TOPICAL ANALGESIC GEL FORMULATIONS

AND METHODS OF USING THEM

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/517,237, filed on June 9, 2017, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This disclosure relates topical analgesic formulations suitable for transdermal use, and to methods of making these formulations.

BACKGROUND OF THE INVENTION

[0003] Disclosed is a topical, transdermal pain and swelling treatment that can be applied directly to injured or sore body parts and deliver appropriate dosing levels of drugs equivalent to those taken orally. Advantageously, total-body dosing for localized pain is no longer necessary due to the effective transdermal drug delivery mechanism of the inventive formulation.

Accordingly, the topical formulations described herein allow for the use of ibuprofen by people with cardiac problems or those with sensitive stomachs, for whom ibuprofen is currently off limits. Other analgesic compounds in addition to or instead of ibuprofen can also be used.

[0004] Previous OTC (over the counter) ibuprofen creams were sold in concentrations of 5- 12%, where dosing could reach as high as 200 mg when locally applied. This high concentration dosage is still common in the prescription drug levels, but has been withdrawn from OTC sale by the FDA. The high concentrations of drug are believed to be necessary to force the drug into the skin. It has been unexpectedly discovered that low concentrations (~ 2%) of analgesic agents such as ibuprofen can be used with the claimed formulation. The combination of chitosan and DMSO is believed to actively transport the ibuprofen through the skin without the need for excessively high dosing concentrations.

BRIEF SUMMARY OF THE INVENTION

[0005] A topical analgesic gel formulation is provided. The analgesic gel formulation comprises an effective amount of an analgesic agent, at least one skin-penetration enhancer, at least one non-aqueous solvent, at least one keratolytic agent, and water.

[0006] A method of treating pain in a mammal is provided. The method comprises the step of applying an effective amount of an analgesic gel topically to mammalian tissue, wherein the analgesic gel comprises an effective amount of an analgesic agent, at least one skin-penetration enhancer, at least one non-aqueous solvent, at least one keratolytic agent, and water.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0007] As used herein, the phrase "effective amount of analgesic agent" refers to a quantity of one or more pharmaceutically active ingredients, as set forth below, capable of producing the desired level of pain relief. Generally, the desired level of pain relief will be such that the individual using the inventive composition will no longer be bothered by the pain he or she felt prior to the administration of the inventive composition.

General

[0008] The compositions of the invention are intended for topical, noninvasive, application to the skin, particularly to the region where the analgesic agent is intended to exert its

pharmacological activity, usually to a region of inflammation, injury or pain to the muscles or joints, or other form of cutaneous disorders or disruptions characterized by skin inflammation and/or hyperproliferative activity in the epidermis.

[0009] In one embodiment, a topical analgesic gel formulation is provided. The analgesic gel formulation comprises an effective amount of an analgesic agent, at least one skin-penetration enhancer, at least one non-aqueous solvent, at least one keratolytic agent, and water. In one embodiment, the water is de-ionized water. In one embodiment, the analgesic agent is a nonsteroidal anti-inflammatory drug.

[0010] Examples of non-steroidal anti-inflammatory drugs (NSAIDs) which can be advantageously administered by the topical formulations of this invention include heteroaryl acetic acids, such as, for example, tolmetin, diclofenac, ketorolac; arylpropionic acids, such as, for example, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin; anthranilic acids (fenamates), such as, for example, mefenamic acid, meclofenamic acid, fhilenamic acid; enolic acids, such as, for example, oxicams (e.g., piroxicam, tenoxicam), pyrazolidinediones (e.g., phenylbutazone, oxyphenthatrazone); alkanones, such as, for example, nabumetone.

However, any approved NSAIDs, such as those listed in the current edition of The Merck Index or the FDA Orange Book, can be used. The aforementioned non-steroidal anti-inflammatory analgesics can be used alone or in combinations of two or more.

