Preparation of solid cyclodextrin complexes for ophthalmic active pharmaceutical ingredient delivery

Abstract

The present disclosure relates to ophthalmic compositions containing solid complexes of active pharmaceutical ingredient and cyclodextrin, to their method of preparation and their uses. The compositions can include an active agent drug/cyclodextrin complex substantially dissolved in an aqueous eye drop vehicle. The ophthalmic composition is generally in the form of a microsus-pension including an active agent complex having a diameter of less than about 100 µm.

1 - 109 . (canceled) 
     
     
         110 . A method of preparing an ophthalmic microsuspension comprising a solid complex of active pharmaceutical ingredient and y-cyclodextrin, said method comprising the steps of:
 a) suspending dexamethasone in an ophthalmically acceptable medium to form a suspension and heating said suspension until the dexamethasone is substantially dissolved in the ophtalmically acceptable medium;   b) suspending y-cyclodextrin in an ophthalmically acceptable medium to form a suspension and heating said suspension until the y-cyclodextrin is substantially dissolved in the ophtalmically acceptable medium;   c) sterilizing the compositions of step a) and b) in an autoclave,   d) mixing the compositions after the sterilizing step c) at a temperature T1 lower than 120° C.; and,   d) cooling the resulting solution to a temperature T2, to obtain an ophthalmic microsuspension comprising a solid complex of dexamethasone and y-cyclodextrin.   
     
     
         111 . The method according to  claim 110 , wherein temperature T1 is 80 to 110° C. 
     
     
         112 . The method according to  claim 110 , wherein temperature T2 is 10 to 40° C. 
     
     
         113 . The method according to  claim 110 , wherein temperature T1 is cooled at step d) to temperature T2 with a rate of 1 to 25° C./min. 
     
     
         114 . The method according to  claim 110 , wherein the time of the heating of step c) is from 10 minutes to 1 hour. 
     
     
         115 . The method according to  claim 110 , wherein the composition at step a) further comprises poloxamer. 
     
     
         116 . The method according to  claim 110 , wherein the viscosity of the microsuspension obtained at step d) is between 4 and 14 cp. 
     
     
         117 . The method according to  claim 110 , wherein the ophtalmically acceptable medium of step a) comprises water and one or more additives selected from the group consisting of a preservative, a stabilizing agent, an electrolyte, a buffering agent and combinations thereof. 
     
     
         118 . The method according to  claim 110 , wherein said active pharmaceutical ingredient is a steroid. 
     
     
         119 . The method according to  claim 110 , wherein said active pharmaceutical ingredient is a dexamethasone. 
     
     
         120 . The method according to  claim 110 , wherein said active pharmaceutical ingredient is a dexamethasone and the amount of dexamethasone present in the microsuspension at step d) is from 1% to 2% by weight based on the volume of the microsuspension. 
     
     
         121 . The method according to  claim 110 , wherein said active pharmaceutical ingredient is a dexamethasone and the amount of dexamethasone present in the microsuspension at step d) is about 1.5% by weight based on the volume of the microsuspension. 
     
     
         122 . The method according to  claim 110 , said active pharmaceutical ingredient is a dexamethasone and, wherein 60 to 95% by weight of the dexamethasone in the microsuspension as obtained at step d) is in the form of solid complex of dexamethasone and γ-cydodextrin. 
     
     
         123 . The method of  claim 110 , in which the amount of y-cyclodextrin in the microsuspension obtained at step d) is from 10 to 18%, even more particularly 12 to 16%, by weight of y-cyclodextrin based on the weight of the composition. 
     
     
         124 . The method of  claim 110 , in which the amount of y-cyclodextrin in the composition obtained at step d) is from 12 to 16%, by weight of y-cyclodextrin based on the weight of the composition. 
     
     
         125 . The method of  claim 110 , wherein the microsuspension obtained at step d) comprises:
 1 to 2% of dexamethasone;   12 to 16% of γ-cyclodextrin;   2.2 to 2.8% of polymer;   0 to 0.2% of stabilizing agent;   0 to 1% of electrolyte; and   water;   wherein the % are % by weight based on the weight of the composition.   
     
     
         126 . The method of  claim 110 , wherein said solid complex has a diameter D50 from 1 µm to 25 µm. 
     
     
         127 . The method of  claim 110 , wherein the microsuspension comprises less than 1% by weight of by-products of the active pharmaceutical ingredient based on the weight of the active pharmaceutical ingredient. 
     
     
         128 . An ophthalmic composition obtainable by the method according to  claim 110 . 
     
     
         129 . The composition of  claim 128 , wherein the ophthalmic composition comprises less than 1% by weight of by-products or impurities based on the weight of the active pharmaceutical ingredient. 
     
     
         130 . A method of treating an ocular condition in a subject in need thereof, comprising topically administering an ophthalmic composition according  claim 128 , in the eye of said subject. 
     
     
         131 . The method of  claim 130 , wherein said ocular condition is selected from uveitis and macular edema.