Ultrasound-induced degradation of PLA and PLGA during microsphere processing: influence of formulation variables.
The effect of probe sonication during microsphere processing on the stability of various aliphatic polyesters based on lactic acid (PLA) and lactic/glycolic acid (PLGA) was investigated. The weight average molecular weight (Mw) of the polymers dissolved in dichloromethane (DCM) generally decreased with an increase in duration and/or intensity of the sonication process. The extent of the Mw-reduction was more pronounced with polymers of high initial Mw and high GA content. Polydispersity indices (PD=Mw/Mn) were nearly unchanged indicating that random chain cleavage is the likely degradation mechanism. From the observation that ultrasound-induced polymer degradation slightly increased in the presence of suspended drug particles acting as cavitation nuclei, it can be concluded that the mechanical stress induced by the implosive collapse of cavitation bubbles is at least partly responsible for the observed effects in PLA/ PLGA solutions. The use of ultrasound for the preparation of W/O, O/W and W/O/W emulsions exhibited different effects depending on the formulation and the type of emulsion. The preparation of W/O emulsions generally lead to Mw-changes comparable to those observed for the corresponding polymer solutions. Fatty acid free bovine serum albumin (BSAff) was found to protect PLA and PLGA against ultrasound-induced degradation in W/O-emulsions due to the formation of a semisolid interfacial film. A tremendous effect not only on the polymer Mw, but also on its PD could be observed, when ultrasound was used to emulsify an organic polymer solution or W/O-emulsion in an external aqueous phase. As this last finding was found to have rather important implications on the drug loading efficiency, the hydration, the degradation and the initial release characteristics of the resulting microspheres, it can be concluded that probe sonication can be a rather critical process step during the preparation of microspheres.
Institute for Pharmaceutical Technology and Biopharmaceutics, Heidelberg University, Germany.
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D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004355:Drug Stability; D019344:Lactic Acid / Q000737:chemistry*; D008863:Microspheres; D011091:Polyesters; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D014465:Ultrasonics
D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide)