Hyun D. Kim

Ungual and trans‐ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis

The application of iontophoresis was demonstrated in the nail drug delivery of terbinafine (TH) recently. This study explored a systematic assessment of this approach to enhance the drug delivery using a novel topical formulation, and the subsequent release of TH from the drug loaded nails. For the first time, a nail on-agar plate model was used to study the release of drug from the iontophoresis (0.5 mA/cm(2)) loaded nails. In addition, the activity of the drug released from the drug loaded nail plate was studied against Trichophyton rubrum. An increase in applied current density and current duration enhanced the transport of TH into and through the nail plate. In vitro release of drug from the iontophoretic loaded nails into agar plates exhibited 2-phase release pattern. The amount of drug released in both of the in vitro models was comparable, and the nails loaded using iontophoresis continued to release levels of TH > 2 orders of magnitude above the minimum inhibitory concentration over at least 52 days. Results indicate that iontophoresis enhances the delivery of terbinafine into and through the nail plate and suggest that the use of this treatment approach could result in a safe and more efficacious outcome with less frequent treatments.

Trans-ungual iontophoretic delivery of terbinafine

Successful treatment of deep-seated nail infections remains elusive as the delivery of efficacious levels of antifungal drug to the site of action is very difficult. The aim of the present study was to attain rapid trans-ungual delivery of an antifungal agent, terbinafine, via the topical route using iontophoresis. Initial studies revealed that application of current (0.5 mA/cm(2)) could significantly enhance the trans-ungual delivery of terbinafine. An increase in the applied current or duration of current application enhanced the trans-ungual delivery of terbinafine. Permeation of terbinafine through the nail and drug load in the nail correlated well with the applied electrical dose. Release of drug from nails loaded using iontophoresis followed a two-phase release profile. Light microscopy studies substantiated the capability of iontophoresis to drive a charged molecule across the nail plate. The results of these studies indicate that iontophoresis could be developed as a potential technique for onychomycosis therapy.

Alteration of the diffusional barrier property of the nail leads to greater terbinafine drug loading and permeation.

The diffusional barrier property of biological systems varies with ultrastructural organization of the tissues and/or cells, and often plays an important role in drug delivery. The nail plate is a thick, hard and impermeable membrane which makes topical nail drug delivery challenging. The current study investigated the effect of physical and chemical alteration of the nail on the trans-ungual drug delivery of terbinafine hydrochloride (TH) under both passive and iontophoretic conditions. Physical alterations were carried out by dorsal or ventral nail layer abrasion, while chemical alterations were performed by defatting or keratolysis or ionto-keratolysis of the nails. Terbinafine permeation into and across the nail plate following various nail treatments showed similar trends in both passive and iontophoretic delivery, although the extent of drug delivery varied with treatment. Application of iontophoresis to the abraded nails significantly improved (P<0.05) TH permeation and loading compared to abraded nails without iontophoresis or normal nails with iontophoresis. Drug permeation was not enhanced when the nail plate was defatted. Keratolysis moderately enhanced the permeation but not the drug load. Ionto-keratolysis enhanced TH permeation and drug load significantly (P<0.05) during passive and iontophoretic delivery as compared to untreated nails. Ionto-keratolysis may be more efficient in permeabilization of nail plates than long term exposure to keratolysing agents.

Transdermal iontophoretic delivery of terbinafine hydrochloride: quantitation of drug levels in stratum corneum and underlying skin.

The objective of this study was to determine the effect of iontophoresis on the delivery of terbinafine hydrochloride (4%, w/w) into and across hairless rat skin. In vitro skin uptake and permeation studies were performed using Franz diffusion cells. Anodal iontophoresis was applied for 1h at current densities of 0.2, 0.3 and 0.4mA/cm(2). In addition, iontophoresis was applied for 15, 30, 45 and 60min. Studies were conducted in which the formulation was either removed or left in contact with the skin following iontophoresis and then passive delivery was assessed 23h later. Tape stripping and skin extraction were performed to quantify drug levels in the stratum corneum and the underlying skin, respectively. The samples were analyzed using HPLC. The amount of drug delivered into the stratum corneum following iontophoresis was not significantly different from the amount delivered passively (p>0.05). However, drug levels in the underlying skin were significantly higher for the iontophoretic group. The amount of terbinafine delivered into the skin layers was influenced by current density and duration of current application. Leaving the drug formulation in contact with the skin during the post-iontophoretic period had a significant effect on drug levels delivered into skin layers. Iontophoresis enhanced the delivery of terbinafine hydrochloride into the skin layers and, therefore, may be used to improve the treatment of skin fungal infections.

