PAIN RELIEF COMPOSITIONS, MANUFACTURE AND USES

Abstract

The present invention relates to TRPV1 selective agonist topical compositions including capsaicinoid and analgesic agent compositions and 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) 2-30% by weight of a capsaicinoid, and ii) 50-95% by weight of an analgesic agent comprising a) a topical salicylate and b) a TRPM8 agonist or a TRPV3 agonist, capable of solubilizing said capsaicinoid, wherein said topical salicylate solubilizes said capsaicinoid, and wherein said composition comprises an amount of analgesic agent sufficient to eliminate or reduce the burning or stinging sensation or erythema created by the topical administration of the capsaicinoid to a mammal, and wherein the composition is in a form selected the group consisting of sprays, gels, emulsions, and mixtures thereof.

2. The composition as claimed in claim 1, wherein said analgesic agent comprises a topical salicylate, a TRPM8 agonist, and a TRPV3 agonist.

3. The composition as claimed in claim 1, wherein said composition is a gel.

4. The composition as claimed in claim 1, wherein said capsaicinoid is capsaicin.

5. The composition as claimed in claim 1, wherein said capsaicinoid is trans-capsaicin or nonivamide.

6. The composition as claimed in claim 1, wherein said TRPM8 agonist is menthol, icilin or eucalyptol.

7. The composition as claimed in claim 1, wherein the TRPV3 agonist is camphor.

8. The composition as claimed in claim 1, wherein said analgesic agent comprises i) methyl salicylate and ii) at least one of menthol, camphor and phenol.

9. The composition as claimed in claim 1, wherein said composition further comprises an alcohol.

10. The composition as claimed in claim 1, wherein said composition comprises: 2-30% by weight of a capsaicinoid, 30-70% by weight methyl salicylate, 1-20% by weight menthol, and 1-20% by weight camphor, wherein the percentage by weight of the methyl salicylate, menthol, and camphor is greater than 50% of the composition.

11. The composition as claimed in claim 1, wherein said composition comprises: 2-30% by weight of a capsaicinoid, 30-75% by weight methyl salicylate and ethanol, 1-20% by weight menthol, and 1-20% by weight camphor, wherein the percentage by weight of the methyl salicylate, menthol, and camphor is greater than 50% of the composition.

12. The composition as claimed in claim 1, wherein said composition comprises: 2-30% by weight of a capsaicinoid, 40-75% by weight methyl salicylate, 10-25% ethanol, 10-20% by weight menthol, and 10-20% by weight camphor.

13. The composition as claimed in claim 1, wherein said composition comprises: 2-30% by weight of capsaicin, 40-75% by weight methyl salicylate 10-25% ethanol, 10-20% by weight menthol, 10-20% by weight camphor, and 0.5-5% phenol.

14. The composition as claimed in claim 11, wherein said composition further comprises glycerol.

15. The composition as claimed in claim 14, wherein said composition is a gel.

16. The composition as claimed in claim 1, wherein said composition further comprises an anti-inflammatory agent.

17. The composition as claimed in claim 1, wherein said composition further comprises a surfactant.

18. The composition as claimed in claim 1, wherein said composition further comprises an NSAID.

19. The composition as claimed in claim 18, wherein the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen, ketoprofen, and diclofenac.

20. The composition as claimed in claim 1, wherein said composition further comprises an odor reducing agent.

21. The composition as claimed in claim 1, wherein said composition further comprises phenol.

22. The composition as claimed in claim 11, wherein said composition further comprises phenol.

23. A composition comprising: 2-30% by weight of a capsaicinoid, methyl salicylate and ethyl alcohol, and phenol, wherein said methyl salicylate and ethyl alcohol solubilize said capsaicinoid, wherein the percentage by weight of the methyl salicylate and phenol is greater than 50% of the composition, and wherein the composition is in a form selected the group consisting of sprays, gels, emulsions, and mixtures thereof.

24. The composition as claimed in claim 23, wherein said composition comprises: 2-30% by weight of a capsaicinoid compound, 30-75% by weight methyl salicylate and ethyl alcohol, and 0.5-5% phenol.

25. A composition comprising: 2-30% by weight of a capsaicinoid, and 70-95% by weight of an analgesic agent comprising a topical salicylate, wherein said topical salicylate solubilizes said capsaicinoid, and wherein said composition comprises an amount of analgesic agent sufficient to eliminate or reduce the burning or stinging sensation or erythema created by the topical administration of the capsaicinoid to a mammal, wherein said composition does not include turpentine oil, and wherein the composition is in a form selected the group consisting of sprays, gels, emulsions, and mixtures thereof.

26. The composition as claimed in claim 25, wherein said analgesic agent comprises a topical salicylate and a TRPM8 agonist.

27. The composition as claimed in claim 25, wherein the composition is a gel.

28. The composition as claimed in claim 25, wherein said analgesic agent is i) methyl salicylate and ii) at least one of menthol, camphor and phenol.

29. The composition as claimed in claim 25, wherein said composition further comprises an alcohol.

30. The composition as claimed in claim 26 wherein said composition further comprises a TPRV3 agonist.

31. The composition as claimed in claim 27, wherein said gel comprises capsaicin, methyl salicylate, camphor and menthol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0094] FIG. 1 shows the tolerability of API-CAPS (0%, 2%, 5%, 10% or 20% capsaicin) following once daily, 60 minute exposure, treatment of osteoarthritic knees for 4 consecutive days. Subjects rated tolerability (burning & stinging sensation) at 15, 30, 45, and 60 minutes after API-CAPS application on a 0-10 numeric rating scale (0=no pain; 10-worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

[0095] FIG. 2 is a plot of the tolerability of API-CAPS (0%, 2%, 5%, 10% or 20% capsaicin) following once daily, 60 minute exposure, treatment of osteoarthritic knees for 4 consecutive days. Subjects rated tolerability (burning & stinging sensation) at 15, 30, 45, and 60 minutes after API-CAPS application on a 0-10 numeric rating scale (0=no pain; 10-worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

[0096] FIG. 3 shows the end of study percent pain reduction from initial osteoarthritic pain level prior to initiation of short-term API-CAPS, 0.25% capsaicin, therapy (two weeks of treatment applied three times per day, five days per week).

[0097] FIG. 4 is a bar chart graph displaying the tolerability of API-CAPS, 0.25% capsaicin, treatment following each application over the course of two weeks of treatment applied three times per day, five days per week. Subjects rated tolerability (burning sensation) on a 0-10 numeric rating scale (0=no pain; 10=worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

[0098] FIG. 5 shows the molecular structures of selected analgesic ingredients: menthol, camphor, methyl salicylate, eucalyptol, lavender oil, and phenol.

DETAILED DESCRIPTION OF THE INVENTION

[0099] The invention relates to compositions, typically liquid solution pharmaceutical formulations, of a TRPV1 selective agonist (i.e. acting as specific agonist for TRPV1 such as does capsaicin) agonist such as capsaicin or a capsaicin derivative/analogue, primarily for the treatment of pain. The compositions include one or more analgesics which reduce or eliminate the burning or stinging pain caused by administration of the TRPV1 selective agonist, thereby making the TRPV1 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 one or more topical analgesics at high concentration(s) such as methyl salicylate, camphor, menthol and phenol, than the same composition without an analgesic. Unlike conventional formulating where a base vehicle is selected and the actives are added thereto, in the formulations of the subject invention, the actives, the analgesics, are the vehicle or are the primary vehicle. The analgesic components of the formulations of the invention together make up typically greater than 50%, or 60%, 70% or greater than 75% by weight of the formulations.

[0100] The present invention provides immediate pain relief from the analgesic agent along with 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, the formulations of the present invention maintain sensation in the skin onto which the formulation has been topically applied.

[0101] 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, antioxidant 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.

[0102] 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 camphor, methyl salicylate and/or alcohol, and menthol, and optionally phenol, which are generally accepted as safe and effective for the temporary relief of minor aches and pains of muscles and joints associated with simple backache, arthritis, strains, bruises and sprains.

[0103] 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.

[0104] It has been demonstrated that the analgesic properties of 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 menthol, camphor, and methyl salicylate, and optionally phenol which also enhances the analgesic properties that minimize the burning/stinging sensation produced following topical application capsaicin. Other suitable/compatible analgesic oils such as peppermint oil (which also contains menthol), eucalyptus oil, lavender oil and other analgesic oils can be added to the topical mixture. Components can also be added which enhance the penetration of the capsaicin into the viable layers of the skin and into subcutaneous tissues.

[0105] 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 certainl cutaneous disorders and neural dysfunctions.

Compounds of the Invention

[0106] The components of the formulations of the invention are discussed below.

[0107] TRPV1 Selective Compounds Including Capsaicinoids, Capsaicin and its Analogues

[0108] According to the present invention, the pain relief composition comprises a therapeutically effective amount of a nerve-inhibiting component—a 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.

[0109] TRPV1 selective agonist compounds of the subject invention include the natural capsaicinoids (Capsaicin Oleoresin), and synthetic (Nonivamide) forms, as well as derivatives (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-00004 CAPSAICIN & CAPSAICINOID PROPERTIES Natural Scoville Capsaicinoid Relative Heat Molecular Name Abbr. MW Amount Units Formula Chemical Structure Capsaicin C 305 69% 10 × 10.sup.6 C.sub.18H.sub.27NO.sub.3 [00002] Dihydro- capsaicin DHC 307 22% 15 × 10.sup.6 C.sub.18H.sub.29NO.sub.3 [00003] Nordihydro- capsaicin NDHC 293 7% 9.1 × 10.sup.6 C.sub.17H.sub.27NO.sub.3 [00004] Homodihydro- capsaicin HDHC 321 1% 8.6 × 10.sup.6 C.sub.19H.sub.31NO.sub.3 [00005] Homo- capsaicin HC 319 1% 8.6 × 10.sup.6 C.sub.19H.sub.29NO.sub.3 [00006] Nonivamide PAVA 293 .sup.(1)0.25% 16 × 10.sup.6 C.sub.17H.sub.27NO.sub.3 [00007] .sup.(1)Constant et al, J. Nat. Prod., 1996, 59, 425-426

[0110] As noted above, 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.

[0111] 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.

[0112] 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).

[0113] 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.

[0114] Both the naturally occurring capsaicin and the synthetic capsaicin analogues that differ slightly in their alkyl chain, have similar pharmacological effects.

[0115] Capsaicin is practically insoluble in water, but freely soluble in alcohol, methyl salicylate, ether, benzene and chloroform. Capsaicin is a lipophilic white crystalline powder; melting point 60-65 degrees C.

[0116] Therapeutically, capsaicin has been used as a topical analgesic. Both the natural and synthetic (forms of capsaicin are available commercially.

[0117] Capsaicinoids in addition to capsaicin are applicable to this invention.

[0118] 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.

[0119] The formulations of the invention typically include 0.075-30% by weight, 0.2-30%, or 2-20%, 2-10% or 5-15% of 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.

Analgesics and Other Components

[0120] The compositions of the subject invention also include an analgesic agent—one 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 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. In one embodiment, the analgesic agent does not include turpentine oil.

[0121] Accordingly, it was discovered that a system of analgesic compounds can function to: (1), solubilize appreciable concentrations of the relatively aqueous insoluble capsaicin and related capsaicinoids and TRPV1 selective agonists; (2), rapidly penetrate the skin surface and underlying dermis and epidermis; and (3) reduce or eliminate the burning and stinging sensation and erythema associated with the topical administration of the TRPV1 (e.g. capsaicin), including reducing thermal hyperalgesia (enhanced sensitivity to heat) associated with the topical administration of the TRPV1 selective agonist (e.g. capsaicin) which can occur hours to days after administration of the TRPV1 selective agonist. The subject invention includes the use of specific topical analgesics that have a fast “onset of action” relative to capsaicin (such as methyl salicylate, menthol, camphor, and phenol) to effectively moderate the burning effect of capsaicin when concomitantly administered with capsaicin topically. Onset of action of a compound is linked to its physicochemical properties; some of which are summarized below.

TABLE-US-00005 Oil Aqueous Log MP Onset of Ingredients MW Soluble Soluble. O/W (° C.) Action Capsaicin 305.41 soluble insoluble 3.327 62-65 moderate Methyl 152.15 Alcohol sparingly 2.23 −9 fast Salicylate miscible Ethyl 46.07 soluble miscible −0.18 −114 fast Alcohol Phenol 94.11 soluble soluble 10 43 fast Menthol 156.26 soluble slightly 2.66 42 fast soluble Camphor 152.23 soluble Slightly 2.089 176 fast soluble Lidocaine 234.34 soluble insoluble 2.359 68 slow Prilocaine 220.31 soluble sparingly 2.11 137 slow Benzocaine 165.19 Soluble sparingly 1.95 90 moderate

[0122] The use of these selected topical analgesics with a fast onset of action effectively moderates the burning effect of capsaicin when concomitantly administered topically, but also provides more immediate pain relief relative to capsaicin. In one embodiment of the invention, the topical analgesic agent has a molecular weight of 160 or less. Capsaicin provides more long term/long lasting pain relief relative to these fast onset of action topical analgesics.

[0123] 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 analgesics such as methyl salicylate, camphor, menthol, and phenol (when compared to the same composition without analgesic), 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.

[0124] The analgesic agent of the invention is one or more agents selected from the group consisting of methyl salicylate and/or alcohol (30-75% by weight), a TRPM8 agonist (e.g. menthol, icilin or eucalyptol), and a TRPV3 agonist (e.g. camphor). The analgesic agent (which can be multiple compounds) is capable of solubilizing the TRPV1 selective agonist. The analgesic components of the formulations of the invention are typically greater than 50% by weight of the formulations.

Topical Salicylates Including Methyl Salicylate

[0125] Methyl salicylate can act as an analgesic and anti-inflammatory agent. Some of the plants which produce it are called wintergreens, hence the common name. Trolamine salicylate, the active ingredient in Aspercreme™ is another salicylate which can be used in topical pain compositions. Esters of methyl salicylate have also been made. It has been found that methyl salicylate can be used advantageously as a solvent to dissolve capsaicinoids.

[0126] The formulations of the invention typically include 30-70% or 40-60% by weight methyl salicylate.

Menthol

[0127] 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 subfamilyM8 (TRPM8) agonist such as icilin or eucalyptol can be used.

[0128] The formulations of the invention include 1-20%, 10-20% by weight menthol.

Camphor Camphor is readily absorbed through the skin and produces a feeling of cooling similar to that of menthol, and acts as slight local anesthetic. Camphor is a naturally occurring compound. Alternatively, another transient receptor potential vanilloid 3 (TRPV3) agonist such as icilin or eucalyptol can be used.

[0129] The formulations of the invention include 1-20%, 10-20%, or 5-15% by weight camphor.

Phenol

[0130] 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.

[0131] The formulations of the invention can include 0-4.6%, advantageously 1-3% phenol. Eugenol/clove oil and thymol/thyme oil or an Essential Oil (see Table II or Table below) can be added in addition to, or as alternative to phenol. Below is a listing of natural analgesic ingredients together with some of their properties.

