Brinzolamide Ophthalmic Formulation Autoclaving Stability
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Solution Overview
Problem
Existing ophthalmic formulations of brinzolamide face challenges with crystallization and agglomeration during preparation and storage, leading to non-uniform dosing, eye irritation, and reduced bioavailability due to its low solubility and crystalline form, which are difficult to manage with conventional sterilization methods that introduce degradation products or require costly equipment like ball mills.
Innovation Solution
A sterile, ophthalmic pharmaceutical formulation is developed using brinzolamide in combination with Soluplus® and polysorbate 80, where the drug is solubilized or remains in a partially amorphous form after autoclaving or heating above 50°C, eliminating the need for equipment like ball mills and enhancing bioavailability and manufacturability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autoclaving is used to sterilize brinzolamide suspension, then sterilization is achieved, but brinzolamide recrystallizes as large needle-shaped crystals upon cooling
Solution Approach 1:
The patent applies preliminary action by adding surfactants (tyloxapol or Triton X) to the brinzolamide slurry before autoclaving. These surfactants pre-condition the system to prevent unwanted crystal formation during the sterilization process, eliminating the need for subsequent ball milling to break down large needles.
Solution Approach 2:
The patent changes the physical-chemical parameters of the system by introducing surfactants that alter the surface properties and crystal growth behavior of brinzolamide. This parameter change prevents the formation of large needle-shaped crystals during autoclaving and cooling, resulting in a stable suspension without requiring mechanical size reduction.
2Length of moving object
If ball milling is used to reduce crystal size, then particle size is reduced, but equipment complexity and manufacturing cost increase
Solution Approach 1:
The patent extracts the problematic crystal formation step by using surfactants to prevent needle crystal formation in the first place. This eliminates the need for the separate ball milling operation, removing the associated equipment complexity and manufacturing steps while still achieving the desired fine particle size distribution.
3Reliability
If conventional sterilization methods are used, then sterilization is achieved, but degradation products are introduced
Solution Approach 1:
The patent converts the potentially harmful effect of heat-induced crystal formation into a benefit by using surfactants to control crystal growth. The same autoclaving process that previously caused problematic needle formation now produces a stable, fine-suspended formulation without degradation products, as the surfactants protect the drug molecules throughout the sterilization process.
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 significantly improved bioavailability and manufacturability by maintaining brinzolamide in a solubilized or amorphous form, reducing the effective dose and avoiding equipment-dependent processing, while ensuring stability and effectiveness in treating elevated intraocular pressure.
Implementation Method 1
the active ingredient with low aqueous solubility (such as brinzolamide) in combination with polymers like Soluplus® and a surfactant like polysorbate 80, is either autoclaved or dissolved after heating above 50° C. Upon cooling, the active ingredient brinzolamide does not precipitate and stays in solution or in a partially amorphous form.
Implementation Method 2
pharmaceutical composition comprising of the stabilized amorphous form of poorly insoluble drugs/active ingredient(s) which resulted in significantly enhanced dissolution and bioavailability over the crystalline form of the compound
Implementation Method 3
conventional sterilization methods cannot be employed in the manufacture of suspensions comprising brinzolamide since the compound recrystallizes as large needle-shaped crystals, upon cooling, after autoclaving.
Implementation Method 4
EP0941094 discloses a process for making brinzolamide suspension by autoclaving of concentrated slurry of brinzolamide and tyloxapol; or brinzolamide and Triton X in milling bottle, and ball milling of the hot slurry after autoclaving
Data Source
AI summary
A sterile aqueous formulation of a carbonic anhydrase inhibitor such as brinzolamide in combination with polymers like Soluplus® and a surfactant like polysorbate 80, as well as methods of preparation thereof, is disclosed. The formulation relates to the highly solubilized or an amorphous form of poorly insoluble drugs/active ingredient(s) to improve its bio-availability and manufacturability.