Preparation of nanoparticles consisted of poly(l-lactide)–poly(ethylene glycol)–poly(l-lactide) and their evaluation in vitro

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Abstract

This study describes the preparation and the evaluation of biodegradable poly(l-lactide)–poly(ethylene glycol)–poly(l-lactide) copolymer (PLA–PEG–PLA) nanoparticles containing progesterone as a model drug. PLA and PLA–PEG–PLA copolymers, whose PEG content ranged from 5.2 to 25.8% (w/w), were polymerized in our laboratory. PEG with weight-average molecular weight (Mw) 6600 or 20 000 was introduced as a hydrophilic segment into a hydrophobic PLA homopolymer. A solvent evaporation method was used to prepare the nanoparticles. The drug trapping efficiencies were around 70% and the weight-averaged mean diameters of the nanoparticles were less than 335 nm. The amount of drug released increased as the PEG content and Mw of PLA–PEG–PLA copolymers increased and the total Mw of copolymers of nanoparticles decreased. The initial burst of drug release was reduced by removing the low Mw fraction from the polymer. During the release test, both the extent to which the copolymers were degraded and the size of the nanoparticles were increased slightly by increasing the content of PEG in the polymers. Drug release from the nanoparticles could potentially be controlled by changing the PEG content, PEG Mw and total Mw of the copolymer. The molecular weight distribution (Mw/Mn, Mn: number-average molecular weight) of copolymers was also an important factor for controlled release.

Introduction

Colloidal carriers are rapidly removed by the reticuloendothelial system (RES), because these particles are easily trapped by phagocytic cells. In recent years, various attempts have been made to change this (Illum and Davis, 1984, Senior et al., 1991, Müller et al., 1992, Stolnik et al., 1994).

Stolnik et al. (1994) showed that poly(lactide-co-glycolide) (PLGA) nanospheres coated biodegradable poly(l-lactide)–poly(ethylene glycol) copolymer (PLA–PEG) were less susceptible to hepatic uptake than naked PLGA nanospheres. PEG-PLGA nanospheres (Gref et al., 1994), methoxy PEG-PLA nanoparticles (Bazile et al., 1995), and PLA-PEG nanoparticles (Verrecchia et al., 1995) remained in the circulation a long time. These characteristics of diblock copolymer nanoparticles are due to the reduction of protein adsorption owing to the formation of a hydrophilic layer and a low surface charge originating in PEG (Stolnik et al., 1994). On the other hand, it was supposed to be difficult for triblock copolymer nanoparticles to evade the RES, because their hydrophilic PEG domains like those PLA–PEG–PLA do not move freely. But we have reported that nanoparticles using this PLA–PEG–PLA triblock copolymer evaded capture by the RES and remained a long time in the circulation (Nakada et al., 1997). The half-life after injection of 3H-progesterone loaded PLA–PEG–PLA nanoparticles was about twice that of 3H-progesterone-loaded PLA nanoparticles and the 3H-progesterone distribution to the liver and spleen after administration of 3H-progesterone PLA–PEG–PLA nanoparticles was about half that of 3H-progesterone PLA nanoparticles.

In this paper, we describe the characteristics of nanoparticles of this PLA–PEG–PLA triblock copolymer in vitro.

Section snippets

Materials

Progesterone, as a model hydrophobic compound with a very short half-life in blood, was purchased from Sigma (MO, USA). Polyoxyethylene (20) sorbitan monooleate (Polysorbate 80) and PEG (weight-average molecular weight (Mw); 6600 and 20 000, respectively) were of reagent grade from Wako Pure Chemical Industries (Osaka, Japan). Polyvinyl alcohol (PVA-203, Kuraray, Tokyo, Japan) was used as supplied. l-Lactide was purchased from Boehringer Ingelheim (Germany).

Polymerization

Bulk polymerization of l-lactide

Characterization of the nanoparticles

Progesterone nanoparticles were prepared by a solvent evaporation method. Values for the mean diameter of distribution and the drug trapping efficiency of each preparations are summarized in Table 3. A typical size distribution graph based on weight is presented in Fig. 1.

The nanoparticles had a mean diameter of 193–335 nm and trapping efficiencies of 65–74%. Both the mean diameter and the trapping efficiency were independent of the polymer composition in this study.

Effect of the release test conditions

The drug release behavior of

Conclusion

In conclusion, we studied progesterone-loaded PLA–PEG–PLA nanoparticles whose release appears to be controlled by the hydrophilic segments introduced into the hydrophobic parent PLA polymer. The amount of drug released was greater with the higher PEG content and Mw, and the lower total Mw of the polymers. Therefore, the drug release from nanoparticles was potentially controlled by PEG content, PEG Mw, and total Mw of the copolymer. Mw/Mn was also an important parameter in the control of drug

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