Jun.5,2003  43  US 2003/0104041 Al  TABLE  81  TABLE  78  TABLE  79  TABLE  82  TABLE  83  TABLE  80  [0436]  Since galanthamine  HBr  is an acid addition salt of  a free base, it reacts with Na  OH.  The concentration of NaOH  in the system after the reaction is completed depends on the  amount of galanthamine  HBr  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  was measured as described  in the Methods section but using a 2.4 cm 2  circular patch.  The  pH  of the galanthamine  HBr  patch increased from 8.73  to 10.56 when the calculated excess NaOH concentration in  the dried patch was increased from 0% to 1.0%. The  pH  of  the formulation without NaOH was 6.53.  [0437]  The in vitro permeation of galanthamine  HBr  through human cadaver skin from these discs was measured  as described in the Methods. Three diffusion cells were used  for each formulation. The receiver solution, 5% ethanol/95%  PBS  buffer (0.05  M KH$_{2}$P0$_{4 }$ with 0.15  M  NaCl,  pH  adjusted  to 6.5), was completely withdrawn and replaced with fresh  receiver solution at each time point.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 galanthamine  HBr  in the receiver solution. The cumulative amount of  galanthamine  HBr  that permeated across the human cadaver  skin was calculated using the measured galanthamine  HBr  concentrations in the receiver solutions.  [0438]  The cumulative amount of galanthamine  HBr  across human cadaver skin at 24 hours increased from 1.254  mg/cm 2  to 1.750 mg/cm$^{2 }$when the calculated excess NaOH  concentration in the dried patch was increased from 0% to  1.0% as compared to 0.624 mg/cm 2  for the formulation  without NaOH.  [0439]  The formulation of Gala-2 provided up to 2-fold  more galanthamine  HBr  flux than in the absence of NaOH  (Gala-1). The highest  pH  formulation evaluated, Gala-3,  provided up to 3-fold more flux than in the absence of  NaOH.  [0440]  An in vitro skin permeation study was conducted  using three hydromorphone hydrochloride transdermal sys› tems, designated Hymo-1, Hymo-2 and Hymo-3, the com› positions of which are set forth in Table 82.  [0441]  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.  [0442]  The theoretical percent weight for each ingredient  after drying ( calculated assuming all volatile ingredients  were completely removed during drying) is set forth in Table  83.  [0443]  Example 24  [0435]  Component Weight and Weight Percent  Based on Total Solution Weight  Gala-1  Gala-2  g(wt%)  g (wt%)  Galanthamine HBr  0.40 (4.7)  0.40 (4.6)  DI Water  NaOH  Glycerin  Benzyl Alcohol  PIE adhesive  (30% solid)  n-Heptane  0.30 (3.5)  0.34 (3.9)  0  0.04 (0.5)  1.00 (11.6)  1.00 (11.5)  0.40 (4.7)  0.40 (4.6)  6.00 (69.8)  6.00 (69.1)  0.50 (5.8)  0.50 (5.8)  Gala-3  g(wt%)  0.40 (4.6)  0.38 (4.3)  0.08 (0.9)  1.00 (11.4)  0.40 (4.6)  6.00 (68.5)  0.50 (5.7)  Cumulative Amount of Galanthamine HBr (mg/cm 2 )  Time  6 hours  18 hours  24 hours  Gala-1  0.140  0.429  0.624  Gala-2  0.480  1.058  1.254  Gala-3  0.475  1.412  1.750  Weight and Theoretical Weight Percent  Based on Dried Film Weight  Gala-1  Gala-2  g(wt%)  g (wt%)  Galanthamine HBr  0.40 (11.1)  0.40 (11.0)  NaOH  0  0.04 (1.1)  Glycerin  1.00 (27.8)  1.00 (27.5)  Benzyl Alcohol  0.40 (11.1)  0.40 (11.0)  PIE adhesive  1.80 (50.0)  1.80 (49.5)  Gala-3  g(wt%)  0.40 (10.9)  0.08 (2.2)  1.00 (27.2)  0.40 (10.9)  1.80 (48.9)  Excess NaOH Concentration (wt%) and pH  Excess NaOH  Concentration  pH  Gala-1  6.53  Gala-2  0%  8.73  Gala-3  1.0%  10.56  Component Weight and Weight Percent  Based on Total Solution Weight  Hymo-1  Hymo-2  g(wt%)  g (wt%)  Hydromorphone HCl  0.20 (2.8)  0.20 (2.7)  DI Water  0.30 (4.1)  0.38 (5.1)  NaOH  0  0.08 (1.0)  Glycerin  1.25 (17.2)  1.25 (16.9)  PIE adhesive  5.00 (69.0)  5.00 (67.6)  (30% solid)  n-Heptane  0.50 (6.9)  0.50 (6.8)  Hymo-3  g (wt%)  0.20 (2.7)  0.43 (5.7)  0.13 (1.7)  1.25 (16.7)  4.00 (66.7)  0.50 (6.7)  Weight and Theoretical Weight Percent  Based on Dried Film Weight  Hydromorphone HCl  NaOH  Hymo-1  g(wt%)  0.20 (6.8)  0  Hymo-2  g (wt%)  0.20 (6.6)  0.08 (2.5)  Hymo-3  g (wt%)  0.20 (6.5)  0.13 (4.1) 