signs of dose intolerance, including dermal irritation, in animals from any of the four dose groups, oral Motrin (2400 mg/day or -60 mg/kg/day), 4% Topical Ibuprofen Gel (16 mg/kg/day), 10% Topical Ibuprofen Gel (40 mg/kg/day) or 10% Topical Ibuprofen Gel (400 mg/kg/day). Topical doses were observed to rapidly enter the stratum corneum of the skin. Complete absorption of the topical dose was, therefore, observed with little or no residue apparent.

[0071] On Day 1, a single dose of each of the above treatments was administered and blood samples were collected at the intervals shown below in Table 7. The mean results from analysis at these pharmacokinetic (PK) intervals are summarized in Table 8 below.

Table 7. Pharmacokinetic Evaluation Intervals

Study Day Time Points

1 Predose, 0 5 1 1 5 ? 4, 8, 12, and 22 hours post dose

2 & 3 4 hours \ 30St first dailv dose administration

5 Predose. and 0 5 1 1 ' 5. 2. 4. 8. 12. and 22 hours ϋost dose Table 8. Summary of plasma and synovial fluid ibuprofen concentrations at selected PK intervals.

22

Synovial Fluid (ng/mL)

[0072] It is clear from the results shown in Table 8 that oral ibuprofen (Motrin® brand) produced higher systemic (plasma) levels of ibuprofen than topical administration. Since the topical doses do show absorption and elimination PK profiles on Day 1 (initial dose) and Day 5 (last dose) and consistently appeared to be well absorbed into the skin, it is obvious that the skin and most likely underlying structures are retaining ibuprofen at high levels with the subsequent slow release of unretained ibuprofen and its metabolites into the plasma.

[0073] This means that topical ibuprofen administered from this formulation is capable of placing a significant amount of ibuprofen into the skin and to bypass the well-known potential for ibuprofen to cause gastrointestinal distress as well as substantially lessening any potential to create toxicological issues for the liver, kidneys and cardiovascular system. As can be observed in the summarized plasma values for ibuprofen profiled in FIGS. 1, 2 and 3, oral administration of ibuprofen produces high plasma levels that rise and fall daily over a few days of repeated administration. Topical exposure to ibuprofen avoids the high plasma concentrations as well as their fluctuation, while placing ibuprofen into the skin and most likely underlying structures in the form of a controlled reservoir that might be valuable in the management of topically localized pain without risk of systemic toxicity or gastrointestinal effects that are well-known with oral dosage forms of ibuprofen.

[0074] In the miniature pig, while it is possible that a considerable amount of ibuprofen might partition into the subcutaneous fat, the tissue partitioning into skin and underlying structures needs to be further studied. There is literature that has studied the partitioning of ibuprofen in skin and this may be of some value in determining how best to approach a determination as to the actual subcutaneous tissue distribution of ibuprofen topical doses for this formulation. Further examination of topically dosed miniature pig skin and underlying tissue ibuprofen concentrations is, therefore, a next rational step to investigate tissue distribution and disposition of ibuprofen delivery from this topical vehicle. [0075] Synovial fluid concentrations of ibuprofen were observed for the oral (Motrin) treated animals and for the high topical dose (400 mg/kg/day) treated animals. There was no measurable levels of ibuprofen in synovial fluid samples taken from animals receiving the low dose topical ibuprofen (16mg/kg/day) or mid level 40 mg/kg/day) treatments. Since the synovial fluid concentration in the high dose topically treated animals were most likely similar to those from the oral treated animals due to variation, it would appear that a significant amount of ibupro fen- laden plasma is mobilizing in the peripheral tissues to the extent that an exposure to joint fluids can occur without observing a high concentration of ibuprofen in the central plasma pool.

[0076] Group 5 Pig follow-on study. Applicants have investigated the distribution of ibuprofen into pig synovial fluid following a dosing regimen that includes dosing directly over joints of live miniature swine to identify and characterize ibuprofen absorption. The formulation used in the study was a one-litre batch having the following composition, prepared by the methods previously described herein:

Table 9.

