TOPICAL COMPOSITIONS FOR PAIN RELIEF, MANUFACTURE AND USE

Abstract

The present invention relates to TRPV1 selective agonist compositions including a capsaicinoid, a surfactant and an extended release agent, and to methods of manufacture and methods of providing pain relief as well as treating a variety of disorders with such compositions.

Claims

1. A composition comprising: i) 0.075-20% by weight of a capsaicinoid, ii) an extended release agent to slow the release of said capsaicinoid from said composition upon administration of said composition to a mammal, and iii) a surfactant, wherein said composition reduces or eliminates the burning and stinging created by said capsaicinoid upon topical administration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0080] The invention provides topical pharmaceutical compositions containing a therapeutically effective amount of a TRPV1 agonist, an extended release agent such as hyaluronic acid, a surfactant, and optionally, one or more penetration enhancers. The pharmaceutical composition is in a form suitable for topical administration to a mammal, typically human. The concentration of capsaicin is typically greater than 0.02 wt. % and less than 20 wt. % of the formulation.

[0081] In one embodiment, the composition comprises a capsaicinoid, hyaluronic acid, a surfactant and one or more penetration enhancers, where said surfactant and one or more penetration enhancers, taken together, constitute at least about 20% by wt., at least about 50% by wt., and up to 70% by wt. of the formulation.

[0082] Penetration enhancers can be an ether, or an alcohol. The formulation can contain one or more penetration enhancers selected from the group consisting of propylene glycol, ethyl alcohol, diethylene glycol monomethyl ether (DGME), and dimethyl sulfoxide, and can contain a nonionic surfactant e.g.s. PS-80 and polyoxy-40 Hydrogenated Castor Oil.

[0083] In an advantageous embodiment, a 0.4 wt. % hyaluronic acid water solution composed of a mixture containing 70 wt. % hyaluronic acid with a molecular weight 11 kDaltons and 30 wt. % hyaluronic acid with a molecular weight of 1,000 kDaltons was added to an alcohol mixture solution containing 0.25 wt. % to 10 wt. % capsaicin dissolved in solublizing and penetrating agents consisting of ethyl alcohol, propylene glycol and PS80 and/or polyoxy 40 hydrogenated castor oil (balance water). The mixture resulted in an optically crystal clear and moderately viscous solution. Adjusting the relative percentages of the hyaluronic acid molecular weights and surfactant composition resulted in variation of viscosity of the mixture.

[0084] Capsaicin formulations of 0.25% wt. % to 10 wt. % as described in the foregoing paragraphs was applied to knees, arms of several subjects via a 3.7 ml roller-ball vial (See Examples). The applied liquid film dried rapidly and minimal discomfort from burning and stinging was experienced. The formulations were relatively odor free.

[0085] Surprisingly, using the methods and compositions of the invention in humans results in less pain or discomfort than administration of conventional capsaicin formulations containing much lower concentrations of capsaicin. Example 2 below shows that, 0.25 wt. % capsaicin liquid formulation produced less burning and stinging than a common liquid capsaicin formulation containing 0.15 wt. % capsaicin.

[0086] The invention provides methods for administration of a TRPV1 agonist such as capsaicin, at a concentration of greater than 1% by wt., greater than 2%, greater than 5%, greater than 8%, or even greater than 10% by wt., without significant burning and stinging.

Compositions of the Invention

[0087] The invention relates to compositions, advantageously liquid aqueous solutions, comprising a TRPV1 selective agonist, and a surfactant capable of solubilizing said TRPV1 selective agonist, wherein said composition has an amount of TRPV1 selective agonist sufficient to decrease the density of functional nociceptive nerve fibers when said composition is applied topically, and said composition has an amount of a extended release agent and surfactant sufficient to eliminate or reduce the burning and/or stinging sensation or erythema created by the topical administration of the TRPV1 selective agonist. The liquid solution of the invention is advantageously an aqueous solution.

[0088] The TRPV1 selective agonists, hyaluronic acid or other extended release agents, surfactants, and excipients suitable for use in the pharmaceutical compositions of the present invention, are those which are pharmaceutically acceptable when applied to human skin, i.e. having acceptable toxicity at the levels used. All components of the formulations of the invention are USP grade. In a preferred embodiment of the invention, the compositions are manufactured in full compliance with GMP regulations of the U.S. FDA.

[0089] In one embodiment, the amount of TRPV1 selective agonist sufficient to decrease the density of functional nociceptive nerve fibers by at least 20%, or at least 50%, after topical application. In another embodiment the composition is 0.20-30% by weight of the TRPV1 selective agonist. The TRPV1 selective agonist can be a vanilloid, or in an advantageous embodiment, a capsaicinoid such as capsaicin.

[0090] When combined with ingredients disclosed herein, the amount of TRPV1 selective agonist, e.g. a capsaicinoid (e.g. trans-capsaicin) in the topical preparation can be from 0.075-30 wt. %, 0.2 wt. % to 30 wt. %, between 1 wt. % and 20 wt. %, e.g. 1 wt. %, 5 wt. %, 10 wt. %, and 20 wt. %.

[0091] The capsaicinoid is prepared for topical application by being incorporated into a pharmaceutically and physiologically acceptable aqueous vehicle for administration with diminished burning sensation upon application. The present invention is directed to the topical administration of capsaicin into discrete localized areas for the treatment and lessening of pain. Significant advantages result from the application of milligram quantities of capsaicin in order to produce therapeutic results through alteration of sensory nerve function (TRPV-1) in a limited area.

[0092] The invention relates to compositions, typically liquid solution pharmaceutical formulations, of a TRPV1 selective agonist (i.e. acting as specific agonist for TRPV1 as capsaicin does) such as capsaicinoid or a capsaicin analogue, primarily for the treatment of pain. The compositions include one or more extended release agents and a surfactant which reduce or eliminate the burning or stinging pain caused by administration of the TRPV1 selective agonist, thereby making the TRPV selective agonist formulation administration tolerable, including in long-term administration. The present application discloses the discovery that a TRPV1 selective agonist containing topical composition is very effective in treating pain in humans and causes significantly less burning pain at the site of the application, when administered with a extended release agent and a surfactant, than the same composition without such components.

[0093] The present invention provides the long lasting pain relief afforded by the TRPV1 selective agonist, e.g. capsaicin, without the same severity of concentration-dependent capsaicin side effects (e.g. stinging and burning) associated with prior art capsaicin formulations. The formulations can provide pain relief for periods of weeks to months dependent upon disease state and severity. Importantly, unlike anesthetics and opiods, the formulations of the present invention do not diminish or eliminate tactile sensation in the skin onto which the formulation has been topically applied.

[0094] The topical formulations, particularly for the treatment of pain, contain higher levels of TRPV1 selective agonists such as capsaicin, than normally used. The subject formulations do not have the discomfort and burning associated with capsaicin formulations of the prior art. The formulations of the TRPV1 selective agonist can include anti-inflammatory, and other additives that contribute to pain relief and the therapeutic treatment of pathological conditions such as arthritis pain, osteoarthritis, joint disorders, muscular pain, neuropathic pain, neck and back pain, shingles, cluster headaches and other disease or health-related conditions.

[0095] The subject invention relates to pharmaceutical topical compositions for delivery of significant quantities of a TRPV1 selective agonist compound such as capsaicin or related compounds via the skin. The components of the composition other than the TRPV1 selective agonist compound are included to reduce or eliminate the burning sensation associated with administration of the TRPV1 selective agonist compound as well as to enhance skin penetration of said TRPV1 selective agonist compound. The additional components are typically hyaluronic acid and a nonionic surfactant such as PS 80, which are generally accepted as safe.

[0096] It has been discovered that incorporation of a sufficient quantity of these ingredients into the capsaicin preparations forms a mixture for the topical treatment of pain such that the initial burning/stinging pain resulting from capsaicin is eliminated or ameliorated. Water concentrations are typically 30-60 wt % or 40-60 wt % of the preparations and can exceed 50% or even 55 wt % of the formulations.

[0097] It has been demonstrated that these ingredients reduce the burning/stinging sensation produced following topical application of a TRPV1 selective agonist compounds such as capsaicin. The compositions of the invention include appreciable quantities of hyaluronic acid and a surfactant, and optionally phenol which minimizes the burning/stinging sensation produced following topical application capsaicin. Components can also be added which enhance the penetration of the capsaicin into the viable layers of the skin and into subcutaneous tissues.

[0098] Accordingly, the present invention provides topical preparations comprising an amount of a TRPV1 selective agonist such as capsaicin effective in initial and long-term or repeated administration to reduce pain associated with certain cutaneous disorders and neural dysfunctions.

[0099] The components of the formulations of the invention are discussed below.

TRPV1 Selective Compounds including Capsaicinoids

[0100] For a general discussion of TRPV1 agonists including capsaicinoids of the invention, see US patent application 2008/0262091, and commonly owned U.S. Ser. No. 13/609,100, each of which is hereby incorporated by reference in its entirety. The term capsaicinoid as used herein includes capsaicin, a capsaicinoid other that capsaicin, i.e. dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, and nonivamide, and a mixture of capsaicin with one or more other capsaicinoids. The amount of drug used being based on a therapeutically dose to a dose of capsaicin. Capsaicin is practically insoluble in water, but freely soluble in ethyl alcohol, diethylene glycol monoethyl ether (DGME), dimethyl sulfoxide (DMSO) and propylene glycol. Capsaicin is a lipophilic white crystalline powder; melting point 60-65 degrees C.

[0101] Alternatively, a capsaicin analogue such as resiniferatoxin, can be administered in place of part or all of the capsaicinoid. The amount of analogue administered being the therapeutically equivalent dose of capsaicin-see US patent application 2008/0262091, hereby incorporated by reference in its entirety. In another embodiment, a TRPV1 agonist other than a capsaicinoid, or capsaicin analogue, is utilized in the formulations and methods of the invention.

[0102] According to the present invention, the pain relief composition comprises a therapeutically effective amount of a nerve-inhibiting componenta TRPV1 selective agonist, which inhibits the nerve endings that signal pain. The TRPV1 selective agonist component is typically a vanilloid, a capsaicinoid, more specifically capsaicin, nonivamide or other capsaicin analogue, or a mixture thereof.

[0103] TRPV1 selective agonist compounds of the subject invention include the natural capsaicinoids (Capsaicin Oleoresin), and synthetic (Nonivamide) forms, as well as analogues of capsaicin. Capsaicin is known by the chemical name N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide. Capsaicin is the main capsaicinoid (typically 69%) in chili peppers, followed by dihydrocapsaicin (typically 22%) and norihydrocapsaicin (typically 7%). Nonivamide is found in trace amounts in chili peppers.

