Prostaglandin compositions and methods for the treatment of vasospasm

Abstract

Compositions and methods for the treatment of vasospasm are provided comprising applying an amount of a semi-solid vasoactive prostaglandin composition to the affected tissue. Also provided are methods of improving microcirculation in a replanted body part.

1 . A semi-solid composition comprising: 
 a vasoactive prostaglandin;    a penetration enhancer;    a polymer thickener selected from the group consisting of a polysaccharide gum and a polyacrylic acid polymer;    a lipophilic component that is selected from the group consisting of an aliphatic C 1  to C 8  alcohol, an aliphatic C 8  to C 30  ester, a liquid polyol and a mixture thereof; water and    a buffer system that provides a buffered pH value for said composition in the range of about 3 to about 7.4.    
     
     
         2 . The composition of  claim 1  wherein the vasoactive prostaglandin is selected from the group consisting of PGE 1 , PGA 1 , PGB 1 , PGF 1α , 19-hydroxy-PGA 1 , 19-hydroxy-PGB 1 , PGE 2 , PGA 2 , PGB 2 , 19-hydroxy-PGA 2 , 19-hydroxy-PGB 2 , PGE 3 , PGF 3 , PGF 3α , a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and a mixture.  
     
     
         3 . The composition of  claim 1  wherein the vasoactive prostaglandin is selected from the group consisting of prostaglandin E 1 , prostaglandin E 2 , a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and a mixture thereof.  
     
     
         4 . The composition of  claim 1  wherein the composition has a viscosity of about 5,000 centipoise (cps) to about 20,000 cps.  
     
     
         5 . The composition of  claim 1  wherein the composition has a viscosity of about 7,000 cps to about 13,000 cps.  
     
     
         6 . The composition of  claim 1  wherein the polysaccharide gum is a shear-thinning polysaccharide gum.  
     
     
         7 . The composition of  claim 6  wherein the shear-thinning polysaccharide gum is a galactomannan gum.  
     
     
         8 . The composition of  claim 6  wherein the shear-thinning polysaccharide gum is a modified galactomannan gum.  
     
     
         9 . The composition of  claim 8  wherein the modified galactomannan gum is a modified guar gum.  
     
     
         10 . The composition of  claim 1  wherein the penetration enhancer is selected from the group consisting of an alkyl-(N-substituted amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol alkanoate, a pharmaceutically acceptable salt thereof and a mixture thereof.  
     
     
         11 . The composition of  claim 10  wherein the penetration enhancer is dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically acceptable salt thereof.  
     
     
         12 . The composition of  claim 1  wherein the lipophilic component comprises at least one aliphatic C 8  to C 30  ester.  
     
     
         13 . The composition of  claim 1  wherein the lipophilic component comprises at least one glyceryl ester selected from the group consisting of monoglycerides, diglycerides, triglycerides, and mixtures thereof.  
     
     
         14 . The composition of  claim 1  wherein the lipophilic component comprises at least one glyceryl ester selected from the group consisting of glyceryl monooleate, triolein, trimyristin, tristearin, and mixtures thereof.  
     
     
         15 . The composition of  claim 1  wherein the buffer system provides a buffered pH value for said composition in the range of about 3 to about 6.5.  
     
     
         16 . The composition of  claim 1  wherein the composition further comprises an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan esters, long chain alcohols, and glyceryl esters.  
     
     
         17 . The composition of  claim 16  wherein the emulsifier comprises at least one glyceryl ester selected from the group consisting of glyceryl monooleate, triolein, trimyristin, tristearin, and mixtures thereof.  
     
     
         18 . The composition of  claim 1  wherein the composition further comprises a fragrance.  
     
     
         19 . The composition of  claim 1  wherein the composition further comprises up to about 5 percent myrtenol, based on the total weight of the composition.  
     
     
         20 . The composition of  claim 1  wherein the composition further comprises a preservative.  
     
