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.
May 02, 2010

Insulin resistance is a common feature characterizing the pathogenesis of Type 2 diabetes mellitus. Epidemiologic studies have found a strong association between insulin resistance and Type 2 diabetes (1). For example, more than 90% of African Americans, Hispanics, and nonhispanic whites with Type 2 diabetes in the United States were identified as insulin resistant (2). Rosiglitazone [(±)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl] methyl]-2, 4-thiazolidinedione, (Z)-2-butenedioate (1:1)], a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control because it has a high affinity for peroxisome proliferators-activated receptor-gamma (PPARγ). Thus, it regulates the transcription of certain insulin-responsive genes and improves insulin sensitivity (3). It controls glucose production, transport, and utilization. Although recent studies claim that the drug could be a risk for cardiac patients, it is still a good option for improving insulin sensitivity (4–6).

Rosiglitazone is a weak base with a molecular weight of 357.44 Da. As a maleate salt, 2 to 8 mg of it is administered in tablet form twice daily, with or without a combination of metformin. However, rosiglitazone is metabolized extensively by n-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid in the liver (7, 8). Therefore, alternative routes such as transdermal delivery may be a good choice to deliver the drug directly into systemic circulation through intact skin by bypassing the hepatic first-pass effect to reduce dose frequency by maintaining a prolonged therapeutic blood level of rosiglitazone.

A transdermal patch is a medicated adhesive patch placed on the skin to deliver drugs into the bloodstream (9). The drug has a log P value of 2.1, which contributes to its lipid solubility and hydrophilicity. The oral absorption of rosiglitazone is 99%. Clearance of the drug, in terms of excretion in breast milk, is unknown; renal excretion of metabolized drug is 64%, and feces show the presence of about 23% of the parent compound. The elimination half-life of the drug is 3–4 h, and total protein binding is 99.8% to albumin. The drug has the volume of distribution of 17.6 L. These factors suggest that the drug is a suitable candidate for transdermal drug-delivery systems (TDDS). The authors evaluated the efficacy of the formulations in streptozotocin (STZ)-induced diabetic rats and examined the pharmacokinetic parameters of drug administered through TDDS in humans. This study describes how to develop a matrix–type transdermal patch containing rosiglitazone maleate using pressure-sensitive adhesives (Duro-Tak 387-2516 and Duro-Tak 87-2852). A blend of Duro-Tak polymers can achieve the desired consistency and tackiness for a TDDS, without any gelling agents. Duro-Tak polymers are acrylate-polymeric solutions containing acrylic acid, methyl acrylate, and 2-ethylhexyl acrylate at different ratios. In the present study, transdermal matrix patches containing rosiglitazone maleate using combinations of polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 in ratios of 4:5 and 4:6 were developed and evaluated in vitro and in vivo.

Materials

Rosiglitazone maleate was obtained as a gift sample from Sun Pharma (Mumbai). Duro-Tak 387-2516 (a semisolid polymer with boiling point of 60 °C, solid content of 41.5%, and viscosity of 4350 cp) and Duro-Tak 87-2852 (a semisolid polymer with a boiling point 65.5 °C, solid content of 33.5%, and viscosity of 2550 cp) were gifts from the National Starch and Chemical Company (Bridgewater, NJ). Polyvinyl alcohol was purchased from S.D. Fine-Chem (Boisar, India). Streptozotocin (STZ) was purchased from Sigma-Aldrich (Bangalore, India). All other chemicals used were of analytical reagent grade.