Botulinum toxin formulations for oral administration

Abstract

Pharmaceutical compositions of a botulinum toxin for oral administration to a patient with a gastrointestinal disorder.

I claim:  
     
         1 . A solid form botulinum toxin oral formulation, comprising: 
 (a) a botulinum toxin, and;    (b) a carrier associated with the botulinum toxin, 
 thereby forming a solid form botulinum toxin oral formulation, wherein: 
 (i) the carrier is formulated to dissolve in and thereby release in the gastrointestinal tract of a patient therapeutic amounts of the botulinum toxin in a gastrointestinal tract of a patient, and;  
 (ii) the solid form botulinum toxin formulation exhibits a gastric retention due to a method selected from the group consisting of mucoadhesion, flotation, sedimentation, expansion, or simultaneous administration of pharmacological agent to delay gastric emptying.  
 
   
     
     
         2 . The oral formulation of  claim 1 , wherein substantial amounts of the botulinum toxin has not be transformed into a botulinum toxoid prior to association of the botulinum toxin with the carrier.  
     
     
         3 . The oral formulation of  claim 1 , wherein significant amounts of the botulinum toxin associated with the carrier have a toxicity which is substantially unchanged relative to the toxicity of the botulinum toxin prior to association of the botulinum toxin with the carrier.  
     
     
         4 . The oral formulation of  claim 1 , wherein the carrier comprises a biocompatible, biodegradable substance selected from the group consisting of flour, sugar and gelatin.  
     
     
         5 . The oral formulation 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.  
     
     
         6 . The oral formulation of  claim 1 , wherein the botulinum toxin is a botulinum toxin type A.  
     
     
         7 . The oral formulation of  claim 1 , wherein the quantity of the botulinum toxin associated with the carrier is between about 1 unit and about 10,000 units of the botulinum toxin.  
     
     
         8 . The oral formulation of  claim 1 , wherein the quantity of the botulinum toxin is between about 10 units and about 2,000 units of a botulinum toxin type A.  
     
     
         9 . The oral formulation of  claim 1 , wherein the botulinum toxin comprises: 
 (a) a first element comprising a binding element able to specifically bind to a neuronal cell surface receptor under physiological conditions,    (b) a second element comprising a translocation element able to facilitate the transfer of a polypeptide across a neuronal cell membrane, and    (c) a third element comprising a therapeutic element able, when present in the cytoplasm of a neuron, to inhibit exocytosis of acetylcholine from the neuron.    
     
     
         10 . A botulinum toxin oral formulation, comprising: 
 (a) a botulinum toxin type A, and;    (b) a carrier associated with the botulinum toxin type A, thereby forming a botulinum toxin oral formulation, wherein the carrier is formulated to release therapeutic amounts of the botulinum toxin type A in a gastrointestinal tract of a patient with a gastric ulcer without a significant immune system response, and wherein the carrier comprises a biocompatible, biodegradable substance, and wherein a controlled gastric retention the solid form can be achieved by a method selected from the group consisting of mucoadhesion, flotation, sedimentation, expansion, or by a simultaneous administration of pharmacological agents which delay gastric emptying.    
     
     
         11 . A botulinum toxin formulation for oral administration to a patient with a gastrointestinal tract, the formulation comprising: 
 (a) biologically active botulinum toxin, and;    (b) a biocompatible, biodegradable and non-toxic carrier associated with the botulinum toxin, wherein the carrier has a characteristic of rapidly degrading in a gastrointestinal system of a patient to thereby release a therapeutic amount the biologically active botulinum toxin into the gastrointestinal system of the patient, without a significant immune system response to the ingested botulinum toxin.    
     
     
         12 . The oral formulation of  claim 1   1 , wherein the carrier comprises a plurality of polymeric microspheres.  
     
     
         13 . The oral formulation of  claim 11 , wherein the carrier comprises a polymeric matrix.  
     
     
         14 . The oral formulation of  claim 11 , wherein the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C 1 , D, E, F and G.  
     
     
         15 . The oral formulation of  claim 11 , wherein the botulinum toxin is a botulinum toxin type A.  
     
     
         16 . The oral formulation of  claim 11 , wherein the quantity of the botulinum toxin associated with the carrier is between about 1 unit and about 10,000 units of the botulinum toxin.  
     
     
         17 . The oral formulation of  claim 11 , wherein the quantity of the botulinum toxin is between about 10 units and about 2,000 units of a botulinum toxin type A.  
     
     
         18 . The oral formulation of  claim 11 , wherein the quantity of the botulinum toxin is between about 100 units and about 30,000 units of a botulinum toxin type B.  
     
     
         19 . A method for using a botulinum toxin oral formulation the method comprising the step of ingesting an oral formulation of a botulinum toxin.  
     
     
         20 . A botulinum toxin oral formulation, comprising: 
 (a) a carrier comprising a polymer selected from the group of polymers consisting of polylactides, polyglycolides and polyanhydrides;    (b) a stabilized botulinum toxin associated with the carrier, thereby forming a botulinum oral formulation, 
 wherein therapeutic amounts of the botulinum toxin can be released from the carrier in a GI tract of a patient.  
   
     
     
         21 . The oral formulation of  claim 20 , wherein the botulinum toxin comprises: 
 (a) a first element comprising a binding element able to specifically bind to a neuronal cell surface receptor under physiological conditions,    (b) a second element comprising a translocation element able to facilitate the transfer of a polypeptide across a neuronal cell membrane, and    (c) a third element comprising a therapeutic element able, when present in the cytoplasm of a neuron, to inhibit exocytosis of acetylcholine from the neuron.    
     
     
         22 . The delivery release system of  claim 21  wherein the therapeutic element can cleave a SNARE protein, thereby inhibiting the exocytosis of acetylcholine from the neuron.  
     
     
         23 . The oral formulation of  claim 19 , wherein the SNARE protein is selected from the group consisting of syntaxin, SNAP-25 and VAMP.