Abstract
To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)–MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)–MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)–MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)–MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN–MN)—in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid—and intradermal injection of ALN. These findings indicate that ALN(TIP)–MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation.
Highlights
Alendronate (ALN), a nitrogen-containing bisphosphonate, is effective in the treatment of bone diseases, including Paget’s disease, malignant hypercalcemia and osteoporosis [1]
The resulting tapered-cone MNs were uniform in size with sharp tips; each MN was approximately 800 μm in height, with a diameter of 160 μm at the base, 40 μm at the tip, and an interspacing of 600 μm between rows of the microneedle arrays
ALN was loaded onto the tips of the MN to a depth of about 200 μm
Summary
Alendronate (ALN), a nitrogen-containing bisphosphonate, is effective in the treatment of bone diseases, including Paget’s disease, malignant hypercalcemia and osteoporosis [1]. Because ALN causes intestinal mucosal damage and its intestinal absorption is limited due to high polarity [2,3], an alternative delivery route for ALN is highly desirable, especially for bedridden elderly patients with bone disease. Of the various strategies available, the transdermal route has received significant attention. In order to solve this problem, a number of methods to improve transdermal drug transport have been evaluated, including chemical absorption enhancers [6], iontophoresis [7], sonophoresis [8], electroporation [9,10] and microneedle arrays (MN) [11]
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