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Introduction Electronically Assisted Drug Delivery: An Overview, B. Berner and S.M. Dinh Home-Based Circadian Optimized Cancer Chemotherapy, W.J.M. Hrushesky Fundamentals Electrical Properties of Skin, J. Singh, S. Dinh, and B. Berner Skin Tolerability: Irritation, S. Amin and H. Maibach Pharmacokinetics and Dynamics of Temporal Delivery, R.R. Burnette Microelectronics, S. Wouters Iontophoresis of Peptides, M.B. Delgado-Charro and R.M. Guy Technical Applications Glucose Monitoring Using Electroosmotic Transdermal Extraction, J.A. Tamada and R.O. Potts Medtronic Synchro Med Infusion System, K. Heruth Electroporation, M. Prausnitz Phonophoresis, J. Kost Index Shelving Guide Category Pharmacology/Pharmaceutical Sciences Subcategory Controlled Release

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).

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 (

The iodate pH oscillator, which oscillates between pH 6.5 and 4.0, is reproducible in a semibatch reactor. pH oscillations of similar period and amplitude were observed when poly(2-acrylamido-2-methyl-1-propanesulfonic acid) was substituted for sulfuric acid. Therefore, a polymer may be used as an alternative reagent, where the polymer actively participates in the reaction instead of serving as an inert reaction medium.

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.

A novel approach to modulate the release of a drug or an active ingredient that avoids the need for external power sources or electronic controllers is described. By changing the pH of a solution relative to the pKa, a drug, enhancer, or solubilizer may be rendered charged or uncharged. Because only the uncharged form of a drug can permeate across lipophilic membranes, a temporally modulated delivery profile may be obtained with a pH oscillator in the donor solution. Ionizable permeants have a buffer capacity, so the feasibility of coupling the mixed Landoldt pH oscillator with membrane diffusion of nicotine or benzoic acid is demonstrated for a single oscillation.

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.

The time-dependent electrical resistance of human cadaver skin was shown to be found by an upper limit at equilibrium and a lower limit at steady state. The time to reach steady state from any initial condition by applying a current was much shorter than the recovery to equilibrium, due to different driving forces. The ratio of the equilibrium to the solution resistances increased with the salt concentration in free solution. This equilibrium relative resistance was sensitive to skin variability, primarily due to its dependence on porosity and pore geometry

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.

This paper describes the application of a pH-sensitive fluorescent probe [2',7'-bis(2-carboxylethyl)-5(6)-carboxyfluorescein or BCECF] to measure intracellular pH (pH(i)) changes in Caco-2 cells. As a function of BCECF's ionization, the fluorescence was monitored at lambda(ex)=440 and 503nm, and lambda(em)=535nm. Time course studies were conducted with the addition of two weak acid delivery agents, one weak base delivery agent, oleic acid, or tetradecylamine. When applicable, 10microM bovine serum albumin or 10mM ammonium chloride was added into the cell suspension to hinder the pH gradient effect. Adding a weak acid at 2, 10, or 50mM to the cell suspension, the pH(i) dropped substantially from 7.4 to 7.1, 6.9, or 6.7, respectively. The pH(i) then increased gradually over a 10-min period but did not return to its initial value. Conversely, the pH(i) increased instantaneously after the addition of a weak base. When Caco-2 cells were placed in solutions with different bulk pH (7.0, 7.5, and 8.0), the lower the pH in which the cells were exposed, the larger the pH(i) drop occurred with the addition of an acid. The results suggest that these weak acids or bases are transported transcellularly across Caco-2 cells.