[0011] Any of the aforementioned NSAIDs can also be administered as pharmacologically acceptable neutral salts. The formulations may be made substantially neutral by addition of a pH modifying agent (base) in an amount to provide a pH in the range of from 6.0 to 8.0, preferably from 6.5 to 7.5, especially preferably from 6.8 to 7.4, such as 7.0. Any of the well-known and pharmacologically safe inorganic or organic basic compounds can be used for this purpose and examples include inorganic salts, such as the sodium or other alkali or alkaline earth metal salts such as hydroxides, e.g., sodium hydroxide or potassium hydroxide; ammonium salt; or organic salt, especially amine salt, such as, for example, diethylamine; diethanolamine, triethanolamine, diisopropanolamine, N-methylglucamine, ethanolamine, isopropylamine, tetrahydroxypropyl ethylene diamine methylamine, ethylamine, propylamine, and the like.

[0012] For any particular formulation, the NSAID and other ingredients can be selected to achieve the desired drug delivery profile and the amount of penetration desired. The optimum pH can be determined and will depend on, for example, the nature of the NSAID, the base, and degree of flux required.

[0013] In one embodiment, the analgesic agent may be ibuprofen, naproxen, flurbiprofen, ketoprofen, or fenoprofen, or pharmaceutically acceptable salts thereof. In another embodiment, the analgesic agent may be ibuprofen or a pharmaceutically acceptable salt thereof. Any physiologically compatible base capable of forming a neutral salt with ibuprofen can be used.

[0014] In one embodiment, the ibuprofen or its pharmaceutically acceptable salt may be present in an amount ranging from 1 to 5 % by weight. In another embodiment, the ibuprofen or its pharmaceutically acceptable salt may be present in an amount ranging from 1 to 2% by weight. In one embodiment, the effective amount of ibuprofen or its pharmaceutically acceptable salt may range from 5 to 10 mg.

[0015] In some embodiments, the inventive compositions may be formulated as gels.

However, other forms, such as, for example, lotions, creams, mousses, aerosols, ointments, lubricants, etc., can be used so long as when applied to the affected area of the skin the formulation will stay in place, i.e., without run-off, for sufficient time, to permit an individual to spread and retain the composition over and on the affected area.

[0016] There are no particular restrictions on poultice bases used for a poultice according to the invention, and any commonly used one can be selected. As examples of components to be contained in such poultice bases there may be mentioned thickening agents, synthetic water- soluble polymers (sodium polyacrylate, polyacrylic acid, polyvinyl alcohol,

polyvinylpyrrolidone, polyethylene oxide, polyvinyl methacrylate, etc.), natural substances (gum arabic, starch, gelatin, methyl cellulose, hydroxypropyl cellulose, alginic acid, sodium alginate, ammonium alginate, carboxymethylcellulose sodium, etc.), humectants (urea, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), fillers (kaolin, zinc oxide, talc, titanium, bentonite, epoxy resins), organic acids (citric acid, tartaric acid, maleic acid, maleic anhydride, succimc acid, etc.), calcium, magnesium, aluminum, etc. water, solubilizers (propylene carbonate, crotamiton, diisopropyl adipate, etc.), tackifiers (rosins, ester gums, polybutene, polyacrylic esters, etc.), rash-preventing agents (diphenhydranune hydrochloride,

chlorpheniramine maleate, glycyrrhizinic acid, dexamethasone, betamethasone, fluocinolone acetonide, etc.) and other additives (salicylic acid, methyl salicylate, glycol salicylate, 1 -menthol, camphor, nonylic vanillylamide, capsicum extract, peppermint oil, Azone ^R , etc.). A poultice according to the invention can be obtained by mixing the aforementioned analgesic agent with a poultice base composed of a mixture of various components selected from the above.

[0017] There are no particular restrictions on plaster bases used for a plaster according to the invention, and any commonly used one can be selected. As examples of components to be contained in such plaster bases there may be mentioned polymer bases, acrylic-based

compositions which are copolymers with vinyl monomers (methacrylic esters, acrylonitrile, vinyl acetate, vinyl propionate, etc.), silicone resins, polyisoprene rubber, polyisobutylene rubber, natural rubber, acrylic rubber, styrene-butadiene-styrene block copolymer, styrene-isoprene- styrene block copolymer; etc., fats/oils or higher fatty acids (almond oil, olive oil, camellia oil, apricot oil, peanut oil, olein oil, liquid paraffin, polybutene, etc.), tackifiers (rosins, rosin- modified maleic acid, hydrogenated rosin esters, etc.), fatty acid metal salts (zinc undecylenate, zinc stearate, calcium stearate, aluminum stearate, magnesium stearate, sodium stearate, zinc palmitate, zinc myristate, magnesium myristate, sodium laurate, zinc laurate), rash-preventing agents, and other additives (salicylic acid, methyl salicylate, glycol salicylate, dl-camphor, 1- menthol, nonylic vanillylamide, capsicum tincture, peppermint oil, crotamiton, Azone ^R , etc.). A plaster according to the invention can be obtained by mixing the aforementioned analgesic agent with a plaster base comprising a mixture of various components selected from the above.

