Jul.  3, 2003  24  US 2003/0124176 Al  [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.  [0283]  Since PPA-HCl is an acid addition salt of a free  base, it reacts with Na OH. The concentration of NaOH in the  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.  [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:  Example 4  [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  TABLE 8  TABLE  7  TABLE 9  Example 3  Excess NaOH Concentration  (wt  %) and pH  Excess NaOH  Concentration  pH  PPA-1  7.33  PPA-2  0.20%  10.08  PPA-3  1.33%  10.16  PPA-4  2.62%  10.88  Component Weight and Weight Percent Based on Total Solution  Wei ht  PPA-1  PPA-2  PPA-3  PPA-4  g(wt%)  g (wt%)  g(wt%)  g(wt%)  PPA-HCl  0.75 (8.5)  0.75 (8.2)  0.75 (8.1)  0.75 (8.1)  NaOH  0  0.165 (1.8)  0.195 (2.1)  0.23 (2.5)  DI water  1.1 (12.4)  1.265 (13.8)  1.295 (14.0)  1.33 (14.3)  PG  0.5 (5.6)  0.5 (5.4)  0.5 (5.4)  0.5 (5.4)  Methylal  1 (11.3)  1 (10.9)  1 (10.8)  1 (10.7)  Heptane  1.5 (16.9)  1.5 (16.3)  1.5 (16.2)  1.5 (16.1)  PIE adhesive 4 (45.2)  4 (43.6)  4 (43.3)  4 (43.0)  (30% solid)  Weight and Theoretical Weight Percent Based on Dried Film Weight  PPA-1  PPA-2  PPA-3  PPA-4  g(wt%)  g (wt%)  g(wt%)  g(wt%)  PPA-HCl  0.75 (30.6)  0.75 (28.7)  0.75 (28.4)  0.75 (28.0)  NaOH  0  0.165 (6.3)  0.195 (7.4)  0.23 (8.6)  PIE adhesive 1.2 (49.0)  1.2 (45.9)  1.2 (45.4)  1.2 (44.8)  PG  0.5 (20.4)  0.5 (19.1)  0.5 (18.9)  0.5 (18.7)  [0282] 