TOPICAL COMPOSITIONS FOR PAIN RELIEF, MANUFACTURE AND USE

Abstract

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

Claims

1. A topical composition comprising by weight percentage: i) 0.1-10% capsaicin; ii) 0.1-0.5% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.3-0.5% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 1-20% ethanol; v) 0-10% diethylene glycol monomethyl ether, vi) 0-10% propylene glycol; vii) 0-15% polysorbate 80; viii) 0-15% polyoxy 40 hydrogenated castor oil; and ix) 30-60% water.

2. The topical composition of claim 1, wherein the capsaicin is in an amount of 0.25-10% by weight.

3. The topical composition of claim 1, wherein the hyaluronic acid with a molecular weight of about 1,000,000 Daltons is in an amount of 0.1-0.2% by weight; and the hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons is in an amount of 0.3-0.4% by weight.

4. The topical composition of claim 1, wherein the ethanol is in an amount of 20% by weight.

5. The topical composition of claim 1, wherein the diethylene glycol monomethyl ether is in an amount of 10% by weight.

6. The topical composition of claim 1, wherein the propylene glycol is in an amount of 10% by weight.

7. The topical composition of claim 1, wherein the polysorbate 80 is in an amount of 2-10% by weight.

8. The topical composition of claim 7, wherein the polysorbate 80 is in an amount of 10% by weight.

9. The topical composition of claim 1, wherein the polyoxy 40 hydrogenated castor oil is in an amount of 0.5-15% by weight.

10. The topical composition of claim 1, wherein the polyoxy 40 hydrogenated castor oil is in an amount of 0% by weight.

11. The topical composition of claim 1, having the following ingredients by weight percentage: i) 0.25% capsaicin; ii) 0.2% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.3% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; viii) 0.5% polyoxy 40 hydrogenated castor oil; and ix) water, q.s.

12. The topical composition of claim 1, having the following ingredients by weight percentage: i) 2% capsaicin; ii) 0.15% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.35% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; vii) 2% polysorbate 80; viii) 5% polyoxy 40 hydrogenated castor oil; and ix) water, q.s.

13. The topical composition of claim 1, having the following ingredients by weight percentage: i) 2% capsaicin; ii) 0.1% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.4% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; vii) 2% polysorbate 80; viii) 5% polyoxy 40 hydrogenated castor oil; and ix) water, q.s.

14. The topical composition of claim 1, having the following ingredients by weight percentage: i) 5% capsaicin; ii) 0.15% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.35% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; viii) 10% polyoxy 40 hydrogenated castor oil; and ix) water, q.s.

15. The topical composition of claim 1, having the following ingredients by weight percentage: i) 5% capsaicin; ii) 0.15% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.35% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; vii) 10% polysorbate 80; and ix) water, q.s.

16. The topical composition of claim 1, having the following ingredients by weight percentage: i) 5% capsaicin; ii) 0.15% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.35% hyaluronic acid with a molecular weight of about 11,000 or 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; vii) 15% PEG-40 hydrogenated castor oil; and ix) water, q.s.

17. A topical composition, having the following ingredients by weight percentage: i) 5% capsaicin; ii) 0.17% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.33% hyaluronic acid with a molecular weight of about 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; vii) 10% polysorbate 80; and ix) 44.50% water.

18. A topical composition, having the following ingredients by weight percentage: i) 0.25% capsaicin; ii) 0.19% hyaluronic acid with a molecular weight of about 1,000,000 Daltons; iii) 0.36% hyaluronic acid with a molecular weight of about 20,000 Daltons; iv) 20% ethanol; v) 10% diethylene glycol monomethyl ether; vi) 10% propylene glycol; viii) 5% polyoxy 40 hydrogenated castor oil; and ix) 54.2% water.

19. A method of treating pain in a mammal suffering from pain comprising topically administering the topical composition of claim 1 to the mammal.

20. The method of claim 19, wherein the mammal is a human.

21. The method of claim 20, wherein the pain is arthritis pain.

22. The method of claim 21, wherein the arthritis pain is osteoarthritis or rheumatoid arthritis pain.

Description

BRIEF DESCRIPTION OF DRAWING(S)

[0227] The FIGURE shows an exemplary 0 to 10 numeric rating scale.