[0018] There are no particular restrictions on ointment bases used for an ointment according to the invention, and any commonly used one, can be selected. As examples of components to be contained in such ointment bases there may be mentioned higher fatty acids or their esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic esters, myristic esters, palmitic esters, diethyl sebacate, hexyl laurate, cetyl isooctanate, etc.), waxes (spermaceti, beeswax, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, methylphenylpolysiloxane, glycol methylpolysiloxane, silicone glycol polymers, etc.), hydrocarbons (hydrophilic vaseline, white vaseline, purified lanolin, liquid paraffin, etc.), water, absorption enhancers (propylene carbonate, diisopropyl adipate, crotamiton, Azone ^R , etc.), humectants (glycerin, propylene glycol, butylene glycol, sorbitol, etc.), rash-preventing agents, and other additives (salicylic acid, methyl salicylate, glycol salicylate, 1 -menthol, camphor, peppermint oil etc.). An ointment according to the invention can be obtained by mixing the aforementioned analgesic agent with an ointment base comprising a mixture of various components selected from the above.

[0019] There are no particular restrictions on cream bases used for a cream according to the invention, and any commonly used one may be selected. As examples of components to be contained in such cream bases there may be mentioned higher fatty acid esters (myristic esters, palmitic esters, diethyl sebacate, hexyl laurate, cetyl isooctanate, etc.), lower alcohols (ethanol, isopropyl alcohol, etc.), carbohydratres (liquid paraffin, squalane, etc.), polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, 2- octyldodecanol, etc.), emulsifiers (polyoxyethylene alltyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, etc.), preservatives (paraoxybenzoic acid esters, etc.), absorption enhancers (propylene carbonate, diethyl sebacate, diisopropyl adipate, crotamiton, Azone ^R , etc.), rash-preventing agents, and other additives (salicylic acid, methyl salicylate, glycol salicylate, 1- menthol, camphor, peppermint oil, etc.). A cream according to the invention can be obtained by mixing the aforementioned analgesic agent with a cream base comprising a mixture of various components selected from the above. Also, a gel cream (a dosage form having properties intermediate between a cream and a gel) according to the invention can be obtained by adding a gelling agent (carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose, etc.) to the aforementioned cream, and further adjusting the pH to 4-8 (preferably 5-6.5) by addition of a neutralizing agent (diisopropylalcohol amines, triethanolamine, sodium hydroxide, etc.).

[0020] There are no particular restrictions on liniment bases used for a liniment according to the invention, and any commonly used one may be selected. As examples of such liniment bases there may be mentioned mixtures composed of 10-70 parts by weight of an alcohol (a

monohydric alcohol (ethanol, propanol, isopropyl alcohol, etc.), polyhydric alcohol

(polyethylene glycol, propylene glycol, butylene glycol, etc.), or the like), up to 55 parts by weight of water, up to 60 parts by weight of a fatty acid ester (an ester of adipic acid, sebacic acid, myristic acid, etc.) and up to 10 parts by weight of a surfactant (poly oxy ethylene alkyl ether). By adding 0.1-10 parts by weight of the non-steroidal anti-inflammatory analgesic, 0.001- 0.2 part by weight of the alkyl ester of gallic acid and 0.01-10 parts by weight of the phenolic radical scavenger to such a liniment base, it is possible to obtain a liniment according to the invention. If necessary, for example, neutralizing agents (for pH adjustment), tackifiers (methyl cellulose, carboxyvinyl polymer, hydroxypropyl cellulose, etc.), rash-preventing agents, and other additives (salicylic acid, methyl salicylate, glycol salicylate, 1 -menthol, camphor;

peppermint oil, capsicum, extract, nonylic vanillylamide, crotamiton, Azone ^R , propylene carbonate, diisopropyl adipate, etc.) may also be added in the liniment of the invention.