PREFACE 1. Naked DNA-Mediated Gene Therapy: Clinical Application of Tissue Inhibitors of Matrix Metalloproteinase 2. Heparin and Gene Microarrays as a New Pharmacodynamic Tool 3. Oral Herparin Prevents Neointimal Growth Following Vascular Injury: Implications for Potential Clinical Use 4. Peptide Vector-Mediated Drug Delivery to the Brain 5. Systemic and Topical Lung Delivery Using the AER, System 6. Controlled Growth Factor Delivery for Tissue Engineering 7. Controlled Drug Delivery to Drug-Sensitive and Multidrug Resistant Cells: Effects of Pluronic Micelles and Ultrasound 8. Preparation of Novel Delivery of Macromolecular Drugs Using Boric Acid Mediated Amidation of Carboxylic Acids and Amenes 9. Loosely Cross-Linked Silicone Elastomer Blends and Topical Delivery 10. Hydrogels by Stereocomplex Formation and their Use As Drug DeliveryMatricies INDEXES AUTHOR INDEXES SUBJECT INDEXES

The concepts of drug delivery are described, focusing on the application of polymer chemistry to design a well-characterized controlled dosage form that produces the desired drug delivery profile. In order to design a system, both drug release from the system, ie, desorption or dissolution, and absorption across the relevant biological membrane are measured. The physiology and barrier properties of different routes of drug delivery, which include oral, rectal, transdermal, buccal, nasal, pulmonary, ocular, and vaginal, are described. The mechanisms that govern drug release from systems include diffusion (including osmotic), chemical, swelling, and external control, such as iontophoresis or electromechanical devices. Examples are given of commercially available systems from each class, including implants, oral osmotic devices, transdermal and ocular systems, and infusion pumps. Characterization of the physical and chemical properties of the system components is described, as well as the different types of manufacturing processes and characterization of the final system, including drug release and adhesion, if relevant. Keywords: Permeation; Drug delivery; Desorption; Routes; Classes; Controlled drug delivery systems; Diffusion controlled; Swelling; Osmotic control; Dydtems characterization; Membranes

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.

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.

A rheological equation of state is developed for a semiconcentrated suspension of stiff fibers in a Newtonian solvent with volume fraction φ in the range (D/L)2

Measurements are reported for the shear stress of a semiconcentrated suspension of rigid fibers in a Newtonian solvent in the startup of steady shear flow. There are n fibers each of length L per unit volume. A variety of different volume fractions of fibers was used; the fiber aspect ratio was varied as well. It is found that the viscous resistance of a randomly oriented fiber suspension is roughly (nL3) times the resistance observed when the particles lie in the planes of shear. The transient shear stress measurements show the rheological properties depend on the total strain and not on shear rate or time separately. Experiments were done in torsional flow between parallel plates separated by distance H to determine the effect of H/L on the measured properties. It is found that there is no effect for H/L>1. Two different models are presented to account for wall effects for H/L

A precise and rapid transient diffusion experiment has been developed to measure the diffusive permeability of hollow fibers. In this experiment a sealed hollow fiber containing a radioactive solute is exposed sequentially to several well-stirred solute-free reservoirs. This method was used to measure the diffusive permeability of collagen and Cuprophan hollow fibers in an isotonic saline solution for a spectrum of 14C labelled solutes: urea, sucrose and polyethylene glycol (PEG). To study the effect of environment on membrane permeability, collagen membranes were investigated with urea, sucrose and tritiated water in the following solutions with varying ionic strength and hydrogen ion concentration: pH2 HCl, distilled water and pH2 HCl with 0.8 M NaCl. In each environment, the membranes showed the expected decreases in diffusive permeaability with increasing molecular weight. Collagen membranes ranged from 4 (urea) to 40 (PEG) times the permeability of Cuprophan membranes. The Cuprophan data are consistent with results obtained elsewhere using scaled-down dialyzers. In response to environmental changes, the diffusive permeability of collagen membranes changed overall by a factor of 3 with the following rank: pH 2 HCl > distilled water > pH2 HCl and 0.8 M NaCl. The hydraulic permeability of these membranes changed by a factor of 2 but in a different order pH2 HCl > pH2 HCl and 0.8 M NaCl > distilled water. These permeability changes can be explained in terms of the known environmental dependence for the structure of collagen membranes and have been shown to be consistent with trends predicted by simple transport models.