Kinetics of the delivery of glyceryl trinitrate and isosorbide dinitrate from the transdermal systems nitropercuten and sorbopercuten in experimentsin vitro

Transdermal therapeutic systems (TTS) are dosage forms which enable the release of active substances to be controlled for extended (from days to weeks) and continuous transdermal administration of a drug into the systemic circulation at a given rate and according to a given kinetic program [1-4]. The application of TTS enables the drug concentration to be stabilized in the blood of patients at a given stationary therapeutic level (as a rule close to the minimum effective)during the whole time of applying the TTS (i.e., with opportune changing of the TTS this time can be indef'mitely long). A TTS enables the metabolism of the bulk of the drug on first pass through the liver to be avoided, and the drug action to be interrupted at any moment by simply removing the TTS from the skin surface. The usefulness of TTS has been demonstrated in the treatment and prophylaxis of serious chronic, particularly cardiovascular, illnesses, since they enable the partial uptake of drugs to be avoided, the possibility of overdosing to be avoided, and the overall quantity of drug passing into the organism to be reduced significantly due to the absence of peak concentrations in plasma, which thereby leads to a significant attenuation of drug side effects. At the present time the TTEs which have been developed abroad and used clinically include glyceryl trinitrate (GTN)Nitroderm, Nitro-Dur, Nitrosic, and Deponit [5-9], isosorbide dinitrate (ISDN) Frandol Tape [10], clonidlne Catapres [11], scopolamine Scopoderm [12], estradiol Estraderm [13], and nicotine Nicotinell, Nicoderm [14, 15], etc. We have developed a family of matrix TTS with various drugs based on an original hydrophilic matrix (Percuten) of which the TTS containing propranolol, Propercuten, has been described by us previously [16]. Data are given in the present work on two other TTS of the same family containing nitrates, viz., Nitropercuten and Sorbotpercuten (the names denote "GNT and ISDN delivered through the skin," respectively). The duration of their action is 1 day since the continuous administration of nitrates for longer may lead to the emergence of tolerance and a short pause is necessary after administering nitrates for a day. The main problem to be solved when developing a TTS with selected drugs is the provision of a rate of transdermal drug supply necessary for therapy. This depends on many factors, particularly on the composition of the polymeric diffusion matrix containing the drug which is the main constructional element of the TTS [1-4], and on the properties of the drug itself. The first stage in the development of a TTS is usually a study of the kinetics of drug supply from the TTS in vitro through a membrane with properties unchanged during the experiment.* Under standard conditions the diffusion characteristics of skin vary and depend on the actual patient and the place of application of the system. The interpretation of data obtained in vivo is therefore more complex than that of data obtained in vitro. We showed previously [ 16] that the matrix TTS containing propranolol, viz., Propercuten, which is related in composition to Nitropercuten and Sorbopercuten, is characterized in experiments in vitro by a high rate of supply of propranolol, constant with time up to the release of 84% of the total drug contained in the matrix. The kinetics of the supply of drug from the diffusion matrix of the TTS through the epidermis of the skin of a human corpse, or a Carbosil polymeric membrane modeling it in in vitro experiments, were described by Fick's first law of diffusion in the following form: