Transdermal botulinum toxin compositions

Abstract

Pharmaceutical compositions for transdermal administration of neurotoxins to a patient include a neurotoxin, such as a botulinum toxin, and an enhancing agent that facilitates absorption of the neurotoxin through the skin of the patient and does not eliminate the bioactivity associated with the neurotoxin. The pharmaceutical compositions are topically applied on a patient, and may be provided in a transdermal patch.

I claim:  
     
         1 . A pharmaceutical composition comprising: 
 a stabilized botulinum toxin; and    at least one enhancing agent for facilitating transdermal delivery of the botulinum toxin into a human patient by enhancing the permeability of the patient's skin.    
     
     
         2 . The composition of  claim 1 , wherein the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C 1 , D, E, F and G.  
     
     
         3 . The composition of  claim 1 , wherein the botulinum toxin is botulinum toxin type A.  
     
     
         4 . The composition of  claim 1 , wherein the botulinum toxin is a purified botulinum toxin.  
     
     
         5 . The composition of  claim 1 , wherein the composition comprises between about 1 units to about 20,000 units of botulinum toxin.  
     
     
         6 . The composition of  claim 1 , wherein the composition comprises an amount of botulinum toxin to achieve a therapeutic effect lasting between 1 month and 5 years.  
     
     
         7 . The composition of  claim 1 , wherein the enhancing agent is an alcohol.  
     
     
         8 . The composition of  claim 7 , wherein the alcohol is a polyalcohol.  
     
     
         9 . The composition of  claim 1 , wherein the enhancing agent comprises a transfersome.  
     
     
         10 . The composition of  claim 1 , wherein the composition comprises a plurality of enhancing agents.  
     
     
         11 . A pharmaceutical composition in a transdermal patch, the pharmaceutical composition comprising: 
 a stabilized botulinum toxin that permeates through a human patient's skin without permeating in significant amount through a blood vessel when the botulinum toxin interacts with an enhancing agent provided in the transdermal patch to cause a therapeutic effect of a disorder associated with exocytosis of a molecule from a cell.    
     
     
         12 . The composition of  claim 11 , wherein the botulinum toxin is provided in a dry state in the transdermal patch before the patch is applied to the patient's skin.  
     
     
         13 . The composition of  claim 11 , wherein the botulinum toxin is botulinum toxin type A.  
     
     
         14 . The composition of  claim 11 , wherein the botulinum toxin is mixed with the enhancing agent after the transdermal patch is applied to the patient's skin.  
     
     
         15 . The composition of  claim 14 , wherein the botulinum toxin mixes with an enhancing agent that is applied to the patient's skin before the transdermal patch is applied to the patient's skin.  
     
     
         16 . A transdermal patch, comprising 
 a pharmaceutical composition, which comprises: 
 a stabilized botulinum toxin; and  
 an enhancing agent that facilitates transdermal administration of the botulinum toxin in a bioactive form to a subdermal target site of a human patient without being administered to the patient's circulatory system; and  
   an adhesive disposed on one side of the transdermal patch to removably secure the patch to the patient's skin.    
     
     
         17 . The transdermal patch of  claim 16 , wherein the adhesive is disposed around a depot containing the pharmaceutical composition.  
     
     
         18 . The transdermal patch of  claim 16 , further comprising a plurality of needles extending from one side of the patch that is applied to the skin, wherein the needles extend from the patch to project through the stratum corneum of the skin without rupturing a blood vessel.  
     
     
         19 . The transdermal patch of  claim 18 , wherein the botulinum toxin is provided in a depot in the patch so that pressure applied to the patch causes botulinum toxin to be directed through the needles and under the stratum corneum.  
     
     
         20 . The transdermal patch of  claim 16 , wherein the botulinum toxin is provided in a dry state in a plurality of wells, each of the wells covered by a membrane that is dissolvable with a fluid, and wherein the enhancing agent mixes with the botulinum toxin as the membrane over a well dissolves so that the absorption of the botulinum toxin is enhanced.  
     
     
         21 . The transdermal patch of  claim 16 , wherein the botulinum toxin is botulinum toxin type A.  
     
     
         22 . A method of reducing neurotransmitter release in a subdermal structure of a patient, the method comprising the steps of: 
 (a) non-chemically disrupting the stratum corneum of the patient's skin to reduce impermeability of the stratum corneum; and    (b) applying botulinum toxin to the skin of the patient in an area that has had the stratum corneum disrupted in step (a).    
     
     
         23 . The method of  claim 22 , wherein the stratum corneum is disrupted by abrasively removing the stratum corneum.  
     
     
         24 . The method of  claim 22 , wherein the stratum corneum is disrupted by applying an adhesive material to the patient's skin, and removing the adhesive material applied thereto.  
     
     
         25 . The method of  claim 22 , wherein the stratum corneum is disrupted by applying ultrasound at a frequency between 20 kHz and less than 10 MHz at an intensity that does not permanently damage the patient's skin.  
     
     
         26 . The method of  claim 22 , wherein the stratum corneum is disrupted by passing electrical current from a first point on the patient's skin to a second point on the patient's skin.  
     
     
         27 . The method of  claim 26 , wherein the electrical current is passed to create a plurality of pores in the stratum corneum to enhance passage of botulinum toxin to the subdermal structures.  
     
     
         28 . The method of  claim 22 , wherein the botulinum toxin is selected from a group of botulinum toxins consisting of types A, B, C, D, E, F, and G.  
     
     
         29 . The method of  claim 22 , wherein the botulinum toxin is applied in a pharmaceutical composition comprising an enhancing agent for enhancing the delivery of the botulinum toxin through the skin.  
     
     
         30 . The method of  claim 22 , wherein the botulinum toxin is incorporated into a transfersome.  
     
     
         31 . A method of relieving pain in a patient caused by a spastic muscle, the method comprising the steps of: 
 (a) applying ultrasound at a frequency between about 10 kHz and 1 MHz to the patient's skin overlying the spastic muscle; and    (b) applying botulinum toxin to the patient's skin that has received the ultrasound in step (a).    
     
     
         32 . The method of  claim 31 , further comprising a step of abrasively removing portions of the stratum corneum of the patient's skin that received the ultrasound.  
     
     
         33 . The method of  claim 31 , wherein the botulinum toxin is botulinum toxin type A.  
     
     
         34 . The method of  claim 31 , wherein the botulinum toxin is administered in a composition comprising an enhancing agent that facilitates penetration of the botulinum toxin through the patient's skin.  
     
     
         35 . The method of  claim 31 , wherein the botulinum toxin is applied in a transdermal patch applied to the patient's skin.