Tigecycline Composition Stabilization via Maltose

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Solution Overview

Problem

Tigecycline undergoes significant degradation through epimerization pathways, particularly at lower pH levels, which existing stabilizers like lactose monohydrate do not fully address, necessitating a more effective stabilizing agent and process for maintaining stability in pharmaceutical compositions.

Innovation Solution

A stable lyophilized pharmaceutical composition comprising Tigecycline and maltose, where the pH is maintained between 3 and 6, preferably 4.3 to 4.9, using a process involving water for injection, inert gas sparging, and lyophilization, with maltose as the primary stabilizing agent to control degradation and keep 4-epimer levels below 3% throughout the shelf life.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If lactose monohydrate is used as stabilizer to control epimerization degradation, then stability against epimerization is improved, but oxidative degradation control is insufficient

Engineering Contradiction:

Improvestability against epimerizationVSAvoidoxidative degradation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines lactose monohydrate with antioxidants (sodium metabisulfite, sodium bisulfite, or sodium sulfite) to create a composite stabilizing system. This composite approach addresses both epimerization (through lactose) and oxidative degradation (through antioxidants), resolving the limitation of using lactose alone.

Inventive Principle:

Principle #40Composite materials

2Reliability

If pH is lowered to control oxidative degradation, then oxidative stability is improved, but epimerization degradation increases

Engineering Contradiction:

Improveoxidative stabilityVSAvoidepimerization degradation

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

Antioxidants serve as intermediary substances that protect tigecycline from oxidative degradation without requiring pH reduction. This allows the pH to be maintained in a range that minimizes epimerization while still providing oxidative protection through the antioxidant mediator.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If oxygen level is reduced to control oxidative degradation, then oxidative stability is improved, but manufacturing complexity increases

Engineering Contradiction:

Improveoxidative stabilityVSAvoidmanufacturing process complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses inexpensive, readily available antioxidants (sodium metabisulfite, sodium bisulfite, or sodium sulfite) that can be easily added during manufacturing. This approach is simpler and more cost-effective than implementing complex oxygen control systems, while achieving comparable oxidative protection.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

4Reliability

If edetate is used to provide stability, then overall stability is improved, but specificity against epimerization is insufficient

Engineering Contradiction:

Improveoverall stabilityVSAvoidcontrol over epimerization

Core Design Contradiction:

ReliabilityVSManufacturing precision

Solution Approach 1:

The patent employs lactose monohydrate specifically targeted at controlling epimerization through its interaction with tigecycline at the molecular level. This provides localized, specific protection against epimerization, while antioxidants provide broader protection against oxidative degradation, creating differentiated stabilization for different degradation pathways.

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 composition achieves stability and reduces 4-epimer levels of Tigecycline to less than 3%, ensuring the pharmaceutical's efficacy and shelf life, as demonstrated by stability studies at various temperatures and humidity levels.

Implementation Method 1

Tigecycline undergoes degradation by two different pathways. One of them is oxidative degradation and another one is epimerization.

Methodology Applied

Scientific EffectEpimerization:

Implementation Method 2

Oxidative degradation can be controlled by lowering pH of the composition. At lower pH, epimerization emerges as the most predominant degradation pathway.

Methodology Applied

Scientific EffectOxidation: Oxidation

Implementation Method 3

Tigecycline is currently marked as TYGACIL® by Wyeth; which contains Tigecycline as active ingredient and lactose monohydrate as inactive ingredient.

Methodology Applied

Scientific EffectFreeze drying: Freeze Drying

Data Source

PatentEP2978426B1Stable tigecycline composition

Publication Date: 2019.11.13 INTAS PHARM LTD

AI summary

The present invention relates to a stable pharmaceutical composition of Tigecycline and process for the preparation of the same. The composition comprises Tigecycline and maltose wherein the pH of the bulk solution or solution after reconstitution is in between 3 -6.