[0021] The vehicle for the forms of the compositions of the invention can include glycols, e.g., propylene glycol, butylene glycol, hexylene glycol, etc. (except in the case of some embodiments as described herein), lower alcohols, e.g., ethanol, isopropanol, and, usually, water. A thickening or gelling agent can optionally be included to facilitate application of the formulation to the skin.

[0022] In some embodiments, a thickening agent such as hydroxypropyl cellulose, can be used. However, any other pharmaceutically acceptable thickening/gelling agent may be used. For example, other thickening agents include cellulosic ethers, polymeric thickening agents, e.g., acrylic acid polymers, Carbopol RTM, thickeners, etc., xanthan gum, guar gum, and the like, as well as inorganic thickeners/gelling agents. The amount of-the thickening agent can be selected to provide the desired product consistency or viscosity to allow for easy application to the skin but which will not be too watery or loose so that it will stay where applied. Generally, depending on its molecular weight, amounts of thickening agent up to about 5% w/w, such as, for example, from 0.1 to about 2% w/w, of the composition will provide the desired effect.

[0023] Other ingredients can be used in the inventive formulations for particular aesthetic and/or functional effects. For example, the formulations can optionally include one or more moisturizers for hydrating the skin and emollients for softening and smoothing the skin.

Glycerin is an example of such a suitable moisturizing additive. When present, the additive will usually be incorporated in an amount of up to about 5 percent by weight of the composition, for example, from about 0.1 to 5% w/w.

[0024] The transdermal formulation for external application of the invention can contain, in addition to the aforementioned anti-inflammatory analgesic, a base selected depending on the dosage form of the formulation. As dosage forms of the transdermal formulation for external application of the invention there may be mentioned patches (poultices, plasters and the like), gels, creams, ointments and liniments.

[0025] The transdermal formulation for external application of the invention can also contain an antioxidant and/or an ultraviolet absorbent. Preferred antioxidants include tocopherol and its ester derivatives, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid and the like.

Preferred ultraviolet absorbents include p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid-based compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like. The respective contents of such an antioxidant and such an ultraviolet absorbent are not particularly restricted, but are preferably 0-10% by weight and more preferably 0-5% by weight based on the total formulation.

[0026] In some embodiments one or more skin-penetration enhancers can be used. The skin- penetration enhancer is preferably non-toxic, non-irritating, and non-allergenic. A variety of skin-penetration enhancers can be used with the inventive formulation, including, but not limited to DMSO (dimethyl sulfoxide), Azone (l-dodecylazacycloheptan-2-one or laurocapran), chitosan, pyrrolidones (e.g. N-methyl-2-pyrrolidone), fatty acids (e.g. oleic acid, lauric acid, myristic acid, and capric acid), terpenes and terpenoids, oxazolidinones (e.g. 4-decyloxazolidin- 2-one), and urea.

[0027] In one embodiment, the skin-penetration enhancer comprises chitosan, DMSO, or combinations thereof. In one embodiment, the chitosan may be present in an amount ranging from 0.1 % to 10 % by weight. In one embodiment, the DMSO may be present in an amount of 0.1 % to 10 % by weight.

[0028] In one embodiment, the analgesic gel formulation comprises non-aqueous solvent. Preferred non-aqueous solvents include saturated and unsaturated C1-C5 alcohols and

polyalcohols. In one embodiment, the non-aqueous solvent comprises ethanol. In another embodiment, the non-aqueous solvent further comprises glycerol. In one embodiment, the glycerol may be present in an amount ranging from 0.1 % to 10 % by weight. In one

embodiment, the ethanol is present in an amount ranging from 35 % to 90 % by weight. In some embodiments, the non-aqueous solvent may be present in an amount ranging from 35 % to 90 % by weight.

[0029] In one embodiment, the analgesic gel formulation comprises one or more keratolytic agents. Keratolytic agents can soften the area of the skin to which they are applied. In some embodiments, the keratolytic agent comprises lactic acid, methyl salicylate, or combinations thereof. In one embodiment, the lactic acid is present in an amount ranging from 0.1 to 10 % by weight.

