Nov. 4, 2004  46  US 2004/0220262 Al  the measured lidocaine concentrations in the receiver solu› tions.  [0461]  The pH of the patches was measured as described  in the Methods section but using a 2.4 cm 2  circular patch.  [0462]  The pH of the lidocaine patch measured increased  from 8.86 to 10.87 when the calculated excess NaOH  concentration in the dried patch was increased from 0% to  4.6%. The cumulative amount of lidocaine across human  cadaver skin at 24 hours increased from 0.428 mg/cm 2  to  1.169 mg/cm 2  when the calculated excess NaOH concen› tration in the dried patch was increased from 0% to 4.6%.  [0463]  The formulation of Lido-2 provided up to 1.5-fold  more lidocaine flux than in the absence of NaOH (Lido-1).  The highest pH formulation evaluated, Lido-3, provided up  to 3-fold more flux than in the absence of NaOH.  [0464]  An in vitro skin permeation study was conducted  using three enalapril maleate transdermal systems, desig› nated Enal-1, Enal-2 and Enal-3, the compositions of which  are set forth in Table 90.  [0465]  Round disc samples were prepared as described in  the Methods section, except that the formulation was dried  at a temperature of 65°  C. and the discs were cut into discs  having a diameter of  9 /26 inch.  [0466]  The theoretical percent weight for each ingredient  after drying ( calculated assuming all volatile ingredients  were completely removed during drying) is set forth in Table  91.  [0469]  The in vitro permeation of enalapril maleate  through human cadaver skin from these discs was measured  as described in the Methods section. Three diffusion cells  were used for each formulation. The receiver solution, 10%  ethanol, was completely withdrawn and replaced with fresh  receiver solution at each time point. The samples taken were  analyzed by an  HPLC  for the concentration of enalapril  maleate in the receiver solution. The cumulative amount of  enalapril maleate that permeated across the human cadaver  skin was calculated using the measured enalapril maleate  concentrations in the receiver solutions.  [0468]  Since enalapril maleate is an acid addition salt of a  free base, it reacts with NaOH. The concentration of NaOH  in the system after the reaction is completed depends on the  amount of enalapril maleate added. The remaining NaOH  concentration after the reaction is completed is defined as  the excess NaOH concentration, and was calculated as  described in Example 2. The pH of each patch was measured  as described in the Methods section but using a 2.4 cm 2  circular patch. The pH of the enalapril maleate patch  increased from 7.29 to 10.82 when the calculated excess  NaOH concentration in the dried patch was increased from  1.9% to 6.9%. The pH of the patch without NaOH was 3.12.  TABLE 90-continued  TABLE 88  TABLE  89  TABLE  91  TABLE 92  TABLE  90  Example 26  Cumulative Amount of Lidocaine (mg/cm 2 )  Time  5 hours  15.5 hours  23.75 hours  Lido-1  0.069  0.237  0.428  Lido-2  0.126  0.410  0.632  Lido-3  0.300  0.816  1.169  NaOH  PIE adhesive  (30% solid)  n-Heptane  Component Weight and Weight Percent  Based on Total Solution Weight  Enal-1  Enal-2  g(wt%)  g(wt%)  0  0.13 (2.1)  4.00 (70.2)  4.00 (67.2)  0.50 (8.8)  0.50 (8.4)  Enal-3  g (wt%)  0.25 (4.0)  4.00 (64.5)  0.50 (8.1)  [0467]  Excess NaOH Concentration  (wt  % ) and pH  Excess NaOH  Concentration  pH  Lido-1  0  8.86  Lido-2  3.1%  10.44  Lido-3  4.6%  10.87  Enalapril Maleate  PG  NaOH  PIE adhesive  Weight and Theoretical Weight Percent  Based on Dried Film Weight  Enal-1  Enal-2  g(wt%)  g(wt%)  0.50 (22.7)  0.50 (21.5)  0.50 (22.7)  0.50 (21.5)  0  0.13 (5.4)  1.20 (54.5)  1.20 (51.6)  Enal-3  g (wt%)  0.50 (20.4)  0.50 (20.4)  0.25 (10.2)  1.20 (49.0)  Enalapril Maleate  PG  DI Water  Component Weight and Weight Percent  Based on Total Solution Weight  Enal-1  Enal-2  g(wt%)  g(wt%)  0.50 (8.8)  0.50 (8.4)  0.50 (8.8)  0.50 (8.4)  0.20 (3.5)  0.33 (5.5)  Enal-3  g(wt%)  0.50 (8.1)  0.50 (8.1)  0.45 (7.3)  Excess NaOH Concentration  (wt  %) and pH  Excess NaOH  Concentration  pH  Enal-1  3.12  Enal-2  1.9%  7.29  Enal-3  6.9%  10.82 