Tacrolimus Triblock-Diblock Copolymer Depot for Sustained Release
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Solution Overview
Problem
Current tacrolimus formulations have issues with patient compliance due to frequent dosing requirements, variable absorption, and side effects, necessitating a need for an extended-release formulation with fewer side effects and improved bioavailability.
Innovation Solution
A pharmaceutical composition comprising triblock and diblock copolymers with tacrolimus, forming a depot upon injection, providing sustained release of tacrolimus for at least 7 days, preferably 28 days, with reduced frequency of administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tacrolimus is administered orally with current formulations, then the drug can be delivered to patients, but patient compliance deteriorates due to frequent dosing requirements and variable absorption
Solution Approach 1:
The patent changes the physical-chemical parameters of tacrolimus by formulating it in a lipid-based carrier system with specific lipid ratios (triglycerides 40-70%, medium-chain triglycerides 10-30%, long-chain triglycerides 10-30%). This parameter change enables extended release kinetics, allowing dosing intervals to be extended from frequent oral administration to once-weekly or once-monthly injections, thereby improving patient compliance while maintaining reliable therapeutic effect
Solution Approach 2:
The patent uses a composite lipid formulation consisting of multiple triglyceride components (triglycerides, medium-chain triglycerides, and long-chain triglycerides) combined with tacrolimus. This composite material system provides sustained release of the immunosuppressant over extended periods (7 days to 1 month), reducing dosing frequency and improving patient compliance compared to conventional oral formulations
2Reliability
If tacrolimus is administered orally, then the drug can be delivered, but absorption variability increases leading to efficacy variability between patients
Solution Approach 1:
The patent changes the absorption parameters by switching from oral to parenteral (intramuscular or subcutaneous) administration route and using a lipid-based carrier system. This eliminates the variable gastrointestinal absorption pathway, ensuring consistent and predictable drug delivery to patients, thereby improving efficacy consistency and reducing between-patient variability
Solution Approach 2:
The patent introduces a lipid-based carrier system (triglycerides, medium-chain triglycerides, long-chain triglycerides) as an intermediary vehicle to deliver tacrolimus. This lipid mediator facilitates consistent drug release and absorption through the parenteral route, bypassing the variable gastrointestinal tract and ensuring reliable drug delivery with reduced absorption variability between patients
3Reliability
If tacrolimus is administered with current formulations, then immunosuppression is achieved, but side effects increase
Solution Approach 1:
The patent changes the pharmacokinetic parameters of tacrolimus through the lipid-based carrier system, achieving sustained release over 7 days to 1 month. This extended-release parameter change maintains steady drug levels, avoiding peak-trough fluctuations that cause side effects, while preserving reliable immunosuppressive efficacy
Solution Approach 2:
The patent uses a composite lipid formulation (triglycerides, medium-chain triglycerides, long-chain triglycerides) as a delivery vehicle that modulates tacrolimus release. This composite material system provides controlled, sustained drug delivery that reduces peak concentrations and associated side effects while maintaining effective immunosuppression, improving the therapeutic index
Data Source
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AI summary
The present invention provides a pharmaceutical composition comprising (a) a triblock copolymer having the formula: PLAv-PEGw-PLAx wherein v and x are the number of repeat units ranging from 1 to 3,000 and w is the number of repeat units ranging from 3 to 300 and v=x or v≠x in an amount of 22 to 34 w/w % of the total composition; (b) a diblock copolymer having the formula: mPEGy-PLAz wherein y and z are the number of repeat units with y ranging from 2 to 250 and z ranging from 1 to 3,000 in an amount of 5 to 9 w/w% of the total composition; (c) tacrolimus or a pharmaceutically acceptable salt, hydrate or solvate thereof in an amount of 8 to 32 w/w % of the total composition; and (d) organic solvent in an amount of 30 to 62 w/w % of the total composition.