TABLE-US-00006 NATURAL FUNCTION ANALGESIC Anti- Anti- Anti- Anti- INGREDIENTS Analgesic Anesthetic Antiseptic Fungal Bacterial Rubefacient inflammatory Pruritic Menthol X X X X X X (Mint Oils) Camphor X X X X X X Wintergreen Oil X X X X X (methyl salicylate) Phenol X X X X X X X Eugenol/Clove oil X X X X X X Thymol/Thyme Oil X X X X X X X X Eucalyptus Oil X X X X X X Peppermint Oil X X X X X X Lavender Oil X X X X X Tea Tree Oil X X X X X X Turpentine Oil X X X X X X

Alcohol

[0132] In another embodiment of the invention, the methyl salicylate is replaced with, or supplemented with an alcohol such as ethyl alcohol or benzyl alcohol, which like methyl salicylate, can solubilize capsaicinoids as well as menthol and camphor. This results in compositions with lower viscosity and shorter drying times. In one embodiment where the methyl salicylate is replaced with ethanol, glycerol can be added to the composition.

Surfactants and Other Agents that Enhance Skin Penetration

[0133] One or more surfactant(s), advantageously non ionic (e.g. polysorbates such as PS80, sorbitan esters (Spans), poloxamers, etc.), can be also be added to the compositions of the invention to enhance the skin penetration of the analgesic and capsaicin compounds. 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 which are utilized in pharmaceutical, cosmetics and food stuffs are especially advantageous because of the compatibility with biological tissues.

[0134] Other penetrating agents include propylene glycol, αBisabolol, and other oil soluble organic compounds known in the art of topical formulation development which can enhance skin penetration.

Anti-Inflammatory Agents

[0135] Apigenin & αBisabolol

[0136] 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 (e.g. apigenin and αbisabolol).

[0137] Apigenin offers some of nature's most potent and effective anti-inflammatory and antioxidant 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).

[0138] αBisabolol is another potent anti-inflammatory sesquiterpene which is known to also have anesthetic, anti-irritant, anti-inflammatory, anti-fungal and anti-microbial properties. αBisabolol is also demonstrated to enhance the percutaneous absorption of certain molecules. αBisabolol 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. Phann. 70:87-94 (1991).)

NSAIDs/Diclofenac Sodium

[0139] 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.

[0140] 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.

[0141] 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.

Odor Reduction Components

[0142] Many topically applied analgesic formulations contain a blend of volatile aromatic compounds and essential oils which are used for the temporary relief of minor aches and pains of muscles and joints associated with simple backache, arthritis, sprains, bruises and strains. For example: White Flower Analgesic Balm consists of the active ingredients: Methyl Salicylate (Wintergreen Oil) 40%, Menthol 15%, Camphor 6% and other ingredients; Eucalyptus Oil 18%, Peppermint Oil 15%, and Lavender Oil 6%. However, all the components of White Flower Analgesic Balm are known for their distinctive odors such that these combined ingredients do contribute to a strong, penetrating pungent, odor that is objectionable for many users and to many individuals who come in contact with the users. Further, the magnitude of the perceived odor of these volatile aromatic compounds and essential oils often increases within closed spaces such as in automobiles, buses, planes, and poorly ventilated rooms, etc. The teachings of this invention are particularly advantageous in the reduction of the severity of these perceived odors from the aforementioned topical analgesic compounds whose combined concentration often exceeds more than 35% by weight of a formulation.

[0143] Inclusion of relatively non-odiferous oils with low ambient vapor pressures such as Aloe Vera, Coconut, Borage and/or Macadamia Nut Oils to formulations containing significant quantities of volatile topical analgesic compounds such as methyl salicylate, camphor and menthol results in a significant reduction in the perception of these strongly penetrating pungent aromatic odors. This effect is particularly useful with formulations having relatively high capsaicin concentrations.

Aloe Vera Oil

[0144] Aloe Vera in Aloe Vera Oil is a nutrient rich ingredient used in skin preparations as it contains Vitamin C, E, Beta-Carotene, and B12, minerals such as magnesium, copper, chromium, calcium, iron and potassium, essential amino acids, plant sterols and lignin.

[0145] Aloe Vera is rich in anti-inflammatory, emollient, anti-fungal, anti-bacterial and anti-viral properties, making it a potent remedy for many skin ailments. The various enzymes in Aloe Vera reduce the itching, swelling and inflammation that often accompany common skin ailments. Aloe Vera has been used to treat wounds, burns, scalds and even sunburn. The plant extract counters bacterial infection while improving circulation and expediting the healing process. Aloe Vera is useful for cell regeneration.

Coconut Oil

[0146] Coconut Oil is useful in the treatment of skin conditions such as eczema, psoriasis, rosacea and various other skin infections; and helps to reduce or eliminate itching and flaking of the skin due to dryness. Coconut Oil contains vitamin E, which is necessary for healthy skin, as well as the medium-chain fatty acids Capric Acid, Caprylic Acid, Caproic Acid and Lauric Acid.

[0147] It moisturizes the skin, either alone or in combination with other oils, and is an exceptional base oil for moisturizing creams and oils and aromatherapy blends. Coconut Oil's antioxidant properties can help delay wrinkles and sagging skin related to aging by preventing the formation of free radicals and strengthening the skin's underlying connective tissues, as well as by limiting the damage caused by excessive sun exposure.

Borage Oil

[0148] Topical application of borage oil has been shown to be effective in preventing and treating inflammatory conditions and skin disorders, such as eczema and dermatitis, in both animals and humans. Although essential fatty acids are important in diet, they can also play an important role when applied topically to the skin. Borage Oil is the richest known source (24%) of an essential fatty acid called gamma-linolenic acid (GLA). These polyunsaturated essential fatty acids are essential for the structure and flexibility of the cell membranes and also play an important role in the construction of the epidermal lipid barrier. They therefore can help normalize trans-epidermal water loss. Borage oil is extremely high in mucilage and also contains pyrrolizdine alkaloids. The main constituents of the oil are vitamin C, saponins, tannins and minerals. The tannins in the oil have a slight tightening effect on the skin and the oil helps to restore moisture and smoothness to dry skin, soothing irritated and damaged skin. Borage oil also helps provide relief to people who suffer from chronic skin disorders, such as eczema and atopic dermatitis.

Macadamia Nut Oil

[0149] This hypoallergenic “oil” contains a high concentration of palmitoleic Acid, 18%, in addition to 60% oleic acid, 2.7% linoleic acid, 3% omega-3 and omega-6. Macadamia Nut Oil indeed is an effective emollient that gives a rich skin feel. The oil has several natural healing properties as well. Many are finding great success using it to help with irritated skin, small wounds, and to reduce the coloration in scars.

[0150] The stability of Macadamia Nut Oil makes it an ideal ingredient for an array of cosmetic applications. Macadamia Nut Oil is known to be a protective oil with a respectable and reasonably quick absorption rate. Macadamia Nut Oil acts in a similar way as does the human sebum that naturally protects and lubricates the skin. The oils regenerative properties make it a quality ingredient for products targeting damaged skin.

Compositions of the Invention

[0151] The invention relates to a compositions, advantageously a liquid solution, comprising a TRPV1 selective agonist, and an analgesic agent 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 analgesic agent 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 a non aqueous solution. If ethanol is in the solution, water can be included. Typically, the water is less than 5%, or advantageously less than 2% by wt. In the compositions of the subject invention, inert ingredients (i.e. other than the TRPV1 selective agonist, and the analgesics) typically comprise less than 25%, 10% or 5% by weight, of the composition.

[0152] The TRPV1 selective agonists, analgesic agents and excipients suitable for use in the pharmaceutical compositions of the present invention, are those which are pharmaceutically acceptable when applied to human skin, ie 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.

[0153] 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.

[0154] The TRPV1 selective agonist can be a vanilloid, or in an advantageous embodiment, a capsaicinoid such as capsaicin.

[0155] The analgesic agent that solubilizes the TRPV1 selective agonist, is one or more agent selected from the group consisting of methyl salicylate (30-70% by weight), a TRPM8 agonist (e.g. menthol, icilin or eucalyptol), and a TRPV3 agonist (e.g. camphor). The analgesic agent is typically greater than 50% by weight of the composition and is capable of solubilizing said TRPV1 selective agonist. [0156] Advantageous components of the compositions of the invention are:
capsaicin or a related compound,
methyl salicylate and/or ethanol,
menthol,
camphor, and optionally
phenol.

[0157] When combined with analgesic/desensitizing ingredients, the amount of capsaicin (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. %.

[0158] The amount of analgesic ingredients to achieve the above effect is greater than 50 wt. %, or in the range of 60 wt. % to 95 wt. % of the preparation.

[0159] Advantageous formulations of the invention include (by weight):

methyl salicylate and/or ethanol ˜30-75 wt. %, advantageously 40-60 wt. %
menthol, ˜1-20 wt. %, advantageously 10-20 wt. %
camphor ˜1-20 wt. %, advantageously 5-15 wt. %, and optionally
phenol 0-4.6 wt. %, advantageously 0.5-2 wt. %.

[0160] Advantageous embodiment of the invention without a TRPV1 selective agonist includes: a composition comprising: [0161] 30-75% by weight methyl salicylate and/or ethanol, [0162] 1-20% by weight menthol, [0163] 1-20% by weight camphor, and [0164] optionally phenol, [0165] wherein the percentage by weight of the methyl salicylate, menthol, and camphor is greater than 50% of the composition;

[0166] In another embodiment, the invention includes

a composition comprising:
a capsaicinoid,
methyl salicylate and/or ethyl alcohol, and
phenol,
wherein the percentage by weight of the methyl salicylate and phenol is greater than 50% of the composition. M ore specifically in this embodiment the composition can comprise:
0.075-30% by weight of a capsaicinoid compound,
30-75% by weight methyl salicylate and/or ethyl alcohol,
and
0.5-5% phenol.

[0167] Table III, IIIA, and IIIB contain a listing of the compositions of several prepared Nonivamide and Capsaicin formulations.

TABLE-US-00007 TABLE III INGREDIENTS OF PREPARED NONIVAMIDE FORMULATIONS Form Form Form Form Form .sup.(16) Form .sup.(16) Form Form Form 1 2 3 4 5 6 7 8 9 INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % .sup.(1) NONIVAMIDE   0.2   1.8 4   1.8 1.8 1.8 1.8   1.8   1.8 .sup.(2) METHYL SALICYLATE 20  35  45  35  49.2 55 55 55  55  .sup.(3) MENTHOL 6 13  15  13  15 15 0 15  0 .sup.(4) CAMPHOR 3 6 8 9 11 0 10 0 10  .sup.(5) PHENOL 0 0 0   1.5 2 0 0 0 0 .sup.(6) αBISABOLOL NATURAL 0 0 0 1 1 0 0 0 0 .sup.(7)HYDROCORTISONE 1 1 1 0 0 0 0 0 0 .sup.(8) POLYSORBATE 80   9.25   9.25   9.25   9.25 9.25 0 0 0 0 .sup.(9) APIGENIN   0.75   0.75   0.75   0.75 0.75 0 0 0 0 .sup.(10) ETHYL ALCOHOL 0 0 0 0 10 20 20 20  20  .sup.(11) GLYCEROL 0 0 0 0 0 8.2 9 0 00  .sup.(12) PROPYLENE GLYCOL 0 0 0 0 0 0 4.2 0 0 Balance Including: .sup.(13) 59.8   .sup.(13) 33.2   .sup.(13) 17.0   .sup.(13) 28.7   0 0 0 .sup.(14) 8.2   .sup.(14) 13.2   Aloe Vera, Coconut & Macadamia Nut Oils TOTAL 100  100  100  100  100 100 100 100  100  Form Form Form Form Form Form Form 10 11 12 13 14 15 16 INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt % Wt % .sup.(1) NONIVAMIDE   1.8   0.25   0.25 5 10  15   1.8 .sup.(2) METHYL SALICYLATE 55  45  45  50  50  50 50  .sup.(3) MENTHOL 0 15  15  15  15  15 15  .sup.(4) CAMPHOR 0 10  10  11  11  10.5 11  .sup.(5) PHENOL 0 2 2 2 2 1.5 2 .sup.(6) αBISABOLOL NATURAL 0 0 0 1 1 1 0 .sup.(7)HYDROCORTISONE 0 0 0 0 0 0 0 .sup.(8) POLYSORBATE 80 0 0   9.25   9.25   9.25 7.4 0 .sup.(9) APIGENIN 0 0   0.75   0.75   0.75 0.60 0 .sup.(10) ETHYL ALCOHOL 20  10  10  0 0 0 0 .sup.(11) GLYCEROL 0 0 0 0 0 0 0 .sup.(12) PROPYLENE GLYCOL 0 0 0 0 0 0 0 Balance Including: .sup.(14) 23.2   .sup.(14) 17.75   .sup.(14) 7.75  .sup.(15) 6 .sup.  .sup.(15) 1 .sup.  0 .sup.(15) 20.2   Aloe Vera, Coconut & Macadamia Nut Oils TOTAL 100  100  100  100  100  100 100  NOTE: .sup.(1) Nonivamide, Aversion Technologies Inc., CAS # 2444-46-4 .sup.(2) Methyl Salicylate, Spectrum Chemical, NF, CAS # 119-36-8 .sup.(3) L-Menthol, Crystal, Spectrum Chemical, USP, CAS # 2216-51-5 .sup.(4) Camphor, Synthetic, Spectrum Chemical, USP, CAS # 76-22-2 .sup.(5) Phenol, Liquefied (Carbolic Acid), USP, Spectrum Chemical, CAS # 108-95-2 .sup.(6) Alpha Bisabolol Natural (96%) from Alpha Aesar, CAS # 515-69-5 .sup.(7)Hydrocortisone, USP, Spectrum CAS 50-23-7 .sup.(8) Polysorbate 80, Super refined, Croda Inc., CAS # 9005-65-6 .sup.(9) Apigenin 98.sup.+%, Skyherb Technologies Co., Ltd, Lot # 0000418019 .sup.(10) Ethyl Alcohol, Graves Grain Alcohol, 190 Proof .sup.(11) Glycerin, Lotioncrafters, USP, CAS # 56-81-5 .sup.(12) Propylene Glycol, .sup.(13) Aloe Vera Oil obtained from Spectrum Chemical, Product # A1612, CAS # 85507-69 .sup.(14) Coconut Oil, Nature's Way EfaGold Coconut Oil, Pure Extra Virgin .sup.(15) Macadamia Nut Oil, CAS #128497-20-1, Lotioncrafters Lot # 1506-3187 .sup.(16) The shaded highlighted columns, Form 6 & 7, experienced phase separation

