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A main issue in controlled delivery of biotechnological products from injectable biodegradable microspheres is to preserve their integrity and functional activity after the microencapsulation process and final sterilization. The present experimental work tested different technological approaches to maintain the biological activity of an encapsulated biotechnological product within PLGA [poly (lactic-co-glycolic acid)] microspheres (MS) after their sterilization by gamma irradiation. GDNF (glial cell line-derived neurotrophic factor), useful in the treatment of several neurodegenerative diseases, was chosen as a labile model protein. In the particular case of optic nerve degeneration, GDNF has been demonstrated to improve the damaged retinal ganglion cells (RGC) survival. GDNF was encapsulated in its molecular state by the water-in-oil-in-water (W/O/W) technique or as solid according to the solid-in-oil-in-water (S/O/W) method. Based on the S/O/W technique, GDNF was included in the PLGA microspheres alone (S/O/W 1) or in combination with an antioxidant (vitamin E, Vit E) (S/O/W 2). Microspheres were sterilized by gamma-irradiation (dose of 25 kGy) at room and low (-78 °C) temperatures. Functional activity of GDNF released from the different microspheres was evaluated both before and after sterilization in their potential target cells (retinal cells). Although none of the systems proposed achieved with the goal of totally retain the structural stability of the GDNF-dimer, the protein released from the S/O/W 2 microspheres was clearly the most biologically active, showing significantly less retinal cell death than that released from either W/O/W or S/O/W 1 particles, even in low amounts of the neurotrophic factor. According to the results presented in this work, the biological activity of biotechnological products after microencapsulation and sterilization can be further preserved by the inclusion of the active molecule in its solid state in combination with antioxidants and using low temperature (-78 °C) during gamma irradiation exposure., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Poly(lactide-co-glycolide) (PLGA) has been extensively investigated for controlled drug release. Because they undergo bulk degradation, they do not allow for a good controlled-release of drugs. The objective of this study is therefore to understand if a multi-layer-cum-irradiation technique would elicit surface erosion from PLGA polymers. A linear loss of mass and film thinning from PLGA films were observed. Also, the erosion of the top layer, of this multi-layered structure, accelerates degradation of the underlying layers. It is this effect that results in the observed pseudo-surface erosion for irradiated multi-layered PLGA.

Currently, gamma-irradiation seems to be a good method for sterilising drug delivery systems made from biodegradable polymers. The gamma-irradiation of microspheres can cause several physicochemical changes in the polymeric matrix. These modifications are affected by the temperature, irradiation dose and nature of the encapsulated drug and additives. This study has aimed to evaluate the influence of temperature during the sterilisation process by gamma irradiation in indomethacin PLGA microspheres including a PEG-derivative. Microspheres were prepared by the solvent evaporation method from o/w emulsion and were then exposed to gamma-irradiation. A dose of 25 kGy was used to ensure effective sterilisation. Some microspheres were sterilised with dry ice protection that guaranteed a low temperature during the process whilst others were sterilised without such dry ice protection. The effects of gamma-irradiation on the characteristics of non-loaded PLGA/PEG-derivative and indomethacin loaded PLGA/PEG-derivative microspheres with and without protection were studied. Non-protected microspheres showed changes in their morphological surface, polymer glass transition temperature, molecular weight and release rate of indomethacin after sterilisation. However, microspheres sterilised with protection did not show significant differences after gamma-irradiation exposure. The sterilisation method was satisfactory when the indomethacin loaded microspheres including a PEG-derivative were exposed to gamma-irradiation at low temperature.

Radioactive holmium-166 loaded poly(L-lactic acid) microspheres are promising systems for the treatment of liver malignancies. The microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method. After preparation, the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. In this paper, the aspects of the production of a (relatively) large-scale GMP batch (4 g, suitable for treatment of 5-10 patients) of Ho-PLLA-MS are described. The critical steps of the Ho-PLLA-MS production process (sieving procedure, temperature control during evaporation and raw materials) were considered and the pharmaceutical quality of the microspheres was evaluated. The pharmaceutical characteristics (residual solvents, possible bacterial contaminations and endotoxins) of the produced Ho-PLLA-MS batches were in compliance with the requirements of the European Pharmacopoeia. Moreover, neutron irradiated Ho-PLLA-MS retained their morphological integrity and the holmium remained stably associated with the microspheres; it was observed that after 270h (10 times the half-life of Ho-166) only 0.3+/-0.1% of the loading was released from the microspheres in an aqueous solution. In conclusion, Ho-PLLA-MS which are produced as described in this paper, can be clinically applied, with respect to their pharmaceutical quality.