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.

Fabrication of two-layer dissolving polyvinylpyrrolidone microneedles with different molecular weights for in vivo insulin transdermal delivery

“…The operation parameters were followed as described in our previous study. 8 Skin penetration depths for different ratios of PVP MNs and the degree of skin repair were observed immediately without histological sections.…”

“…The diabetic mice were induced as described in a previous study. 8 All animal experiments were approved by the Chang Gung University in accordance with the guidelines for animal experimentation (IACUC approval number: CGU15-044). Male BALB/c mice with an average weight of approximately 27 g (provided by the National Laboratory Animal Center, Taiwan) were injected with streptozocin (STZ, Sigma, USA) in 0.1 ml of a sodium citrate buffer (0.05 M, pH 4.5), 200 mg kg À1 .…”

“…[4][5][6] Dissolvable MN patches loaded with insulin are an alternative solution for an effective, painless, discreet, and selfadministered method for glucose regulation. 7,8 Several types of dissolving polymers have been used in previous studies to fabricate soluble MNs, including collagen, hyaluronic acid, 9,10 PMVE/MA, 11,12 carboxymethylcellulose (CMC), 8,13 polyvinylpyrrolidone (PVP), 14,15 sodium alginate, 16 and silk. 17 Mechanical properties, material cost, fabrication convenience, and inammation risk are the important parameters when choosing materials.…”

Low-cost and cleanroom-free fabrication of microneedles

“…Different studies have shown that intradermal administration of specific drugs using microneedles increases the therapeutic efficacy compared to the intramuscular and the subcutaneous routes 5 . As reported previously, the dissolving microneedle patch can rapidly release the drug in skin; this is an efficient way to deliver large molecules like insulin 6 . Thus, microneedles provide easier route for transdermal drug delivery for molecules that are not readily absorbed topically.…”

A Review on Bioengineering Approaches to Insulin Delivery: A Pharmaceutical and Engineering Perspective

“…In one research, Lee et al. used gelatin and sodium carboxymethyl cellulose to fabricate microneedles and illustrated a surefire result in releasing insulin . PassPort is an insulin patch, which is anticipated to enter to the market soon .…”