Lipoic acid choline ester compositions and methods of use

Abstract

Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of lipoic acid choline ester or derivatives thereof and a non-aqueous excipient mixed in an aqueous solution. Also provided herein are non-aqueous compositions prepared by mixing the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient. The non-aqueous compositions can be further mixed with the aqueous solution.

What is claimed: 
     
         1 . A pharmaceutical composition comprising a therapeutically effective amount of lipoic acid choline ester and a non-aqueous excipient, mixed in an aqueous solution having a pH of 4 to 6, wherein at least 95% of the lipoic acid choline ester is present in the pharmaceutical composition, as measured by HPLC, following storage at 25° C. under 40% relative humidity for 3 months. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein less than 2% of the lipoic acid choline ester is degraded following storage at 25° C. under 40% relative humidity for 3 months. 
     
     
         3 . The pharmaceutical composition of  claim 1  or  claim 2 , having less than 12% total drug related impurities based on area-under-the-curve as determined by HPLC following storage at 25° C. under 40% relative humidity for 3 months. 
     
     
         4 . The pharmaceutical composition of any of  claims 1 - 3 , having less than 7% of a drug related impurity based on area-under-the-curve as determined by HPLC following storage at 25° C. under 40% relative humidity for 3 months, wherein the drug related impurity is characterized by a relative retention time of 1.12 to 1.14. 
     
     
         5 . The pharmaceutical composition of any of  claims 1 - 4 , having less than 4% of a drug related impurity based on area-under-the-curve as determined by HPLC following storage at 25° C. under 40% relative humidity for 3 months, wherein the drug related impurity is characterized by a relative retention time of 0.65 to 0.66. 
     
     
         6 . The pharmaceutical composition of any of  claims 1 - 5 , characterized by one or more of the following:
 (a) having a concentration of the lipoic acid choline ester of 1% to 10% by weight of the composition;   (b) having a concentration of a preservative of 0.005% to 0.1% by weight of the composition;   (c) having a biochemical energy source of 0.1% to 5% by weight of the composition; and   (d) having a concentration of glycerol of 0.5% to 5% by weight of the composition.   
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the preservative is benzalkonium chloride and the biochemical energy source is alanine. 
     
     
         8 . The pharmaceutical composition of any of  claims 1 - 7 , wherein the lipoic acid choline ester has a counter ion selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate, succinate, benzoate, and anion of glutamic acid. 
     
     
         9 . A method of improving accommodative amplitude in a lens, comprising administering to the lens an effective amount of the pharmaceutical composition of any of  claims 1 - 8 . 
     
     
         10 . A method of treating or preventing presbyopia in a subject, comprising administering to an eye of the subject an effective amount of the pharmaceutical composition of any of  claims 1 - 8 . 
     
     
         11 . A non-aqueous composition comprising lipoic acid choline ester or derivatives thereof and a non-aqueous excipient. 
     
     
         12 . The non-aqueous composition of  claim 11 , wherein the non-aqueous excipient is substantially miscible with water. 
     
     
         13 . The non-aqueous composition of  claim 11  or  claim 12 , wherein the non-aqueous excipient is a non-hydrolytic solvent. 
     
     
         14 . The non-aqueous composition of any of  claims 11 - 13 , wherein the non-aqueous excipient is an alcohol. 
     
     
         15 . The non-aqueous composition of  claim 14 , wherein the alcohol is a polyol. 
     
     
         16 . The non-aqueous composition of  claim 15 , wherein the polyol is glycerol. 
     
     
         17 . The non-aqueous composition of  claim 15 , wherein the polyol is propylene glycol. 
     
     
         18 . The non-aqueous composition of  claim 11 , wherein the non-aqueous excipient is a semifluorinated alkane. 
     
     
         19 . The non-aqueous composition of any of  claims 11 - 18 , comprising a non-aqueous solution obtained by mixing lipoic acid choline ester with the non-aqueous excipient. 
     
     
         20 . The non-aqueous composition of  claim 19 , wherein the mixing is conducted at a temperature of 20° C. to 100° C. 
     
     
         21 . The non-aqueous composition of  claim 20 , wherein the mixing is conducted at a temperature of 37° C. to 80° C. 
     
     
         22 . The non-aqueous composition of any of  claims 11 - 21 , wherein the concentration of lipoic acid choline ester or derivatives thereof is in a range of 0.1% to 40% by weight of the composition. 
     
