Permeability of glibenclamide through a PAMPA membrane: The effect of co-amorphization.

Co-amorphous systems are an attractive alternative for amorphous solid polymer dispersions in the formulation of poorly soluble drugs. Several studies have revealed that co-amorphous formulations can enhance the dissolution properties of poorly-soluble drugs and stabilize them in the amorphous form. However, the interplay between the drug dissolution rate, drug supersaturation and different co-formers on membrane permeability of the drug for co-amorphous formulations remains unexplored. By using side-by-side chambers, separated by a PAMPA (parallel artificial membrane permeability assay) membrane, we were able to simultaneously test dissolution and passive membrane permeability of the co-amorphous combinations (1:1 molar ratio) of a poorly soluble drug glibenclamide (GBC) in combination with two amino acids, either serine (SER) or arginine (ARG). In addition, a known passive permeability enhancer sodium lauryl sulfate (SLS) was included in the co-amorphous mixtures at two concentration levels. The mixtures were also characterized with respect to their solid-state properties and physical stability. It was found that GBC mixtures with ARG and SLS had superior dissolution and physical stability properties which was attributable to the strong intermolecular interactions formed between GBC and ARG. These formulations also had optimal permeability properties due to their high concentration gradient promoting permeation and possible permeation enhancing effect of the co-formers ARG and SLS. Thus, simultaneous testing of dissolution and permeation through a PAMPA membrane may represent a simple and inexpensive tool for screening the most promising amorphous formulations in further studies.

An optical method for continuous monitoring of the dissolution rate of pharmaceutical powders.

Monitoring systems providing fast and reliable, even on-line data, from a distinct process stage or final product are needed in drug development, from the early stages of drug discovery until the drug product manufacturing procedures. This includes also processes involving solid particles, such as drug dissolution. However, the existing in vitro drug dissolution test methods suffer limitations, such as long sampling times of 30-60s and thus the inability to be adapted to continuous monitoring, time consuming sample preparation and consumption of large amounts of reagents. In this study, an optical method for monitoring the dissolution rate of pharmaceutical powders was evaluated with model drugs having different dissolution rates. The measuring system consisted of a laser source, light detector, oscilloscope, magnetic stirrer and sample vessel. The intensity of laser light transmitted through the dissolution medium was recorded and displayed by the oscilloscope. Dissolution curves were produced by fitting the raw data with mathematical functions. The optical method was found to be resource-saving, reliable and capable of detecting differences in even rapid dissolution rates of drug compounds. This technique might have targets of application in real-time monitoring of processes in many different sectors, including the pharmaceutical industry.

Effect of prophylactic antibiotics on antimicrobial resistance of viridans streptococci in the normal flora of cataract surgery patients.

PURPOSE: To evaluate the effect of prophylactic treatment including vancomycin in the irrigating solution and topical chloramphenicol on antimicrobial resistance in viridans-group streptococci in the normal flora of patients having cataract surgery. SETTING: Department of Ophthalmology, Turku University Central Hospital and Antimicrobial Research Laboratory, National Public Health Institute, Turku, Finland. METHODS: Minimal inhibitory concentrations (MICs) of 15 antimicrobials were determined for 529 viridans streptococci isolated from throat, nasopharyngeal, and conjunctival swabs of 23 patients on 4 sampling occasions: before cataract surgery and 1 day, 1 month, and 3 months after surgery. Resistance mechanisms of erythromycin-resistant isolates were studied by the double-disk test and polymerase chain reaction of resistance genes. RESULTS: No statistically significant changes occurred in the proportions of isolates with elevated MICs between different sampling occasions. Resistance to vancomycin or chloramphenicol was not found. Resistance to tetracycline, erythromycin, penicillin, quinupristin-dalfopristin, clindamycin, levofloxacin, and moxifloxacin was found on different sampling occasions in 27.9% to 38.7%, 13.1% to 21.8%, 11.5% to 19.4%, 8.9% to 16.9%, 2.3% to 5.6%, 0% to 2.4%, and 0% to 2.2% of the isolates, respectively. Of the erythromycin-resistant isolates, 80.8% had the M phenotype and mefA gene and 19.2% has the macrolide-lincosamide-streptogramin B phenotype and ermB gene. CONCLUSIONS: Development of resistance of viridans streptococci in the normal flora to vancomycin and chloramphenicol during prophylactic use with uneventful cataract surgery is unlikely; the effect on resistance patterns of other antimicrobials is minor. Routine use of prophylactic vancomycin is discouraged, however, because of the lack of scientific proof of its efficacy in preventing postoperative endophthalmitis.