Assessment of skin safety of a new glyceryl trinitrate transdermal patch -Animal and human studies

The experimental models and the studies in man employed to assess the skin and general safety of a newly developed glyceryl trinitrate (GTN, CAS 55-63 -0) transdermal patch, hereinafter coded EPI, are described. EPI was found well tolerated by the skin after single or 28-day repeated ep icutaneous application on the rabbit, devoid of phototoxicity in the mouse, devoid of skin sensitizing potential in the guinea pig and devoid of photo sensitizing effects in the guinea pig. Tested were also, with negative resu lts, the cytotoxic, hemolytic and genotoxic potential, the presence of bact erial endotoxins, the systemic and intracutaneous toxicity, and the possibl e conjunctival irritant effects. The application of EPI for 14 consecutive days on the thoracic skin of 28 h ealthy volunteers did not provoke subjective discomfort such as itching, bu rning or pain, or objective skin lesions. On the application site a light a nd transient erythema was often found demonstrating the transcutaneous abso rption of the vasodilating GTN from the patch. The 14-day application was f ollowed after two weeks by the application of a challenge EPI patch to dete ct a possible skin sensitization by EPI. No skin reaction was elicited, sho wing that also in man EPI is devoid of skin sensitizing potential. During t he 14-day application of EPI several GTN commonly induced systemic adverse reactions were observed, particularly headache, confirming the systemic bio availability of GTN from the patch. Headache rapidly disappeared after remo val of the patch, in parallel with the decrease of the blood concentrations of GTN and of its active metabolites, consistently with the previous pharm acokinetic findings. This is an advantage of the administration of GTN with the transdermal patch because, in the case of unbearable headache, the pat ient is relieved by the simple removal of the patch.