In vivo iontophoretic delivery and pharmacokinetics of salmon calcitonin.

In vivo iontophoretic delivery of salmon calcitonin (SCT) in hairless rats using a self-contained wearable and disposable iontophoretic patch was investigated. Iontophoretic patches with built-in proprietary Zn/AgCl electrodes were used. SCT was formulated in citrate buffer (50mM, pH 4.0) to impart a positive charge for anodal iontophoresis. SCT was delivered intravenously to determine primary pharmacokinetic parameters. Pharmacokinetics of iontophoretic delivery of SCT was compared with subcutaneous route of administration. Blood samples were collected through tail vein and analyzed for serum SCT and calcium levels. Pharmacokinetic parameters were calculated by non-compartmental analysis. An average current of 0.43+/-0.01 mA was maintained during patch application. Iontophoretic patches delivered SCT at an average infusion rate of 177.9+/-58.7 ng/(min kg) and an average steady state concentration of 7.58+/-1.35 ng/ml was achieved. There was no difference between the calcium lowering effect of iontophoretic patch and subcutaneous injection (p>0.05). Clearance and half-life of SCT after IV administration were found to be 16.8+/-0.9 ml/(min kg) and 33.5+/-3.3 min, respectively. The iontophoretic delivery of SCT was well defined by a one-compartment model with zero-order infusion. Iontophoretic patch delivered therapeutically relevant concentrations of SCT in hairless rats and delivery was comparable to conventional routes.

Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention.

BACKGROUND AND PURPOSE: Iontophoresis is a process that uses bipolar electric fields to propel molecules across intact skin and into underlying tissue. The purpose of this study was to describe and experimentally examine an iontophoresis drug delivery model. SUBJECTS AND METHODS: A mechanistic model describing delivery was studied in vitro using agarose gels and was further tested in vivo by evaluation of cutaneous vasoconstriction following iontophoresis in human volunteers. RESULTS: In vitro cathodic iontophoresis at 4 mA and 0.1 mA each delivered dexamethasone/dexamethasone phosphate (DEX/DEX-P) from a 4-mg/mL donor solution to a depth of 12 mm following a 40 mA minute stimulation dosage. Delivery of DEX/DEX-P to at least the depths of the vasculature in humans was confirmed by observation of cutaneous vasoconstriction. This cutaneous vasoconstriction was longer lasting and greater in magnitude when using low-current, long-duration (approximately 0.1 mA) iontophoresis compared with equivalent dosages delivered by higher-current, shorter-duration (1.5-4.0 mA) iontophoresis. DISCUSSION AND CONCLUSION: From data gathered with the gel model, the authors developed a model of a potential mechanism of drug depot formation following iontophoresis. The authors believe this drug depot formation to be due to exchange of drug ions for chloride ions as the ionic current carriers. Furthermore, diffusion, not magnitude of current, appears to govern the depth of drug penetration. Although the authors did not address the efficacy of the drug delivered, the results of human experiments suggest that current magnitude and duration should be considered as factors in treating musculoskeletal dysfunctions with iontophoresis using DEX/DEX-P at a concentration of 4 mg/mL.

Quantification of total dexamethasone phosphate delivery by iontophoresis.

The total amount of dexamethasone phosphate transferred into the human body as a function of iontophoresis has not previously been determined, despite its widespread clinical use in the treatment of localized inflammation. The objective of this study was to document the optimal parameters required for clinical iontophoresis of dexamethasone phophate. Results were achieved by the experiment of in vitro evalutations of dexamethasone phosphate iontophoresis and by in vivo estimations of drug amounts (milligrams) iontophoresed into healthy human volunteers. The in vitro evaluations were conducted to quantify total dexamethasone phosphate amounts transferred as a function of dosage (milliAmp-minutes), to evaluate the efficiency of the delivery based on dexamethasone phosphate only (pure) donor solutions compared with dexamethasone phosphate + salts (coformulated) donor solutions, and to compare the delivery from the negative electrode (cathode) with that from the positive electrode (amode). The in vivo drug amounts were estimated by the use of the formulation conditions determined from the in vivo testing. The in vitro evaluations were conducted with side-by-side glass diffusion cells, which measured iontophoretic and passive delivery across an ultrafiltration membrane. The in vivo experiments were conducted on five healthy human volunteers who were wearing a low-voltage iontophoreses system. Total drug delivery was ascertained by the difference between the initial drug load and a final residual amount determined by extraction. The in vitro results demonstrated increased dexamethasone phosphate delivery with higher iontophoretic dosages and with the pure dexamethasone phosphate formulation. Delivery from the anode was significantly lower than that from the cathode. After an 80-mA-minute drug-delivery was administered, the in vivo iontophoretic delivery was measured to be 1.40 +/- 0.23 mg, and the corresponding passive delivery was 0.26 +/-0.16 mg. The in vitro experiments confirm iontophoretic delivery of dexamethasone phosphate across artificial membranes, and the in vivo experiments suggest that drug is delivered into human skin.