Y. W. Chien

Iontophoretic delivery of drugs: Fundamentals, developments and biomedical applications

Abstract Iontophoretic drug delivery implies the delivery of ionic (charged) drugs into the body by the use of electric current. The technique is not new and has been used clinically in delivering medication to surface tissues for several decades. However, its potential is recently being rediscovered for transdermal systemic delivery of ionic drugs including peptide/protein drugs which are normally difficult to administer except by parenteral route. The technique has been observed to enhance the transdermal permeation of ionic drugs severalfold, and this can expand the horizon of transdermal controlled drug delivery for systemic medication. However, miniaturization of iontophoretic devices and electrodes and prevention of any possibility of skin burns are required to make this technique useful for biomedical applications. While the literature on iontophoretic systemic drug delivery is relatively recent and not extensive, the published results on clinical usage and other related aspects can be quite informative and could stimulate and assist the readers to explore other biomedical applications. This article is intended to review old as well as very recent literature on the technique, methodology, clinical findings, influencing factors, relevant electronics and other related aspects of iontophoretic drug delivery, and to provide the readers a comprehensive overview of the state-of-art of this potential new area of biomedical research.

Systemic delivery of therapeutic peptides and proteins

Abstract Peptide/protein drugs are increasingly becoming a very important class of therapeutical agents as a result of our gaining more understanding of their role in physiology and pathology as well as the rapid advances in the field of biotechnology/genetic engineering. These drugs are easily degraded by proteolytic enzymes in the gastrointestinal tract and thus are generally not suitable for oral administration. Currently, they are mostly delivered by parenteral administration. Because they are extremely short-acting, repeated injections are often required. To minimize the health hazard by constant injection, there is an urgent need to search for non-parenteral routes of administration as well as to develop formulations with controlled delivery features. Routes of administration that have been investigated include nasal, ocular, rectal, buccal and transdermal. The mode of delivery can also be very important. In the case of luteinizing hormone-releasing hormone analogs, opposite pharmacological effects could be observed depending on whether they are delivered in a pulsatile pattern or in a continuous manner. Self-regulating systems which will release drug based on the needs of the body (feedback mechanism) have also been developed for some peptide/protein drugs, like insulin. Special considerations are required for the formulation, pharmacokinetic and analytical aspects of peptide/protein drugs. Further work is needed on these aspects and on the routes of administration for commercial viability of therapeutic peptides/proteins.

Iontophoresis-facilitated transdermal delivery of verapamil I. In vitro evaluation and mechanistic studies

Abstract The feasibility of using iontophoresis to enhance the permeation rate of verapamil, in ionic form, was investigated in vitro using the skin of hairless mouse and hairless rat. A specially designed power source was used to deliver pulsed direct current. A number of physicochemical and electrochemical variables which might affect iontophoretic transport of the charged molecule were studied with an aim towards exploring the mechanisms involved. The permeation rate of verapamil ion (VH + ) was observed to increase with an increase in drug concentration, donor solution pH, as well as with current density. On the other hand, increasing the concentration of a competing ion, like Na + , in the donor was noted to first reduce the permeation rate of VH + and then cause some increase in drug flux. Using optimum iontophoresis conditions, the skin permeation rate of VH + can be enhanced substantially. This enhancement is due to both an increase in permeation rate and a decrease in lag time compared to passive diffusion.

Nasal delivery of progestational steroids in ovariectomized rabbits: I. progesterone — comparison of pharmacokinetics with intravenous and oral administration

Abstract Transnasal delivery of progesterone was studied in rabbits employing a nasal spray and a specially designed controlled delivery nasal device. The device is cylindrically shaped for better insertion into the nasal cavity, and is walled with a microporous membrane to permit controlled delivery of progesterone from a suspension formulation to the nasal mucosa. Ovariectomized New Zealand white rabbits were chosen as the animal model after preliminary studies which indicated that ovary-intact rabbits have significant fluctuations in endogenous progesterone levels. The pharmacokinetics of progesterone were evaluated in a cross-over study comparing i.v., oral, nasal device and nasal spray treatments. Using i.v. data as the reference, the systemic bioavailability of progesterone delivered by nasal device and nasal spray was calculated to be 72.4% and 82.5%, respectively. This was substantially greater than the oral bioavailability of 7.9%. The nasal device was observed to achieve a more prolonged and elevated plasma level of progesterone than the other routes of administration. The nasal spray and nasal delivery device will be employed as tools to study and to compare the effect of immediate and controlled drug release on nasal bioavailability of drugs.

