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[0279] Even though patch Keto-2 contained 7.3% NaOH, the cumulative amount of ketoprofen that permeated across the human cadaver skin at 24 hours (61.7 µg/cm 2 ) was only slightly higher than that from the formulation without NaOH (Keto-1, 35.2 µg/cm 2 ). This may be due to the consumption of NaOH by the reaction between NaOH and ketoprofen, which reduced the NaOH concentration to only 0.05% as the excess NaOH concentration. This result indicated that the permeation of ketoprofen could be enhanced with an excess NaOH concentration as low as 0.05%. 

[0280] The cumulative amount of ketoprofen that perme› ated across human cadaver skin at 24 hours increased from 61.7 µg/cm 2 to 402.7 µg/cm 2 when the calculated excess NaOH concentration in the dried patch was increased from 0.05% to 1.38% (Keto-4), i.e., up to about 7-fold more flux was obtained than in the absence of NaOH. The cumulative amount of ketoprofen that permeated across human cadaver skin at 24 hours from the formulation with an excess NaOH concentration of 1.00% (Keto-3, 315.8 µg!cm 2 ) is about 5 times higher than that from the formulation with an excess NaOH concentration of 0.05% (Keto-2, 61.7 µg/cm 2 ). 

[0281] An in vitro skin permeation study was conducted using four phenylpropanolamine hydrochloride (PPA-HCl) transdermal systems, designated PPA-1, PPA-2, PPA-3, and PPA-4, the compositions of which are set forth in Table 7. Round disc samples were prepared as described in the Methods section. The theoretical percent weight for each ingredient after drying ( calculated assuming all volatile ingredients were completely removed during drying) is set forth in Table 8. 

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[0282] 

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[0283] Since PPA-HCl is an acid addition salt of a free base, it reacts with Na OH. The concentration of NaOH in the 

## Example 3 

system after the reaction is completed depends on the amount of PPA-HCl added. The remaining NaOH concen› tration after the reaction is completed is defined as the excess NaOH concentration, and was calculated as described in Example 2. The pH was measured as described in the Methods section. The pH of the PPA-HCl patch increased from 10.08 to 10.88 when the calculated excess NaOH concentration in the dried patch was increased from 0.20% to 2.62%, while the pH of the patch without NaOHwas 7.33. Skin irritation could be related to the pH of the patch, which depends on the excess NaOH concentration. 

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[0284] The in vitro permeation of PPA-HCl through human cadaver skin from these discs was measured as described in the Methods section. Three diffusion cells were used for each formulation. The cells were filled with DI water. The receiver solution was completely withdrawn and replaced with fresh DI water at each time point. The samples taken were analyzed by an HPLC for the concentration of PPA-HCl in the receiver solution. The cumulative amount of PPA-HCl that permeated across the human cadaver skin was calculated using the measured PPA-HCl concentrations in the receiver solutions, which were plotted versus time and are described below. 

[0285] Even though patch PPA-2 contained 6.3% NaOH, the cumulative amount of PPA-HCl that permeated across the human cadaver skin at 24 hours from this formulation (1.35 mg/cm 2 ) was only slightly higher than that from the formulation without NaOH (PPA-1, 0.56 mg/cm 2 ). This may be due to the consumption of NaOH by the reaction between NaOH and PPA-HCl, which reduced the NaOH concentra› tion to only 0.20% as the excess NaOH concentration. This result indicated that the permeation of PPA-HCl could be enhanced with an excess NaOH concentration as low as 0.20%. The cumulative amount of PPA-HCl across human cadaver skin at 24 hours increased from 1.35 mg/cm $^{2 }$to 5.99 mg/cm $^{2 }$when the calculated excess NaOH concentration in the dried patch was increased from 0.20% to 2.62% (PPA-4), i.e., up to about 4-fold more flux was obtained than in the absence of NaOH. The cumulative amount of PPA-HCl across human cadaver skin at 24 hours from the formulation with an excess NaOH concentration of 1.33% (PPA-3, 5.2 mg/cm 2 ) is about 4 times higher than that from the formu› lation with an excess NaOH concentration of 0.20% (PPA-2, 1.35 mg/cm 2 ). 

[0286] A human skin irritation study was performed using seven transdermal systems, which are listed below: 

[0287] Keto-5 (containing no ketoprofen, no NaOH) 

[0288] Keto-6 (containing ketoprofen, no NaOH) 

[0289] Keto-7 

[0290] Keto-8 

[0291] Keto-9 

[0292] Keto-10 

## Example 4 

