Skin Permeation of Rosiglitazone from Transdermal Matrix Patches - Pharmaceutical Technology

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Skin Permeation of Rosiglitazone from Transdermal Matrix Patches
The authors demonstrate that sustained-release delivery can help avoid the risk of sudden higher-blood concentration of a drug to avoid toxicity.

Pharmaceutical Technology
Volume 34, Issue 5, pp. 56-72

In vitro skin-permeation study. A modified Keshary–Chien (40-mL capacity diffusion cell) was used for the in vitro skin-permeation study. A square section of excised human cadaver skin (R.G. Kar Medical College, Kolkata, India) was stripped of adhering fat and visceral debris. The skin was stored at -80 C. The thawed skin was then tied with an adhesive tape so that its dorsal side faced upward. A measured portion of transdermal film was placed on the skin, keeping the backing membrane facing upward on the donor compartment. The donor compartment containing the skin and the patch was placed on the reservoir compartment of the diffusion cell containing 20% v/v PEG 400 in normal saline (10, 16). The temperature was maintained at 37 0.5 C using an air-circulating water jacket. The solution in the receiver compartment was continuously stirred using a magnetic bead (17).

One mL of sample was withdrawn at various time intervals and replaced with 1 mL of 20% v/v PEG 400 in normal saline. The absorbance of the samples was measured in a UV–vis spectrophotometer (Genesys, Thermoelectocorporation) at 318 nm, after appropriate dilution and filtration, against a blank (20% v/v PEG 400 in normal saline). To eliminate the interference of material leaching from the skin or the patch, a control diffusion cell with patch without drug was run in each experiment. The difference in absorbance between the test sample and the control sample was considered the absorbance caused by the drug at a particular time point. The mean cumulative amount of drug permeated per square centimeter of skin was plotted against the time.

In vivo study in animals. The animals used for in vivo experiments were adult Sprague–Dawley rats of either sex weighing 150–200 g. The animals were housed individually in polypropylene cages and were fed the standard pellet diets and water ad libitum. They were kept in a 12-h light–dark cycle at 25 1 C and 45–55% relative humidity. The in vivo experimental protocol was approved by the Institutional Animal Ethics Committee, Jadavpur University, Kolkata, India.

Experimental design. Animals were divided into seven groups of six rats each. Group I animals (i.e., the normal control) were treated with citrate buffer, pH 4.5. Diabetes was induced in the other rats. After an overnight fast, rats were made diabetic by a single intraperitoneal injection of STZ (Sigma Chemical Company, Mumbai, India) (60 mg/kg, i.p.) dissolved in cold citrate buffer (pH 4.5). After 24 h, all STZ-treated rats showed blood glucose levels between 250 and 350 mg/dL and were considered for further experiments. The diabetic condition of the animals stabilized for five consecutive days. On the sixth day, the experiment was started. Group II animals served as diabetic control. The hair on the backside of the rats in Groups III, IV, V, VI, and VII was removed with a depilatory cream (Anne French, Wyeth Limited, Hyderabad, India). Transdermal patches (each of 4.4 cm2) with Duro-Tak 387-2516 and Duro-Tak 87-2852 in ratios of 4:5 and 4:6, respectively, without drugs were applied to Group III and IV animals. Transdermal patches (4.4 cm2 each) of Duro-Tak 387-2516 and Duro-Tak 87-2852 in ratios of 4:5 and 4:6, respectively, each containing 4 mg of rosiglitazone maleate, were applied to Group V and Group VI animals (see Figure 1). Group VII animals were given 5 mg of the drug solution per 1 kg of body weight orally using a round-tipped stainless-steel needle attached to a 1-mL syringe. All the animals were fasted overnight, but water was given ad libitum, blood was taken from a tail vein, and blood glucose was determined at intervals of 0, 12, 24, and 48 h using OneTouch glucometers (Accu-Check, Roche Diagnostics, Germany).

In vivo study in humans. This study was performed after receiving approval from the Institutional Ethics Committee at Jadavpur University in Kolkata, India.

Selection of volunteers. Five male volunteers between 24 and 32 years old were selected. The volunteers weighed between 55 and 65 kg each. They had no significant chronic ailments and no history of hypersensitivity, cardiac malfunction, or contraindication to rosiglitazone. They did not receive any medications one month before or during the study, and had not been involved in any clinical trial during the previous six months. Each gave written consent and was selected on a random basis.

Figure 2
Application of the patch. Formulation I was selected for in vivo study on humans because it had the most suitable physicochemical properties and the best permeation profile. Patches were applied on the neck region behind the ear. The application area (see Figure 2) was not washed for the duration of the experiment (i.e., 48 h).

Collection of blood samples. Blood samples of 5 mL were withdrawn from each participant over a period of 48 h at predetermined time intervals of 2, 4, 8, 24, and 48 h. Because permission had been obtained to collect blood five times only from each volunteer in 48 h, the authors selected those time points to understand the initial and subsequent trend of the amount of drug in the blood during that period. The blood samples were withdrawn, collected in vials containing ethylene diamine tetra-acetic acid (10 mg/mL of blood), and plasma was separated.


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