CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit under 35 U.S.C. § 1 19(e) to U.S. Provisional

Application No. 61/884,948, filed September 30, 2013, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates generally to compositions comprising topical permeation enhancers for the purposes of formulating cosmetic and pharmaceutical products, specifically compositions comprising N-alkyl substituted lactams (e.g., valerolactams), including methods of transdermal delivery of cosmetic and/or therapeutic solvents, solutes, macromolecules, small molecules or other compounds across the cornified layers of the skin.

BACKGROUND INFORMATION

[0003] Transdermal solute/drug delivery market remains limited to a narrow range of drugs due to challenges associated with skin permeation and skin irritation. Em ergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic and hydrophobic compounds,

macromolecules,and conventional drugs for new therapeutic and cosmetic uses.

[0004] The epidermis is composed of 4 or 5 layers depending on the region of skin being considered. The cornified layer is composed of 10 to 30 layers of polyhedral, anucleated corneocytes (final step of keratinocyte differentiation), with the palms and soles having the most layers. Corneocytes are surrounded by a protein envelope (cornified envelope proteins), filled with water-retaining keratin proteins, attached together through corneodesmosomes and surrounded in the extracellular space by stacked layers of lipids. Most of the barrier functions of the epidermis localize to this layer. The cornified layer is highly impermeant to hydrophilic solutes such as the active ingredients found in many cosmetics and medicines. Penetration of said barrier is a desirable goal in applied pharmacology.

[0005] Transdermal systems are a desirable form of drug delivery because of the obvious advantages over other routes of delivery. Transdermal delivery provides convenient and pain-free self-administration for patients. It eliminates frequent dosing administration and plasma level peaks and valleys associated with oral dosing and injections to maintain a constant drug concentration and a drug with a short half-life may be delivered easily. All this leads to enhanced patient compliance, especially when long-term treatment is required, as in chronic pain treatment and smoking cessation therapy. Avoidance of hepatic first-pass metabolism and the GI tract for poorly bioavailable drugs is another advantage of transdermal delivery. Transdermal drug delivery systems may be used in combination with other therapies, for example, radiotherapy or chemotherapy, which therapies may impede convenient oral intake of drug because of, for instance, nausea or gastroparesis. Some patients may be in such a state that oral intake as such is no longer possible (e.g., cancer patients). Patients with impaired mental capacities, e.g. elderly patients, often forget or refuse to take necessary daily medication.

[0006] Transdermal systems are generally inexpensive when compared with other therapies on a monthly cost basis, for example, patches are designed to deliver drugs from 1 to 7 days. The other advantage of transdermal delivery is that multiple dosing or variable-rate (rate controlled) delivery of drugs is possible. The general acceptability of transdermal products by patients is very high.

[0007] Another advantage of topical and transdermal drug delivery is the reduction of systemic side effects. On the other hand, delivery of drugs by these routes adds the potential for side effects in the form of skin irritation at the delivery site. Skin irritation reactions include irritant contact dermatitis (ICD), an inflammatory response caused by repeated or direct exposure of the skin to weak irritants, and allergic contact dermatitis (ACD), delayed, and T-cell-mediated inflammatory response to a specific allergen. ICD reactions range from erythema and scaling to necrotic burns while ACD reactions include erythema, edema, and occasionally vesiculation. Factors that contribute to skin irritation include,fo r example, changes in the physiological pH of the skin, disruption of the stratum corneum barrier (i.e., delipidization, hydration and disruption of stratum corneum lipid packing), immunological and physiological reactions, bacteria proliferation at the delivery site, and chemical/pharmacological features of the drug or vehicle.

[0008] While it is difficult to predict the irritation potential of chemical permeation enhancers, the formulation used to deliver a drug can influence the appearance and degree of skin irritation. Hydrogels, for instance, have been reported to reduce skin irritation by absorbing moisture from the skin's surface. Reinforcing the protective barrier of the skin by addition of an emollient to topical formulations has been shown to reduce or prevent skin irritation.

[0009] The stratum corneum is a formidable barrier to exogenous agents including drugs. It is generally understood that for enhancers, increased potency is directly correlated with increased skin irritation. Difficulty in reducing the irritation of these agents has been expressed since the same mechanisms responsible for increasing permeation is thought to cause irritation. While potent enhancers are effective at transiently compromising the integrity of the stratum corneum barrier, their action is not entirely limited to the stratum corneum and the interaction with viable epidermis can cause cytotoxicity and irritation. Studies performed with the objective of reducing the irritancy potential of permeation enhancers without decreasing their potency have met with limited success. For example, pre-application of steroids to the skin and incorporation of steroid or anti-irritants into irritant formulations has been demonstrated to reduce skin reactions, however, steroids may have their own side effects, including but not limited to, increase in appetite, difficulty sleeping, changes in mood, and changes in blood pressure.

[0010] What is needed is a delivery vehicle which allows for enhanced penetration across the cornified layer and at the same time does not cause skin irritation.

SUMMARY OF THE INVENTION

[0011] The present disclosure relates to penetration enhancers that do not cause skin irritation while at the same time overcome the barrier limitation of the cornified layer of skin, including compositions comprising N-alkyl substituted lactams and methods of transdermal delivery of solvents, solutes, macromolecules, small molecules or other compounds using such N-alkyl substituted lactams. [0012] In embodiments, a composition including a permeation enhancer is disclosed, where the enhancer may contain Formula I:

(I) where n is a saturated alkyl having 12 to 14 or 12 to 16 carbon atoms; and a cargo molecule, where the cargo molecule is a cosmetic ingredient or a pharmaceutical agent.

