Atropine pharmaceutical compositions
The inventive subject matter is directed to compositions and methods for sterile and storage stable low-dose atropine formulations with improved stability. Most preferably, the compositions presented herein are substantially preservative free and exhibit less than 0.35% tropic acid from degradation of atropine. Advantageously, contemplated formulations are also substantially free of preservatives.
1. A method of increasing storage stability of atropine in a liquid low-dose ophthalmic formulation, comprising:
formulating an aqueous solution with a low-strength buffer system that includes a first and second buffer component, wherein the low-strength buffer system has a concentration of equal or less than 75 mM buffer including atropine or a pharmaceutically acceptable salt thereof at a low dose, wherein the low dose is equal or less than 0.05 wt % of the ophthalmic formulation;
including into the aqueous solution a pharmaceutically acceptable salt, a viscosity modifier, and optionally a chelator;
including into the aqueous solution atropine or a pharmaceutically acceptable salt thereof at a low dose, wherein the low dose is equal or less than 0.05 wt % of the ophthalmic formulation;
combining the aqueous solution with a sterile viscosity modifier solution to produce an ophthalmic formulation having a dynamic viscosity of between 5 and 50 cP; and
adjusting pH of the ophthalmic formulation to a pH between 5 and 6; and
wherein the ophthalmic formulation after storage over at least two months at 25° C. and 60% relative humidity contains equal or less than 0.35% tropic acid formed from degradation of the atropine.
2. The method of claim 1 , further comprising including into the aqueous solution a low-strength buffer system that includes a first and second buffer component, wherein the low-strength buffer system has a concentration of equal or less than 75 mM buffer, and wherein the first and second buffer components are monobasic and dibasic sodium phosphate, respectively.
3. The method of claim 1 2 , wherein the low-strength buffer system has a concentration of equal or less than 50 mM buffer.
4. The method of claim 1 , wherein the pharmaceutically acceptable salt is sodium chloride and wherein the salt is present in the ophthalmic atropine composition in an amount of 0.5 wt % (+/−0.2 wt %) of the ophthalmic formulation.
5. The method of claim 1 , wherein the aqueous solution comprises the chelator, wherein the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.
6. The method of claim 5 , wherein the chelator is ethylenediaminetetraacetic acid (EDTA).
7. The method of claim 1 , wherein the aqueous solution comprises the chelator, and wherein the chelator is present in an amount of 0.01 wt % (+/−20% abs.) of the ophthalmic formulation.
8. The method of claim 1 , wherein the viscosity modifier is a cellulosic viscosity modifier.
9. The method of claim 8 , wherein the cellulosic viscosity modifier is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.
10. The method of claim 8 , wherein the cellulosic viscosity modifier is present in an amount of 0.5 wt % (+/−0.1 wt %) of the ophthalmic formulation.
11. The method of claim 8 1 , wherein the cellulosic sterile viscosity modifier solution is prepared as a separate heat sterilized solution, and combined with the aqueous solution containing the buffer system, the pharmaceutically acceptable salt, the viscosity modifier, the chelator, and the atropine or the pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the low dose is between 0.01 wt % and 0.02 wt % of the ophthalmic formulation.
13. The method of claim 1 , wherein the low dose is between 0.001 wt % and 0.01 wt % of the ophthalmic formulation.
14. The method of claim 1 , wherein the low dose is equal or less than 0.01 wt % of the ophthalmic formulation.
15. The method of claim 1 , wherein aqueous solution is formulated using deoxygenated water.
16. The method of claim 1 , wherein the pH is between 5.5 (+/−0.2) and 6.0 (+/−0.2).
17. The method of claim 1 , wherein the atropine or a pharmaceutically acceptable salt thereof is atropine sulfate.
18. The method of claim 1 , further comprising a step of filter sterilizing the ophthalmic formulation aqueous solution prior to combining the aqueous solution with the sterile viscosity modifier solution.
19. The method of claim 18 , wherein the step of sterilizing comprises sterile filtration.
20. The method of claim 1 , further comprising a step of filling the ophthalmic formulation into a multi-dose container.