Steven M. Dinh

Intelligent Materials for Controlled Release

This volume examines recent developments in the use of intelligent materials and systems for drug delivery. Controlled release technology is moving from being a simple carrier of active agents to becoming a powerful and flexible method that permits subtle modulation of the delivery profile based on the needs of the biological host. The chapters collected here cover recent advances in materials with responsive properties, novel concepts in controlled release technology, new applications, and microanalytical techniques for rapid and accurate measurements of small samples.

An in vivo investigation of the rabbit skin responses to transdermal iontophoresis.

To optimize the benefits of transdermal iontophoresis, it is necessary to develop a suitable animal model that would allow for extensive assessments of the biological effects associated with electro-transport. Rabbit skin responses to iontophoresis treatments were evaluated by visual scoring and by non-invasive bioengineering parameters and compared with available human data. In the current density range 0.1-1.0 mA/cm(2) applied for 1 h using 0.9% w/v NaCl and 0.5 mA/cm(2) for up to 4 h, no significant irritation was observed. 2 mA/cm(2) applied through an area of 1 cm(2) for 1 h resulted in slight erythema at both active electrode sites but without significant changes in transepidermal water loss (TEWL) and laser Doppler velocimetry (LDV). A value of 4 mA/cm(2) under similar conditions caused moderate erythema at the anode and cathode with TEWL and LDV being significantly elevated at both sites; 1 mA/cm(2) current applied for 4 h, caused moderate erythema at both anode and cathode; and 1 mA/cm(2) applied for 1 h caused no irritation when the area of exposure was increased from 1 to 4.5 cm(2). When significant irritation and barrier impairment occurred, the erythema was resolved within 24 h with barrier recovery complete 3-5 days post-treatment. Rabbit skin thus shows promise as an acceptable model for iontophoresis experiments.

Transdermal iontophoretic delivery of methylphenidate HCl in vitro

Methylphenidate is prescribed orally for Attention Deficit Disorder in children and adults, and for narcolepsy patients. Methylphenidate has a short plasma half-life (1-2 h) and thus needs to be frequently administered for effective therapy. Such therapy has limitations in terms of patient compliance, particularly in young children. For such reasons, the development of a transdermal dosage form of methylphenidate may be useful. This study was undertaken to evaluate the passive and electrically assisted transport (iontophoresis) of methylphenidate from aqueous methylphenidate hydrochloride solutions across excised human skin. A maximum flux of 12.0 micrograms/(cm2 h) of protonated methylphenidate was estimated from the passive transport data at pH 3.5. Iontophoresis significantly enhanced protonated methylphenidate transport as compared with passive delivery. From the present experiments, the efficiency of iontophoretic delivery of methylphenidate was approximately 700 micrograms/(mA h). Based on in vitro skin flux data, the daily dose of 15-40 mg methylphenidate can be achieved using a current density of 0.5 mA/cm2 and a minimum transport area of 2-5 cm2 for 24-h application, or an area of 4-10 cm2 for 12-h (daytime) application. From methylphenidate skin flux values, methylphenidate mobility of 2.2 x 10(-4) cm2/(V s) was estimated, which compares reasonably with its free solution mobility of 6.6 x 10(-4) cm2/(V s).

Microelectrochemical systems for drug delivery

Iontophoresis is the transport of a therapeutic compound through the skin by means of an electrical current. In iontophoretic applications, the skin resistance is highly variable (10 kΩ cm 2 -5 MΩ cm 2 ), current levels are high (0.1-10 mA) and treatment durations are short ( < 24 h). Small size batteries for portable applications (watches, calculators) are optimized for low current levels and a long operational lifetime. Current battery technologies are not suited for iontophoresis applications, hence, new battery technologies are a prerequisite to fully exploit the therapeutic advantages of iontophoresis.

Enhanced transport in a therapeutic transdermal system.

Ethanol was incorporated into a transdermal therapeutic device to enable the controlled delivery of enhancer and drug to the skin surface. A variety of control membrane laminates were examined for swelling and adhesion strength following equilibration with ethanolic solutions to identify a mechanically stable control membrane laminate. In vitro skin permeation analysis of the control membrane laminate showed that ethanol flux was linearly related to the ethanol volume fraction. A reservoir-type therapeutic transdermal system incorporating ethanol was developed to provide constant release of drug and ethanol through skin for 24 h. In vitro ethanol skin permeation rates were constant for 24 h and adhesion was stable over 16 wk at 40 degrees C using a transdermal reservoir device.

Sorption and transport of ethanol and water in poly(ethylene-co-vinyl acetate) membranes

Abstract The ability to control the fluxes and the relative composition of multiple species permeating across a membrane would be invaluable to the design of controlled release systems. The counter-diffusion of ethanol and water across poly(ethylene-co-vinyl acetate) [P(E-co-VAc)] membranes was investigated as a case study. Ethanol and water fluxes across these membranes were measured from the changes of the refractive indices in the donor and receiver solutions. Ethanol and water solubilities in the membranes were determined by a sorption and desorption method. Ethanol absorption followed a Flory-Huggins isotherm, whereas water absorption exhibited a maximum due to opposing factors between the plasticization of the membrane by ethanol and the driving force of water. Ethanol and water diffusivities in the membranes were calculated from the flux and solubility data. In a 37% vinyl acetate P(E-co-VAc) membrane, ethanol permeability was found to increase exponentially with ethanol activity in the membrane; whereas water permeability decreased with water activity in the membrane. Transport models were developed to estimate ethanol and water fluxes across a 37% vinyl acetate P (E-co-VAc) membrane, given any set of compositions in the donor and receiver solutions. The counterdiffusing fluxes of ethanol and water across this membrane were found to be approximately linearly dependent. Additionally, the model suggested that a 37% P (E-co-VAc) membrane slightly favors water over ethanol, in separating ethanol and water by pervaporation.

Temporally controlled transdermal system: biphasic transdermal delivery of nitroglycerin

Abstract A novel biphasic transdermal drug delivery system was developed to provide a technology of varying the temporal rate of the drug input to optimize the chronopharmacological response. The biphasic profile of a drug across skin was obtained by using a permeation enhancer to provide a high initial flux, and a subsequently lower flux by the rapid depletion of the enhancer from a finite volume reservoir. A pseudo-steady-state model was developed to guide the formulation and the design of this system. The performance of a nitroglycerin biphasic transdermal system was demonstrated in vitro, using aqueous ethanol as an enhancer.

In vitro characterization of a solvent-controlled nitroglycerin transdermal system

A well-controlled solvent-based system for transdermal delivery of nitroglycerin has been developed. This system is fully characterized with respect to the effect of ethanol and nitroglycerin concentration in the reservoir on the steady-state flux profile in vitro. The nitroglycerin flux and ethanol flux through the system and skin are linearly proportional to the ethanol concentration in the donor compartment of the system. The ethanol volume fraction in the donor controls the permeability of the CML/skin laminate. As ethanol concentration controls the flux of nitroglycerin from the system through skin, it is possible to reduce intersubject variation in nitroglycerin transdermal delivery through the transdermal system design.