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[0300] Ten healthy human subjects were included in the skin irritation study. Each subject wore seven patches listed above on the arms for 24 hours. An adhesive film with a diameter of 7 /2 inch was applied over each system on the skin except the petrolatum patch to secure the system and to make the system occlusive for 24 hours. After 24 hours, the patches were removed and the skin was scored on a 0-4 scale. The scoring scale employed is listed below. The skin was scored again at 48 hours. 

[0301] The in vitro permeation of ketoprofen through human cadaver skin from formulations Keto-7, Keto-8, Keto-9, and Keto-10, was measured as described in the Methods section. Three diffusion cells were used for each formulation. 

[0302] Normal saline was used as the receiver solution. The receiver solution was collected at 24 hours and analyzed 

by an HPLC for the concentration of ketoprofen. The cumulative amount of ketoprofen that permeated across the human cadaver skin at 24 hours, was calculated using the measured ketoprofen concentrations in the receiver solu› tions. The excess NaOH concentrations for these four keto› profen systems, were calculated as described in Example 2, and the pH of the patches was measured as described in the Methods section. 

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[0303] The cumulative amount of ketoprofen that perme› ated across the human cadaver skin at 24 hours increased from 0.17 mg/cm 2 to 1.52 mg/cm 2 when the calculated 

0 = negative + - equivocal reaction (0.5) 1 - erythema 2 = erythema and induration 3 = erythema, induration and vesicles 4 - bullae 

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excess NaOH concentration in the dried patch was increased from 3.22% to 5.01 %. The excess NaOH concentration and the cumulative amount of ketoprofen across skin at 24 hours and the patch pH for Keto-8 was 0.34 mg/cm 2 and 10.81 respectively, which was about the same as those for Keto-3 shown in Example 2 (0.32 mg/cm 2 , pH=l0.10). However, the excess NaOH concentration for Keto-8 (3.92%) was higher than that for Keto-3 (1.00%), which may be due to the consumption of NaOH through reactions between NaOH and components other than ketoprofen in the Keto-8 formu› lation. 

[0304] The irritation scores obtained indicate that irrita› tion from this patch was insignificant. 

[0305] The formulation of Keto-8 provided up to 2-fold more ketoprofen flux than the lowest pH formulation evalu› ated (Keto-7). The formulation of Keto-9 provided up to 3-fold more flux, while the highest pH formulation evalu› ated, Keto-10, provided up to 9-fold more flux than in the absence of NaOH. 

[0306] An in vitro skin permeation study was conducted using four ibuprofen transdermal gels, designated lbu-1, lbu-2, lbu-3, and lbu-84, the compositions of which are set forth in Table 13. 

[0307] The excess NaOH concentrations for these four ibuprofen gels, were calculated as described in Example 2, and the pH of the gels was directly measured using a pH meter. The pH of the ibuprofen gel ( determined using the procedures of the previous examples) increased from 6.58 to 12.22 when the calculated excess NaOH concentration in the gel was increased from 0% to 1.74%. The skin irritation could be related to the pH of the gel, which depends on the excess NaOH concentration. 

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[0308] The in vitro permeation of ibuprofen through human cadaver skin from these gels was measured in a slightly different manner than as described in the Methods section. Three diffusion cells were used for each formula- 

## Example 5 

