Safety & Toxicology of Zep-3 & Zep-4
S.I.S has conducted a large variety of pre-clinical studies in accordance with the requirements of the health regulatory authorities and in order to support the development processes of Zep-3 and Zep-4 creams as products and to establish their safety and efficacy.
The drug permeation study revealed that during the 24 hrs experiment, ZEP-3 API and Zep-4 peptides have a very low absorption profile across the skin (less than 1%) while a significant amount of drug is accumulated in the skin.
In order to cover the regulatory basic genotoxicology battery, Zep-3 and Zep-4 peptides were tested under GLP conditions for mutagenicity, clastogenicity and aneugenic activity potential. Zep-3 and Zep-4 peptides were assayed for mutagenicity by the Bacterial Reverse Mutation Test (Ames test) in vitro and were shown to be non-mutagenic for all the used test strains. The clastogenicity potential of Zep-3 and Zep-4 were determined using the Chromosomal aberration Test in vitro. The results confirmed that ZEP-3 and Zep-4 did not induce an increase in numerical and structural chromosome aberrations in the cultured human peripheral blood lymphocytes. Similar result were obtained in the Micronucleus Test in vitro where Zep-3 and Zep-4 did not exhibit clastogenic or aneugenic activity in cultured human peripheral blood lymphocytes.
To reject possible effects of Zep-3 and Zep-4 creams topical application on the skin, Zep-3 and Zep-4 cream final formulation were tested under GLP conditions for its potential to produce dermal irritation and/or skin sensitization. In the skin irritation test all the erythema/edema scores per all observation time points in all tested animals were 0, and according to the calculated PII Zep-3 and Zep-4 creams exhibit a negligible irritating effect on rabbit skin. Similar results were obtained in the skin sensitization study resulting in erythema scores 0 per all observation time points in all the tested animals confirming that Zep-3 and Zep-4 cream have no potential of producing skin sensitization.
Based on the above study results Zep-3 and Zep-4 API peptides as well as the final ZEP-3 cream drug product; were both shown to be well tolerated with an established safety profile.
Safety studies were carried out in rats in which the following end points were recorded: body weight Vitality blood picture Internal organs histopathology No adverse side effects were observed at twice a week administration (topical or I.V.) of high dosages for 200 days. Dermal Permeability was tested using the ear-skin pig model. Zep-3 and Zep-4 show permeability profile below 1% after 24 hrs. Significant amount of drug accumulated in the skin.