TABLE-US-00002 TABLE 2 CAPSAICIN & CAPSAICINOID PROPERTIES Capsai- Natural Scoville cinoid Relative Heat Molecular Name Abbr. MW Amount Units Formula Chemical Structure Capsaicin C 305 69% 16 10 C H.sub.27NO.sub.3 [00002] Dihydro- capsaicin DHC 307 22% 15 10 C H NO.sub.3 [00003] Nordihydro- capsaicin NDHC 293 7% 9.1 10 C.sub.17H.sub.27NO.sub.3 [00004] Homo- dihydro- capsaicin HDHC 321 1% 8.6 10 C.sub.19H NO.sub.3 [00005] Homo- capsaicin HC 319 1% 8.6 10 C H NO.sub.3 [00006] Nonivamide PAVA 293 .sup.(1)0.25% 9.2 10 C.sub.17H.sub.27NO.sub.3 [00007] .sup.(1)Constant et al. J. Nat. Prod. 1996, 59, 425-426 indicates data missing or illegible when filed

[0104] As noted above in TABLE 2, capsaicin and several related compounds are called capsaicinoids. Nonivamide, the vanillylamide of n-nonanoic acid (also PAVA) is used as a reference substance for determining the relative pungency of capsaicinoids as well as being used as a food additive to add pungency.

[0105] Capsaicin and dihydrocapsaicin together make up 80-90% of the capsaicinoids found in chili peppers. The different capsaicinoid compounds have slight structural variations in the hydrocarbon tail, changing their ability to bind to the nerve receptors and their ability to penetrate layers of receptors on the tongue, mouth, and throat.

[0106] Capsaicinoids are very similar in structure, varying only by the length of along hydrocarbon portion (that is, a portion containing only carbon and hydrogen atoms), and by the presence or absence of one carbon-to-carbon double bond in that hydrocarbon portion (carbon-carbon double bonds). Both the naturally occurring capsaicin and the synthetic versions that differ slightly in their alkyl chain, have similar pharmacological effects.

[0107] Nonivamide is present in chili peppers but is commonly manufactured synthetically. It is more heat-stable than capsaicin. Ointments sold to relieve arthritis and muscle pain often contain nonivamide. Application of the ointment on the skin is claimed to result in a warm to burning sensation and pain relief for several hours.

[0108] Resiniferatoxin (RTX) is a very potent capsaicin analogue. Other TRPV1 selective agonists include anandamide, and NADA. Many additional agonists are disclosed in U.S. Pat. Nos. 7,943,166 and 7,632,519, each of which is hereby incorporated by reference in its entirety. Some capsaicin analogues are described in U.S. Pat. No. 5,962,532, hereby incorporated by reference in its entirety.

[0109] The formulations of the invention typically include 0.075-30% by weight, 0.2-30%, or 2-20%, 2-10% or 5-15% of a capsaicinoid (e.g. capsaicin), or related compounds. When the TRPV1 selective agonist is other than capsaicin, since potency can vary, the amount of agonist in the formulation is that amount which achieves the same results achieved by the weight percent ranges noted herein for capsaicin.

Extended Release Agents

[0110] It has been found that inclusion of certain compounds which slow the release of a capsaicinoid from the formulation (causing extended release), result in diminished burning and stinging effects. Advantageously, the extended release agent will release said capsaicinoid over a period of greater than 15 minutes, 30 minutes, 1 hour, or greater than 4 hours. In one embodiment, the capsaicinoid is released over a period greater than a week. Typically a higher dose will be released over a longer time period. In one embodiment of the invention, the extended release agent is not a glycosaminoglycan or a proteoglycan.

Hyaluronic Acid

[0111] The molecular weight of hyaluronic acid (HA) of the invention advantageously ranges from 3 kDaltons to 1,000 kDaltons. In certain embodiments, the formulations can include high molecular weight hyaluronic acid of greater than 800 kDaltons, i.e. 1000, 2000, 3000, 4000 or 5000 kDaltons. In certain embodiments, the formulations can include low molecular weight hyaluronic acid of less than 200 kDalton, advantageously less than 20 kDalton, more advantageously less than 15 kDalton. The hyaluronic acid component of the solubilized capsaicin formulations forms a polysaccharide network within the aqueous solution that contributes to a delayed and prolonged release of capsaicin thus contributing to minimizing the discomfort from the application of capsaicinoid.

[0112] HA has been extensively utilized in cosmetic products because of its viscoelastic properties and excellent biocompatibility. Application of HA containing cosmetic products to the skin is reported to moisturize and restore elasticity thereby achieving an anti-wrinkle effect.

[0113] The high solubilization of capsaicin using the nonionic surfactants PS 80 and/or Cremophor RH 40, together with hyaluronic acid, a substance that is naturally present in the human body that occurs in various tissues (skin, synovial fluids of joints and connective tissues), contribute to ameliorating the burning and stinging associated with capsaicin formulations. In an advantageous embodiment, <0.5 wt. % hyaluronic acid and its salts (0.35 wt. % HA<50 kDaltons and 0.15 wt. % HA ranging from 800 to 1,200 kDaltons), significantly contributes to a reduction in the capsaicin associated burning and stinging reaction. The high MW hyaluronic acid used in the Examples herein had an average molecular weight of 1000 kDaltons. While not wishing to be bound by theory, it is believed that the addition of the hyaluronic acid component to the capsaicin forms a polysaccharide network within the aqueous solution that causes capsaicin to be released more slowly in a controlled manner that results in a lessening of the burning and stinging pain.

[0114] The physiological function of the stratum corneum, the outermost and non-viable layer of the skin, is to act as a protective barrier for the body and as such it is particularly effective at preventing the permeation of hydrophilic molecules including some drugs into deeper skin layers, where viable cells are located. Low molecular weight (MW) HA provides better penetration abilities than higher MW HA and, accordingly, influenced the expression of many genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes which are reported to be reduced in aged and photo-damaged skin. These different molecular properties of high and low MW HA generated different in-vivo effects with pronounced moisturization and elasticity properties shown for high MW HA and marked reduction of wrinkles demonstrated for low MW HAs. The increased activity at decreasing molecular weight can be explained by the more efficient skin penetration of the smaller HA molecules. (Farwick, M., et al. Low Molecular Weight Hyaluronic Acid: Its Effects on Epidermal Gene. Expression and Skin Aging, International Journal for Applied Science.)

[0115] Low molecular weight hyaluronic acid can penetrate the epidermal layer of the skin and seep into a deeper region, where it supplements the water loss and helps restore the natural cell regenerative qualities in skin. The high MW hyaluronic acid works on the epidermal level and offers a protective effect, hydrating and healing the protective barrier of the skin. This provides a smoother skin surface. Combining the low and high HA molecular weights utilizes the unique characteristics and benefits of the two types of HA to reduce the burning and stinging effects of capsaicinoids.

[0116] Advantages of HA for dermal administration of capsaicin are: surface hydration and film formation enhance the permeability of the skin to topical drugs, it promotes drug retention and localization in the epidermis; and it exerts an anti-inflammatory action (medium and high-molecular-weight HA). In one embodiment of the invention, the hyaluronic acid is in the form of a cross-linked hydrogel.

Collagen and Elastin

[0117] Collagen is the main structural protein of the various connective tissues in animals. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendons, ligaments and skin, and is also abundant in corneas, cartilage, bones, blood vessels, the gut, and intervertebral discs.

[0118] Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of vertebrates and used in places where mechanical energy is required to be stored.

[0119] Collagen and/or elastin with a capsaicinoid is advantageous in the treatment of pain including OA pain. The addition of the collagen and/or elastin component to a solubilized capsaicin formulation forms a protein network within the aqueous solution that contributes to a delayed and prolonged release of capsaicin thus contributing to minimizing the burning discomfort from either topical application or injection of capsaicin. Additionally, upon injection with a capsaicinoid these naturally occurring high molecular weight proteins function to control the rate of capsaicin release to the nerves to reduce burning, provide lubrication to the sliding bone surfaces as well as provide building materials for bone cartilage repair. Addition of hyaluronic acid to capsaicinoid formulations containing either or both these naturally occurring high molecular weight proteins further optimizes tolerability and efficacy. In the compositions of the invention, the collagen or elastin must be in the form of a liquid or gel.

Bioresorbable Polymer Matrix

[0120] A bioresorbable polymer matrix, e.g. a cross-linked oxidized dextran hydrogel, can also be used in the formulations of the invention as the extended release agent. See U.S. Pat. No. 8,435,565 hereby incorporated by reference in its entirety.

Surfactants

[0121] One or more surfactants, advantageously non ionic (e.g. polysorbates such as PS80, Cremophor RH 40 (polyoxy 40 hydrogenated castor oil), sorbitan esters (Spans), poloxamers, cetyl alcohol, cetostearyl alcohol, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, stearyl alcohol etc.), can be also be added to the compositions of the invention to solubilize the capsaicinoid and enhance the skin penetration of the capsaicinoids. They can ameliorate the initial stinging pain caused by capsaicin (or related compounds) in admixture with the pharmaceutically acceptable carrier ingredients for topical administration. Fatty acid ester non-ionic surfactants that are utilized in pharmaceutical, cosmetics and foodstuffs are advantageous because of the compatibility with biological tissues.

[0122] A surfactant, such as a nonionic surfactant, e.g. PS 80 and/or Cremophor RH 40 (polyoxy 40 hydrogenated castor oil) (alternatively, Solute HS 15), can be combined with hyaluronic acid and one or more of the pharmaceutically acceptable vehicles described herein so that the surfactant serves as a wetting agent, solubilizer, and emulsifier and contribute to minimizing the stinging or burning discomfort associated with capsaicinoid administration.

[0123] Further, surfactant/capsaicin (or other capsaicinoid(s)) concentrates can be formed for use in the formulations and methods of the invention as described in commonly owned U.S. Pat. No. 8,637,569 hereby incorporated by reference in its entirety.

[0124] In one embodiment of the invention, a surfactant is not present in the composition. An example is where the capsaicinoid concentration is less than 0.25% by wt.

