Aug. 30, 2012  44  US 2012/0220962 Al  [0447]  The pH of the lidocaine patch measured increased  from 8.86 to 10.87 when the calculated excess NaOH con› centration 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 concentration in  the dried patch was increased from 0% to 4.6%.  [0448]  The formulation ofLido-2 provided up to 1.5-fold  more lidocaine flux than in the absence of NaOH (Lido-I).  The highest pH formulation evaluated, Lido-3, provided up to  3-fold more flux than in the absence ofNaOH.  [0449]  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.  [0450]  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 /16 inch.  [0451]  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.  [0444]  Since the reaction between lidocaine and NaOH is  not expected to be significant, the concentration ofNaOH in  the system is assumed to be independent from the amount of  lidocaine added. Therefore, the NaOH concentration listed in  Table 87 equals the excess Na OH concentration, calculated as  described in Example 2.  [0445]  The in vitro permeation oflidocaine 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solution, 5% ethanol/95% PBS  buffer (0.05 M KH$_{2}$PO$_{4 }$ with 0.15 M NaCl, pH adjusted to  6.5), was completely withdrawn and replaced with fresh  receiver solution at each time point. The samples taken were  analyzed by an HPLC for the concentration oflidocaine in the  receiver solution. The cumulative amount oflidocaine across  human cadaver skin was calculated using the measured  lidocaine concentrations in the receiver solutions.  [0452]  Since enalapril maleate is an acid addition salt of a  free base, it reacts with NaOH. The concentration ofNaOH 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 concentra› tion in the dried patch was increased from 1.9% to 6.9%. The  pH of the patch without NaOH was 3.12.  [0446]  The pH of the patches was measured as described in  the Methods section but using a 2.4 cm.sup.2 circular patch.  TABLE 88  TABLE 89  TABLE 91  TABLE 90  Example 26  TABLE 87  TABLE 86  Component Weight and Weight Percent  Based on Total Solution Weight  Lido-!  Lido-2  Lido-3  g(wt%)  g(wt%)  g(wt%)  Lidocaine  0.50 (9.1)  0.50 (8.9)  0.50 (8.8)  PG  0.50 (9.1)  0.50 (8.9)  0.50 (8.8)  Water  0  0.07 (1.2)  0.11 (1.8)  PIB adhesive  4.00 (72.7)  4.00 (70.9)  4.00 (70.1)  (30% solid)  NaOH  0  0.07 (1.2)  0.11 (1.8)  n-Heptane  0.50 (9.1)  0.50 (8.9)  0.50 (8.8)  Component Weight and Weight Percent  Based on Dried Film Weight  Lido-!  Lido-2  Lido-3  g(wt%)  g(wt%)  g(wt%)  Lidocaine  0.50 (22.7)  0.50 (22.0)  0.50 (21.7)  PG  0.50 (22.7)  0.50 (22.0)  0.50 (21.7)  PIB adhesive  1.20 (54.4)  1.20 (52.9)  1.20 (52.1)  NaOH  0  0.07 (3.1)  0.11 (4.6)  Cumulative Amount ofLidocaine (mg/cm 2 )  Time  5 hours  15.5 hours  23.75 hours  Lido-!  0.069  0.237  0.428  Lido-2  0.126  0.410  0.632  Lido-3  0.300  0.816  1.169  Excess NaOH Concentration (wt%) and pH  ExcessNaOH  Concentration  pH  Lido-!  0  8.86  Lido-2  3.1%  10.44  Lido-3  4.6%  10.87  Enalapril Maleate  PG  DI Water  NaOH  PIB adhesive  (30% solid)  n-Heptane  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)  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%)  0.50 (8.1)  0.50 (8.1)  0.45 (7.3)  0.25 (4.0)  4.00 (64.5)  0.50 (8.1)  Enalapril Maleate  PG  NaOH  PIB 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) 