Jun.5,2003  26  US 2003/0104041 Al  [0300]  Ten healthy human subjects were included in the  skin irritation study. Each subject wore seven patches listed  above on the arms for 24 hours. An adhesive film with a  diameter of  7 /2 inch was applied over each system on the skin  except the petrolatum patch to secure the system and to  make the system occlusive for 24 hours. After 24 hours, the  patches were removed and the skin was scored on a 0-4  scale. The scoring scale employed is listed below. The skin  was scored again at 48 hours.  excess NaOH concentration in the dried patch was increased  from 3.22% to 5.01 %. The excess NaOH concentration and  the cumulative amount of ketoprofen across skin at 24 hours  and the patch pH for Keto-8 was 0.34 mg/cm 2  and 10.81  respectively, which was about the same as those for Keto-3  shown in Example 2 (0.32 mg/cm 2 ,  pH=l0.10). However,  the excess NaOH concentration for Keto-8 (3.92%) was  higher than that for Keto-3 (1.00%), which may be due to the  consumption of NaOH through reactions between NaOH  and components other than ketoprofen in the Keto-8 formu› lation.  [0304]  The irritation scores obtained indicate that irrita› tion from this patch was insignificant.  [0305]  The formulation of Keto-8 provided up to 2-fold  more ketoprofen flux than the lowest pH formulation evalu› ated (Keto-7). The formulation of Keto-9 provided up to  3-fold more flux, while the highest pH formulation evalu› ated, Keto-10, provided up to 9-fold more flux than in the  absence of NaOH.  [0306]  An in vitro skin permeation study was conducted  using four ibuprofen transdermal gels, designated lbu-1,  lbu-2, lbu-3, and lbu-84, the compositions of which are set  forth in Table 13.  [0301]  The in vitro permeation of ketoprofen through  human cadaver skin from formulations Keto-7, Keto-8,  Keto-9, and Keto-10, was measured as described in the  Methods section. Three diffusion cells were used for each  formulation.  [0302]  Normal saline was used as the receiver solution.  The receiver solution was collected at 24 hours and analyzed  by an  HPLC  for the concentration of ketoprofen. The  cumulative amount of ketoprofen that permeated across the  human cadaver skin at 24 hours, was calculated using the  measured ketoprofen concentrations in the receiver solu› tions. The excess NaOH concentrations for these four keto› profen systems, were calculated as described in Example 2,  and the  pH  of the patches was measured as described in the  Methods section.  [0307]  The excess NaOH concentrations for these four  ibuprofen 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.  [0303]  The cumulative amount of ketoprofen that perme› ated across the human cadaver skin at 24 hours increased  from 0.17 mg/cm 2  to 1.52 mg/cm 2  when the calculated  [0308]  The in vitro permeation of ibuprofen through  human cadaver skin from these gels was measured in a  slightly different manner than as described in the Methods  section. Three diffusion cells were used for each formula- TABLE 14  TABLE  12  TABLE 13  Example  5  0  = negative  + - equivocal reaction (0.5)  1 - erythema  2  = erythema and induration  3 = erythema, induration and vesicles  4 - bullae  Ibuprofen  NaOH  Ethanol  DI water  HPMCP  Component Weight and Weight Percent Based on  Total Solution Weight  Ibu-1  Ibu-2  Ibu-3  g(wt%)  g(wt%)  g(wt%)  0.6 (36.8)  0.6 (32.3)  0.6 (31.6)  0  0.115 (6.2)  0.135 (7.1)  0.4 (24.5)  0.4 (21.5)  0.4 (21.1)  0.6 (36.8)  0.715 (38.4)  0.735 (38.7)  0.03 (1.8)  0.03 (1.6)  0.03 (1.6)  Ibu-4  g(wt%)  0.6 (31.1)  0.15 (7.8)  0.4 (20.7)  0.75 (38.9)  0.03 (1.6)  Excess NaOH Concentration (wt%), Cumulative  Permeation Amount (mg/cm 2 ),  pH  Keto-7  Keto-8  Keto-9  Excess NaOH  3.22%  3.92%  4.47%  Concentration  Cumulative  0.17  0.34  0.54  permeation amount  pH  10.06  10.81  11.04  Keto-10  5.01%  1.52  11.18  Excess NaOH Concentration  (wt  %) and pH  Excess NaOH  Concentration  pH  Ibu-1  4.57  Ibu-2  Ibu-3  0%  0.98%  6.58  11.83  Ibu-4  1.74%  12.22 