SKIN IRRITATION SCALE

[0228] Skin irritation was quantified by the subject using the following definitions: [0229] 0=no evidence of irritation [0230] 1=minimal erythema, barely perceptible [0231] 2=definite erythema, readily visible; minimal edema or minimal papular response [0232] 3=erythema and papules [0233] 4=definite edema [0234] 5=erythema, edema, and papules [0235] 6=vesicular eruption [0236] 7=strong reaction spreading beyond test results

Results

[0237] There was no burning or signs of skin irritation at any of the test sites of skin prior to application of the formulations.

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

Conclusions

[0238] The 0.15% M/A formulation demonstrated tolerability comparable to that of CapZaicin. Burning scores were identical at 1 minute and 40 minutes post application; however at 20 minutes post application the 0.15% M/A formulation was 1 unit higher in scored burning. Skin irritation scores were identical at 1 minute, 20 minutes and 40 minutes post application; however CapZaicin induced skin reddening following a hot shower 2 hours post application whereas the 0.15% M/A formulation did not induce skin irritation.

[0239] The addition of 1% hyaluronic acid dramatically reduced the burning sensation and skin irritation induced by a 0.25% capsaicin aqueous formulation containing ethoxydiglycol and propylene glycol as penetration enhancers.

Example 3

Topical Application of the 0.25% Capsaicin-HA Formulations

[0240] A group of 2 adult males and 2 adult females of normal health and ranging in ages from 35 to 55 applied multiple topical application of 4 formulations from 3.7 ml roller-ball applicators as noted in TABLE 6. The subjects noted that the 0.25 wt. % HA/capsaicin formulation was the most tolerable in term of the burning and erythema ratings. The average burning and erythema ratings for the 4 subjects are summarized in TABLE 6.

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

Example 4

Topical Application of the 2% Capsaicin-HA Formulations

[0241] A 40 year old female of normal health applied multiple topical application of 2% trans-capsaicin formulations as noted in Table 3 on her forearm with a 3.7 ml roller-ball applicator. Burning sensations were rated on a scale of 0-10. Erythema (reddening) was rates on a scale of 0-10. (0 no erythema). Erythema (reddening) was rated on a scale of 0-10. The subject experienced the absence of both burning and erythema for both the 2% Cap-HA Form 2 and 2% Cap-HA Form 3 formulations. Burning and stinging recordings for the 2% M/A formulation of <3 were experienced for 60 minutes post application time frame. Details of the subject's comments relating to the topical application of the 3 formulations are summarized in the Tables below. [0242] A) 2% Cap-HA Form 2 (Formulation 3 in Table 3)—Initially this application site showed no noticeable sensitivity. No irritation/erythema throughout the test. There was no burning sensation or redness prior to the 60 minute timepoint. Upon washing of the product in hot water, a slight itching sensation and erythema occurred, at time of reading both were at a 1. This quickly reached a zero within 30 minutes of washoff. [0243] B) 2% Cap-HA Form 3 (Formulation 3 in Table 3)—Initially this application site showed no noticeable sensitivity. No irritation/erythema throughout the timeframe. It is important to note there was what could be described as a pleasant warming of the area 18 hours later when showering. This warming dissipated within 30 minutes post shower. [0244] C) .sup.(1)2% MA—Initially this application site showed barely noticeable sensitivity, described as an itching sensation. There was mild irritation/erythema upon initial application. The burning sensation increased to a 2.5 at the 10 minute mark. The burning sensation gradually dissipated to a mild itching. The burning sensation increased to a 3 immediately upon exposure to hot water and remained at this level for 10 minutes following. Pain then gradually decreased to 0 over the course of 40 minutes following wash off. No erythema or pain was noticeable until a shower the next day. At which time there was a light erythema and a mild burning characterized as a 3. This pain dissipated within 30 minutes. [0245] Note: .sup.(1)Composition: Capsaicin, 2 wt. %; Methyl Salicylate, 50 wt. %; Menthol, 15 wt. %; Camphor, 11 wt. %; Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

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

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

Example 5

Topical Application of the 2% Capsaicin-HA Formulations

[0246] A 50-year old male of normal health applied a single topical application of three 2 wt. % trans-capsaicin formulations via a roller ball applicator. The burning and erythema ratings are summarized in Table 9. Both formulations containing HA had similar burning and erythema ratings for the 60 minute post application duration as noted in Table 9. The subject rated the 2 wt. % M/A formulation as slightly more burning and more irritating than the HA formulations. All levels of burning and erythema were considered to be well within the “tolerable” level for topical use in the subject's opinion.

