Aug. 6, 2009  35  US 2009/0197849 Al  [0379]  The pH of the patches was measured as described in  the Methods section. The pH of the diclofenac sodium patch  increased from 7.40 to 10.38 when the calculated excess  NaOH concentration in the dried patch was increased from  0%to 1.8%.  [0380]  The in vitro permeation of diclofenac sodium  through human cadaver skin from these discs was measured  as described in the Methods section. Twelve diffusion cells  were used for each formulation. The cells were filled with  10% ethanol/90% water solution. At each time point, the pH  at the interface between skin and the patch for three diffusion  cells was measured by removing the receiving fluid, remov› ing the clamp and the donor chamber, gently teasing the patch  away from the skin with tweezers, leaving the skin on the  receiver chamber, measuring the pH of the solution on the  skin by placing the microelectrode directly onto the skin  surface.  [0381]  The cumulative amount of diclofenac sodium across  human cadaver skin was calculated using the measured  diclofenac sodium concentrations in the receiver solutions.  [0382]  The cumulative amount of diclofenac sodium across  human cadaver skin at 24 hours increased from 34.6 µg/cm 2  to 3257.7 µg/cm $^{2 }$when the calculated excess NaOH concen› tration in the dried patch was increased from 0% to 1.8%. The  cumulative amount of diclofenac sodium across human  cadaver skin at 24 hours from the system containing 0.4%  NaOH (Diclo-10) was 227.7 µg/cm 2 ,  which was about six  times higher than that from the formulation without NaOH  (34.6 µg/cm 2 ,  Diclo-9). This result indicated that the perme› ation of diclofenac sodium across human skin could be  enhanced by a NaOH concentration as low as 0.4%.  [0383]  The formulation ofDiclo-10 provided up to 7-fold  more diclofenac sodium flux than in the absence of NaOH  (Diclo-9). The formulation of Diclo-11 provided up to  50-fold more flux, while the highest pH formulation evalu› ated, Diclo-12, provided up to 94-fold more flux than in the  absence ofNaOH.  [0384]  The measured pHs at the skin/patch interface are  listed below.  *  Could not be measured because there was not enough solution at the inter› face.  [0385]  The pHs at the interface between skin and the patch  remained about the same, even though the concentration of  NaOH was increased from 0.4% to 1.8%. It was difficult to  measure the pH of interface between skin and patch for the  formulations without NaOH or with a low NaOH concentra› tion because there was not enough solution on the top of the  skin.  [0386]  Since the pH measurement for the interface between  the skin and patch may be difficult for low NaOH concentra› tions, the pHs of the receiver solutions were measured at  various time points as references. The pHs of receiver solu› tions indicated that the pHs depend on the time interval  between sampling, the NaOH concentration in the patch and  the time point. The pHs at the 3-hour time point increased  from 8.0 to 10.8 when the NaOH concentration in the patch  was increased from 0.4% to 1.8%.  [0387]  An in-vitro skin permeation study was conducted  using three alendronate sodium transdermal systems, desig› nated, Al-1, Al-2 andAl-3, the compositions of which are set  forth in Table 66.  [0388]  Round disc samples were prepared in a manner  similar to that 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.  [0389]  The theoretical percent weight for each ingredient  after drying ( calculated assuming all the volatile ingredients  were completely removed during drying) is listed in Table 67.  TABLE 66  TABLE 64  TABLE 65  TABLE 63  Example 20  ExcessNaOH  Concentration  pH  Excess NaOH Concentration (wt%) and pH  Diclo-9  0  7.40  Diclo-10  0.4  8.99  Diclo-11  0.7  10.71  Diclo-12  1.8  10.38  pHs at the Interface between Skin and Patch  Time  Diclo-9  Diclo-10  Diclo-11  Diclo-12  3 hours  11.0  10.3  6 hours  11.0  11.2  9.8  10 hours  8.5  10.9  10.7  10.2  24 hours  9.7  10.1  9.4  Cumulative Amount ofDiclofenac Sodium (µg/cm 2 )  Time  Diclo-9  Diclo-10  Diclo-11  Diclo-12  3 hours  7.5  1.5  33.4  257.7  6 hours  39.6  18.3  269.3  793.3  10 hours  63.2  49.3  654.4  1652.2  24 hours  34.6  227.7  1733.8  3257.7  Component Weight and Weight Percent Based on Total Solution  Wei ht  Al-1  Al-2  Al-3  g(wt%)  g(wt%)  g(wt%)  Alendronate sodium  0.30 (3.2)  0.30 (3.2)  0.30 (3.2)  Glycerin  1.00 (10.8)  1.00 (10.6)  1.00 (10.5)  NaOH  0  0.05 (0.5)  0.10 (1.1)  PIB adhesive  7.5 (80.6)  7.5 (79.8)  7.5 (78.9)  (30% solid)  Heptane  0.50 (5.4)  0.50 (5.3)  0.50 (5.3)  DI water  0  0.05 (0.5)  0.10 (1.1) 