Aug. 6, 2009  28  US 2009/0197849 Al  TABLE 28  TABLE31  TABLE 29  TABLE 30  TABLE32  TABLE33  Component Weight and Weight Percent Based on Dried Film Weight  Est-4  Est-5  Est-6  Est-7  g(wt%)  g(wt%)  g(wt%)  g(wt%)  Estradiol  0.03 (2.0)  0.03 (1.9)  0.03 (1.7)  0.03 (1.5)  K$_{3}$PO$_{4 }$ 0  0.1 (6.3)  0.3 (16.9)  0.48 (24.5)  PG  0.25 (16.9)  0.25 (15.8)  0.25 (14.0)  0.25 (12.8)  PIB adhesive  1.2 (81.1)  1.2 (76.0)  1.2 (67.4)  1.2 (61.2)  Component Weight and Weight Percent Based on Total Solution Weight  Est-11  Est-12  Est-13  Est-14  g(wt%)  g(wt%)  g(wt%)  g(wt%)  Estradiol  0.03 (0.5)  0.03 (0.4)  0.03 (0.4)  0.03 (0.4)  Na$_{2}$CO$_{3 }$ 0  0.11 (1.6)  0.3 (4.1)  0.45 (6.1)  DI water  0.5 (8.0)  1.2 (16.9)  1.2 (16.5)  1.2 (16.2)  Methyl alcohol  0.5 (8.0)  0.5 (7.1)  0.5 (6.9)  0.5 (6.7)  PIB adhesive  4 (63.7)  4 (56.4)  4 (55.0)  4 (53.8)  (30% solid)  PG  0.25 (4.0)  0.25 (3.5)  0.25 (3.4)  0.25 (3.4)  Heptane  1 (15.9)  1 (14.1)  1 (13.7)  1 (13.5)  Excess  K$_{3}$P0$_{4 }$ Concentration (wt%) and pH  Est-4  Est-5  Est-6  Est-7  Excess K$_{3}$PO$_{4 }$ 0%  6.3%  16.9%  24.5%  Concentration  pH  6.4  8.89  10.83  9.87  Cumulative Amount ofEstradiol (µg/cm 2 )  Time  Est-4  Est-5  Est-6  Est-7  5 hours  0.2  1.2  2.1  1.5  16.5 hours  0.4  3.9  7.6  3.7  20 hours  0.5  4.6  8.8  4.4  24hours  0.6  5.6  10.2  5.3  Component Weight and Weight Percent Based on Total Solution Weight  Est-11  Est-12  Est-13  Est-14  g(wt%)  g(wt%)  g(wt%)  g(wt%)  Estradiol  0.03 (2.0)  0.03 (1.9)  0.03 (1.7)  0.03 (1.6)  Na$_{2}$CO$_{3 }$ 0  0.11 (6.9%)  0.3 (16.9%)  0.45 (23.3)  PIB  1.2 (81.1)  1.2 (75.5)  1.2 (67.4)  1.2 (62.2)  adhesive  PG  0.25 (16.9)  0.25 (15.7)  0.25 (14.0)  0.25 (13.0)  (Est-4). The formulation of Est-6 provided up to 1 7-fold more  flux than in the absence ofK$_{3}$ PO$_{4}$ .  [0329]  An in vitro skin permeation study was conducted  using four estradiol transdermal systems, designated Est-1,  Est-12, Est-13, and Est-14, the compositions of which are set  forth in Table 31. The matrix patches were prepared and  evaluated using the same procedures as set forth in Example  1. The theoretical percent weight for each ingredient after  drying ( calculated assuming all the volatile ingredients were  completely removed during drying) is listed in Table 32.  [0324]  Since estradiol is not expected to react with K$_{3}$ PO$_{4}$ ,  the K$_{3}$ PO$_{4 }$ concentration listed in Table 28 equals the excess  K$_{3}$ PO$_{4 }$ concentration, calculated as described in Example 7.  [0325]  The pH of each patch was measured as described in  the Methods section. The pH of the estradiol patch increased  from 6.4 to 10.83 when the K$_{3}$ PO$_{4 }$ concentration in the dried  patch was increased from 0% to 16.9%. However, the pH of  the estradiol patch decreased from 10.83 to 9.87 when the  K$_{3}$ PO$_{4 }$ concentration in the dried patch was further increased  from 16.9% to 24.5%.  [0327]  The cumulative amount of estradiol that permeated  across the human cadaver skin at 24 hours for Est-5 (5.6  µg/cm 2 ) with a calculated excess K $_{3}$PO$_{4 }$ concentration of  6.3% was about nine times higher than that from the formu› lation without K$_{3}$ PO $_{4 }$(Est-PK!, 0 .6 µg/  cm 2 ). This result indi› cated that the permeation of estradiol is enhanced by K$_{3}$ PO$_{4}$ .  The cumulative amount of estradiol across human cadaver  skin at 24 hours increased from 5.6 to 10.2 when the excess  K$_{3}$ PO$_{4 }$ concentration in the dried patch was increased from  6.3% to 16.9%. When the excess K$_{3}$ PO$_{4 }$ concentration in the  dried patch was further increased from 16.9% to 24.5%, the  cumulative amount of estradiol across human cadaver skin at  24 hours decreased from 10.2 to 5 .3 µg/cm 2 .  This decrease in  flux may be because the high concentration ofK$_{3}$ PO$_{4 }$ made  the adhesive matrix more hydrophobic and the amount of  K$_{3}$ PO$_{4 }$ that could be dissolved by the small amount of water  on the top of the skin was reduced.  [0328]  The formulations ofEst-5 and Est-7 provided up to  9-fold more estradiol flux than in the absence of K$_{3}$ PO$_{4 }$ [0332]  The cumulative amount of estradiol across human  cadaver skin was calculated using the measured estradiol  concentrations in the receiver solutions.  [0330]  Since estradiol is not expected to react with  Na$_{2}$CO$_{3}$ , the Na$_{2}$CO$_{3 }$ concentration listed in Table 32 equals  the excess Na$_{2}$CO$_{3 }$ concentration, calculated as described in  Example 6.  [0331]  The pH of each patch was measured as described in  the Methods section. The pH of the estradiol patch measured  using the procedures listed above increased from 7 .48 to  10.51 when the Na$_{2}$CO$_{3 }$ concentration in the dried patch was  increased from 0% to 16.9%. However, when the Na$_{2}$CO$_{3 }$ concentration in the dried patch was further increased from  16.9% to 23.3%, the pH of the estradiol patch remained about  the same.  Excess Na$_{2}$CO$_{3 }$Concentration (wt%) and pH  Excess Na$_{2}$CO$_{3 }$ Concentration  pH  Est-11  0%  7.48  Est-12  Est-13  6.9%  16.9%  9.87  10.51  Est-14  23.3%  10.49  [0326]  The cumulative amount of estradiol across human  cadaver skin was calculated using the measured estradiol  concentrations in the receiver solutions.  Example 10 