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

Abstract

Transdermal drug delivery systems (TDDS) have been challenged to increase the permeation rate of drugs through the skin and experimental strategies have included the use of chemical enhancers and physical methods. Of these, chemical enhancers have contributed most to the development of TDDS. Approximately 20 products of TDDS were launched on the US market by the end of 2008. Thus the penetration of small molecules through the skin can be enhanced by chemical enhancers.1) However, triggering of skin irritation and other safety concerns limit their use. As examples of physical absorption enhancement methods, iontophoresis, electroporation, and ultrasound have been investigated.2-6) Iontophoresis uses an electric field to drive ionized molecules across the skin by electrophoresis and nonionized molecules by electroosmosis. Despite concerns about skin irritation, iontophoresis may be useful for delivery of some peptides including insulin. 7) In particular, TDDS of lidocaine by iontophoresis was launched onto the US market in 2004. Also, transient enhancement of skin permeability of both small drugs and macromolecules has been shown by electroporation and ultrasound. 8,9) Recent advances in microfabrication technology have made it possible to prepare microneedles that have a possible application as novel TDDS. Since the first publication by Henry et al. 10) in 1998, microfabrication techniques for the production of silicon, metal, glass and polymer microneedle arrays with micrometer dimensions have been reported. [11][12][13][14] The microneedles are either solid or hollow and possess a geometrical shape. Microneedle TDDS are roughly defined by a micron-sized needle preparation through and by which drug is percutaneously administered. Microneedle TDDS are classified as follows: (1) extremely small needles through which drug solution can be injected into the skin; (2) metallic and/or silastic microneedles on whose surface drug is coated; and (3) metallic and/or silastic microneedles with which conduits (micropores) are made on the skin and drug solution is applied after removing the microneedles. Fully to understand the function of microneedles, the physiology of the skin must be considered. There are no blood vessels in the epidermis. Deeper, there are blood capillaries in the dermis, which forms the bulk of skin volume and contains living cells and nerves. When microneedle arrays are inserted into the skin, conduits are created for the penetration of drug across stratum corneum (SC). Once a drug penetrates the SC, it can diffuse rapidly through the deeper tissue and permeate into the underlying capillaries for systemic absorption.Our previous studies suggest that macromolecules such as insulin, 15,16) erythropoietin (EPO), 17,18) interferon, 19) and recombinant human growth hormone 20) are well absorbed through rat skin by self-dissolving micropile preparations about 2-3 mm in length with an outer diameter of 0.3-0.4 mm. In addition, a self-dissolving micropile array (SDMA), comprising 10 lines and 10 columns, was...

Microneedles for drug and vaccine delivery

“…Dissolving microneedles have been used to deliver EPO [121, 126], low molecular weight heparin [117], leuprolide acetate [123], desmopressin [122], and human growth hormone [122, 124, 201]. Coated microneedles have administered desmopressin [97], salmon calcitonin[202], and PTH (1-34) [89, 203–204].…”

Two-Layered Dissolving Microneedles for Percutaneous Delivery of Peptide/Protein Drugs in Rats

“…An approximately 300 µm length from the top of dissolving microneedles was inserted into the skin, where dissolving microneedles encountered environmental water: Caspers et al reported that the water content in the skin was as high as 70% (44). In our previous report, pharmacokinetic evaluation of dissolving microneedles containing erythropoietin (EPO) was performed in rats and dogs, and species difference was studied (45). Higher BA of EPO was obtained in dogs, 65.9-69%, than in rats, 39.4%.…”

Polymeric microneedles for transdermal protein delivery

“…For example, protein denaturation during administration and/or subsequent storage process can result in limited therapeutic efficiency, altered regulatory response and impaired vaccination efficiency [53–55]. Besides the maintenance of bioactivity, the therapeutic efficacy is also impacted by the drug absorption efficiency, which is determined by the chemical properties, the structural differences of the drug and the physiological conditions of the skin [56,57]. Cellular permeability related to the molecular size is also critical: proteins/peptides of less than approximately 5000 Da could transverse the skin layer and blood capillaries easily compared to those with the molecular weight greater than 20,000 Da [54,58,59].…”