Polymeric nanoparticles – Influence of the glass transition temperature on drug release

https://doi.org/10.1016/j.ijpharm.2016.12.025Get rights and content

Abstract

The physico-chemical characterisation of nanoparticles is often lacking the determination of the glass transition temperature, a well-known parameter for the pure polymer carrier. In the present study the influence of water on the glass transition temperature of poly (DL-lactic-co-glycolic acid) nanoparticles was assessed. In addition, flurbiprofen and mTHPP as model drugs were incorporated in poly (DL-lactic-co-glycolic acid), poly (DL-lactic acid), and poly (L-lactic acid) nanoparticles. For flurbiprofen-loaded nanoparticles a decrease in the glass transition temperature was observed while mTHPP exerted no influence on this parameter.

Based on this observation, the release behaviour of the drug-loaded nanoparticles was investigated at different temperatures. For all preparations an initial burst release was measured that could be attributed to the drug adsorbed to the large nanoparticle surface. At temperatures above the glass transition temperature an instant drug release of the nanoparticles was observed, while at lower temperatures less drug was released. It could be shown that the glass transition temperature of drug loaded nanoparticles in suspension more than the corresponding temperature of the pure polymer is the pivotal parameter when characterising a nanostructured drug delivery system.

Introduction

The encapsulation of drugs into colloidal systems has become a very popular method to achieve drug targeting and enhance drug efficiency (Torchilin, 2007). Polymer based nanoparticles are a prominent representative of colloidal systems besides liposomes and drug-polymer conjugates (Petros and DeSimone, 2010). Different natural or synthetic materials are used for nanoparticle preparation. Especially poly (lactic acid) (PLA) and its copolymer with glycolic acid, poly (DL-lactic-co-glycolic acid) (PLGA), are commonly used for particle preparation due their distinct biodegradability and biocompatibility (Alexis, 2005).

The characterisation of such colloidal systems most often includes the determination of particle diameter and size distribution via dynamic light scattering as well as further analytics concerning the morphology, i.e. scanning electron microscopy (SEM). Additionally, in many cases the determination of surface charge is performed in order to estimate colloidal stability and aggregation tendency (Peltonen and Hirvonen, 2008). However, the determination of the glass transition temperature (Tg) of nanoparticles in aqueous dispersion is less established, although Tg represents an important parameter of the pure polymer carrier. In most cases when Tg of the resulting polymeric nanoparticle system is quantified, a solid sample is analysed with the focus on the physical state of the embedded drug in terms of drug crystallisation or the formation of a solid solution (Dillen et al., 2004, Pamujula et al., 2004, Sant et al., 2005). Nevertheless, the relevance of Tg in aqueous nanoparticle dispersions is often underestimated. Especially for drug-loaded nanoparticles where a drug substance is incorporated in a polymeric matrix there are manifold interactions between the polymer chains and the drug due to their physical closeness.

Another characteristic of drug-loaded polymeric nanoparticles is the release profile. There are several factors that may influence drug release from the nanoparticulate system, e.g. drug solubility, diffusion, polymer biodegradation, particle size, and drug loading. For instance, there is a direct correlation between drug loading and initial burst release as well as subsequent release rate of the encapsulated amount (Kumari et al., 2010). Furthermore, the effect of different emulsifiers or steric stabilisers used in various concentrations for particle preparation also contributes to the release profile. For example the use of 0.5% instead of 5% poly (vinyl alcohol) (PVA) during nanoparticle preparation leads to an increased release of encapsulated bovine serum albumin (BSA) (Sahoo et al., 2002). Furthermore, the liberation of paclitaxel from PLGA nanoparticles is decreased when using 1,2-dipalmitoylphosphatidylcholin (DPPC) as an emulsifier instead of PVA (Feng and Huang, 2001). In addition, Budhian et al. described that the ratio of lactic to glycolic acid in the polymeric matrix additionally affects the burst release from haloperidol-loaded PLGA nanoparticles (Budhian et al., 2008). Moreover, other authors addressed the influences of the release medium on drug release from PLGA microspheres (Faisant et al., 2006). The release of 5-fluorouracil is strongly dependent on the osmolarity, buffer concentration, pH value, and temperature of the chosen incubation medium. However, when considering these studies a correlation between Tg of drug-loaded nanoparticles and temperature dependent release behaviour is not described so far.

The present study is focussed on a relationship between Tg influencing parameters and release profile kinetics. Glass transition temperatures of unloaded PLGA nanoparticles in dry form and in aqueous suspension were examined to reveal possible effects of the used emulsifier and stabilisers. In a second step, drug-loaded PLGA nanoparticles were characterised for drug loading, Tg, and physical state of the incorporated model drugs flurbiprofen and 5,10,15,20-tetra(m-hydroxyphenyl)porphyrin (mTHPP) (Fig. 1). Both drugs were chosen because of their poor water solubility in combination with an insufficient transport across biological barriers which necessitates suitable drug formulation strategies such as the incorporation in colloidal dosage forms (Meister et al., 2013, Grünebaum et al., 2015).The release behaviour of the model drugs from PLGA nanoparticles was compared to nanoparticles based on DL-PLA and L-PLA, in order to compare typical biodegradable and approved starting materials for nanoparticle preparation. By using different temperature profiles the release behaviour could be correlated to Tg properties of the respective nanoparticle formulation.

Section snippets

Materials

PLGA (Resomer® RG502H, inherent viscosity 0.16–0.24 dl/g), DL-PLA (Resomer® R203H, inherent viscosity 0.25–0.35 dl/g), and L-PLA (Resomer® L206S, inherent visosity 0.8–1.2 dl/g) were obtained from Evonik Industries AG (Darmstadt, Germany). mTHPP was kindly provided from biolitec research GmbH (Jena, Germany). Flurbiprofen (FBP), human serum albumin (HSA), poly (vinyl alcohol) (PVA), and mannitol were purchased from Sigma Aldrich (Steinheim, Germany). The purity of the drugs was ≥98.5% according to

Results

In the present study nanoparticles based on the polymers PLGA, DL-PLA, and L-PLA were prepared in combination with the lipophilic drugs flurbiprofen and mTHPP (Fig. 1). The different nanoparticle samples were analysed with regard to the relationship between Tg influencing parameters and release profile kinetics. The design of the study is outlined in Fig. 2.

Prior to the DSC analysis of the nanoparticle samples, the thermal stability of both drugs was assessed. Flurbiprofen as well as mTHPP

Discussion

The glass transition temperature is a well defined parameter for the pure polymer of nanoparticle preparation. Amorphous polymers are characterised by their Tg indicating the temperature range within the polymer changes from being hard and brittle to a more soft and plastic manner. However, Tg of the resulting polymeric nanoparticle matrix is not necessarily the same as Tg of the pure polymer and is often unknown or not regarded. The close examination of Tg of different PLGA-, DL-PLA-, and

Conclusion

The present study investigated the influencing factors on Tg of different polymeric nanoparticles. The importance of water as a plasticising agent on amorphous polymers could be verified. Furthermore, the drug dependent influences on nanoparticles Tg were evaluated. It has to be noted that the molecular size, structure, and hydrophilicity of the used drug are relevant parameters with a crucial influence on Tg of the resulting nanoparticle system. Small and more hydrophilic molecules like

Declaration of interest

The authors report no declarations of interest.

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