Polymers–gamma ray interaction. Effects of gamma irradiation on modified release drug delivery systems for oral administration
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):where 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).
References (19)
- et al.
Poly(ethylene oxide) (PEO) and different molecular weight PEO blends monolithic devices for drug release
Biomaterials
(1993) - et al.
Press-coated tablets for time-programmed release of drugs
Biomaterials
(1993) - et al.
Sustained-release oral delivery of theophylline by use of polyvinyl alcohol and polyvinyl alcohol-methyl acrylate polymers
J. Pharm. Sci.
(1994) Mechanism of sustained action medication. Theoretical analysis of rate of release of solid drug dispersed in solid matrices
J. Pharm. Sci.
(1963)Drug release from compressed hydrophilic POLYOX-WSR tablets
J. Pharm. Sci.
(1995)- et al.
High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage forms
Int. J. Pharm.
(2000) - et al.
Chemical and physical stability of hydroxypropylmethylcellulose matrices containing diltiazem HCl after gamma-irradiation
J. Pharm. Sci.
(2003) - et al.
A simple equation for description of solute release. I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or disc
J. Control. Release
(1987) - et al.
Water soluble drug delivery system based on a non-biological bioadhesive polymeric system
Il Farmaco
(1994)