     
         23 . The non-aqueous composition of any of  claims 11 - 22 , wherein the lipoic acid choline ester has a counter ion selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate, succinate, benzoate, and anion of glutamic acid. 
     
     
         24 . An ophthalmic formulation comprising the non-aqueous composition of any of  claims 11 - 23  mixed in an aqueous solution. 
     
     
         25 . The ophthalmic formulation of  claim 24 , wherein the aqueous solution comprises a buffer. 
     
     
         26 . The ophthalmic formulation of  claim 24  or  claim 25 , having a pH of 4 to 8. 
     
     
         27 . The ophthalmic formulation of  claim 26 , having a pH of 4.5. 
     
     
         28 . The ophthalmic formulation of any of  claims 24 - 27 , comprising at least one ingredient selected from the group consisting of a biochemically acceptable energy source, a preservative, a buffer agent, a tonicity agent, a surfactant, a viscosity modifying agent, and an antioxidant. 
     
     
         29 . The ophthalmic formulation of any of  claims 24 - 28 , wherein the non-aqueous composition is sterilized before mixing in the aqueous solution. 
     
     
         30 . The ophthalmic formulation of any of  claims 24 - 29 , wherein the aqueous solution is a sterilized solution. 
     
     
         31 . The ophthalmic formulation of any of  claims 24 - 30 , characterized by one or more of:
 (a) having a concentration of the lipoic acid choline ester or derivatives thereof from 1% to 10% by weight of the formulation;   (b) having a concentration of a preservative 0.005% to 0.1% by weight of the formulation;   (c) having a pH of 4 to 6;   (d) having a biochemical energy source of 0.1% to 5% by weight of the formulation;   (e) having a concentration of glycerol of 0.5% to 5% by weight of the formulation; and   (f) having a shelf-life stability of greater than 3 months.   
     
     
         32 . The ophthalmic formulation of  claim 31 , wherein the preservative is benzalkonium chloride and the biochemical energy source is alanine. 
     
     
         33 . A method of improving accommodative amplitude in a lens, comprising administering to the lens an effective amount of the non-aqueous composition of any of  claims 11 - 23  or the ophthalmic formulation of any of  claims 24 - 32 . 
     
     
         34 . A method of treating or preventing presbyopia in a subject, comprising administering to an eye of the subject an effective amount of the pharmaceutical composition of any of  claims 11 - 23  or the ophthalmic formulation of any of  claims 24 - 32 . 
     
     
         35 . A system comprising a first compartment, a second compartment, and a seal separating the first and second compartments, wherein the first compartment comprises a non-aqueous composition of an active ingredient and a non-aqueous excipient, the second compartment comprises an aqueous solution, and wherein the system is activated upon breaking the seal and mixing the non-aqueous solution with the aqueous solution. 
     
     
         36 . The system of  claim 35 , wherein the active ingredient is lipoic acid choline ester or derivatives thereof and the non-aqueous excipient is an ophthalmically acceptable excipient. 
     
     
         37 . The system of  claim 35  or  claim 36 , wherein the aqueous solution comprises a buffer. 
     
     
         38 . The system of any of  claims 35 - 37 , wherein both the non-aqueous composition and the aqueous solution are sterilized. 
     
     
         39 . The system of any of  claims 35 - 38 , wherein the active ingredient in the system has a shelf-stability of more than 3 months. 
     
     
         40 . The system of  claim 39 , wherein the active ingredient in the system has a shelf-stability of more than 6 months. 
     
     
         41 . The system of any of  claims 35 - 40 , wherein the active ingredient in the system after activation has a shelf-stability of more than 3 months. 
     
     
         42 . A method of storing an active ingredient that is susceptible to hydrolysis in an aqueous solution, the method comprising (a) providing the active ingredient in a first compartment; (b) providing the aqueous solution in a second compartment; and (c) separating the first and second compartments with a seal, wherein the active ingredient in the first compartment is not in contact with the aqueous solution until just prior to usage by breaking the seal. 
     
     
         43 . The method of  claim 42 , wherein the active ingredient in the first compartment is a lyophilized powder or is mixed with a non-hydrolytic solvent. 
     
     
         44 . The method of  claim 42  or  43 , wherein the active ingredient is lipoic acid choline ester or derivatives thereof, or a peptide.