Brimonidine Tartrate Ophthalmic Solution pH and Preservative Optimization
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Solution Overview
Problem
Brimonidine tartrate's efficacy is reduced at higher pH due to ionization, leading to poor ocular permeability, and existing preservatives like benzalkonium chloride can be irritating and incompatible with brimonidine, necessitating a more effective and stable ophthalmic formulation.
Innovation Solution
An aqueous ophthalmic composition comprising brimonidine tartrate, hydroxypropyl methylcellulose, and benzododecinium bromide, without anionic cellulosic polymers, at a pH less than 6.5, which enhances drug penetration and stability while using a non-irritating preservative.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the pH of the ophthalmic composition is increased to reduce brimonidine ionization, then ocular permeability is improved, but drug stability and solubility are compromised
Solution Approach 1:
The patent optimizes the pH parameter to a specific range (5.5-6.5) that balances brimonidine ionization state for adequate permeability while maintaining drug stability and solubility. This parameter optimization resolves the contradiction by finding the optimal operating point rather than maximizing one extreme.
Solution Approach 2:
The formulation combines brimonidine tartrate with hydroxypropyl methylcellulose (a non-ionic cellulose derivative) as an adjuvant. This composite formulation enhances ocular permeability through mechanisms that do not require high pH, thereby maintaining drug stability while achieving the desired permeability effect.
2Reliability
If conventional preservatives like benzalkonium chloride are used, then preservation is effective, but ocular irritation and drug incompatibility occur
Solution Approach 1:
The patent removes benzalkonium chloride and other conventional preservatives from the formulation. By eliminating these harmful preservatives entirely, the formulation achieves preservation through alternative means (likely the hydroxypropyl methylcellulose matrix and optimized pH environment) without causing ocular irritation or drug incompatibility.
Solution Approach 2:
Hydroxypropyl methylcellulose serves as an intermediary substance that provides both viscosity enhancement and preservation properties. This non-ionic polymer creates a protective environment that maintains drug stability and provides preservative action without the irritating effects of conventional preservatives.
3Quantity of substance
If brimonidine is formulated at lower pH to enhance solubility, then solubility is improved, but ocular permeability is reduced due to increased ionization
Solution Approach 1:
The patent formulates brimonidine tartrate with hydroxypropyl methylcellulose as a composite system. The non-ionic cellulose derivative acts as an adjuvant that enhances ocular permeability through mechanisms independent of pH-dependent ionization, allowing the formulation to maintain low pH for solubility while achieving adequate permeability through the composite effect.
Solution Approach 2:
Hydroxypropyl methylcellulose acts as an intermediary that facilitates drug delivery across the ocular barrier. This polymer creates a vehicle that carries the ionized brimonidine molecule across the cornea through mechanisms that do not depend on the drug's ionization state, thereby resolving the solubility-permeability trade-off.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulation achieves statistically significant intraocular pressure lowering efficacy comparable to Alphagan® P, with improved stability and reduced irritation, demonstrating effective drug delivery and prolonged action.
Implementation Method 1
Without being bound by theory, it is believed that such a polymer reduces the surface tension to around 0.045 N/m (45 dynes/cm) from about 0.072 N/m (72 dynes/cm), thereby helping to spread the drop more effectively around the ocular surface.
Implementation Method 2
Moreover, due to its viscosity, it is believed to increase retention of the drop in eye.
Implementation Method 3
wherein the preservative is benzododecinium bromide
Data Source
AI summary
The present invention provides an aqueous ophthalmic composition comprising an alpha-2 adrenergic receptor agonist and a non-ionic cellulosic polymer, the solution having a pH less than 6.5. The present invention also provides an aqueous ophthalmic composition comprising an alpha-2 adrenergic receptor agonist and a benzododecinium halide. Also provided are methods of manufacture, use and method of reducing intraocular pressure in the patient in need thereof.