(12) United States Patent (10) Patent No.: US 9,155,714 B2 Cebulski Et Al
US009 155714B2
(12) United States Patent (10) Patent No.: US 9,155,714 B2 Cebulski et al. (45) Date of Patent: Oct. 13, 2015
(54) COMPOSITIONS COMPRISING AN 2012fO2O1902 A1 8, 2012 Modak et al. AROMATIC ALCOHOL AND A TRPV1 2013/0202543 A1 8/2013 Kiper et al. 2013,0230609 A1 9/2013 Modak et al. ANTAGONIST, AND USES THEREOF FOREIGN PATENT DOCUMENTS (71) Applicant: JOHNSON & JOHNSON CONSUMER INC. Skillman, NJ (US) WO WOOO67705 * 11, 2000 WO WO 2009/087242 A2 T 2009 (72) Inventors: Slawomir Cebulski, Flemington, NJ WO WO 2009087242 A2 * 7, 2009 (US); Michelle Garay, Pittstown, NJ WO WO 2011, 131474 A2 10/2011 (US); Karien J. Rodriguez, Dunwoody, OTHER PUBLICATIONS GA (US); Michael D. Southall, The Honest Company. “Phenoxyethanol.” (C) 2012. Available from: < Pennington, NJ (US); Simarna Kaur, http://blog.honest.com/what-is-phenoxyethanol/ >.* Neshanic Station, NJ (US) EWG Skin Deep Cosmetics Database. “Benzyl alcohol.” (C) 2007. Available from:
TABLE 3 TABLE 5-continued Phenoxyethanol 3 nM Phenoxyethanol 2 InM Phenoxyethanol 3 nM Phenoxyethanol 2 InM Capsazepine Maximum RFU % of Maximum RFU % of AMG9810 Maximum RFU 96 of In- Maximum RFU % of nM (meant SD) Inhibition (mean + SD) Inhibition 5 (nM) (meant SD) hibition (meant SD) Inhibition 1OOOO 106.49 4.15 75.89 79.39 2.79 72.34 O.1526 412.30 - 110.68 261.54 - 114.76 2SOO 99.71 - 6.08 77.43 84.79 2.68 7046 O 224.26 - 42.60 21639, 45.19 625 7S.71 - 3.39 82.86 57.76 2.15 79.88 156 101.59 2.44 77.00 87.54 8.38 69.50 39 176.52, 75.37 60.04 75.06 6.64 73.85 10 10 340.96 12.96 22.82 154.95 19.56 46.01 2 486.75 153.02 236108.91 17.73 TABLE 6 O6104 351.36 32.21 20:46 21 O.O3 + 46.34 26.82 Capsaicin 300 nM Capsaicin 100 nM O.1526 SO8.45 81.79 319.33 77.43 O 441.7636.68 287.00 25.75 AMG9810 Maximum RFU 9% of Maximum RFU 96 of 15 (nM) (meant SD) Inhibition (meant SD) Inhibition 1OOOO 44.15 - 220 94.95 47.OO 1129 94.47 TABLE 4 2SOO 78.33 46.56 91.OS 85.41 20.60 89.95 625 747.36 77.35 14.59 735.36 114.75 13.45 Capsaicin 300 nM Capsaicin 100 nM 156 958.56 16.66 916.79 31.53 2O 39 975.3S 32.01 942.69 88.43 Capsazepine Maximum RFU % of Maximum RFU % of O 87S.OS SS.11 849.62+ 7.O2 (nM) (Mean it SD) Inhibition (Mean + SD) Inhibition 1OOOO 58.73 440 93.18 45.31 - 14.17 93.00 2SOO 31.08344 96.39 27.614.95 95.73 EXAMPLE 3 625 28.36 3.16 96.71 24.395.19 96.23 25 156 51.2014.34 94.05 29.36 6.46 95.46 SYMSITIVE 1609 Reduces Cat Flux Induced by 39 SS7.38 79.48 35.26 18795 - 177.88 70.95 Phenoxyethanol or Capsaicin 10 771.64. 25.92 10.37 461.29 - 221.27 28.71 2 850.93 28.6S 1.16 665.8390.25 O 860.95 33.14 647.05 33.18 SYMSITIVE1609 was tested for activity as a TRPV-1 antagonist using the Calcium Flux Test using two different 30 concentrations of phenoxyethanol in DMSO. It was also tested using the Calcium Flux Test in which phenoxyethanol TABLE 5 was replaced with capsaicin. The results are shown in Tables 7 and 8, respectively. Concentrations of phenoxyethanol and Phenoxyethanol 3 nM Phenoxyethanol 2 nM capsaicin are reported in milimolar (mM) and nanomolar AMG9810 Maximum RFU 96 of In- Maximum RFU 9% of (nM), respectively, but concentrations of SYMSITIVE1609 (nM) (meant SD) hibition (meant SD) Inhibition are reported in % V/v. In Table 