[0030] In some embodiments, the concentration of keratolytic agent may be proportional to the concentration of the skin-penetration enhancer in the formulation. In certain embodiments, the concentration of keratolytic agent may be essentially equivalent to the concentration of the skin- penetration enhancer in the formulation. For example, in some embodiments, the concentration of lactic acid may be essentially equivalent to the concentration of chitosan powder in the formulation.

[0031] In one embodiment, the ratio of the skin-penetration enhancer to the non-aqueous solvent is about 0.055 to 1. In one embodiment, the ratio of DMSO to ethanol is 0.055 to 1.

[0032] Also provided herein is a method of treating or reducing pain in a mammal. The method comprises applying an effective amount of an analgesic gel topically to mammalian tissue. The analgesic gel formulation comprises an effective amount of an analgesic agent, at least one skin-penetration enhancer, at least one non-aqueous solvent, at least one keratolytic agent, and water. In one embodiment, the water is de-ionized water.

[0033] In some embodiments, other forms of the formulation are suitable for use in this method. For example, dosage forms such as lotions, creams, mousses, aerosols, ointments, and lubricants can also be effectively used to treat or reduce pain in a mammal. [0034] Although the formulations described herein are typically applied to skin tissue, any tissue can be effectively treated with the inventive compositions provided that the tissue can be exposed to the inventive compositions for a time sufficient to deliver an effective therapeutic dose, and provided that no discomfort ensues from applying the composition to the tissue. In some embodiments, the tissue comprises human skin, mucous membranes, buccal tissue, or combinations thereof.

[0035] Any of the aforementioned analgesic agents can be used in the described method. In one embodiment, the analgesic agent comprises ibuprofen. In one embodiment, the effective amount of the analgesic gel has an average applied dosage of 5 to 10 mg of ibuprofen.

EXAMPLES

1. General Methods

[0036] Unless otherwise noted, all chemicals were obtained from commercial sources and used without further purification.

Example 1 : Analgesic Gel Formulation

[0037] Example 1 describes a typical inventive analgesic gel formulation. In one embodiment, two solutions are prepared according to the methods set forth below. Although specific amounts of reagents are used herein, the absolute amounts can be increased or decreased as necessary to produce the desired amount of analgesic gel.

[0038] Table 1 : Components of Analgesic Gel Formulation

Substance

Chitosan Powder, > 95% deacetylation

Lactic Acid, 85%, CAS# 50-21-5

Glycerol, 99%+, CAS# 56-81-5

Deionized H ₂ 0, CAS# 7732-18-5

Ethanol, 200 proof, CAS# 64-17-5

Dimethyl Sulfoxide, "DMSO", 99%, CAS# 67-68-5

Ibuprofen, USP grade, CAS# 15687-27-1

Methyl Salicylate, 99%, CAS# 119-36-8

Method of Preparing Solution 1 [0039] Chitosan powder (30 g), glycerol (100 g), and 840 g of de-ionized water were added sequentially into a 1 L glass bottle. The resulting solution was typically dispersed (not dissolved) due to settling of the chitosan powder. To the resulting dispersion, lactic acid (30 g) was added with stirring. Upon addition of the lactic acid, the solution became clear and form a thick, clear gel of 3 % chitosan.

Method of Preparing Solution 2

[0040] Ibuprofen powder (20 g), methyl salicylate (20 g), dimethyl sulfoxide (25 g), and absolute ethanol (455 mL) were added sequentially in to a 1 L glass bottle. The bottle was capped, and the contents vigorously shaken to produce a solution.

Method of Preparing the Analgesic Gel

[0041] Solution 1 (480 g of 3% chitosan gel) was added to solution 2. The mixture was shaken and mixed until the solution appearance changed from cloudy to totally clear, without any visible cloudy sections. A clear, gel with bubbles dispersed throughout resulted.

[0042] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Illustrative embodiments of suitable methods, products, and systems.

[0043] As used below, any reference to methods, compositions, or articles is understood as a reference to each of those methods, compositions, or articles disjunctively (e.g., "Illustrative embodiment 1-4 is understood as illustrative embodiment 1, 2, 3, or 4.").

