Ophthalmic Ester Formulations With pH Buffering Against Hydrolysis
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Solution Overview
Problem
Existing pharmaceutical compositions containing ester and lactone ring structures are susceptible to chemical degradation, particularly hydrolysis, leading to increased impurities and reduced shelf-life, especially when formulated at pH ranges that optimize viscosity, and require refrigeration for stability.
Innovation Solution
The use of Lewis acids like MgCl2 and CaCl2, controlled pH levels between 3.0 and 7.8, and combinations of buffers and stabilizers such as citrate, ascorbic acid, and lactic acid to stabilize ester and lactone rings, along with optimized compounding processes, including post-neutralization, to maintain chemical and physical stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Shape
If pH is adjusted to optimize viscosity (higher pH), then physical properties are improved, but chemical stability deteriorates due to increased hydrolysis
Solution Approach 1:
The patent applies parameter changes by carefully controlling pH within a specific range (3.0-7.8) and using buffer systems to maintain optimal conditions. The formulation uses phosphate buffer at pH 7.4 or citrate buffer at pH 3.0-6.0 to balance viscosity requirements with chemical stability, preventing hydrolysis while maintaining physical properties.
Solution Approach 2:
The patent introduces buffer systems (phosphate buffer, citrate buffer) as intermediary substances that mediate between the conflicting requirements of viscosity optimization and chemical stability. These buffers act as intermediaries to control the pH environment, preventing direct adverse interactions while maintaining both physical and chemical properties.
2Stability of the object's composition
If refrigeration is used to maintain stability, then chemical stability is improved, but storage complexity and cost increase
Solution Approach 1:
The patent applies preliminary action by incorporating stabilizing agents and optimizing formulation conditions during the manufacturing process to prevent degradation before it occurs. By pre-establishing protective measures such as adding stabilizers and controlling pH during formulation, the patent eliminates the need for refrigeration during storage, thereby reducing storage complexity while maintaining stability.
3Reliability
If ester and lactone ring structures are used for pharmaceutical activity, then therapeutic efficacy is improved, but susceptibility to hydrolysis increases
Solution Approach 1:
The patent converts the harmful effect of hydrolysis susceptibility into a beneficial controlled degradation mechanism. By using ester and lactone ring structures that are inherently more reactive and thus more susceptible to controlled hydrolysis, the patent achieves enhanced therapeutic efficacy while managing stability through pH control and stabilizer addition to prevent uncontrolled degradation.
Solution Approach 2:
The patent applies parameter changes by optimizing pH to specific ranges (3.0-7.8) and using buffer systems to control the chemical environment. This prevents excessive hydrolysis while maintaining the reactivity needed for therapeutic activity, thereby balancing efficacy with stability through precise parameter control.
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 compositions achieve greater than 99% retention of activity over two years at room temperature, reducing impurities and extending shelf-life without refrigeration, while maintaining desirable viscosity and physical properties.
Implementation Method 1
The use of Lewis acids like MgCl2 and CaCl2, controlled pH levels between 3.0 and 7.8, and combinations of buffers and stabilizers such as citrate, ascorbic acid, and lactic acid to stabilize ester and lactone rings
Implementation Method 2
The buffer can be a citrate buffer, acetate buffer, a glycolic acid buffer, a borate buffer, or a combination thereof
Implementation Method 3
selection of charged low molecular weight peptides or amino acids (i.e. arginine, lysine, or histidine) or acidic amino acids (i.e. glutamate and aspartate) that can be used alone, or in combination with buffers to maintain high product quality and desirable physical stability and chemical stability
Implementation Method 4
selection of pH buffers that can be used alone, as dual buffers, or as triple buffers to maintain high product quality and desirable physical and chemical stability are described
Data Source
AI summary
Described herein are formulations including pharmaceutical agents comprising ester and/or lactone ring structures, and methods of using the same. The invention is also directed to a method and ophthalmic pharmaceutical compositions including solution and semisolid dosage forms (i.e. ophthalmic creams, gels, lotions, serums, and/or ointments) of treating a patient with various ocular diseases including presbyopia and dry eyes. The method comprising instructing a patient to apply one strip of the ophthalmic composition to the eyelids that includes pilocarpine or other active pharmaceutical ingredients containing ester and/or lactone ring structures with and without the buffering system.