Mechanisms of solute and drug transport in relaxing, swellable, hydrophilic glassy polymers

Abstract

Water and solute or drug transport in crosslinked polymeric materials was investigated to determine the effects of polymer morphology, composition and solute properties on transport behavior. Two crosslinked polymer systems, poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (P(HEMA-co-MMA)) and poly(vinyl alcohol) (PVA), were used in water transport and solute release experiments. Structural parameters of the polymers investigated in this work included the initial polymer molecular weight, the nominal crosslinking ratio, and the copolymer composition. Swelling rates, water diffusion coefficients and the diffusional Deborah number, De, were used to characterize the water uptake process. Swelling rates correlated well with the polymer network mesh sizes; the slowest rate of water uptake was observed in P(HEMA-co-MMA) samples containing large quantities of methyl methacrylate. Initial crosslinking ratios had a sizable effect on water uptake in crosslinked PVA samples but not in the P(HEMA-co-MMA) polymers. Drug release rates, drug diffusion coefficients and the swelling interface number, Sw, were used to characterize solute transport. Release experiments were conducted using eight solutes: theophylline, triamterene, oxprenolol HCl, buflomedil HCl, vitamin B₁₂, dextran, inulin and myoglobin. Release rates decreased with increasing solute molecular weight. A molecular weight cut-off, beyond which drug release was greatly hindered by the hydrogel mesh size, was established for each polymer tested.

Introduction

Controlled delivery of bioactive agents has been a major field of research over the last 30 years. A variety of methods have been used to target biologically active molecules to specific sites and extend their therapeutic lifetimes once inside the body. Polymeric drug carrier systems have several advantages in optimizing patient treatment regimes. In particular, swelling-controlled release systems [1] are capable of delivering drugs at constant rates over an extended period of time. In these systems, the rate of drug delivery is controlled by the balance between drug (solute) diffusion across a concentration gradient, the polymer relaxation occurring as the crosslinked polymer imbibes water, and the osmotic pressure occurring during the swelling process [2], [3]. This osmotic pressure is related to the high drug concentration inside the network. Swelling-controlled release systems are particularly valuable [1], [3], due to possibilities of achieving zero-order release. This is done by modification of the transport properties of the device, and by engineering specific polymer carriers.

An important goal of drug delivery is to obtain a constant release rate for a prolonged time. Therefore, Case II transport, in which transport rates are independent of time, has been investigated by many researchers [2], [3], [4] in attempts to create long-term drug delivery devices. Several efforts to achieve zero-order drug delivery have been made, including creative device geometries, front synchronization [5], [6] and parabolic initial drug concentration profiles [7]. Swelling-controlled hydrogels and membrane reservoir devices have so far shown the most promise.

Penetrant uptake behavior into crosslinked polymers has been investigated over the past several decades, with notable contributions made to the understanding of deviations from classical Fickian diffusion [8], [9], [10], [11]. This general behavior, known as anomalous transport, is bound by pure Fickian diffusion and Case II transport which have been observed in several polymer/penetrant systems [11]. Transport in all of these physical situations can generally be reduced to three types of driving forces: a penetrant concentration gradient, a polymer stress gradient, and osmotic forces.

Swelling-controlled release systems are based on the above principles, where a polymeric carrier can counterbalance normal Fickian diffusion by hindering the release of an imbedded solute or drug, leading to an extended period of drug delivery under zero-order release conditions [12]. In addition, the presence of a polymer network surrounding a drug or protein molecule has also been shown to act as a stabilizer [13], maintaining biological activity until the solute is released.

Many experimental variables can affect water uptake in glassy polymers. The effects of sample geometry on water uptake as described by the power law model presented in Eq. (1) have been investigated previously [14], [15]. Here, M_t/M_∞ is the fractional drug released from the polymer at time, t, and n is a diffusional exponent that determines the release mechanism.

$$\text{M}{}_{\mathrm{<mtext>t</mtext>}}\text{M}{}_{\mathrm{\infty }}\text{=kt}{}^{\mathrm{n}}$$

The effects of crosslinking density [16], drug loading [4], and copolymer composition [13] on swelling kinetics have also been determined experimentally for specific systems. Recently, Colombo et al. [17] determined that there is a strong correlation between swelling front motion, or the sharp barrier between glassy and swollen regions in the polymer, and drug release kinetics, with Case II drug release resulting when water diffusional and polymer dissolution fronts are synchronized. However, Eq. (1) may be less applicable to polymers releasing high-molecular-weight drugs.

Swellable hydrophilic polymers have been used for the purpose of prolonged drug delivery and drug targeting [3]. Delivery systems based on relaxing hydrogels are capable of slow release of an imbedded drug, with release controlled by the rate of swelling and relaxation of the polymer [1], [18].

One of the first observations of non-Fickian transport in a matrix device was made by Roseman and Higuchi [19], who studied the release of drugs from silicone matrices. Although these were not swellable systems, experimental findings showed that drug interactions with the polymer caused deviations from Fickian diffusion. The effects of polymer/drug interactions and loading concentration on drug release profiles can be very pronounced as shown by Pham and Lee [20] who investigated the front behavior in three grades of hydroxypropylmethyl cellulose loaded with fluorescein as a model drug. Similarly, Brown et al. [21] studied the effects of osmotic pressure on sodium salicylate release from non-swellable matrices. Super Case II transport was observed due to a large increase in osmotic pressure driving forces at the time when solvent fronts met.

In our research group, there has been much work on controlled release from swellable systems. For example, we have shown [8], [9], [22] that solute size and polymer composition had profound effects on release profiles. We also developed [23] a model to predict solute diffusion in polymers. In this model, the presence of the polymer network could retard solute diffusion, through three primary variables: the molecular weight between crosslinks, the equilibrium volume swelling ration, and the solute radius.

Swelling and relaxational behavior of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (P(HEMA-co-MMA)) polymers were observed by Davidson and Peppas [4] who determined polymer relaxation times by mechanical stress relaxation experiments and used them to calculate the diffusional Deborah number (De), a dimensionless parameter relating solvent uptake to macromolecular relaxation. Korsmeyer et al. [9] investigated significant dimensional changes during swelling, monitored these swelling fronts using polarized light, and studied the effect of polymer composition on drug release. They were also able to estimate diffusion coefficients through pulsed gradient spin echo nuclear magnetic resonance (PGSE-NMR) spectroscopy.

Franson and Peppas [13] observed the swelling front motion using polarized light to view stressed regions in P(HEMA-co-MMA) and related gels when exposed to water. They noted the importance of gel history on the swelling behavior. After a dry sample was swollen to equilibrium, some macromolecular chains could be disentangled to yield a different structure and different swelling kinetics upon subsequent swelling processes. They also correlated the diffusional exponent, n, of Eq. (1) to polymer composition. They introduced the swelling interface number, Sw, as an important dimensionless parameter to characterize water transport in comparison to solute release. They showed that Sw values correlated with the order of release, n, in an inverse logarithmic fashion. Finally, Ritger and Peppas [15] studied various sample geometries, and determined appropriate values of n for spherical, cylindrical and planar devices. In addition, they used the aspect ratio to determined the appropriate exponent for a system varying from 0.5 for slab geometries to 0.43 for cylinders, to 0.45 for spheres.

Despite the extensive pharmaceutically-relevant literature that shows unequivocally that anomalous and Case-II transport of water has been observed in many systems, it is disheartening to read the disorientation applied by certain researchers in the pharmaceutical field [24] who claim that relaxation has never been observed in water/polymer systems! The present work is one more proof of the failure of such sweeping statements in the pharmaceutical literature.