7, mass ratios of SYMSI 1OOOO 65.74 - 4.33 70.69 59.78 - 3.84 72.37 TIVE1609 to phenoxyethanol are also reported (molecular 2SOO 6859 - 4.15 69.42 58.OO 5.34 73.19 weight of phenoxyethanol of 138.16 g/mol, a density of phe 625 58.16 1.97 74.07 SSS38.48 7434 noxyethanol of 1.1 g/mL, and a density of SYMSITIVE 1609 156 7S.S9 10.97 66.29 58.21 S.97 73.19 40 of 0.95 g/mL). g ... : it, s97 E. : g 5. These results demonstrate that treatment with SYMSI 2 265.0252.11 2O2.96 - 18.01 6.20 TIVE 1609 not only reduces phenoxyethanol-induced cal O6104 40529 - 152.93 - 189.72 - 34.94 12.32 cium flux, but is capable of reducing this flux at low ratios of SYMSITIVE1609 to phenoxyethanol. TABLE 7
Phenoxyethanol 3 mM Phenoxyethanol 2 mM
SYMSITIVE Max RFU Ratio (m/m) Max RFU Mass Ratio 1609 (mean % of SYMSITIVE: (meani % of SYMSITIVE: (% viv) SD) Inhibition Phenoxyethanol SD) Inhibition Phenoxyethanol
O.O4839 52.56 - 79.62 1:0.9 48.89 4.25 72.44 1:0.6 6.41 O.O1613 49.86 - 80.67 1:2.7 52.45 2.42 70.44 1:1.8 5.59 O.OOS38 73.49 71.51 1:8 55.66 - 2.52 68.63 1:54 11.30 O.OO179 2O0.63 - 22.22 1:24 137.07 22.75 1:16 15.30 9.64 O.OOO60 263.43 19O.OO 1:48.7 3.66 1:73 48.44 O 257.93 177.43 39.06 19.36 US 9,155,714 B2 9 10 TABLE 8 continued while slowly lowering the temperature to room temperature. pH was adjusted to a target of 5.6 using citric Capsaicin 100 nM acid. SYMSITIVE1609 Maximum RFU % of A composition according the invention, Composition E1. (% viv) (meant SD) Inhibition was prepared using the ingredients shown in Table 11. O.04839 707.54 269.73 29.73 O.O1613 713.35 621.33 29.15 TABLE 11 O.OOS38 1119.65 140.29 O.OO179 1293.49 40.06 Inventive Example, El O.OOO60 1305.23 33.35 10 O 1 OO6.9174.51 Trade Name INCI Name % wt
Deionized Water Water 81.9 Texapon N70A Sodium Lauryl Sulfate 3.7 EXAMPLE 4 Tween 28-LQ PEG-80 Sorbitan Laurate S.O 15 Miranol HMD Sodium Lauroamphoacetate 2.0 Preparation of Formulated Cleansing Compositions TegoBetain L7V Cocamidopropyl Betain 6.4 Phenoxetol Phenoxyethanol 2.0 Hydrolite CG Caprylyl Glycol 1.O A comparative cleansing composition (Comparative SymSitive 1609 trans-4-tert-butylcyclohexanol 1.O Example C1) was prepared using the ingredients listed in Citric Acid (50% solution) Citric Acid C.S Table 9:
TABLE 9 The composition shown in Table 11 was prepared as fol Comparative Example, Cl lows. Water was added to a glass beaker and heated to 60° C. 25 Texapon N70A was mixed in until fully dissolved. While Trade name INCI Name % wt mixing, Tween 28-LQ, Miranol HMD and TegoBetain L7V Deionized Water Water 79.9 were added and the mixing was continued until the mixture Texapon N70A Sodium Lauryl Sulfate 3.7 was clear. Hydrolite CG, Phenoxetol, and SYMSITIVE 1609 Tween 28-LQ PEG-80 Sorbitan Laurate S.O were then added at the same time and mixing was continued Miranol HMD Sodium Lauroamphoacetate 2.0 while slowly lowering the temperature to room temperature. TegoBetain L7V Cocamidopropyl Betain 6.4 30 Phenoxetol Phenoxyethanol 2.0 pH was adjusted to the target of 5.6 using citric acid. Hydrolite CG Caprylyl Glycol 1.0 Citric Acid Citric Acid C.S (50% solution) EXAMPLE 5 35 The composition shown in Table 9 above was prepared as Inventive Example, E1 Reduces Ca' Flux follows. Water was added to a glass beaker and heated to 60° Compared