A Novel Apremilast Nail Lacquer Formulation for the Treatment of Nail Psoriasis.

The objective was to prepare a novel nail lacquer formulation to improve the ungual and trans-ungual delivery of apremilast for the potential treatment of nail psoriasis. Nail lacquer formulation was prepared using Eudragit® S 100 as a film-forming polymer and the mixture of ethanol, ethyl acetate, and water as a solvent system. As a result of high-throughput screening studies, dexpanthenol and salicylic acid were found to be the potential penetration enhancers. After 7 days of in vitro studies, the cumulative amount of apremilast delivered by the nail lacquer formulation across the nail plate was found to be ~3-fold (0.52 ± 0.07 µg/cm2) more compared to control (nail lacquer formulation without enhancers) (0.19 ± 0.02 µg/cm2). The cumulative amount of apremilast retained in the nail plate in the case of nail lacquer formulation was 1.26 ± 0.18 µg/mg which was found to be ~2-fold more compared to control (0.57 ± 0.07 µg/mg). Human subject studies were performed on the nails of thumb and index finger of six volunteers for 15 days. As a result, the cumulative amount of apremilast retained in the free distal edge of the nail plate in the case of nail lacquer was found to be ~2-fold (0.93 ± 0.14 µg/mg) more related to control (0.41 ± 0.04 µg/mg). As a conclusion, nail lacquer formulation was found to be capable of delivering a substantial amount of apremilast into the nail apparatus; thus, it can be a potential option for the treatment of nail psoriasis.

Trans-ungual Delivery of AR-12, a Novel Antifungal Drug.

AR-12 is a novel small molecule with broad spectrum antifungal activity. Recently, AR-12 was found to be highly active against Trichophyton rubrum, one of the predominantly responsible organisms that cause onychomycosis. The primary objective of this project was to investigate the ability of AR-12 to penetrate into and across the human nail plate followed by improving its trans-ungual permeation using different penetration enhancers. TranScreen-N™, a high throughput screening method was utilized to explore the potential nail penetration enhancers to facilitate the drug delivery through the nail. This screen demonstrated that dexpanthenol and PEG 400 were the most efficient enhancers. The in vitro permeation studies were performed across the human cadaver nail plates for 7 days with three AR-12 (5% w/v) formulations containing 10% w/v dexpanthenol (Formulation A), 10% w/v PEG 400 (Formulation B), and a combination of 10% w/v dexpanthenol + 10% w/v PEG 400 (Formulation C). The in vitro studies concluded that dexpanthenol and PEG 400 were able to deliver a significant amount of AR-12 into and across the nail plate that was found to be more than MIC 50 level of the drug.

Iontophoresis for drug delivery into the nail apparatus: exploring hyponychium as the site of delivery.

In present studies, a hyponychium pathway (from ventral side of the nail plate) was investigated as a potential route of drug delivery into the nail apparatus using iontophoresis as an active physical method. In vitro transport studies were performed across the human nail plate using sodium fluorescein as a marker substrate for 24 h. After transport studies, the amount of sodium fluorescein extracted from an active diffusion area of the nail plate in case of iontophoresis was found to be ∼54-folds more to that of passive. The amount of sodium fluorescein retained in the peripheral area of the nail plate after application of iontophoresis was found to be ∼30-folds more relative to passive. Ex vivo transport studies were performed on excised human cadaver toe using terbinafine hydrochloride as a model drug for three days (8 h/day). The amount of terbinafine retained in the nail plate after application of iontophoresis (3.43 ± 1.34 µg/mg) was ∼20-folds more when compared with passive (0.17 ± 0.10 µg/mg). The amount of drug extracted from the nail bed and nail matrix was 1.73 ± 0.12 µg/mg and 0.55 ± 0.22 µg/mg, respectively. On the other hand, there was no detectable amount of terbinafine found in the nail bed and nail matrix in case of control (passive delivery). These studies show that the iontophoretic drug delivery through hyponychium region to other parts of the nail apparatus could be a potential way of onychomycosis treatment.

Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain.

The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.

Emerging therapies for the treatment of ungual onychomycosis.

INTRODUCTION: Onychomycosis, a common fungal infection in the finger and toe nails, affects approximately 2-8% of the worldwide population. Fungal infection is more complicated in those who suffer from conditions, such as diabetes, peripheral vascular diseases and compromised immune diseases. AREA COVERED: Onychomycosis treatment has been classified on the basis of location of infection in the toes and fingers and infectious agents (dermatophytes fungi, yeast and non-dermatophyte molds). In this review, the available therapies (traditional and device based) and their limitations for the treatment of onychomycosis have been discussed. EXPERT OPINION: The success rate with topical nail products has been minimal. The main reason for this poor success rate could be attributed to the lack of complete understanding of the pathophysiology of the disease and clinical pharmacokinetic data of drugs in the infected nail apparatus.

Trans-ungual delivery of itraconazole hydrochloride by iontophoresis.

Itraconazole (ITR) is a potent antifungal drug. However, poor aqueous solubility limits its permeation ability across the human nail plate. Therefore, in this project, ITR was converted to hydrochloride salt (ITR-HCl) to improve its solubility and to render it amenable to iontophoresis. ITR-HCl was characterized by spectroscopic methods and antifungal efficacy was evaluated in comparison to the base. In vitro and ex vivo transport studies (passive and iontophoresis) were carried out across the porcine hoof membrane and excised human cadaver toe using two different protocols; continuous delivery of drug for 24 h and pulsed delivery of drug for 3 days (8 h/day). The antifungal efficacy of ITR-HCL was comparable to ITR. Iontophoresis was found to be more effective than passive mode of delivery of ITR-HCL. In both iontophoresis as well as passive mode of delivery, the pulsed protocol resulted in more ungual and trans-ungual delivery of drug than continuous protocol. ITR-HCL could be delivered into and across the nail plate by iontophoresis. Human cadaver toe appears to be a good model to investigate the ungual delivery of drugs.