[0077] The Group 5 study was recently performed, entitled "Oral and Dermal Dose Tolerance and Pharmacokinetic Study of Ibuprofen in Miniature Swine (Pilot, Non-GLP). Group 5:" According to the protocol, two (2) healthy naϊve Hanford miniature swine (1 male and 1 female) were selected and assigned to Treatment Group 5. On Study Day 1, the test article (10% Ibuprofen) was administered once topically to both the right and left stifle (knee joints). On Study Days 2-4 the test article was administered topically to same joints, 4 times per day. Animals were dosed at the levels presented in Table 10. Pharmacokinetic blood samples were to be collected at the intervals specified in Table 11. Urine, synovial fluid, and skin tissue samples will be collected following collection of the final blood sample collection and subsequent euthanasia (within 4 hours) on Study Day 6. Variables to be evaluated are presented in Table 12.

Table 9. Details of Experimental Study Design.

a. Only one dose will be administered on Study Day 5.

b. Right and left stifle (knee joints) Table 11. Pharmacokinetic Evaluation Intervals.

Group 5

Study Day Time Points a

1 Predose, O S 1 1 S 9 4 K , 12, and 22 hours post dose

5 Predose. and O S 1 1 S 4 K O and 22 hours ϋost dose a The plasma samples will be stored on dry ice and/or at < -7O⁰C before shipping to bioanalytical site for analysis. The actual collection time will be recorded in the raw data.

Table 12. Variables to be Evaluated and Intervals

a^' Urine will be collected via direct bladder tap at necropsy and will be stored at < -70oC and be retained for future analysis at the request of the Sponsor.

[0078] Topical joint administration for each animal was as follows: The surrounding areas of each animal's right and left stifle (knee joint) were clipped with an electric clipper at least 8 hours before the initial dose application. The dose area was about 3 inches above and below the center of the joint and approximately 3 inches on either side of the joint. The corners of the area were marked and the actual dose surface area for each animal's joint documented. The dose area was be gently wiped clean with gauze, moistened with water. Following cleaning, any remaining water within the dose area was removed with gauze and/or paper towel. The dose formulation was be drawn into a syringe/pipette and the volume recorded in the raw data. The dose formulation was applied to the dose area using a gloved-hand or pipette tip.. The applied dose formulation was spread out on the skin surface surrounding the joint.

[0079] Synovial Fluid Collection. Group 5 Animals: On Study Day 6 (22-26 hours post the final dose administration on Study Day 5), synovial fluid (target - 0.5 mL) was collected from each dosed joint (right and left stifle) and from 1 or 2 non-dosed joint(s) (right and/or left carpus) following euthanasia via percutaneous arthrocentesis (or other appropriate method). Following collection, synovial fluid samples were placed on dry ice prior to storage (< -70⁰C).

[0080] Tissue collection for Group 5 Animals: Following the collection of synovial fluid, 3 skin samples (including muscle and fat) were collected from both dosed and non-dosed joints. Following collection, each sample was separated into three parts (skin, fat, and muscle), weights obtained for each, and will frozen on dry ice and stored at <-70°C. Reason: To evaluate the dermal absorption of the test article when applied to the joints.

[0081] Preliminary results for Group 5 animals. For animal 5M2 there were 5 samples provided. Per the protocol, 4 samples were to be obtained from each animal (R, L Carpus (wrists) and R, L Stifle (knees)). The stifles were dosed and the carpuses were not dosed. For animal 5M2, a left hock (ankle) and left hip sample were provided in place of the left stifle. Investigators ran 4 of the 5 samples, those that had sufficient volume for multiple re-runs. The curve looked good - results are as follows for Ibuprofen in synovial fluid: Left Hip: 3927 ng/mL; Right Carpus: 261 ng/niL; Left Carpus: 238 ng/mL; Right Stifle: 690 ng/niL

[0082] These preliminary results show that the formulation vehicle is clearly capable of delivering a drug substance of the nature of ibuprofen salt into the skin for subsequent partitioning and distribution into underlying tissues. Further evaluation of this vehicle as well as its variants are planned to determine the extent to which other drug substances including biologies (e.g., peptides) might be facilitated to enter the skin and underlying subcutaneous structures as well as the bloodstream depending on their physicochemical characteristics and adjustments of formulation variables.