with Comparative Example, C1 C. Texapon N70A was mixed in until fully dissolved. While mixing, Tween 28-LQ, Miranol HMD and TegoBetain L7V The compositions of Comparative Examples C1 and C2 were added and mixing was continued until the mixture was 40 were tested for calcium flux levels using the Calcium Flux clear. Hydrolite CG and Phenoxetol were added at the same Test. The results are shown in Table 12, and demonstrate that time and mixing was continued while slowly lowering the formulated cleansing compositions including phenoxyetha temperature to room temperature. pH was adjusted to a target nol (with or without additional preservative caprylyl glycol) of 5.6 using citric acid. induce calcium flux. Another comparative cleansing composition, Comparative 45 Example C2, was prepared using the ingredients listed in Table 10: TABLE 12 Comparative Example, Cl Comparative Example, C2 TABLE 10 50 **P < 0.05 **P < 0.05 Comparative Example, C2 Cleanser Maximum RFU Compared to Maximum RFU Compared to (% viv) (meant SD) Vehicle (meant SD) Vehicle Trade name INCI Name % wt O.12S 129.6229.43 :::::: 146.97 - 23.41 :::::: Deionized Water Water 80.9 O.0625 8O34 14.75 :::::: 72.OS 8.81 :::::: Texapon N70A Sodium Lauryl Sulfate 3.7 55 O.O313 40.667.89 ins 33.42 8.32 ins Tween 28-LQ PEG-80 Sorbitan Laurate S.O O.O156 27.364.73 ins 18.51 - 1.09 ins Miranol HMD Sodium Lauroamphoacetate 2.0 Vehicle 34.60 - 5.58 TegoBetain L7V Cocamidopropyl Betain 6.4 (Cleanser Phenoxetol Phenoxyethanol 2.0 with no Citric Acid Citric Acid q.S - pH adjuster phenoxy (50% solution) 60 ethanol) ni's: Not statistically significant The composition shown in Table 10 was prepared as fol ** Statistically significant lows. Water was added to a glass beaker and heated to 60° C. Texapon N70A was mixed in until fully dissolved. While Inventive Example, E1 was also tested using the Calcium mixing, Tween 28-LQ, Miranol HMD and TegoBetain L7V 65 Flux Test. The results are shown in Table 13 and compared were added and mixing was continued until the mixture was against the results for Comparative Example C1, reproduced clear. Phenoxetol was added at the same time and mixing was from Table 12. US 9,155,714 B2 11 12 These results demonstrate that inclusion of SYMSI TABLE 14-continued TIVE 1609 in a cleansing formulation with phenoxyethanol Phenoxy- Phenoxy inhibits calcium flux caused by the phenoxyethanol in a man ethanol ethanol Capsaicin ner that increases with the amount of the cleansing formula 3 mM 2 mM 300 nM tion. 5 Maximum RFU Maximum RFU Maximum RFU Compound (Mean + SD) (Mean + SD) (Mean + SD) TABLE 13 Diphenhydramine 312.62 67.77 158.25 O.69 899.35 - 10.60 25 M Lidocaine 100 M 205.92 - 16.97 116.25 - 25.92 ind Comparative 10 Lidocaine 25 LM 197.45 41.14 124.96 - 22.24 ind Example, C1 Inventive Example, E1 Vehicle 216.86 - 36.93 155.87 46.55 896.85 - 16.71 ind = not determined Cleanser Maximum RFU Maximum RFU % of The results show that none of hydrocortisone, diphenhy (% viv) (meant SD) (meant SD) Inhibition 15 dramine or lidocaine were effective at reducing phenoxyetha nol-induced calcium flux in TRPV-1-expressing HEK293 O.0625 80.34 14.75 29.23 S.77 63.62 cells. Thus, not all analgesic agents are TRPV-1 antagonists. O.03125 40.667.89 17.67 4.68 56.54 EXAMPLE 7 O.O1563 27.364.73 