[0013] In one aspect, the pharmaceutical agent includes antibacterial agents, antifungal agents, steroids, retinoids, antihistamines, radical scavengers, antihypertensives, cardiovascular drugs, sex hormones, anti-diabetics, hypnotics, hyperemic agents, anti-Parkinson agents, local anesthetics, anticoagulants, analgesics, antimigraine, and chemotherapeutic agents.

[0014] In another aspect, the cosmetic ingredient includes soaps, antidandruff agents, antiseborrheic agents, keratolytic agents, keratoplastic agents, salicylic acid, allantoin, sulfur products, urea, ceramides, vitamins, plant extracts, organ extracts, hormones, corticoids, citric acid, orotic acid, lipoic acid, amino acids, polyethoxylated fatty alcohols, fatty acids, sorbitan, fatty acid esters, alkyl phosphates, oils, preservatives, colorants, perfume oils, and combinations thereof.

[0015] In one aspect, the permeation enhancer is present at a concentration between about 0.0001% by weight to about 9% by weigh ln an other aspect, the permeation enhancer does not irritate the skin.

[0016] In one aspect, the composition comprises a patch, spray, gel, cream, powder, lotion, cosmetic or liquid. In a related aspect, the patch topically delivers a pharmaceutical agent at an effective rate over an extended period of time.

[0017] In one aspect, for formula (I), n is 14. [0018] In another embodiment, a method for enhancing the penetration of a cosmetic ingredient or pharmaceutical agent through the cornified layer of a subject is disclosed including contacting the cornified layer of the subject with a composition containing a permeation enhancer of Formula I:

(I) where n is a saturated alkyl having 12 to 14 or 12 to 16 carbon atoms; and a cosmetic ingredient or a pharmaceutical agent, where the cosmetic ingredient or pharmaceutical agent would be impermeable to the cornified layer or penetrate at a lower rate in the absence of the permeation enhancer.

[0019] In one embodiment, a kit is disclosed including a permeation enhancer of Formula I:

(I) where n is a saturated alkyl having 12 to 14 or 12 to 16 carbon atoms; a label; a container; one or more buffers; and a set of instructions for enhancing the penetration of a cosmetic ingredient or pharmaceutical agent through the cornified layer of a subject.

[0020] In a related aspect, the subject is a human.

[0021] In another embodiment, a use of a permeation enhancer comprising Formula I:

(I) wherein n is a saturated alkyl having 12 to 14 or 12 to 16 carbon atoms in the preparation of a medicament for enhancing the penetration of a cosmetic ingredient or pharmaceutical agent through the cornified layer of a subject is disclosed, where the cosmetic ingredient or pharmaceutical agent would be impermeable to the cornified layer or would penetrate at a lower rate in the absence of the permeation enhancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 shows transdermal penetration of the drug metformin in the presence of two transdermal penetration enhancers: MFC (microfibrillated cellulose) and the delivery system Vx (Permeation enhancer of Formula I where n is 14), measuring UV absorbance as a function of time.

[0023] FIG. 2 shows transdermal penetration of the drug metothrexae in the presence of two transdermal penetration enhancers: MFC (microfibrillated cellulose) and the delivery system Vx (Permeation enhancer of Formula I where n is 14), measuring UV absorbance as a function of time.

[0024] FIG. 3 shows an accelerated aging test for N-alkyl valerolactam of Formula I, n =14. Degradation of the Valerolactam was determined over a 29 week period by measuring the absorbance of the sample at 310 nm (1 % N-alkyl valerolactam/99% EtOH).

[0025] FIG. 4 shows the results of a viability assay of CA- 1 cells incubated for 24 hours at 37 °C with various concentrations (0.4 to 2% w/v) of N-alkyl valerolactam of Formula I, n =14. Cell viability was determined by the MTT cell proliferation assay. The absorbance of the formazan dye produced in the presence of 0.4 to 2% valerolactam was measured at 595 nm and was taken as a measure of cell viabil ity. The control sample contained no valerolactam. [0026] FIG. 5 shows the results of a viability assay of N-Tert Keratinocytes incubated for 24 hours at 37 °C with various concentrations (0.4 to 2% w/v) of N-alkyl valerolactam of Formula I, n =14. Cell viability was determined by the MTT cell proliferation assay. The absorbance of the formazan dye produced in the presence of 0.4 to 2% valerolactam was measured at 595 nm and was taken as a measure of cell viability. The control sample contained no valerolactam.

DETAILED DESCRIPTION OF THE INVENTION

[0027] Before the present composition, methods, and methodologies are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

[0028] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, references to "an agent " includes one or more agents, and/or compositions of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, as it will be understood that modifications and variations are encompassed within the spirit and scope of the instant disclosure.

[0030] In embodiments, the N-alkyl substituted lactams as disclosed herein enhance the percutaneous absorption of topically administered physiologically active agents, e.g., drugs , growth factors, radical scavengers, and the like.

[0031] As used herein, "permeation enhancer" means substance that temporarily changes the nature of the skin barrier (i.e., the stratum corneum) so that the passage of molecules across this barrier is facilitated. [0032] As used herein, "cutaneous irritation" means a complex biological reaction to exogenous stimuli applied to the skin or caused by damage to the skin barrier, identified by, for example, superficial pH, transepidermal water loss, skin hydration, skin color, blood flow,and barrier resistance.

[0033] As used herein, "barrier function" means intactness of the stratum corneum barrier of the skin and its ability to deter chemicals, microbes,and loss of water from the viable skin layers.

