Controlled release delivery system for nasal application of neurotransmitters

Abstract

This invention relates to a galenical gel formulation for nasal administration of neurotransmitters/neuromodulators such as dopamine, serotonin or pregnenolone and progesterone. The special lipophilic or partly lipophilic system of the invention leads to high bioavailability of the active ingredient in plasma and brain caused by sustained serum levels and/or direct or partly direct transport from nose to the brain.

1 . A formulation for nasal application comprising:
 (a) at least one active ingredient selected from the groups consisting of a neurotransmitter and a neuromodulator agent;   (b) at least one lipophilic or partly lipophilic carrier;   (c) a compound or a mixture of compounds having surface tension decreasing activity in an amount effective for generating contact of the formulation with a hydrophilic mucous membrane; and optionally   (d) a viscosity-regulating agent.   
   
   
       2 . The formulation according to  claim 1 , wherein the at least one active ingredient is a neurotransmitter selected from the group consisting of acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine, glutamate, gamma aminobutyric acid, aspartate, glycine, adenosine, ATP, GTP, Substance P, N-acetylaspartylglutamate, Oxytocin, Vasopressin, Endorphin, zinc, nitric oxide, carbon monoxide, and chemical modifications of such molecules. 
   
   
       3 . The formulation according to  claim 2 , wherein the neurotransmitter is selected from the group consisting of dopamine, serotonin, epinephrine and norepinephrin. 
   
   
       4 . The formulation according to  claim 3 , wherein the neurotransmitter is dopamine. 
   
   
       5 . The formulation according to  claim 1 , wherein the at least one active ingredient is a neuromodulator agent. 
   
   
       6 . The formulation according to  claim 5 , wherein the neuromodulator agent is a neurosteroid. 
   
   
       7 . The formulation according to  claim 6 , wherein the neurosteroid is selected from the group consisting of pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone, estradiol, progesterone, 3α-hydroxy-5α-pregnane-20-one, metabolites of such molecules, and chemical modifications of such molecules. 
   
   
       8 . The formulation according to  claim 6 , wherein the neurosteroid is pregnenolone. 
   
   
       9 . The formulation according to  claim 1 , wherein the at least one active ingredient is L-DOPA. 
   
   
       10 . The formulation according to  claim 1 , wherein the active ingredient is about 0.01% to about 6% by weight of the formulation. 
   
   
       11 . The formulation according to  claim 1 , wherein the active ingredient is about 4% by weight of the formulation. 
   
   
       12 . The formulation according to  claim 1 , wherein the at least one lipophilic carrier or partly lipophilic carrier comprises an oil. 
   
   
       13 . The formulation according to  claim 12 , wherein the oil is a vegetable oil. 
   
   
       14 . The formulation according to  claim 12 , wherein the oil is castor oil. 
   
   
       15 . The formulation according to  claim 1 , wherein the amount of oil is about 30% to about 95% by weight of the formulation. 
   
   
       16 . The formulation according to  claim 1 , wherein the amount of oil is about 90% by weight of the formulation. 
   
   
       17 . The formulation according to  claim 1 , wherein component (c) comprises at least one surfactant selected from the group consisting of lecithin, fatty acid ester of polyvalent alcohols, of sorbitanes, of polyoxyethylensorbitans, of polyoxyethylene, of sucrose, of polyglycerol and/or at least one humectant selected from the group consisting of sorbitol, glycerine polyethylene glycol, and macrogol glycerol fatty acid ester, or a mixture thereof. 
   
   
       18 . The formulation according to  claim 17 , wherein component (c) comprises an oleoyl macrogolglyceride or a mixture of oleoyl macrogolglycerides. 
   
   
       19 . The formulation according to  claim 17 , wherein component (c) is about 1% to about 20% by weight of the formulation. 
   
   
       20 . The formulation according to  claim 17 , wherein component (c) is about 4% by weight of the formulation. 
   
   
       21 . The formulation according to  claim 1 , further comprising a viscosity-regulating agent. 
   
   
       22 . The formulation according to  claim 21 , wherein the viscosity-regulating agent comprises a thickener or gelling agent selected from the group consisting of cellulose and cellulose derivatives, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides and lanolin, or a mixture thereof. 
   
   
       23 . The formulation according to  claim 22 , wherein the viscosity-regulating agent is colloidal silicon dioxide. 
   
   
       24 . The formulation according to  claim 21 , wherein the viscosity-regulating agent is about 0.5% to about 10% by weight of the formulation. 
   
   
       25 . The formulation according to  claim 21 , wherein the viscosity-regulating agent is about 4% by weight of the formulation. 
   
   
       26 . A formulation for nasal application comprising:
 (a) dopamine or L-DOPA in an amount of about 2% by weight;   (b) castor oil in an amount of about 90% by weight;   (c) a compound or a mixture of compounds comprising an oleoyl macrogolglyceride or a mixture of oleoyl macroglyverides in an amount of about 4% by weight and having surface tension decreasing activity in an amount effective for generation of contact of the formulation with water; and optionally   (d) colloidal silicon dioxide in an amount of about 4% by weight.