Bioavailability and Pharmacokinetic Profile of Glyceryl Trinitrate and of Glyceryl Dinitrates during Application of a New Glyceryl Trinitrate Transdermal Patch

Abstract

The pharmacokinetics and bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolites, i.e. 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0), were compared during a single 24-h application of a new GTN transdermal patch (Epinitril 10, hereinafter called EPI-10) or a reference patch (hereinafter called ND-10) releasing 10 mg GTN in 24 h. The study was an open, randomized balanced cross-over study on 24 healthy male volunteers to whom the patches were applied to the antero-lateral part of the thorax in two periods separated by a 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and at 0.5, 2 and 3 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope-labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). The ratios of the AUCs of GTN, 1,2-GDN and 1,3-GDN measured during application of EPI-10 or of ND-10 were within the 0.85-1.25 limits required to assess equivalence of the extent of bioavailability. The ratios of the Cmax were within said limits for the signal metabolite 1,2-GDN and only slightly below (0.78-1.16) for the parent GTN. EPI-10 can therefore be considered equivalent to ND-10 also with regard to the rate of bioavailability. Under both patches GTN reached steady-state levels after 3-6 h of patch application and remained on sustained levels during the whole 24-h application. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h. Both patches were well tolerated at the application site. For its small size, thinness and transparency, EPI-10 is very patient friendly, a quality that improves compliance with the therapeutic regimen.

Assessment of Skin Safety of a New Glyceryl Trinitrate Transdermal Patch

“…Their rapid appearance after patch application proves the effective performance of the patch in delivering GTN through the skin. The ADRs are purely functional and disappear very rapidly after removal of the patch, in parallel with the decrease of the blood concentrations of GTN and of its active metabolites demonstrated in previous studies [28,29]. This is a notable advantage of the administration of GTN with the transdermal patch.…”

“…The absence of a primary irritation of the skin by EPI was confirmed by the single 24-h-applications of EPI-10 carried out in a previous study on 24 healthy subjects [29], as well as by the single 24-h applications of EPI-5, EPI-10 and EPI-15 on 18 healthy subjects [28].…”

“…A similar incidence of headache was reported in previous studies with single applications of EPI. In fact, in the bioavailability study [29] headache had an incidence of 83 % under EPI-10 and of 88 % under the reference GTN patch. In the cross-over single application dose-response study [28] the incidence of headache was 72 %, 100 % and 94 % respectively under EPI-5, EPI-10 and EPI-15.…”

“…With the goal to further improve these characteristics, we have developed a GTN transdermal patch using a new technology that avoids absorption enhancers and increases the transdermal absorption [31]. The pharmacokinetic performance of the new GTN patch was previously described [28,29] as well as its pharmaceutical characteristics [30]. In this publication we report the in vitro and in vivo models and the studies in man employed to assess the skin and general safety of the newly developed GTN transdermal patch.…”

Plasma Levels of Glyceryl Trinitrate and Dinitrates during Application of Three Strengths of a New Glyceryl Trinitrate Transdermal Patch

“…With this prospective we have developed a GTN transdermal patch using a new technology that avoids absorption enhancers and increases the transdermal apsorption [19]. The pharmacokinetic pattern in plasma of GTN and of its active metabolites during application of this new patch (coded EPI-10) were investigated in a previous publication [18] and found equivalent to those of a widely used GTN patch releasing 10 mg GTN in 24 h (ND-10). Since different patients need for their disease different doses of GTN, the new transdermal patch was developed in three strengths coded EPI-5, EPI-10 and EPI-15 with the aim to achieve release rates of 5, 10 and 15 mg GTN, respectively, in 24 h of application.…”