[0034] As used herein, "transepidermal water loss" means the evaporation of water from the skin's surface as well as a physical tool for assessing perturbations of the skin barrier

[0035] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

[0036] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0037] The compounds of Formulas (I) may be prepared, for example, by ring closure of suitable di-functional compounds to form cyclic amides. In embodiments, the concentration of permeation enhancers in formulations for absorption of active agents across the stratum corneum barrier ranges from about 0.0001 % to about 19%,0. 0001% to about 10%, about 0.0001% to about 9%, about 0.0001% to about 5%, about 0.0001% to about 4%,about 0.0001% to about 3%, about 0.0001% to about 2%, about 0.0001% to about 1 %, about 0.0001% to about 0.2%, about 0.0001% to about 0.1 %, about 0.0001 % to about 0.01% and about 0.0001% to about 0.001 % by wt. of the composition. [0038] In one aspect, the permeation enhancer is present at a concentration between about 0.0001% by weight to about 9% by weight, 0.001 % by weight to about 9% by weight, 0.01 % by weight to about 9% by weight, 0.1% by weight to about 9% by weight, 0.0001% by weight to about 5% by weight, 0.001% by weight to about 5% by weight, 0.01 % by weight to about 5% by weight, 0.1 % by weight to about 5% by weight, 0.0001 % by weight to about 4% by weight, 0.001% by weight to about 4% by weight, 0.01 % by weight to about 4% by weight, 0.1% by weight to about 4% by weight, 0.0001 % by weight to about 3% by weight, 0.001% by weight to about 3% by weight, 0.01% by weight to about 3% by weight and 0.1 % by weight to about 3% by weight, 0.0001% by weight to about 2% by weight, 0.001 % by weight to about 2% by weight, 0.01% by weight to about 2% by weight, 0.1% by weight to about 2% by weight, 0.0001% by weight to about 1% by weight, 0.001% by weight to about 1% by weight, 0.01% by weight to about 1% by weight, 0.1% by weight to about 1% by weight, 0.0001 % by weight to about 0.1% by weight, 0.001 % by weight to about 0.1% by weight, 0.01 % by weight to about 0.1% by weight and 0.05% by weight to about 0.1 % by weight.. In another aspect, the permeation enhancer is present at a concentration less than 50% by weight, 40% by weight, 30% by weight, 20% by weight, 19% by weight, 18% by weight, 17% by weight, 16% by weight, 15% by weight, 14% by weight, 13% by weight, 12% by weight, 1 1% by weight, 10% by weight, 9% by weight, 8% by weight, 7% by weight, 6% by weight, 5% by weight, 4% by weight, 3% by weight, 2% by weight, 1 % by weight, 0. 1 % by weight, 0.01 % by weight, 0.001 % by weight, and 0.0001 % by weight. In another aspect, the permeation enhancer does not irritate the skin.

[0039] In embodiments, the compositions may comprise at least one pharmaceutical agent, including, but not limited to, an antibacterial agent, an antifungal agent, an active steroid, an antihistaminic agent, antihypertensives and other cardiovascular drugs, sex hormones, antidiabetics, hypnotics, anti-Parkinson drugs, local anesthetics, anticoagulants, analgesics, and antimigraine drugs. The pharmaceutical agents may be used at a safe and effective level in the compositions according to the invention, being in general from about 0.001 % to about 30% by weight of the composition, less than 1 % by weight of composition, less than 0.1% by weight of composition, less than 0.01 % by weight of composition, less than 0.001%) by weight of composition, or less than 0.0001% by weight of the composition. However, as will be apparent to one of skill in the art, levels outside this range may also be used. [0040] Examples of antibacterial agents which may be used in this invention include, but are not limited to, penicillins, cephalosporins, penicillinase, erythromycins, tetracyclines, chloramphenicols, streptomycins, and the like.

[0041] Examples of retinoids include, but are not limited to, retinol, retinal, tretinoin, retinoic acid, Retin-A, isotretinoin, alitretinoin, etretinate, acitretin, tazarotene, bexarotene, and adapalene.

[0042] Dosage forms for topical applications may include solutions, nasal sprays, lotions, ointments, creams, gels, suppositories, sprays, aerosols as well as devices such as skin patches, bandages and dressings containing a composition according to the invention. Typical conventional pharmaceutical carriers which make up the foregoing dosage forms include water, acetone, isopropyl alcohol, ethyl alcohol, polyvinylpyrrolidone, propylene glycol, fragrances, gel-producing materials, mineral oil, stearyl alcohol, steric acid, spermaceti, sorbitan monoleate, "Polysorbates", "Tweens", and the like.

[0043] The amount of the composition and thus of the pharmaceutical agent therein, to be administered will obviously be an effective amount for the desired result expected therefrom. This, of course, may be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which is achieved with the enhancer, the dosage of the active agent may often be decreased from that generally applicable.

[0044] As used herein the term "topical" is intended to include application to all external membrane barriers including the cutaneous or epidermis regions and the mucous membranes including the gastrointestinal tract, the respiratory tract and the genitourinary tract.

[0045] The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed and various systems for accomplishing this are disclosed in numerous technical journals, handbooks and patents. These systems may deliver controlled amounts of drugs to patients for extended periods of time ranging in duration from several hours to several days. [0046] Interestingly, it has now been found that solutes/drugs in the presence of permeation enhancers as disclosed herein may be administered through intact skin at a rate which is sufficient to attain therapeutically meaningful plasma levels.

[0047] In embodiments, the permeation enhancers as disclosed herein may be used for cosmetic compositions. In ot her embodiments, a pharmaceutical drug formulation comprising the permeation enhancers is also disclosed.

[0048] In embodiments, the permeation enhancers of the present disclosure are used in methods of transdermal delivery of solutes, molecules or other compounds. In embodiments, methods of treating subjects in need thereof by administering the permeation enhancers together with a suitable drug are disclosed.

[0049] In embodiment, a feature of permeation enhancers is their ability to enhance the transport of solutes of various sizes and shapes across the skin.