TABLE-US-00011 TABLE 9 Burning & Erythema Post Application Measurements 1 minute post 10 minutes post 20 minutes post 30 minutes post 45 minutes post 60 minutes post Test application application application application application application Formulations Burning Erythema Burning Erythema Burning Erythema Burning Irritation Burning Erythema Burning Erythema (1) 2% Cap- 1.5 0 2 0 2.5 0.5 2.5 0.5 2.5 0.5 2.0 1 HA Form 2 (2) 2% Cap- 1.5 0 2 0 2.5 0.5 2.5 0.5 2.5 0.5 2.0 1 HA Form 3 2% M/A 1 0 2.5 0.5 3 1 3.5 1 3.0 0.5 2.5 1 Note: (1) Formulation #3 in Table 3 (2) Formulation #4 in Table 3 (3) Composition: Capsaicin, 2 wt. %; Methyl Salicylate, 50 wt. %; Menthol, 15 wt. %; Camphor, 11 wt. %; Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

Example 6

Topical Application of the 5% and 10% Capsaicin Formulations

[0247] A 79 year old male took part in an evaluation of both the 5 wt. % and 10 wt. % capsaicin-HA to evaluate the burning and erythema effect of capsaicin. The burning effect was rated on a scale of (0-10) and at the same time erythema reddening was also determined by eye on a scale of (1-5).

[0248] Application of the 5 wt. % capsaicin-HA formulation via 3.7 ml roller-ball bottle was undertaken to achieve an initial dosing on a 25 cm.sup.2 (5 cm×5 cm) area of skin on his left arm, 20 cm below the elbow joint on the underside of his left arm. Several passes of the roller-ball were undertaken to the entire 25 cm.sup.2 application area.

[0249] Similarly, application of 10 wt. % capsaicin-HA formulation via 3.7 ml roller-ball bottle was undertaken to achieve an initial dosing on a 25 cm.sup.2 (5 cm×5 cm) area of skin on his left arm, 20 cm above the elbow joint on the upper side of the right arm. Several passes of the roller-ball were applied to the 25 cm.sup.2 application area.

[0250] The observed burning and erythema results are summarized in Tables 10 and 11. The subject noted a gradual increase in the burning sensation to a 3 level for the 5 wt. % capsaicin and a level 2.5 for the 10 wt. % capsaicin formulation at the 20 minute mark followed by a gradual decrease to zero after 60 minutes. The subject noted a slight itching that lasted for about 5 to 15 minutes after fluid application.

[0251] In both cases the level of burning for both the 5 wt. % and 10 wt. % Capsaicin/HA formulation were well tolerated.

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

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

Example 7

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

[0252] A 71-year old female of normal health applied a single topical application of the 5 wt. % capsaicin-HA formulation to her left forearm and the 10 wt. % capsaicin-HA formulation to her right forearm in a manner similar to that described in Example 6. The observed burning and erythema results are summarized in TABLES 12 and 13. The level of burning for both the 5 wt. % and 10 wt. % Capsaicin/HA formulation were well tolerated.

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

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

Example 8

[0253] Topical Application of 2%, 5% and 10% CAPSAICIN-HA Formulation with PS80 to Rats

[0254] A small rat study was conducted utilizing the capsaicin-HA formulations below:

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

[0255] A single administration of the 2% and 5% capsaicin formulations for 30 minutes was tolerated in the rats. A single administration of the 10% capsaicin formulation for 30 minutes was not well tolerated in the rats.

Example 9

[0256] Topical Application of 10% CAPSAICIN-HA Formulation with PS80 to a Human

[0257] A 53-year old male of normal health applied a single topical application of 10% trans-capsaicin hyaluronic acid (HA) PS80 solution for 120 minutes prior to washing off. This formulation was formulated with PS80 as the surfactant. Composition of the formulation is shown in the following table.

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

[0258] Application of formulation via 10 mg roller-ball bottle was undertaken to achieve a liberal “glistening” dose over a 15 in.sup.2 (5 inch×3 inch) area of skin on right knee covering half the knee cap and the space just above the knee cap. Several passes of the roller-ball were undertaken to the entire application area to achieve this liberal dosing of formulation.

