Effect of vasoactive agents on the dermatopharmacokinetics and systemic disposition of model compounds, salicylate and FITC-dextran 4 kDa, following intracutaneous injection of the compounds
Introduction
Recently, various transdermal drug delivery devices have been developed to bypass the permeation barrier of the stratum corneum and to deliver drugs directly into skin tissues. For instance, non-needle syringes are utilized to deliver insulin and growth hormone to patients (Verrips et al., 1998, Bremseth and Pass, 2001). A spraying device containing estradiol named Estradiol MDTS® has been developed by Acrux (West Melbourne, VIC, Australia) where EvaMist™ produces high pressure to administer the drug directly into the stratum corneum and viable epidermis (Finnin and Hadgraft, 2006). Microneedle arrays are also utilized to deliver drugs transdermally, with many micro-scale needles in two dimensions. Solid and hollow needles have already been designed (Teo et al., 2005), made of metal (Martanto et al., 2004), melted sugar (Miyano et al., 2005) or biodegradable polymer (Park et al., 2006). They can be applied like dermal patches, but they are not conventional dermal patches but intracutaneous (i.c.) injectors. As these technologies are different from conventional transdermal formulations and completely avoid the stratum corneum barrier, it is believed that these devices will be the next generation of topical formulations.
We have already analyzed dermatopharmacokinetics after i.c. infusion of drug solution to each depth of the skin membrane to evaluate the utility of these types of delivery systems (Yoshida et al., 2002). As a result, i.c. injection is very useful to deliver drugs to the systemic circulation and underlying muscle from the application site of skin, although it is not a common administration method for therapeutic drugs except for tuberculin reaction and diagnosis of anaphylaxis reaction. The dermatopharmacokinetics after injection was greatly affected by cutaneous blood flow at the injection site as well as the osmotic pressure of the applied solution. Thus, the physicochemical properties of applied drugs (i.e., molecular weight and protein binding), injection medium (i.e., volume and osmolarity) and body environment (i.e., cutaneous temperature and blood flow) must have a great influence on the dermatopharmacokinetics after direct injection into cutaneous tissues.
Skin permeation of topically applied drugs can be increased by several chemical enhancers (Obata et al., 2000) and percutaneous absorption of the drugs (uptake into the systemic circulation) can be regulated by vasoactive agents (Higaki et al., 2005) as well as chemical enhancers. It is clear that the stratum corneum must be the biggest barrier against the skin permeation of drugs. When the drugs are administrated by evading the stratum corneum barrier; i.e., by i.c. injection, the effect of vasoactive agents may be much higher on the drug absorption into the systemic circulation. In the present study, therefore, we paid attention to the blood flow in skin. We have reported (Sugibayashi et al., 1999) that drug absorption to the systemic circulation after topical application was inhibited by a vasoconstrictor agent, epinephrine. It was also reported (Singh and Roberts, 1994, Bernards and Kopacz, 1999) that epinephrine or phenylephrine was applied at the same time to prolong the retention time of lidocaine in the tissues. Since the effect of vasoactive agents must be greater after i.c. injection than after topical application, the combination with vasoactive agents provides more suitable properties for drug targeting and delivery after i.c. injection. Phenylephrine and tolazoline were used as a model α-blocker and α-agonist, respectively, to change cutaneous blood flow after i.c. injection in the present study. Sodium salicylate (SA; MW 160) and fluorescein isothiocyanyte-labeled dextran 4 kDa (FD-4; MW 3,820) were selected as model drugs, and dermatopharmacokinetics and systemic disposition after the i.c. injection of SA and FD-4 were determined with and without combination with vasoactive agents.
Section snippets
Materials
Sodium salicylate and tolazoline HCl were supplied by Wako Pure Chemical Industries (Osaka, Japan). FD-4 and phenylephrine HCl were supplied by Sigma–Aldrich (St. Louis, Missouri, U.S.A.). Other chemicals and solvents were of reagent grade and were used without further purification.
Animals
Male Wistar rats, weighing of 300 ± 20 g, were purchased from Saitama Experimental Animals (Sugito, Saitama, Japan). The rats were anesthetized with urethane (1.0 g/kg, i.p.) and the hair on their abdomen was shaved.
Theoretical
In our previous report, the effect of the osmotic pressure of solution and injection volume on the dermatopharmacokinetics and systemic disposition of SA after i.c. injection was estimated using a compartment model (Fig. 1) consisting of skin, muscle, and central and peripheral compartments (Yoshida et al., 2007). These methods are suitable to understand the pharmacokinetics of topically applied drugs, especially to quantitatively assess the migration rate from one organ to another. Changes of
Cutaneous blood flow following i.c. injection of vasoactive agents
Fig. 2 shows the time courses of cutaneous blood flow after i.c. injection of vasoactive agents/PBS. The vertical axis shows % of the cutaneous blood flow at time t against that before administration. No change in cutaneous blood flow was observed, being similar to non-treatment of i.c. saline injection. In contrast, blood flow decreased within 5 min after i.c. injection of phenylephrine, and returned to the value before administration within 2 h. On the other hand, blood flow slowly increased
Discussion
The present i.c. injection can be adopted for direct delivery to viable skin by evading the permeation barrier of the stratum corneum. We evaluated changes in cutaneous blood flow after i.c. injection of vasoactive agents and compared with changes in the pharmacokinetics of model drugs in the present study. The dose of vasoactive agents was adjusted to an adequate concentration in cutaneous tissues within the present experiment period. In other words, vasoconstriction was more potent by the
Conclusions
Cutaneous blood flow changed by the addition of vasoactive agents, and this change in blood flow greatly affected the dermatopharmacokinetics (drug migration from the skin to muscle and systemic circulation) after i.c. injection. Since the permeation rate through the stratum corneum of most drugs topically applied is very slow in conventional transdermal systems, enhancement of skin permeation may be necessary to achieve adequate therapeutic effects. Since cutaneous vessel permeation must be a
Acknowledgement
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (18590036 to KS).
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