Cyclodextrin Salt Formulations for Solubility With Lower Osmolality
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Solution Overview
Problem
Pharmaceutical compounds with basic amines, such as rotigotine, eletriptan, copanlisib, and others, face challenges in formulation due to limited solubility, hydrophobicity, and ionic properties, making widespread use difficult.
Innovation Solution
Formulating pharmaceutical compositions using complexing agents like acid-substituted cyclodextrins, specifically sulfobutylether-β-cyclodextrin, at molar ratios of 1:1 to 1:4, to form salts with these compounds, enhancing solubility and reducing osmolality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional salt formulations are used to improve solubility, then solubility is improved, but osmolality increases and tissue irritation occurs
Solution Approach 1:
The patent uses complexing agents (cyclodextrins, hydroxypropylbeta-cyclodextrin, sulfobutyletherbeta-cyclodextrin) as intermediary substances to form inclusion complexes with the pharmaceutical compound. This mediator approach allows the drug to be solubilized without forming traditional high-osmolality salts, thereby reducing tissue irritation while maintaining improved solubility
Solution Approach 2:
The invention creates composite formulations consisting of the pharmaceutical compound combined with complexing agents in specific molar ratios (1:1 to 1:4). This composite material approach enables simultaneous achievement of enhanced solubility and reduced osmolality, eliminating the trade-off present in conventional salt formulations
2Quantity of substance
If complexing agents are used at high molar ratios to improve solubility, then solubility is improved, but formulation complexity increases
Solution Approach 1:
The patent optimizes the complexing agent to pharmaceutical compound molar ratio to a specific range (1:1 to 1:4), using only the necessary amount of complexing agent to achieve maximum solubility improvement. This avoids excessive use that would increase formulation complexity unnecessarily, while still achieving the desired solubility enhancement
Solution Approach 2:
The invention systematically optimizes key parameters including the molar ratio of complexing agent to pharmaceutical compound (1:1 to 1:4), pH range (4-7), and complexing agent concentration (10-600 mg/mL). By controlling these parameters within specific ranges, the formulation achieves improved solubility while maintaining manageable complexity
3Reliability
If traditional salt forms are used to enhance bioavailability, then bioavailability is improved, but hydrophobicity and solubility limitations persist
Solution Approach 1:
The complexing agents act as mediators that form inclusion complexes with the hydrophobic pharmaceutical compound, providing a hydrophilic exterior that enhances solubility while protecting the hydrophobic interior. This mediator approach improves both solubility and bioavailability simultaneously, overcoming the limitations of traditional salt forms
Solution Approach 2:
The invention changes the physical-chemical parameters of the pharmaceutical compound by forming inclusion complexes, which alters the solubility profile and enhances bioavailability. The specific molar ratios (1:1 to 1:4) and pH control (4-7) optimize these parameter changes to achieve both improved solubility and bioavailability
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 exhibit improved solubility, reduced osmolality, and lower irritant effects, facilitating subcutaneous, intramuscular, sublingual, oral, rectal, transvaginal, or intranasal administration with enhanced bioavailability and reduced tissue irritation.
Implementation Method 1
the plurality of acidic functional groups comprise an acidic group which acts as a counterion for the protonated nitrogen atom of the pharmaceutical compound
Implementation Method 2
a complexing agent, wherein the complexing agent is an acid-substituted cyclodextrin comprising a plurality of acidic functional groups
Data Source
AI summary
Provided herein are pharmaceutical formulations and pharmaceutical compound salts which utilize complexing agents as counterions. Such formulations and salts are useful for treating a variety of disease and disorders.