Ronald A. Siegel

pH-controlled release from hydrophobic/polyelectrolyte copolymer hydrogels

Abstract Hydrophobic polyamine copolymer hydrogels, loaded with caffeine, release the drug at rates that vary sharply with pH. At neutral pH virtually no caffeine is released, while at pH 3 and 5 the drug is released with near-zero order kinetics, the release rate being greater at pH 3. Water sorption was measured concurrently, and the release of caffeine closely follows water uptake at pH 3 and 5, providing strong evidence for a moving front mechanism for sorption and release.

Controlled release of polypeptides and other macromolecules.

The use of polymeric matrices for the controlled release of polypeptides and other macromolecular drugs is reviewed. Three principal mechanisms of release include diffusion of the polypeptide through the polymer, erosion of the polymer matrix, and the application of magnetic fields to force more drug out of the matrix. The diffusion controlled systems generally utilize ethylene-vinyl acetate copolymer. The advantage of these systems is facile manipulation of the pore structure to obtain desired release kinetics. Release of many different polypeptides from these systems for periods of months has been demonstrated. Bioerosion provides the advantage that the polymer system does not need to be retrieved. Magnetism provides a mechanism whereby desired increases and decreases in polypeptide release rates can be achieved on demand.

A hydrogel-actuated environmentally sensitive microvalve for active flow control

This paper reports on the fabrication and test of a hydrogel-actuated microvalve that responds to changes in the concentration of specific chemical species in an external liquid environment. The microvalve consists of a thin hydrogel, sandwiched between a stiff porous membrane and a flexible silicone rubber diaphragm. Swelling and deswelling of the hydrogel, which results from the diffusion of chemical species through the porous membrane is accompanied by the deflection of the diaphragm and hence closure and opening of the valve intake orifice. A phenylboronic-acid-based hydrogel was used to construct a smart microvalve that responds to the changes in the glucose and pH concentrations. The fastest response time (for a pH concentration cycle) achieved was 7 min using a 30-/spl mu/m-thick hydrogel and a 60-/spl mu/m-thick porous membrane with 0.1 /spl mu/m pore size and 40% porosity.

Fundamentals and applications of controlled release drug delivery

The Need for Drugs and Drug Delivery Systems.- Overview of Controlled Release Mechanisms.- Hydrophobic Polymers of Pharmaceutical Significance.- Hydrogels.- Biodegradable Polymers in Drug Delivery Systems.- Diffusion Controlled Drug Delivery Systems.- Swelling Controlled Drug Delivery Systems.- Degradable Polymeric Carriers for Parenteral Controlled Drug Delivery Systems.- Porous Systems.- Targeted Delivery Using Biodegradable polymeric Nanoparticles.- Liposomes in Drug Delivery.- Receptor Mediated Delivery Systems for Cancer Therapeutics.- Biological Rhythms, Drug Delivery, and Chronotherapeutics.- Site Specific Controlled Release for Cardiovascular Disease - Translational Direction.- Drug Delivery Systems to Fight Cancer.- Applications of Vaccine Delivery in Infectious Diseases.- Tissue Engineering in Drug Delivery.- The Shaping of Controlled Release Drug Product Development by Emerging Trends in the Commercial, Regulatory and Political Macro-Environment

An explanation for the controlled release of macromolecules from polymers

Abstract Controlled release systems composed of hydrophobic polymers such as ethylene—vinyl acetate copolymer have proven useful for releasing various polypeptides and other macromolecules for over 100 days. However, the release mechanism has never been elucidated. Evidence by microscopy is presented suggesting that release occurs through interconnecting pores formed by the macromolecules themselves. A mathematical model has been developed and used to predict the release rates of different proteins.

Hydrophobic weak polyelectrolyte gels: Studies of swelling equilibria and kinetics

This article summarizes studies of the equilibrium and kinetic swelling properties of a class of hydrophobic weak polyelectrolyte copolymer gels synthesized from n-alkyl methacrylates (hydrophobic) and N,N-dimethylaminoethyl methacrylate (weak base). We present evidence for a pH-driven swelling phase transition, and consider the effect of pH buffers on equilibria. A simple model based on ideal Donnan equilibrium is able to predict qualitative trends but is unsuccessful in making quantitative predictions of buffer effects on swelling equilibria. Buffers also strongly influence swelling kinetics. It is demonstrated that suitably chosen buffers can act as proton carriers which, under the right circumstances, speed up swelling and deswelling substantially.