[0044] Illustrative embodiment 1 is a topical analgesic gel formulation, comprising an effective amount of an analgesic agent, at least one skin-penetration enhancer, at least one nonaqueous solvent, at least one keratolytic agent, and water.

[0045] Illustrative embodiment 2 is the formulation of any preceding or subsequent illustrative embodiment, wherein the analgesic agent is ibuprofen. [0046] Illustrative embodiment 3 is the formulation of any preceding or subsequent illustrative embodiment, wherein the ibuprofen is present in an amount ranging from 1 to 5 % by weight.

[0047] Illustrative embodiment 4 is the formulation of any preceding or subsequent illustrative embodiment, wherein the ibuprofen is present in an amount ranging from 1 to 2% by weight.

[0048] Illustrative embodiment 5 is the formulation of any preceding or subsequent illustrative embodiment, wherein the effective amount of ibuprofen ranges from 5 to 10 mg.

[0049] Illustrative embodiment 6 is the formulation of any preceding or subsequent illustrative embodiment, wherein the skin-penetration enhancer comprises chitosan, DMSO, or combinations thereof.

[0050] Illustrative embodiment 7 is the formulation of any preceding or subsequent illustrative embodiment, wherein the chitosan is present in an amount ranging from 0.1% to 10 % by weight.

[0051] Illustrative embodiment 8 is the formulation of any preceding or subsequent illustrative embodiment, wherein the DMSO is present in an amount of 0.1 % to 10 % by weight.

[0052] Illustrative embodiment 9 is the formulation of any preceding or subsequent illustrative embodiment, wherein the non-aqueous solvent comprises ethanol.

[0053] Illustrative embodiment 10 is the formulation of any preceding or subsequent illustrative embodiment, wherein the non-aqueous solvent further comprises glycerol.

[0054] Illustrative embodiment 11 is the formulation of any preceding or subsequent illustrative embodiment, wherein the glycerol is present in an amount ranging from 0.1 % to 10 % by weight.

[0055] Illustrative embodiment 12 is the formulation of any preceding or subsequent illustrative embodiment, wherein the ethanol is present in an amount ranging from 35 % to 90 % by weight.

[0056] Illustrative embodiment 13 is the formulation of any preceding or subsequent illustrative embodiment, wherein the keratolytic agent comprises lactic acid, methyl salicylate, or combinations thereof. [0057] Illustrative embodiment 14 is the formulation of any preceding or subsequent illustrative embodiment, wherein the lactic acid is present in an amount ranging from 0.1 % to 10 % by weight.

[0058] Illustrative embodiment 15 is the formulation of any preceding or subsequent illustrative embodiment, wherein the ratio of the skin-penetration enhancer to the non-aqueous solvent is about 0.055 to 1.

[0059] Illustrative embodiment 16 is the formulation of any preceding or subsequent illustrative embodiment, wherein the ratio DMSO to ethanol is about 0.055 to 1.

[0060] Illustrative embodiment 17 is the formulation of any preceding or subsequent illustrative embodiment, wherein the water is de-ionized water.

[0061] Illustrative embodiment 18 is a method of treating pain in a mammal, comprising applying an effective amount of an analgesic gel topically to mammalian tissue, wherein the analgesic gel comprises: an effective amount of an analgesic agent; at least one skin-penetration enhancer; at least one non-aqueous solvent; at least one keratolytic agent; and water.

[0062] Illustrative embodiment 19 is the method of any preceding or subsequent illustrative embodiment, wherein the tissue comprises human skin, mucous membranes, buccal tissue, or combinations thereof.

[0063] Illustrative embodiment 20 is the method of any preceding or subsequent illustrative embodiment, wherein the analgesic agent is ibuprofen.

[0064] Illustrative embodiment 21 is the method of any preceding or subsequent illustrative embodiment, wherein the effective amount of the analgesic gel has an average applied dosage of 5 to 10 mg of ibuprofen.

[0065] The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individual recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated or clearly contradicted by context.

[0066] Various embodiments of the invention have been described herein. It should be recognized that these embodiments are merely illustrative of the present invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated or otherwise clearly contradicted by context.