Iontophoresis-facilitated transdermal delivery of verapamil. II. Factors affecting the reversibility of skin permeability

Wearley, Lorraine; Liu, Jue-Chen; Chien, Yie W.

doi:10.1016/0168-3659(89)90091-6

Cited by 34 publications

(11 citation statements)

References 20 publications

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“…Electrical conductance measurements also showed recovery, either complete or to within a factor of 3 of pre-pulse values. However, elevated post-pulsing fluxes could be caused not only by irreversible alterations of skin structure but also by the efflux of calcein "loaded" into the skin during high fluxes during pulsing (23,24). .…”

Section: Resultsmentioning

confidence: 99%

Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery.

Prausnitz

Bose

Langer

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

577

275

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Mammalian skin owes its remarkable barrier function to its outermost and dead layer, the stratum corneum. Transdermal transport through this region occurs predominantly through intercellular lipids, organized largely in bilayers. Electroporation is the creation of aqueous pores in lipid bilayers by the application of a short (microseconds to milliseconds) electric pulse. Our measurements suggest that electroporation occurs in the intercellular lipid bilayers of the stratum corneum by a mechanism involving transient structural changes. Flux increases up to 4 orders of magnitude were observed with human skin in vito for three polar molecules having charges between -1 and -4 and molecular weights up to slightly more than 1000. Similar flux increases were observed in vivo with animal skin. These results may have significance for drug delivery and other medical applications.Transdermal drug delivery offers a number of potential advantages over conventional methods, such as pills and injections: (i) no degradation due to stomach, intestine, or first pass of the liver, (ii) probable improved patient compliance because of a user-friendly method, and (iii) potential for steady or time-varying controlled delivery (1-4). Nevertheless, very few drugs can be administered transdermally at therapeutic levels, due to the low permeability and lipophilic nature of human skin. As a result, fewer than 10 drugs are now clinically administered transdermally. However, the market for these drugs exceeds one billion dollars in the United States alone, indicating the importance of this delivery method. Therefore, significant enhancement of transdermal drug delivery has the potential for major impact on medicine.

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Section: Resultsmentioning

confidence: 99%

Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery.

Prausnitz

Bose

Langer

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

577

275

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“…However, others have shown little or no change in flux over a broad concentration range for a number of solutes. [12][13][14][15] The rate of ion transport through pores that have no fixed charges is generally proportional to the ion concentration according to Fick's law. However, with a charged pore the ion flow may be diffusion limited, and so the membrane (pore) conductivity reaches a limiting value at high concentrations when the pores become saturated.…”

Section: Discussionmentioning

confidence: 99%

Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

Al-Khalili

Meidan²,

Michniak³

2003

AAPS PharmSci

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INTRODUCTIONBuspirone hydrochloride (BH) is an orally administered anxiolytic that is structurally and pharmacologically distinct from all other anxiolytics, including benzodiazepines and barbiturates. It differs from other anxiolytics in that it does not possess anticonvulsant or muscle relaxant properties, does not impair psychomotor function, and does not cause sedation or physical dependence. BH is used to treat generalized anxiety disorder and anxiety caused by alcohol craving or smoking cessation, as well as attention deficit hyperactivity disorder in children.Since 1984, BH has been used in children and adolescents with anxiety disorders, and researchers have reported significant improvement with its use.1 The reported side effects were very mild, and many clinical trials have shown the superiority of BH over other traditional stimulant-based treatments. 2,3The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm 2 resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel resulted in a synergistic effect when combined with iontophoresis. Menthol was the most active enhancer, and when combined with iontophoresis it was possible to deliver 10 mg/cm 2 /day of buspirone hydrochloride.Although BH is rapidly absorbed in humans, it undergoes extensive first-pass metabolism such that the unchanged compound accounts for only 1% of the radioactivity in the plasma after oral administration of a 20-mg single dose of BH. Moreover, the average elimination half-life of unchanged BH after single doses of 10 to 40 mg is about 2 to 3 hours. 4 Consequently, treatment with BH typically requires 3 daily doses of between 5 and 20 mg each. Because of the chronic nature of the treatment, a reduction in the number of daily doses would be advantageous, as it should radically improve patient compliance. Thus, an effective transdermal buspirone delivery system would be expected to have a great impact on therapy success.

