Methods for Making and Delivering Rho-Antagonist Tissue Adhesive Formulations to the Injured Mammalian Central and Peripheral Nervous Systems and uses Thereof

Abstract

The present invention provides methods for making, delivering and using formulations that combine a therapeutically active agent(s) (such as for example a Rho antagonist(s)) and a flowable carrier component capable of forming a therapeutically acceptable matrix in vivo (such as for example tissue adhesives), to injured nerves to promote repair and regeneration and regrowth of injured (mammalian) neuronal cells, e.g. for facilitating axon growth at a desired lesion site. Preferred active agents are known Rho antagonists such as for example C3, chimeric C3 proteins, etc. or substances selected from among known trans-4-amino(alkyl)-1-pyridylcarbamoylcyclohexane compounds or Rho kinase inhibitors. The system for example may deliver an antagonist(s) in a tissue adhesive such as, for example, a fibrin glue or a collagen gel to create a delivery matrix in situ. A kit and methods of stimulating neuronal regeneration are also included.

1 . An axon growth stimulation kit comprising
 a first container means for containing a flowable carrier component or two or more separate components capable once intermingled of forming a flowable carrier component, said flowable carrier components each being capable of forming a therapeutically acceptable matrix in vivo at a nerve lesion site and   a second container means for containing a therapeutically active agent for facilitating axon r growth at the lesion site   wherein said therapeutically active agent is releasable from said in vivo matrix into the adjacent external environment.   
     
     
         2 . An axon growth stimulation kit as defined in  claim 1  comprising means for
 dispersing the therapeutically active agent in said flowable carrier component so as to form a flowable axon growth stimulation composition and   means for deliverying the flowable axon growth stimulation composition to the lesion site.   
     
     
         3 . An axon growth stimulation kit as defined in  claim 1  wherein said therapeutically . acceptable matrix is a collagen matrix. 
     
     
         4 . An axon growth stimulation kit as defined in  claim 1  wherein said therapeutically acceptable matrix is a fibrin matrix. 
     
     
         5 . A biocompatible composition comprising: (i) at least one supplement selected from the group consisting of therapeutically active agents for facilitating axon growth; and (ii) a flowable carrier component capable of forming a therapeuticallly acceptable matrix in vivo at a nerve lesion site; wherein said supplement is releasable from said matrix into the adjacent external environment. 
     
     
         6 . A biocompatible composition as defined in  claim 5  wherein said therapeutically acceptable matrix is a collagen matrix. ; 
     
     
         7 . A biocompatible composition as defined in  claim 5  wherein said therapeutically acceptable matrix is a fibrin matrix. 
     
     
         8 . A method for the preparation of a flowable biocompatible composition comprising admixing (i) at least one supplement selected from the group consisting of therapeutically active agents for facilitating axon growth and (ii) a flowable carrier component capable of forming a therapeuticallly acceptable matrix in vivo at a nerve lesion site; wherein said supplement is releasable from said matrix into the adjacent external environment. 
     
     
         9 . A method as defined in  claim 8  wherein said therapeutically acceptable matrix is a. collagen matrix. 
     
     
         10 . A method as defined in  claim 8  wherein said, therapeutically acceptable matrix is a fibrin matrix.