In vitro apparatus for controlled release studies and intrinsic rate of permeation

Abstract The hydrodynamic characteristics of an in vitro apparatus for membrane moderated controlled drug release studies were investigated by measuring a dissolution rate from benzoic acid disk. An empirical correlation was developed for estimating the mass transfer coefficient. A simple method for correcting the effect of diffusion boundary layer on the rate of drug permeation was also described. The intrinsic rates of progesterone, testosterone and hydrocortisone through the silicone membrane were then evaluated by the correction method described.

Long-term permeation kinetics of estradiol: (IV) A theoretical approach to the simultaneous skin permeation and bioconversion of estradiol esters

AbstractA theoretical non-steady-state treatment was developed to analyze the kinetics of metabolism during the course of dermal uptake or skin permeation of estradiol esters across the hairless mouse skin. The first-order rate constants for the metabolism reaction of estradiol acetate → estradiol and estradiol diacetate → estradiol acetate → estradiol were determined. The theoretical drug concentration profile calculated from the present model was found to be agreed reasonably well with the experimental data determined in the early stage of skin uptake/metabolism studies (<24 hr). For the skin permeation of estradiol acetate and diacetate and their concurrent metabolism, the experimental Q vs. t profiles were also observed to agree well with the theoretical results for a period of up to 28 hr. A deviation was observed at later phase of experiments, which can be attributed to the reduction in enzyme activity during the permeation studies, possibly due to the result of skin aging.

Effect of physicochemical properties of adhesive on the release, skin permeation and adhesiveness of adhesive-type transdermal drug delivery systems (a-TDD) containing silicone-based pressure-sensitive adhesives

Abstract Adhesive dispersion-type transdermal drug delivery (a-TDD) systems consisting of a monolayer of drug-loaded adhesive matrix were developed from three types of silicone-based pressure-sensitive adhesives. The adhesive polymers were tailored such that two of them were lipophilic (Bio-PSA ® X7-2920 and Dow Corning ® -355 Medical Adhesive) and one was relatively hydrophilic (E8086 ® adhesive) in nature. Three steroids viz., progesterone, testosterone and hydrocortisone, were used as model penetrants and their release from the a-TDD systems and permeation through skin were investigated. The adhesive properties of these systems were also studied. The partial and total solubility parameters of these adhesive polymers were also determined. The release of steroid molecules was observed to be a complex function of the physicochemical properties of the drug and polymer. The adhesiveness as determined from a standard peel test indicated that incorporation of the drug in higher drug loading doses results in a loss of adhesiveness. The results suggest that the chemical nature of the polymer is an important consideration when studying such adhesives for transdermal drug delivery.

Controlled drug release from silicone coated tablets: preliminary evaluation of coating techniques and characterization of membrane permeation kinetics

Abstract Investigations were conducted to evaluate the feasibility of using a silicone elastomer as coating material to control the release of drugs from the oral tablet. A two-component silicone elastomer system was utilized to coat tablets fabricated from progesterone and some of its hydroxyl derivatives both with and without a binder. Several coating techniques were explored for application of polymer dispersion onto tablet surfaces on a laboratory scale. The effects of these methods on drug release were found to differ. The effect of tablet binder content on the release of drug was also evaluated. Another goal was to study the effects of drug structure on steroid permeation through the resulting applied silicone coatings.

Stratum Corneum Reservoir Capacity Affecting Dynamics of Transdermal Drug Delivery

AbstractA number of researches 1-5 have reported the observations of reservoir capacity in human stratum corneum since Vickers clearly demonstrated this phenomenon in 1963 6. Both lipophilic and hydrophilic drugs may be trapped in the matrix-structure of stratum corneum and diffuse out very slowly due to strong binding and/or markedly low diffusivlty (10 −10-10 −11cm 2 /S) 7, 8. since it affects significantly the dynamics of transdermal drug delivery, the reservoir capacity of the stratum corneum should be thoroughly investigated before a transdermal drug delivery system is developed. In spite of the evidence of the stratum corneum reservoir effect, its mechanism has not yet been fully elucidated. There is no quantitative interpretation reported in the literature which could assist us to gain a fundamental understanding the dynamic characteristics of stratum corneum reservoir capacity.

Methods for determining partial solubility parameters of potential film-coating polymers

The partial solubility parameters of a film-coating polymer can be useful in formulating a good film-coating solution. Three experimental methods were used to determine the partial solubility parameters for a commercially available silicone polymer, Silastic Q7–4735. Prior to the initiation of the curing process, solutions of the polymer were examined by viscometry and turbidimetry. The cured polymer was evaluated by swelling measurements. Results of viscosity and swelling were found to agree. The solubility parameters δd and δp were determined to be 7.44–7.56 (cal/ml)12 and 0.23–1.69 (cal/ml)12, respectively. However, turbidity was shown to be a poor method for determining solubility parameters.