Physiologically controlled release from an in situ forming liposomal depot

Area of Science:

• Biomaterials Science
• Drug Delivery Systems
• Pharmacology

Background:

• Poor treatment adherence is a significant global health problem, increasing morbidity, mortality, and healthcare expenses.
• Controlled-release depots offer a promising strategy to improve patient compliance, especially when frequent dosing is difficult.
• Existing long-acting injectable formulations face challenges like poor injectability, delayed drug onset, and complex manufacturing.

Purpose of the Study:

• To develop and characterize a thermoresponsive, in situ forming liposomal depot (TILD) for modulating the release of membrane-associated drugs.
• To evaluate the in vivo performance of TILD for sustained drug delivery following subcutaneous administration.
• To utilize molecular simulations for rational system design and validation of physiological cue responsiveness.

Main Methods:

• Design and synthesis of a thermoresponsive liposomal depot system.
• Utilizing buprenorphine as a model analgesic drug for release studies.
• Employing molecular simulations to guide system design and predict behavior.
• Conducting structural and colloidal characterizations to validate responsiveness.
• Performing in vivo studies in rats and Beagle dogs to assess depot formation, drug levels, and pharmacodynamics.

Main Results:

• TILD demonstrated tunable drug release in response to subcutaneous divalent cations and body temperature.
• Molecular simulations successfully guided the design of the thermoresponsive liposomal depot.
• In vivo studies showed stable depot formation and maintained therapeutic buprenorphine levels for up to four days in rats and dogs.
• Pharmacodynamic studies confirmed prolonged analgesia in rats, validating the system's efficacy.

Conclusions:

• The thermoresponsive, in situ forming liposomal depot (TILD) is a viable platform for sustained subcutaneous drug delivery.
• TILD effectively modulates drug release based on physiological cues, offering potential to improve treatment adherence.
• This novel formulation demonstrates potential for long-acting delivery of membrane-associated drugs, addressing limitations of current injectable therapies.