Roflumilast Ophthalmic Formulation for pH and Particle Stability
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Solution Overview
Problem
There is a need for stable and effective ophthalmic formulations of roflumilast that can be manufactured under sterile conditions while maintaining optimal potency, particle size distribution, and stability, addressing challenges such as poor tolerability, patient compliance, and sensitivity to active and inactive ingredients in existing ocular drugs.
Innovation Solution
The formulation includes a viscosity agent, surfactant, and buffer, with a pH range of 6.0 to 6.7, and methods involving sterilization techniques like dry heat or gamma radiation to create a stable suspension with particle sizes less than 10 μm, ensuring sterility and reducing hydrolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If roflumilast is formulated for ophthalmic delivery at tolerable pH, then patient tolerability is improved, but solubility and stability deteriorate due to extremely low solubility at target pH
Solution Approach 1:
The patent adjusts the pH of the ophthalmic formulation to a specific range (pH 6.0-6.7) to balance patient tolerability with drug solubility and stability. This parameter optimization allows the formulation to maintain roflumilast in a stable state while remaining tolerable for ocular administration, resolving the contradiction between tolerability and stability.
Solution Approach 2:
The patent introduces specific excipients and formulation components that act as intermediaries to enhance roflumilast solubility and stability at the target pH. These intermediaries facilitate drug delivery by improving the physicochemical properties of the formulation without compromising patient tolerability.
2Reliability
If sterile manufacturing conditions are implemented, then product safety is improved, but manufacturing complexity and cost increase
Solution Approach 1:
The patent employs pre-sterilization of individual components before final formulation assembly. This preliminary action allows each excipient and active ingredient to be sterilized separately under controlled conditions, then combined in a sterile environment, thereby ensuring product safety while managing manufacturing complexity through staged processing.
3Productivity
If particle size is reduced to less than 10 μm for effective ocular delivery, then delivery efficacy is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent employs multi-stage milling and classification processes with periodic intervention to achieve and maintain particle sizes less than 10 μm. This periodic action allows for incremental size reduction with intermediate screening and control steps, improving delivery efficacy while managing manufacturing precision requirements through staged processing.
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 reduced hydrolysis rates, maintains potency, and ensures sterility, providing a stable and effective ophthalmic delivery system for roflumilast.
Implementation Method 1
The inventors have identified that roflumilast undergoes hydrolysis at low potencies in certain ophthalmic pharmaceutical compositions. The inventors have discovered the ophthalmic pharmaceutical compositions of the present invention can reduce the rate of hydrolysis. In certain embodiments, the pH of the ophthalmic pharmaceutical compositions is between about 6.0 and 6.7, which can reduce the rate of hydrolysis of roflumilast, thereby minimizing the rate of other substances in the agent, and enhancing product purity and potency.
Implementation Method 2
methods involving sterilization techniques like dry heat or gamma radiation to create a stable suspension with particle sizes less than 10 μm, ensuring sterility and reducing hydrolysis
Data Source
AI summary
The present invention relates to stable, ophthalmic pharmaceutical formulations of the phosphodiesterase-4 inhibitor, roflumilast, and methods of making the same. Novel ophthalmic pharmaceutical formulations of roflumilast can comprise a viscosity agent, a surfactant, and a buffer. In preferred embodiments, the pH of the ophthalmic pharmaceutical composition is between 6.0 and 6.7. Methods of making stable, ophthalmic pharmaceutical formulations of roflumilast can include separate active and inactive ingredient processes. Further, the methods can include clarity filtration to mitigate particle size aggregation and to create an optimized suspension. Further, the methods can include terminal sterilization of the final drug product.