     
         21 . The composition of  claim 1  wherein the composition further comprises a topical anesthetic.  
     
     
         22 . A method of treating vasospasm in a subject needing such treatment comprising the step of: 
 applying to the region of the subject's tissue requiring treatment an effective amount of a semi-solid composition, the composition comprising:    a vasoactive prostaglandin;    a penetration enhancer;    a polymer thickener selected from the group consisting of a shear-thinning polysaccharide gum and a shear-thinning polyacrylic acid polymer;    a lipophilic component that is selected from the group consisting of an aliphatic C 1  to C 8  alcohol, an aliphatic C 8  to C 30  ester, a liquid polyol and a mixture thereof; water and    a buffer system that provides a buffered pH value for said composition in the range of about 3 to about 7.4.    
     
     
         23 . The method of  claim 22  wherein the tissue is skin.  
     
     
         24 . The method of  claim 22  wherein the tissue is vascular extima.  
     
     
         25 . The method of  claim 22  wherein the vasoactive prostaglandin is selected from the group consisting of prostaglandin E 1 , prostaglandin E 2 , a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and a mixture thereof.  
     
     
         26 . The method of  claim 22  wherein the penetration enhancer is selected from the group consisting of an alkyl-(N-substituted amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol alkanoate, a pharmaceutically acceptable salt thereof and a mixture thereof.  
     
     
         27 . The method of  claim 22  wherein the penetration enhancer is dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically acceptable salt thereof.  
     
     
         28 . The method of  claim 22  wherein the lipophilic component comprises at least one aliphatic C 8  to C 30  ester.  
     
     
         29 . A method of improving microcirculation in a replanted body part in a subject needing such treatment comprising the step of: 
 applying to the vascular extima of the blood vessels an effective amount of a semi-solid composition comprising a vasoactive prostaglandin;    a penetration enhancer;    a polymer thickener selected from the group consisting of a polysaccharide gum and a polyacrylic acid polymer;    a lipophilic component that is selected from the group consisting of an aliphatic C 1  to C 8  alcohol, an aliphatic C 8  to C 30  ester, a liquid polyol and a mixture thereof; water and    a buffer system that provides a buffered pH value for said composition in the range of about 3 to about 7.4.    
     
     
         30 . The method of  claim 29  further comprising the step of applying an effective amount of the semi-solid prostaglandin composition to the skin of the replanted body part and adjacent skin of the body.  
     
     
         31 . The method of  claim 29  wherein the vasoactive prostaglandin is selected from the group consisting of prostaglandin E 1 , prostaglandin E 2 , a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and a mixture thereof.  
     
     
         32 . The method of  claim 29  wherein the composition has a viscosity of about 5,000 centipoise (cps) to about 20,000 cps.  
     
     
         33 . The method of  claim 29  wherein the composition has a viscosity of about 7,000 cps to about 13,000 cps.  
     
     
         34 . The method of  claim 29  wherein the polysaccharide gum is a shear-thinning polysaccharide gum.  
     
     
         35 . The method of  claim 34  wherein the shear-thinning polysaccharide gum is a galactomannan gum.  
     
     
         36 . The method of  claim 34  wherein the shear-thinning polysaccharide gum is a modified galactomannan gum.  
     
     
         37 . The method of  claim 36  wherein the modified galactomannan gum is a modified guar gum.  
     
     
         38 . The method of  claim 29  wherein the penetration enhancer is selected from the group consisting of an alkyl-(N-substituted amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol alkanoate, a pharmaceutically acceptable salt thereof and a mixture thereof.  
     
     
         39 . The method of  claim 29  wherein the penetration enhancer is dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically acceptable salt thereof.  
     
     
         40 . The method of  claim 29  wherein the lipophilic component comprises at least one aliphatic C 8  to C 30  ester.  
     
     
         41 . The method of  claim 29  wherein the polymer thickener is a polyacrylic acid polymer.  
     