[0125] Examples of formulations of the invention with the surfactant PS 80 are shown below:

TABLE-US-00003 2%, 5%, and 10% CAPSAICIN-HA FORMULATIONS (Optically Clear Single Phase Formulations) 2 wt. % 5 wt. % 10 wt. % INGREDIENTS HA-Cap HA-Cap HA-Cap CAPSAICIN (Formosa) 2 5 10 POLYSORBATE 80 7 10 13 (Super Refined - Croda) ETHYL ALCOHOL 20 20 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 10 10 METHYL ETHER (DGME) PROPYLENE GLYCOL 10 10 10 .sup.(1)HA (~1,000K Daltons) 0.17 0.17 0.12 .sup.(1)HA SLMW (~20K Daltons) 0.33 0.33 0.25 .sup.(1)DISTILLED WATER 50.50 44.50 36.63 TOTAL 100 100 100

[0126] Examples of formulations of the invention with the surfactant Cremophor RH 40 are shown below:

TABLE-US-00004 HA-CAPSAICIN FORMULATIONS % 2% 5% 10% 15% 20% Cap-HA Cap-HA Cap-HA Cap-HA Cap-HA Cap-HA INGREDIENTS (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) CAPSAICIN (Formosa) 0.25 2 5 10 15 20 CREMOPHOR RH 40 5 7 10 12 16 16 ETHYL ALCOHOL 20 20 20 20 20 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 10 10 10 10 10 (DGME) PROPYLENE GLYCOL 10 10 10 10 10 10 .sup.(1) HYALURONIC ACID AQUEOUS 54.75 51 45 38 29 24 SOLUTION TOTAL 100 100 100 100 100 100 Note: .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt.% Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.
Agents that Enhance Skin Penetration

[0127] Diethylene glycol monoethyl ether (DGME) is a penetration enhancer (and solvent) useful in the formulations of the invention. It is commercially available as Transcutol (Gattefoss Corp., Paramus, N.J.). DGME is both an effective solvent and penetrating agent for capsaicinoids. Other penetrating agents include propylene glycol, ethoxydiglycol, and dimethyl isosorbide, each known in the art of topical formulation development to enhance skin penetration.

[0128] Alcohols including ethyl alcohol, benzyl alcohol, glycerol, propanol, isopropyl alcohol, polyethylene glycol, polyethylene glycols, etc. can be added to the formulations as effective capsaicin solubilizing and penetrating agents. Addition of an alcohol results in compositions with lower viscosity and shorter drying times.

[0129] Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula (CH.sub.3).sub.2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It penetrates the skin very readily and has the unusual property that many individuals perceive a garlic-like taste in the mouth after contact of DMSO with the skin.

Analgesic Agents

[0130] The compositions of the subject invention also include an analgesic agentone or more analgesics. As used herein, an analgesic agent is a compound or compounds which, when topically applied, reduces pain or burning sensation without loss of tactile sensation. The analgesics agents of the invention do not include a capsaicinoid and do not include an opioid. Further, the analgesic agents do not include a topical local anesthetic, such as lidocaine (or procaine, amethocaine, cocaine lidocaine (also known as Lignocaine), prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine) in the TRPV1 specific agonist containing formulations. These caine local anesthetics have not been effective in sufficiently moderating the burning effect of capsaicin when administered concomitantly with capsaicin topically; they have a slower onset of action relative to capsaicin. To reduce the burning sensation, these caine local anesthetics are typically administered in advance of capsaicin attempting to elicit sufficient anesthetic action prior to the burning sensation associated with capsaicin.

[0131] The present application includes the discovery that topical TRPV1 selective agonist containing compositions have significantly less burning pain at the site of the application when combined with topical analgesic and/or anesthetic agents (when compared to the same composition without analgesic and/or anesthetic agents), and are extremely effective in treating pain in mammals including humans. As used herein, topical refers to administration of the composition to a defined area of the body such as a defined area of skin surface or mucous membrane.

Menthol

[0132] Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils that produces a feeling of cooling. Advantageously, (1)-menthol (natural menthol derived from peppermint oil) is used in the subject invention for analgesic effects. Alternatively, another transient receptor potential subfamily M8 (TRPM8) agonist such as icilin or eucalyptol can be used.

[0133] The formulations of the invention can include 1-20%, 5-15% by wt, or 10-20% by weight menthol.

Methyl Salicylate and Camphor

[0134] The formulations can also include methyl salicylate (1-20% by wt, 5-15% by wt, or 10-20% by wt), and camphor (1-20% by wt, 2-10% by wt, or 10-20% by wt). See Examples 12 and 13 below.

Phenol

[0135] Phenol cools and numbs skin on contact, making it an effective topical analgesic ingredient. It also kills germs, and reduces the risk for infection in minor skin irritations. It has been used medically for over 100 years, for these and other applications. Because it can improve the effectiveness of a preparation at relieving itching, phenol is added to formulations meant for the relief of insect bites and stings, sunburn, and other painful and itchy skin conditions.

[0136] The formulations of the invention can include 0-4.6 wt. %, advantageously 0.1-0.5 wt. % phenol.

[0137] Eugenol/clove oil and thymol/thyme oil can be added in addition to, or as alternative to phenol.

Anti-Inflammatory Agents

[0138] An effective amount of an inflammation control component, which reduces or relieves inflammation, swelling, redness, and/or pain in the joints and muscles associated with inflammation, can be added.

Anti-Inflammatory Polyphenols and Sesquiterpenes

[0139] Many polyphenols are known to have anti-inflammatory activity. Examples are flavonoids (e.g. apigenin) and curcumin. Apigenin offers some of nature's most potent and effective anti-inflammatory and anti-oxidant properties. It can be included in the formulation to further enhance therapeutic efficacy. Apigenin has a broad range of anti-inflammatory properties and has been cited for the ability to block the production of compounds that cause pain; e.g., the arthritis causing substance cyclooxygenase (COX). The addition of apigenin to a mixture of capsaicin in the constituents of the subject pain relieving formulations can be accomplished using the high temperature surfactant technology where apigenin is first dissolved in PS80 at elevated temperatures to form a concentrate that is then added to the mixture (see US Application US 2011/0311592 A1).

[0140] Bisabolol is another potent anti-inflammatory sesquiterpene which is known to also have anesthetic, anti-irritant, anti-inflammatory, anti-fungal and anti-microbial properties. Bisabolol is also demonstrated to enhance the percutaneous absorption of certain molecules. Bisabolol helps transport active ingredients transdermally by enhancing skin penetration. (R. Kadir and B. W. Barry. Alpha-Bisabolol, a Possible Safe Penetration Enhancer for Dermal and Transdermal Therapeutics. Int. J Pharm. 70:87-94 (1991).)

NSAIDs/Diclofenac Sodium

[0141] In further embodiments of the invention, a Non-Steroidal Anti-Inflammatory Agent (NSAID) is co-administered with the TRPV-1 selective agonist formulations. The NSAID and the TRPV-1 selective agonist can be administered together as a single composition (where a topical NSAID is used) or administered as separate compositions (where a topical or not topical NSAID is used). The NSAID can be administered before, after or at the same time as the TRPV-1 selective agonist by the same or different routes of administration. For example, the TRPV-1 selective agonist can be administered topically while the NSAID agent can be administered orally, topically or parentally. NSAIDs useful as adjunctive agents in the formulations of the present invention include aspirin (acetylsalicylic acid), ibuprofen, naproxen, diclofenac, benoxaprofen, ketoprofen, indomethacin etc., and mixtures thereof. As used herein, NSAID does not include methyl salicylate.

[0142] Combining an NSAID such as a diclofenac salt with capsaicin in a topical formulation combines two established pain relieving agents which function via two different mechanisms of action (MOAs); i.e., TRPV1 nerve defunctionalizer and a potent COX-2 inhibitor. Solubility studies were conducted (see below) and formulations were prepared containing the NSAID, diclofenac sodium, together with the TRPV1 selective agonist, capsaicin, utilizing the subject invention.

[0143] TABLE 3 lists components of several prepared capsaicin formulations. These formulations are discussed in the Examples.

TABLE-US-00005 TABLE 3 Ingredients Of Capsaicin Topical Formulations No. 1 No. 2 No. 3 No. 4 No. 5 No. 5A No. 6 0.25% 0.25% 2% 2% 5% 5% 10% lngredient Cap Cap-HA Cap-HA Cap-HA Cap-RA Cap-HA Cap-HA Topical Ranges Form 2 Form 2 Form 2 Form 3 Form 2 Form 2 Form 2 Ingredients (Wt. %) Function (Wt. %) (Wt. %) (Wt. %) (Wt. %) (Wt. %) (Wt. %) (Wt. %) .sup.(1) Capsaicin 0.1-10 Defunctionalization of 0.25 0.25 2.0 2.0 5.0 5.0 10 TRPV-1 sensory neurons Hyaluronic Acid 0-0.5 Viscosity enhancer & 0.20 0.15 0.10 0.15 0.15 0.15 ~1,000K Daltons moisturizing agent Hyaluronic Acid 0-0.5 Viscosity enhancer & 0.30 0.35 0.40 0.35 0.35 0.35 ~11K Daltons moisturizing agent Ethyl Alcohol 1-20 Solvent 20 20 20 20 20 20 20 DGME 0-10 Solvent & penetration 10 10 10 10 10 10 10 enhancer Propylene Glycol 0-10 Solvent & penetration 10 10 10 10 10 10 10 enhancer .sup.(2) Polysorbate 80 0-15 Surfactant, emulsifier & 2 2 10 solubilizing agent .sup.(3)PEG-40 0-15 Surfactant, emulsifier & 0.50 5 5 10 15 Hydrogenated solubilizing agent Castor Oil Water 30-60 Solvent q.s. q.s. q.s. q.s. q.s. q.s. q.s. Note: .sup.(1) Trans-Capsaicin, Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, USP 30 .sup.(2) Super-refined Polysorbate-80, Croda Inc., Edison, NJ .sup.(3)Cremophor RH 20, BASF Corp, Florham Park, NJ

[0144] In other embodiments, the formulation can be a spray or gel. Topical compositions of the present invention can be formulated as an emulsion using water and a surfactant or emulsifying system, along with the liquid formulations discussed above.

Methods of Making the Formulations

[0145] The method of making the formulation containing capsaicin and hyaluronic acid includes the preparation of hyaluronic acid and capsaicin solutions followed by the blending of these solutions to produce the formulation. Typically, the preparation of the hyaluronic acid water solution (composed of a mixture containing 70 wt. % hyaluronic acid with a molecular weight 11 kDaltons, and 30 wt. % hyaluronic acid with a molecular weight of 1,000 kDaltons, was added to an alcohol mixture solution containing 0.25 wt. % to 10 wt. % capsaicin dissolved in solublizing (penetrating) agents consisting of ethyl alcohol, propylene glycol, and polyoxy 40 hydrogenated castor oil or PS80 (balance water). Adjusting the relative percentages of the hyaluronic acid molecular weights and surfactant composition resulted in variation of viscosity of the mixture. Example 1 provides details of the preparation of a 2 wt. % capsaicin HA formulation. Methods of making other capsaicinoid formulations are similar to the above.