[0050] In embodiments, the permeation enhancer is present at various concentration in compositions comprising cargo molecule present in soluble form wherein soluble form comprises hydrophilic, hydrophobic, lipophilic, lipophobic and neutral lipophilic environment.

[0051] In embodiments, the cargo molecule is hydrophilic, hydrophobic, lipophilic, lipophobic and/or neutral lipophilic.

[0052] In embodiments,a proc ess for inducing and maintaining a disease reducing effect is disclosed, for example, an antitumor effect, which comprises administering a pharmaceutical drug to a subject in need thereof through an area of intact skin at a therapeutically effective rate for a select period of time. In cases where extended period of time are required,a m edical patch may be used to deliver the drug and enhancer.

[0053] Topical drugs include, but are not limited to, for example, astringents, emollients, moisturizers, antipruritics, antiseborrheics, antimicrobials, and anti-inflammatory agents. These drugs may be applied to the skin by a variety of delivery systems, for example, shampoos, rinses, powders, lotions, sprays, creams, emulsions, ointments, and gels. In embodiments, the agent for promoting health or wellness comprises one or more drugs for treating, for example, a bacterial, fungal, parasitic, or viral skin disease or an immune-mediated, endocrine, neoplastic, or metabolic disease. In embodiments, the agent for promoting health or wellness comprises one or more antioxidants. In embodiments, the agent for promoting health or wellness comprises one or more vitamins.

[0054] Any appropriate dermatological agent may be administered by the subject methods. Typically, the dermatological agent has anti-inflammatory and/or anti-proliferative and/or immunomodulatory properties. It shall be understood that the dermatological agents described herein should not be considered to be limiting in any manner in that many other dermatological agents not referenced herein may be utilized to practice the subject invention, including dermatological agents yet to be discovered.

[0055] By "topical formulation" it is meant that the dermatological agent is present in a form that is capable of application to the surface of the skin and is able to be absorbed through the skin. Such topical formulations of dermatological agents are typically in the form of a cream, lotion, ointment, gel, solution, foam, powder, and the like. The concentration of the

dermatological agent will depend on the particular agent, the particular disease disorder, the host, the site of application, and the like.

[0056] Various classes of dermatological agents may be utilized in accordance with the subject invention. As such, any dermatological agent may be employed that has desirable therapeutic properties for the particular skin disorder being treated. In embodiments, the topical formulation of a dermatological agent applied to the surface of the skin is a steroid. Thus, in accordance with the subject invention, any class of steroid may be employed in accordance with the subject invention. That is, Class I steroids (very potent steroids), Class II steroids (potent steroids), Class III steroids (moderately potent steroids) and Class IV steroids (relatively mild steroids), etc., may be used with the subject invention, as long as they are in a form for topical application. A variety of steroids are known in the art for treatment of disorders affecting the skin and include, but are not limited to: triamcinolone, triamcinolone acetonide, clobetasol, clobetasol propionate, clobetasone butyrate, desonide, alclometasone, flurandrenolide, desoximetasone, betamethasone, loteprednol, fluorometholone, difluprednate, momethasone furoate, diflorasone diacetate, diflucortolone valerate, fluocinonide, amcinonide, halcinonide, fluocinolone acetonide, flumetasone pivalate, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha- methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone,

dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone. A combination or mixture of one or more of the above

dermatological agents may be employed.

[0057] However, the subject invention is not limited to dermatological agents that include steroids. Accordingly, in certain embodiments, the dermatological agent applied to the surface of the skin is not a steroid. For example, the dermatological agent may be an anti-bacterial agent such as mupirocin (e.g., BACTROBAN®), etc., an anti-viral agent such as topical acyclovir (e.g., ZOVIRAX®), etc., an anti-fungal agent such as nystatin, miconazole, amphotericin, econazole, etc., an anti-acne agent such as benzoyl peroxide, a vitamin A derivative, a vitamin D derivative, a vitamin E derivative, etc. Other non-steroidal agents are known in the art and include, but are not limited to: calcipotriol (e.g., DOVONEX®), pimecrolimus (e.g., ELIDEL®), tacrolimus (e.g., PROTOPIC®), tazarotene (e.g., TAZORAC®), coal tar, anthralin (e.g., Psoriatectm), salicylic acid, sulfur products such as colloidal sulfur, etc. A combination or mixture of one or more of the above dermatological agents may be employed, e.g., a combination of coal tar, salicylic acid and colloidal sulfur (e.g., MG217™). In embodiments, a combination or mixture of one or more non-steroidal agents may be used with one or more steroidal agents.

[0058] Once the appropriate topical formulation of dermatological agent is selected, an effective or optimal amount of the topical formulation is applied to a skin surface. As will be apparent to those of skill in the art, the effective or optimal amount wi ll vary depending on the particular dermatological agent employed, the particular disease state being treated, etc. The topical formulation may be applied to any convenient topical site. Topical sites of interest include, but are not limited to: arms, legs, face, neck, torso, penis etc. Application may be accomplished in any convenient manner and may be dictated at least in part by the form of the topical formulation, i.e., whether the topical formulation is present as a cream, lotion, ointment, gel, solution, foam, powder, spray etc., the container holding the formulation, etc. For example, the topical formulation may be sprayed onto a skin surface, rolled-onto a skin surface, or a subject may apply the topical formulation using a swab, finger, and the like. Other protocols for applying a topical formulation are known to those of skill in the art and may be employed in accordance with the subject methods.

[0059] Topical agents available for the treatment of psoriasis include emollients, keratolytics, coal tar, topical corticosteroids, dithranol (anthralin), topical vitamin D3 analogues and tazarotene.