12.44 2.63 54.54 O.OO781 19.04 11.59 13.722.29 27.94 2O Irritants Such as Sodium Bicarbonate do not Induce O.OO391 22.35 - 3.21 13.85 2.96 38.04 Calcium Flux in TRPV-1 Expressing Cells O.OO195 3438 4.23 31.02 - 4.57 9.76 Benzyl alcohol and sodium bicarbonate were tested using O.OOO98 39.83 1.83 45.16 1.95 25 the Calcium Flux Test. Both of these compounds are known to induce skin irritation in vivo (Bagley, D. M. et al. (1996) Toxicol In Vitro 10(1): 1-6.) The results are shown in Table 15. TABLE 1.5
Benzyl **P < 0.05 Sodium **P < 0.05 Alcohol Maximum RFU Compared Bicarbonate Maximum RFU Compared (mM) (meant SD) to Vehicle (mM) (meant SD) to Vehicle 4 362.51 - 126.09 :::::: O.S 3.39 2.66 ins 2 13S45 - 12.15 ins O.25 124.90 - 8.41 :::::: 1 11351 - 4.70 ins O.12S 114.34 - 6.46 ins O.S 104.45 - 12.50 ins O.0625 102.15 - 4:19 ins O.25 6445 28.15 ins O.03125 109.99 - 1.37 ins Vehicle 101.19 - 2.56 Vehicle 98.80 - 12.93 nis: Not statistically significant ** Statistically significant
EXAMPLE 6 In this test, benzyl alcohol did not show statistically sig nificant activity for TRPV-1 activation at doses of 2 mM and Hydrocortisone, Diphenhydramine or Lidocaine do below. However, as shown in Example 9, benzyl alcohol does not Reduce Phenoxyethanol-Induced Calcium Flux exhibit such activity at lower doses as well. The difference in 45 results may arise from optimization of the test method to in TRPV-1 Expressing Cells lower the background readings (the vehicle alone was The analgesics hydrocortisone, diphenhydramine and approximately 9 RFU in Example 9, Table 19, versus lidocaine, all of which have been shown to be effective at approximately 101 RFU in Table 15 above), resulting in reducing neurosensory responses, such as itch and sting (see higher sensitivity of the assay showing statistically significant Lin, T. K. et al. (2013) J Invest Dermatol 133(2): 469-478: 50 changes for the lower doses of benzyl alcohol. Yosipovitch, G. et al. (2003) Lancet 361 (9358): 690-694; and These results also demonstrate that not all skin irritants, Walling, H. W. etal. (2010) Clin Cosmet Investig Dermatol 3: i.e., sodium bicarbonate, activate TRPV-1. 99-117) were tested using the Calcium Flux Test. The results EXAMPLE 8 are shown in Table 14. 55 Additional Inventive Examples TABLE 1.4 A composition according to the invention, Composition Phenoxy- Phenoxy ethanol ethanol Capsaicin E2, is prepared by blending the ingredients listed in Table 16: 3 mM 2 mM 300 nM Maximum RFU Maximum RFU Maximum RFU TABLE 16 Compound (Mean + SD) (Mean + SD) (Mean + SD) Inventive Example E2 Hydrocortisone 225.1938.09 160.6630.14 963.83 - 65.21 100 M Trade Name INCI Name % wt Hydrocortisone 25 M 309.90 + 40.00 171.65 + 83.27 950.97+ 49.52 Diphenhydramine 19547 53.34 141.61 33.91 825.379.95 65 Deionized Water Water 82.8 100 M Texapon N70A Sodium Lauryl Sulfate 3.7 US 9,155,714 B2 13 14 TABLE 16-continued A composition according to the invention is prepared by blending the ingredients listed in Table 18: Inventive Example E2 TABLE 1.8 Trade Name INCI Name % wt 5 Inventive Example, E4 Tween 28-LQ PEG-80 Sorbitan Laurate S.O Miranol HMD Sodium Lauroamphoacetate 2.0 Trade Name INCI Name wt % TegoBetain L7V Cocamidopropyl Betain 6.4 Deionized Water Water 69.04 Phenoxetol Phenoxyethanol 2.0 10 Sodium Chloride Sodium Chloride O.O1 Hydrolite CG Caprylyl Glycol 1.O Hydrolite CG Caprylyl Glycol 1.O SymSitive 1609 trans-4-tert-butylcyclohexanol O.1 SymSitive 1609 trans-4-tert-butylcyclohexanol 1.O Citric Acid (50% solution) Citric Acid C.S Snow White Petrolatum Petrolatum 4.OO Isofol. 