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Development of 5-iodo-2'-deoxyuridine milling process to reduce initial burst release from PLGA microparticles
A Gèze1, M C Venier-Julienne, D Mathieu
1UPRES EA 2169, Faculté de Pharmacie, Angers, France.
Abstract:
The aim of this study was to prepare 5-iodo-2'-deoxyuridine (IdUrd) loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with a reduced initial burst in the in vitro release profile, by modifying the drug grinding conditions. IdUrd particle size reduction has been performed using spray-drying or ball milling. Spray-drying significantly reduced drug particle size with a change of the initial crystalline form to an amorphous one and led to a high initial burst. Conversely, ball milling did not affect the initial IdUrd crystallinity. Therefore, the grinding process was optimized to emphasize the initial burst reduction. A first step allowed us to set qualitative parameters such as ball number (7) and cooling with liquid nitrogen to obtain a mean size reduction and a narrow distribution. In a second step, three parameters including milling speed, drug amount and time were studied by a response surface analysis. The interrelationship between drug amount and milling speed was the most significant factor. To reduce particle size it should be necessary to use a moderate speed associated with a sufficient drug amount (400-500 mg). IdUrd release from microparticles prepared by the o/w emulsion/extraction solvent evaporation process with the lowest crystalline particle size (15.3 microns) was studied. Burst effect could be reduced significantly. Concerning the first phase of drug release, the burst was 8.7% for 15.3 microns compared to 19% for 19.5 microns milled drug particles.
Insights
Optimizing ball milling of 5-iodo-2'-deoxyuridine (IdUrd) reduced microsphere burst release. Controlled particle size and crystallinity are key for predictable drug delivery from poly(d,l-lactide-co-glycolide) (PLGA) systems.
Area of Science:
- Biomaterials Science
- Drug Delivery Systems
- Nanotechnology
Background:
- Poly(d,l-lactide-co-glycolide) (PLGA) microspheres are widely used for controlled drug delivery.
- Initial burst release can limit the efficacy of microsphere-based therapeutics.
- 5-iodo-2 -deoxyuridine (IdUrd) is an important radiosensitizing agent.
Purpose of the Study:
- To reduce the initial burst release of IdUrd from PLGA microspheres.
- To investigate the effect of drug grinding conditions on IdUrd particle characteristics and subsequent release profiles.
- To optimize the ball milling process for IdUrd particle size reduction while maintaining crystallinity.
Main Methods:
- IdUrd particle size reduction via spray-drying and ball milling.
- Optimization of ball milling parameters (ball number, cooling, speed, drug amount, time) using response surface analysis.
- Preparation of PLGA microspheres using the o/w emulsion/solvent evaporation method.
- In vitro drug release studies to quantify burst effect.
Main Results:
- Spray-drying led to amorphous IdUrd and a high initial burst release.
- Ball milling maintained IdUrd crystallinity, with optimized conditions yielding a mean particle size of 15.3 microns.
- Optimized ball milling (moderate speed, 400-500 mg drug amount) significantly reduced the initial burst release (8.7% vs. 19% for larger particles).
Conclusions:
- Controlled particle size and crystallinity of IdUrd through optimized ball milling are crucial for minimizing burst release from PLGA microspheres.
- The developed method offers a strategy for enhancing the predictability and efficacy of IdUrd-loaded microsphere formulations.
- Further research can explore the long-term stability and in vivo performance of these optimized microspheres.