ECTS: 15
Vejleder: René Holm
Background of the project:
Parenteral PLGA microspheres and in situ forming gels have garnered considerable attention compared, which attributed to several unique advantages of PLGA, including: 1) lower toxicity and local tolerance at the injection site, 2) enhanced control over drug loading and release profile, and 3) the ability of the formulations to retain water soluble compounds (Park et al., 2021; Garner et al., 2021; Gonella et al., 2022). FDA has thus far approved PLGA microspheres and PLGA base in situ forming gels as a drug delivery system for small molecules, peptides, and proteins, offering release durations ranging from 1 week to 6 months (Alidori et al., 2024).
The mechanisms of drug release from PLGA-based microparticles or PLGA based gels involve multiple factors, but the most important is drug diffusion and polymer degradation (by hydrolysis). After administration, PLGA degrades into nontoxic components, lactic and glycolic acids, which are either metabolized or excreted from the body (Shive and Anderson, 1997). The degradation opens more water-accessible space leading to the interior of the particle/gel (Freiberg and Zhu, 2004).
In vitro release investigations of both systems are normally conducted in PBS pH 7.4 at 37 °C as this is physiological relevant and often link well to the observed in vivo release. Release from a one moth depot however takes one month, hence approaches for predictive faster release investigations would be beneficial from a drug development approach. Degradation by hydrolysis can often be linked to a temperature dependency and hence a correlation that may follow the Arrhenius equation, which will be investigated in this project.
Problem formulation
Can the Arrhenius equation be used to speed up the release time in a predictive manner from PLGA basef formulations?
Methods
The study will definition of relevant formulation system with focus on in situ forming gels and investigation of the release from these at different temperatures.
Analytical techniques including and high-performance liquid chromatography (HPLC), but other techniques may be relevant as well
Guidance
There will be scheduled meetings every two weeks where the student is expected to present results, interpretations and what is subsequently planned – and from here a professional discussion is taken. In addition, there will always be the possibility of ad hoc guidance meeting.
References
Park, K.; Otte, A.; Sharifi, F.; Garner, J.; Skidmore, S.; Park, H.; Jhon, Y. K.; Qin, B.; Wang, Y. Formulation composition, manufacturing process, and characterization of poly(lactide-co-glycolide) microparticles. J. Control. Rel. 2021, 329, 1150-1161.
Garner, J.; Skidmore, S.; Hadar, J.; Park, H.; Park, K.; Kuk Jhon, Y.; Qin, B.; Wang, Y. Analysis of semi-solvent effects for PLGA polymers. Int. J. Pharm. 2021, 602, 120627.
Gonella, A.; Grizot, S.; Liu, F.; López Noriega, A.; Richard, J. Long-acting injectable formulation technologies: challenges and opportunities for the delivery of fragile molecules. Expert Opin. Drug Deliv. 2022, 19, 927-944.
Alidori S, Subramanian R, Holm R. Patient-Centric Long-Acting Injectable and Implantable Platforms─An Industrial Perspective. Mol Pharm. 2024;21(9):4238-4258.
Shive, M. S.; Anderson, J. M. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Deliv. Rev. 1997, 28, 5-24.
Freiberg, S.; Zhu, X. X. Polymer microspheres for controlled drug release. Int. J. Pharm. 2004, 282, 1-18.