TABLE-US-00008 TABLE IIIA INGREDIENTS OF PREPARED CAPSAICIN FORMULATIONS Form Form Form Form Form Form Form Form Form Form 1A 2A 3A 4A 5A 6A 7A 8A 9A 10A INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % .sup.(1) CAPSAICIN, NATURAL 0.25 1.8 0 0 0 0 0 0 0 0 .sup.(2) TRANS-CAPSAICIN 0 0 0.25 0.25 2.0 2.0 5.0 10.0 15.0 20 .sup.(3) METHYL SALICYLATE 0 0 50 50 50 50 50 50 50 50 .sup.(4) MENTHOL 0 0 15 15 15 15 15 15 15 15 .sup.(5) CAMPHOR 0 0 11 11 11 11 11 11 11 11 .sup.(6) PHENOL 0 0 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 .sup.(7) POLYSORBATE 80 9.25 9.25 0 9.25 0 9.25 0 0 0 0 .sup.(8)APIGENIN 0.75 0.75 0 0.75 0 0.75 0 0 0 0 .sup.(9) WHITE FLOWER 89.75 88.2 0 0 0 0 0 0 0 0 ANALGESIC BALM .sup.(10) MACADAMEA NUT OIL 0 0 22.25 12.25 20.50 10.50 17.50 12.50 7.50 2.50 TOTAL 100 100 100 100 100 100 100 100 100 100 NOTE: .sup.(1) Natural Capsaicin, Sigma Aldrich, Product # 360376, CAS # 404-86-4, 65% Capsaicin & 35% Dihydrocapsaicin .sup.(2) Trans-Capsaicin, Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, Batch # 30111007N, USP 30 .sup.(3) Methyl Salicylate, Spectrum Chemical, (NF, CAS # 119-36-8) .sup.(4) L-Menthol, Crystal, Spectrum Chemical, USP, CAS # 2216-51-5 .sup.(5) Camphor, Synthetic, Spectrum Chemical, USP, CAS # 76-22-2 .sup.(6) Phenol, Liquefied, USP, Spectrum Chemical, CAS # 108-95-2 .sup.(7) Polysorbate 80, Super refined, Croda Inc., CAS # 9005-65-6 .sup.(8)Apigenin 98.sup.+%, Skyherb Technologies Co., Ltd, Lot # 0000418019 .sup.(9) White Flower Analgesic Balm, Contains 40% Methyl Salicylate, 15% Menthol, 6% Camphor, 18% Eucalyptus Oil, 15% Peppermint Oil, & 6% Lavender Oil .sup.(10) Macadamia Nut Oil, Lotioncrafters Lot # 1506-3187

TABLE-US-00009 TABLE IIIB INGREDIENTS OF PREPARED ESSENTIAL OIL-FREE CAPSAICIN FORMULATIONS Form Form Form Form .sup.(9) Form .sup.(9) Form Form Form Form Form Form Form 1B 2B 3B 4B 5B 6B 7B 8B 9B 10B 11B 12B INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % .sup.(2) TRANS-CAPSAICIN 0 0.25 2.0 5.0 0 5.0 0 0.25 2.0 5.0 10 0 .sup.(2) ETHYL ALCOHOL 50 50 50 50 0 0 22.5 22.25 20.5 17.5 12.5 0 .sup.(3) METHYL SALICYLATE 0 0 0 0 50 50 50 50 50 50 50 50 .sup.(4) MENTHOL 15 15 15 15 15 15 15 15 15 15 15 15 .sup.(5) CAMPHOR 11 11 11 11 11 11 11 11 11 11 11 11 .sup.(6) PHENOL 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 .sup.(7) GLYCERIN, USP 22.5 22.25 20.5 17.5 22.5 17.5 0 0 0 0 0 0 .sup.(8) MINERAL OIL, USP 0 0 0 0 0 0 0 0 0 0 0 22.5 TOTAL 100 100 100 100 100 100 100 100 100 100 100 100 NOTE: .sup.(1) Trans-Capsaicin, Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, USP 30 .sup.(2) Ethyl Alcohol, Graves Grain Alcohol, 190 Proof .sup.(3) Methyl Salicylate, Spectrum Chemical, NF, CAS # 119-36-8 .sup.(4) L-Menthol, Crystal, Spectrum Chemical, USP, CAS # 2216-51-5 .sup.(5) Camphor, Synthetic, Spectrum Chemical, USP, CAS # 76-22-2 .sup.(6) Phenol, Liquefied (Carbolic Acid), USP, Spectrum Chemical, CA 108-95-2 .sup.(7) Glycerin, Lotioncrafters, USP, CAS # 56-81-5 .sup.(8) Mineral Oil, USP Grade, CVS .sup.(9) The shaded highlighted columns, Form 5B & 6B, experienced phase separation

[0168] 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

[0169] Capsaicin, nonivamide, camphor and menthol are solids at room temperatures with melting points of 60-62° C., 54° C., 175-177° C., and 42-45° C., respectively. Significantly, methyl salicylate functions as the prime solubilizing agent for the relatively aqueous insoluble solid capsaicin, camphor and menthol ingredients. Methyl salicylate is a liquid at room temperature (with a melting point of −9° C.) and with concentration levels up to 75 wt. %, is the formulation's most concentrated ingredient. (As noted in Table III, the analgesic agent concentration exceeded >50% for several of the formulations.)

[0170] A series of solubility experiments verified that the solubility levels of nonivamide in methyl salicylate exceeded 25 wt. %. The addition of nonivamide powder to the 30 wt. % nonivamide/methyl salicylate solution at ambient temperature and also cooling the 30 wt. % nonivamide/methyl salicylate solution to −10° C. for 10 hours did not result in the precipitation of nonivamide thereby indicating the utility of the methyl salicylate as a solvent. Further, there was no evidence of any precipitation of nonivamide from the concentrated 30 wt. % nonivamide solution after 2 weeks of storage at 5° C. Similar results were obtained with capsaicin.

[0171] Consequently, methyl salicylate functions as a primary component in a mixture of compounds to: (1), solubilize appreciable concentrations of the relatively aqueous insoluble capsaicin, related capsaicinoids and other solid ingredients including menthol and camphor; (2), penetrate the skin surface and underlying dermis and epidermis; and (3), reduce or eliminate the burning and stinging (B&S) sensation associated with the topical administration of a capsaicinoid.

[0172] Initial capsaicin formulations with concentrations ranging from 0.25-10.0 wt. % were prepared with White Flower Analgesic Balm and apigenin/Polysorbate 80 concentrate as detailed in Example 1 below. White Flower Analgesic Balm consists of the ingredients: Methyl Salicylate (Wintergreen Oil) 40%, Menthol 15%, Camphor 6% and Eucalyptus Oil 18%, Peppermint Oil 15%, and Lavender Oil 6%.

[0173] Example 1 describes the preparation Formulation 2A (Table IIIA) of a 1.8 wt. % Capsaicin, 0.75 wt. % Apigenin & White Flower Analgesic Balm Formulation.

[0174] Example 2 describes the preparation of Formulation 9 (Table III) containing a Nonivamide concentration of 1.8 wt. %.

[0175] Example 3 describes the preparation of Formulation 4 (Table III) containing a Nonivamide concentration of 1.8 wt. %.

[0176] Example 4 describes the preparation of Formulation 11 (Table III) containing a Nonivamide concentration of 0.25 wt. %.

[0177] Example 5 describes the preparation of Formulation 7A (Table IIIA) containing a Trans-Capsaicin concentration of 5 wt. %.

[0178] Example 6 describes the preparation of Formulation 6A (Table IIIA) containing a Trans-Capsaicin concentration of 2.0 wt. %.

[0179] Example 7 describes the preparation of Formulation 3B (Table IIIB), an alcohol based formulation, containing a Trans-Capsaicin concentration of 2.0 wt. %.

[0180] Example 8 describes the preparation of Formulation 9B (Table IIIB) containing ethyl alcohol and a Trans-Capsaicin concentration of 2.0 wt. %.

[0181] Example 9 describes methods of using the formulations.

[0182] Example 10 describes human skin tests of nonivamide and trans-capsaicin formulations.

[0183] Example 11 describes treatment of shoulder pain with trans-capsaicin 0.25% and 2.0% formulations.

[0184] Example 12 describes API-CAPS-001: a randomized, single-blind, multiple dose study of the safety and tolerability of API-CAPS in subjects with osteoarthritis of the knee.

[0185] Example 13 describes API-CAPS-004: 0.25% API-CAPS topical treatment for osteoarthritis pain in hands and knees of adult patients.

[0186] Example 14 describes API-CAPS-005: multiple dose case studies of treatment with API-CAPS for pain from osteoarthritis in the elderly.

[0187] Example 15 describes components elimination comparison.

[0188] Example 16 describes API-CAPS-002, cohort 1: 0.25% API-CAPS (0.25% w/w trans-capsaicin, USP) & capzasin HP arthritis pain relief analgesic cream (0.1% capsaicin).

[0189] Example 17 describes diclofenac solubility studies.

Methods of Using the Formulations

Pain

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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, oral pain, and pain caused by injury, amongst others. The formulations can be used to relieve aches and pains of muscles and joints.

[0194] 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

[0195] The composition of the present invention can be used topically by rubbing over an area to be treated. A typical method of use is to 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.

[0196] 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.

[0197] 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

[0198] 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. 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

Intranasal

[0203] When used intranasally, capsaicin irritates the nasonasal area. However, the area becomes desensitized to the irritation after repeated use. Nerve endings responsible for rhinorrhea, sneezing, and congestion become desensitized when capsaicin is applied to the nasal mucosa. Capsaicin use has been targeted at patients presenting congestion, rhinorrhea, sneezing, or a combination of these symptoms. Clinical studies revealed a 60% reduction in nasal airway resistance. In most patients, effectiveness continued for more than 4 months.

Kits

[0204] The invention also includes kits comprising a liquid TRPV1 selective agonist composition, and

[0205] a non-occlusive applicator device. The kit can also include a cleaning solution for removal of residual TRPV1 selective agonist such as polyethylene glycol.

[0206] 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 the 1.8 wt. % Capsaicin, 0.75 wt. % Apigenin & White Flower Analgesic Balm Formulation

Form 2A, TABLE IIIA

Step I—Preparation of the Apigenin/Polysorbate 80 (PS80) Concentrate

[0207] Ingredients include: [0208] 9.25 grams of Super Refined PS80, CRODA, Inc. CAS #9005-65-6 [0209] 0.75 grams of Apigenin powder, Skyherbs Technologies Co., Lot #0000418019

Procedure:

[0210] 1. Add 9.25 grams of the Super Refined PS80 to a 50 cc “Pyrex” beaker. [0211] 2. Add 0.75 grams of Apigenin powder to the PS80. [0212] 3. Heat the PS80/Apigenin mixture to a temperature slightly in excess of ˜275° C. At about 200° C., it will be observed that the mixture will take on a light brown/reddish color which will darken when the Apigenin is completely solubilized at 275° C. [0213] 4. The Apigenin/PS80 solution is set aside and allowed to cool to <100° C.

Step II— the Preparation of a Liquid Solution of Selected Ingredients

Ingredients:

[0214] 88.2 grams of While Flower Analgesic Balm [0215] 1.8 grams of Capsaicin, Natural, Sigma Aldrich, CAS #404-86-4

Procedure:

[0216] 1. Obtain the “tare weight” of a 200 cc beaker & add 88.2 grams of White Flower Analgesic Balm. [0217] 2. Add 1.8 grams of Capsaicin, Natural to the mixture from Step 1. Heat the mixture to about 40 to 50° C. to hasten the dissolving of the Capsaicin powder. (Note: Adhere to safety precautions in the handling of the powder. [0218] 3. Heat the above mixture to 40° C. to 50° C. while stirring to hasten the solution of the capsaicin. [0219] 4. Allow the solution mixture from Step 3 to cool to room temperature.

Step III—the Combining of the Step I & II Solutions Mixtures & Subsequent Centrifuging

[0220] Ingredients include: [0221] The solution mixture from STEP I [0222] The solution mixture from STEP II.

Procedure:

[0223] 1. The Apigenin/PS80 solution from STEP I is added to the solution mixture from STEP II and the combined mixture is thoroughly stirred. [0224] 2. The solution mixture from Step 1 is now ready to be centrifuged for 30 minutes in a MicroCentrifuge with a fixed speed of 3,100 RPM for 30 minutes (A Thermo Fischer Model 004480 F Microcentrifuge with slots for 6 15 ml centrifuge tubes).

[0225] The solution mixture from Step 1 is evenly divided amongst the 15 ml centrifuge tubes which are placed within the centrifuge. The centrifuge's timer is then set for 30 minutes which then activates the spinning process. [0226] 3. At the conclusion of the centrifugation process from Step 2, the supernatant liquid from each of the centrifuge tubes is decanted into a 200 ml Pyrex beaker. [0227] 4. The mixture from Step 3 is now ready for subsequent packaging.

Example 2

Preparation of 100 grams of the 1.8% Nonivamide/Apigenin Formulation

Form 9, TABLE III

Step I—the Preparation of a Liquid Solution of Selected Ingredients & Capsaicin

Ingredients:

[0228] 55 grams of NF grade Methyl Salicylate, Spectrum Chemical, CAS #119-36-8 [0229] 10 grams of USP grade Camphor, Spectrum Chemical, CAS #76-22-2 [0230] 1.8 grams of Nonivamide obtained from Aversion Technologies CO.; Bowie, Md., CAS #2444-46-4 [0231] 20 grams of Ethyl Alcohol, Graves grain alcohol, 190 Proof

Procedure:

[0232] 1. Obtain the “tare weight” of a 200 cc beaker & add 55 grams of NF grade Methyl Salicylate. [0233] 2. Add 10 grams of USP grade Camphor flakes to the mixture of Step 1. Heat the mixture to 40° C. to hasten the dissolving of the Camphor flakes while stirring. [0234] 3. Add 1.8 grams of Nonivamide to the mixture from Step 2. Heat the mixture to 40 to 50° C. to hasten the dissolving of the Nonivamide powder. (Note: Adhere to safety precautions in the handling of the powder.) [0235] 4. Allow the solution mixture from Step 3 to cool to room temperature and add 20 grams of Ethyl Alcohol.

Step II—the Addition of Other Ingredients to the Liquid Solution from Step I

[0236] Ingredients include: [0237] The solution mixture from STEP I [0238] 13.2 grams of Coconut Oil, Nature's Way EfaGold Coconut Oil, Pure Extra Virgin

Procedure:

[0239] 1. Add 13.2 grams of the Aloe Vera Oil to the mixture from Step I and thoroughly stir the resulting solution mixture. The mixture is now ready for subsequent packaging.

Example 3

Preparation of 100 Grams of the 1.8% Nonivamide/Apigenin Formulation

Form, 4 TABLE III

Step I—Preparation of the Apigenin/Polysorbate 80 (PS80) Concentrate

[0240] Ingredients include: [0241] 9.25 grams of Super Refined PS80, CRODA, Inc. CAS #9005-65-6 [0242] 0.75 grams of Apigenin powder, Skyherbs Technologies Co., Lot #0000418019

Procedure:

[0243] 1. Add 9.25 grams of the Super Refined PS80 to a 50 cc “Pyrex” beaker. [0244] 2. Add 0.75 grams of Apigenin powder to the PS80. [0245] 3. Heat the PS80/Apigenin mixture to a temperature slightly in excess of 275° C. At about 200° C., the it will be observed that the mixture will take on a light brown/reddish color which will darken when the Apigenin is completely solubilized at 275° C. [0246] 4. The Apigenin/PS80 solution is set aside and allowed to cool to <100° C.

