Transdermal Delivery of Insulin from a Novel Biphasic Lipid System in Diabetic Rats

Abstract

Noninvasive transdermal insulin delivery could provide diabetic patients with sustained physiological levels of basal insulin in a pain-free manner. We have developed a novel transdermal lipid-based system (Biphasix) suitable for macromolecule delivery across the skin. The objective of this study was to evaluate the pharmacological effects of the Biphasix-insulin delivery system in a diabetic rat model. Transdermal patches (one per animal) containing Biphasix-insulin formulation (10 mg of recombinant human insulin dose) were applied to the shaved abdominal skin of streptozotocin-induced diabetic rats for 48 h. Blood glucose was monitored every 2-4 h using a Lifescan glucose meter. Serum insulin levels were analysed by enzyme-linked immunosorbent assay. A decrease in blood glucose of 43.7 +/- 3.8% (mean +/- SEM, n = 25) was observed compared with initial blood glucose levels. The duration of the response was 51.5 +/- 3.7 h (mean +/- SEM, n = 25). Serum insulin after application of the transdermal Biphasix-insulin patch was 20.08 +/- 5.44 micro IU/mL (mean +/- SEM, n = 13) during the steady state, which was not statistically different from the insulin levels obtained 2 h after subcutaneous injection of 1 mg of recombinant human insulin solution. Insulin bioavailability from the transdermal Biphasix-insulin patches was 21.5 +/- 6.9% (mean +/- SEM, n = 13) based on serum insulin and 39.5 +/- 8.5% (mean +/- SEM, n = 25) based on the pharmacodynamic blood glucose-lowering effects. The Biphasix system successfully delivered insulin transdermally, as evidenced by a significant sustained decrease in blood glucose in diabetic rats, with a corresponding increase in serum insulin. These results support the feasibility of developing a transdermal insulin patch for human applications.

Recent advances in topical delivery of proteins and peptides mediated by soft matter nanocarriers

“…Further studies substantiated these findings (Foldvari, 2010;King et al, 2003). However, dermally applied insulin is still less effective in glucose lowering compared to oral, pulmonary, or buccal application (oral: 20-50%, pulmonary: 45-80%, buccal: 15-75% versus 25-38% in dermal) (King et al, 2002).…”

“…In general, these vesicles have aqueous, oily, and micellar compartments which are surrounded by concentric phospholipid bilayers and allow a flexible composition for optimized encapsulation efficiencies and tailored viscosity (Foldvari, 2010). Biphasic vesicles were studied for the topical delivery of, e.g., insulin (6 kDa) (King et al, 2002(King et al, , 2003, interferon alpha (19 kDa) King et al, 2013), albumin (60 kDa) (Foldvari, 2010), or antigens like hen egg lysozyme (14 kDa), leukotoxin (100 kDa), or staphylococcal enterotoxin (28 kDa) (Baca-Estrada et al, 2000).…”

“…One interesting application was described by King et al who investigated the effectiveness of lipid-based biphasic vesicles (Biphasix™) for dermal insulin delivery (King et al, 2002). The biphasic vesicles consisted of a complex mixture of soya phosphatidylcholine, cholesterol, propylene glycol, and linoleamidopropyl-PG-dimonium chloride phosphate.…”

(Phospho)lipid-based Nanosystems for Skin Administration

“…King and co-workers developed biphasic vesicles-based novel delivery system Biphasix TM as a superior delivery system for transdermal delivery of insulin. Basal levels of insulin were 22 observed in the serum of diabetic rats treated with Biphasix-insulin up to 3 days after patch application [114]. In consequent experiments, the authors proved that lymphatic transport of insulin after non-invasive topical administration is taking place [115].…”

Ultrasound Mediated Transdermal Insulin Delivery in Pigs Using a Lightweight Transducer

“…This low permeability is mainly attributed to the outermost skin layer, stratum corneum, which consists of a condensed and ordered structure of cells, keratinocytes, compassed by lipid bilayers. Once the drug crosses stratum corneum, the next epidermal layer is less problematic to traverse, and consequently the drug can reach the capillary bed to be absorbed (6,7).…”