Macrolide Inclusion Complexes with Gamma Cyclodextrin

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Solution Overview

Problem

Macrolides such as Rapamycin and its derivatives have poor aqueous solubility and stability, leading to degradation and reduced bioavailability, which is not effectively addressed by existing formulations that use polymeric matrices or cyclodextrins, especially when in amorphous or finely micronized forms.

Innovation Solution

Formation of inclusion complexes with gamma cyclodextrin, which increases stability and solubility without using organic solvents, allowing for the creation of stable aqueous solutions and formulations for oral, ophthalmic, topical, and parenteral use, including immunosuppressive agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If macrolides are used in amorphous or finely micronized forms to increase solubility, then solubility is improved, but stability deteriorates due to oxidative degradation

Engineering Contradiction:

ImprovesolubilityVSAvoidstability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The macrolide molecule is nested within the hydrophobic cavity of gamma-cyclodextrin, forming an inclusion complex. This nesting protects the macrolide from oxidative degradation while the outer hydrophilic surface of cyclodextrin enhances solubility. The guest-host inclusion structure simultaneously addresses both solubility and stability requirements.

Inventive Principle:

Principle #7Nested doll (Nesting)

Solution Approach 2:

Gamma-cyclodextrin acts as an intermediary between the hydrophobic macrolide and the aqueous environment. It provides a protective microenvironment that prevents direct contact between the macrolide and oxidizing agents, while its hydrophilic exterior facilitates interaction with water, thereby resolving the contradiction between solubility enhancement and stability maintenance.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If polymeric matrices are used to stabilize macrolides, then stability is improved, but water solubility deteriorates due to poor solubility of the polymers

Engineering Contradiction:

ImprovestabilityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

Instead of using polymeric matrices with poor water solubility, the invention changes the stabilizing agent to gamma-cyclodextrin, which has superior water solubility properties. This parameter change in the stabilizing agent's chemical structure (from synthetic polymer to cyclic oligosaccharide) simultaneously maintains stability while dramatically improving water solubility.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If alpha or beta cyclodextrins are used to form inclusion complexes, then some stability improvement is achieved, but solubility enhancement is insufficient compared to gamma cyclodextrin

Engineering Contradiction:

ImprovestabilityVSAvoidsolubility enhancement

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The invention selects gamma-cyclodextrin specifically because its cavity size and hydrophobicity provide optimal local quality for accommodating macrolide molecules. The larger cavity of gamma-cyclodextrin compared to alpha or beta variants provides better fit and interaction, resulting in superior solubility enhancement while maintaining stability.

Inventive Principle:

Principle #3Local quality

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 gamma cyclodextrin complexes significantly enhance the stability and solubility of macrolides, preventing degradation and maintaining bioavailability, as evidenced by increased chromatographic purity and solubility data, with gamma cyclodextrin showing superior performance compared to alpha and beta cyclodextrins.

Implementation Method 1

Formation of inclusion complexes with gamma cyclodextrin, which increases stability and solubility

Methodology Applied

Scientific EffectInclusion complex formation: Absorption (physical)

Data Source

PatentUS9169269B2Water-soluble solid pharmaceutical inclusion complexes and their aqueous solutions for oral, ophthalmic, topical or parenteral use containing a macrolide and certain cyclodextrins

Publication Date: 2015.10.27 AMRI ITAL SRL

AI summary

This invention relates to new water-soluble solid pharmaceutical inclusion complexes and their aqueous solutions for oral, ophthalmic, topical or parenteral use containing a macrolide and certain cyclodextrins.More particularly the invention relates to new water-soluble solid pharmaceutical inclusion complexes and their solutions in aqueous solvents, said compositions containinga) as an active ingredient a macrolide such as Rapamycin, Pimecrolimus, Temsirolimus, Everolimus or Tacrolimus in an amorphous form and optionally in the form of their polymorphic hydrates or solvates e.g. solvates formed with acetone or ethanol.b) a large surface cyclodextrin, such as gamma cyclodextrin—whereby the weight ratio of said macrolide to said cyclodextrin ranges between 1:111 and 1:333.