Transdermal Delivery of Insulin Using Trypsin as a Biochemical Enhancer

Abstract

There are 30 million patients with diabetes mellitus worldwide, and 1.2 million new patients are diagnosed each year, including a growing number of children and young adults. 1)However, insulin has been administered only by parenteral routes for the therapeutic control of type 1 diabetes; many patients typically require injections of insulin a minimum of two to three times per day. To improve patient convenience and compliance, alternative routes have been investigated including nasal, oral, transdermal, buccal, ocular, rectal, and vaginal pathways. 2) Transdermal delivery of insulin can prevent its metabolization and the first-pass effect and may thus be an optimal route of administration. However, delivery of large molecules by the transdermal route is also limited by the unique bioarchitecture of skin, which has primarily evolved as a protective barrier against the entry of microorganisms and water.3)The stratum corneum (SC) barrier can be partially overcome by disruption of the lipid structure using fatty acids and surfactants as chemical penetration enhancers. [4][5][6] However, these enhancers are only useful for small molecules, 6,7) and it is difficult to achieve meaningful permeation of large peptides. Most recent research has focused on the use of electrical energy to increase drug flux across the skin, including techniques such as iontophoresis, sonophoresis, electroporation, etc. [8][9][10] Unfortunately, the large, complex, and relatively uncharged insulin molecule still cannot across the intercellular lipid layer of the SC. The transport rate of hexameric insulin by iontophoresis across mouse skin has been low and variable.11) Monomeric insulin analogues carrying two additional negative charges have demonstrated transport rates 50-100-fold higher than those of hexameric insulin. However, the quantity of delivery is still not sufficiently high to provide an effective basal insulin level (1 IU/h). 11)To overcome the barrier presented by the SC, proteolytic enzymes maybe used as skin penetration enhancers because their action is highly specific toward proteins and their molecular size is too large to permeate the viable epidermis. Such enzymes perhaps alter skin permeability by provoking biochemical and metabolic events within skin. For more than 50 years, proteolytic enzymes such as trypsin have been extensively used in laboratory settings for in vitro epidermal separation and keratinocyte isolation.12-15) The unique ability of proteases to cause selective epidermal separation has been in part explained by the proteolytic degradation of desmosomal proteins in the SC, which leads to cell dissociation. 16,17) Recently, several endogenous proteases occurring in the epidermis have been found to play important roles in regulating epidermal cell desquamation.18-21) Based on these findings, several therapeutic applications have been attempted for wound debridement and epidermal ablation. [22][23][24] However, no studies have examined the use of such proteolytic enzymes as a penetration enhancers for t...

Getting Drugs Across Biological Barriers

“…Trypsin enhanced the penetration of insulin, resulting in reduction of blood glucose levels in rats. [186] Mechanistic studies suggested that trypsin could disturb the structure of keratin in the SC via proteolysis but appeared to have no effect on the lipid bilayers. [186] Trypsin can also enhance the transdermal permeation of other macromolecules such as FITC-labelled dextrans and FITC-insulin.…”

Self-Dissolving Micropile Array Chip as Percutaneous Delivery System of Protein Drug

“…Many scientists have taken up the challenge of developing a transdermal DDS for insulin. [22][23][24][25] Iontophoresis is a powerful device for the transdermal delivery of poorly permeable drugs. TDDS have already been developed for lidocaine and are now used clinically.…”

Visualization and characterisation of defined hair follicle compartments by Fourier transform infrared (FTIR) imaging without labelling

“…Endmember 5 has high abundances in the periphery of the mapped area and shows a relatively high amount of lipid, as indicated by the strong band at 1744 cm À1 , assigned to ester carbonyl mode of lipids [30,31]. It also naturally has a large amount of protein, as evinced by the intensity of the bands at 1648 and 1532 cm À1 [3,28,32].…”