[0060] Topical agents include benzoyl peroxide (BP), and BP 5%/erythromycin 3%

(BENZAMYCIN™). BP is often tried first for both non-inflammatory and mild inflammatory acne, but can produce erythema and peeling, and improvement takes 1-2 months. Topical antibiotics include clindamycin and erythromycin, with improvements taking 1-2 months.

Azelaic acid 20% (AZELEX™) has mild antibacterial effects. Further, systemic antibiotics include tetracycline and its analogs (doxycycline and minocycline), which are used in low doses for years or until the end of the acne prone years. However, bacterial resistance may occur, such that the antibiotics need to be changed or substituted with BP.

[0061] Further additives which the preparations of the permeation enhancers as disclosed may contain are the hair- and scalp-care substances and medical active ingredients customary in cosmetics, such as, for example, antidandruff agents, products having an antiseborrheic effect, substances having a keratolytic and keratoplastic effect such as salicylic acid, al!antoin, sulfur products, urea, ceramides, antimicrobials, vitamins, plant extracts or organ extracts, hormones, corticoids, hyperemic agents such as nicotinic acid and derivatives thereof, organic acids such as citric acid, orotic acid, lipoic acid, amino acids, polyethoxylated fatty alcohols, fatty acids, sorbitan fatty acid esters, alkyl phosphates and oils, e.g., fatty acid esters, and in addition preservatives, colors,and perfum e oils. [0062] Further preparations include an amebicide, a broad spectrum antibiotic, a medium spectrum antibiotic, a fungal medication, a monobactam, an anti-viral agent, erythromycin, penicillin, cephalosporin, and a combination thereof.

[0063] Further, topical skin care agents may include herbal medicines and combinations thereof may be included in the invention. The herbal medicine may treat more than one condition. Suitable herbal medicines include, but are not limited to, antifungal agents such as Centaurea Cyanus, Kalmia Latifolia and the like; antihistamine agents such as Mandragora Vernalis, Tanacetum Parthenium and the like; anti- infective agents such as Acacia Catechu, Aloe Barbadensis, Convallaria Majalis, Echinacea, Eucalyptus, Mentha Piperita, Rosa Canina, Sassafras Albidum, and the like; anti-inflammatory agents such as Fragaria Vesca, Matricaria Chamomilla, Salvia Officinalis and the like; antipruritic agents such as Anagallis Arvensis, Oenothera Biennis, Verbena Officinalis and the like; skin and mucous membrane agents such as Aesculus Hippocastanum, Avena Sativa, Baptista Tinctoria, Digitalis Purpurea, Hamamelis Virginiana, Helianthus Annuus, Hypericum Perforatum, Lawsonia Inermis, Nerium Odoratum and the like; and wound care agents such as Calendula Officinalis, Cinnamomum Verum, Coffea Arabica, Cola Acuminata, Solidago Species and the like.

[0064] Other compositions may include ( 1 ) anti-microbial compounds that contain silver, such as silver sulfadiazine. This compound is very widely used for treating burn wounds, since it has broad-spectrum anti-microbial activity, and does not pose a severe risk of an undesired allergic or immune response; (2) other types of antibiotics, such as a combination of three topical antibiotics (neomycin, polymyxin, and bacitracin) that are widely used in ointments that are commonly called "triple antibiotic" or "NEOSPORIN"™ ointments; (3) hormones, such as hormones that stimulate the growth or division of fibroblasts or other types of skin cells, follicular cells, nerve cells, etc.; (4) anti-inflammatory compounds, such as hydrocortisone and various salts and derivatives thereof, other similar drugs derived from steroids, and various "nonsteroidal anti-inflammatory drugs" (NSAID's, such as ibuprofen and naproxen) which can help reduce pain and/or inflammation; (5) topical pain-reducing agents (such as benzocaine, lidocaine, etc.) that can reduce pain, itching, and/or other unwanted neuronal activity, by mechanisms such as stimulating inhibitory neuronal receptors that are normally triggered by gamma-amino-butyric acid (GABA) or other neurotransmitters that inhibit, rather than stimulate, nerve cell activation; (6) drugs which have anti-nausea, anti-convulsant, or other desired effects, such as scopolamine or other agents that can help reduce unwanted neuronal activity by blocking or reducing neuronal stimulation caused by excitatory neurotransmitters such as acetyl-choline, glutamate, or aspartate; (7) drugs which can reduce cravings, such as cravings for nicotine, alcohol, or other substances that can impair recovery by a seriously injured patient; (8) zinc compounds that help promote wound healing (see, e.g., M.S. Agren, "Studies on zinc in wound healing," Acta Dermato- Venereology, Supplement 154: 1 -36 (1990) and U.S. Pat. No. 4,847,083 (Clark 1989), each of which is incorporated by reference in its entirety) and which can reduce the risk of viral infection (e.g., Y. J. Gordon et al, "Irreversible inhibition of herpes simplex virus replication in BSC-1 cells by zinc ions," Antimicrob. Agents Chemother. 8: 377-380 (1975), and U.S. Pat. No. 5,545,673 (Kelly 1996), each of which is incorporated by reference in its entirety); and, (9) drugs that can help modify and control the rate of connective tissue growth and/or blood vessel growth in badly burned or otherwise damaged tissue. In some situations, growth-accelerating drugs are used to accelerate the wound-closure process, even at the risk of increased fibrotic scar tissue, in locations where the scars will not be highly visible, or when a massive burn or chemical wound or similar injury poses a severe threat of death. In other situations, such as facial or hand wounds where cosmetic appearance and skin flexibility are very important, other types of drugs might be used to minimize the creation of fibrotic scar tissue.

