Preservative removal from eye drops

Abstract

A BAK removal device is constructed as a plug of microparticles of a hydrophilic polymeric gel that displays a hydraulic permeability greater than 0.01 Da. The polymer hydrophilic polymeric gel comprises poly(2-hydroxyethyl methacrylate) (pHEMA). The particles are 2 to 100 μm and the plug has a surface area of 30 mm2 to 2 mm2 and a length of 2 mm to 25 mm and wherein the microparticles of a hydrophilic polymeric gel has a pore radius of 3 to 60 μm.

1 .- 24 . (canceled) 
     
     
         25 . A multi-dosing device for delivery of a solution, comprising:
 a bottle comprising:   a reservoir comprising the solution disposed therein, wherein the solution comprises a hydrophobic therapeutic agent and a preservative;   an outlet extension; and   a preservative removing device disposed within the outlet extension and comprising a porous hydrophilic polymeric matrix, wherein upon delivery of the solution through the outlet extension the porous hydrophilic polymeric matrix is configured to remove at least 50% of a preservative and retain at least 50% of the hydrophobic therapeutic agent within the solution.   
     
     
         26 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix has a partition coefficient for the preservative from the solution of at least 100. 
     
     
         27 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix comprises particles. 
     
     
         28 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix is preloaded with the preservative at 1 to 90% of saturation of the preservative in the porous hydrophilic polymeric matrix. 
     
     
         29 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix comprises poly hydroxyl ethyl methacrylate (pHEMA), poly hydroxyl ethyl methacrylate-co-methacrylic acid, or a combination thereof. 
     
     
         30 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix has interconnected pores, wherein the pores have an average radius of 1 to 60 μm. 
     
     
         31 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix is partitioned as microparticles with cross-sections of 2 to 100 pm. 
     
     
         32 . The multi-dosing device of  claim 25 , wherein the hydraulic permeability is greater than 0.01 Da. 
     
     
         33 . The multi-dosing device of  claim 25 , wherein the preservative is an alcohol, a paraben, EDTA, chlorhexidine, or a quaternary ammonium preservative. 
     
     
         34 . The multi-dosing device of  claim 33 , wherein the quaternary ammonium preservative is benzalkonium chloride (BAK) 
     
     
         35 . The multi-dosing device of  claim 34 , wherein the porous hydrophilic polymeric matrix is preloaded with the BAK at a concentration of one to 100 times that of the solution in the bottle. 
     
     
         36 . The multi-dosing device of  claim 28 , wherein the porous hydrophilic polymeric matrix is preloaded with a second preservative. 
     
     
         37 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix includes the hydrophobic therapeutic agent at a level below saturation. 
     
     
         38 . The multi-dosing device of  claim 25 , wherein the porous hydrophilic polymeric matrix is saturated with the hydrophobic therapeutic agent. 
     
     
         39 . The multi-dosing device of  claim 25 , wherein the hydrophobic therapeutic agent comprises dexamethasone, bimatoprost, or latanoprost. 
     
     
         40 . The multi-dosing device of  claim 29 , wherein the porous hydrophilic polymeric matrix comprises a cross-linker and wherein the cross-linker comprises ethylene glycol dimethacrylate or SR9035. 
     
     
         41 . The multi-dosing device of  claim 25 , wherein a partition coefficient of the porous hydrophilic polymeric matrix for the hydrophobic therapeutic agent is within a range from 10 to 50. 
     
     
         42 . The multi-dosing device of  claim 25 , further comprising a preservative source to maintain the preservative concentration in the solution. 
     
     
         43 . The multi-dosing device of  claim 25 , wherein the hydrophobic therapeutic agent comprises a combination of naphazoline and pheniramine maleate. 
     
     
         44 . The multi-dosing device of  claim 25 , wherein the preservative removing device when dry has dimensions smaller than the internal dimensions of the outlet extension, and wherein the preservative removing device when wet has dimensions larger than the internal dimensions of the outlet extension. 
     
     
         45 . A method of administering a hydrophobic therapeutic agent using a multi-dosing device, comprising:
 providing a bottle comprising:   an outlet extension;   a reservoir comprising a solution disposed therein, wherein the solution comprises the hydrophobic therapeutic agent, a preservative; and   a preservative removing device disposed within the outlet extension and comprising a porous hydrophilic polymeric matrix, wherein the preservative removing device when dry has dimensions smaller than the internal dimensions of the outlet extension, and wherein the preservative removing device when wet has dimensions larger than the internal dimensions of the outlet extension, and wherein upon delivery of the solution through the outlet extension the porous hydrophilic polymeric matrix is configured to remove at least 50% of a preservative and retain at least 50% of the hydrophobic therapeutic agent within the solution.   
     
     
         46 . The method of  claim 45 , further comprising delivering the solution through the outlet extension.