Preservative-free ophthalmic pharmaceutical formulation
The present invention relates to a process for manufacturing an ophthalmic formulation of a carbonic anhydrase inhibitor, hydroxyl ethyl cellulose (HEC), and a beta-adrenergic antagonist for use in the treatment of ocular hypertension and glaucoma wherein the ophthalmic pharmaceutical formulation is devoid of benzalkonium chloride or any other preservatives. The present process for manufacturing is simpler, cost effective process to prepare the pharmaceutical ophthalmic formulation in a single tank, without the use of additional tanks that can be sterile filtered.
1. A method of manufacturing a sterile, preservative free ophthalmic formulation solution without steam sterilization or autoclaving comprising:
a) heating a first mixture comprising a first solution that consists essentially of hydroxyethyl cellulose dissolved in water and is devoid of any preservative to a temperature of about 94° C. to about 97° C. for a sufficient time to produce a second mixture comprising a second solution having viscosity of about 100±10 centipoise and devoid of any preservative;
b) dissolving a carbonic anhydrase inhibitor in the second mixture to produce a third mixture comprising a third solution that is devoid of any preservative, wherein the carbonic anhydrase inhibitor comprises dorzolainide, or a salt thereof;
c) adjusting pH of the third mixture to between 5.5 to 6.0 to produce a fourth mixture comprising a fourth solution that is devoid of any preservative and heating the fourth mixture to between 43° C. to 47° C.; and
d) sterilizing the fourth mixture by aseptic filtration which comprises filtration through a sterilization filter having a pore size of about 0.2 microns to produce a fifth mixture which is a sterile, preservative free ophthalmic formulation solution that is devoid of any preservative and that is produced without steam sterilization or autoclaving.
2. The method of claim 1 further comprising dissolving a beta adrenergic antagonist in the second mixture to produce the third mixture.
3. The method of claim 1 further comprising dissolving a buffering agent and a tonicity adjusting agent in the second mixture to produce the third mixture.
4. The method of claim 1 wherein the fifth mixture comprises about 0.05% (w/v) to about 5% (w/v) of the carbonic anhydrase inhibitor.
5. The method of claim 2 wherein the fifth mixture comprises about 0.01% (w/v) to about 1% (w/v) of the beta adrenergic antagonist.
6. The method of claim 1 wherein the carbonic anhydrase inhibitor consists of dorzolamide hydrochloride.
7. The method of claim 2 wherein the beta adrenergic antagonist is timolol maleate.
8. The method of claim 7 wherein the fifth mixture comprises about 2% dorzolamide hydrochloride (w/v) and about 0.5% timolol maleate (w/v).
9. The method of claim 7 wherein the fifth mixture comprises about 1% dorzolamide hydrochloride (w/v) and about 0.5% timolol maleate (w/v).
10. The method of claim 1 wherein the first mixture is heated at about 95° C. for sufficient time to produce the second mixture.
11. The method of claim 1 wherein the first mixture is heated for about 7 to about 8 hours to produce the second mixture.
12. The method of claim 3 wherein the buffering agent is sodium citrate dihydrate.
13. The method of claim 3 wherein the tonicity adjusting agent is mannitol.
14. The method of claim 1 wherein the pH of the third mixture is adjusted to about 5.6 ±0.1 with a sodium hydroxide solution to produce the fourth mixture.
15. The method of claim 1 , which comprises heating the fourth mixture to 45° C. prior to sterilization.
16. The method of claim 1 further comprising cooling the second mixture to about 25° C. to 35° C. prior to dissolving the carbonic anhydrase inhibitor.
17. The method of claim 1 wherein the first mixture, second mixture, third mixture, and fourth mixture are produced in a single tank.
18. The method of claim 1 further comprising adding one or more of a surfactant and an antioxidant to the ophthalmic formulation.