Elsevier

Journal of Controlled Release

Volume 57, Issue 2, 1 February 1999, Pages 171-185
Journal of Controlled Release

PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug

https://doi.org/10.1016/S0168-3659(98)00116-3Get rights and content

Abstract

The nanoprecipitation technique for preparation of nanoparticles suffers the drawback of poor incorporation of water soluble drugs. The aim of this study was therefore to assess various formulation parameters to enhance the incorporation of a water soluble drug (procaine hydrochloride) into poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared by this technique. Approaches investigated for drug incorporation efficiency enhancement included the influence of aqueous phase pH, replacement of procaine hydrochloride with procaine dihydrate and the inclusion of excipients: poly(dl-lactide) (PLA) oligomers, poly(methyl methacrylate-co-methacrylic acid) (PMMA–MA) or fatty acids into the formulation. The nanoparticles produced were submicron size (<210 nm) and of low polydispersity. It was found that an aqueous phase pH of 9.3, replacement of procaine hydrochloride with procaine dihydrate and the incorporation of PMMA–MA, lauric and caprylic acid into the formulation could enhance drug incorporation efficiency without the size, morphology and nanoparticle recovery being adversely influenced. For instance changing the aqueous phase pH from 5.8 to 9.3 increased nanoparticle recovery from 65.1 to 93.4%, drug content from 0.3 to 1.3% w/w and drug entrapment from 11.0 to 58.2%. However, the presence of high ratios of lauric acid and procaine dihydrate in the formulation adversely affected the morphology and size of the nanoparticles. Also, PLA oligomers were not considered a feasible approach since it decreased drug entrapment from 11.0 to 8.4% and nanoparticle recovery from 65.1 to 19.6%. Drug release from nanoparticles appears to consist of two components with an initial rapid release followed by a slower exponential stage. This study has demonstrated that formulation variables can be exploited in order to enhance the incorporation of a water soluble drug into PLGA nanoparticles by the nanoprecipitation technique.

Introduction

The potential of site specific drug delivery in optimising drug therapy [1] has given impetus to significant advancements in the pharmaceutical engineering of novel dosage forms such as nanoparticles, which are solid colloidal polymeric carriers less than 1 μm in size [2]. Several review articles have highlighted the ability of such nanoparticles to reduce associated adverse effects of various drugs 1, 3, 4. Some of the commonly reported methods of preparing nanoparticles from biodegradable polymers include solvent evaporation [5], monomer polymerisation [6], nanoprecipitation [7] and the salting out procedure [8]. The nanoprecipitation method developed by Fessi et al. [9] represents an easy and reproducible technique and has been widely used by several research groups to prepare nanoparticles 7, 10, 11. This method is based on the interfacial deposition of a polymer following displacement of a semi-polar solvent miscible with water from a lipophilic solution [9].

A nanoparticle system with maximal drug loading and a high entrapment efficiency will reduce the quantity of carrier required for the administration of sufficient amount of active compound (drug) to the target site as well as drug wastage during manufacturing. Mainly water insoluble drugs have been incorporated into nanoparticles using the nanoprecipitation technique with typical drug content values being: indomethacin, 2.0% w/w [9] or 5.8% w/w [12]; dexamethasone, 0.9% w/w [9] and itraconozole, 4.1% w/w [13]. However, in our hands this technique suffers the drawback of a poor incorporation efficiency of water soluble drugs due to rapid migration and therefore loss of drug into the aqueous phase. Furthermore, while the literature is replete with studies investigating drug incorporation into particles by the solvent evaporation method 14, 15, 16, a lack of published data on approaches to promote the incorporation of water soluble drugs by the nanoprecipitation method exists.

Hence, the main aim of the present study was to assess formulation parameters to enhance the incorporation of a water soluble drug into PLGA nanoparticles by the nanoprecipitation technique. PLGA was selected since the poly(esters), including poly(lactic acid), poly(glycolic acid) and their copolymers, have emerged as the most widely used and studied class of biodegradable polymers for pharmaceutical use due to their biocompatibility and biodegradability [17]. The physicochemical characteristics, particle morphology and in vitro release behaviour of the drug loaded nanoparticles have also been elucidated. In all investigations, procaine hydrochloride has been used as a model drug due to its water solubility, ease of analysis, ready availability and cost. Also, due to its cationic nature it is possible to promote electrostatic interactions with anionic excipients.

Section snippets

Materials

Poly(dl-lactide-co-glycolide) (PLGA, 50:50, Mw=10 000 Da) was synthesised by Zeneca Pharmaceuticals (Macclesfield, UK) and was used as obtained. Poly(dl-lactide) (PLA) oligomers (Mw=2000 Da) were synthesised in our laboratories. Procaine hydrochloride (pKa=9), HEPES (as sodium salt), Phosphate buffered saline (PBS) tablets, caprylic acid (C8H15O2Na) and lauric acid (C12H23O2Na) were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Poly(methyl methacrylate-co-methacrylic acid) [–CH2C(CH3

Influence of the theoretical loading of procaine hydrochloride

The starting procedure involved the production of PLGA nanoparticles with procaine in its salt form and using water pH 5.8 as the aqueous phase. In order to establish the maximum amount of drug that could be incorporated into nanoparticles at such conditions, the initial approach involved increasing the theoretical loading of procaine hydrochloride in the formulation from 1 to 10% w/w. The results showed that this led to a corresponding increase in drug content from 0.2 to 4.6% w/w; however the

Conclusions

Initially PLGA nanoparticles loaded with procaine hydrochloride were prepared by the nanoprecipitation method in water pH 5.8 as the aqueous phase. Small, spherical and submicron sized (<210 nm) nanoparticles were obtained. However, drug content and drug entrapment were very low. This study therefore investigated the influence of various formulation variables on enhancing the incorporation efficiency of procaine hydrochloride, a model for a water soluble drug. An increase in the aqueous phase

Acknowledgements

This work was funded by the DTI and partnering companies (Zeneca Pharmaceuticals, Danbiosyst, Oxford Molecular, CSMA) (grant number GR/J57889).The authors would like to thank Zeneca Pharmaceuticals for the supply of PLGA polymer, Mr Trevor Riley (Department of Pharmaceutical Sciences, University of Nottingham) for the PLA oligomer synthesis, Mr Trevor Gray (Department of Histopathology, Queens Medical Centre) for assistance with TEM and Ms Alexandra Schmidt (Department of Mathematics,

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