[0259] Rating of stinging/burning (S&B) and Redness (Erythema) are shown in the table below as a function of time following topical application.

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

[0260] In the table above, the S&B Scale of 0 to 10 is a representation of “stinging and burning” where a zero represents an absence of any S&B, a 1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is the worst pain imaginable. Likewise, the 0 to 5 Erythema scale represents the amount of reddening visually observed where a zero is an absence of reddening, a 1 indicates slight reddening of the skin, a 3 indicates a dark red color and a 5 is purple.

[0261] Overall subject observed a gradual onset of a slight, but very tolerable, burning and stinging sensation over the first 40 minutes following application, followed by a gradual decrease after that point until the 120 minute mark, at which time a very slight S&B sensation still remained. In more detail, a slight S&B sensation rated at a 1 was felt after only 2 minutes, and rose to a 2 rating after 10 minutes. Maximum S&B rated at a 2.5 (on a scale of 0-10) was observed after 40 minutes. The S&B sensation slowly and gradually increased prior to the 40 minute mark. This maximum of 2.5 rated S&B sensation was observed to be quite tolerable at its peak, and then and gradually dissipated beyond the 40-minute mark. From the 40-minute mark on the subject observed a gradual reduction of S&B sensation until the 100 minute mark, at which time the S&B level was observed as a very slight 0.5 rating (on a scale of 1-10). This very slight 0.5 S&B rating continued until the end of the 120 minute period recorded. All levels of irritation were considered to be well within a “tolerable” level for topical use in subject's opinion.

[0262] In addition, reddening (erythema) and reduction of reddening of the entire 50 cm.sup.2 application area was observed over the initial 120 minute period following application. Subject observed a reddening rated at a 0.5 (on a scale of 1-5) after 5 minutes, to a rating of 1.0 after 10 minutes, and a rating of 1.5 after 20 minutes. This reddening rating of 1.5 was the maximum level observed and lasted from the 20 minute mark until the 40 minute mark. Reddening gradually lessened after the 40-minute mark and was down to an S&B rating of 0.5 after 100 minutes. This slight reddening of 0.5 rating was still observed at the end of the 120 minute period recorded. Reddening was uniform and no blotching or other form of inconsistent effect was observed. The area of reddening did not expand beyond the area of application: only skin area directly treated with the formulation had erythema associated with it. Skin did not become more sensitive during the 120 minute application of the formulation.

Example 10

[0263] Topical Application of 10% CAPSAICIN-HA Formulation with PS80 to a Human

[0264] A 41-year old female of normal health applied a single topical application of 10% trans-capsaicin hyaluronic acid (HA) PS80 solution for 120 minutes prior to washing off. The composition of this formulation is shown in the following table.

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

[0265] Application of formulation via 10 mg roller-ball bottle was undertaken to achieve a liberal “glistening” initial dosing on a 8 in.sup.2 (4 inch×2 inch) area of skin on the inner right forearm. Several passes of the roller-ball were undertaken to the entire application area to achieve this liberal dosing of formulation.

[0266] Rating of stinging/burning (S&B) and Redness (Erythema) are shown in the table below as a function of time following topical application.

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

[0267] In the table above, the S&B Scale of 0 to 10 is a representation of “burning and stinging” where a zero represents an absence of any S&B, a 1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is the worst pain imaginable. Likewise, the 0 to 5 Erythema scale represents the amount of reddening visually observed where a zero is an absence of reddening, a 1 indicates slight reddening of the skin, a 3 indicates a dark red color and a 5 is purple.

[0268] A slight stinging sensation rated at a 1 was felt after 5 minutes, and stayed steady until the 100 minute mark where it gradually decreased. The maximum S&B rated at a 1 (on a scale of 0-10) was observed through 90 minutes. This 1 rated S&B was observed to be quite tolerable. From the 100-minute mark on, the subject observed a gradual reduction of S&B sensation. The very slight 0.5 S&B continued until the end of the 120 minute period recorded. All levels of irritation were well within a “tolerable” level for topical use in subject's opinion.