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“…During the current-off period, the permeant is desorbing from the skin by passive diffusion until the emptying of the drug reservoir inside the skin. 26,27) The desorption time of diclofenac salts from skin after 20 min current-on period may be shorter than 10 min. Hence the maximum diclofenac iontophoretic delivery would never be reached during 20 min/10 min on/off current application.…”

Section: Effect Of Current Densitymentioning

confidence: 99%

Influence of Electrical and Chemical Factors on Transdermal Iontophoretic Delivery of Three Diclofenac Salts.

Fang

Wang

Huang

et al. 2001

Biological & Pharmaceutical Bulletin

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Diclofenac has been widely used, systemically and locally, as an antiinflammatory agent. It has been reported that orally administered diclofenac undergoes hepatic first-pass metabolism and considerable gastrointestinal disturbances.1,2) Transdermal delivery is suitable for diclofenac to overcome these two major shortcomings of oral therapy. Iontophoresis is defined as the migration of ions when an external electric field is passed through a vehicle containing charged compounds. Based on the literature, the permeation of ionic drugs such as diclofenac can be facilitated by the application of iontophoresis. 3)Several variables may influence the transdermal iontophoretic permeation of drug molecules, including physicochemical properties of the drug, the vehicle composition, the electrical factors and skin barrier properties. 4,5) The aim of the present study was to investigate the influence of electrical and chemical factors of iontophoresis on in vitro transdermal permeation of diclofenac. Three diclofenac salts with various physicochemical and pharmacokinetic properties including diclofenac sodium (DFS), diclofenac potassium (DFP), and diclofenac diethylammonium (DFD) were utilized as model drugs to compare the differences of these salts in iontophoretic behaviors. The electrical and chemical variables examined in this study such as current density, drug concentration, ionic strength and iontophoretic application mode can control and optimize the delivery rate of diclofenac salts. Moreover, the magnitude of drug iontophoretic permeability can be influenced by the type and quantity of ions present in vehicle.6) The experiment and mechanism of this effect was also demonstrated in the present study. MATERIALS AND METHODSMaterials Diclofenac sodium (DFS), diclofenac potassium (DFP), and diclofenac diethylammonium (DFD) were gifts kindly provided by Novartis Pharmaceutical Co., Switzerland. Sodium chloride (NaCl), potassium chloride (KCl), and diethylammonium chloride (C 4 H 12 ClN) were supplied by Merck Co., Germany. All other chemicals and solvents were of analytical grade.In Vitro Permeation Experiments The in vitro permeation study was performed by using side-by-side glass diffusion cells. The skin of female nude mouse (11-12 weeks old) was used as the model membrane in this study. A 8 ml citrate-phosphate buffer (pH 7.4; 0.06 M) was used as the medium for receptor compartment. The drug concentration in the donor compartment was 12.5 mM. The drug was more than 99.9% ionized in the donor compartment of pH 7.4 citrate-phosphate buffer because of its pK a value of 4.16.7) The available diffusion area between cells was 0.785 cm 2 . The stirring rate and temperature were kept at 600 rpm and 37°C. At appropriate intervals, 200 ml aliquots of the receptor medium were withdrawn and immediately replaced by an equal volume of fresh buffer.Application of Iontophoresis A pair of Ag/AgCl wires with an effective working length of 15 mm was immersed in the buffer solution as electrodes, with the cathode in the donor compartmen...

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Iontophoresis-facilitated transdermal delivery of verapamil. II. Factors affecting the reversibility of skin permeability

Cited by 34 publications

References 20 publications

Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery.

Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery.

Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

Influence of Electrical and Chemical Factors on Transdermal Iontophoretic Delivery of Three Diclofenac Salts.

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