Liquid Pentablock Co-Polymer Formulations for Sustained Delivery of Therapeutics

Abstract

Provided herein are amphiphilic polymers compositions for making aqueous formulations. In one aspect, a solution composition for delivery and release of active ingredients comprises a block co-polymer having formula: PEG-PCL-PLA-PCL-PEG or PGA-PCL-PEG-PCL-PGA or PLA-PCL-PEG-PCL-PLA or PCL-PLA-PEG-PLA-PCL or PCL-PGA-PEG-PGA-PCL. The block co-polymers are biodegradable, stable and compatible with hydrophilic, hydrophobic, and combinations thereof, biologic or chemical active agents. In some embodiments, the block co-polymers enable sustained and/or continuous release of various active agents. In certain embodiments, the block co-polymers can be used to make an artificial tear preparation, a lubricant for joints or wound cover or adhesive.

1 . A composition for delivery of an active ingredient, comprising a block polymer having the formula of PEG-PCL-PLA-PCL-PEG or PGA-PCL-PEG-PCL-PGA or PLA-PCL-PEG-PCL-PLA or PCL-PLA-PEG-PLA-PCL or PCL-PGA-PEG-PGA-PCL in the form of an aqueous dispersion, wherein PEG is polyethylene glycol and has an average molecular weight of about 100 to about 10,000 Da and a molecular weight percentage of at least 25%, wherein preferably PEG has an average molecular weight of about 500 to about 5,000 Da;
 wherein PCL is poly(ε-caprolactone) and has an average molecular weight of about 100 to about 3000 Da, preferably about 200 to about 2000 Da, and more preferably about 300 to about 1500 Da;   wherein PLA is polylactic acid having an average molecular weight of about 100 to about 5,000 Da, preferably about 150 to about 3000 Da, and more preferably about 200 to about 1500 Da;   wherein PGA is polyglycolic acid having an average molecular weight of about 100 to about 5,000 Da, preferably about 150 to about 3000 Da, and more preferably about 200 to about 1500 Da; and   wherein the polymer preferably has a total molecular weight of about 1,500 to about 20,000 Da, more preferably about 2,000 to about 15,000 Da, even more preferably about 2500 to about 10,000 Da.   
     
     
         2 . The composition according to  claim 1 , wherein the polymer does not visibly gel at about body temperature instantly. 
     
     
         3 . The composition according to  claim 1 , wherein the polymer is a non-gelling polymer and the composition further comprises a gelling polymer wherein the non-gelling polymer prevents instant gelation of the gelling polymer. 
     
     
         4 . The composition according to  claim 3 , wherein the gelling polymer is present at about 0.01 to about 25 wt % of liquid formulation, preferably about 1 to about 15 wt %, more preferably about 2 to about 10 wt %. 
     
     
         5 . The composition according to  claim 4 , further comprising an active ingredient that is hydrophobic and is dissolved in the gelling polymer. 
     
     
         6 . The composition according to  claim 1 , wherein the non-gelling polymer is present at between about 0.01 wt % and about 50 wt % of liquid formulation, preferably about 1 to about 35 wt %, more preferably about 2 to about 25 wt %. 
     
     
         7 . The composition according to  claim 6 , further comprising an aqueous medium and an active ingredient admixed therein. 
     
     
         8 . The composition according to  claim 7 , wherein the aqueous medium is water or aqueous buffer. 
     
     
         9 . The composition according to  claim 7 , wherein the active ingredient is present at about 0.01 wt % to about 50 wt % of liquid formulation, preferably about 0.1 to about 30 wt %, more preferably about 0.2 to about 10 wt %. 
     
     
         10 . The composition according to  claim 7 , wherein the active ingredient is a biologic or chemical agent. 
     
     
         11 . The composition according to  claim 7 , wherein the active ingredient is hydrophobic or hydrophilic, or a mixture of hydrophobic and hydrophilic ingredients. 
     
     
         12 . A method for preparing an aqueous formulation of a hydrophobic active ingredient, comprising:
 dissolving the hydrophobic active ingredient in a gelling polymer, and   admixing with the composition of  claim 1 , wherein the non-gelling polymer is present at about 0.01 to about 49.9 wt % of liquid formulation, preferably about 1 to about 35 wt %, more preferably about 2 to about 25 wt %.   
     
     
         13 . An artificial tear or lubricant for joint or wound cover or adhesive comprising an aqueous solution of the composition of  claim 1 . 
     
     
         14 . The artificial tear of  claim 13  wherein the aqueous solution includes one or more of hydrophilic polymer excipients, tonicity agents, buffers, sugars selected from trehalose, mannose, D-galactose, and lactose, preservatives, co-solvents or antioxidants etc. 
     
     
         15 . The artificial tear of  claim 14  wherein the aqueous solution has a pH ranging from about 5.0 to about 8.0, preferably about 6.6 to about 7.4, and more preferably about 7.0. 
     
     
         16 . A method of delivering an active ingredient to a mammal in need thereof, comprising:
 providing the composition of  claim 1  admixed with an active ingredient, wherein the polymer is present at between about 0.01 wt % and about 50 wt % of liquid formulation, preferably about 1 to about 35 wt %, more preferably about 2 to about 25 wt %; wherein the composition is in the form of a reasonably clear polymer dispersion; and   administering the composition to a mammal;   wherein preferably the method provides sustained release of the active ingredient.   
     
     
         17 . The method of  claim 16 , wherein said administering is by a topical (e.g., ocular or dermal surface), oral or parenteral route. 
     
     
         18 . The method of  claim 16  wherein the polymer clears at a release rate substantially similar to an active ingredient, allowing for repeat applications without interfering biologically or physically with a prior application. 
     
     
         19 . The method of  claim 16 , wherein the polymer biodegrades successively into substituent blocks, which are not substantially physiologically harmful, and wherein the polymer and the substituent blocks from biodegradation are tolerated in vivo such that long-term or repeat applications are feasible. 
     
     
         20 . The method of  claim 16 , wherein the composition is administered to an ocular surface and provides relief or sustained release of the active ingredient for 1-48 hours or longer. 
     
     
         21 . (canceled)