[0269] In addition, reddening (erythema) and reduction of reddening of the entire application area was observed over the initial 120 minute period following application. Subject observed a reddening rated at a 1 (on a scale of 1-5) after 5 minutes, to a rating of 1.5 after 10 minutes that continued past the 90 minute mark. Reddening gradually lessened after the 100-minute mark and was down to a 0.5 for the duration. This slight reddening of 0.5 rating was still observed at the end of the 120 minute period recorded. Reddening was uniform and no blotching or other form of inconsistent effect was observed. The area of reddening did not expand beyond the area of application: only skin area directly treated with the formulation had erythema associated with it.

[0270] Skin did not become more sensitive during the 120 minute application of the formulation.

Example 11

[0271] Four Daily Dose Treatments of Osteoarthritis with a 10% Capsaicin-HA Formulation

[0272] A 59 year old man suffering from severe and advanced osteoarthritis used a 10% capsaicin hyaluronic acid formulation once a day on four successive days for mitigation of osteoarthritis pain. The formulation used contained 10% w/w capsaicin along with hyaluronic acid (HA) and utilized Cremaphore RH40 as a stabilization agent (see Table below). This man was Caucasian, obese with degenerative joint disease (osteoarthritis) especially in the knees, bilaterally, with severe degeneration of medial and lateral meniscus and articular cartilage bilaterally, right greater than left. At the time, pain was marginally controlled with Tramadol 50-100 mg tid, giving partial relief, bringing the pain level down to approximately 4 on the pain scale, with sharp shooting pains that scale up to 8-9.

Efficacy

[0273] The subject noted that “After treating my worse knee (right) with the 10% formulation for one hour a day for four days, my pain relief improved to a pain level of 2, making my more troublesome knee the better, most pain free knee. The sharp shooting pains also improved and were much less frequent with the momentary severe pain levels only reaching 5. This change for the better lasts for weeks.”

Tolerability

[0274] The subject noted that “My stinging/burning sensation while applying the treatment was only a trace, less than 1 by my estimate. The sting/burn only slightly increases in the shower, at most to a 1 on the pain scale. While in the shower there was a mild, manageable cough as I rinsed the treated area, fortunately this was only momentary because the formulation washes away easily, quickly and completely.”

Overall Assessment

[0275] The subject was very pleased with the results.

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

Example 12

[0276] Single Dose Pulse Treatment of Osteoarthritis with a 10% Capsaicin-HA Formulation

[0277] A 79 year old man with a history of moderate to severe Osteoarthritis in multiple joints (successful hip replacement in 2008) used a 10% capsaicin HA formulation several times for mitigation of arthritis pain in both his hip and shoulder joints. The formulation used contained 10% w/w capsaicin along with hyaluronic acid (HA) and utilized Cremaphore RH40 as a stabilization agent (see Table below).

Efficacy:

[0278] The subject applied the above mentioned formulation several times on both his left hip and his right shoulder to control osteoarthritis pain. He applied the 10% Capsaicin HA formulation on an “as needed” basis, which on average was estimated to be once every two weeks. When he applied the formulation, he generally left it on for at least one hour prior to washing off. He did not repeat doses on back to back days, but instead applied a single dose, and then waited until the pain returned to apply another dose. When a single dose of this 10% capsaicin formulation with hyaluronic acid was applied, the arthritis pain was completely eliminated in his shoulder joint for approximately two weeks. Similarly, pain was reduced by approximately 80% when applied on his arthritic hip joint, and significant pain did not return to his hip joint for duration of about 2 weeks from a single dose. The average time to return of pain in both joints was approximately 2 weeks. He was very pleased with the convenience of 1 to 2 weeks of pain relief from the capsaicin following each single dose.

Tolerability:

[0279] The subject noted that the application of this formulation was very tolerable (not irritating). He observed no burning and stinging (B&S) irritation upon application to his shoulder joint for all applications to his shoulder. When he applied the formulation to his hip joint (avoiding the groin and buttocks areas) the maximum S&B sensation was never greater than a 2 rating on a scale of 0 to 10 (defined as zero meaning no S&B sensation, 5 denoting intolerable pain and 10 representing the worst pain imaginable). Erythema (reddening) was non-existent on his shoulder joint upon application, and was estimated at a rating or 1.5 (on a scale of 0 to 5) when the formulation was applied to his hip joint (ratings defined as zero representing an absence of reddening, a 3 as dark red and a 5 as purple). In terms of both S&B sensation and erythema, the subject found the formulation to be very tolerable.

