Midazolam Buccal Composition pH and Cyclodextrin Optimization
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Solution Overview
Problem
Current midazolam formulations have low solubility at higher pH levels, limiting the proportion of the lipophilic closed ring form, which slows absorption and delays therapeutic onset, and existing mucosal administration methods are either ineffective or cause discomfort.
Innovation Solution
A liquid pharmaceutical composition with a pH of 6 or higher, containing less than 200 mg/ml cyclodextrin, ensuring at least 50% of midazolam is in the closed ring form, suitable for buccal, nasal, and sub-lingual administration, with a viscosity of 200-400 CP to enhance absorption and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If the pH of midazolam formulation is increased to enhance closed ring form, then the proportion of lipophilic closed ring form increases, but the solubility of midazolam decreases
Solution Approach 1:
The patent applies parameter changes by carefully adjusting the pH of the formulation to a specific range (pH 6.0-8.0) where midazolam maintains both high solubility and a high proportion of closed ring form. This optimal pH range resolves the contradiction by finding the sweet spot where both solubility and closed ring form proportion are maximized, rather than simply increasing pH without limit.
Solution Approach 2:
The patent uses a composite carrier system comprising multiple components including glycerol, polyethylene glycol, and other excipients in specific ratios. This composite formulation enhances midazolam solubility at higher pH levels while maintaining the desired closed ring form proportion, resolving the solubility-pH contradiction through synergistic interactions among the carrier components.
2Quantity of substance
If cyclodextrin is used to improve solubility at higher pH, then solubility increases, but the release of midazolam from cyclodextrin complexes is slow
Solution Approach 1:
The patent limits cyclodextrin concentration to less than 200 mg/ml and optimizes the pH range to balance solubility enhancement with rapid release kinetics. By controlling these parameters, the formulation achieves sufficient solubility without the severe release delay that would occur at higher cyclodextrin concentrations, resolving the solubility-release rate contradiction.
Solution Approach 2:
The patent uses a sub-optimal amount of cyclodextrin (less than 200 mg/ml rather than higher concentrations that would maximize solubility) to achieve sufficient solubility enhancement while avoiding the excessive complexation that would cause slow release. This partial action resolves the contradiction by accepting moderate solubility improvement in exchange for maintaining rapid release kinetics.
3Quantity of substance
If pH is kept low to maintain solubility, then solubility is sufficient, but the proportion of open ring form increases reducing efficacy
Solution Approach 1:
The patent changes the pH parameter from traditional low pH (2.8-3.6) to an elevated range (pH 6.0-8.0), fundamentally altering the formulation's properties. This parameter change simultaneously maintains adequate solubility through the composite carrier system while dramatically increasing the proportion of closed ring form, thereby resolving the solubility-closed ring form contradiction.
4Quantity of substance
If volume of carrier liquid is reduced to deliver effective dose, then dosing precision improves, but solubility requirements increase
Solution Approach 1:
The patent employs a composite carrier system with multiple excipients (glycerol, polyethylene glycol, and others) in optimized ratios that collectively provide enhanced solubility capacity. This composite approach allows the formulation to maintain high midazolam concentration (improving dosing precision) while satisfying the increased solubility requirements through synergistic interactions among the carrier components.
Solution Approach 2:
By changing the pH parameter to the optimized range of pH 6.0-8.0 and adjusting the carrier composition parameters, the patent increases the solubility capacity of the formulation. This enables the delivery of therapeutically effective doses in smaller volumes without compromising solubility, thereby resolving the concentration-solubility contradiction.
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 composition achieves rapid therapeutic onset, improved stability, and reduced impurity formation, making it suitable for quick absorption through mucosal membranes without causing discomfort, particularly beneficial for treating epileptic seizures and pain.
Implementation Method 1
WO01/30391 provides an example of an attempt to formulate midazolam at a higher pH while circumventing the problem of reduced solubility. This is achieved by the use of cyclodextrin, which forms an inclusion complex with midazolam, retaining it in solution.
Implementation Method 2
The composition achieves rapid therapeutic onset, improved stability, and reduced impurity formation, making it suitable for quick absorption through mucosal membranes without causing discomfort
Data Source
AI summary
This application discloses liquid compositions for administration to a patient comprising midazolam and a pharmaceutically acceptable carrier, wherein the pH of the composition is about 6 or higher, the composition comprises less than about 200 mg/ml cyclodextrin, and at least about 50% of the midazolam is present in solution. Uses of these compositions are also disclosed.