Methods of Using the Formulations

Pain

[0146] The compositions of the present invention discussed above can be used for treating various conditions associated with pain by attenuating pain at a specific site. The components of the formulations are typically administered concomitantly. Examples of conditions to be treated include, but are not limited to, nociceptive pain (pain transmitted across intact neuronal pathways), neuropathic pain (pain caused by damage to neural structures), pain from nerve injury (neuromas and neuromas in continuity), pain from neuralgia (pain originating from disease and/or inflammation of nerves), pain from myalgias (pain originating from disease and/or inflammation of muscle), pain associated with painful trigger points, pain from tumors in soft tissues, pain associated with neurotransmitter-dysregulation syndromes (disruptions in quantity/quality of neurotransmitter molecules associated with signal transmission in normal nerves) and pain associated with orthopedic disorders such as conditions of the foot, knee, hip, spine, shoulders, elbow, hand, head and neck.

[0147] Neuropathic pain generally involves abnormalities in the nerve itself, such as degeneration of the axon or sheath. For example, in certain neuropathies the cells of the myelin sheath and/or Schwann cells may be dysfunctional, degenerative and may die, while the axon remains unaffected. Alternatively, in certain neuropathies just the axon is disturbed, and in certain neuropathies the axons and cells of the myelin sheath and/or Schwann cells are involved. Neuropathies may also be distinguished by the process by which they occur and their location (e.g. arising in the spinal cord and extending outward or vice versa). Direct injury to the nerves as well as many systemic diseases can produce this condition including AIDS/HIV, Herpes Zoster, syphilis, diabetes, and various autoimmune diseases. Neuropathic pain is often described as burning, or shooting type of pain, or tingling or itching pain and may be unrelenting in its intensity and even more debilitating than the initial injury or the disease process that induced it.

[0148] The receptors involved in pain detection are aptly enough referred to as nociceptor-receptors for noxious stimuli. These nociceptors are free nerve endings that terminate just below the skin as to detect cutaneous pain. Nociceptors are also located in tendons and joints, for detection of somatic pain and in body organs to detect visceral pain. Pain receptors are very numerous in the skin, hence pain detection here is well defined and the source of pain can be easily localized. In tendons, joints, and body organs the pain receptors are fewer. The source of pain therefore is not readily localized. Apparently, the number of nociceptors also influences the duration of the pain felt. Cutaneous pain typically is of short duration, but may be reactivated upon new impacts, while somatic and visceral pain is of longer duration. It is important to note that almost all body tissue is equipped with nociceptors. As explained above, this is an important fact, as pain has primary warning functions. Nociceptive pain preferably includes, but is not limited to post-operative pain, cluster headaches, dental pain, surgical pain, pain resulting from severe burns, postpartum pain, angina, genitor-urinary tract pain, pain associated with sports injuries (tendonitis, bursitis, etc.) and pain associated with joint degeneration and cystitis.

[0149] Topical preparations of the compositions of the present invention find use as a topical therapy for a variety of skin disorders that involve pain and itching, such as postherpetic neuralgia, diabetic neuropathy, psoriasis, cluster headache, postmastectomy pain syndrome, rhinopathy, oral mucositis, cutaneous allergy, detrusor hyperreflexia, loin pain/hematuria syndrome, neck pain, amputation stump pain, reflex sympathetic dystrophy, pain due to skin tumor and arthritis, including rheumatoid arthritis, osteoarthritis, diabetic neuropathy, psoriasis, pruritus (itching), cluster headache, post-surgical pain, tendonitis, oral pain, and pain caused by injury, amongst others. The formulations can be used to relieve aches and pains of muscles and joints.

[0150] In addition, the preparations of the present invention also find use in topical therapy for: sciatica, fibromyalgia, gout, shingles, eczema, cutaneous allergy conditions, cutaneous inflammatory conditions, cutaneous microbial/fungal infections, trigeminal neuralgia, sinus and nasal congestion, sinus pressure, sinusitis, rhinitis, allergic rhinitis, hyperreactive rhinopathy, nasal polyps, nasal obstruction, sinus infection, dry eye syndrome, chronically dry eyes, anal/genital itch, perianal disease, brachioradial puritus, hemorrhoids, onychomycosis, aural stimulation for non-obstructive dysphagia to improve swallowing function, tinnitus, migraines, dandruff and hair growth.

[0151] As used herein, a therapeutically effective amount refers to the quantity or dose of an agent to produce a clinically desired result such as a biological or chemical response, or reduction or elimination of a symptom of a disease or condition, e.g. reduction in or elimination of pain

Administration

Topical

[0152] The compositions of the present invention can be used topically by applying over an area to be treated. A typical method of use is to apply or rub the formulation over the entire area, until the formulation disappears, and use about 1 to 3 or 4 times daily. Additionally, the amount of formulation used can be gradually increased with each successive application. Topical administration can continue for 1-7 days, weeks, or months.

[0153] When combined with ingredients disclosed herein, the amount of capsaicinoid (e.g. trans-capsaicin) in the topical preparation can be from 0.075-30 wt. %, 0.2 wt. % to 30 wt. %, between 1 wt. % and 20 wt. %, e.g. 1 wt. %, 5 wt. %, 10 wt. %, and 20 wt. %.

[0154] In certain embodiments, the administration of a TRPV1 selective agonist, such as capsaicin, formulations at the discrete site provides pain attenuation or pain relief for at least about 48 hours to about 16 weeks.

[0155] Several methods are available for the dispensing of the capsaicin formulations on the skin's surface. TRPV1 selective agonist containing formulation can be applied by physical means including applicator pads, swabs, or other devices intended to apply the formulations in a thin film such as roller bottles, felt tip or sponge tip applicators.

Roller Bottles

[0156] For liquids formulations, dispensers can include bottles with a constriction to facilitate fluid droplet application to the skin. Especially advantageous for capsaicin containing liquid formulations are tubes and/or bottles with a sponge or a roll on applicator.

[0157] Roll on bottles (also referred to as roller bottles) are especially advantageous. The roll on bottle greatly simplifies the dispensing of the fluid on the skin's surface. No finger rubbing or Q-tip application is required. The movement of the roller ball on the skin massages the fluid into the skin.

[0158] The roll on bottle has a plastic, glass or metal roll on ball and glass or suitable plastic housing. As the ball rolls it picks up the solution and applies it to the skin's surface. The caps of roll on bottles may contain a special ring on the inner side. This ring presses on the ball when the cap is tightly shut. The pressure on the ball prevents leakage of the product.

[0159] After filling the bottles, the roll on housing and ball are fitted into the mouth of the bottle. The roll on housing and ball is fitted by pushing the housing into the mouth of the bottle.

[0160] Precise control over where the formulation is applied important. The roller-ball provides a more precise control where the formulation is to be applied, to avoid contact with eyes, contact lenses, tender skin, clothing, etc. The roll on bottle minimizes the likelihood of causing lip and/or eye burning since finger application is not required to spread a film of the capsaicin solution on the body.

[0161] The roll on bottle configuration allows the TRPV1 selective agonist compositions to be applied as a thin homogeneous film. Generally, the application of a thin film formulation is rapidly absorbed into the skin's surface following application. In several embodiments, substantially complete disappearance of the film is complete within 15 minutes following application, and more usually within 10 minutes, or with some embodiments, even less than 5 minutes after application.

Kits

[0162] The invention also includes kits comprising a liquid TRPV1 selective agonist composition, and a sustained release agent and surfactant, and a non-occlusive applicator device. The kit can also include a cleaning solution for removal of residual TRPV1 selective agonist such as polyethylene glycol.

[0163] The present invention will be further understood after careful consideration is given to the following non-limiting examples thereof.

EXAMPLES

Example 1

Preparation of 100 Grams of 2% Cap-HA Form 2 Topical Formulation

Ingredients:

[0164] 2 grams of Trans-Capsaicin Powder, Aversion Technologies, Bowie, Md., USP [0165] 0.15 grams of Sodium Hyaluronic Acid Powder, Making Cosmetics Inc., Snoqualmie, Wash. [0166] 0.35 grams of Sodium Hyaluronic Acid (SLMW) Powder, Making Cosmetics Inc., Snoqualmie, Wash. [0167] 20 grams of Ethyl Alcohol, Graves Grain Alcohol, 190 Proof [0168] 10 grams of DGME (Ethoxydiglycol), Lotioncrafter Inc., Eastsound, Wash. [0169] 10 grams of Propylene Glycol, Lotioncrafter Inc., Eastsound, Wash. [0170] 2 grams of Super-refined Polysorbate 80, Croda Inc. Florham Park, N.J. [0171] 5 grams of Cremophor RH 20, BASF Corp, Florham Park, N.J. [0172] q.s. Distilled Water

Step IPreparation of the Hyaluronic Acid Solution

[0173] 1. Obtain the tare weight of a 200 cc Pyrex beaker & add 0.15 grams of Sodium Hyaluronic Acid Powder and 0.35 grams of Sodium Hyaluronic Acid (SLMW) Powder. [0174] 2. Slowly add cold (40 F.) 50 grams of distilled water to the mixture from Step 1 while vigorously stirring, Set aside this mixture for 2 hours while occasionally stirring until all the powder is dissolved and a uniformly optically clear mixture is achieved.

Step IIPreparation of the Capsaicin Solution

[0175] 1. Add 2 grams of Trans-Capsaicin powder to a 140 cc Pyrex beaker. [0176] 2. Add 20 grams of Ethyl Alcohol to the capsaicin powder in Step 1 and slowly stir. [0177] 3. Add 10 grams of DGME (Ethoxydiglycol) to the mixture of Step 2 and slowly stir. [0178] 4. Add 10 grams of Propylene Glycol to the mixture of Step 3 and slowly stir. [0179] 5. Stir the solution mixture from Step 4 and heat on a hot plate to a temperature of 40 C. until all the trans-capsaicin powder is completely dissolved. [0180] 6. Allow the solution from Step 5 to cool to ambient temperatures.

Step IIIthe Blending of Mixtures from Steps I & II to Produce the 2% Cap-HA Form 2 Formulation

[0181] 1. Add the liquid contents from STEP II to the HA mixture of STEP I and thoroughly stir. [0182] 2. Add 5 grams of Cremophor RH 20 to the mixture from Step 1 and thoroughly stir. [0183] 3. Add 5 grams of Super-refined Polysorbate 80 to the mixture from Step 2 and thoroughly stir. [0184] 4. The mixture from Step 4 is heated to about 50 C. on a hot plate while stirring. [0185] 5. The mixture from Step 4 is cooled to ambient temperatures. [0186] 6. The mixture from Step 8 is now ready for subsequent packaging.

