Aqueous pharmaceutical compositions containing borate-polyol complexes
View Patent ↗The present invention is directed to the provision of multi-dose, ophthalmic compositions. The compositions possess sufficient antimicrobial activity to satisfy USP preservative efficacy requirements, as well as similar preservative standards (e.g., EP and JP). The compositions include at two different polyols in conjunction with borate and a low concentration of benzalkonium chloride.
1. A multi-dose ophthalmic composition, comprising:
a therapeutically effective amount of brimonidine;
a first polyol, the first polyol being selected from mannitol, sorbitol or a combination thereof wherein the concentration of the first polyol in the composition is at least 0.15 w/v % but is less than 0.5 w/v %;
a second polyol, the second polyol being selected from propylene glycol, glycerine or a combination thereof wherein the concentration of the second polyol in the composition is at least 0.3 w/v % but less than 1.2 w/v % of the composition;
borate in the composition at a concentration that is at least 0.1 w/v % but less than about 0.5 w/v %;
BAC as an anti-microbial preservative, the concentration of BAC in the composition being greater than 0.0007 w/v % but less than 0.0035 w/v %; and
water;
wherein the composition has a pH that is at least 4 but less than 7.0.
2. A composition as in claim 1 wherein the composition exhibits a log order reduction of microbial inoculum of at least 2 logs (99%) by 6 hours, 3 logs by 24 hours, and no recovery after 28 days for bacteria and a log order reduction of microbial inoculum of 2 logs (99%) by 7 days, and no increase thereafter.
3. A composition as in claim 1 wherein the concentration of the first polyol is at least 0.25 w/v % but is less than about 0.35 w/v %.
4. A composition as in claim 1 wherein concentration of the BAC is less than 0.0025 w/v % of the composition.
5. A composition as in claim 1 wherein concentration of the BAC is less than 0.0015 w/v % of the composition.
6. A composition as in claim 1 wherein the first polyol is mannitol and the second polyol is propylene glycol.
7. A composition as in claim 1 wherein the composition is substantially free of any preservatives other than benzalkonium chloride.
8. A composition as in claim 1 wherein the resistance provided by the composition to normalization of tear pH after instillation in the eye is less than 25 μl of 1 M NaOH/mL of composition.
9. A composition as in claim 1 further comprising a therapeutically effective amount of brinzolamide.
10. A composition as in claim 1 further comprising an anionic polymer.
11. A composition as in claim 10 wherein the anionic polymer is selected from xanthan gum or a carboxyvinyl polymer.
12. A composition as in claim 10 wherein the composition is a suspension with a therapeutic agent suspended in solution.
13. A composition as in claims 1 wherein the composition is free of any anti-infective or anti-biotic ophthalmic drug.
14. A composition as in claim 12 wherein the suspension is redispersed with no more than 15 seconds of vigorous shaking.
15. A multi-dose ophthalmic composition, comprising:
a therapeutically effective amount of brimonidine;
a first polyol, the first polyol being selected from mannitol, sorbitol or a combination thereof and wherein the concentration of the first polyol in the composition is at least 0.15 w/v % but no greater than 0.5 w/v %;
a second polyol, the second polyol being selected from propylene glycol, glycerine or a combination thereof wherein the concentration of the second polyol in the composition is at least about 0.3 w/v % but less than about 1.2w/v % borate in the composition at a concentration that is at least 0.1 w/v % but less than about 0.5 w/v %;
anionic polymer;
BAC as an anti-microbial preservative, the concentration of BAC in the composition being greater than 0.0007 w/v % but less than 0.0035 w/v %; and
water;
wherein the composition is free of any preservatives other than benzalkonium chloride and wherein the composition has a pH that is at least 4 but less than 7.
16. A composition as in claim 15 wherein the resistance provided by the composition to normalization of tear pH after instillation in the eye is less than 15 μl of 1 M NaOH/mL of composition.
17. A composition as in claim 15 wherein the composition is a suspension with a therapeutic agent suspended in solution and wherein the viscosity of the suspension is greater than 20 cps but less than 500 cps with the viscosity of the suspension being measured at a high shear rate of sec −1 at room temperature.
18. A composition as in claim 17 wherein the suspension is redispersed with no more than 15 seconds of vigorous shaking.
19. A composition as in claim 15 wherein the composition is free of any anti-infective or anti-biotic ophthalmic drug.
20. A composition as in claim 15 wherein the composition is configured for administration to the eye of the mammal repeatedly for an extend period of time of and is administered at least once a week and wherein the eye of the mammal has been diagnosed with an eye disorder that is suitably treated with chronic administration of the therapeutic agent.
21. A composition as in claim 20 wherein the eye disorder is elevated intraocular pressure.
22. A multi-dose ophthalmic composition, comprising:
a therapeutically effective amount of brimonidine;
mannitol at a concentration in the composition that is at least 0.15 w/v % but no greater than 0.5 w/v %;
propylene glycol at a concentration in the composition that is at least 0.3 w/v % but no greater than 1.2 w/v %;
borate in the composition at a concentration that is at least 0.25 w/v % but less than about 0.35 w/v %;
carboxyvinyl polymer at a concentration in the composition that is at least about 0.1 w/v % but less than about 1.2 w/v %;
BAC as an anti-microbial preservative, the concentration of BAC in the composition being greater than 0.0007 w/v % but less than 0.0035 w/v %; and
water;
wherein:
i. the composition is free of any preservatives other than benzalkonium chloride;
ii. the resistance provided by the composition to normalization of tear pH after instillation in the eye is less than 15 μl of 1 M NaOH/mL of composition;
iii. the composition is a suspension with a therapeutic agent agent suspended in solution;
iv. the viscosity of the suspension is greater than 20 cps but less than 500 with the viscosity of the suspension being measured at a high shear rate of sec- 1 at room temperature;
v. the composition is free of any anti-infective or anti-biotic ophthalmic drug; and
vi. the pH of the composition is at least 4 but less than 7.0.
23. A composition as in claim 22 wherein the therapeutic agent in brinzolamide.