Self-Preserved Ophthalmic Compositions via Zinc-Borate Synergy
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Solution Overview
Problem
Multi-dose pharmaceutical compositions, particularly ophthalmic solutions, face challenges in maintaining sterility without conventional antimicrobial preservatives, as low concentrations may be insufficient for microbial preservation, potentially leading to infections, and high concentrations can be toxic to the cornea.
Innovation Solution
The use of very low concentrations of zinc ions in combination with borate or borate/polyol complexes, along with propylene glycol, while limiting multivalent metal cations and ionized salts, to achieve self-preservation and meet preservative efficacy standards without conventional preservatives.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antimicrobial preservatives are used at high concentrations to ensure microbial preservation, then preservative efficacy is improved, but toxicological effects on the cornea increase
Solution Approach 1:
The patent changes the concentration parameter of zinc ions to a very low range (0.0005-0.005% w/v, or 0.01-0.1 mM), which is significantly lower than conventional preservatives. This parameter change allows achieving preservative efficacy while minimizing toxicological effects on the cornea, as the low concentration reduces irritation and toxicity risks.
Solution Approach 2:
The patent creates a composite preservative system combining zinc ions with borate or borate/polyol complexes. This composite approach enhances the antimicrobial activity through synergistic interactions, allowing very low concentrations of zinc to achieve sufficient preservative efficacy while maintaining corneal safety.
2Object-affected harmful factors
If conventional antimicrobial preservatives are used at low concentrations to reduce toxicological effects, then corneal safety is improved, but preservative efficacy becomes insufficient leading to microbial contamination
Solution Approach 1:
The patent combines zinc ions with borate or borate/polyol complexes to create a composite preservative system. The borate component forms complexes with zinc ions that enhance antimicrobial activity through synergistic effects, allowing low concentrations to achieve sufficient preservative efficacy while maintaining corneal safety.
Solution Approach 2:
The patent employs multi-functional components where borate or borate/polyol complexes serve dual purposes: they act as buffering agents to maintain pH stability and simultaneously enhance the antimicrobial activity of zinc ions. This multi-functionality allows low concentrations to achieve both corneal safety and adequate preservative efficacy.
3Object-affected harmful factors
If multi-dose ophthalmic compositions are formulated without conventional preservatives to eliminate toxicity, then corneal safety is improved, but the compositions become vulnerable to microbial contamination
Solution Approach 1:
The patent creates a self-preserving system where zinc ions at very low concentrations provide intrinsic antimicrobial activity without requiring conventional preservatives. The composition serves its own preservation needs through the synergistic interaction between zinc ions and borate complexes, eliminating the need for additional preservative agents and their associated toxicities.
Solution Approach 2:
The patent formulates a composite system combining zinc ions with borate or borate/polyol complexes that provides inherent preservative efficacy. This composite approach enables the composition to resist microbial contamination without conventional preservatives, achieving both safety and efficacy requirements.
4Reliability
If zinc ion concentration is increased to enhance antimicrobial activity, then preservative efficacy is improved, but toxicological effects on the cornea increase
Solution Approach 1:
The patent combines zinc ions with borate or borate/polyol complexes to create a synergistic preservative system. The borate component enhances the antimicrobial activity of zinc ions, allowing very low concentrations (0.0005-0.005% w/v) to achieve sufficient preservative efficacy while minimizing toxicological effects on the cornea.
Solution Approach 2:
The patent optimizes the concentration parameter of zinc ions to a very low range (0.01-0.1 mM), which is significantly lower than what would be required without borate enhancement. This parameter change, combined with the synergistic borate interaction, achieves adequate antimicrobial activity while reducing toxicity and irritation risks.
Data Source
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AI summary
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.