Effects of Heparin on Topical Use of Plasters Containing a Non-Steroidal Anti-Inflammatory Drug

Abstract

The present invention provides for a method of improving the release of non-steroidal anti-inflammatory drugs (NSAIDs) from a plaster or bandage comprising an adhesive layer with a pharmaceutically acceptable NSAID together with heparin or a heparinoid. The invention also provides for methods of reducing muscle hyperalgesia in subjects without spontaneous pain.

1 - 10 . (canceled) 
     
     
         11 . A method of administering diclofenac from a transdermal patch containing diclofenac and heparin, the method comprising:
 topically applying a treatment transdermal patch containing diclofenac and heparin to the skin of a subject for no more than 24 hours,   wherein prior to the topical application, the treatment transdermal patch had been identified as having release characteristics comprising:
 (i) retention of all of the heparin after releasing diclofenac; and 
 (ii) release of a higher amount of diclofenac compared to a transdermal patch 
   comprising diclofenac but not heparin, by assessing an equivalent test transdermal patch containing diclofenac and heparin using an in vitro method that quantifies the relative release of diclofenac and heparin to demonstrate the release characteristics of the patches;   wherein the treatment transdermal patch and the test transdermal patches each comprise:
 a substrate layer; 
 an adhesive layer in the form of a polymeric hydrogel matrix, the adhesive layer comprising:
 an effective amount of diclofenac or a pharmaceutically acceptable salt thereof, 
 sodium ethylenediamine tetraacetate, 
 heparin, 
 at least one thickening agent, 
 at least one wetting agent, and 
 at least one cross-linking agent; and 
 
 a protective film which can be removed at the moment of use; 
   wherein the in vitro method of quantifying the relative release of diclofenac and heparin from a transdermal patch comprises the steps:   a) applying the test transdermal patch to a first side of a membrane in vitro,   b) sampling a receiving buffer in contact with a second side of the membrane and after 24 hours sampling the test transdermal patch;   c) determining the amount of diclofenac in the sample of the receiving buffer and determining the amount of heparin in the sample of the test transdermal patch; and   d) comparing the amount of diclofenac released from the test transdermal patch through the membrane into the receiving buffer with the amount of heparin retained in the test transdermal patch.   
     
     
         12 . The method of  claim 11 , wherein the diclofenac or pharmaceutically acceptable salt thereof is diclofenac epolamine. 
     
     
         13 . The method of  claim 12 , wherein the effective amount of diclofenac epolamine is between 0.1 and 5 wt % with respect to the hydrogel matrix. 
     
     
         14 . The method of  claim 13 , wherein the effective amount of diclofenac epolamine is between 0.3 and 3 wt % with respect to the hydrogel matrix. 
     
     
         15 . The method of  claim 11 , wherein the concentration of the heparin is between 0.05 and 1 wt % with respect to the hydrogel matrix. 
     
     
         16 . The method of  claim 11 , wherein the membrane is a silicon membrane. 
     
     
         17 . The method of  claim 16 , wherein the receiving buffer has a pH value of 7.4, and wherein the amount of diclofenac released from the test transdermal patch through the membrane into the receiving buffer is 48.23±14.37 μg/cm 2  after 24 hours. 
     
     
         18 . The method of  claim 11 , wherein the membrane and the receiving buffer are contained in an open chamber diffusion cell system. 
     
     
         19 . The method of  claim 18 , wherein the open chamber diffusion cell system is a Franz Cell System. 
     
     
         20 . The method of  claim 11 , wherein the amount of diclofenac in the sample is determined using HPLC. 
     
     
         21 . The method of  claim 11 , wherein steps b) and c) of the in vitro method are repeated at least once at a different sampling time. 
     
     
         22 . The method of  claim 21 , wherein the in vitro method further comprises determining a diclofenac permeation rate. 
     
     
         23 . The method of  claim 22 , wherein the receiving buffer has a pH value of 7.4, and wherein the diclofenac or pharmaceutically acceptable salt thereof is diclofenac epolamine and the diclofenac permeation rate is determined to be 2.01±0.60 μg/cm 2 /hour. 
     
     
         24 . The method of  claim 11 , wherein in step c) of the in vitro method, the amount of heparin in the sample is determined using a heparin Anti-factor Xa chromogenic assay. 
     
     
         25 . The method of  claim 11 , wherein the thickness of the membrane is 0.25 mm. 
     
     
         26 . The method of  claim 11 , wherein the thickness of the membrane is 0.5 mm. 
     
     
         27 . The method of  claim 11 , wherein the subject has a minor soft tissue injury. 
     
     
         28 . The method of  claim 11 , wherein the subject has a minor strain, sprain, or contusion.