Iontophoresis mediated in vivo intradermal delivery of terbinafine hydrochloride

The objective of this study was to investigate the use of iontophoresis for the delivery of terbinafine hydrochloride (TH) into hairless rat skin in vivo. Drug formulation was applied to the abdominal skin and studies were performed using anodal iontophoresis. A current density of 250 microA/cm(2) was applied for 10, 15 and 20 min. Tape stripping and skin extraction were performed thereafter. For depot clearance studies, 20 min treatment was followed by tape stripping and skin extraction at 12, 24 and 48 h. Results indicated that iontophoresis delivered significantly more drug into the deeper skin as compared to controls (p<0.05). Drug levels in the stratum corneum (SC) and underlying skin increased with increasing duration of current application. Depot clearance studies suggested drug depletion within 24 h from SC. A redistribution of terbinafine from the SC to the underlying skin over time was observed. Drug was detectable in the underlying skin for at least 48 h suggesting that formation of a drug depot persisted for at least 2 days following iontophoretic treatment. Thus, iontophoresis of TH may be useful in delivering higher drug levels more rapidly into the superficial and deep seated skin infection sites to form a depot providing sustained release.

Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion

Background The objective of this study was to compare the efficacy of cyclosporin (CsA)-encapsulated liposomes with the commercially available CsA emulsion (Restasis®) for the treatment of dry eye syndrome in rabbits. Methods Liposomes containing CsA were prepared by the supercritical fluid (SCF) method consisted of phosphatidylcholine from soybean (SCF-S100) and egg lecithins (SCF-EPCS). An in vitro permeation study was carried out using artificial cellulose membrane in Franz diffusion cells. Dry eye syndrome was induced in male albino rabbits and further subdivided into untreated, Restasis®-treated, EPCS, and S100-treated groups. Tear formation in the dry-eye-induced rabbits was evaluated using the Schirmer tear test. All formulations were also evaluated by ocular irritation tests using the Draize eye and winking methods with the determination of CsA concentration in rabbit tears. Results After the treatment, the Schirmer tear test value significantly improved in EPCS-treated (P=0.005) and S100-treated (P=0.018) groups compared to the Restasis®-treated group. The AUC0–24 h for rabbit’s tear film after the administration of SCF-S100 was 32.75±9.21 μg·h/mg which was significantly higher than that of 24.59±8.69 μg·h/mg reported with Restasis®. Liposomal CsA formulations used in this study showed lower irritation in rabbit eyes compared with Restasis®. Conclusion These results demonstrate that the novel SCF-mediated liposomal CsA promises a significant improvement in overcoming the challenges associated with the treatment of dry eyes.

Transdermal and intradermal iontophoretic delivery of dexamethasone sodium phosphate: quantification of the drug localized in skin

In this study, the effect of iontophoresis on the transdermal and intradermal delivery of dexamethasone sodium phosphate (DEX-P) was examined in vitro and in vivo in the hairless rat model by skin permeation studies, tape stripping, and skin extraction. Cathodal or anodal iontophoresis (ITP) was performed and samples were analyzed by HPLC. In vitro experiments revealed that cathodal ITP significantly enhanced the cumulative amount of DEX-P permeating through the skin when compared to passive and anodal delivery. Tape stripping and skin extraction studies performed in vivo after ITP showed enhanced deposition of the drug in the stratum corneum and underlying skin when compared to passive delivery. The DEX-P and DEX depot formed in the stratum corneum and underlying skin were retained for at least 48 h and 24 h, respectively. In conclusion, ITP demonstrated potential as a feasible enhancement technique to drive the drug into and through the skin in significant amounts as compared to passive delivery.

Intracorneal melatonin delivery using 2-hydroxypropyl-β-cyclodextrin ophthalmic solution for granular corneal dystrophy type 2

Melatonin (MT), an effective antioxidant, has therapeutic implications for granular corneal dystrophy type 2 (GCD2) treatment. Eye drop formulations containing cyclodextrins (CDs) were studied with the objective of improving MT solubility, stability, and ocular absorption, while decreasing eye irritation. MT complexes with αCD, βCD, γCD, and 2-hydroxypropyl-βCD (HPβCD) were characterized by phase solubility studies, which demonstrated Higuchis AL-type phase solubility profiles. The MT/HPβCD complex showed the highest MT solubility (2.75mg/mL). Ocular irritation experiments showed HPβCD inclusion alleviated irritation of the eye. After administration of MT formulations to rabbit corneas, each harvested cornea was separated into corneal epithelium, stroma, and endothelium. MT concentrations in the corneal epithelium, stroma, and endothelium for the F1-treated group were 55.5±9.24, 26.7±2.66, and 21.1±1.77μM while those for the F2-treated group were 127.2±21.01, 43.7±16.93, and 51.0±13.91μM, respectively. Stability studies for 60days showed no significant change in pH, osmolarity, and MT content. In conclusion, MT/HPβCD formulations can lower irritation, enhance MT stability, and improve therapeutic efficacy.