Polymers–gamma ray interaction. Effects of gamma irradiation on modified release drug delivery systems for oral administration

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Abstract

The aim of this work is to verify the efficiency of two kinds of matrix tablets formulations containing PEO or PVA as retarding polymer. Moreover, since in the last years the exposure to ionizing radiation is a more and more used method to reduce bacterial charge in pharmaceutical products, the effects of gamma irradiation on these two kinds of polymers has been evaluated. The study is performed on matrix tablets containing diltiazem HCl, as model drug, and polyethylene oxides (PEO) of two different molecular weights or polyvinylalchool (PVA) of medium degree of hydrolysis, as drug release modulators. Dissolution of the matrices, release of diltiazem and morphological behaviour of the samples, before and after exposure to increasing doses of gamma irradiation, are investigated in order to verify their stability.

The results show that the ionizing radiation does not modify significantly the dissolution trend of the PVA samples; on the contrary, the dissolution and the morphological behaviour of the PEO matrices is strongly affected by the radiation dose received. In particular, the dissolution rate of the irradiated PEO tablets dramatically increases as a function of the irradiation dose and the swelling process, which characterised the non-irradiated PEO samples, was replaced by a rapid erosion process responsible for the quickly dissolution of the matrices. The changes of the dissolution and morphological PEO tablets performances could be explained by a breaking of the polymeric chains (shown by EPR studies) as a consequence of the exposure to gamma rays. These chemical–structural modifications of the polymers are responsible for the reduced efficacy of the PEO systems in controlling the drug release rate.

Introduction

Matrix systems, composed of an active drug dispersed in a hydrophilic soluble polymer, are the most commonly used extended release dosage forms for oral administration.

During dissolution, matrix tablets containing these kinds of polymers swell upon contact with the dissolution medium and form a gel layer at their surface (Hogan, 1989). The gel layer, its texture and thickness controls the drug release process. The characteristics of the layer depend on the solvent penetration rate, on the degree of swelling and on the erosion rate of the matrix. Among the hydrophilic polymers employed in the preparation of matrix type oral dosage forms, hydroxypropylmethylcellulose (HPMC) is the most commonly used. Recently it has been demonstrated that also polyethylene oxide (PEO) can be used as retarding polymer in the formulation of oral drug delivery system (Maggi et al., 2000). This is a good candidate for the use in matrix tablets (Kim, 1995, Kim, 1998): PEOs have good hydration and swelling properties, are not affected by the pH of the gastrointestinal tract, thanks to the non-ionic properties of the polymer, and the drug release process is independent from the environmental pH (Polyox, Technical Bulletin).

The drug release kinetics from PEO matrix tablets is strongly related to the polymer molecular weight. The release mechanism can be governed by swelling and drug diffusion or by swelling and polymer erosion depending upon the percentage and on the molecular weight of the PEO used. Generally, for low molecular weight products the prevailing mechanism of drug release is the polymer erosion rate, whereas, for high molecular weight, swelling of the polymeric material is the dominant step in controlling release kinetics (Apicella et al., 1993, Cappello et al., 1994).

Polyvinylalcohol (PVA) is used in the form of crosslinked hydrogel in a large number of biomedical applications (such as contact lenses, implants and artificial organs). Recently, this polymer has been used as a drug release modulator in the formulation of hydrophilic matrix tablets (DiLuccio et al., 1994, Quintanar-Guerrero et al., 1999, Moeckel and Lippold, 1993). PVA is a swellable polymer; its swelling behaviour depends on the degree of hydrolysis of the corresponding polyvinylacetate precursor. In fact, if the polymer is completely hydrolysed, it acts as a disintegrant because in water it swells but does not form a gel layer because of intra- and inter-molecular hydrogen bonds between polymer hydroxyl groups. But, the presence of acetate groups in the polymer weakens the inter-molecular hydroxyl bonds and the polymer is able to gelify.

The aim of this work is to verify the efficiency of two kinds of matrix tablet formulations, containing PEO or PVA (characterised by a degree of hydrolysis of 88 mol%) as retarding polymers. Moreover, since in the last years the exposure to ionizing radiation is a more and more used method to reduce bacterial charge in food, cosmetic and pharmaceutical products, the stability of these two kinds of polymers after gamma irradiation has been evaluated.

The study is performed on matrix tablets, containing diltiazem hydrochloride, as model drug, and polyethylene oxide (PEO) of two different molecular weights or polyvinylalcohol (PVA) of medium degree of hydrolysis, as drug release modulators. The dissolution and morphological behaviour of the matrices, before and after exposure to increasing doses of gamma rays, are investigated in order to verify their stability.

In a recent work Maggi et al. (2003) investigated the chemical stability of diltiazem HCl to gamma irradiation. The EPR analysis showed the presence of degradation products, but the HPLC measures revealed that no significant differences were found in the drug content of the HPMC tablets before and after irradiation at the maximum level (50 kGy). This indicates that the DTZ degradation products formed (and detected by EPR) were present only on traces and drug content of the dosage forms is unchanged. Starting from the assumption that this drug is stable to gamma rays, the aim of the present work is to investigate if gamma radiation may be responsible for the alteration of the characteristics of the polymer employed as carrier able to control the drug release from the dosage form. EPR studies are carried out to define the possible modifications of the polymers induced by this high-energy radiation. Moreover, if any modification is detected, the polymer viscosity was measured before and after gamma irradiation.

Section snippets

Materials

Polyethylene oxide (Polyox WSR of molecular weights 2×106 and 7×106) was kindly donated by Union Carbide (Danbury, CT, USA) and diltiazem hydrochloride by Profarmaco S.p.A. (Milan, Italy). Polyvinylalcohol (Erkol W40-140) with a degree of hydrolysis of 88.7 mol% was supplied by Erkol-Acetex Chimica s.r.l. (Milan, Italy). A 4% (w/v) aqueous solution of PVA has a viscosity of 40 cps, Hoppler viscosity at 20 °C (values as stated by the supplier).

Methods

PEO and PVA matrices were prepared mixing the polymer

Results and discussion

The data from dissolution tests performed on the three formulations (W40, X2 and X7) were analysed with the empirical equation (Ritger and Peppas, 1987):MtM=ktnwhere Mt/M is the fraction of drug released; k is a constant characteristic of the system and n is the exponent for the release kinetics. For n=0.5 drug release follows a Fickian transport mechanism, 0.5<n<1 represents an anomalous diffusion and n=1 a zero order release kinetic. A linear regression analysis of the logarithmic form of

Conclusions

The exposure to increasing doses of gamma irradiation has different effects on the polymers employed in this work as drug modulators: PVA tablets are not affected by this kind of radiation and are able to guarantee a good control of the drug release process even after irradiation with higher dose level. On the other hand, PEO matrices are strongly affected by gamma irradiation and their ability to control drug release fails. Before and after irradiation, a different dissolution and

Acknowledgements

This work was supported by the Ministero dell’Istruzione, dell’Università e della Ricerca (COFIN 2002) and by the University of Pavia (Progetto di Ateneo).

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