Step II— the Preparation of the Selected Ingredients & Nonivamide Mixture

Ingredients:

[0247] 35 grams of NF grade Methyl Salicylate, Spectrum Chemical, CAS #119-36-8 [0248] 13 grams of USP grade Menthol, Spectrum Chemical, CAS #2216-51-5 [0249] 9 grams of USP grade Camphor, Spectrum Chemical, CAS #76-22-2 [0250] 1.8 grams of Nonivamide obtained from Aversion Technologies Co.; Bowie, Md., CAS #2444-46-4

Procedure:

[0251] 1. Obtain the “tare weight” of a 200 cc beaker & add 35 grams of NF grade Methyl Salicylate [0252] 2. Add 13 grams of USP grade menthol crystals to the Methyl Salicylate (Step 1). [0253] 3. Add 9 grams of USP grade Camphor flakes to the mixture of Step 2. Heat the mixture to 40° C. to hasten the dissolving of the menthol & Camphor while stirring. [0254] 4. Add 1.8 grams of Nonivamide to the mixture from Step 3. Heat the mixture to 40 to 50° C. to hasten the dissolving of the Nonivamide powder. (Note: Adhere to safety precautions in the handling of the powder.)

Step III—the Combining of the Step I & II Solutions Mixtures & Subsequent Centrifuging

[0255] Ingredients include: [0256] The solution mixture from STEP I [0257] The solution mixture from STEP II.

Procedure:

[0258] 1. The Apigenin/PS80 solution from STEP I is added to the solution mixture from STEP II and the combined mixture is thoroughly stirred. [0259] 2. The solution mixture from Step 1 is now ready to be centrifuged for 30 minutes in a MicroCentrifuge with a fixed speed of 3,100 RPM for 30 minutes (A Thermo Fischer Model 004480 F Microcentrifuge with slots for 6 15 ml centrifuge tubes). The solution mixture from Step 1 is evenly divided amongst the 15 ml centrifuge tubes which are placed within the centrifuge. The centrifuge's timer is then set for 30 minutes which then activates the spinning process. [0260] 3. At the conclusion of the centrifugation process from Step 2, the supernatant liquid from each of the centrifuge tubes is decanted into a 200 ml Pyrex beaker.

Step IV—the Addition of Other Ingredients to the Supernatant Liquid from Step III

[0261] Ingredients include: [0262] The solution mixture from STEP III [0263] 1 gram of Apha Bisabolol Natural, Aloha Aesar, CAS #515-69-5 [0264] 1.5 grams of Liquefied Phenol USP grade, Spectrum Chemical, CAS #108-95-2 [0265] 28.7 grams of Aloe Vera Oil, Spectrum Chemical, Product #A1612, CAS #85507-69

Procedure:

[0266] 1. Add 1 gram of Alpha Bisabolol Natural to the solution mixture from STEP III. [0267] 2. Add 1.5 grams of Liquefied Phenol USP grade to the solution mixture from Step 1 and stir the resulting solution mixture. [0268] 3. Add 28.7 grams of Aloe Vera Oil to the mixture from Step 2 and thoroughly stir the resulting solution mixture. [0269] 4. The mixture from Step 3 is now ready for subsequent packaging.

Example 4

Preparation of 100 grams of the 0.25% Nonivamide/Apigenin Formulation

Form 11, TABLE III

Step I—the Preparation of a Liquid Solution of Selected Ingredients & Capsaicin

Ingredients:

[0270] 45 grams of NF grade Methyl Salicylate, Spectrum Chemical, CAS #119-36-8 [0271] 15 grams of USP grade Menthol, Spectrum Chemical, CAS #2216-51-5 [0272] 10 grams of USP grade Camphor, Spectrum Chemical, CAS #76-22-2 [0273] 2 grams of Liquefied Phenol U.S.P., Spectrum Chemical, CAS #108-95-2 [0274] 1.8 grams of Nonivamide, Aversion Technologies Co.; Bowie, Md., CAS #2444-46-4 [0275] 10 grams of Ethyl Alcohol, Graves grain alcohol, 190 Proof Procedure: [0276] 1. Obtain the “tare weight” of a 200 cc beaker & add 45 grams of NF Methyl Salicylate. [0277] 2. Add 15 grams of USP grade Menthol flakes to the mixture of Step 1. [0278] 3. Add 10 grams of USP grade Camphor flakes to the mixture of Step 2. Heat the mixture to 40° C. to hasten the dissolving of the Camphor flakes while stirring. [0279] 4. Add 2 grams of USP grade Liquefied Phenol to the mixture of Step 3. [0280] 5. Add 1.8 grams of Nonivamide to the mixture from Step 4. Heat the mixture to 40 to 50° C. to hasten the dissolving of the Nonivamide powder. (Note: Adhere to safety precautions in the handling of the powder.) [0281] 6. Allow the solution mixture from Step 5 to cool to room temperature and add 20 grams of Ethyl Alcohol.

Step II— the Addition of Other Ingredients to the Liquid Solution from Step I

[0282] Ingredients include: [0283] The solution mixture from STEP I [0284] 17.75 grams of Coconut Oil, Nature's Way EfaGold Coconut Oil, Pure Extra Virgin

Procedure:

[0285] 1. Add 17.75 grams of Aloe Vera Oil to the mixture from Step I and thoroughly stir the resulting solution mixture. The mixture is now ready for subsequent packaging.

Example 5

Preparation of 100 Grams of the 5.0% Trans-Capsaicin Formulation

Form 7A, TABLE IIIA

STEP I—the Blending of the Ingredients to Produce the 5.0% Capsaicin Formulation

Ingredients:

[0286] 50.0 grams of Methyl Salicylate, Spectrum Chemical, NF, CAS #119-36-8 [0287] 15.0 grams of Menthol, Crystal, Spectrum Chemical, USP, CAS #2216-51-5 [0288] 11.0 grams of Camphor, Spectrum Chemical, USP, CAS #76-22-2 [0289] 1.5 grams of Liquefied Phenol, Spectrum Chemical, CAS #108-95-2 [0290] 5.0 grams of Trans-Capsaicin Powder, Aversion Technologies, Bowie, Md., USP [0291] 17.5 grams of Macadamia Nut Oil, Lotioncrafters Lot #1506-3187

Procedure:

[0292] 1. Add 50.0 grams of NF grade Methyl Salicylate to 250 cc “Pyrex” beaker. [0293] 2. Add 15.0 grams of USP grade Menthol Crystals to the Methyl Salicylate in Step 1. [0294] 3. Add 11.0 grams of Camphor flakes to the mixture in Step 2. [0295] 4. Heat the above mixture to 50° C. to 60° C. while stirring to hasten the solution of the solid Menthol & Camphor. [0296] 5. Add 5.0 grams of Trans-Capsaicin to the heated mixture from Step 5 while gently stirring to solubilize the Trans-Capsaicin. [0297] 6. Allow the solution from Step 5 to cool to 30° C. to 35° C. & then add 1.5 grams of Liquefied Phenol to the solution. [0298] 7. Add 17.5 grams of Macadamia Nut Oil to the solution from Step 6 & thoroughly stir. [0299] 8. Set aside the mixture & allow it to cool to ambient temperatures. [0300] 9. The mixture from Step 8 is now ready for subsequent packaging.

Example 6

Preparation of 100 Grams of the 2.0% Trans-Capsaicin/Apigenin

Form 6A, TABLE IIIA

[0301] Ingredients include: [0302] 9.25 grams of a Super Refined PS80, CRODA, Inc., CAS #9005-65-6 [0303] 0.75 grams of Apigenin powder, Skyherbs Technologies Co., Lot #0000418019 Procedure: [0304] 1. Add 9.25 grams of the highly purified PS80 to a 50 cc “Pyrex” beaker. [0305] 2. Add 0.75 grams of Apigenin powder to the PS80. [0306] 3. Heat the PS80/Apigenin mixture to a temperature slightly in excess of 275° C. At about 200° C., the it will be observed that the mixture will take on a light brown/reddish color which will darken when the Apigenin is completely solubilized at 275° C. [0307] 4. The Apigenin/PS80 solution is set aside and allowed to cool to <100° C.

STEP II— the Blending of the Ingredients to Produce the 5.0% Capsaicin Formulation

Ingredients:

[0308] 50.0 grams of Methyl Salicylate, Spectrum Chemical, NF, CAS #119-36-8 [0309] 15.0 grams of Menthol, Crystal, Spectrum Chemical, USP, CAS #2216-51-5 [0310] 11.0 grams of Camphor, Spectrum Chemical, USP, CAS #76-22-2 [0311] 1.5 grams of Liquefied Phenol, Spectrum Chemical, CAS #108-95-2 [0312] 5.0 grams of Trans-Capsaicin Powder, Powder, Aversion Technologies, Bowie, Md., USP 30 [0313] 17.5 grams of Macadamia Nut Oil, Lotioncrafters Lot #1506-3187 [0314] 10.0 grams of Apigenin/Polysorbate 80 Concentrate from STEP I.

Procedure:

[0315] 1. Add 50.0 grams of NF grade Methyl Salicylate to 250 cc “Pyrex” beaker. [0316] 2. Add 15.0 grams of USP grade Menthol Crystals to the Methyl Salicylate in Step 1. [0317] 3. Add 11.0 grams of Camphor flakes to the mixture in Step 2. [0318] 4. Heat the above mixture to 50° C. to 60° C. while stirring to hasten the solution of the solid Menthol & Camphor. [0319] 5. Add 5.0 grams of Trans-Capsaicin to the heated mixture from Step 4 while gently stirring to solubilize the Trans-Capsaicin. [0320] 6. Allow the solution from Step 5 to cool to 30° C. to 35° C. & then add 1.5 grams of Liquefied Phenol to the solution. [0321] 7. Add 17.5 grams of Macadamia Nut Oil to the solution from Step 6 & thoroughly stir. [0322] 8. Add the 10 grams of the Apigenin/Polysorbate Concentrate from STEP I to the solution from Step 7 and thoroughly stir. [0323] 9. Set aside the mixture from Step 8 & allow it to cool to ambient temperatures. [0324] 10. The mixture from Step 9 is now ready for subsequent packaging.

Example 7

Preparation of 100 grams of the 2.0% Trans-Capsaicin/50% Ethyl Alcohol/20.5% Glycerin Formulation Form 3B, TABLE IIIB

STEP I—the Blending of the Ingredients to Produce the 5.0% Capsaicin Formulation

Ingredients:

[0325] 50.0 grams of Ethyl Alcohol, Graves Grain Alcohol, 190 Proof [0326] 15.0 grams of Menthol, Crystal, Spectrum Chemical, USP, CAS #2216-51-5 [0327] 11.0 grams of Camphor, Spectrum Chemical, USP, CAS #76-22-2 [0328] 1.5 grams of Liquefied Phenol, Spectrum Chemical, CAS #108-95-2 [0329] 2.0 grams of Trans-Capsaicin Powder, Powder, Aversion Technologies, Bowie, Md., USP 30 [0330] 20.5 grams of Glycerin, Lotioncrafters, USP CAS #56-81-5

Procedure:

[0331] 1. Add 50.0 grams of Ethyl Alcohol to 250 cc “Pyrex” beaker. [0332] 2. Add 15.0 grams of USP grade Menthol Crystals to the Methyl Salicylate in Step 1. [0333] 3. Add 11.0 grams of Camphor flakes to the mixture in Step 2. [0334] 4. Heat the above mixture to 40° C. to 50° C. while stirring to hasten the solution of the solid Menthol & Camphor. [0335] 5. Add 2.0 grams of Trans-Capsaicin to the heated mixture from Step 5 while gently stirring to solubilize the Trans-Capsaicin. [0336] 6. Allow the solution from Step 5 to cool to 30° C. to 35° C. & then add 1.5 grams of Phenol to the solution. [0337] 7. Add 20.5 grams of Glycerin to the solution from Step 6 & thoroughly stir. [0338] 8. Set aside the mixture & allow it to cool to ambient temperatures. [0339] 9. The mixture from Step 8 is now ready for subsequent packaging.

Example 8

Preparation of 100 Grams of the 2.0% Trans-Capsaicin/50% Methyl Salicylate/20.5% Ethyl Alcohol Formulation

Form 9B, TABLE IIIB

STEP I—the Blending of the Ingredients to Produce the 5.0% Capsaicin Formulation

Ingredients:

[0340] 50.0 grams of Methyl Salicylate, Spectrum Chemical, NF, CAS #119-36-8 [0341] 15.0 grams of Menthol, Crystal, Spectrum Chemical, USP, CAS #2216-51-5 [0342] 11.0 grams of Camphor, Spectrum Chemical, USP, CAS #76-22-2 [0343] 1.5 grams of Liquefied Phenol, Spectrum Chemical, CAS #108-95-2 [0344] 2.0 grams of Trans-Capsaicin Powder, Powder, Aversion Technologies, Bowie, Md., USP 30 [0345] 20.5 grams of Ethyl Alcohol, Graves Grain Alcohol, 190 Proof

Procedure:

[0346] 1. Add 50.0 grams of Methyl Salicylate to 250 cc “Pyrex” beaker. [0347] 2. Add 15.0 grams of USP grade Menthol Crystals to the Methyl Salicylate in Step 1. [0348] 3. Add 11.0 grams of Camphor flakes to the mixture in Step 2. [0349] 4. Heat the above mixture to 40° C. to 50° C. while stirring to hasten the solution of the solid Menthol & Camphor. [0350] 5. Add 2.0 grams of Trans-Capsaicin to the heated mixture from Step 5 while gently stirring to solubilize the Trans-Capsaicin. [0351] 6. Allow the solution from Step 5 to cool to 30° C. to 35° C. & then add 1.5 grams of Phenol to the solution. [0352] 7. Add 17.5 grams of Ethyl Alcohol to the solution from Step 6 & thoroughly stir. [0353] 8. Set aside the mixture & allow it to cool to ambient temperatures. [0354] 9. The mixture from Step 8 is now ready for subsequent packaging.

Example 9

Human Skin Test of Natural Capsaicin, Nonivamide and Trans-Capsaicin Formulations

[0355] First Test—OTC “CapZasin” and Nonivamide

[0356] Adult male and female of normal health tested the following formulations:

[0357] Formulation #1. OTC “CAPZASIN” containing 0.15% natural capsaicin (in roll-on dispenser)

[0358] Formulation #2. OTC “CAPZASIN” 0.10 natural capsaicin (cream)

[0359] Formulation #3. 0.25% Nonivamide concentration, Formulation 12, TABLE III (45% methyl salicylate, 15% menthol, 10% camphor, 9.25% PS80, 0.75% apigenin, 10% ethyl alcohol, 7.75% coconut oil)

[0360] Formulation #4. 1.8% Nonivamide concentration, Formulation 4, TABLE III, (35% methyl salicylate, 13% menthol, 9% camphor, 9.25% PS80, 0.75% apigenin, 1.5% phenol, 1% alpha bisabolol, 28.7% aloe vera oil)

[0361] Subjects applied the above formulations to the topside (dorsal) of the right forearm.

