Effect of permeation enhancers on buccal absorption.

This paper reports an investigation on matrices based on the mucoadhesive polymers hydroxypropylmethylcellulose and sodium alginate, intended for sublingual administration of 1 mg lorazepam (LZ, 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one, CAS 846-49-1). The effect of different amounts of three permeation enhancers, cetylpyridinium chloride (CPC), polyethoxylated castor oil (PCO) and polyethylene glycol dodecyl ether (PGDE) on LZ permeation from the matrices was investigated using three models: (a) cultured monolayer of human buccal epithelial cells; (b) hamster cheek pouch mucosa in vitro, and (c) buccal administration to rabbits in vivo. In the first two models the presence of promoters, except when present at the higher concentrations, increased the drug permeation rate. The permeation-reducing effect was rationalized on the basis of micellar complexation of the drug. In the living rabbit (c) model, only CPC at the highest tested concentration was moderately active, while in the cultured cell model activity differences among the enhancers were less evident. Different effects of the promoters in the ex vivo and in vivo models were tentatively explained on the basis of the structural characteristics of the absorbing membranes. The present study, while confirming the efficacy of CPC as promoter in models involving biological membranes, does not provide conclusive data on the validity of the cultured cells model for assessment of buccal drug absorption.

Comparison of liposome-encapsulated acyclovir with acyclovir ointment: ocular pharmacokinetics in rabbits.

A positively charged liposomal formulation for topical administration of acyclovir (ACV) was investigated in comparison with a commercial ACV ointment, by determining the pharmacokinetic profile of the drug in the aqueous humor of rabbits after topical administration. The ointment was tested at two different strengths: undiluted (3.0%) and diluted to the same ACV concentration as the liposomal vehicle (0.12%). A liquid formulation containing ACV plus "empty" liposomes and an isotonic aqueous ACV solution were also tested. The applied ACV dose was 0.18 mg, except for the full-strength (3.0%) ointment, in which case it was 1.5 mg. The ACV liposomal dispersion (LIPO-ACV) produced a significantly higher drug concentration profile in the aqueous with respect the three reference formulations containing the same ACV concentration, and showed a 90-minute plateau. The aqueous humor ACV concentration maintained by LIPO-ACV during the plateau was in the upper range of the ID(50)s (0.01 to 0.7 microg/mL) reported for Herpes simplex type 1. In spite of the much higher dose (1.5 versus 0.18 mg), the area under curve (AUC) produced by the full-strength 3.0% ointment was only 1.6 times greater than that corresponding to the liposomal vehicle. In vitro release tests through a cellophane membrane substantiated the concept that positively charged liposomal formulations owe their efficacy to interactions with the positively charged corneal epithelium.

A collaborative evaluation of the cytotoxicity of two surfactants by using the human corneal epithelial cell line and the WST-1 test.

This study was undertaken to investigate the use of the in vitro test WST-1, an assay of cell proliferation and viability, for a preliminary safety evaluation of topical ophthalmic preparations. The cytotoxicity of two surfactants, benzalkonium chloride (BAC) and polyoxyethylene-20-stearyl ether (Brij78, PSE) was independently investigated in four laboratories in the EU by using an immortalized human corneal epithelial (HCE) cell line. The HCE cells were exposed to BAC and PSE for 5 min, 15 min, and 1 hour, and the results of the HCE-WST-1 tests were collected and compared. After one-hour exposure, the EC(50) values in BAC-treated cells in the presence of serum ranged between 0.0650 +/- 0.0284 (mean +/- SD) mM, and those in the absence of serum 0.0296 +/- 0.0081 mM. The corresponding values for PSE were 0.0581 +/-.0300 mM and 0.0228 +/-.0063 mM. There were variations in the results between different laboratories, with coefficients of variation ranging from 31 to 121%, mean 58%. The use of one-hour exposure time is to be preferred, and the elimination of serum in the culture medium is recommended to avoid both underestimation of toxic effects and variability of the test results.

Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin.

Aim of this study was to evaluate solid lipid nanoparticles (SLN) as carriers for topical ocular delivery of tobramycin (TOB). The SLN were in the colloidal size range (average diameter below 100 nm; polydispersity index below 0.2) and contained 2.5% TOB as ion-pair complex with hexadecyl phosphate. The preocular retention of SLN in rabbit eyes was tested using drug-free, fluorescent SLN (F-SLN): these were retained for longer times on the corneal surface and in the conjunctival sac when compared with an aqueous fluorescent solution. A suspension of TOB-loaded SLN (TOB-SLN) containing 0.3% w/v TOB was administered topically to rabbits, and the aqueous humour concentration of TOB was determined up to six hours. When compared with an equal dose of TOB administered by standard commercial eyedrops, TOB-SLN produced a significantly higher TOB bioavailability in the aqueous humour.

Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouse skin.

Purpose of the present investigation was to evaluate six terpene-containing essential oils for their capacity to promote permeation of estradiol (ES) through hairless mouse skin in vitro. Tests on cajuput, cardamom, melissa, myrtle, niaouli and orange oil, all used at the 10% w/w concentration in propylene glycol (PG), evidenced niaouli oil (NIA) as the best permeation promoter for ES. Tests on the main terpene components of NIA (1,8 cineole, alpha-pinene, alpha-terpineol and D-limonene), evaluated neat (10% w/w in PG) or in admixture, confirmed the better promoting activity of whole NIA. The present data point to the validity of complex terpene mixtures, such as that composing NIA, as transdermal penetration enhancers for moderately lipophilic drugs like ES.