[0065] Further preparations are envisaged, such as ALTABAX (retapamulin) for the treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes; AMEVIVE (alefacept) for moderate to severe chronic plaque psoriasis; AVITA Gel Treatment for acne. BACTROBAN Cream, treatment for secondarily infected traumatic skin lesions. BENZAMYCIN (erythromycin 3%-benzoyl peroxide 5% topical gel) for the topical treatment of acne vulgaris; BOTOX

Cosmetic (botulinum toxin type A) for the temporary improvement in the appearance of glabellar lines (brow furrow); Cefazolin and Dextrose USP for respiratory tract infections;

CHLORAPREP (chlorhexidine gluconate) for use as a patient preoperative skin preparation; Clindamycin phosphate topical gel; for once a day treatment of acne vulgaris; Clindamycin Phosphate Topical Solution USP 1% Generic equivalent of CLEOCIN Topical Solution 1% Condylox Gel 0.5% (pokofilox), treatment for external genital and perianal warts; Dermagraft- TC Treatment for partial-thickness and severe burns; Desonate (desonide) for the treatment of atopic dermatitis; DIFFERJN (adapalene gel) Gel, 0.1% for treatment for acne; DYNABAC treatment for acute bacterial exacerbations (chronic bronchitis and skin infections); ELIDEL Topical cream for the treatment of atopic dermatitis; ERIVEDGE (vismodegib) for the treatment of basal cell carcinoma; ESTROSTEP (norethindrone acetate and ethinyl estradiol) for the treatment of moderate acne vulgaris; EXTINA (ketoconazole) for the treatment of seborrheic dermatitis; FINACEA (azelaic acid) Gel, 15% Gel formulation for the treatment of rosacea; FINEVI Topical cream for the treatment of mild to moderate inflammatory acne vulgaris; FIRAZYR (icatibant) for the treatment of acute attacks of hereditary angioedema; GRALISE (gabapentin) for the treatment of postherpetic neuralgia; HORIZANT (gabapentin enacarbil) for the treatment of postherpetic neuralgia; IAMIN Gel wound dressing; Iontocaine needle- free anesthetic; 1VYBLOCK Treatment for poison ivy, poison oak, and poison sumac; KLARON (sodium sulfacet amide lotion ) Lotion, 10% treatment for adult acne; LAMISIL (terbinafine hydrochloride) DERMAGEL, 1 % treatment for tinea pedis (athlete's foot); LAMISIL (terbinafine hydrochloride) Solution, 1% for the treatment of athlete's foot, jock itch and ringworm;

LAMISIL Solution, 1% topical treatment for tinea (pityriasis) versicolor, althete's foot, jock itch, and ringworm; LAVIV (azfieel-T). For the improvement of nasolabial fold wrinkles in adults; LUSTRA treatment for ultraviolet- induced skin discolorations; LUXIQ (betamethasone valerate) Foam treatment for dermatoses of scalp; MENTAX (1% butenafine HCI cream) Treatment for athlete's foot; MENTAX (1 % butenafine HCl cream) treatment for tinea corporis (ringworm) and tinea cruris (groin fungus); MENTAX (1 % butenafine HCl cream) treatment for athlete's foot; MET OLOTION Treatment of inflammatory papules and pustules of rosacea; MINOXIDIL Topical Solution 2% for Women Generic equivalent of ROGAINE; NORITATE treatment for rosacea; OMNICEF treatment against various bacterias; PICATO (ingenol mebutate) gel for the treatment of actinic keratosis; PROPECIA treatment for male baldness; PROTOPIC (tacrolimus) ointment for short-term and intermittent long-term treatment of moderate to severe atopic dermatitis; REGRANEX (becaplermin) Gel treatment for diabetic foot ulcers; RENOVA (tretinoin emollient cream) treatment for facial wrinkles, brown spots, and surface roughness associated with chronic sun exposure; RETIN-A MICRO (tretinoin gel) microsphere, 0.1% treatment for acne; Skin Exposure Reduction Paste Against Chemical Warfare Agents

(SERPACWA) to reduce absorption of chemical warfare agents through the skin; SKLICE (ivermectin) lotion for the treatment of head lice; STELARA (ustekinumab) for the treatment of plaque psoriasis; Sulfamylon treatment used to control bacterial infections on excised burn wounds; SYLATRON (peginterferon alfa-2b) for the treatment of melanoma; TAZORAC topical gel treatment for Psoriasis, Acne Vulgaris; TEFLARO (ceftaroline fosamil) for the treatment of bacterial skin infections and bacterial pneumonia; Thalomid Treatment for moderate to severe erythema nodosum leprosum (ENL); TYGACIL (tigecycline) for the treatment of complicated skin and skin structure and intra-abdominal infections and bacterial pneumonia; VELTIN (clindamycin phosphate and tretinoin) for the treatment of acne vulgaris; VERDESO (desonide) for the treatment of atopic dermatitis; VIBATIV (telavancin) for the treatment of complicated skin and skin structure infections; XYZAL (levocetirizine di hydrochloride) for the treatment of seasonal and perennial allergic rhinitis and urticaria; YERVOY (ipilimumab) for the treatment of metastatic melanoma; ZELBORAF (vemurafenib) for the treatment of BRAF + melanoma; and ZYCLARA (imiquimod) for the treatment of actinic keratoses of the face and scalp.

[0066] The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g.,a compound and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g.,a co mpound and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g.,t he administration of three or more active ingredients.

[0067] The term "pharmaceutical composition" refers to a mixture of a compound with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

Pharmaceutical Composition/Formulation

[0068] In embodiments, the compounds described herein are formulated into pharmaceutical compositions. In embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;

Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated by reference in its entirety.

[0069] Provided herein are pharmaceutical compositions comprising a permeation enhancer as disclosed, a compound and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In embodiments, the compounds described are administered as pharmaceutical compositions in which a compound is mixed with other active ingredients, as in combination therapy.

Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In embodiments, the pharmaceutical compositions include one or more active compounds.

[0070] In embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. In embodiments, the mammal is a human. In embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0071] In embodiments, a compound is formulated in an aqueous solution. In embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In specific embodiments, solutions include physiologically compatible buffers and/or excipients.

[0072] In embodiments, the compounds are administered topically. The compounds described herein are formulated into a variety of topically administrate compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0073] In other embodiments, the compounds are formulated for transdermal administration. In embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In embodiments, the transdermal delivery of a compound is accomplished by means of iontophoretic patches and the like. In embodiments, transdermal patches provide controlled delivery of a compound. In embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In embodiments, permeation enhancers as disclosed are used to increase absorption. Permeation enhancers may be used in conjunction with absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in embodiments, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and

predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0074] Transdermal formulations described herein may be administered using a variety of devices which have been described in the art. For example, such devices include, but are not limited to, U.S. Pat. Nos. 3,598, 122, 3,598,123, 3,710,795, 3,731 ,683, 3,742,951 , 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031 ,894, 4,060,084, 4,069,307, 4,077,407, 4,201,21 1, 4,230, 105, 4,292,299, 4,292,303, 5,336, 168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946, 144, each of which is incorporated by reference herein in its entirety,

[0075] The transdermal dosage forms described herein may incorporate certain

pharmaceutically acceptable excipients which are conventional in the art. In embodiments, the transdermal formulations described herein may include at least three components: ( 1) a formulation of a compound; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations may include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In embodiments, the transdermal formulations may include a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In embodiments, the transdermal formulations described herein maintain a saturated or supersaturated state to promote diffusion into the skin.

[0076] Pharmaceutical compositions also, optionally include solubilizing agents to aid in the solubility of a compound. The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example, polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0077] Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0078] Additionally, pharmaceutical compositions optionally include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0079] Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0080] Still other pharmaceutical compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxy ethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0081] Still other pharmaceutical compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0082] In certain embodiments, pharmaceutical aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0083] In embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers herein. In embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0084] In embodiments, the formulations described herein include one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (h) about 0.1.% to about 1 % w/v methionine, (c) about 0.1% to about 2% w/v monothioglycero!, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001 % to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

Combination Treatments

[0085] In general, the compositions described herein and, in embodiments where

combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and in some embodiments, because of different physical and chemical characteristics; are administered by different routes. In embodiments, the initial administration is made according to established protocols, and then, based upon the observed effects, the dosage, modes of administration and times of administration is modified by the skilled clinician.

[0086] It is understood that in some embodiments, the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors. These factors include the disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, in other embodiments, the dosage regimen actually employed varies widely and therefore deviates from the dosage regimens set forth herein.

[0087] In embodiments, compositions comprising combinations of compounds with anticancer agents are intended to be covered. In some embodiments, examples of anti-cancer agents include, but are not limited to, the following: cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate, other topoisomerase inhibitors (e.g., irinotecan, topotecan, camptothecin, etc.) or any derivative related agent of the foregoing. In other embodiments, examples of anti-cancer agents include sulfonated precursors of thymidine and 4- thiothymidine or derivatives thereof e.g. USA Patent No. 8,410,125 (incorporated by reference in its entirety).The combinations of compounds and other anti-cancer agents described herein encompass additional therapies and treatment regimens with other agents in some embodiments. Such additional therapies and treatment regimens can include another anti-cancer therapy in some embodiments. Alternatively, in other embodiments, additional therapies and treatment regimens include other agents used to treat adjunct conditions associated with the cancer or a side effect from such agent in the combination therapy. In further embodiments, adjuvants or enhancers are administered with a combination therapy described herein. [0088] Additional anti-cancer therapies include chemotherapy, radiotherapy, immunotherapy, gene therapy, surgery or other therapies that are capable of negatively affecting cancer in a patient, such as for example, by killing cancer cells, inducing apoptosis in cancer cells, reducing the growth rate of cancer cells, reducing the incidence or number of metastases, reducing tumor size, inhibiting tumor growth, reducing the blood supply to a tumor or cancer cells, promoting an immune response against cancer cells or a tumor, preventing or inhibiting the progression of cancer, or increasing the lifespan of a subject with cancer.

[0089] As used herein, the term "pharmaceutically acceptable carrier" means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject.

[0090] A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0091] The active ingredient combinations of the invention can be provided as components of a pharmaceutical pack. The two drugs can be formulated together or separately and in individual dosage amounts.

[0092] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.0001 % and 100% (w/w) active ingredient.

[0093] Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.

[0094] As used herein, an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. [0095] Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

[0096] Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose,

hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0097] Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0098] Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

[0099] A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

[00100] Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e. such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

[00101] Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 0.0001 % to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. Low boiling propellants generally include liquid propellants having a boiling point of below 65° F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.0001 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).

[00102] As used herein, "additional ingredients" include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other "additional ingredients" which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., which is incorporated herein by reference.

[00103] The acti ve ingredient combinations of the invention may be provided as components of a pharmaceutical pack, referred to herein as a "kit". The two components (e.g., a drug and permeation enhancer) may be formulated together or separately and in individual dosage amounts.

Dosage

[00104] Dosage levels of the primary drug useful for alleviating the recurrent medical affliction include any therapeutically effective dosages of the primary drugs approved by the FDA.

[00105] The following examples are intended to illustrate but not limit the invention. EXAMPLES

Example 1. Transdermal penetration study to assess the extent of transdermal penetration of drugs metothrexae and metformin across human skin using two transdermal penetration enhancers: MFC and the delivery system Vx.

