Self preserved aqueous pharmaceutical compositions

A technology of composition and ophthalmic composition, applied in the field of actic, can solve problems such as blindness and loss of visual function

Active Publication Date: 2009-08-26
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This is also a serious problem because eye infections caused by Pseudomonas aeruginosa

Method used

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  • Self preserved aqueous pharmaceutical compositions
  • Self preserved aqueous pharmaceutical compositions
  • Self preserved aqueous pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A-E

[0091] The formulations of Examples A-E were evaluated to determine the effect of buffer anions on preservative efficacy. As detailed below, the formulations of Examples A and B contained no buffer. Although these formulations meet USP preservative efficacy requirements, the presence of a buffering system is still highly desirable in order to prevent pH excursions over the shelf life of the commercial product (ie, up to two years or more). The formulation of Example C contained a borate / polyol buffer system, but this system had minimal buffer capacity. As with the formulations of Examples A and B, the formulation of Example C met the USP requirements. The formulations of Examples D and E contained significantly higher concentrations of buffer and thus had greater buffer capacity. However, the presence of relatively large amounts of buffer anions renders the formulations unsatisfactory for preservative efficacy. Thus, the comparison of Examples A-E illustrates the necessary ...

Embodiment F-J

[0099] In these examples, the amount of sorbitol was reduced to 1% while the concentration of boric acid was maintained at 1% to reduce the concentration of buffer anions. In addition, Examples G, I and J contained 0.75% propylene glycol. The anion buffer concentration in all 5 examples was about 19 mM.

[0100] The compositions of Examples F and G contained 0.18 mM zinc. It has much higher activity against Staphylococcus aureus than the formulations of Examples D and E above. In particular, the compositions of Examples F and G meet USP preservation standards for Staphylococcus aureus. However, although the antibacterial activity against Escherichia coli was improved compared with Examples D and E at zinc ion concentrations of 0.18 mM (Examples F and G) and 0.36 mM (Examples H and I), it was 14 days is not sufficient to consistently meet USP corrosion protection standards. Increasing the zinc concentration to 1.8 mM (Example J) improved the antibacterial activity of the so...

Embodiment K-N

[0106] In these examples, the level of sorbitol was reduced to 0.25%, while the concentration of boric acid was kept at 1% to reduce the concentration of buffer anions. Additionally, the compositions of Examples L-N contained 0.75% propylene glycol. The formulations of Examples K and L had an anion buffer concentration of about 4 mM, which is within the preferred range of less than 5 mM described herein. The anti-E. coli activity of these compositions was significantly improved at a zinc concentration of 0.18 mM (0.0025 w / v %) relative to the formulations of Examples F-J, and the compositions met USP preservative standards. In Examples M and N, the pH was adjusted to 5.5 and 6.5, respectively, while maintaining USP preservative efficacy. The results obtained for a representative composition of the invention, the formulations of Examples K-N, further demonstrate the importance of limiting buffer anion concentrations to meet preservative efficacy requirements.

[0107]

[0...

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PUM

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Abstract

The present invention is directed to the provision of multi-dose, self-preserved 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), without requiring the presence of conventional anti-microbial preservative agents, such as benzalkonium chloride. The compositions are effectively preserved by a balanced ionic buffer system containing zinc ions at a concentration of 0.04 to 0.9 mM, preferably 0.04 to 0.4 mM. One aspect of the balanced buffer system is limitation of the amount of buffering anions present to a concentration of 15 mM or less, preferably 5 mM or less. In a preferred embodiment, the compositions also contain borate or, most preferably, one or more borate/polyol complexes. The use of propylene glycol as the polyol in such complexes is strongly preferred. Limiting the amount of divalent metals other than zinc and the amount of ionized salts present has also been determined to be important to maximize the antimicrobial activity of the balanced buffer systems.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial Nos. 60 / 827,411 and 60 / 826,529, filed September 28, 2006 and September 21, 2006, respectively. Background of the invention [0003] The present invention relates to self-preserved (self-preserved) pharmaceutical compositions, and more particularly, the present invention relates to providing aqueous multi-dose pharmaceutical compositions formulated to have sufficient antimicrobial activity to meet United States Pharmacopoeia (USP) and other Preservative efficacy requirements of similar national guidelines, the pharmaceutical composition does not require conventional antimicrobial preservatives such as benzalkonium chloride, polyquaternium-1, hydrogen peroxide (eg sodium perborate) or chlorine-containing agents. This self-preserving capability is based on the unique combination and standardization of formulation ingredients. [0004] Many pharma...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K47/02A61K47/10A61K47/26
Inventor B·P·卡布拉M·A·乔罕L·W·施内德尔韩维新
Owner NOVARTIS AG
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