Biocompatibility of an Injectable In Situ Forming Depot for Peptide Delivery

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ABSTRACT

Poly(ethyleneglycol) 500 dimethylether (PEG500DME) was tested as a novel solvent for the manufacture of an injectable in situ forming depot (ISFD) containing poly(d,l-lactide-co-glycolide) (PLGA). The sustained release of pasireotide from the ISFD was evaluated in vitro and in vivo. Furthermore, the local tolerability of the delivery system using PEG500DME was investigated in subcutaneous (s.c.) tissue over 48 days. A flow-through cell was used to determine the in vitro drug release from the ISFD in comparison to a peptide suspension without polymer. The biocompatibility as well as the pharmacokinetic profile of the ISFD was investigated in rabbits. A prolonged peptide release over at least 48 days with an initial burst lower than 1% was observed in vitro for the ISFD compared to the suspension without polymer. A similar tissue response as it was observed for other common PLGA delivery systems was found upon histopathological examination of tissue from the administration site in rabbits. A sustained release of at least 48 days in vivo confirmed the in vitro observation including the low initial plasma concentration levels. Two ISFDs with different peptide loads were used to correlate the in vitro and in vivo data (IVIVC). Overall, the functionality of the ISFD containing PEG500DME as a novel solvent was demonstrated in vitro and in vivo. In addition, the local tolerability of the system confirmed the biocompatibility of PEG500DME in parenteral depots.

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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