Jun.5,2003  36  US 2003/0104041 Al  [0373]  The cells were filled with  DI  water as a receiver  solution. The  DI  water had been degased to remove air  bubbles. The receiver solution was completely withdrawn  and replaced with fresh  DI  water at each time point.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 concen› tration of oxytocin in the receiver solution. The cumulative  amount of oxytocin across human cadaver skin was calcu› lated using the measured oxytocin concentrations in the  receiver solutions for each time point, which were listed in  Table 48. The skin was pretreated with 1 % NaOH for the  specified pretreatment time period.  [0374]  An in-vitro skin permeation study was conducted  using four diclofenac sodium transdermal systems, desig› nated Diclo-1, Diclo-2, Diclo-3, and Diclo-4, the composi› tions of which are set forth in Table 49. Round disc samples  were prepared as described in the Methods section. The  theoretical percent weight for each ingredient after drying  ( calculated assuming all the volatile ingredients were com› pletely removed during drying) is listed in Table 50.  [0376]  Since diclofenac sodium is not expected to react  with NaOH, the NaOH concentration listed in Table 50  equals the excess NaOH concentration, calculated as  described in Example 2.  [0377]  The  pH  of the patches was measured as described  in the Methods section. The  pH  of the diclofenac sodium  patch increased from 7.17 to 11.28 when the calculated  excess NaOH concentration in the dried patch was increased  from 0% to 3.6%.  [0378]  The in vitro permeation of diclofenac sodium  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  10% ethanol/90% water solution. The receiver solution was  completely withdrawn and replaced with fresh ethanol/water  solution at each time point. The samples taken were ana› lyzed by an  HPLC  for the concentration of diclofenac  sodium in the receiver solution. The cumulative amount of  diclofenac sodium across human cadaver skin was calcu› lated using the measured diclofenac sodium concentrations  in the receiver solutions.  [0379]  The cumulative amount of diclofenac sodium  across human cadaver skin at 24 hours increased from 28.4  µg!cm 2  to 3647.3  µg/cm $^{2 }$when the calculated excess NaOH  concentration in the dried patch was increased from 0% to  3.6%. The cumulative amount of diclofenac sodium across  human cadaver skin at 24 hours from the system containing  1.3% NaOH (Diclo-2) was 2439.6  µg/cm 2 ,  which was about  85 times higher than that from the formulation without  NaOH (28.4  µg/cm 2 ,  Diclo-1).  TABLE  48  TABLE  SO-continued  TABLE  51  TABLE  49  TABLE  52  TABLE  50  Example 16  Cumulative Amount of Oxytocin (µg/cm 2 )  5 hr  11 hr  24 hr  Time  Pretreatment  Pretreatment  Pretreatment  4.25 hours  0.45  53.42  13.23  14.75 hours  0.97  67.97  21.06  24 hours  0.97  75.36  30.97  Diclofenac  sodium  PG  NaOH  PIE  adhesive  (30%  solid)  Heptane  DI water  Component Weight and Weight Percent Based on  Total Solution Weight  Diclo-1  Diclo-2  Diclo-3  g(wt%)  g(wt%)  g (wt%)  0.6 (9.2)  0.6 (9.1)  0.6 (9.0)  0.9 (13.9)  0.9 (13.7)  0.9 (13.6)  0  0.D35 (0.5)  0.05 (0.8)  4 (61.5)  4 (60.9)  4 (60.6)  1 (15.4)  1 (15.2)  1 (15.2)  0  0.D35 (0.5)  0.05 (0.8)  Diclo-4  g(wt%)  0.6 (9.0)  0.9 (13.4)  0.1 (1.5)  4 (59.7)  (14.9)  0.1 (1.5)  [0375]  Diclofenac  sodium  PG  NaOH  Component Weight and Weight Percent Based  on Dried Film Weight  Diclo-1  Diclo-2  Diclo-3  g(wt%)  g(wt%)  g (wt%)  0.6 (22.2)  0.6 (21.9)  0.6 (21.8)  0.9 (33.3)  0.9 (32.9)  0.9 (32.7)  0  0.D35 (1.3)  0.05 (1.8)  Diclo-4  g(wt%)  0.6 (21.4)  0.9 (32.1)  0.1 (3.6)  PIE  adhesive  (30%  solid)  Component Weight and Weight Percent Based  on Dried Film Weight  Diclo-1  g (wt%)  1.2 (44.4)  Diclo-2  g(wt%)  1.2 (43.9)  Diclo-3  g (wt%)  1.2 (43.6)  Diclo-4  g (wt%)  1.2 (42.9)  Excess NaOH Concentration  (wt  %) and pH  Excess NaOH  Concentration  pH  Diclo-1  0  7.17  Diclo-2  1.3  10.59  Diclo-3  1.8  10.72  Diclo-4  3.6  11.28  Cumulative Amount of Diclofenac Sodium  (µg!cm 2 )  Time  Diclo-1  Diclo-2  Diclo-3  Diclo-4  5 hours  0.5  659.0  1437.8  2010.5  10.5 hours  4.7  1587.6  2619.3  2992.9  20 hours  18.8  2273.7  3263.0  3513.1  24 hours  28.4  2439.6  3420.6  3647.3 