28 Dodecylhexadecanol 2.50 Dow Corning Q7-9120 (20 CS) Dimethicone 1.25 15 Kessco IPP Isopropyl Palmitate 3.00 The composition shown in Table 16 above is prepared as Varisoft TA-100 Distearyldimonium Chloride S.OO follows. Water is added to a glass beaker and heated to 60° C. Glycerin Glycerin 12.00 Texapon N70A is mixed in until fully dissolved. While mix Phenoxetol Phenoxyethanol 1.O ing, Tween 28-LQ, Miranol HMD and TegoBetain L7V are added and mixing is continued until the mixture is clear. Hydrolite CG, Phenoxetol, and SYMSITIVE1609 are then The composition shown in Table 8 is prepared as follows. added at the same time and mixing is continued while slowly Water is added to a process vessel. Mixing is begun and salt is lowering the temperature to room temperature. pH is adjusted added and mixed until dissolved. Heat is applied and mixing to the target of 5.6 using citric acid. continued until to 85°C. is reached. Varisoft TA100 is added, as is petrolatum and Isofol 28, DC Q7-9120 20 cs., and A composition according to the invention, Composition 25 isopropyl palmitate. The composition is mixed at 85°C. for E3, is prepared by blending the ingredients listed in Table 17: another 10-15 minutes. The composition is then removed from heat, mixed again and cooled. At 40°C., Phenoxetoland TABLE 17 SYMSITIVE 1609 are added, and then the sample is q.s. with Inventive Example, E3 30 water and continued to mix and cool to 30-35°C. Trade Name INCI Name % wt EXAMPLE 9 Purified Water Water 86.95 Carbomer Cross-linked polyacrylic O.6O acid 35 VERSENENA Disodium EDTA O.2O Benzyl Alcohol and Phenethyl Alcohol Induce Dimethicone Dow Corning Q7-9120 S.O Calcium Flux Via TRPV-1 Receptor Silicone Brij 72 Steareth-2 0.75 Brij 721 Steareth-21 1...SO Benzyl alcohol and phenethyl alcohol were tested at a Finsolv TN C12-15 Alkyl Benzoate 2.0 series of concentrations in DMSO for activity as a TRPV-1 Phenoxetol Phenoxyethanol 2.0 40 SymSitive 1609 trans-4-tert- 1.O agonist as described in Example 1. The results are shown in butylcyclohexanol Table 19. Concentrations of benzyl alcohol and phenethyl alcohol are reported in units of% w/v. Both benzyl alcohol and phenethyl alcohol showed dose The composition shown in Table 17 is prepared as follows. 45 dependent increases in intracellular calcium flux in TRPV-1- An oil phase is prepared by adding C 12-15 alkylbenzoate to transfected HEK cells. For both compounds, the increase in a clean glass beaker. Agitation is begun and the vessel is Maximum RFU values versus the control vehicle was statis heated to 55-60° C. When the oil phase reaches 55° C. or tically significant across a wide range of amounts. These higher, Brij 72, Brij 721 and SYMSITIVE1609 are added. findings demonstrate activation of the TRPV-1 receptor by When the oil phase reaches 55-60° C., it is held at that tem 50 perature and mixed for 15 min (or until uniform). The tem benzyl alcohol and phenethyl alcohol. perature is then held at 55-60°C. with mixing