Additional Method of Preparation of 100 Grams of the 2% Cap-HA Topical Formulations

Ingredients:

[0187] Trans-Capsaicin Powder, CAS #404-86-4, Formosa Labs, Taoyuan, Taiwan [0188] Sodium Hyaluronic Acid Powder (1,000 kDa), Making Cosmetics Inc., Snoqualmie, Wash. [0189] Sodium Hyaluronic Acid (SLMW) Powder, Making Cosmetics Inc., Snoqualmie, Wash. [0190] Ethyl Alcohol, Graves Grain Alcohol, 190 Proof [0191] DGME (Ethoxydiglycol), Lotioncrafter Inc., Eastsound, Wash. [0192] Propylene Glycol, Lotioncrafter Inc., Eastsound, Wash. [0193] Polysorbate 80, Croda Inc. Florham Park, N.J. [0194] Cremophor RH 20, BASF Corp, Florham Park, N.J. [0195] Distilled Water

Step IPreparation of the Hyaluronic Acid Solution

[0196] 1. To a tared weight 500 cc Pyrex beaker add 1.95 grams of Sodium Hyaluronic Acid Powder (1,000 kDa) and 1.05 grams of Sodium Hyaluronic Acid (SLMW, 20 kDa) Powder.
2. Slowly add 297 grams of 40 F. distilled water to the beaker from Step 1 with stirring at nominally 500 rpm for nominally 5 minutes. Set this mixture aside for at least 2 hours and occasionally stir until all the powder is dissolved and a uniformly optically clear solution is achieved.

Step IIPreparation of the Capsaicin Solution

[0197] 1. To a tared weight 140 cc Pyrex beaker add 2 grams of Trans-Capsaicin powder.
2. Add 20 grams of Ethyl Alcohol to the capsaicin powder in Step 1 and slowly stir at about 50 rpm with a spatula.
3. Add 10 grams of DGME (Ethoxydiglycol) to the mixture of Step 2 and slowly stir at about 50 rpm with a spatula.
4. Add 10 grams of Propylene Glycol to the mixture of Step 3 and slowly stir at about 50 rpm with a spatula.
5. Add 7 grams of surfactant (such as Polysorbate-80 or Cremophor RH 20) to the mixture of Step 4 and slowly stir at about 50 rpm with a spatula.
6. Stir the solution mixture from Step 5 at about 50 rpm with a spatula while heating on a hot plate to a temperature of 50 C. until a uniform solution is achieved.
7. Allow the solution from Step 6 to cool to ambient temperature.
Step IIthe Blending of Mixtures from Steps I & 11 to Produce the 2% Cap-HA Formulation.
1. Slowly add 51 grams of the HA mixture of STEP I to the Capsaicin Solution of STEP H while stirring at about 50 rpm with a spatula.
2. Stir the solution mixture from Step 1 at about 50 rpm with a spatula while heating on a hot plate to a temperature of 50 C. until a uniform solution is achieved.
3. Allow the solution from Step 6 to cool to ambient temperature.
4. The solution from Step 3 is now ready for subsequent packaging and use.

Example 2

Topical Application of the 0.25% Capsaicin-HA Formulations

[0198] This study assessed the tolerability of four topical capsaicin formulations by recording burning sensations and skin irritation on the right and left thigh of a 59-year old male of normal health. The formulations were applied with a roller-ball applicator.

TABLE-US-00006 TABLE 4 Capsaicin Test Formulations CapZaicin .sup.(1)0.25% .sup.(2) 0.25% No-Fuss 0.15% Cap Cap-HA Applicator Ingredients M/A Form-2 Form-2 (Walgreens) Capsaicin 0.15 0.25 0.25 0.15 Methyl Salicylate 50 Camphor 11 Liquefied Phenol 0.5 Ethyl Alcohol 23.35 20 20 (Grain alcohol) DGME 10 10 Propylene Glycol 10 10 (PG) Cremophor RH-40 0.5 Hyaluronic 0.15 Acid ~1,000K Daltons Hyaluronic 0.35 Acid ~20K Daltons Distilled Water 59.75 58.75 Other 15% Carbomer, Menthol Glycerin, PG, SD Alcohol (35%), Tri- ethanolamine, Water Note: .sup.(1)Formulation No. 1 in Table 3. .sup.(2) Formulation No. 2 in Table 3.

Formulation Application

[0199] Each formulation was applied to an area measuring 25 square centimeters (55 cm) of skin located on the dorsal thigh. Each formulation was randomly assigned to either the right or left thigh. The application of the formulation involved a non-overlapping serpentine pass of the roller ball or applicator over the skin area that moistened the skin and resulted in a thin film of solution.

[0200] The subject evaluated tolerability prior to dosing, one minute after dosing, at 20 minutes and 40 minutes post-dose and at 2 hours after taking a hot shower. Burning was quantified on a 0-10 Numeric Rating Scale using the Wong-Baker faces as a guide. Skin irritation was quantified using a standard 0 to 7 rating scale Burn Rating Scale.

[0201] The subject rated burning pain for each site of formulation application, using the following 0 to 10 numeric rating scale, with the Wong-Baker faces scale as a guideline.

BRIEF DESCRIPTION OF DRAWING(S)

[0202] The FIGURE shows an exemplary 0 to 10 numeric rating scale.

Skin Irritation Scale

Skin Irritation was Quantified by the Subject Using the Following Definitions:

[0203] 0=no evidence of irritation [0204] 1=minimal erythema, barely perceptible [0205] 2=definite erythema, readily visible; minimal edema or minimal papular response [0206] 3=erythema and papules [0207] 4=definite edema [0208] 5=erythema, edema, and papules [0209] 6=vesicular eruption [0210] 7=strong reaction spreading beyond test results

Results

[0211] There was no burning or signs of skin irritation at any of the test sites of skin prior to application of the formulations.

TABLE-US-00007 TABLE 5 Burning & Erythema Post Application Measurements For 4 Topical Capsaicin Formulations After Hot Shower 2 1 minute post 20 minutes post 40 minutes post hours post Test application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Erythema 0.15% M/A 2 0 2 0 0 0 3 0 .sup.(1)0.25% Cap 3 0 2 0 0 0 6 2 Form 2 very red .sup.(2) 0.25% Cap- 0 0 0 0 0 0 0 0 HA Form 2 .sup.(3)CapZaicin 2 0 1 0 0 0 3 1 0.15% red Note: .sup.(1)Formulation #1 in Table 3 .sup.(2) Formulation #2 in Table 3 .sup.(3)Composition: Capsaicin, 0.15 wt. %; Carbomer, Glycerin, PG, SD Alcohol (35%), Triethanolamine, Water

CONCLUSIONS

[0212] The 0.15% M/A formulation demonstrated tolerability comparable to that of CapZaicin. Burning scores were identical at 1 minute and 40 minutes post application; however at 20 minutes post application the 0.15% M/A formulation was 1 unit higher in scored burning. Skin irritation scores were identical at 1 minute, 20 minutes and 40 minutes post application; however CapZaicin induced skin reddening following a hot shower 2 hours post application whereas the 0.15% M/A formulation did not induce skin irritation.

[0213] The addition of 1% hyaluronic acid dramatically reduced the burning sensation and skin irritation induced by a 0.25% capsaicin aqueous formulation containing ethoxydiglycol and propylene glycol as penetration enhancers.

Example 3

Topical Application of the 0.25% Capsaicin-HA Formulations

[0214] A group of 2 adult males and 2 adult females of normal health and ranging in ages from 35 to 55 applied multiple topical application of 4 formulations from 3.7 ml roller-ball applicators as noted in TABLE 6. The subjects noted that the 0.25 wt. % HA/capsaicin formulation was the most tolerable in term of the burning and erythema ratings. The average burning and erythema ratings for the 4 subjects are summarized in TABLE 6.

TABLE-US-00008 TABLE 6 Burning & Erythema Post Application Measurements For 4 Topical Capsaicin Formulations (Average of 4 Subjects) After Hot Shower 2 1 minute post 20 minutes post 40 minutes post hours post Test application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Erythema 0.15% MIA 0.2 0 2.5 0 1.2 0.3 4.7 1 .sup.(1)0.25% Cap 0.8 0 1.6 0.5 1.3 0.5 4.0 2 .6 Form 2 .sup.(2)0.25% Cap- 0.3 0 0.6 0.3 0.6 0.5 2.3 0.9 HA Form 2 .sup.(3)CAPSAICIN 0.6 0 1.7 0.5 1.3 1.0 3.8 1.3 0.15% Note: .sup.(1)Formulation #1 in Table 3 .sup.(2)Formulation #2 in Table 3 .sup.(3)Composition: Capsaicin, 0.15 wt.%; Carbomer, Glycerin, PG, SD Alcohol (35%), Triethanolamine, Water

Example 4

Topical Application of the 2% Capsaicin-HA Formulations

[0215] A 40 year old female of normal health applied multiple topical application of 2% trans-capsaicin formulations as noted in Table 3 on her forearm with a 3.7 ml roller-ball applicator. Burning sensations were rated on a scale of 0-10. Erythema (reddening) was rates on a scale of 0-10. (0 no erythema). Erythema (reddening) was rated on a scale of 0-10. The subject experienced the absence of both burning and erythema for both the 2% Cap-HA Form 2 and 2% Cap-HA Form 3 formulations. Burning and stinging recordings for the 2% M/A formulation of <3 were experienced for 60 minutes post application time frame. Details of the subject's comments relating to the topical application of the 3 formulations are summarized in the Tables below. [0216] A) 2% Cap-HA Form 2 (Formulation 3 in Table 3)Initially this application site showed no noticeable sensitivity. No irritation/erythema throughout the test. There was no burning sensation or redness prior to the 60 minute timepoint. Upon washing of the product in hot water, a slight itching sensation and erythema occurred, at time of reading both were at a 1. This quickly reached a zero within 30 minutes of washoff. [0217] B) 2% Cap-HA Form 3 (Formulation 3 in Table 3)Initially this application site showed no noticeable sensitivity. No irritation/erythema throughout the timeframe. It is important to note there was what could be described as a pleasant warming of the area 18 hours later when showering. This warming dissipated within 30 minutes post shower. [0218] C) .sup.(1)2% MAInitially this application site showed barely noticeable sensitivity, described as an itching sensation. There was mild irritation/erythema upon initial application. The burning sensation increased to a 2.5 at the 10 minute mark. The burning sensation gradually dissipated to a mild itching. The burning sensation increased to a 3 immediately upon exposure to hot water and remained at this level for 10 minutes following. Pain then gradually decreased to 0 over the course of 40 minutes following wash off. No erythema or pain was noticeable until a shower the next day. At which time there was a light erythema and a mild burning characterized as a 3. This pain dissipated within 30 minutes. [0219] Note: (1) Composition: Capsaicin. 2 wt. %: Methyl Salicylate, 50 wt. %: Menthol, 15 wt. %: Camphor. 11 wt. %: Ethyl Alcohol. 19.5 wt. %: Phenol 1.35 wt. %. Water, 1.15 wt.

