Hypotonic microbicidal formulations and methods of use

Abstract

Hypotonic microbicidal compositions including an antimicrobial, such as an antiviral compound, and a pharmaceutically acceptable carrier in a solution formulation having hypotonic osmolarity have been developed for administration rectally to the gastrointestinal mucosa. In a preferred embodiment for use in preventing or decreasing HIV infection, the microbicidal is tenofovir, or a prodrug or derivative thereof. The formulations may include additional agents such as surfactants to enhance cleansing, buffers, or preservatives. Polymers may be included for osmolarity as well as comfort.

We claim: 
     
         1 . A hypotonic microbicidal composition comprising an effective amount of a microbiocide to inhibit infection or replication in a pharmaceutically acceptable carrier suitable for administration rectally or vaginally. 
     
     
         2 . The composition of  claim 1  wherein the microbiocide is an antiviral. 
     
     
         3 . The composition of  claim 2 , wherein the antiviral is a nucleoside reverse transcription inhibitor (NRTI) selected from the group consisting of tenofovir, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, and hexadecyloxypropyl tenofovir. 
     
     
         4 . The composition of any one of  claims 1-3  having an osmolarity between 50 and 280 mOsm. 
     
     
         5 . The composition of any one of  claims 1-4  having an osmolarity between 100 and 200 mOsm. 
     
     
         6 . The composition of any one of  claims 1-5  comprising sodium, preferably 25 mM sodium. 
     
     
         7 . The composition of  claim 6  further comprising potassium. 
     
     
         8 . The composition of any one of  claims 1-7  comprising hydrogel forming polymer that undergoes sol-gel transitions when at or above a critical gelling concentration (CGC) and at or above the critical gelling temperature at or below 37° C. 
     
     
         9 . The composition of  claim 8  wherein the polymer is selected from the group consisting of polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymers and tetra-functional block copolymers based on ethylene oxide and propylene oxide. 
     
     
         10 . The composition of any one of  claims 1-9  in a container for administration as an enema. 
     
     
         11 . The composition of  claim 10  wherein the container contains a solution or a dry formulation which is hydrated at the time of use. 
     
     
         12 . A method for administration of a microbiocide comprising administering to the subject rectally an effective amount of the microbicidal composition of any one of  claims 1-11 . 
     
     
         13 . The method of  claim 12  wherein the microbiocide composition is administered prior to or post receptive anal intercourse (RAI). 
     
     
         14 . The method of any of  claims 12  and  13 , wherein the microbiocidal composition is administered in one dose. 
     
     
         15 . The method of any one of  claims 12-14  wherein the microbiocidal is administered to produce an effective amount in the colon for a period of more than a day, more preferably for seven days.