until addition to water phase. TABLE 19 A water phase is prepared by adding water to a clean glass Benzyl Alcohol Maximum RFU beaker. Agitation is begun and the vessel is heated to 55-60 55 (% w/v) (meant SD) C. Disodium EDTA is added. At 55-60°C., the ingredients are O.04 608.23 - 10.21 O.O13072 1608 - 12.61 mixed for 15 minor until homogeneous. The temperature is O.OO4357 43.913.74 then held at 55-60°C. with mixing for phasing. The oil phase O.OO1452 1994 - 3.08 is added to the water phase with increased agitation and then OOOO484 15.75 1.8 60 OOOO161 10.95 - 0.23 mixed at high speed for 10-20 min. At 50° C. or lower, 5.38E-OS 13.23 - 6.33 dimethicone is added. At 40° C. or lower, Phenoxetol is 1.79E-05 10.17 119 added. The phases are then mixed for 10 minor until uniform. S.98E-06 7.25 O.71 199E-06 9.36 OS2 Sodium hydroxide is added (target pH was 5.4). The compo 6.64E-07 9.37 - 1.66 sition is then mixed for 10 minor until uniform. This is mixed 65 O 9.54 - 1.6 until uniform. Water is then added to QS and the composition was then mixed for 10 minutes. US 9,155,714 B2 15 16 TABLE 20 EXAMPLE 11
Phenethyl Alcohol Maximum RFU (% w/v) (meant SD) Capsazepine Reduces Ca' Flux Induced by Phenethyl Alcohol O.12 7SS.212.89 O.04 S48.S. 37.22 O.O13 18592 28.6 Capsazepine was tested for activity as a TRPV-1 antagonist O.OO44 70.431.61 O.OO15 25.95 - 0.85 with different concentrations of phenethyl alcohol in DMSO OOOO48 14.41 3.06 as described in Example 2. 10 OOOO16 10.14 - 4.39 The results are shown in Tables 23 and 24. OOOOOS4 8.66 - 0.82 OOOOO18 10.71 - 234 The results demonstrate that treatment with a TRPV-1 OOOOOO6 7.99 - 1.93 antagonist reduces phenethyl alcohol-induced calcium flux. OOOOOO2 12.8 1.35 O 12.89 - 1.79 15 TABLE 23
Phenethyl 10 M without Alcohol Capsazepine Capsazepine EXAMPLE 10 (% w/v) Max RFU Max RFU Capsazepine Reduces Ca' Flux Induced by Benzyl O.12 345.95 605.31 42.85% Alcohol O.04 26.42 44118 94.01% O.O13 4.56 123.10 96.30% O.OO44 11.56 26.36 56.15% 25 Capsazepine was tested for activity as a TRPV-1 antagonist O.OO15 11.68 8.68 with different concentrations of benzyl alcohol in DMSO as OOOO48 11.71 10.59 described in Example 2. OOOO16 11.64 7.21 The results are shown in Tables 21 and 22. OOOOOS4 6.90 7.70 The results demonstrate that treatment with a TRPV-1 30 OOOOO18 1360 5.43 antagonist reduces benzyl alcohol-induced calcium flux. OOOOOO6 13.70 S.48 OOOOOO2 12.76 6.43 TABLE 21 O 1344 11...SO
Benzyl 10 M without 35 Alcohol Capsazepine Capsazepine % (% w/v) Max RFU Max RFU Inhibition TABLE 24
O.04 1882 410.41 95.41% without O.O13072 10.48 93.35 88.78% 10 M Capsazepine O.OO4357 8.14 31.54 74.18% 40 Phenethyl Capsazepine Maximum O.OO1452 11.63 14.03 Alcohol Maximum RFU RFU (meani OOOO484 8.17 11.38 OOOO161 7.95 8.44 (% w/v) (meant SD) SD) OOOOOS38 10.90 5.38 O.12 364.66 - 13.76 580.443.06 37.18% OOOOO179 892 4.38 O.04 39.895.81 470.23 - 7.11 91.52% OOOOOOS98 946 4.25 O.O13 12.323.27 2OO.O2 6.15 93.84% OOOOOO199 11.32 3.07 45 O.OO44 15.660.4 79.18 O.23 80.22% 6.64E-07 11.79 7.66 O.OO15 18.5 - O.S 40.5 + 0.05 54.32% O 13.30 3.65 OOOO48 20.58 0.6 31.36 3.52 OOOO16 1948 - 0.51 22.15 0.76 OOOOOS4 21473.93 21.75 - 4.01 OOOOO18 18.180.59 17.58 0.7 TABLE 22 50 OOOOOO6 18 O.75 17.74 - 1.46 OOOOOO2 18.03 - 3.35 12.283.52 10 M