Mechanistic studies of macromolecular drug release from macroporous polymers. II. Models for the slow kinetics of drug release

Abstract The release of protein drugs such as bovine serum albumin (BSA) from poly mers such as macroporous poly(ethylene-co-vinyl acetate) (EVAc) matrices has been shown previously to be much slower than would be predicted from simple considerations of aqueous diffusion. Since drug is released through waterfilled pores, it is necessary to determine the mechanism underlying release retardation. Three mechanisms are considered: (1) concentration-dependent diffusion, (2) random pore topology, and (3) constricted pore geometry. The first two mechanisms are shown to be insufficient, in themselves or together, to account for the order of magnitude of retardation that is observed. The third mechanism, pore constrictions, can account for arbitrarily high retardations. Since the three mechanisms are essentially independent, their contributions to retardation can be considered to be multiplicative.

Engineering Targeted In Vivo Drug Delivery. I. The Physiological and Physicochemical Principles Governing Opportunities and Limitations

A physiologically based model is presented to aid prediction of the pharmacological benefits to be derived from the administration of a drug as a targeted drug–carrier combination. An improvement in the therapeutic index and an increase in the therapeutic availability are the primary benefits sought. A measure of the former is obtained from the value of the drug targeting index, a newly derived parameter. Both the drug targeting index and the therapeutic availability are directly calculable. The minimum information needed for approximating both parameters is the candidate drugs total-body clearance and some knowledge of the target sites anatomy and blood flow. Drugs with high total-body clearance values that are known to act at target tissues having effective blood flows that are small relative to the blood flow to the normal eliminating organs will benefit most from combination with an efficient, targeted carrier. Direct elimination of the drug at the target site or at the tissue where toxicity originates dramatically improves the drug targeting index value. The fraction of drug actually released from the carrier at both target and nontarget sites can radically affect index values. In some cases a 1% change in the fraction of the dose delivered to the target can result in a 50% change in the drug targeting index value. It is argued that most drugs already developed have a low potential to benefit from combination with a drug carrier. The approach allows one to distinguish clearly those drugs that can benefit from combination with targeted in vivo drug carriers from those drugs that cannot.

Mechanistic studies of macromolecular drug release from macroporous polymers. I: Experiments and preliminary theory concerning completeness of drug release

Abstract The release of the model polypeptide drug bovine serum albumin (BSA) from macroporous ethylene-vinyl acetate copolymer matrices has been investigated over a wide range of drug loadings and particle sizes. At low drug loadings a fraction of the drug is released relatively quickly from the matrix surface, but the remainder of the drug is virtually trapped within the matrix and is released at an extremely slaw rate. At high drug loadings all drug is released. A simple model of drug trapping, based on a modification to percolation theory, is proposed. The model predictions are qualitatively in agreement with the data, but are unable to predict certain quantitative features. It is suggested that the discrepancies are due to a nonuniform distribution of drug in the matrices, which is shown to exist by scanning electron microscopy.

Hard and soft micro- and nanofabrication: An integrated approach to hydrogel-based biosensing and drug delivery

We review efforts to produce microfabricated glucose sensors and closed-loop insulin delivery systems. These devices function due to the swelling and shrinking of glucose-sensitive microgels that are incorporated into silicon-based microdevices. The glucose response of the hydrogel is due to incorporated phenylboronic acid (PBA) side chains. It is shown that in the presence of glucose, these polymers alter their swelling properties, either by ionization or by formation of glucose-mediated reversible crosslinks. Swelling pressures impinge on microdevice structures, leading either to a change in resonant frequency of a microcircuit, or valving action. Potential areas for future development and improvement are described. Finally, an asymmetric nano-microporous membrane, which may be integrated with the glucose-sensitive devices, is described. This membrane, formed using photolithography and block polymer assembly techniques, can be functionalized to enhance its biocompatibility and solute size selectivity. The work described here features the interplay of design considerations at the supramolecular, nano, and micro scales.