Ophthalmic Compound Composition With pH-Tuned Glaucoma Stability
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Solution Overview
Problem
Current glaucoma treatments, particularly dual and triple compound preparations, suffer from poor therapeutic efficacy, numerous side effects, and poor patient compliance due to increased preservative exposure and incompatibility issues between Rho kinase inhibitors like netarsudil and β-adrenergic receptor blockers, leading to instability and precipitation in certain pH ranges.
Innovation Solution
A dual and triple compound ophthalmic medicine composition is developed, utilizing a salt engineering strategy to combine netarsudil with β-adrenergic receptor blockers (timolol, carteolol, betaxolol, or metipranolol) and optionally a prostaglandin analog, formulated in a boric acid-sodium borate buffer solution with pH 4.5 to 5.4 to enhance stability and reduce administration frequency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If netarsudil and β-adrenergic receptor blocker are combined in a dual compound preparation, then the therapeutic effect on reducing intra-ocular pressure is improved, but incompatibility issues arise leading to instability and precipitation in certain pH ranges
Solution Approach 1:
The patent applies parameter changes by precisely controlling the pH value of the formulation to fall within the range of 4.5 to 5.4, which is the optimal pH range where both netarsudil and β-adrenergic receptor blocker maintain stability and compatibility. This parameter optimization resolves the incompatibility issue while preserving the synergistic therapeutic effect of the combination preparation.
2Reliability
If two types of unilateral preparations are combined for use, then the intra-ocular pressure control is improved, but the administration frequency and preservative exposure increase leading to poor safety and side effects
Solution Approach 1:
The patent merges two separate unilateral preparations (netarsudil and β-adrenergic receptor blocker) into a single dual compound preparation. This combination allows patients to receive both medications through one administration, reducing the total frequency of eye drop applications and thereby decreasing cumulative preservative exposure and associated side effects, while maintaining effective intra-ocular pressure control.
3Ease of operation
If dual compound preparation is used to reduce administration frequency, then patient compliance is improved, but incompatibility between drugs leads to precipitation and instability
Solution Approach 1:
The patent resolves the compatibility issue by optimizing the pH parameter of the formulation to the specific range of 4.5 to 5.4. Within this pH range, the chemical stability of both netarsudil and β-adrenergic receptor blocker is maintained, preventing precipitation and ensuring solution stability. This parameter control enables the creation of a compatible dual compound preparation that can be administered once daily, improving patient compliance without sacrificing drug stability.
Data Source
AI summary
The present disclosure provides ophthalmic dual and triple compound medicine compositions for treating glaucoma and ocular hypertension. Through a salt modification technology, stability of the medicine compositions is improved remarkably. The dual compound medicine composition is prepared from netarsudil free alkali or pharmaceutically acceptable salts of the same and a β-adrenergic receptor blocker. The triple compound medicine composition is prepared from the netarsudil free alkali or the pharmaceutically acceptable salts of the same, the β-adrenergic receptor blocker and a prostaglandin analog. The dual and triple compound medicine compositions have excellent stability when pH is in a range from 4.5 to 5.4, an effective dose of the medicine composition of the present disclosure is applied to eyes of a patient in need once a day at bedtime or close to bedtime, an intra-ocular pressure can be reduced efficiently and quickly, the intra-ocular pressure remains in a physiological range for a longer time, side effects are minor, and patient compliance is high.