Elsevier

Polymer

Volume 41, Issue 13, June 2000, Pages 4781-4792
Polymer

Biodegradable comb polyesters. Part II. Erosion and release properties of poly(vinyl alcohol)-g-poly(lactic-co-glycolic acid)

https://doi.org/10.1016/S0032-3861(99)00710-7Get rights and content

Abstract

Poly(lactic acid) (PLA) and its random copolymers with glycolide (PLG) were modified by grafting onto hydrophilic macromolecular backbones, such as poly(vinyl alcohol) (PVA), to increase both hydrophilicity and to manipulate the polymer structure. The resulting branched PVA-g-PLG offers the possibility to manipulate physico-chemical properties, such as molecular weight and glass transition temperature. The degradation and erosion rates required for continuous release of hydrophilic macromolecules differs significantly from linear PLG. Microspheres were prepared to investigate the release of hydrophilic dextran as a function of polymer structure.

A reduction of the poly(lactic-co-glycolic acid) chain lengths in PVA-g-PLG caused a change in erosion profiles from bulk erosion to a surface front erosion mechanism, when the molecular weight of the PLG side chains was below 1000 g/mol, which is equal to water-solubility when cleaved from the backbone. Drug release rates from microspheres were significantly influenced by the polymer structure. A reduction of the PLG chain lengths led to increasing erosion controlled release rates, while an increase of the molecular weight of the core PVA resulted in a more diffusion controlled release mechanism. Release profiles could be adjusted over a broad range from ca. 14 days to 3 months. In combination with the possibility of avoiding accumulation of acidic breakdown products in the delivery device, PVA-g-PLG are of particular interest for parenteral delivery systems containing proteins, peptides or oligonucleotides.

Introduction

Aliphatic polyesters, such as poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) and their random copolymers poly(lactide-co-glycolide) (PLG) are widely used for parenteral drug delivery systems [1], [2]. While drug delivery systems for parenteral administration of peptides have become commercially available, hydrophilic macromolecular drugs, such as proteins, still present a formidable challenge for continuous or infusion-like drug release both under in-vitro and in-vivo conditions. Possible interactions between proteins and hydrophobic matrix polymers can lead to deactivation and denaturation of these sensitive molecules. Therefore, the search for new biomaterials allowing protein, antisense, oligonucleotide or gene delivery remains an ambitious goal [3], [4].

Successful delivery of these hydrophilic, macromolecular drugs from microspheres or implants strongly depends on the properties of the polymers used for encapsulation, affecting water uptake, thermo-mechanical properties, rates of biodegradation (cleavage of chemical bonds leading to a reduction of molecular weight) and erosion (mass loss) [5], [6], [7], [8]. The erosion mechanism for linear PLA and PLG is controversially discussed in the literature [8], [9], [10], [11]. Autocatalysis by acidic degradation products, which are retained in the polymer matrix, is thought to accelerate degradation of PLG chains inside the delivery device. Consequently, the protein in the polymeric matrix is exposed to a microenvironment of increasing acidity. In combination with elevated temperatures and hydrophobic surfaces, sensitive proteins are known to become inactivated [12].

In spite of considerable efforts, drug release rates often deviate from an ideal “infusion like” profile, generated by zero-order release kinetics. Polyphasic drug release profiles can be modified either by formulation approaches or by selection of more appropriate biodegradable polymers. While the release properties of biodegradable microspheres can be influenced to a limited extent by formulation ameters, polymer modifications provide a broader spectrum of control during the erosion phase.

Two strategies have been proposed for modifications of polyesters with regard to parenteral protein drug delivery [5], [13]: for one, increasing polyester hydrophilicity should result in faster water uptake and swelling of the polymer matrix, affecting protein release during pore-diffusion phase [14], [15]. Or secondly, grafting short PLG chains onto hydrophilic backbone molecules should lead to graft polymers with accelerated erosion behavior, because the degradation products become soluble in water after few cleavage steps [16], [17].

The aim of this study was to investigate the effect of grafting hydrophobic PLG onto poly(vinyl alcohol) (PVA) with respect to both physico-chemical properties of the branched PVA-g-PLG, as well as functional properties as biodegradable carriers, namely degradation and release properties [5], [18], [19], [20], [21], [22].

Section snippets

Polymer synthesis

The following designation will be used to specify different PVA-g-PLGs, aa-bb-cc, the first digits (a) designate the molecular weight of the PVA backbone in g/mol×1000, followed by the degree of hydrolysis (b) and (c) the relative amount of backbone hydroxyl groups per carboxylic acid repeating unit in mol%. The synthesis and characterization of PVA-g-PLG was reported earlier [22]. Briefly, ring-opening polymerization of lactide and glycolide in the presence of the backbone PVA was carried out

Results and discussion

The branched structure of PVA-g-PLG can be adjusted by variation of feed composition and reaction conditions [22]. Using PVA as backbone, polymers with higher molecular weights are obtained (e.g. polymers 1 and 6, Table 1), than those accessible with linear PLG under similar reaction conditions [22]. Low content of PVA in the feed, corresponding to few polymerization propagation centers, yielded PVA-g-PLG with very high Mw (HMW-PVA-g-PLG). In this case up to ca. 300 PLG chains are connected to

Conclusions

Manipulation of both the three-dimensional structure and the hydrophilicity of polyesters by grafting PLG chains onto PVA as backbone resulted in biomaterials with attractive properties, especially for the controlled delivery of hydrophilic proteins and peptides. It was possible to change the degradation and erosion profiles by parameters, such as PLG chain lengths and composition as well as PVA molecular weight in a systematic manner. The degradation mechanism can be switched from bulk to a

Acknowledgements

Support of the project Ki 592-I-I by Deutsche Forschungsgemeinschaft is gratefully acknowledged.

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