Nov. 4, 2004  41  US 2004/0220262 Al  TABLE  64  TABLE  66  TABLE  67  TABLE 65  TABLE 68  [0413]  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 /26 inch.  [0414]  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.  [0407]  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  concentration 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  permeation of diclofenac sodium across human skin could  be enhanced by a NaOH concentration as low as 0.4%.  [0408]  The formulation of Diclo-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  SO-fold more flux, while the highest pH formulation evalu› ated, Diclo-12, provided up to 94-fold more flux than in the  absence of NaOH.  [0409]  The measured pHs at the skin/patch interface are  listed below.  [0410]  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  concen› tration because there was not enough solution on the top of  the skin.  *  Could not be measured because there was not enough solution at the  interface.  [0411]  Since the pH measurement for  the interface  between the skin and patch may be difficult for low NaOH  concentrations, the pHs of the receiver solutions were mea› sured at various time points as references. The pHs of  receiver solutions 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%.  [0412]  An in-vitro skin permeation study was conducted  using three alendronate sodium transdermal systems, desig› nated, Al-1, Al-2 and Al-3, the compositions of which are set  forth in Table 66.  [0418]  The in vitro permeation of alendronate 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 receiver solution, PBS  [0417]  The pH of the patches was measured as described  in the Methods section but using a 2.4 cm 2  circular patch.  The pH of the alendronate sodium patch increased from 5.50  to 9.66 when the calculated excess NaOH concentration in  the dried patch was increased from 0% to 2.7%.  [0416]  Even though alendronate sodium may behave as an  acid and react with NaOH, the amount of NaOH consumed  by this reaction was not determined. For the ease of com› parison, it was assumed that the reaction between alendr› onate sodium and NaOH was not significant. Therefore, the  NaOH concentration listed in Table 67 equals the excess  NaOH concentration, calculated as described in Example 2.  [0415]  Example 20  Time  3 hours  6 hours  10 hours  24 hours  pHs at the Interface between Skin and Patch  Diclo-9  8.5  Diclo-10  11.0  11.0  10.9  9.7  Diclo-11  11.2  10.7  10.1  Diclo-12  10.3  9.8  10.2  9.4  Cumulative Amount of Diclofenac Sodium (,ugicm 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 Weight  Al-1  Al-2  g(wt%)  g(wt%)  Alendronate sodium  0.30 (3.2)  0.30 (3.2)  Glycerin  NaOH  PIE adhesive  (30% solid)  Heptane  DI water  1.00 (10.8)  1.00 (10.6)  0  0.05  (0.5)  7.5 (80.6)  7.5 (79.8)  0.50 (5.4)  0.50 (5.3)  0  0.05  (0.5)  Al-3  g(wt%)  0.30 (3.2)  1.00 (10.5)  0.10 (1.1)  7.5 (78.9)  0.50 (5.3)  0.10 (1.1)  Component Weight and Weight Percent  Based on Dried Film Weight  Al-1  Al-2  g(wt%)  g(wt%)  Alendronate sodium  0.30 (8.5)  0.30 (8.3)  Glycerin  1.00 (28.2)  1.00 (27.8)  NaOH  0  0.05  (1.4)  PIE adhesive  2.25 (63.4)  2.25 (62.5)  Al-3  g(wt%)  0.30 (8.2)  1.00 (27.4)  0.10 (2.7)  2.25 (61.6)  Excess NaOH Concentration  (wt  %) and pH  Excess NaOH  Concentration  pH  Al-1  0  5.50  Al-2  1.4%  6.66  Al-3  2.7%  9.66 