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

Example 13

Capsaicin—HA Formulations Containing Analgesics

[0280] A 1 wt. % hyaluronic acid water solution composed of a mixture containing 70% Hyaluronic Acid with a molecular weight 20K Daltons and 30% hyaluronic acid with a molecular weight 1,00K Daltons, was added to an alcohol mixture solutions containing 0.25 wt. % and 2.0 wt. % Capsaicin dissolved in 20% ethyl alcohol and 10% propylene glycol and 15 wt. % and 17 wt. % Cremophor™ RH 40, respectively. Optically crystal clear and moderately viscous solutions were formed. Adjusting the relative percentages of hyaluronic acid molecular weights could vary the viscosity of the mixture.

[0281] Both the 0.25% wt. % and 2.0 wt. % capsaicin formulations (see Table below) as described in the foregoing paragraphs were applied to an 80 year old male subject's right forearm via a 5 ml roller-ball vial. The applied liquid film dried in a few minutes.

[0282] Minimal discomfort from burning & stinging was experienced. Significantly, the formulations containing 10 wt. % methyl salicylate were relatively odor free.

TABLE-US-00023 CAPSAICIN-ANALGESIC-HA-FORMULATIONS ¼% 2% Cap-HA Cap-HA INGREDIENTS FUNCTION (wt. %) (wt. %) Capsaicin (Formosa) TRPV1 Agonist 0.25 2 Methyl Salicylate Analgesic Agent & 10 10 Penetrant Menthol Cooling Agent & 5 5 Penetrant Camphor Anesthetic Agent 2 2 Penetrant Cremophor RH 40 Surfactant & 15 17 Solubilizer Ethyl Alcohol Solubilizer & 20 20 (Grain Alcohol) Penetrant Diethylene Glycol Solubilizer & 0 0 Monoethyl Ether (DGME) Penetrant Propylene Glycol Solubilizer & 10 10 Penetrant .sup.(1) Hyaluronic Acid Moisturizer & 37.75 34 Aqueous Solution Humectant TOTAL 100 100 Note: .sup.(1) The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.

Example 14

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

[0283] The purpose of this study was to evaluate tolerability and erythema created by the inclusion of topical analgesics to a capsaicin hyaluronic acid (HA) formulation following topical application. A 53 year old male applied two distinct formulations of 2% capsaicin HA (one formulation with topical analgesics and one without) on a single knee side by side. Burning and stinging (S&B) along with skin redness were quantified following topical application in order to evaluate the tolerability and erythema characteristics singularly and comparatively with the two formulations. The compositions of the two formulations are shown below as Formulation 1 (Capsaicin HA) and Formulation 2 (Capsaicin HA plus Analgesics).

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

TABLE-US-00025 Formulation 2 Composition Capsaicin HA plus Analgesics Formulation INGREDIENTS FUNCTION wt. % Capsaicin (Formosa) TRPV1 Agonist 2 Methyl Salicylate Analgesic & Solvent 10 Menthol Analgesic & Cooling 5 Camphor Analgesic 2 Cremophor RH 40 Surfactant 17 Ethyl Alcohol (Grain Alcohol) Solvent 20 Diethylene Glycol Solvent 0 Monoethyl Ether (DGME) Propylene Glycol Solvent & Humectant 10 .sup.(1) Hyaluronic Acid Aqueous Solution Moisturizer & Humectant 34 TOTAL 100 [0284] Note: [0285] .sup.(1)The Hyaluronic Acid Aqueous Solution contains 0.65 wt. % Hyaluronic Acid SLMW (˜20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000K Daltons) and 99 wt. % Distilled Water.

[0286] Formulation 1 below is a 2% capsaicin HA formulation. Formulation 2 below consists of 2% Capsaicin HA along with several well-known natural analgesic compounds. Tolerability (S&B) was assessed using a scale of 0 to 10, where a zero represents an absence of any S&B, a 1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is the worst pain imaginable. Likewise, the 0 to 5 Erythema scale represents the amount of reddening visually observed on the skin where a zero rating is an absence of reddening, a 1 rating indicates slight reddening of the skin, a 3 rating indicates a dark red color, and a 5 is purple.

