COMPOSITIONS AND METHODS FOR STORAGE STABLE OPHTHALMIC DRUGS
The present invention is related to methods of stabilizing an ophthalmic drug by adding a surfactant and a viscosity enhancer to the ophthalmic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius, filling the composition into a container; and storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius. The present invention is further directed to a container prepared by the methods of the present invention.
1 . A method of stabilizing an ophthalmic drug comprising the following steps:
a) adding a surfactant and a viscosity enhancer to the ophthalmic drug to create a composition wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius;
b) filling the composition from step a) into a container; and
c) storing the container at a temperature from about 2 degrees Celsius to about 25 degrees Celsius.
2 . The method of claim 1 , wherein the ophthalmic drug is selected from the group consisting of aceclidine, latanoprost and combinations thereof.
3 . The method of claim 1 , wherein the ophthalmic drug is aceclidine.
4 . The method of claim 1 , wherein the surfactant is selected from the group consisting of polysorbates, poloxamers, polyoxyl alkyls, cyclodextrins, ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctanesulfonate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, lignosulfonate, sodium lauryl sulfate, a olefin sulfonate, ammonium laureth sulfate, sodium ester lauryl sulfate, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyl dichlorobenzene ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyl trimethylammonium bromide, cetyl trimethylammonium chloride, cetrimonium bromide, cethexonium bromide, alkyl-amphoacetates, alkenyl-amphoacetates, alkyl-amphodiacetates, alkenyl-amphodiacetates, alkylamphopropionates, alkylamphodipropionates, alkyl amphohydroxypropyl sultaines and combinations thereof.
5 . The method of claim 1 , wherein the viscosity enhancer is selected from the group consisting of gums, cellulose derivatives, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymer and combinations thereof.
6 . The method of claim 1 , wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is about 150 centipoise or more.
7 . The method of claim 6 , wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is about 300 centipoise or more.
8 . The method of claim 1 , wherein the container is stored at a temperature from about 2 to about 8 degrees Celsius.
9 . The method of claim 8 , wherein the container is stored at a temperature of about 5 degrees Celsius.
10 . The method of claim 1 , wherein the composition is filled into the container under an inert gas overlay.
11 . The method of claim 1 , wherein the filling step creates a head space in the container and the head space is purged with an inert gas.
12 . The method of claim 1 , wherein the container comprises a closure and a vessel wherein a portion of the closure and a portion of the vessel are sealed with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil.
13 . The method of claim 1 , wherein the container is disposed in a second container that is formed with or lined with an anti-leaching material selected from the group consisting of biaxially-oriented polyethylene terephthalate, polytetrafluorethylene and aluminum foil.
14 . A container comprising an ophthalmic drug prepared by the process comprising the steps of:
a) providing a container;
b) filling the container with a composition comprising an ophthalmic drug, a surfactant and a viscosity enhancer, preferably under an inert gas overlay, preferably nitrogen, wherein the composition has a viscosity of about 25 centipoise or less at a shear rate of 1/1000 per second at 25 degrees Celsius and a viscosity of about 70 centipoise or more at shear rate of 1 per second at 25 degrees Celsius;
c) capping the container; and
d) storing the container at a temperature from about 2 to about 25 degrees Celsius.
15 . The container of claim 14 , wherein the ophthalmic drug is selected from the group consisting of aceclidine, latanoprost and combinations thereof.
16 . The container of claim 14 , wherein the ophthalmic drug is aceclidine.
17 . The container of claim 14 , wherein the surfactant is selected from the group consisting of polysorbates, poloxamers, polyoxyl alkyls, cyclodextrins, ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctanesulfonate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, lignosulfonate, sodium lauryl sulfate, a olefin sulfonate, ammonium laureth sulfate, sodium ester lauryl sulfate, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, alkyl-dimethyl dichlorobenzene ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyl trimethylammonium bromide, cetyl trimethylammonium chloride, cetrimonium bromide, cethexonium bromide, alkyl-amphoacetates, alkenyl-amphoacetates, alkyl-amphodiacetates, alkenyl-amphodiacetates, alkylamphopropionates, alkylamphodipropionates, alkyl amphohydroxypropyl sultaines and combinations thereof.
18 . The container of claim 14 , wherein the viscosity enhancer is selected from the group consisting of gums, cellulose derivatives, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymer and combinations thereof.
19 . The container of claim 14 , wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is of about 150 centipoise or more.
20 . The container of claim 19 , wherein the viscosity at shear rate of 1 per second at 25 degrees Celsius is of about 300 centipoise or more.
21 . The container of claim 14 , wherein the container is stored at a temperature from about 2 to about 8 degrees Celsius.
22 . The container of claim 21 , wherein the container is stored at a temperature of about 5 degrees Celsius.
23 . The container of claim 14 , wherein after step b) and prior to step c) a head space created during the filling step is purged with an inert gas.
24 . The container of claim 14 , wherein the inert gas is nitrogen.