without O 17.460.4 17.98 - 0.83 Capsazepine Capsazepine Benzyl Maximum Maximum Alcohol RFU (mean it RFU (mean it % SD) SD) Inhibition 55 EXAMPLE 12 O.04 28.72 1.5 424.01 - 2.92 93.23% O.O13072 21.7 O2 124.54 - 13.18 82.58% O.OO4357 15.33 SS. 7S 2.68 72.51% O.OO1452 15.7 2.1 30.81 - 0.98 SYMSITIVE 1609 Reduces Cat Flux Induced by OOOO484 17.15 - 1.46 25.835.34 Benzyl Alcohol OOOO161 1983 - 3:44 16.17 - 1.16 60 OOOOOS38 1844 - O.O7 17.1342 OOOOO179 1821 - 2.76 17.O.S. O.19 SYMSITIVE1609 was tested for activity as a TRPV-1 OOOOOOS98 16.77 - 1.48 17.820.88 antagonist as described in Example 3 with different concen OOOOOO199 1874 - 218 183.24 6.64E-07 1824 - 2.53 13.85 - 1.83 trations of benzyl alcohol in DMSO. The results are shown in O 1824 - 1.3 16.68 016 65 Table 25. Concentrations of benzyl alcohol are reported in % w/v but concentrations of SYMSITIVE 1609 are reported in % w/v. US 9,155,714 B2 17 18 TABLE 25 TABLE 26-continued
O.05% ww. O.05% viv without Symsitive without Symsitive Symsitive Benzyl Maximum Symsitive Phenethyl Maximum Maximum Alcohol RFU Maximum RFU Alcohol RFU (mean it RFU (meani (% w/v) (meant SD) (meant SD) %. Inhibition (% w/v) SD) SD) %. Inhibition O.04 76.898. SS 608.23 - 10.21 87.36% O.O13 19248 185.92 28.6 89.78% O.O13072 33.14 - 3.51 1608 - 12.61 79.39% O.OO44 25.222.31 704 31.61 64.17% O.OO4357 29.71 - 0.46 43.913.74 32.33% O.OO15 27.46 - 5:12 25.95 - 0.85 O.OO1452 24.12 2.33 1994 - 3.08 10 OOOO48 27.05 - 1.28 14.41 3.06 OOOO484 25.7 - 1.62 15.75 1.8 OOOO16 25.211.56 10.14 - 4.39 OOOO161 30.72 - 1.65 10.95 - 0.23 OOOOOS4 26.05 - 0.64 8.66 - 0.82 OOOOOS38 27.91 - 0.47 13.23 - 6.33 OOOOO18 21.02 0.79 10.71 - 234 OOOOO179 25.07 - 1.14 10.17 119 OOOOOO6 17.15 S.43 7.99 - 1.93 S.98E-06 25.56 - 1.86 7.25 O.71 OOOOOO2 18.15 2.97 12.8 1.35 199E-06 20.276.14 9.36 O.52 15 O 21.77 - 18 12.89 - 1.79 6.64E-07 24.22 2.38 9.37 - 1.66 O 23.1 - 1.61 9.54 - 1.6 What is claimed is: 1. A method of reducing irritation induced by topical appli cation of an aromatic alcohol having the formula: EXAMPLE 13 SYMSITIVE 1609 Reduces Cat Flux Induced by Phenethyl Alcohol
SYMSITIVE 1609 was tested for activity as a TRPV-1 25 antagonist as described in Example 3 with different concen trations of phenethyl alcohol in DMSO. The results are shown wherein X is an oxygenatom or absent and Y is C1-C2 alkyl: in Table 26. Concentrations of phenethyl alcohol are reported said method comprising topically applying said aromatic in 96 w/v but concentrations of SYMSITIVE 1609 are alcohol with a TRPV-1 antagonist. reported in % V/v. 30 2. The method of claim 1, wherein said aromatic alcohol is selected from the group consisting of phenoxyethanol, benzyl TABLE 26 alcohol, phenethyl alcohol, and mixtures thereof. 3. The method of claim 1, wherein the aromatic alcohol is O.05% viv without phenoxyethanol. Symsitive Symsitive Phenethyl Maximum Maximum 35 4. The method of claim 1, wherein said TRPV-1 antagonist Alcohol RFU (mean it RFU (mean it inhibits the calcium flux of the aromatic alcohol by at least (% w/v) SD) SD) %. Inhibition about 12% as measured by the Calcium Flux Test. O.12 464.85 - 56.24 7SS.212.89 38.45% 5. The method of claim 1, wherein said TRPV-1 antagonist O.04 92.46 - 21.67 S48.S. 37.22 83.14% is 4-tertiary butyl cyclohexanol. k k k k k