TABLE-US-00009 TABLE 7 Burning & Erythema Post Application Measurements 1 minute post 10 minutes post 20 minutes post 30 minutes post 45 minutes post 60 minutes post Test application application application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Irritation Burning Erythema Burning Erythema .sup.(1) 2% Cap-HA 0 0 0 0 0 0 0 0 0 0 0 0 Form 2 .sup.(2) 2% Cap-HA 0 0 0 0 0 0 0 0 0 0 0 0 Form 3 2% M/A 1.5 1.5 2.5 2 2 3 2 3 2 3 2 3 Note: .sup.(1) Formulation #3 in Table 3 .sup.(2) Formulation #4 in Table 3 .sup.(3) Composition: Capsaicin, 2 wt. %: Methyl Salicylate, 50 wt. %: Menthol, 15 wt. %; Camphor, 11 wt. %; Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

TABLE-US-00010 TABLE 8 Burning & Erythema Post Application Measurements Immediate Post Wash-Off 18 hours later Test (with hot water) during Shower Formulations Burning Erythema Burning Erythema .sup.(1) 2% Cap-HA 1 0 1 0.5 Form 2 .sup.(2) 2% Cap-HA 0 0 1 0 Form 3 .sup.(3) 2% M/A 3 3.5 3 0.5 Note: .sup.(1) Formulation #3 in Table 3 .sup.(2) Formulation #4 in Table 3 .sup.(3) Composition: Capsaicin, 2 wt. %; Methyl Salicylate, 50 wt. %; .sup.Menthol, 15 wt. %; Camphor, 11 wt. %; Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

Example 5

Topical Application of the 2% Capsaicin-HA Formulations

[0220] A 50-year old male of normal health applied a single topical application of three 2 wt. % trans-capsaicin formulations via a roller ball applicator. The burning and erythema ratings are summarized in Table 9. Both formulations containing HA had similar burning and erythema ratings for the 60 minute post application duration as noted in Table 9. The subject rated the 2 wt. % M/A formulation as slightly more burning and more irritating than the HA formulations. All levels of burning and erythema were considered to be well within the tolerable level for topical use in the subject's opinion.

TABLE-US-00011 TABLE 9 Burning & Erythema Post Application Measurements 1 minute post 10 minutes post 20 minutes post 30 minutes post 45 minutes post 60 minutes post Test application application application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Irritation Burning Erythema Burning Erythema .sup.(1) 2% Cap-HA 1.5 0 2 0 2.5 0.5 2.5 0.5 2.5 0.5 2.0 1 Form 2 .sup.(2) 2% Cap-HA 1.5 0 2 0 2.5 0.5 2.5 0.5 2.5 0.5 2.0 1 Form 3 2% M/A 1 0 2.5 0.5 3 1 3.5 1 3.0 0.5 2.5 1 Note: .sup.(1) Formulation #3 in Table 3 .sup.(2) Formulation #4 in Table 3 .sup.(3) Composition: Capsaicin, 2 wt. %; Methyl Salicylate, 50 wt. %; Menthol, 1.5 wt. %; Camphor, 11 wt. %; Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

Example 6

Topical Application of the 5% and 10% Capsaicin Formulations

[0221] A 79 year old male took part in an evaluation of both the 5 wt. % and 10 wt. % capsaicin-HA to evaluate the burning and erythema effect of capsaicin. The burning effect was rated on a scale of (0-10) and at the same time erythema reddening was also determined by eye on a scale of (1-5).

[0222] Application of the 5 wt. % capsaicin-HA formulation via 3.7 ml roller-ball bottle was undertaken to achieve an initial dosing on a 25 cm.sup.2 (5 cm5 cm) area of skin on his left arm, 20 cm below the elbow joint on the underside of his left arm. Several passes of the roller-ball were undertaken to the entire 25 cm application area.

[0223] Similarly, application of 10 wt. % capsaicin-HA formulation via 3.7 ml roller-ball bottle was undertaken to achieve an initial dosing on a 25 cm.sup.2 (5 cm5 cm) area of skin on his left arm, 20 cm above the elbow joint on the upper side of the right arm. Several passes of the roller-ball were applied to the 25 cm.sup.2 application area.

[0224] The observed burning and erythema results are summarized in Tables 10 and 11. The subject noted a gradual increase in the burning sensation to a 3 level for the 5 wt. % capsaicin and a level 2.5 for the 10 wt. % capsaicin formulation at the 20 minute mark followed by a gradual decrease to zero after 60 minutes. The subject noted a slight itching that lasted for about 5 to 15 minutes after fluid application.

[0225] In both cases the level of burning for both the 5 wt. % and 10 wt. % Capsaicin/HA formulation were well tolerated.

TABLE-US-00012 TABLE 10 Burning & Erythema Post Application Measurements 1 minute post 10 minutes post 20 minutes post 30 minutes post 45 minutes post 60 minutes post Test application application application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Irritation Burning Erythema Burning Erythema .sup.(1) 5% Cap-HA 0 0 .sup.(3) 2 0 3.0 0 1.5 0 0.5 0.5 0 0 Form 2 .sup.(2) 10% Cap-HA 0 0 .sup.(3) 2.50 0 2.5 0.5 2.0 0 1 0 0 0 Form 3 Note: .sup.(1) Formulation #5 in Table 3 .sup.(2) Formulation #6 in Table 3 .sup.(3) Slight itching experienced

TABLE-US-00013 TABLE 11 Burning & Erythema Post Application Measurements Immediate Post Wash-Off 18 hours later Test (with hot water) during Shower Formulations Burning Erythema Burning Erythema .sup.(1) 5% Cap-HA 1 0.5 1 0.5 Form 2 .sup.(2) 10% Cap-HA 2 0.5 0 0 Form 3 Note: .sup.(1) Formulation #5 in Table 3 .sup.(2) Formulation #6 in Table 3

Example 7

Topical Application of the 5% and 10% Capsaicin-HA Formulations

[0226] A 71-year old female of normal health applied a single topical application of the 5 wt. % capsaicin-HA formulation to her left forearm and the 10 wt. % capsaicin-HA formulation to her right forearm in a manner similar to that described in Example 6. The observed burning and erythema results are summarized in TABLES 12 and 13. The level of burning for both the 5 wt. % and 10 wt. % Capsaicin/HA formulation were well tolerated.

TABLE-US-00014 TABLE 12 Burning & Erythema Post Application Measurements 1 minute post 10 minutes post 20 minutes post 30 minutes post 45 minutes post 60 minutes post Test application application application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Irritation Burning Erythema Burning Erythema .sup.(1) 5% Cap-HA 0 0 .sup.(3) 1 0.5 3.0 0.5 2.0 0.5 0.5 0 0 0 Form 2 .sup.(2) 10% Cap-HA 0 0 .sup.(3) 3.0 1 2.5 1 2.0 0 1 0 0.5 0 Form 3 Note: .sup.(1) Similar to Formulation #5 in Table 3 .sup.(2) Similar to Formulation #6 in Table 3 .sup.(3) Slight itching experienced

TABLE-US-00015 TABLE 13 Burning & Erythema Post Application Measurements Immediate Post Wash-Off 18 hours later Test (with hot water) during Shower Formulations Burning Erythema Burning Erythema .sup.(1) 5% Cap-HA 3 1 2 1 Form 2 .sup.(2) 10% Cap-HA 2 1 2 0 Form 3 Note: .sup.(1) Similar to Formulation #5 in Table 3 .sup.(2) Similar to Formulation #6 in Table 3

Example 8

[0227] Topical Application of 2%. 5% and 10% CAPSAICIN-HA Formulation with PS80 to Rats

[0228] A small rat study was conducted utilizing the capsaicin-HA formulations below:

TABLE-US-00016 2%, 5%, and 10% CAPSAICIN-HA FORMULATIONS (Optically Clear Single Phase Formulations) 2 wt. % 5 wt. % 10 wt. % INGREDIENTS HA-Cap HA-Cap HA-Cap CAPSAICIN (Formosa) 2 5 10 POLYSORBATE 80 7 10 13 (Super Refined - Croda) ETHYL ALCOHOL 20 20 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 10 10 METHYL ETHER (DGME) PROPYLENE GLYCOL 10 10 10 .sup.(1)HA (~1,000K Daltons) 0.17 0.17 0.12 .sup.(1)HA SLMW (~20K Daltons) 0.33 0.33 0.25 .sup.(1)DISTILLED WATER 50.50 44.50 36.63 TOTAL 100 100 100

[0229] A single administration of the 2% and 5% capsaicin formulations for 30 minutes was tolerated in the rats. A single administration of the 10% capsaicin formulation for 30 minutes was not well tolerated in the rats.

Example 9

[0230] Topical Application of 10% CAPSAICIN-HA Formulation with PS80 to a Human

[0231] A 53-year old male of normal health applied a single topical application of 10% trans-capsaicin hyaluronic acid (HA) PS80 solution for 120 minutes prior to washing off. This formulation was formulated with PS80 as the surfactant. Composition of the formulation is shown in the following table.

TABLE-US-00017 Composition of the 10% HA-CAPSAICIN FORMULATION INGREDIENTS wt. % CAPSAICIN (Formosa) 10 POLYSORBATE 80 (PS80) 13 (Super Refined - Croda) ETHYL ALCOHOL 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 METHYL ETHER (DGME) PROPYLENE GLYCOL 10 HA (~1,000K Daltons) 0.12 HA SLMW (~20K Daltons) 0.25 DISTILLED WATER 36.63 TOTAL 100

[0232] Application of formulation via 10 mg roller-ball bottle was undertaken to achieve a liberal glistening dose over a 15 in (5 inch3 inch) area of skin on right knee covering half the knee cap and the space just above the knee cap. Several passes of the roller-ball were undertaken to the entire application area to achieve this liberal dosing of formulation.

[0233] Rating of stinging/burning (S&B) and Redness (Erythema) are shown in the table below as a function of time following topical application.