[0362] After 30 minutes Subject A reported most S&B from Formulation #1 while Subject B reported most S&B from formulation #2. Subjects A & B reported no S&B, during the first 30 minute period for Formulations #3 & #4.

[0363] After 60 minutes Subject A reported most S&B from Formulation #1 while Subject B reported most S&B from formulation #2. Subjects A & B reported no S&B, during the first 60 minute period for Formulations #3 & #4.

[0364] After 90 minutes Subject A reported most S&B from Formulation #1 while Subject B reported most S&B from formulation #2. After 90 minutes Subject A reported redness of skin along with S&B from Formulation #1 and redness of skin without S&B from Formulation #4. After 90 minutes Subject B did not report any redness of skin. After 90 minutes Subject A washed off all formulations with rubbing alcohol. While showering 24 hours later, Subject A still felt some S&B from formulation #1.

[0365] Both Subjects A & B, using a scale of 1-10 with 10 being the most S&B, reported a maximum level of 2-3 for the above trial during the first 90 minute period for Formulations #1 & #2. Both Subjects A & B reported no S&B, during the first 90 minute period for Formulations #3 & #4.

[0366] Subject B did NOT wash off the formulations at all and 12 hours later, still felt some S&B from Formulations #1 & #2. Subject B 12 hours later still felt some S&B from Formulations #1 & #2 at level 3.

[0367] After 24 hours, Subject A still felt some S&B from formulations #1 & at level 2. After 24 hours, both Subjects A & B reported no S&B for formulations #3 & #4.

Second Test —Trans-Capsaicin at 5%, 10% and 15%

Formulations 7A, 8A & 9A TABLE IIIA

[0368] Same adult male and female subjects of normal health (A and B) also tested the following Trans-Capsaicin formulations (referred to here as “Capsaicin”):

[0369] 1. 5% Capsaicin concentration (50% methyl salicylate, 15% menthol, 11% camphor, 17.5% macadamia nut oil, 1.5% phenol)

[0370] 2. 10% Capsaicin concentration (50% methyl salicylate, 15% menthol, 11% camphor, 12.5% macadamia nut oil, 1.5% phenol)

[0371] 3. 15% Capsaicin concentration (50% methyl salicylate, 15% menthol, 11% camphor, 7.5% macadamia nut oil, 1.5% phenol)

[0372] Each subject applied the above formulations to the topside (dorsal) of the left forearm. “Stinging & Burning” sensations (S&B) were rated on a scale of 0 to 10. Erythema (reddening) observations were rated on a scale of 0 to 5 (0 being no erythema):

After 10 Minutes:

Subject A Reported:

[0373] S&B (stinging and burning) of 1 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 1 with a 15% Capsaicin concentration
Erythema of 0 (zero) with all three Capsaicin concentrations

Subject B Reported:

[0374] S&B of 2 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 2 with a 15% Capsaicin concentration
Erythema of 0 (zero) with all three Capsaicin concentrations

After 20 Minutes:

Subject A Reported:

[0375] S&B of 1 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 1 with a 15% Capsaicin concentration
Erythema of 0 (zero) with 5% Capsaicin concentration
Erythema of 1 with both 10% & 15% Capsaicin concentrations

Subject B Reported:

[0376] S&B of 2 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 2 with a 15% Capsaicin concentration
Erythema of 0 (zero) with all three Capsaicin concentrations

After 30 Minutes:

Subject A Reported:

[0377] S&B of 0 (zero) with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 1 with a 15% Capsaicin concentration
Erythema of 0 (zero) with 5% Capsaicin concentration
Erythema of 2 with both 10 & 15% Capsaicin concentrations

Subject B Reported:

[0378] S&B of 2 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 2 with a 15% Capsaicin concentration
Erythema of 0 (zero) with all three Capsaicin concentrations

After 40 Minutes:

Subject A Reported:

[0379] S&B of 0 (zero) with a 5% Capsaicin concentration
S&B of 1 with a 10% Capsaicin concentration
S&B of 1 with a 15% Capsaicin concentration
Erythema of 0 (zero) with 5% Capsaicin concentration
Erythema of 2 with both 10 & 15% Capsaicin concentrations

Subject B Reported:

[0380] S&B of 1 with a 5% Capsaicin concentration
S&B of 1 with a 10% Capsaicin concentration
S&B of 1 with a 15% Capsaicin concentration
Erythema of 0 (zero) with all three Capsaicin concentrations

After 50 Minutes:

Subject A Reported:

[0381] S&B of 0 (zero) with a 5% Capsaicin concentration
S&B of 0 (zero) with a 10% Capsaicin concentration
S&B of 0 (zero) with a 15% Capsaicin concentration
Erythema of 0 (zero) with 5% Capsaicin concentration
Erythema of 1 with both 10% & 15% Capsaicin concentrations

Subject B Reported:

[0382] S&B of 0 (zero) with a 5% Capsaicin concentration
S&B of 0 (zero) with a 10% Capsaicin concentration
S&B of 0 (zero) with a 15% Capsaicin concentration
Erythema 0 (zero) with all three Capsaicin concentrations

After 90 Minutes:

Subject A Reported:

[0383] S&B of 0 (zero) with a 5% Capsaicin concentration
S&B of 1 with a 10% Capsaicin concentration
S&B 0 (zero) with a 15% Capsaicin concentration
Erythema of 0 (zero) with 5% Capsaicin concentration
Erythema of 1 with both 10% & 15% Capsaicin concentrations

Subject B Reported:

[0384] S&B of 0 (zero) with a 5% Capsaicin concentration
S&B of 0 (zero) with a 10% Capsaicin concentration
S&B of 0 (zero) with a 15% Capsaicin concentration
Erythema 0 (zero) with all three Capsaicin concentrations

After 150 Minutes:

Subject A Reported:

[0385] S&B of 1 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 2 with a 15% Capsaicin concentration
Erythema of 0 (zero) with 5% Capsaicin concentration
Erythema 1 with both 10% & 15% Capsaicin concentrations

Subject B Reported:

[0386] S&B of 2 with a 5% Capsaicin concentration
S&B of 2 with a 10% Capsaicin concentration
S&B of 2 with a 15% Capsaicin concentration
Erythema of 0 (zero) with all three Capsaicin concentrations

[0387] After 150 minutes: residual formulations were washed-off the skin using soap and cold water.

Example 10

Human Skin Tests of Nonivamide and Trans-Capsaicin Formulations

Nonivamide Formulation (Formulation 13, TABLE III)

5% Nonivamide

[0388] 50-year old male of normal health applied single topical application of 5.0% nonivamide solution (50% methyl salicylate, 15% menthol, 11% camphor, 9.25% PS80, 0.75% apigenin, 6% macadamia nut oil, 2% phenol, 1% alpha bisabolol) for 90 minutes prior to washing off with soap and water.

[0389] A single application of formulation via several passes from a roller-ball bottle was made to a 50 cm.sup.2 area (7 cm×7 cm) of skin on subject's arm, 20 cm above the elbow joint on the top side of subject's left arm. Stinging and Burning sensations (S&B) were rated on a scale of 0-10. Erythema (reddening) was rates on a scale of 0-5 (0 no erythema).

[0390] Subject observed a gradual onset of a slight, but tolerable, burning sensation over the first 20 minutes following application. Maximum irritation (S&B) rated at 2.5 (on a scale of 0 to 10) was observed after 20 minutes. This 2.5 irritation level continued for 20 minutes until the 40-minute mark. From the 40 minute mark to the 60 minute mark, the subject observed a gradual reduction of irritation such that as of the 60 minute mark the irritation level was a 1.5 rating (on a scale of 0 to 10). Complete cessation of irritation had occurred by the 80-minute mark. All levels of irritation were considered to be well within a “tolerable” level for topical use in subject's opinion.

[0391] In addition, reddening (erythema) and subsequent cessation of reddening of the entire 50 cm.sup.2 application area was observed over the initial 90 minute period of application. Subject observed a reddening rated of a 1 (on a scale of 0 to 5) after 5 minutes, to a rating of 2 after 10 minutes, and a rating of 3 after 15 minutes. The 3 rating was the maximum observed and continued at this level for 25 minutes until the 40 minute mark. Reddening gradually lessened beginning after the 40-minute mark and was completely gone after 70 minutes following application. Reddening was uniform and no blotching or other form of inconsistent effect was observed. By the 20-minute mark, the area of reddening had expanded beyond the 50 cm.sup.2 application area by 1.5 cm in all directions to encompass a total area of reddening of 72 cm.sup.2. This was deemed due to the spreading of the formulation over the surface of the skin outside the original application site.

Finalgon—European OTC Product (0.4% Nonivamide)

[0392] For comparison purposes, subject applied a European OTC Nonivamide product called Finalgon which contains a Nonivamide concentration of 0.4%. In this application of 0.4% Finalgon subject (50 year old male of normal health) observed a relatively intense burning sensation which was significantly greater than that which occurred with the application of 5.0% Nonivamide of the invention. Subject rated the Finalgon-induced burning sensation at a 5 to 6 (on the same scale of 0 to 10) 30 minutes after application. In addition, a more severe form of erythema was experienced on the Finalgon area of application relative to the 5.0% Nonivamide formulation of the invention. Subject rated the Finalgon-induced erythema at a 4 (on the same scale of 0 to 5 used to estimate erythema) 30 minutes after application. Subject believed the S&B and erythema were “intolerable” 30 minutes following application and Finalgon was washed off at that point.

Trans-Capsaicin Formulations

5% Trans-Capsaicin Formulation 7A, Table IIIA

[0393] A 50-year old male of normal health applied a single topical application of 5% trans-capsaicin (50% methyl salicylate, 15% menthol, 11% camphor, 17.5% macadamia nut oil, 1.5% phenol) solution for 120 minutes prior to washing off.

[0394] Application of the formulation via a 10 ml roller-ball bottle on a 50 cm.sup.2 (7 cm×7 cm) area of skin arm, 20 cm below the elbow joint on the underside (ventral) of subject's right forearm (a relatively sensitive area of skin). Several passes of the roller-ball were undertaken to cover the entire 50 cm.sup.2 application area.

[0395] Subject observed a gradual onset of a mild, but tolerable, burning sensation over the first 20 minutes following application. This irritation was observed and rated (on a scale of 0-10) to be a 1 after 2 minutes, a 2 after 5 minutes and a 3 after 20 minutes. Maximum irritation rated at a 3 was observed after 20 minutes. This irritation rating of a 3 irritation continued for only 10 minutes until the 30-minute mark. The irritation level had decreased to a rating of 2 by the 40 minute mark. From the 40-minute mark to the 80-minute mark, the subject observed a gradual reduction of irritation, which was observed to be reduced from a 2 rating to a 0.5 rating (on a scale of 0-10) over this period. Complete cessation of irritation occurred at the 120 minute mark. All levels of irritation were considered to be well within a “tolerable” level for topical use in subject's opinion. In addition, reddening (erythema) and the subsequent cessation of reddening of the entire 50 cm.sup.2 application area was observed over the initial 90 minute period following application. Subject observed a reddening rated at a 1 (on a scale of 0-5) after 10 minutes, to a rating of 1.5 after 20 minutes, and a rating of 2 after 30 minutes. This reddening rating of 2 was the maximum level observed and lasted from the 30 minute mark until the 60 minute mark. Reddening gradually lessened after the 60-minute mark and was completely gone after 120 minutes following application. Reddening was uniform and no blotching or other form of inconsistent effect was observed. By the 20-minute mark, the area of reddening had expanded beyond the 50 cm.sup.2 application area by 1.5 cm in all directions to encompass a total area of reddening of 72 cm.sup.2 due to the spreading of the formulation over the surface of the skin outside of the original application site.

[0396] After 20 minutes, the skin area of application became more sensitive to touch. Sensitivity to touch decreased after 60 minutes.

0.1% and 0.15% OTC Product Trans-Capsaicin Formulations

First Test:

[0397] For comparison purposes, subject (50 year old male) had previously applied two U.S. OTC products which each contain capsaicin as its active ingredient. These two OTC products were CAPZASIN-HP (containing 0.1% capsaicin) and GELLERT Joint Care (containing 0.17% capsaicin). Products were both creams and were applied to the inner (ventral) side of subject's left arm (a relatively sensitive area of skin). The application of 0.1% CAPZASIN-HP and 0.17% GELLERT Joint Care caused subject a burning sensation which was about the same as that observed for application of 5.0% Trans-Capsaicin. For 0.1% CAPZASIN-HP and GELLERT Joint Care the burning sensation was rated at a 2.5 and a 3 respectively (on the same scale of 0 to 10 used to estimate burning/S&B in 5% Trans-Capsaicin formulation) 30 minutes after application. Subject considered the burning irritation from both U.S. OTC products to be “intense” yet still within a “tolerable” level for topical use. A slight erythema was observed for both U.S. OTC products. Subject rated erythema in both cases at a 1 (on the same scale of 0 to 5 used to estimate erythema) 30 minutes after application.

Second Test:

[0398] Subject applied the same two OTC products tested above a second time, but this time on a different area of the skin. CAPZASIN-HP (containing 0.1% capsaicin) and GELLERT Joint Care (containing 0.17% capsaicin) are both creams and were applied to the inner (ventral) side of subject's lower left leg. After 20 minutes CAPZASIN-HP and GELLERT Joint Care had a burning sensation rating of a 1 and a 2, respectively (on the same scale of 0 to 10 used to estimate burning/S&B in 5% Trans-Capsaicin formulation). After 30 minutes each had a burning rating of a 1.5 and 2.5 respectively (the maximum observed for each). From the 30 minute mark to the 90 minute mark both OTC products showed a gradual lessening of the burning sensation such that none was observed by the 90 minute mark in both products. Leg was tanned and no erythema (rating 0) was observed.

10% Trans-Capsaicin Formulation 8A, TABLE IIIA

[0399] A 50-year old male of normal health applied a single topical application of 10% trans-capsaicin ((50% methyl salicylate, 15% menthol, 11% camphor, 12.5% macadamia nut oil, 1.5% phenol)) solution for 120 minutes prior to washing off.

[0400] Application of formulation via 10 mg roller-ball bottle was undertaken to achieve an initial dosing on a 50 cm.sup.2 (7 cm×7 cm) area of skin on his 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 20 cm.sup.2 application area.

[0401] Subject observed a slight itching a minute after application. Subject noticed a gradual increase in burning sensation over the first 20 minutes until a burning level of 2 (on a scale of 0-10) was observed at the 20 minute mark. The burning sensation remained at a 2 level for 10 minutes until the 30 minute mark. At the 40 minute mark, the burning sensation level had increased to a 2.5, where it remained for 20 minutes until the 60 minute mark. Maximum irritation was rated at a 2.5 (on a scale of 0-10). At the 90-minute mark the burning sensation had dropped to a 2 level. From that point forward subject observed a gradual reduction of irritation. The burning sensation level had decreased to a rating of 1 (on a scale of 0-10) by the 120-minute mark. By the 180-minute mark, the subject noted that the irritation was no more than a 0.5 rating. All levels of irritation were considered to be well within a “tolerable” level for topical use in subject's opinion.