[0083] The animal study results, and particularly the presence in synovial fluid of the active ingredient administered (ibuprofen), and its absence in the blood, reinforce the use of the compositions as drug delivery vehicles. Indeed, the results suggest that the compositions when applied topically can deliver active ingredients to synovial and lymphatic systems, without delivering the active ingredients to the blood. The compositions are useful for delivering drugs to synovial and/or lymphatic systems, and may be particulary useful in treating any disease of such systems, such as lymphomas or other non-blood diseases.

[0084] While there have been described herein the principles of the invention, it is to be understood by those skilled in the art that this description is made only by way of example and not as a limitation to the scope of the invention.

Claims

1. A composition for topical delivery to a host, the composition comprising an aqueous formulation of one or more pharmaceutical agents; at least one alkoxylated alcohol humectant, and at least one high molecular weight hydrophilic colloid viscosity increasing agent.

2. The composition of claim 1, further comprising at least one emulsifying agent.

3. The composition of claim 2, further comprising at least one preservative.

4. The composition of claim 2, further comprising at least one solvent that comprises an alcohol.

5. he composition of claim 1, wherein (a) the alkoxylated alcohol humectant is methoxypolyethylene glycol; and (b) the high molecular weight hydrophilic colloid viscosity increasing agent is selected from one or more of the group consisting of carboxymethylcellulose and hydroxy ethylcellulose; and which is from about 0.1% to about 2% by weight of the composition.

6. A composition for topical delivery of at least one active ingredient to a host comprising a formulation containing at least one of either niacin or niacinamide, one or more pharmaceutical agents, at least one alkoxylated alcohol humectant, and at least one high molecular weight hydrophilic colloid viscosity increasing agent, at least one emulsifying agent, at least one aqueous solvent, and optionally at least one of propylene glycol and glycerin.

7. The composition of claim 6, further comprising at least one preservative.

8. The composition of claim 7, further comprising at least one preservative, with the proviso that the preservative is not an alkyl hydroxybenzoate.

9. The composition of claim 7, with the proviso that the aqueous solvent does not comprise a C1-C6 alkanol.

10. The composition of claim 7, wherein the aqueous solvent comprises an alcohol.

11. The composition of claim 6, wherein the alkoxylated alcohol humectant is methoxypolyethylene glycol, and wherein the high molecular weight hydrophilic colloid viscosity increasing agent is selected from one or more of the group consisting of carboxymethylcellulose and hydroxyethylcellulose.

12. The composition of claim 11, wherein the emulsifying agent is at least one of polyvinyl alcohol or a sorbate.

13. The composition of claim 11, wherein: (a) the active ingredient includes either niacin or niacinamide at less than about 5% by weight; (b) the high molecular weight hydrophilic colloid viscosity increasing agent is selected from one or more of the group consisting of carboxymethylcellulose and hydroxyethylcellulose and which is present at less than about 5% by weight of the composition; (c) the alkoxylated alcohol humectant is methoxypolyethylene glycol which is present at between 5% to about 10% by weight of the composition, and (d) the emulsifying agent is polyvinyl alcohol which is present at less than about 5% by weight.

14. The composition of claim 6 or claim 11, wherein the pharmaceutical agent consists of at least one NSAID.

15. The composition of claim 6 or claim 11, wherein the pharmaceutical agent is not a NSAID.

16. A method of making a pharmaceutical composition, the method comprising: preparing a first part by combining and mixing at least water, an emulsifier , a thickening agent an alkoxylated alcohol humectant, at least one of propylene glycol or glycerin (or both); preparing a second part by combining at least one of niacin or niacinamide with at least one pharmaceutical agent, adding a first solvent followed by mixing, adding a second solvent followed by mixing; and optionally adding a third solvent followed by mixing; and adding the first part to the second part followed by mixing until the composition is substantially homogeneous.

17. The method of claim 16, wherein the emulsifier is selected from the group consisting of sorbates and vinyl alcohols.

18. The method of claim 17, wherein the thickening agent is hyaluronic acid.

19. The method of claim 17, wherein the humectant is methoxypolyethylene glycol

20. The method of claim 17, wherein the first solvent comprises water, and wherein at least one of the second and optional third solvents are different from the first solvent.