TABLE-US-00018 S&B Erythema Minutes Scale 0-10 Scale 0-5 2 1 0 5 1.5 .5 10 2 1 20 2 1.5 30 2 1.5 40 2.5 1.5 60 2 2 80 1 1.5 90 1 1 100 0.5 0.5 120 0.5 0.5

[0234] In the table above, the S&B Scale of 0 to 10 is a representation of stinging and burning where a zero represents an absence of any S&B, a 1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is the worst pain imaginable. Likewise, the 0 to 5 Erythema scale represents the amount of reddening visually observed where a zero is an absence of reddening, a 1 indicates slight reddening of the skin, a 3 indicates a dark red color and a 5 is purple.

[0235] Overall subject observed a gradual onset of a slight, but very tolerable, burning and stinging sensation over the first 40 minutes following application, followed by a gradual decrease after that point until the 120 minute mark, at which time a very slight S&B sensation still remained. In more detail, a slight S&B sensation rated at a 1 was felt after only 2 minutes, and rose to a 2 rating after 10 minutes. Maximum S&B rated at a 2.5 (on a scale of 0-10) was observed after 40 minutes. The S&B sensation slowly and gradually increased prior to the 40 minute mark. This maximum of 2.5 rated S&B sensation was observed to be quite tolerable at its peak, and then and gradually dissipated beyond the 40-minute mark. From the 40-minute mark on the subject observed a gradual reduction of S&B sensation until the 100 minute mark, at which time the S&B level was observed as a very slight 0.5 rating (on a scale of 1-10). This very slight 0.5 S&B rating continued until the end of the 120 minute period recorded. All levels of irritation were considered to be well within a tolerable level for topical use in subject's opinion.

[0236] In addition, reddening (erythema) and reduction of reddening of the entire 50 cm.sup.2 application area was observed over the initial 120 minute period following application. Subject observed a reddening rated at a 0.5 (on a scale of 1-5) after 5 minutes, to a rating of 1.0 after 10 minutes, and a rating of 1.5 after 20 minutes. This reddening rating of 1.5 was the maximum level observed and lasted from the 20 minute mark until the 40 minute mark. Reddening gradually lessened after the 40-minute mark and was down to an S&B rating of 0.5 after 100 minutes. This slight reddening of 0.5 rating was still observed at the end of the 120 minute period recorded. Reddening was uniform and no blotching or other form of inconsistent effect was observed. The area of reddening did not expand beyond the area of application: only skin area directly treated with the formulation had erythema associated with it. Skin did not become more sensitive during the 120 minute application of the formulation.

Example 10

[0237] Topical Application of 10% CAPSAICIN-HA Formulation with PS80 to a Human

[0238] A 41-year old female of normal health applied a single topical application of 10% trans-capsaicin hyaluronic acid (HA) PS80 solution for 120 minutes prior to washing off. The composition of this formulation is shown in the following table.

TABLE-US-00019 Composition of the 10% HA-CAPSAICIN FORMULATION INGREDIENTS wt. % CAPSAICIN (Formosa) 10 POLYSORBATE 80 (PS80) 13 (Super Refined - Croda) ETHYL ALCOHOL 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 METHYL ETHER (DGME) PROPYLENE GLYCOL 10 HA (~1,000K Daltons) 0.12 HA SLMW (~20K Daltons) 0.25 DISTILLED WATER 36.63 TOTAL 100

[0239] Application of formulation via 10 mg roller-ball bottle was undertaken to achieve a liberal glistening initial dosing on a 8 in.sup.2 (4 inch2 inch) area of skin on the inner right forearm. Several passes of the roller-ball were undertaken to the entire application area to achieve this liberal dosing of formulation.

[0240] Rating of stinging/burning (S&B) and Redness (Erythema) are shown in the table below as a function of time following topical application.

TABLE-US-00020 S&B Erythema Minutes Scale 0-10 Scale 0-5 2 0 0 5 1 1 10 1 1 20 1 1.5 30 1 1.5 40 1 1.5 60 1 1.5 80 1 1.5 90 1 1.5 100 0.5 0.5 120 0.5 0.5

[0241] In the table above, the S&B Scale of 0 to 10 is a representation of burning and stinging where a zero represents an absence of any S&B, a 1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is the worst pain imaginable. Likewise, the 0 to 5 Erythema scale represents the amount of reddening visually observed where a zero is an absence of reddening, a 1 indicates slight reddening of the skin, a 3 indicates a dark red color and a 5 is purple.

[0242] A slight stinging sensation rated at a 1 was felt after 5 minutes, and stayed steady until the 100 minute mark where it gradually decreased. The maximum S&B rated at a 1 (on a scale of 0-10) was observed through 90 minutes. This 1 rated S&B was observed to be quite tolerable. From the 100-minute mark on, the subject observed a gradual reduction of S&B sensation. The very slight 0.5 S&B continued until the end of the 120 minute period recorded. All levels of irritation were well within a tolerable level for topical use in subject's opinion.

[0243] In addition, reddening (erythema) and reduction of reddening of the entire application area was observed over the initial 120 minute period following application. Subject observed a reddening rated at a 1 (on a scale of 1-5) after 5 minutes, to a rating of 1.5 after 10 minutes that continued past the 90 minute mark. Reddening gradually lessened after the 100-minute mark and was down to a 0.5 for the duration. This slight reddening of 0.5 rating was still observed at the end of the 120 minute period recorded. Reddening was uniform and no blotching or other form of inconsistent effect was observed. The area of reddening did not expand beyond the area of application: only skin area directly treated with the formulation had erythema associated with it.

[0244] Skin did not become more sensitive during the 120 minute application of the formulation.

Example 11

[0245] Four Daily Dose Treatments of Osteoarthritis with a 10% Capsaicin-HA Formulation

[0246] A 59 year old man suffering from severe and advanced osteoarthritis used a 10% capsaicin hyaluronic acid formulation once a day on four successive days for mitigation of osteoarthritis pain. The formulation used contained 10% w/w capsaicin along with hyaluronic acid (HA) and utilized Cremaphore RH40 as a stabilization agent (see Table below). This man was Caucasian, obese with degenerative joint disease (osteoarthritis) especially in the knees, bilaterally, with severe degeneration of medial and lateral meniscus and articular cartilage bilaterally, right greater than left. At the time, pain was marginally controlled with Tramadol 50-100 mg tid, giving partial relief, bringing the pain level down to approximately 4 on the pain scale, with sharp shooting pains that scale up to 8-9.

Efficacy

[0247] The subject noted that After treating my worse knee (right) with the 10% formulation for one hour a day for four days, my pain relief improved to a pain level of 2, making my more troublesome knee the better, most pain free knee. The sharp shooting pains also improved and were much less frequent with the momentary severe pain levels only reaching 5. This change for the better lasts for weeks.

Tolerability

[0248] The subject noted that My stinging/burning sensation while applying the treatment was only a trace, less than 1 by my estimate. The sting/burn only slightly increases in the shower, at most to a 1 on the pain scale. While in the shower there was a mild, manageable cough as I rinsed the treated area, fortunately this was only momentary because the formulation washes away easily, quickly and completely.

Overall Assessment

[0249] The subject was very pleased with the results.

TABLE-US-00021 Formulation Composition Table INGREDIENTS wt. % CAPSAICIN (Formosa) 10 CREMOPHOR RH 40 12 ETHYL ALCOHOL (Grain Alcohol) 20 ETHOXYDIGLYCOL (DGME) 10 PROPYLENE GLYCOL 10 .sup.(1) HYALURONIC ACID AQUEOUS SOLUTION 38 TOTAL 100 Note: .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.

Example 12

[0250] Single Dose Pulse Treatment of Osteoarthritis with a 10% Capsaicin-HA Formulation

[0251] A 79 year old man with a history of moderate to severe Osteoarthritis in multiple joints (successful hip replacement in 2008) used a 10% capsaicin HA formulation several times for mitigation of arthritis pain in both his hip and shoulder joints. The formulation used contained 10% w/w capsaicin along with hyaluronic acid (HA) and utilized Cremaphore RH40 as a stabilization agent (see Table below).

Efficacy:

[0252] The subject applied the above mentioned formulation several times on both his left hip and his right shoulder to control osteoarthritis pain. He applied the 10% Capsaicin HA formulation on an as needed basis, which on average was estimated to be once every two weeks. When he applied the formulation, he generally left it on for at least one hour prior to washing off. He did not repeat doses on back to back days, but instead applied a single dose, and then waited until the pain returned to apply another dose. When a single dose of this 10% capsaicin formulation with hyaluronic acid was applied, the arthritis pain was completely eliminated in his shoulder joint for approximately two weeks. Similarly, pain was reduced by approximately 80% when applied on his arthritic hip joint, and significant pain did not return to his hip joint for duration of about 2 weeks from a single dose. The average time to return of pain in both joints was approximately 2 weeks. He was very pleased with the convenience of 1 to 2 weeks of pain relief from the capsaicin following each single dose.

Tolerability:

[0253] The subject noted that the application of this formulation was very tolerable (not irritating). He observed no burning and stinging (B&S) irritation upon application to his shoulder joint for all applications to his shoulder. When he applied the formulation to his hip joint (avoiding the groin and buttocks areas) the maximum S&B sensation was never greater than a 2 rating on a scale of 0 to 10 (defined as zero meaning no S&B sensation, 5 denoting intolerable pain and 10 representing the worst pain imaginable). Erythema (reddening) was non-existent on his shoulder joint upon application, and was estimated at a rating or 1.5 (on a scale of 0 to 5) when the formulation was applied to his hip joint (ratings defined as zero representing an absence of reddening, a 3 as dark red and a 5 as purple). In terms of both S&B sensation and erythema, the subject found the formulation to be very tolerable.

TABLE-US-00022 Formulation Composition Table INGREDIENTS wt. % CAPSAICIN (Formosa) 10 CREMOPHOR RH 40 12 ETHYL ALCOHOL (Grain Alcohol) 20 ETHOXYDIGLYCOL (DGME) 10 PROPYLENE GLYCOL 10 .sup.(1) HYALURONIC ACID AQUEOUS SOLUTION 38 TOTAL 100 Note: .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.

Example 13

[0254] CapsaicinHA formulations containing Analgesics

[0255] A 1 wt. % hyaluronic acid water solution composed of a mixture containing 70% Hyaluronic Acid with a molecular weight 20K Daltons and 30% hyaluronic acid with a molecular weight 1,00K Daltons, was added to an alcohol mixture solutions containing 0.25 wt. % and 2.0 wt. % Capsaicin dissolved in 20% ethyl alcohol and 10% propylene glycol and 15 wt. % and 17 wt. % Cremophor RH 40, respectively. Optically crystal clear and moderately viscous solutions were formed. Adjusting the relative percentages of hyaluronic acid molecular weights could vary the viscosity of the mixture.