[0402] In addition, reddening (erythema) and cessation of reddening of the entire 50 cm.sup.2 application area was observed over a 180 minute period following application. Subject observed a reddening rated at 0.5 (on a scale of 0-5) after 10 minutes, to a rating of 1.5 after 20 minutes, a rating of 2.5 after 30 minutes and a rating of 3 after 60 minutes. This reddening rating of 3 was the maximum level. After the 60 minute mark, the reddening gradually lessened and was completely gone after 180 minutes following application. Reddening was uniform and no blotching or other form of inconsistent effect was observed.

[0403] By the 20 minute mark, the area of reddening had expanded beyond the 50 cm.sup.2 application area by 1.5 cm in all directions to encompass a total area of reddening of 72 cm.sup.2.

[0404] The area became sensitive to the touch after the 15 minute mark. This sensitivity increased and eventually subsided over time and intensity in a manner that was consistent with the observation of erythema.

10% Trans-Capsaicin Formulation with Ethanol and Methyl Salicylate Formulation 11B, TABLE IIIB

[0405] A normally healthy 50-year old male applied a single topical application of a 10% Trans-Capsaicin (50% methyl salicylate, 15% menthol, 11% camphor, 1.5% phenol, 12.5% ethyl alcohol) solution for 80 minutes prior washing off the residual formulation from the application area.

[0406] The liquid formulation was applied to a 50 cm.sup.2 (7 cm×7 cm) area of skin on the left shoulder via a 10 ml roller-ball bottle. Absorption of the formulation was almost immediate and the area of skin to which formulation was applied was almost dry after one minute, and completely dry after two minutes.

[0407] A minute after application, subject noted a slight itching on the application area. Subject noticed a gradual increase in burning sensation over the first 10 minutes. On a scale of (0-10), the subject indicated a burning (S&B) level of 1 at the 10 minute mark. The burning sensation remained relatively constant at a 1 level for the next 40 minutes (i.e., from the 10 to 50 minute mark. At the 60 minute mark the burning sensation had dropped to a 0.5 level. By the 80-minute mark, the subject noted that the irritation was gone, and the recordation was ended. The subject indicated that the maximum irritation (S&B) was rated at a 1.0 (on a scale of 0-10) and that all levels of irritation were considered to be well within a “tolerable” level for topical use in subject's opinion, and in fact hardly noticeable.

[0408] Additionally, minimal reddening (erythema) of the entire 50 cm.sup.2 application area was observed over the 80 minute duration following application. The subject indicated a reddening level at 0.5 (on a scale of 0-5) after 5 minutes, which gradually increased to a 1.0 after 10 minutes, a 1.5 after 20 minutes. This reddening rating of 1.5 was the maximum level observed. At the 60 minute mark, the reddening had gradually decreased to a level of 0.5, and remained constant at 0.5 when recordation was ended 80 minutes following application. Reddening was uniform and no blotching was observed, The subject observed that the area of erythema did not spread beyond the application area.

Example 11

Treatment of Shoulder Pain with Trans-Capsaicin 0.25% and 2.0% Formulations

Formulations 3A & 5A, TABLE IIIA

[0409] A 57-year old male of normal health applied multiple topical applications of 0.25% trans-capsaicin (50% methyl salicylate, 15% menthol, 11% camphor, 22.25% macadamia nut oil, 1.5% phenol) solution followed by 2.0% trans-capsaicin solution (50% methyl salicylate, 15% menthol, 11% camphor, 20.5% macadamia nut oil, 1.5% phenol) for the treatment of shoulder pain. Applications of formulation via a 10 ml roller-ball bottle were applied twice daily to the right shoulder. The area of application was ˜40 cm.sup.2 (5 cm×8 cm) of skin.

[0410] The 0.25% trans-capsaicin solution was applied initially twice-a-day for 2 days. The subject experienced no redness (erythema) and no stinging or burning at any time following the four topical applications of the formulation. The subject reported significant relief of shoulder pain but elected to go to a higher concentration of trans-capsaicin for potential increased efficacy.

[0411] The 2.0% trans-capsaicin solution was applied twice-a-day for 3 days. The subject experienced no redness (erythema) at any time following the six topical applications of the formulation. Levels of burning and stinging were reported as tolerable. No burning and stinging were experienced immediately (first hours) following application. Two events of moderate burning were experienced: first, on the second day while showering with hot water and then during the third night while sleeping. In both cases the level of burning was tolerable. The subject reported significant relief of shoulder pain and increased mobility and ability to use his right arm.

Example 12

[0412] API-CAPS-001: A Randomized, Single-Blind, Multiple Dose Study of the Safety and Tolerability of API-CAPS in Subjects with Osteoarthritis of the Knee

Hypothesis/Study Objective

[0413] The effect of the novel API-CAPS composition is expected to minimize the burning effect of capsaicin following topical application to tolerable levels while the formulation provides pain relief and enhanced joint mobility in the topical treatment of pain associated with osteoarthritis. The objective was to evaluate the efficacy, mobility improvement and tolerability of API-CAPS when applied topically for the treatment of pain from osteoarthritis of the knee. Five concentrations of API-CAPS (0%, 2%, 5%, 10% and 20% w/w trans-capsaicin, USP) were used in this study.

TABLE-US-00010 API-CAPS FORMULATION COMPOSITIONS 0% 2% 5% 10% 20% INGREDIENTS (Wt. %) (Wt. %) (Wt. %) (Wt. %) (Wt. %) TRANS-CAPSAICIN 0.0 2.0 5.0 10 20 ETHYL ALCOHOL 22.5 20.5 17.5 12.5 2.5 METHYL SALICYLATE 50 50 50 50 50 MENTHOL 15 15 15 15 15 CAMPHOR 11 11 11 11 11 PHENOL 1.5 1.5 1.5 1.5 1.5 TOTAL 100 100 100 100 100

Study Design

[0414] Chronic pain relief resulting from capsaicin is known to be dose dependent and temporary. Topical capsaicin is well tolerated except for a potential acute skin sensation of burning in the area of administration that diminishes over time and with multiple applications. Capsaicin products currently on the market are limited by this acute side effect. API-CAPS formulations were created to minimize potential capsaicin skin burning sensation and efficacious in topical pain treatment.

[0415] This was a phase 1, randomized, single-blind, multiple-dose, study of adult subjects with pain from osteoarthritis of the knee, conducted at two investigational centers. Each of the subject's knees (two knees per subject) was separately and randomly assigned in a 1:5 ratio to receive one of five concentrations (0%, 2%, 5%, 10% or 20% capsaicin) of API-CAPS and each knee was individually treated. Study medication was applied once daily to the skin of each knee independently by trained site staff at the investigational study centers for 4 consecutive days. The skin associated with the application site remained uncovered for 60 minutes after API-CAPS was applied. After 60 minutes, the area was cleansed by trained personnel to remove any residual formulation from the surface of the skin. Subjects were not allowed to apply the solution themselves or take the medication home. Subjects were instructed to avoid exposing the treated skin to any form of heat (hot water, vigorous exercise, direct sunlight, heating pad, etc.) until 24 hours after their final API-CAPS treatment. Subjects were also told not to apply any topical substances to the treated skin area and to avoid wearing tight clothing at the site of application during this time. If the subject experienced intolerable pain or severe irritation from the study medication after they left the clinic, they were allowed to apply cold water, ice, or a cold pack, and they were allowed to also take oral pain medications to ease the pain. All evaluations were performed at the study sites. Each subject signed an Informed Consent Form and had all questions answered before any study procedures were performed.

Study Data

[0416] Thirty subjects were enrolled and treated in this study. Of the 30 enrolled subjects, nine did not complete the full 4 applications per the protocol. Of these nine subjects: five discontinued the study in connection with Adverse Events and four did not return for unnamed reasons. Adverse events consisted of coughing deemed “possibly” or “probably” related to the study, resulting from multiple subjects treated with formulations on both knees utilizing the same small poorly ventilated waiting room at one or both sites. One subject, MTR, reported using oral medication for pain of burning. All Adverse Events were resolved.

[0417] Rating of Osteoarthritis (OA) Pain: the level of Osteoarthritis (OA) Pain was assessed (rated) by all subjects prior to each application and recorded by trained professionals. Data utilized here were those Osteoarthritis (OA) Pain ratings recorded prior to initiation of treatment and those prior to the fourth application of one of five API-CAPS formulations to both knees of each subject. Ratings utilized included those from all 21 patients receiving 4 applications and two receiving 2 and 3 applications respectively (23 total subjects). Subjects rated the current Osteoarthritis (OA) Pain in their joints on a 0-10 numeric pain rating scale (0=no pain; 10=worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide. Additionally, subjects were asked whether their Osteoarthritis (OA) Pain was “Better”, “Same” or “Worse” than prior to the 2.sup.nd, 3.sup.rd and 4.sup.th applications.

[0418] Tolerability Assessment (current burning skin sensation): the burning ensation on the skin was assessed (rated) by all subjects following each application and recorded by trained professionals. Data utilized here were those burning sensation ratings recorded at 15, 30, 45, and 60 minutes following each application of one of the five API-CAPS formulations to both knees of each subject. Tolerability ratings utilized included all 21 patients receiving 4 applications and two receiving 2 and 3 applications respectively (23 total subjects). At each time interval subjects rated the current burning sensation on a 0-10 numeric rating scale (0=no pain; 10=worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

[0419] Mobility Assessment (enhanced joint mobility): mobility in the treated joints was assessed by all subjects prior to each application and recorded by trained professionals. Data utilized here were those mobility assessments recorded prior to each application of one of five API-CAPS formulations to both knees of each subject. Assessments utilized included those from all 21 patients receiving 4 applications and two receiving 2 and 3 applications respectively (23 total subjects). Subjects were asked whether their “ability to use the joint” was “Better”, “Same” or “Worse” than pre-treatment levels prior to the 2.sup.rd, 3.sup.rd and 4.sup.th applications.

Results

[0420] Efficacy of API-CAPS Treatment

[0421] The summary of percent improvement in Osteoarthritic (OA) Pain prior to initiation of short-term treatment are shown in the following Table.

TABLE-US-00011 PAIN REDUCTION AS A FUNCTION OF CAPSAICIN CONCENTRATION (Based on the pain reduction from the 1st visit to the follow-up visit at end of study) CAPSAICIN NUMBER OF PAIN CONCENTRATION KNEES REDUCTION (Wt. %) TREATED (%) 0 12 100.sup.  2 8 100.sup.  5 8 100.sup.  10 10  88.sup.(1) 20 8 100.sup.  Note: .sup.(1)One subject experienced a 40% pain reduction level for both knees

[0422] Tolerability of API-CAPS Treatment

[0423] The combined API-CAPS tolerability for the right and left kness for capsaicin concentrations of 0%, 2%, 5%, 10%, and 20% are shown in FIG. 1. The tolerability readings are considered well within the range of what would be considered “tolerable” therapy for the treatment of osteoarthritis pain.

[0424] The summary of the tolerability of API-CAPS treatment over the course of the four days of treatment at 15, 30, 45 and 60 minutes following each application are shown in FIG. 2.

Conclusions

[0425] Topical API-CAPS treatment of osteoarthritis pain was very effective. The reduction in Osteoarthritis (OA) Pain was dramatic. The percent improvement in osteoarthritis pain prior to the 4.sup.th dose ranged from >45% to 100% from initial osteoarthritis pain levels prior to initiation of this short-term course of therapy. At the follow-up visit at the end of study the percent improvement in osteoarthritis pain ranged from 88% to 100%. There was a trend for greater efficacy in mitigation of osteoarthritis pain with increasing capsaicin concentration when comparing responses to treatment of left versus right contralateral knees with different capsaicin concentrations in the same patient. When asked whether their Osteoarthritis (OA) Pain was “Better”, “Same” or “Worse” prior to the 2.sup.rd, 3.sup.rd and 4.sup.th applications, subjects replied “better” in 122 out of 123 replies, with one recording “worse”.

[0426] Topical API-CAPS treatment in this study was demonstrated to be highly tolerable as evidenced in the graphics above. At each concentration level of one of five API-CAPS formulations, subjects rated their burning sensations to be overwhelmingly either non-existent or well within a range of tolerability. Tolerability ratings averaged 2.2 upon the first application, 1.3 after the fourth application and trended down over time. The literature on topical capsaicin tolerability clearly teaches that different people sense a potential transient burning sensation to capsaicin to different degrees and that this sensation can vary from one exposure to the next. This is evident in our findings. In this study, capsaicin tolerability was, in general, found to be dose (capsaicin-concentration) dependent; with the 20% capsaicin concentration having the greater incidence of tolerability values ranging above 6 and the frequency of burning and stinging sensations decreased following repetitive treatments. At capsaicin concentrations below 20% tolerability readings typically ranged from 0 to 6 and are considered well within the range of what would be considered “tolerable” therapy for the treatment of osteoarthritis pain.

Example 13

API-CAPS-004: 0.25% API-CAPS Topical Treatment for Osteoarthritis Pain in Hands and Knees of Adult Patients

Hypothesis/Study Objective

[0427] The effect of the novel API-CAPS composition is expected to minimize the burning effect of capsaicin following topical application to tolerable levels while the formulation provides pain relief and enhanced joint mobility in the topical treatment of pain associated with osteoarthritis. The objective was to evaluate the efficacy, mobility improvement and tolerability of 0.25% API-CAPS when applied topically for the treatment of pain from osteoarthritis of the hand and knee.

TABLE-US-00012 API-CAPS Formulation Composition 0.25% INGREDIENTS (Wt. %) TRANS-CAPSAICIN 0.25 ETHYL ALCOHOL 22.25 METHYL SALICYLATE 50 MENTHOL 15 CAMPHOR 11 PHENOL 1.5 TOTAL 100

Study Design

[0428] Chronic pain relief resulting from capsaicin is known to be dose dependent and temporary. Topical capsaicin is well tolerated except for a potential acute skin sensation of burning in the area of administration which diminishes over time and with multiple applications. Capsaicin products currently on the market are limited by this acute side effect. API-CAPS was created to minimize potential capsaicin skin burning sensation and be efficacious in topical pain treatment.

[0429] This was a multiple-dose study of adult subjects with pain from osteoarthritis of the hand and knee, conducted at two investigational sites API-CAPS was applied three times per day, five days per week, for two weeks to the skin of the afflicted hand or knee by trained site staff. The skin associated with the application site remained uncovered for 60 minutes after API-CAPS was applied. After 60 minutes, the area was cleansed by trained personnel to remove any residual formulation from the surface of the skin. Subjects were then instructed to avoid exposing the treated skin to any form of heat (hot water, vigorous exercise, direct sunlight, etc.) for 24 hours. Subjects were also told not to apply any topical substances to the treated skin area and to avoid wearing tight clothing at the site of application during this time. If the subject experienced intolerable pain or severe irritation from the study medication after they left the clinic, they were allowed to apply cold water, ice, or a cold pack. All evaluations were performed at the study sites. Each subject signed an Informed Consent Form and had all questions answered before any study procedures were performed. Subjects were not allowed to apply the solution themselves or take the medication home.