     
         42 . The method of  claim 29  wherein the lipophilic component comprises at least one glyceryl ester selected from the group consisting monoglycerides, diglycerides, triglycerides, and mixtures thereof.  
     
     
         43 . The method of  claim 29  wherein the lipophilic component comprises at least one glyceryl ester selected from the group consisting of glyceryl monooleate, triolein, trimyristin, tristearin, and mixtures thereof.  
     
     
         44 . The method of  claim 29  wherein the acidic buffer system provides a buffered pH for the composition in the range of about 3 to about 6.5.  
     
     
         45 . The method of  claim 29  wherein the composition further comprises an emulsifier selected from the group consisting of sucrose esters, polyoxyethylene sorbitan esters, long chain alcohols, and glyceryl esters.  
     
     
         46 . The method of  claim 29  wherein the emulsifier comprises at least one glyceryl ester selected from the group consisting of glyceryl monooleate, triolein, trimyristin, tristearin, and mixtures thereof.  
     
     
         47 . The method of  claim 29  wherein the composition further comprises a fragrance.  
     
     
         48 . The method of  claim 29  wherein the composition further comprises up to about 5 percent myrtenol, based on the total weight of the composition.  
     
     
         49 . The method of  claim 29  wherein the composition further comprises a preservative.  
     
     
         50 . The method of  claim 29  wherein the composition further comprises a topical anesthetic.  
     
     
         51 . The method in accordance with  claim 1  wherein the composition further comprises a topical anesthetic.  
     
     
         52 . A method of improving local microcirculation in a tissue comprising: 
 applying to the surface of the tissue an effective amount of a semi-solid composition, the composition comprising a vasoactive prostaglandin selected from the group consisting of prostaglandin E 1 , prostaglandin E 2 , a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and a mixture thereof;    a penetration enhancer selected from the group consisting of an alkyl (N-substituted amino) ester elected from the group consisting of an alkyl-(N-substituted amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol alkanoate, a pharmaceutically acceptable salt thereof and a mixture thereof;    a polymer thickener selected from the group consisting of a polysaccharide gum and a polyacrylic acid polymer;    a lipophilic component that is selected from the group consisting of an aliphatic C 1  to C 8  alcohol, an aliphatic C 8  to C 30  ester, a liquid polyol and a mixture thereof; water and    a buffer system that provides a buffered pH value for said composition in the range of about 3 to about 7.4.    
     
     
         53 . The method of  claim 52  further comprising the step of applying the semi-solid composition to the vascular extima of the blood vessels supplying the tissue.  
     
     
         54 . The method of  claim 52  wherein the surface to which the composition is applied is the surface of the skin.  
     
     
         55 . The method of  claim 52  wherein the polysaccharide gum is a shear-thinning polysaccharide gum.  
     
     
         56 . The method of  claim 55  wherein the shear-thinning polysaccharide gum is a galactomannan gum.  
     
     
         57 . The method of  claim 55  wherein the shear-thinning polysaccharide gum is a modified galactomannan gum.  
     
     
         58 . The method of  claim 57  wherein the modified galactomannan gum is a modified guar gum.  
     
     
         59 . The method of  claim 52  wherein the polymer thickener is a polyacrylic acid polymer.  
     
     
         60 . The method of  claim 52  wherein the penetration enhancer is dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically acceptable salt thereof.  
     
     
         61 . The method of  claim 52  wherein the lipophilic component comprises at least one aliphatic C 8  to C 30  ester.  
     
     
         62 . A method of preventing reperfusion injury of an affected tissue comprising the steps of: 
 providing the composition of  claim 1;  and    applying the composition to the surface of the affected tissue.    
     
     
         63 . The method of  claim 62  further comprising the step of applying the composition to the vascular extima of blood vessels supplying the affected tissue.  
     
     
         64 . The method of  claim 62  wherein the normal blood perfusion volume is restored in the affected tissue in no more than ten minutes.