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.

Effect of temperature and light on the stability of latanoprost and its clinical relevance.

PURPOSE: To examine the effect of controlled heat and ultraviolet exposures on the stability of latanoprost (Xalatan, Pharmacia & Upjohn, Kalamazoo, MI) using high-performance liquid chromatography to derive practical recommendations for patients regarding its use and storage. METHODS: Using serial dilution of a latanoprost stock solution, varying concentrations were prepared to obtain a standard curve. The accuracy and precision of the high-performance liquid chromatography assay conditions were validated using between-day and within-day studies. The original latanoprost containers were stored at 4, 25, 50, and 70 degrees C, and the concentration of latanoprost remaining was measured by high-performance liquid chromatography at different times for up to 1 month. In addition, the original latanoprost containers were exposed to known amounts of ultraviolet A and B radiation for 4 hours, and the concentration of latanoprost was measured at 1-hour intervals using high-performance liquid chromatography. RESULTS: The increased temperature studies showed that latanoprost remained stable at 4 and 25 degrees C for the 30-day study duration. Analysis of concentration versus time curves for 50 and 70 degrees C yielded a t90 (time for 10% degradation) of 8.25 and 1.32 days, respectively. Ultraviolet B radiation caused a rapid degradation of latanoprost, whereas ultraviolet A radiation was less effective in causing the degradation of latanoprost. CONCLUSIONS: Latanoprost exhibits thermal and solar instability and should ideally be stored below room temperature and in the dark. The importance of these storage conditions should be conveyed clearly to the patient.

Influence of degree of substitution of cyclodextrins on their colligative properties in solution.

The purpose of this study was to investigate the effect of the total degree of substitution (TDS) on the colligative properties of substituted cyclodextrins (CDs; i.e., beta- and gamma-cyclodextrins substituted with sulfobutylether or hydroxypropyl groups) in solution. The osmotic pressure (OP) of aqueous CD solutions was determined over the concentration range 100-350 mmol/kg using vapor pressure osmometry. A chloride ion-selective electrode was used to help determine the possible mechanism for any CD-water interactions that might occur by measuring the chloride-ion activity of a sodium chloride solution containing various CDs. Titration microcalorimetry was used to verify that sodium chloride did not interact with the CDs, thereby permitting the chloride ion activity to be utilized as an indicator of any possible CD-water interaction. The results indicate that CDs with different total degrees of substitution (TDS) exhibit different colligative properties in solution. It was observed that increases in the degree of substitution of the CD produced an increased OP. All substituted CDs exhibited an OP above their theoretical values, whereas the OP of the unsubstituted gamma-CD was below its expected value, likely due to self-association. The results obtained with the chloride-ion selective electrode did not exhibit a consistent trend; however, it was observed that changes in the TDS caused significant changes in the activity of chloride ions in solution. These findings are of interest in using CDs to formulate parenteral and ophthalmic solutions where the OP of the solutions must be considered.

Investigation of the utility of an in vitro release test for optimizing semisolid dosage forms.

Current literature indicates that an in vitro release test (IVRT) can serve as a research tool during the course of developing topical formulations. The purpose of this study was therefore to investigate the ability of an IVRT to select the topical semisolid formulations with the most rapid release rate of the model drug ketoprofen from two closely related hydrogels in a simulated product development process. Two glycols with distinct differences in their physical-chemical properties, Transcutol P (ethoxydiglycol) and propylene glycol, were incorporated into Carbopol 980 and Poloxamer 407 formulations. The release rate of ketoprofen was determined utilizing different receptor media and conditions, i.e., phosphate buffer pH 7.4, isopropyl myristate (IPM), and a combination of an IPM soaked membrane and phosphate buffer (pH 7.4) as receptor fluid. The results indicated that the conditions chosen could affect greatly the conclusions concerning the formulations. The only observable trend was that Transcutol P-containing formulations tended to permit a faster ketoprofen release than propylene glycol-containing formulations when utilizing IPM as a receptor component. This was attributed to the mutual miscibility of Transcutol P in IPM. It can be concluded that, for the purpose of formulation screening in the early phases of product development, an IVRT will only be useful for predicting the amount of drug available for absorption if the receptor medium has properties that closely mimic human skin. These results illustrate the importance of selecting suitable receptor components and indicate that it may be necessary to consider alternatives to the commonly used synthetic membranes.

A simplified and rapid high-performance liquid chromatographic assay for ketoprofen in isopropyl myristate.

A high-performance liquid chromatographic (HPLC) procedure for quantitating ketoprofen in isopropyl myristate (IPM), a compound widely used as a receptor medium in drug diffusion studies of topical aqueous-based formulations, is developed. Previously reported HPLC assays for ketoprofen in IPM have employed relatively complex and tedious methods for purifying the IPM prior to injection onto the HPLC column. The present assay method utilizes a direct injection of the IPM-based sample onto a new reversed-phase ODS column and employs ultraviolet detection at 265 nm. Propyl paraben is employed as the internal standard. The mobile phase consists of acetonitrile-methanol-water (36:54:10, v/v/v) at a flow rate of 1.2 mL/min. The calibration curves are linear (correlation coefficient r > or = 0.988) over concentration ranges of 0.625-10 micrograms/mL and 6.25-100 micrograms/mL. The within-day and between-day precision exhibit coefficients of variation of 1.3-3.3%, and the accuracy (reported as relative error of the mean) varies from -1.9% to 0.6%. The retention times for ketoprofen and propyl paraben are approximately 2.3 and 3.3 min, respectively. The total run time per sample is approximately 7 min. The minimum quantitatable concentration is approximately 0.625 microgram/mL. The assay is stability-indicating, rapid, reproducible, sensitive, and readily adaptable for assaying other non-steroidal anti-inflammatory drugs.