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 epicutaneous application on the rabbit, devoid of phototoxicity in the mouse, devoid of skin sensitizing potential in the guinea pig and devoid of photosensitizing effects in the guinea pig. Tested were also, with negative results, the cytotoxic, hemolytic and genotoxic potential, the presence of bacterial endotoxins, the systemic and intracutaneous toxicity, and the possible conjunctival irritant effects. The application of EPI for 14 consecutive days on the thoracic skin of 28 healthy volunteers did not provoke subjective discomfort such as itching, burning or pain, or objective skin lesions. On the application site a light and transient erythema was often found demonstrating the transcutaneous absorption of the vasodilating GTN from the patch. The 14-day application was followed after two weeks by the application of a challenge EPI patch to detect a possible skin sensitization by EPI. No skin reaction was elicited, showing that also in man EPI is devoid of skin sensitizing potential. During the 14-day application of EPI several GTN commonly induced systemic adverse reactions were observed, particularly headache, confirming the systemic bioavailability of GTN from the patch. Headache rapidly disappeared after removal of the patch, in parallel with the decrease of the blood concentrations of GTN and of its active metabolites, consistently with the previous pharmacokinetic findings. This is an advantage of the administration of GTN with the transdermal patch because, in the case of unbearable headache, the patient is relieved by the simple removal of the patch.
Santoro
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Department of Regulatory Affairs, Rotta Research Laboratorium, Monza, Italy.
Rovati
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LC
Setnikar
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D000269:Adhesives; D000279:Administration, Cutaneous; D000328:Adult; D000818:Animals; D003692:Delayed-Action Preparations; D017484:Dermatitis, Phototoxic / Q000473:pathology; D004304:Dosage Forms; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000009:adverse effects*; D011817:Rabbits; D023422:Skin Irritancy Tests; D014466:Ultraviolet Rays; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects*
D000269:Adhesives; D003692:Delayed-Action Preparations; D004304:Dosage Forms; D014665:Vasodilator Agents; D005996:Nitroglycerin