Study Data

[0430] Sixty-one subjects were enrolled in this study. Fifty-seven subjects completed the study. Of the 61 enrolled subjects, four did not return for personal reasons. No treatment related adverse events were reported.

[0431] Rating of Osteoarthritis (OA) Pain: the level of Osteoarthritis (OA) Pain was assessed (rated) by all subjects prior to each application and recorded by trained professionals. Arthritis pain was rated on a 0-10 numeric scale (0=no pain; 10=worst pain imaginable) using the Wong-Baker Faces Rating Scale as a guide. If the patient had bilateral pain and both sides were treated and data for each side (right and left) was collected independently. Initial OA pain level data were collected at either day 1 or day 2. The first value recorded for pain level was used in the subsequent analysis of percent pain reduction achieved at the end of study.

[0432] Tolerability Assessment (current burning skin sensation): the burning sensation on the skin was assessed (rated) by all subjects before treatment with API-CAPS and just prior to washing the skin area (60 minutes after medication application) and recorded by trained professionals. The subjects rated the current burning sensation on a 0-10 numeric rating scale (0=no pain; 10=worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

[0433] Mobility Assessment (enhanced joint mobility): mobility in the treated joints was assessed by all subjects prior to each application and recorded by trained professionals. Subjects were asked whether their “ability to use the joint” was “Better”, “Same” or “Worse” than pre-treatment levels prior to the starting treatment.

Results

[0434] Efficacy of API-CAPS Treatment

[0435] FIG. 3 shows the summary of end of study percent improvement in Osteoarthritic (OA) Pain with short-term treatment (two weeks of treatment applied three times per day, five days per week).

[0436] Tolerability of API-CAPS Treatment

[0437] A summary of the tolerability of API-CAPS treatment following each application over the course of two weeks of treatment applied three times per day, five days per week is shown in FIG. 4.

Conclusions

[0438] Topical API-CAPS treatment of osteoarthritis pain was very effective as evidenced by the graphics above. The percent improvement in osteoarthritis pain at the end of study ranged from 0% to 100% from initial osteoarthritis pain levels prior to initiation of this short-term course of therapy; with almost all subjects achieving >40% reduction in pain.

[0439] Topical API-CAPS treatment in this study was demonstrated to be highly tolerable as evidenced in the graphics above. The literature on topical capsaicin tolerability clearly teaches that different people sense a potential transient burning sensation to capsaicin to different degrees and that this sensation can vary from one exposure to the next. This is evident in our findings. In this study, capsaicin tolerability was, in general, found to be excellent; with most subjects reporting no burning and the preponderance tolerability values well below 6. These tolerability values are considered well within the range of what would be considered “tolerable” therapy for the treatment of osteoarthritis pain. Topical API-CAPS treatment in this study was also demonstrated to enhance mobility, presumably due to the dramatic decrease in Osteoarthritis (OA) Pain. When asked whether their mobility was “Better”, “Same” or “Worse” prior to each applications, subjects replied “better” in 2313 cases, the “same” in 50 cases, and “worse” in only one case.

Example 14

[0440] API-CAPS-005: Multiple Dose Case Studies of Treatment with API-CAPS for Pain from Osteoarthritis in the Elderly

Hypothesis/Study Objective

[0441] The effect of the novel API-CAPS composition is expected to minimize the burning effect of capsaicin following topical application to tolerable levels while the formulation provides efficacy in the topical treatment of pain associated with osteoarthritis. The objective was to evaluate the efficacy and tolerability of API-CAPS when applied topically for the treatment of pain from osteoarthritis in the elderly. Three concentrations of API-CAPS (2%, 5%, and 10% w/w trans-capsaicin, USP) were available to the Investigators for use in this study.

TABLE-US-00013 API-CAPS FORMULATION COMPOSITIONS 2% 5% 10% INGREDIENTS (Wt. %) (Wt. %) (Wt. %) TRANS-CAPSAICIN 2.0 5.0 10 ETHYL ALCOHOL 20.5 17.5 12.5 METHYL 50 50 50 SALICYLATE MENTHOL 15 15 15 CAMPHOR 11 11 11 PHENOL 1.5 1.5 1.5 TOTAL 100 100 100

Study Design

[0442] Chronic pain relief resulting from capsaicin is known to be dose dependent and temporary. Topical capsaicin is well tolerated except for a potential acute skin sensation of burning in the area of administration which diminishes over time and with multiple applications. Capsaicin products currently on the market are limited by this acute side effect. API-CAPS was created to minimize this burning skin sensation.

[0443] The Investigators identified eight subjects who could benefit from treatment with API-CAPS and who meet standard eligibility criteria. Each subject signed an Informed Consent Form (ICF) prior to treatment with API-CAPS. For each subject, one joint was topically treated 5 times with the same strength of API-CAPS, with one application each day. API-CAPS was applied to the same joint each time, and the concentration was not increased or decreased. The clinician administered API-CAPS. The skin associated with the application site remained uncovered for 60 minutes after API-CAPS was applied. After 60 minutes, the area was cleansed by trained personnel to remove any residual formulation from the surface of the skin. Subjects were not allowed to apply the solution themselves or take the medication home. Subjects were instructed to avoid exposing the treated skin to any form of heat (hot water, vigorous exercise, direct sunlight, heating pad, etc.) until 24 hours after their final API-CAPS treatment. Subjects were also told not to apply any topical substances to the treated skin area and to avoid wearing tight clothing at the site of application during this time. If the subject experienced intolerable pain or severe irritation from the study medication after they left the clinic, they may apply cold water, ice, or a cold pack, and they may also take oral pain medications to ease the pain.

[0444] The Investigator consulted with each of the eight subjects to determine the proper concentration for treatment (2%, 5%, and 10% API-CAPS). The Investigator considered the severity of osteoarthritis pain, the subject's capacity for tolerating a burning skin sensation (potential side effect), and the area of skin where the medication would be applied (target skin area). The 10% concentration was considered most appropriate for subjects with chronic osteoarthritis of long duration who have exhausted other options. Rating of Osteoarthritis (OA) Pain: Prior to each medication treatment, subjects rated the current pain in their joint from osteoarthritis on a 0-10 numeric pain rating scale (0=no pain; 10=worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

[0445] Tolerability Assessment (current burning skin sensation): Burning skin sensation was assessed by the patient just prior to treatment, at 30 minutes after API-CAPS application, and at 60 minutes post-application on a 0-10 numeric rating scale (0=no pain; 10=worst pain imaginable) in conjunction with the Wong-Baker Faces Rating Scale as a guide.

Results

[0446] Efficacy of API-CAPS Treatment

[0447] A measure of osteoarthritic pain at the start of the study (prior to first treatment) and at the end of the study for each of the eight subjects is summarized in the following Tables.

TABLE-US-00014 % PAIN LEVEL REDUCTION DOSING WITH API-CAPS Capsaicin Concentration (%) 2 2 5 5 5 5 10 10 Subject Initials M D C V E A V D J E S M R A A R C D Start Pain Level 3 4 6 7 7 10 6 10 (0-10 Scale) End Pain Level 2 0 4 0 4 4 0 3 (0-10 Scale) Pain Level Change 1 4 2 7 3 6 6 7 Pain Level 33 100 33 100 43 60 100 70 Reduction (%)

TABLE-US-00015 AVERAGE TOLERABILITY SCORE (0-10 Scale) Patient Group Treatment Times - (Minutes) (All Patients) 0 30 60 All Visits NA 3.35 3.07 Days 2-6 1.24 3.41 3.31 Day 1 0.00 3.00 2.38 Day 2 0.50 0.25 0.75 Day 4 3.00 3.50 4.13 Day 5 0.67 6.25 5.14 Day 6 0.00 4.00 2.00

Conclusions

[0448] Topical API-CAPS treatment of osteoarthritis pain was very effective; percent improvement in osteoarthritis pain at the end of study ranged from 33% to 100% from initial osteoarthritis pain levels prior to initiation of this short-term course of therapy.

[0449] The literature on topical capsaicin tolerability clearly teaches that different people sense a potential transient burning sensation to capsaicin to different degrees and that this sensation can vary from one exposure to the next. This is evident in our findings. Six out of eight subjects (75%) participating in this study generally encountered burning sensations at levels considered to be “tolerable” (6 and below). However, two of the eight subjects (25%) experienced individual tolerability readings as high as 9 or 10 at several reading points during the study. Both subjects of these extreme cases occurred with the application of the 5% concentration. Averaging tolerability ratings of these two highly sensitive subjects into the tolerability data set raises the overall tolerability averages significantly. The median values of the tolerability readings ranged from 0 to 6 and are considered well within the range of what would be considered “tolerable” therapy for the treatment of osteoarthritis pain.

Example 15

Components Elimination Comparison

[0450] Two individuals took place in a trial designed to explore the differences in the capsaicin burning sensation caused by the elimination of one or more individual components from the embodiment of the invention including menthol camphor and phenol. Subject #1 (50 year old healthy male) applied six (6) distinct capsaicin formulations on six (6) separate areas of skin on his thighs (3 per leg). Each application site was approximately 20 cm.sup.2 (5 cm×4 cm) in area.

[0451] Subject #2 (39 year old healthy female) applied the same six (6) distinct capsaicin formulations simultaneously on six (6) separate areas of skin on her inner left arm (above and below the inside crease of the elbow joint). Each application site was approximately 8 cm.sup.2(2 cm×4 cm) in area. Both areas are considered to be relatively sensitive areas of skin and as such were chosen in order to distinguish differences in burning sensations as much as possible. The formulations applied are presented below:

TABLE-US-00016 APPLIED FORMULATIONS No Phenol, No Phenol, Camphor, Camphor, No No No Menthol Menthol 10% MA Menthol Camphor Phenol w/Mac Oil w/EtOH Subj1 Subj2 Subj1 Subj2 Subj1 Subj2 Subj1 Subj2 Subj1 Subj2 Subj1 Subj2 Capsaicin 10 10 5 5 5 5 5 5 5 5 5 5 Methyl 50 50 50 50 50 50 50 50 50 50 50 50 Salicate Ethyl 12.5 12.5 32.5 32.5 28.5 28.5 19 19 0 0 45 45 Alcohol Menthol 15 15 0 0 15 15 0 0 0 0 0 0 Camphor 11 11 11 11 0 0 15 15 0 0 0 0 Phenol 1.5 1.5 1.5 1.5 1.5 1.5 11 11 0 0 0 0 Macadamia 0 0 0 0 0 0 0 0 45 45 0 0 Nut Oil

[0452] Note that three of the six formulations eliminates one single compound respectively (menthol, camphor or phenol) amongst the various combinations of compounds comprising the inventive compositions. The other two formulations are variations which exclude all three of these compounds: menthol, camphor and phenol. The 6 formulation applied is 10% capsaicin formulation with none of the active components removed. The six (6) formulations were all applied upon each subject within 2 minutes of one another. At the time increments of 5, 10, 15, 20, 30, 45, 60, 90 and 120 the levels of the burning sensation were taken for all application sites and rated on a scale of 1-10. Relative comparisons between application sites were facilitated dramatically by the simultaneous application of formulations. Each application site was rated on a scale of 1-10 for the burning sensation at each time interval.

[0453] Erythema reddening was also rated (measured by eye) at the same time increments for all six (6) application sites. Relative comparisons between applications sites were facilitated by the simultaneous application of formulations. At each time increment, erythema was rated on a scale of (1-5).

TABLE-US-00017 Burning Sensation Results TIME FORMULATIONS AFTER 5% CAP 5% CAP 5% CAP 5% CAP 5% CAP DOSING 10% Cap MA no MA no MA No No PhCaMe No PhCaMe (minutes) MA Menthol Camphor Phenol w/Mac Nut Oil w/EtOH Subject #1 5 0.5 1.0 1.0 1.0 1.5 1.5 10 0.5 1.0 1.0 1.5 1.5 1.5 15 0.5 1.0 1.5 1.5 2.0 2.0 20 1.0 1.5 1.5 2.0 2.5 3.0 30 1.5 2.0 1.5 2.0 3.0 3.5 45 1.5 2.5 2.0 2.0 3.5 3.5 60 1.0 2.5 2.0 2.0 3.0 3.0 75 1.0 2.5 2.0 2.5 2.5 2.5 90 1.0 2.5 2.0 2.5 2.5 2.5 120 1.0 2.5 2.0 2.5 2.5 2.0 Subject #2 5 0.0 0.5 0.0 0.5 0.0 0.0 10 0.0 1.0 0.0 2.0 0.0 0.5 15 0.0 2.0 1.0 2.0 0.0 1.0 20 0.0 2.0 1.0 1.0 1.0 1.5 30 0.0 2.0 1.0 1.0 1.0 1.5 45 0.0 2.5 0.0 1.0 1.0 1.0 60 0.0 2.5 0.0 1.0 1.0 0.0 75 0.0 2.5 0.0 0.0 2.0 0.0 90 0.0 2.5 0.0 0.0 2.0 0.0 120 0.0 2.5 0.0 0.0 1.0 0.0

TABLE-US-00018 Erythema Results TIME FORMULATIONS AFTER 5% CAP 5% CAP 5% CAP 5% CAP 5% CAP DOSING 10% Cap MA no MA no MA No No PhCaMe No PhCaMe (minutes) MA Menthol Camphor Phenol w/Mac Nut Oil w/EtOH Subject #1 5 0.5 1.0 1.0 1.0 1.5 1.5 10 0.5 1.0 1.0 1.5 1.5 1.5 15 0.5 1.0 1.5 1.5 2.0 2.0 20 1.0 1.5 1.5 2.0 2.5 3.0 30 1.5 2.0 1.5 2.0 3.0 3.5 45 1.5 2.5 2.0 2.0 3.5 3.5 60 1.0 2.5 2.0 2.0 3.0 3.0 75 1.0 2.5 2.0 2.5 2.5 2.5 90 1.0 2.5 2.0 2.5 2.5 2.5 120 1.0 2.5 2.0 2.5 2.5 2.0 Subject #2 5 0.0 0.0 0.0 0.0 0.0 0.0 10 0.5 2.0 0.5 1.0 0.5 0.5 15 0.5 2.5 0.5 1.0 0.5 1.0 20 0.0 2.5 0.5 2.0 1.0 1.0 30 0.0 2.5 0.5 2.0 1.0 0.5 45 0.0 2.5 1.0 2.0 2.0 0.0 60 0.0 2.5 1.0 2.0 2.0 0.0 75 0.0 2.5 0.0 1.0 2.0 0.0 90 0.0 2.5 0.0 0.0 2.0 0.0 120 0.0 2.5 0.0 0.0 1.0 0.0

Example 16

API-CAPS-002, Cohort 1: 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) & Capzasin HP Arthritis Pain Relief Analgesic Cream (0.1% Capsaicin)

Hypothesis/Study Objective

[0454] The effect of the novel API-CAPS composition is expected to minimize the burning effect of capsaicin following topical application to tolerable levels. The objective of this study was to assess the tolerability of 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) compared to Capzasin HP Arthritis Pain Relief Analgesic Cream (0.1% Capsaicin).

