ABSTRACT
OBJECTIVE: Ocular bioadhesive minitablets containing gentamicin and vancomycin were developed using different powder mixtures of pregelatinized starch and Carbopol (physical or cospray-dried mixtures). METHODS: Drug content, antimicrobial activity, and radical formation of the powders used for tablet preparation were evaluated immediately and 30 days after gamma sterilization. Tablet properties and in vitro drug release from the sterilized minitablets were determined. Storage stability of vancomycin and gentamicin in sterilized bioadhesive mixtures was examined by LC-UV/MS and a microbiological assay, respectively. A bioadhesive powder mixture containing only vancomycin was irradiated by X electron-magnetic radiation to evaluate vancomycin stability following sterilization through irradiation. RESULTS: The antimicrobial activity of gentamicin against Staphylococcus epidermidis was not altered in comparison to nonsterilized formulations. Only after an overkill dose of 50 kGy, the concentration of vancomycin decreases to an extent that was pharmaceutically significant. No significant difference in radiation stability between drug substance and product (i.e., powder mixture) was observed. A shift in stability profile was not observed at 6 weeks after irradiation. All other degradation products were present only in small quantities not exceeding 1.0%. The in vitro drug release from the minitablets prepared with physical powder mixtures of pregelatinized starch and Carbopol® 974P NF (96 : 4) was faster compared to the cospray-dried mixtures of starch with Carbopol® 974P NF (ratio: 95:5 and 85:15). The electron paramagnetic resonance signals of the radicals formed during sterilization were still visible after storage for 30 days. The slug mucosal irritation test indicated mild irritation properties of the bioadhesive powder mixtures although no tissue damage was observed.
Subject(s)
Anti-Bacterial Agents/pharmacology , Excipients/chemistry , Gentamicins/pharmacology , Vancomycin/pharmacology , Acrylic Resins , Adhesiveness , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/toxicity , Drug Stability , Drug Storage , Gastropoda , Gentamicins/administration & dosage , Gentamicins/toxicity , Humans , Mucous Membrane/drug effects , Polyvinyls/chemistry , Staphylococcus epidermidis/drug effects , Starch/chemistry , Tablets , Toxicity Tests , Vancomycin/administration & dosage , Vancomycin/toxicityABSTRACT
The objective of this study was to limit the test procedure time of the Slug Mucosal Irritation test to one day and to determine whether it is a relevant and reliable method to predict the eye irritation potential of chemicals. The irritation potential of several eye reference chemicals can be estimated by the amount of mucus produced when tested at a 1% concentration (60 min). Since some in vivo irritating chemicals did not influence this endpoint the effect of increasing concentrations on membrane damage was investigated. This study revealed that when tested at a 3.5% concentration (60 min) the underestimated chemicals induced an increased protein and/or enzyme release. A two-step classification prediction model was developed that classified the chemicals first by the amount of mucus produced (1%, 60 min). Chemicals that did not affect this endpoint were classified based on the membrane damage induced by a second treatment (3.5%, 60 min). The results were compared with the corresponding EU classification (NI, R36 and R41) and 71% of the chemicals were correctly classified with a specificity and sensitivity of 75% and 94%, respectively. Repeated testing of the chemicals revealed a good intra-laboratory reproducibility. The test seems to be a promising method for screening the eye irritating potential of chemicals.
Subject(s)
Animal Testing Alternatives/methods , Eye Diseases/etiology , Irritants/toxicity , Mollusca/physiology , Mucous Membrane/drug effects , Toxicity Tests/methods , Animals , Irritants/classification , Mucous Membrane/metabolism , Mucus/metabolism , Reproducibility of Results , Sensitivity and Specificity , Time FactorsABSTRACT
The purpose of this study was to evaluate the biocompatibility of different Amioca/poly(acrylic acid) and Amioca/Carbopol 974P co-spray dried mixtures with an alternative mucosal irritation test using slugs. The irritation potential of the mixtures was measured by the amount of mucus produced during a repeated 30-min contact period. Additionally, membrane damage was assessed by measuring the protein and enzyme release from the body wall of slugs after treatment. All the Amioca/poly(acrylic acid) co-spray dried mixtures (50:50 and 25:75 ratios) induced slight irritation of the mucosal tissue as was demonstrated by the significantly increased mucus production however no increased protein and enzyme release was detected. Co-spray dried Amioca/Carbopol 974P mixtures containing 40% and more Carbopol 974P demonstrated a significantly higher mucus production and release of cytosolic LDH, indicating membrane damage. The total mucus production of the slugs treated with the co-spray dried mixtures containing up to 20% Carbopol 974P was significantly higher compared to the blank slugs. However, these mixtures induced no membrane damage since no additional effect on the protein release and no enzyme release was detected. By co-spray drying up to 20% Carbopol 974P could be incorporated without showing a distinct sign of irritation. These mixtures can be considered as potentially safe bioadhesive carriers.
