Biocompatibility of an Injectable In Situ Forming Depot for Peptide Delivery
Section snippets
INTRODUCTION
Injectable in situ forming depots (ISFDs) are drug delivery systems, that form a solid or semisolid drug reservoir upon the parenteral injection of a drug solution or suspension. Some of these systems are based on a solution of a hydrophobic polymer dissolved in a water miscible organic solvent. This type of ISFD shows polymer precipitation upon injection into an aqueous environment, induced by solvent diffusion and water intrusion.
Polyesters, such as poly(d,l-lactide)s (PLA) and poly(d,l
Materials
PLGA with 50% d,l-lactide and 50% glycolide was purchased from Boehringer Ingelheim Pharma KG (Ingelheim, Germany). The inherent viscosity of PLA50GA5012 in a solution of 0.1% in chloroform was 0.16–0.24 dL/g (weight average Mw = 12,000 Da). PEG500DME with a molecular weight of 500 Da was a kind gift from Clariant (Burgkirchen, Germany). The model peptide pasireotide pamoate was provided by Novartis Pharma AG (Basel, Switzerland). All chemicals were used without further purification.
Aseptic Preparation of Peptide Depot Suspensions
A polymer
In Vitro Release Kinetics
First a peptide suspension in PEG500DME was used to investigate the in vitro release of the drug substance in contact with the solvent, in the absence of a polymer. Since pasireotide pamoate is a poorly water-soluble salt, only 61.6 ± 0.2% drug was released over a duration of 48 days (Fig. 1). The in vitro release profile of an ISFD comprising 20% (w/w) PLA50GA5012 in PEG500DME with 5% (w/w) peptide, also illustrated in Figure 1 showed a very low initial release (burst) of 0.2%. The ISFD
CONCLUSION
The local tolerability study of an ISFD comprising of PEG500DME showed an immune response similar to that described in literature for PLGA containing systems.5 Therefore, PEG500DME can be considered a novel biocompatible solvent for parenteral administration of ISFD. In addition, a prolonged in vitro and in vivo peptide release was demonstrated for two different peptide loads. The correlation of the normalized in vitro and the cumulative AUC of the in vivo results represents a promising
ACKNOWLEDGMENTS
The authors would like to thank B. Mueller and R. Hegi (Novartis Pharma, Basel, Switzerland) for the technical support
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