Testosterone Cypionate Composition to Prevent Cold-Storage Crystals
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Solution Overview
Problem
Conventional testosterone cypionate intramuscular injection drug products form crystals when exposed to temperatures below room temperature, leading to pain and local tissue damage during administration.
Innovation Solution
Stable injectable pharmaceutical compositions comprising testosterone cypionate, a pharmaceutically acceptable oil vehicle, and benzyl alcohol, aged at controlled temperatures to prevent crystal formation, with benzyl alcohol concentration ranging from 1% to 3% w/v.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional testosterone cypionate intramuscular injection is stored at temperatures below room temperature, then storage stability is improved, but crystal formation occurs causing pain and tissue damage
Solution Approach 1:
Benzyl alcohol is introduced as an intermediary substance that mediates between the testosterone cypionate and the storage conditions. It forms a eutectic mixture with the testosterone ester, creating a liquid solid dispersion that prevents crystal formation while allowing stable storage at lower temperatures. The benzyl alcohol acts as a protective agent that interferes with the crystallization process.
Solution Approach 2:
The invention changes the physical-chemical parameters of the formulation by adjusting the concentration of benzyl alcohol (1-3% w/v) and the ratio of oil vehicle to ester. This parameter modification creates a eutectic system with a lowered melting point, allowing the composition to remain liquid or amorphous at storage temperatures below room temperature without crystal formation.
2Object-affected harmful factors
If benzyl alcohol concentration is increased to prevent crystal formation, then crystal prevention is improved, but potential toxicity and local tissue reaction increase
Solution Approach 1:
The invention optimizes the parameter of benzyl alcohol concentration within a specific range (1-3% w/v) that is sufficient to prevent crystal formation through eutectic mixture formation, while avoiding excessive concentrations that would cause toxicity. This parameter optimization balances effectiveness with safety.
Solution Approach 2:
The formulation is designed as a single-use intramuscular injection, where the benzyl alcohol serves its protective function during the brief injection process and then dissipates. The short duration of exposure minimizes the risk of cumulative toxicity, and the benzyl alcohol is metabolized quickly by the body.
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 remain stable for up to 6 months at 2-8°C without crystal formation, improving patient compliance and convenience by preventing pain and tissue damage.
Implementation Method 1
The invention relates to stable, injectable compositions that do not exhibit crystal formation under storage conditions... the pharmaceutical composition according to the present application comprises a pharmaceutically effective amount of testosterone or a pharmaceutically acceptable ester thereof... and an effective amount of benzyl alcohol... do not exhibit crystal formation for 6 months when stored at a temperature of about 2° C. to about 8° C.
Implementation Method 2
These pharmaceutical compositions are suitable for injectable administration (e.g., subcutaneous or intramuscular), and are stable over the shelf life of the product... a process for stabilizing testosterone containing pharmaceutical compositions by ageing them at a temperature range of 20-60° C. for at least 48 hours, prior to packaging and labeling.
Data Source
AI summary
Stable pharmaceutical compositions are provided, comprising a pharmaceutically effective amount of testosterone or a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable oil vehicle, and a stabilizing amount of benzyl alcohol, for example, about 1% to 3% weight/volume of benzyl alcohol. The present invention also provides a process for stabilizing testosterone-containing pharmaceutical compositions by ageing them at a temperature of about 20° C. to about 60° C. for at least 48 hours, e.g., prior to secondary packing and labeling. These compositions were stable over the shelf life of the product, without exhibiting crystal formation, even upon storing at temperatures of about 2° C. to about 8° C. Other aspects of the invention relate to methods for making such pharmaceutical compositions and methods of using such pharmaceutical compositions for hormone replacement therapy, e.g., in a male patient having a condition associated with symptoms of deficiency or absence of endogenous testosterone.