[0256] Both the 0.25% wt. % and 2.0 wt. % capsaicin formulations (see Table below) as described in the foregoing paragraphs were applied to an 80 year old male subject's right forearm via a 5 ml roller-ball vial. The applied liquid film dried in a few minutes. Minimal discomfort from burning & stinging was experienced. Significantly, the formulations containing 10 wt. % methyl salicylate were relatively odor free.

TABLE-US-00023 CAPSAICIN-ANALGESIC-HA-FORMULATIONS % 2% Cap-HA Cap-HA INGREDIENTS FUNCTION (wt. %) (wt. %) Capsaicin (Formosa) TRPV1 Agonist 0.25 2 Methyl Salicylate Analgesic Agent & 10 10 Penetrant Menthol Cooling Agent & 5 5 Penetrant Camphor Anesthetic Agent 2 2 Penetrant Cremophor RH 40 Surfactant & 15 17 Solubilizer Ethyl Alcohol Solubilizer & 20 20 (Grain Alcohol) Penetrant Diethylene Glycol Solubilizer & 0 0 Monoethyl Ether (DGME) Penetrant Propylene Glycol Solubilizer & 10 10 Penetrant .sup.(1) Hyaluronic Acid Moisturizer & 37.75 34 Aqueous Solution Humectant TOTAL 100 100 Note: .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.

Example 14

Comparison of Tolerability and Erythema Following Topical Application of Two (2%) Capsaicin HA Formulations: Effect of the Inclusion of Analgesics

[0257] The purpose of this study was to evaluate tolerability and erythema created by the inclusion of topical analgesics to a capsaicin hyaluronic acid (HA) formulation following topical application. A 53 year old male applied two distinct formulations of 2% capsaicin HA (one formulation with topical analgesics and one without) on a single knee side by side. Burning and stinging (S&B) along with skin redness were quantified following topical application in older to evaluate the tolerability and erythema characteristics singularly and comparatively with the two formulations. The compositions of the two formulations are shown below as Formulation 1 (Capsaicin HA) and Formulation 2 (Capsaicin HA plus Analgesics).

TABLE-US-00024 Formulation 1 Composition Capsaicin HA Formulation INGREDIENTS wt. % CAPSAICIN (Formosa) 2 CREMOPHOR RH 40 7 ETHYL ALCOHOL (Grain Alcohol) 20 Diethylene Glycol Monoethyl Ether (DGME) 10 PROPYLENE GLYCOL 10 .sup.(1) HYALURONIC ACID AQUEOUS SOLUTION 51 TOTAL 100

TABLE-US-00025 Formulation 2 Composition Capsaicin HA plus Analgesics Formulation INGREDIENTS FUNCTION wt. % Capsaicin (Formosa) TRPV1 Agonist 2 Methyl Salicylate Analgesic & Solvent 10 Menthol Analgesic & Cooling 5 Camphor Analgesic 2 Cremophor RH 40 Surfactant 17 Ethyl Alcohol (Grain Alcohol) Solvent 20 Diethylene Glycol Monoethyl Ether Solvent 0 (DGME) Propylene Glycol Solvent & Humectant 10 .sup.(1) Hyaluronic Acid Aqueous Moisturizer & Humectant 34 Solution TOTAL 100 [0258] Note: [0259] .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % [0260] Hyaluronic Acid SLMW (20K Daltons), 035 wt. % Hyaluronic [0261] Acid 1,000K Daltons) and 99 wt. % Distilled Water.

[0262] Formulation 1 below is a 2% capsaicin HA formulation. Formulation 2 below consists of 2% Capsaicin HA alone with several well-known natural analgesic compounds. Tolerability (S&B) was assessed using a scale of 0 to 10, where a zero represents an absence of any S&B, a 1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is the worst pain imaginable. Likewise, the 0 to 5 Erythema scale represents the amount of reddening visually observed on the skin where a zero rating is an absence of reddening, a 1 rating indicates slight reddening of the skin, a 3 rating indicates a dark red color, and a 5 is purple.

[0263] A 53 year old male applied both formulations at the same time. The two formulations were applied side by side and then Tolerability (S&B) and Erythema (reddening) ratings were taken for each formulation application over a 120 minute period. The ratings are shown in S&B Table and Redness Table below. The tolerability of Formulation 2 (2% Capsaicin HA plus Analgesics) was not only at the extreme low end of the tolerability scales by both measures, but was even lower than Formulation 1 (2% Capsaicin HA) by direct comparison. For Formulation 1, a maximum S&B rating of 2.0 and a maximum Erythema rating of 1.5 were observed by the 20 minute time point. Both ratings gradually decreased to zero by the 90 minute time point. For Formulation 2, a maximum S&B rating of 1.5 was observed at the 30 minute time point, and then gradually decreased to zero by the 90 minute time point. Formulation 2 Erythema maximum was observed by the 20 minute time point at a rating of 0.5 and this rating decreased to zero by the 60 minute time point.

TABLE-US-00026 S&B Table Tolerability Comparisons (Scale 0 to 10) Elapsed Time of Formulation Formulation Rating #1 Rating #2 Rating 2 Minutes 0.5 0 5 Minutes 1.0 0.5 10 Minutes 1.5 1.0 20 Minutes 2.0 1.5 30 Minutes 2.0 1.0 45 Minutes 1.0 0.5 60 Minutes 0.5 0 90 Minutes 0 0 120 Minutes 0 0

TABLE-US-00027 Redness Table Erythema Comparisons (Scale 0 to 5) Elapsed Time of Formulation Formulation Rating #1 Rating #2 Rating 2 Minutes 0 0 5 Minutes 0.5 0 10 Minutes 1.0 0 20 Minutes 1.0 0.5 30 Minutes 1.5 0.5 45 Minutes 1.0 0.5 60 Minutes 0.5 0 90 Minutes 0 0 120 Minutes 0 0

[0264] Despite containing 2% capsaicin, both formulations were observed to be very tolerable in terms of both the stinging and burning sensation (S&B), as well as visual reddening (Erythema). Furthermore, addition of analgesics to 2% Capsaicin HA (Formulation 2, Capsaicin HA plus Analgesics) resulted in lower ratings of both S&B sensation and erythema relative to 2% Capsaicin HA (Formulation 1, Capsaicin HA).

Example 15

[0265] Single Dose Treatment of Back Muscles with a 10% Capsaicin-HA Formulation

[0266] A 79 year old man used a 10% capsaicin HA formulation for mitigation of pain in his back due to his back muscles seizing up in spasm and causing intense pain. The formulation used contained 10% w/w capsaicin along with hyaluronic acid (HA) and utilized Cremaphore RH40 as a stabilization agent (see Table below).

Efficacy:

[0267] A 79 year old man still with an active lifestyle (and a history of back problems) was playing tennis when his back went out while picking up a tennis ball. He collapsed on the court, and any attempt to move caused him intense pain that he rated as an 8 on a scale of 0 to 10 (where zero is an absence of pain and a 10 is the worst pain imaginable). The subject was practically immobilized and lay flat on his back on the tennis court and required assistance to get up and be moved to a bed. He reported that the muscles in his middle and lower back has seized up from an abnormality with a nerve in his back (doctors had previously explained to him). Previously when this problem had occurred he required many days of bed rest to recover. Once in bed, he requested his wife to apply 10% capsaicin and hyaluronic acid (with Cremaphore RH40) formulation over a 1212 area on his back where the muscles had seized up in spasm. About 90% of the treatment area consisted of muscle with the spine in the middle. When a single dose of this 10% capsaicin formulation with hyaluronic acid was applied, the pain was eliminated in his back within 20 minutes following application. The muscles in his back had relaxed. The muscle spasms were gone and he began to move around in normal motions without pain over the course of one hour. At the end of two hours, he felt normal and went out and resumed his tennis game. The capsaicin with HA formulation had provided relief that previously had only been achieved from days of bed rest and restricted activity.

Tolerability:

[0268] The subject observed the topical application of this formulation to be very tolerable (not irritating). He observed only minor Stinging and Burning (S&B) irritation upon application to his back. When the formulation was applied to the relatively large area on his back he gradually felt a warming sensation grow over the initial 2 to 3 minutes following application. The subject noted this was a comforting sensation. He observed that at its maximum, the Stinging and Burning sensation (S&B) was rated at no more than a 2.5 on a scale of 0 to 10 (defined as zero meaning no S&B sensation, 5 denoting intolerable pain and 10 representing the worst pain imaginable). Erythema (reddening) was present across the entire area of application very evenly, and appeared at its worst to look like a mild sunburn. At its worst, this erythema was estimated at a rating of 1.5 on a scale of 0 to 5: where a zero represents a complete absence of erythema, a 1 is slight reddening, a 3 as dark red and a 5 as purple. In terms of both S&B sensation and erythema, the subject found the formulation to be very tolerable.

TABLE-US-00028 Formulation Composition Table INGREDIENTS wt. % CAPSAICIN (Formosa) 10 CREMOPHOR RH 40 12 ETHYL ALCOHOL (Grain Alcohol) 20 ETHOXYDIGLYCOL (DGME) 10 PROPYLENE GLYCOL 10 .sup.(1) HYALURONIC ACID AQUEOUS SOLUTION 38 TOTAL 100 Note: .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.

Example 16

[0269] Tolerability of a 5% Capsaicin-HA Formulation Containing Polysorbate 80 to Knees Afflicted with Osteoarthritis

TABLE-US-00029 Formulation Composition Table Ingredients Function Wt. % Capsaicin Defunctionalization of 5.0 TRPV-1 sensory neurons Hyaluronic Viscosity enhancer & 0.15 Acid ~1,000K moisturizing agent Daltons Hyaluronic Viscosity enhancer & 0.35 Acid ~11K moisturizing agent Daltons Ethyl Alcohol Solvent 20 DGME Solvent & penetration 10 enhancer Propylene Glycol Solvent & penetration 10 enhancer Polysorbate 80 Surfactant, emulsifier & 10 solubilizing agent Water Solvent q.s.

[0270] A 70 year old man applied a 5% capsaicin HA formulation containing polysorbate 80 (composition shown in table above) to both of his knees afflicted with osteoarthritis. The man experienced no burning and stinging or pruritus for 32 minutes (duration of study) following topical application.

[0271] While the invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

[0272] All documents and other information sources cited herein are hereby incorporated in their entirety by reference.