Pharmaceutical latrunculin formulations

Abstract

The present invention relates to an aqueous pharmaceutical formulation comprising at least one latrunculin and the formulation does not contain a substantial amount of dimethyl sulfoxide. In one embodiment, the present invention is directed to an aqueous pharmaceutical formulation comprising at least one latrunculin in an amount of 0.001-2% w/v, a non-ionic surfactant in an amount of 0.01-2% w/v, and a tonicity agent to maintain a tonicity between 200-400 mOsm/kG, at a pH between 4 to 8, wherein the latrunculin, the surfactant, and the tonicity agent are compatible in the formulation, and the formulation does not contain a substantial amount of dimethyl sulfoxide. The formulation is stable for at least six month at refrigerated temperature. The present invention further provides a method of reducing intraocular pressure, a method of treating glaucoma, a method of inhibiting wound healing after trabeculectomy, and a method of inhibiting angiogenesis.

1 . An aqueous pharmaceutical formulation comprising at least one latrunculin in an amount of 0.001-2% w/v, a non-ionic surfactant selected from the group consisting of polysorbates, tyloxapol, polyoxyl castor oil, polaxamers, and polyoxyl stearates, in an amount of 0.01-2% w/v, and a non-ionic tonicity agent to maintain a tonicity between 200-400 mOsm/kG, at a pH between 4 to 8, wherein the latrunculin, the surfactant, and the tonicity agent are compatible in the formulation, and the formulation does not contain more than 0.1% v/v of dimethyl sulfoxide. 
     
     
         2 . An aqueous pharmaceutical formulation according to  claim 1 , wherein said formulation does not contain more than 0.01% v/v of dimethyl sulfoxide. 
     
     
         3 . An aqueous pharmaceutical formulation according to  claim 2 , wherein said formulation does not contain more than 0.001% v/v of dimethyl sulfoxide. 
     
     
         4 . An aqueous pharmaceutical formulation according to  claim 1 , wherein said formulation does not contain any dimethyl sulfoxide. 
     
     
         5 . The aqueous pharmaceutical formulation according to  claim 1 , wherein the formulation does not contain more than 0.1% v/v ethanol. 
     
     
         6 . The aqueous pharmaceutical formulation according to  claim 1 , further comprising 1-100 mM buffer suitable to maintain the pH between 4-6, wherein said buffer is citrate buffer, acetate buffer, citrate/phosphate buffer, maleate buffer, tartarate buffer, or a combination thereof. 
     
     
         7 . The aqueous pharmaceutical formulation according to  claim 1 , further comprises a chelating agent and/or a preservative. 
     
     
         8 . An aqueous pharmaceutical formulation according to  claim 1 , wherein said non-ionic surfactant is a polysorbate. 
     
     
         9 . The aqueous pharmaceutical formulation according to  claim 1 , wherein said non-ionic tonicity agent is mannitol or dextrose. 
     
     
         10 . The aqueous pharmaceutical formulation according to  claim 1 , wherein said non-ionic tonicity agent is glycerol, polyethylene glycol, or propylene glycol. 
     
     
         11 . The aqueous pharmaceutical formulation according to  claim 1 , wherein said latrunculin is latrunculin B. 
     
     
         12 . The aqueous pharmaceutical formulation according to  claim 1 , wherein said latrunculin is latrunculin A or des-methyl latrunculin B. 
     
     
         13 . The aqueous pharmaceutical formulation according to  claim 1 , wherein said latrunculin is in an amount of 0.005-0.02% w/v. 
     
     
         14 . The aqueous pharmaceutical formulation according to  claim 1 , wherein said non-ionic surfactant is polyoxyl castor oil, and said tonicity agent is glycerol or propylene glycol. 
     
     
         15 . An aqueous pharmaceutical formulation comprising at least one latrunculin in an amount of 0.001-2% w/v, 0.05-1.5% w/v of polysorbate, 4-5% w/v of mannitol, 5-50 mM of citrate, 0.005-0.5% w/v of EDTA, and 0.001-1% w/v benzethonium chloride, wherein the formulation has a pH of 4-6 and does not contain more than 0.01% v/v of DMSO. 
     
     
         16 . The aqueous pharmaceutical formulation according to  claim 15 , wherein the latrunculin is latrunculin B in an amount of 0.005-0.02% w/v. 
     
     
         17 . The aqueous pharmaceutical formulation according to  claim 16 , comprising 0.02% w/v of latrunculin B, 1% w/v of polysorbate, 4.5% w/v mannitol, 5-50 mM citrate, 0.05% w/v of EDTA, and 0.01% w/v benzethonium chloride, wherein the formulation has a pH of 4-6 and does not contain more than 0.01% v/v of DMSO. 
     
     
         18 . A method of reducing intraocular pressure in a mammal, comprising the step of administering to a mammal in need of treatment the aqueous pharmaceutical formulation of  claim 1 . 
     
     
         19 . A method of reducing intraocular pressure in a mammal, comprising the step of administering to a mammal in need of treatment the aqueous pharmaceutical formulation of  claim 15 . 
     
     
         20 . A method of reducing intraocular pressure in a mammal, comprising the step of administering to a mammal in need of treatment the aqueous pharmaceutical formulation of  claim 17 .