Atropine pharmaceutical compositions
View Patent ↗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 preparing a storage stable liquid low-dose atropine ophthalmic formulation, comprising:
formulating in a first container a low-strength buffer low-dose atropine solution using a first solvent, wherein the first solvent consists essentially of a first aqueous solvent, and subjecting the low-strength buffer low-dose atropine solution to sterile filtration to obtain a sterile low-strength buffer low-dose atropine solution;
wherein the low-strength buffer has a first and a second buffer component that form a low-strength buffer system having a concentration of equal or less than 75 mM in the ophthalmic formulation, wherein the atropine is present in an amount of equal or less than 0.05 wt % of the ophthalmic formulation;
wherein the low-strength buffer low-dose atropine solution further comprises a tonicity agent and a chelator;
formulating in a second container a polymer solution using a second solvent, wherein the second solvent consists essentially of a second aqueous solvent, and autoclaving the polymer solution to obtain a sterile polymer solution;
wherein the polymer solution comprises a polymer to modify viscosity of the low-strength buffer low-dose atropine solution upon combination;
combining the sterile low-strength buffer low-dose atropine solution and the sterile polymer solution to obtain a sterile liquid low-dose ophthalmic formulation, and filling the sterile liquid low-dose ophthalmic formulation after combining into a single-use or multi-use container; 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 , wherein the first and second buffer components are monobasic and dibasic sodium phosphate, respectively.
3. The method of claim 1 , wherein the low-strength buffer system has a concentration of equal or less than 50 mM buffer in the ophthalmic formulation.
4. The method of claim 1 , wherein the atropine is present in an amount of between 0.01 wt % and 0.02 wt % of the ophthalmic formulation.
5. The method of claim 1 , wherein the atropine is present in an amount of between 0.001 wt % and 0.01 wt % of the ophthalmic formulation.
6. The method of claim 1 , wherein the atropine is present in an amount of equal or less than 0.01 wt % of the ophthalmic formulation.
7. The method of claim 1 , wherein the tonicity agent is a pharmaceutically acceptable salt.
8. The method of claim 7 , 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.
9. The method of claim 1 , wherein the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.
10. The method of claim 9 , wherein the chelator is ethylenediaminetetraacetic acid (EDTA).
11. The method of claim 1 , wherein the chelator is present in an amount of 0.01 wt %+/−20% of the ophthalmic formulation.
12. The method of claim 11 , wherein the polymer is a cellulosic polymer.
13. The method of claim 12 , wherein the cellulosic polymer is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.
14. The method of claim 12 , wherein the cellulosic polymer is present in an amount of equal or less than 0.5 wt %+/−0.1 wt % of the ophthalmic formulation.
15. The method of claim 1 , further comprising a step of adjusting the pH of the low-strength buffer low-dose atropine solution to a pH between 5 and 6.
16. The method of claim 15 , wherein the pH is between 5.5 and 6.0.
17. The method of claim 1 , wherein the step of combining comprises mixing the sterile low-strength buffer low-dose atropine solution and the sterile polymer solution for at least 30 minutes.
18. The method of claim 17 , further comprising a step of filling the ophthalmic formulation into a multi-dose container.