title: Formulation of two-layer dissolving polymeric microneedle patches for insulin transdermal delivery in diabetic mice.
abstract: Dissolving microneedles (MNs) display high efficiency in delivering poorly permeable drugs and vaccines. Here, two-layer dissolving polymeric MN patches composed of gelatin and sodium carboxymethyl cellulose (CMC) were fabricated with a two-step casting and centrifuging process to localize the insulin in the needle and achieve efficient transdermal delivery of insulin. In vitro skin insertion capability was determined by staining with tissue-marking dye after insertion, and the real-time penetration depth was monitored using optical coherence tomography. Confocal microscopy images revealed that the rhodamine 6G and fluorescein isothiocyanate-labeled insulin (insulin-FITC) can gradually diffuse from the puncture sites to deeper tissue. Ex vivo drug-release profiles showed that 50% of the insulin was released and penetrated across the skin after 1 h, and the cumulative permeation reached 80% after 5 h. In vivo and pharmacodynamic studies were then conducted to estimate the feasibility of the administration of insulin-loaded dissolving MN patches on diabetic mice for glucose regulation. The total area above the glucose level versus time curve as an index of hypoglycemic effect was 128.4 ± 28.3 (% h) at 0.25 IU/kg. The relative pharmacologic availability and relative bioavailability (RBA) of insulin from MN patches were 95.6 and 85.7%, respectively. This study verified that the use of gelatin/CMC MN patches for insulin delivery achieved a satisfactory RBA compared to traditional hypodermic injection and presented a promising device to deliver poorly permeable protein drugs for diabetic therapy. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 84-93, 2017.
authors.affiliation: Graduate Institute of Biochemical and Biomedical Engineering, Chang-Gung University, Taoyuan city, 33302, Taiwan.|Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan.
authors.forename: I-Chi
authors.initials: IC
authors.lastname: Lee
authors.affiliation: Graduate Institute of Biochemical and Biomedical Engineering, Chang-Gung University, Taoyuan city, 33302, Taiwan.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Lin
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, Chang-Gung University, Taoyuan city, 33302, Taiwan.
authors.forename: Jwu-Ching
authors.initials: JC
authors.lastname: Shu
authors.affiliation: Graduate Institute of Biochemical and Biomedical Engineering, Chang-Gung University, Taoyuan city, 33302, Taiwan.
authors.forename: Shau-Wei
authors.initials: SW
authors.lastname: Tsai
authors.affiliation: Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Tao-yuan, 33305, Taiwan.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Electrical Engineering, Chang-Gung University, Taoyuan city, 33302, Taiwan.
authors.forename: Meng-Tsan
authors.initials: MT
authors.lastname: Tsai
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems / Q000295:instrumentation* / Q000379:methods*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009339:Needles; D013552:Swine
chemical_list: D007328:Insulin
keywords: carboxymethyl cellulose; diabetic therapy; gelatin; transdermal delivery; two-layer dissolving polymer microneedle patch