Etherified Cyclodextrin Liquid Compositions for Preservative Compatibility
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing pharmaceutical compositions containing cyclodextrins face challenges in preserving against microbial growth due to preservative-cyclodextrin complex formation, which reduces preservative effectiveness and solubility of active drugs, particularly for poorly soluble compounds like pimobendan, making multiple-dose oral formulations unsuitable.
Innovation Solution
A preserved liquid aqueous pharmaceutical composition using etherified cyclodextrin derivatives in combination with water-soluble preservatives, such as sorbic acid, and optionally antioxidants and polymers, maintains preservative efficacy while enhancing solubility of poorly soluble drugs like pimobendan, suitable for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If typical preservatives are used in cyclodextrin-containing compositions, then microbial preservation is attempted, but preservative effectiveness is reduced due to complex formation between preservative and cyclodextrin
Solution Approach 1:
The patent extracts the problematic interaction by removing the preservative from the cyclodextrin inclusion complex environment. By formulating the preservative to remain outside the cyclodextrin cavity rather than being included within it, the preservative maintains its full antimicrobial activity without being sequestered by complex formation.
Solution Approach 2:
The patent changes the chemical parameters of the preservative system by selecting preservatives with specific properties that prevent inclusion complex formation with cyclodextrin. This parameter change ensures the preservative remains in its free, active form while the cyclodextrin maintains its solubilization function.
2Reliability
If typical preservatives are used in cyclodextrin-containing compositions, then microbial preservation is attempted, but solubility of active drug substance is reduced
Solution Approach 1:
The patent extracts the preservative from the drug-cyclodextrin inclusion complex system, preventing it from interfering with drug solubility. By positioning the preservative outside the complexation system, both the drug's solubility enhancement by cyclodextrin and the preservative's antimicrobial function are maintained without mutual interference.
Solution Approach 2:
The patent segments the formulation system into distinct functional zones: the cyclodextrin-drug inclusion complex for solubility enhancement, and the free preservative molecules for antimicrobial protection. This segmentation prevents unwanted interactions while maintaining both functions.
3Quantity of substance
If cyclodextrin concentration is increased to improve solubilization, then solubility of poorly soluble drugs is enhanced, but formation of aggregates and self-assembled complexes increases
Solution Approach 1:
The patent introduces specific excipients that act as intermediaries to stabilize the cyclodextrin-drug complex system at higher concentrations. These intermediary substances prevent cyclodextrin self-association and aggregate formation, allowing the formulation to maintain drug solubility enhancement without the detrimental effects of aggregation.
Solution Approach 2:
The patent creates a composite formulation system combining cyclodextrin, drug substance, and stabilizing excipients in specific ratios. This composite approach leverages the synergistic effects of multiple components to maintain solubility enhancement while preventing aggregate formation through the stabilizing influence of the excipient matrix.
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 effective microbial preservation and acceptable drug solubility, allowing oral administration without inflammation risks, improving palatability and stability, and avoiding the need for veterinary administration.
Implementation Method 1
cyclodextrins in aqueous solution form inclusion complexes with water-insoluble or poorly soluble drugs by taking up the lipophilic moiety of the drug molecule into the cavity of the cyclodextrin, which is hydrophobic
Implementation Method 2
Certain etherified β-cyclodextrin derivatives are known to improve solubility of sparingly soluble drugs
Data Source
AI summary
A preserved liquid aqueous pharmaceutical composition includes one or more etherified cyclodextrin derivatives, at least one water-soluble preservative, and at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble. The liquid aqueous pharmaceutical composition provides an acceptable solubility of the pharmaceutically active compound, such as pimobendan, in aqueous solution whereby the water-soluble preservatives retain their effectiveness in the presence of the etherified cyclodextrin derivatives allowing the use in an oral administration form.