[0287] A 53 year old male applied both formulations at the same time. The two formulations were applied side by side and then Tolerability (S&B) and Erythema (reddening) ratings were taken for each formulation application over a 120 minute period. The ratings are shown in S&B Table and Redness Table below. The tolerability of Formulation 2 (2% Capsaicin HA plus Analgesics) was not only at the extreme low end of the tolerability scales by both measures, but was even lower than Formulation 1 (2% Capsaicin HA) by direct comparison. For Formulation 1, a maximum S&B rating of 2.0 and a maximum Erythema rating of 1.5 were observed by the 20 minute time point. Both ratings gradually decreased to zero by the 90 minute time point. For Formulation 2, a maximum S&B rating of 1.5 was observed at the 30 minute time point, and then gradually decreased to zero by the 90 minute time point. Formulation 2 Erythema maximum was observed by the 20 minute time point at a rating of 0.5 and this rating decreased to zero by the 60 minute time point.

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

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

[0288] Despite containing 2% capsaicin, both formulations were observed to be very tolerable in terms of both the stinging and burning sensation (S&B), as well as visual reddening (Erythema). Furthermore, addition of analgesics to 2% Capsaicin HA (Formulation 2, Capsaicin HA plus Analgesics) resulted in lower ratings of both S&B sensation and erythema relative to 2% Capsaicin HA (Formulation 1, Capsaicin HA).

Example 15

[0289] Single Dose Treatment of Back Muscles with a 10% Capsaicin-HA Formulation

[0290] A 79 year old man used a 10% capsaicin HA formulation for mitigation of pain in his back due to his back muscles seizing up in spasm and causing intense pain. The formulation used contained 10% w/w capsaicin along with hyaluronic acid (HA) and utilized Cremaphore RH40 as a stabilization agent (see Table below).

Efficacy:

[0291] A 79 year old man still with an active lifestyle (and a history of back problems) was playing tennis when his back “went out” while picking up a tennis ball. He collapsed on the court, and any attempt to move caused him intense pain that he rated as an 8 on a scale of 0 to 10 (where zero is an absence of pain and a 10 is the worst pain imaginable). The subject was practically immobilized and lay flat on his back on the tennis court and required assistance to get up and be moved to a bed. He reported that the muscles in his middle and lower back has seized up from an abnormality with a nerve in his back (doctors had previously explained to him). Previously when this problem had occurred he required many days of bed rest to recover. Once in bed, he requested his wife to apply 10% capsaicin and hyaluronic acid (with Cremaphore RH40) formulation over a 12″×12″ area on his back where the muscles had seized up in spasm. About 90% of the treatment area consisted of muscle with the spine in the middle. When a single dose of this 10% capsaicin formulation with hyaluronic acid was applied, the pain was eliminated in his back within 20 minutes following application. The muscles in his back had relaxed. The muscle spasms were gone and he began to move around in normal motions without pain over the course of one hour. At the end of two hours, he felt normal and went out and resumed his tennis game. The capsaicin with HA formulation had provided relief that previously had only been achieved from days of bed rest and restricted activity.

Tolerability:

[0292] The subject observed the topical application of this formulation to be very tolerable (not irritating). He observed only minor Stinging and Burning (S&B) irritation upon application to his back. When the formulation was applied to the relatively large area on his back he gradually felt a warming sensation grow over the initial 2 to 3 minutes following application. The subject noted this was a comforting sensation. He observed that at its maximum, the Stinging and Burning sensation (S&B) was rated at no more than a 2.5 on a scale of 0 to 10 (defined as zero meaning no S&B sensation, 5 denoting intolerable pain and 10 representing the worst pain imaginable). Erythema (reddening) was present across the entire area of application very evenly, and appeared at its worst to look like a mild sunburn. At its worst, this erythema was estimated at a rating of 1.5 on a scale of 0 to 5: where a zero represents a complete absence of erythema, a 1 is slight reddening, a 3 as dark red and a 5 as purple. In terms of both S&B sensation and erythema, the subject found the formulation to be very tolerable.

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

Example 16

[0293] Tolerability of a 5% Capsaicin-HA Formulation Containing Polysorbate 80 to Knees Afflicted with Osteoarthritis

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

[0294] A 70 year old man applied a 5% capsaicin HA formulation containing polysorbate 80 (composition shown in table above) to both of his knees afflicted with osteoarthritis. The man experienced no burning and stinging or pruritus for 32 minutes (duration of study) following topical application.

[0295] While the invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

[0296] All documents and other information sources cited herein are hereby incorporated in their entirety by reference.