The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin.
The aim of the present study was to develop novel insulin-loaded microneedle arrays (MNs) fabricated from hyaluronic acid (HA), and characterize their applicability in the transdermal delivery of insulin. The shape of MNs was observed via scanning electron microscopy. The characteristics of these novel insulin-loaded MNs, including hygroscopy, stability, drug release profiles, and dissolution properties, were evaluated from a clinical application point-of-view. Transepidermal water loss (TEWL) was measured to investigate the piercing properties of MNs, and the recovery of the skin barrier after the removal of MNs to confirm their safety. Additionally, the transdermal absorption of insulin from MNs was examined via an in vivo absorption study in diabetic rats. The length of MNs was 800 μm with a base diameter of 160 μm and a tip diameter of 40 μm. MNs were found to maintain their skin piercing abilities for at least 1h, even at a relative humidity of 75%. After storing insulin-loaded MNs for a month at -40, 4, 20, and 40 °C, more than 90% of insulin remained in MNs at all temperatures, indicating that insulin is highly stable in MNs at these storage conditions. It was also found that insulin is rapidly released from MNs via an in vitro release study. These findings were consistent with the complete dissolution of MNs within 1h of application to rat skin in vivo. Therefore, the novel HA MNs possess self-dissolving properties after their dermal application, and insulin appears to be rapidly released from these MNs. A significant increase in TEWL was observed after the application of MNs. However, this parameter recovered back to baseline within 24h after the removal of MNs. These findings indicate that the transdermal transport pathway of insulin, which was created by the MNs, disappeared within 24h, and that the skin damage induced by the MNs was reversible. Furthermore, a dose-dependent hypoglycemic effect and transdermal delivery of insulin were observed after a dermal treatment with insulin-loaded MNs in vivo. A continuous hypoglycemic effect was observed after 0.25 IU of insulin was administered to skin via MNs. Additionally, lower peak plasma insulin levels, but higher plasma insulin concentrations after 2 h, were achieved with 0.25 IU of insulin administered via MNs as compared to the subcutaneous administration of insulin of the same dose. Pharmacodynamic and pharmacokinetic parameters indicated that insulin administered via MNs was almost completely absorbed from the skin into the systemic circulation, and that the hypoglycemic effect of insulin-loaded MNs was almost similar to that of the subcutaneous injection of insulin. These findings indicate that the novel insulin-loaded MNs fabricated from HA are a very useful alternative method of delivering insulin via the skin into the systemic circulation without inducing serious skin damage. Therefore, HA MNs may be an effective and safe method of transdermal insulin delivery in the clinic.
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Shu
S
Liu
Mei-na
MN
Jin
Ying-shu
YS
Quan
Fumio
F
Kamiyama
Hidemasa
H
Katsumi
Toshiyasu
T
Sakane
Akira
A
Yamamoto
D000279:Administration, Cutaneous; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D016503:Drug Delivery Systems; D006820:Hyaluronic Acid / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D009339:Needles; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D006820:Hyaluronic Acid