Aug. 6, 2009  25  US 2009/0197849 Al  TABLE 13  TABLE 15  TABLE 16  TABLE 14  TABLE 17  [  03 04]  The excess N aO H concentrations for these four ibu› profen gels, were calculated as described in Example 2, and  the pH of the gels was directly measured using a pH meter.  The pH of the ibuprofen gel ( determined using the procedures  of the previous examples) increased from 6.58 to 12.22 when  the calculated excess NaOH concentration in the gel was  increased from 0% to 1.74%. The skin irritation could be  related to the pH of the gel, which depends on the excess  NaOH concentration.  patches were prepared and evaluated using the same proce› dures as set forth in Example 3. The theoretical percent  weight for each ingredient after drying ( calculated assuming  all the volatile ingredients were completely removed during  drying) is listed in Table 16.  [0305]  The in vitro permeation ofibuprofen through human  cadaver skin from these gels was measured in a slightly dif› ferent manner than as described in the Methods section. Three  diffusion cells were used for each formulation. Normal saline  was used as the receiver solution. The entire receiver solution  was collected and replaced with fresh saline at each time  point. The receiver solution collected was analyzed by an  HPLC for the concentration of ibuprofen. The cumulative  amount of ibuprofen across human cadaver skin was calcu› lated using the measured ibuprofen concentrations in the  receiver solutions, which were plotted versus time and are  described below.  [0306]  The cumulative amount of ibuprofen across human  cadaver skin at 24 hours increased from 0.33 mg/cm $^{2 }$to 5.74  mg/cm $^{2 }$when the calculated excess NaOH concentration in  the gel was increased from 0% to 1.74% (Ibu-4), i.e., up to  about 17-fold more flux was obtained than with the formula› tion having 0% excess NaOH concentration. The cumulative  amount of ibuprofen that permeated across the human  cadaver skin at 24 hours from the formulation with an excess  NaOH concentration of0.98% (Ibu-3, 1.12 mg/cm 2 )  is about  3 times higher than that from the formulation with an excess  NaOH concentration of0% (Ibu-2, 0.33 mg/cm 2 ).  [0308]  Since PPA-HCl is a salt of a free base, it reacts with  Na$_{2}$CO$_{3}$ .  The concentration ofNa$_{2}$CO$_{3 }$ in the system after the  reaction is completed depends on the amount of PPA-HCl  added. The remaining sodium carbonate concentration after  the reaction is completed is defined as "excess Na$_{2}$CO$_{3 }$ con› centration," which is defined by the following equation.  The excess Na$_{2}$CO$_{3 }$ for these four PPA-HCl systems was  calculated, and the pH was measured as described in the  Methods section. The pH of the PPA-HCl patch increased  from 9.81 to 10.17 when the calculated excess Na$_{2}$CO$_{3 }$ con› centration in the dried patch was increased from 0.4% to  16.7%.  [Na2CO3 exmJ~[Na2CO3 Ma1J-[Na2CO3  needed for  neutralization]  [0307]  An in vitro skin permeation study was conducted  using four phenylpropanolamine hydrochloride transdermal  systems, designated PPA-5, PPA-6, PPA-7, and PPA-8, the  compositions of which are set forth in Table 15. The matrix  [0309]  The cumulative amount of PPA-HCl across human  cadaver skin was calculated using the measured PPA-HCl  concentrations in the receiver solutions.  Example 6  Component Weight and Weight Percent Based  on Total Solution Weight  Ibu-1  Ibu-2  Ibu-3  Ibu-4  g(wt%)  g(wt%)  g(wt%)  g(wt%)  Ibuprofen  0.6 (36.8)  0.6 (32.3)  0.6 (31.6)  0.6 (31.1)  NaOH  0  0.115 (6.2)  0.135 (7.1)  0.15 (7.8)  Ethanol  0.4 (24.5)  0.4 (21.5)  0.4 (21.1)  0.4 (20.7)  DI water  0.6 (36.8)  0.715 (38.4)  0.735 (38.7)  0.75 (38.9)  HPMCP  0.03 (1.8)  0.03 (1.6)  0.03 (1.6)  0.03 (1.6)  Component Weight and Weight Percent Based  on Total Solution Weight  PPA-5  PPA-6  PPA-7  PPA-8  g(wt%)  g(wt%)  g(wt%)  g(wt%)  PPA-HCl  0.5 (6.7)  0.5 (5.7)  0.5 (5.6)  0.5 (5.5)  Na 2 CO 3  0  0.29 (3.3)  0.44 (5.0)  0.74 (8.1)  DI water  1.0 (13.5)  2.0 (23.0)  2.0 (22.6)  2.0 (21.9)  Methyl alcohol  0.5 (6.7)  0.5 (5.7)  0.5 (5.6)  0.5 (5.5)  PG  0.2 (2.7)  0.2 (2.3)  0.2 (2.3)  0.2 (2.2)  HPMC  0.01 (0.1)  0.01 (0.1)  0.01 (0.1)  0.01 (0.1)  Heptane  1.2 (16.2)  1.2 (13.8)  1.2 (13.6)  1.2 (13.1)  PIB adhesive  4 (54.0)  4 (46.0)  4 (45.2)  4 (45.2)  (30% solid)  Excess NaOH Concentration (wt%) and pH  ExcessNaOH  Concentration  pH  Ibu-1  4.57  Ibu-2  0%  6.58  Ibu-3  0.98%  11.83  Ibu-4  1.74%  12.22  Weight and Theoretical Weight Percent Based on Dried Film Weight  PPA-5  PPA-6  PPA-7  PPA-8  g(wt%)  g(wt%)  g(wt%)  g(wt%)  PPA-HCl  0.5 (26.2)  0.5 (22.7)  0.5 (21.3)  0.5 (18.9)  Na 2 CO 3  0  0.29 (13.2)  0.44 (18.7)  0.74 (27.9)  PG  0.2 (10.5)  0.2 (9.1)  0.2 (8.5)  0.2 (7.5)  HPMC  0.01 (0.5)  0.01 (0.5)  0.01 (0.4)  0.01 (0.4)  PIB adhesive  1.2 (62.8)  1.2 (54.5)  1.2 (51.1)  1.2 (45.3)  (30% solid)  Excess Na$_{2}$CO$_{3 }$Concentration (wt%) and pH  Excess Na 2 CO 3  Concentration  pH  PPA-5  6.54  PPA-6  0.4%  9.81  PPA-7  6.7%  9.86  PPA-8  16.7%  10.17 