[00106] Materials: human skin was obtained from abdominal reduction surgery courtesy of Prof Harry Navsaria, ICMS, Queen Mary University. Franz cells were obtained from Permegear Inc. All common lab chemicals ordered from Sigma.

[00107] Procedure: Skin samples were placed at the interface of the Franz cells which had been filled with PBS. In the upper chamber of the cells, three solutions were introduced as follows: Control: 80% PBS, 10% Ethanol, 10% drugs (1 mg/mL).M FC: 50% MFC, 10% Ethanol, 30% PBS, 10% drugs.V: 80 % Vx (N-alkyl valerolactam of Formula I, n = 14), 10% Ethanol, 10% Drugs. Samples were taken from the lower chamber at t=0, 4, 6 and 24 hours into the experiment. Absorbances readings were taken at 280 nm (methotrexate) and 300 nm (metformin). Results of the studies are shown in Figures 1 and 2. As can be seen in the Figures, drug penetration afforded by the Vx formulation is far greater than that of the MFC system or control.

[00108] Example 2. Characterization of the stability of N-laurel valerolactam by an accelerated aging test.

[00109] N-alkyl valerolactam of Formula I, n =14 was stored at 37 °C and 50% RH (relative humidity) in an incubator for 29 weeks. Aliquots were taken every week and diluted in ethanol at a 1% N-alkyl valerolactam/99% EtOH. Absorbance of the diluted aliquots was measured at 310 nm with a Nanodrop spectrometer. The absorbance of the diluted aliquots was used to determine the % residual N-alkyl valerolactam of Formula I, n =14. The results are shown in Table 1 and Figure 3. The results show that the valerolactam is a stable compound comprising approximately 95% of the molecule after a 29 week period. Table 1

Week A (310) % residual

0 0.572 100.00

1 0.573 100.17

2 0.571 99.83

3 0.574 100.35

4 0.572 100.00

5 0.575 100.52

6 0.573 100.17

7 0.572 100.00

8 0.572 100.00

9 0.565 98.78

10 0.566 98.95

1 1 0.569 99.48

12 0.565 98.78

13 0.567 99.13

14 0.557 97.38

15 0.565 98.78

16 0.56 97.90

17 0.563 98.43

18 0.556 97.20

19 0.561 98.08

20 0.56 97.90

21 0.552 96.50

22 0.555 97.03

23 0.548 95.80

24 0.548 95.80

25 0.548 95.80

26 0.548 95.80

27 0.55 96.15

28 0.55 96.15

29 0.546 95.45

[00110] Example 3. Cell viability assay of alkylvalerolactam delivery system. CA-1 cells or N-Tert Keratinocytes grown in normal growth medium were incubated with various concentrations (0.4 to 2% w/v) of N-alkyl valerolactam of Formula I, n =14. The cells were then incubated for 24 hours at 37 °C with 50% RH and 10% C0 ₂ . The normal growth medium was then removed and replaced with normal growth medium containing 5 mM MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The cells were incubated for a further 3 hours at 37 °C with 50% RH and 10% C0 ₂ . The formazan dye produced was then dissolved in a solution of DMSO (dimethylsulfoxide) and the absorbance measured at 595 nm was taken as a measure of cell viability. Control samples contained no alkylvalerolactam. The assay results for the cell viability of CA-1 cells are shown in Table 2 and Figure 4 and for N-Tert Keratinocytes in Table 3 and Figure 5.

Table 2

Sample Reading 1 Reading 2 Reading 3 Average Stdev

Control 0.625 0.64 0.63 0.632 0.008

0.40% 0.632 0.634 0.618 0.628 0.009

0.80% 0.601 0.617 0.629 0.616 0.014

1.20% 0.606 0.619 0.623 0.616 0.009

1.60% 0.636 0.62 0.635 0.630 0.009

2% 0.633 0.63 0.637 0.633 0.004

Table 3

Sample Reading 1 Reading 2 Reading 3 Average Stdev

Control 0.324 0.331 0.335 0.330 0.006

0.40% 0.327 0.331 0.34 0.333 0.007

0.80% 0.33 0.337 0.332 0.333 0.004

1.20% 0.325 0.339 0.345 0.336 0.010

1.60% 0.345 0.331 0.334 0.337 0.007

2% 0.338 0.328 0.342 0.336 0.007

[00111] The MTT cell proliferation assay is a colorimetric assay routinely used in the art to measure the activity of cellular enzymes that reduce the tetrazolium dye, MTT, to insoluble formazan, giving a purple color (see e.g. J Immunol Methods. 1983 Dec 16;65(l-2):55-63;

incorporated by reference in its entirety). The assay measures cytotoxcity and provides a reflection of the viable cells. The results in Tables 2-3 and Figures 4-5 show that N-alkyl valerolactam was not toxic.

[00112] Example 4. Cell toxicity assay of alkylvalerolactam delivery system. N-Tert human Keratinocytes were incubated in DMEM (Dulbecco's Modified Eagle's Medium) in the presence of various concentrations (0.1 to 60% w/v) of N-alkyl valerolactam of Formula I, n =14,fo r 48 hours at 37 °C under optimal RH and CO2 conditions following which they were assayed for cell viability using the MTT assay. N-alkyl valerolactam of Formula I, n =14 starts to be toxic at about 20% concentration (w/v) with complete killing of the cells at about 60%. About 0.1% w/v concentration of N-alkyl valerolactam of Formula I, n =14,w as found to be optimal for cell growth.

[00113] Transdermal penetration tests and the toxicity tests indicate that valerolactam derivative of instant invention is an effective transdermal enhancer of solute transport and not toxic. Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

[00114] All references disclosed herein are incorporated by reference in their entireties.