TABLE-US-00019 API-CAPS Formulation Composition 0.25 INGREDIENTS (Wt. %) TRANS-CAPSAICIN 0.25 ETHYL ALCOHOL 22.25 METHYL SALICYLATE 50 MENTHOL 15 CAMPHOR 11 PHENOL 1.5 TOTAL 100

Study Design

[0455] This was a single-blind, single dose, over-the-counter (OTC) product marketing study in 12 adult healthy volunteers, conducted at a single study center. Test Materials consist of 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) compared to Capzasin HP Arthritis Pain Relief Analgesic Cream (0.1% Capsaicin). These two Test Materials were applied to contralateral sites on the subject's back by the site staff following subject's signed Informed Consent Form after having all questions answered before any study procedures may be performed. The screening procedures established eligibility for study participation, and included demographics, height, weight, vital signs, medical history, brief physical exam (optional), and evaluation of inclusion and exclusion criteria.

[0456] Subjects were instructed to shower or bathe the evening before or morning of Treatment. Each of the two contralateral areas of Test Material application were 49 square centimeters (7×7 cm); just below the right and left shoulder blades on the subject's back. The Test Materials were applied randomly to one side or the other of the back (right or left).

[0457] The subjects evaluated tolerability prior to dosing, one minute after dosing, and every 15 minutes post-dose for 2 hours. Tolerability was measured by the subject's evaluation of a skin sensation of burning on a 0-10 Numeric Rating Scale (where 0 is no sensation and 10 is very severe burning, i.e., worst pain imaginable) using the Wong-Baker faces as a guide.

[0458] Skin irritation (dermatologic evaluation) was assessed by a trained clinical evaluator prior to dosing, and at 30 minutes, 1 hour, and 2 hours post-dose using a standard 0 to 7 rating scale (where 0 is no evidence of irritation and 7 is a strong reaction spreading beyond test site). The same evaluator performed all assessments for a subject.

[0459] After completion of the 2-hour post-dose evaluations, the site staff cleansed the subject's back to remove any residual product and subjects were instructed to avoid exposing their back to any form of heat (hot water, vigorous exercise, direct sunlight, etc.) for 24 hours. Subjects were released from the clinic and instructed to contact the study staff if they had any adverse experiences that are potentially related to the Test Materials.

Results

[0460]

TABLE-US-00020 Subjective Assessments (Burning) 0.25% API- Capzasin HP Arthritis CAPS (0.25% Pain Relief w/w Trans- Analgesic Cream Capsaicin, USP) (0.1% Capsaicin) N= 12 12 Mean 0.11 0.10 Std Dev 0.21 0.20 Median 0.00 0.00 Range 0.00-0.70 0.00-0.50 Paired t-test P = 0.9279

TABLE-US-00021 Dermatologic Evaluations 0.25% API- Capzasin HP Arthritis CAPS (0.25% Pain Relief w/w Trans- Analgesic Cream Capsaicin, USP) (0.1% Capsaicin) N= 12 12 Mean 0.33 0.31 Std Dev 0.22 0.50 Median 0.25 0.00 Range 0.00-0.75 0.00-1.5 Paired t-test P = 0.8977

Conclusions

[0461] Both 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) and Capzasin HP Arthritis Pain Relief Analgesic Cream (0.1% Capsaicin) are comparable (p≥0.05) and very tolerable with respect to potential capsaicin-induced burning as well as comparable (p≥0.05) and very tolerable in potential skin irritation.

API-CAPS-002, Cohort 2: 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) & Capzasin No-Mess Applicator (0.15% Capsaicin)

Hypothesis/Study Objective

[0462] The effect of the novel API-CAPS vehicle is expected to minimize the burning effect of 0.25% capsaicin following topical application to tolerable levels. The objective of this study was to assess the tolerability of 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) compared to Capzasin No-Mess Applicator (0.15% Capsaicin).

TABLE-US-00022 API-CAPS Formulation Composition 0.25 INGREDIENTS (Wt. %) TRANS-CAPSAICIN 0.25 ETHYL ALCOHOL 22.25 METHYL SALICYLATE 50 MENTHOL 15 CAMPHOR 11 PHENOL 1.5 TOTAL 100

Study Design

[0463] This was a single-blind, single dose, over-the-counter (OTC) product marketing study in 12 adult healthy volunteers, conducted at a single study center. Test Materials consist of 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) compared to Capzasin No-Mess Applicator (0.15% Capsaicin). These two Test Materials were applied to contralateral sites on the subject's back by the site staff following subject's signed Informed Consent Form after having all questions answered before any study procedures may be performed. The screening procedures established eligibility for study participation, and included demographics, height, weight, vital signs, medical history, brief physical exam (optional), and evaluation of inclusion and exclusion criteria.

[0464] Subjects were instructed to shower or bathe the evening before or morning of Treatment. Each of the two contralateral areas of Test Material application were 49 square centimeters (7×7 cm); just below the right and left shoulder blades on the subject's back. The Test Materials were applied randomly to one side or the other of the back (right or left).

[0465] The subjects evaluated tolerability prior to dosing, one minute after dosing, and every 15 minutes post-dose for 2 hours. Tolerability was measured by the subject's evaluation of a skin sensation of burning on a 0-10 Numeric Rating Scale (where 0 is no sensation and 10 is very severe burning, i.e., worst pain imaginable) using the Wong-Baker faces as a guide.

[0466] Skin irritation (dermatologic evaluation) was assessed by a trained clinical evaluator prior to dosing, and at 30 minutes, 1 hour, and 2 hours post-dose using a standard 0 to 7 rating scale (where 0 is no evidence of irritation and 7 is a strong reaction spreading beyond test site). The same evaluator performed all assessments for a subject.

[0467] After completion of the 2-hour post-dose evaluations, the site staff cleansed the subject's back to remove any residual product and subjects were instructed to avoid exposing their back to any form of heat (hot water, vigorous exercise, direct sunlight, etc.) for 24 hours. Subjects were released from the clinic and instructed to contact the study staff if they had any adverse experiences that are potentially related to the Test Materials.

Results

[0468]

TABLE-US-00023 Subjective Assessments (Burning) 0.25% API- Capzasin HP Arthritis CAPS (0.25% Pain Relief w/w Trans- Analgesic Cream Capsaicin, USP) (0.1% Capsaicin) N= 12 12 Mean 0.55 0.01 Std Dev 0.94 0.03 Median 0.2 0.00 Range 0.00-3.40 0.00-0.10 Paired t-test P = 0.0739

TABLE-US-00024 Dermatologic Evaluations 0.25% API- Capzasin HP Arthritis CAPS (0.25% Pain Relief w/w Trans- Analgesic Cream Capsaicin, USP) (0.1% Capsaicin) N= 12 12 Mean 0.21 0.00 Std Dev 0.28 0.00 Median 0.13 0.00 Range 0.00-0.75 0.00-0.00 Paired t-test P = 0.0172

[0469] Both 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) and Capzasin No-Mess Applicator (0.15% Capsaicin) are comparable (p≥0.05) and very tolerable with respect to potential capsaicin-induced burning as well as very tolerable in potential skin irritation.

Example 17

Diclofenac Solubility Studies

[0470] Experimental Solubility Procedures and Results

[0471] All solubility samples were prepared in 20 gram sample size. The ingredients of each test samples were weighed to the nearest 0.01 grams. The 20 gram samples were mixed in 50 cc Pyrex glass beakers.

[0472] All solubility studies were performed with “Diclofenac Sodium Salt” obtained from Sigma Aldrich, St. Louis, Mo. (CAS #15307-79-6; Sigma-Aldrich Catalog No. D6899; Lot #BCBB7312; M.P. 275-277° C.)

The molecular structure of Diclofenac Sodium is shown below:

##STR00008##

[0473] The ingredients were thoroughly mixed at ambient temperatures ranging from 75° F. to 80° F.

[0474] The solvents that indicated little or negligible solubility levels of diclofenac sodium at room temperature were heated to about 35° C. to determine if the increased temperature would impact the solubility of the diclofenac sodium. However, the elevated temperature level of 35° C. did not have a significant impact in increasing the diclofenac sodium in those mixtures where the diclofenac solubility levels were “sparingly soluble to insoluble”.

TABLE-US-00025 DICLOFENAC SAMPLE SODIUM NUMBER SOLVENT/SOLVENT MIXTURES SOLUBILITY 1 98 wt. % .sup.(1)Methyl Salicylate, Sparingly 2 wt. % .sup.(9)Diclofenac Sodium Soluble/ Insoluble 2 50 wt. % .sup.(1)Methyl Salicylate, 15 wt. Sparingly % .sup.(2)Menthol, 11 wt. % .sup.(3)Camphor, Soluble/ 1.5 wt. % .sup.(4)Phenol, 20.5 wt. % Insoluble .sup.(5)Macademia Nut Oil, 2 wt. % .sup.(9)Diclofenac Sodium 3 98 wt. % .sup.(6)Ethyl Alcohol, 2 wt. % .sup.(10)Completely .sup.(9)Diclofenac Sodium Soluble 4 98 wt. % .sup.(7)Transcutol, 2 wt. % .sup.(10)Completely Diclofenac Sodium Soluble 5 88 wt. % Methyl Salicylate, 10 wt. % .sup.(10)Completely Ethyl Alcohol, 2 wt. % Soluble .sup.(9)Diclofenac Sodium 6 50 wt. % Methyl Salicylate, 15 wt. % Sparingly Menthol, 11 wt. % Camphor, 1.5 wt. Soluble/ % Phenol, 18.5 wt. % Macademia Insoluble Nut Oil, 2 wt. % .sup.(9)Diclofenac Sodium 7 50 wt. % Methyl Salicylate, 15 wt. % .sup.(10)Completely Menthol, 11 wt. % Camphor, 1.5 wt. Soluble % Phenol, 18.5 wt. % Ethyl Alcohol, 2 wt. % .sup.(8)Capsaicin, 2 wt. % .sup.(9)Diclofenac Sodium 8 50 wt. % Methyl Salicylate, 15 wt. % .sup.(10)Completely Menthol, 11 wt. % Camphor, 1.5 wt. Soluble % Phenol, 10.5 wt. % Ethyl Alcohol, 2 wt. % .sup.(8)Capsaicin, 2 wt. % .sup.(9)Diclofenac Sodium NOTE: .sup.(1)Methyl Salicylate, Spectrum Chemical, NF, CAS #119-36-8 .sup.(2)L-Menthol, Crystal, Spectrum Chemical, USP, CAS #2216-51-5 .sup.(3)Camphor, Synthetic, Spectrum Chemical, USP, CAS #76-22-2 (4)Phenol, Liquefied (Carbolic Acid), USP, Spectrum Chemical, CA 108-95-2 .sup.(5)Macadamia Nut Oil, Lotioncrafters Lot #1506-3187, CAS #128497-20-1 .sup.(6)Ethyl Alcohol, Graves Grain Alcohol, 190 Proof .sup.(7)Transcutol ™, (Ethoxydiglycol), Lotioncrafters, Lot # CAS #111-90-0 .sup.(8)Trans-Capsaicin, Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, USP 30, CAS #404-86-4 .sup.(9)Diclofenac Sodium, Lot # BCBB7312, Sigma-Aldrich Catalog No. D6899, CAS #15307-79-6 .sup.(10)Samples 3, 4, 5 & 7 were placed in sealed 16 cc Pyrex vials and placed in a freezer maintained at ~5° F. for 48 hours. There was no visible evidence of any precipitates formed. Further, no visible evidence of precipitation. was observed after >5 days at ambient conditions. All solutions were totally transparent & all mixtures completely miscible.

[0475] The table below includes the compositions of 7 completely miscible and transparent diclofenac sodium and capsaicin liquid solutions that were prepared.

TABLE-US-00026 The Composition of the Miscible Liquid Solution SAMPLE NUMBER 1 2 3 4 5 6 7 INGREDIENTS (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) .sup.(1)CAPSAICIN 0 2 2 0.25 2 5 10 .sup.(2)DICLOFENAC SODIUM 2 2 2 1.5 1.5 1.5 1.5 .sup.(3)METHYL SALICYATE 0 50 50 50 50 50 50 .sup.(4)MENTHOL 0 15 15 15 15 15 15 .sup.(5)CAMPHOR 0 11 11 11 11 11 11 .sup.(6)PHENOL 0 1.5 1.5 1.5 1.5 1.5 1.5 .sup.(7)ETHYL ALCOHOL 20 0 18.5 20.75 19 16 11 .sup.(8)MACADAMIA NUT OIL 78 10.5 0 0 0 0 0 .sup.(9) TRANSCUTOL 0 8 0 0 0 0 0 NOTE: .sup.(1)Trans-Capsaicin, Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, USP 30, CAS # 404-86-4 .sup.(2)Diclofenac Sodium, Sigma-Aldrich Catalog No. D6899; Lot # BCBB7312, CAS # 15307-79-6 .sup.(3)Methyl Salicylate, Spectrum Chemical, NF, CAS # 119-36-8 .sup.(4)L-Menthol, Crystal, Spectrum Chemical, USP, CAS # 2216-51-5 .sup.(5)Camphor, Synthetic, Spectrum Chemical, USP, CAS # 76-22-2 .sup.(6)Phenol, Liquefied (Carbolic Acid), USP, Spectrum Chemical, CA 108-95-2 .sup.(7)Ethyl Alcohol, Graves Grain Alcohol, 190 Proof .sup.(8)Macadamia Nut Oil,, Lotioncrafters Lot # 1506-3187, CAS # 128497-20-1 .sup.(9) Transcutol, (Ethoxydiglycol), Lotioncrafters, Lot# Lot# 034A00429324-3426, CAS #111-90-0

[0476] It is evident that alcohols (ethyl alcohol and/or ethoxydiglycol) are required to effect the solubility of Diclofenac salts within the oil based ingredients of the capsaicin vehicles. Significantly, as noted in Sample 5 of the table above, an ethyl alcohol content of 10% results in the complete solution of 2% Diclofenac Sodium within in a liquid solution containing 88% methyl salicylate. Total solubility/miscibility of this 2% Diclofenac sodium solution was observed after exposure to 5° F. (−15° C.) for 48 hours. Formulations with ethyl alcohol concentration >10 wt. % will result in the solubility of higher diclofenac salt concentrations.

[0477] Based on the results of the aforementioned solubility experiments, it was concluded that the ethyl alcohol capsaicin vehicle was capable of maintaining complete solubility/miscibility with concentrations of <2 wt. % Diclofenac Sodium salts.

[0478] While the invention has been described with reference to an exemplary embodiment, 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.

[0479] All documents and other information sources cited herein are hereby incorporated in their entirety by reference.