Christopher S. Brazel

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

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.

Modeling of drug release from Swellable polymers

The water Swelling and drug diffusion from initially hydrophilic, glassy polymer matrices were modeled using concentration-dependent diffusion equations for water and drug. The transport equation for water incorporated a relaxation-dependent mechanism. These equations were solved with an appropriate boundary condition incorporating a relaxation-dependent Deborah number. Experimental results from drug release from PVA and PHEMA samples were used to determine the validity of the model.

Pulsatile local delivery of thrombolytic and antithrombotic agents using poly(N-isopropylacrylamide-co-methacrylic acid) hydrogels

Hydrogels of poly(N-isopropylacrylamide-co-methacrylic acid) were synthesized and investigated as pH- and temperature-triggered delivery devices for antithrombotic agents. For hydrogels containing greater than 75 mol% NIPAAm, the pH and temperature sensitivity both influenced the overall swelling behavior of the networks. Streptokinase and heparin were loaded into these hydrogels and their release characteristics were determined under pulsatile conditions. The hydrogels synthesized in this study were capable of pulsatile streptokinase release, with at least one order of magnitude difference in release rates between the swollen and collapsed hydrogel states. However, the much smaller heparin molecule diffused equally rapidly in the collapsed and swollen polymer states.

Dimensionless analysis of swelling of hydrophilic glassy polymers with subsequent drug release from relaxing structures.

Two dimensionless parameters, the diffusional Deborah number, De, and the swelling interface number, Sw, were used as indicators of solvent and solute transport behavior in swellable hydrogel systems. Polymer relaxation and concentration-dependent diffusion led to dynamically swelling polymers which displayed Fickian, Case II, or anomalous transport behavior. Experimental systems studied included crosslinked samples of poly(vinyl alcohol), designated PVA, and poly(2-hydroxyethyl methacrylate-co-methyl methacrylate), designated P(HEMA-co-MMA). Model solutes with molecular weights ranging from 200 to 17,000 were used to investigate release properties from these networks. Characteristic polymer relaxation times and swelling front velocities were determined experimentally. To gain an understanding of how polymer morphology and solute properties affected transport behavior, the calculated values of De and Sw were correlated to the diffusional exponent, n, used commonly to indicate the time dependence of sorption and release. The swelling interface number was found to correlate particularly with the transport kinetics, indicating anomalous and Case II solute transport when the Sw values were near 1.0.

Temperature- and pH-sensitive terpolymers for modulated delivery of streptokinase

Controlled release devices were designed which respond to changes in pH and temperature by reversibly swelling and deswelling to control release of streptokinase. Copolymer hydrogels composed of N-isopropylacrylamide (NIPAAm) and methacrylic acid (MAA) as well as terpolymer hydrogels containing NIPAAm, acrylic acid (AA), and 2-hydroxyethyl methacrylate (HEMA) were synthesized. Hydrogels containing NIPAAm display a change in swelling behavior across the lower critical solubility temperature of PNIPAAm, whereas hydrogels with MAA and AA swelled only at high pH values due to the ionization of carboxylic pendant groups. HEMA was chosen as a third component to add mechanical strength and integrity to the hydrogel. Pulsatile pH- and temperature-dependent swelling studies were performed to determine the extent and rate at which the hydrogels swell in response to changing conditions. Results showed that increasing the NIPAAm concentration in the copolymers or terpolymers resulted in a higher degree of temperature-sensitive swelling. Synthesis of a terpolymer in which segments rich in NIPAAm were distributed within P(AA-co-HEMA) chains led to hydrogels displaying increased temperature sensitivity. Streptokinase was incorporated into the hydrogels, and its release was observed under the combined effects of temperature and pH. The streptokinase release pattern followed the swelling state of the hydrogel, with drug release occurring at a significantly higher rate from the most swollen hydrogels.

Temperature- and pH- Sensitive Hydrogels for Controlled Release of Antithrombotic Agents

Polymeric hydrogels capable of reversible swelling with changes in environmental temperature and pH were synthesized and studied as matrix systems capable of controlled release of antithrombotic drugs to the site of a blood clot. Monomers N-isopropylacrylamide (NIPAAm) and methacrylic acid (MAA) were chosen for the temperature- and pHdependent swelling characteristics of their polymers, respectively. Equilibrium swelling studies were performed as functions of pH and of temperature, and kinetic swelling studies were performed on the thermally responsive gels as a function of time after the gel was subjected to a step-change in temperature. Experimental results indicate that P(NIPAAmco- MAA) hydrogels can be synthesized so that they are either pH- or temperaturesensitive, depending upon the composition of the network. The pure PNIPAAm gels showed a lower critical solubility temperature (LCST) of around 32°C, below which the gel was in its swollen state, and above which the gel collapsed. As the amount of methacrylic acid in the gels was increased, the degree of swelling in deionized water decreased and the temperature sensitivity was lost. The hydrogels containing MAA displayed a transition in swelling behavior between pH 4 and 6. The mesh sizes of the hydrogel networks were calculated from the results of the swelling studies by Flory-Rehner theory. A kinetic experiment on the temperature-sensitive pure PNIPAAm hydrogel showed that the polymer network collapsed rapidly upon temperature changes across the LCST.

Controlled Release Systems Using Swellable Random and Block Copolymers and Terpolymers

Recent advances on the use of N-isopropyl acrylamide-containing random and block copolymers and terpolymers are presented. Such systems are shown to be dependent on temperature and pH (if acrylic acid is an added comonomer). Their temperature-dependence is significantly increased in the presence of block domains prepared by co- or terpolymerization. They are suited for release of fibrinolytic enzymes and anti thrombotic agents. Ultrapure poly(vinyl alcohol) gels are also studied for release of ketansarin and related wound healing enhancers.