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Purpose: Feasibility study of two-layered dissolving microneedles for percutaneous delivery of peptide/proteins using recombinant human growth hormone (rhGH) and desmopressin (DDAVP)., Methods: Two-layered dissolving microneedles were administered percutaneously to the rat skin. Plasma rhGH and DDAVP concentrations were measured by EIA and LC/MS/MS. In vivo dissolution and diffusion rates of drugs in the skin were studied using tracer dyes, lissamine green B (LG) for rhGH and evans blue (EB) for DDAVP. Diffusion of drugs vertically into the skin was studied using FITC-dextran (MW = 20 kDa)-loaded dissolving microneedles. Stability experiments were performed at -80°C and 4°C., Results: The absorption half-lives, t (1/2a), of rhGH and DDAVP from dissolving microneedles were 23.7 ± 4.3-28.9 ± 5.2 and 14.4 ± 2.9-14.1 ± 1.1 min; the extents of bioavailability were 72.8 ± 4.2-89.9 ± 10.0% and 90.0 ± 15.4-93.1 ± 10.3%, respectively. LG and EB disappeared from the administered site within 2 h and 3 h after administration. Five green fluorescein spots were detected at 15 s and enlarged transversally at 30 s. FITC-dextran was delivered into the microcapillaries at 5 min and 10 min. The rhGH and DDAVP were stable in dissolving microneedles for one month at -80°C and 4°C., Conclusions: Results suggest that the two-layered dissolving microneedles are useful as an immediate-release transdermal DDS for peptide/protein drugs.

Erythropoietin (EPO) was successfully loaded on self-dissolving micropile array (SDMA) chip using chondroitin sulfate as the base polymer. "Drug glue" was prepared by adding EPO solution to chondroitin sulfate solution and SDMA was formed by micromolding fabrication technology. One SDMA chip, 1.0x1.0 cm, contained 100 micropile arrays. Two types of SDMA, partially-loaded SDMA (p-SDMA) and fully-loaded SDMA (f-SDMA), were prepared. The mean lengths of the SDMAs were 474.8+/-8.1 microm for p-SDMA and 473.4+/-5.2 microm for f-SDMA. The diameters of the array basements were 288.4+/-4.5 microm (p-SDMA) and 294.6+/-3.2 microm (f-SDMA). EPO content was 25.0+/-3.8 IU (p-SDMA) and 125.9+/-26.7 IU (f-SDMA). After percutaneous administration of each SDMA chip to rats, maximum serum EPO concentrations (C(max)) were 30.5+/-4.2 mIU/ml for p-SDMA and 32.4+/-5.0 mIU/ml for f-SDMA. The mean areas under the serum EPO concentration vs. time curves (AUC) were 534.0+/-102.4 mIU.h/ml (p-SDMA) and 523.1+/-50.4 mIU.h/ml (f-SDMA). Bioavailability (BA) values of EPO delivered from SDMAs were calculated to be 39.4% for p-SDMA and 7.7% for f-SDMA. Dose-dependency of the serum EPO concentration vs. time curve was studied using p-SDMA chip containing less EPO, 11.6+/-1.06 IU. Good dose-dependency was observed for C(max) and AUC. The p-SDMA chip was also evaluated in dogs. One or two p-SDMA chips, where 1 chip contained 22.4 IU of EPO, were percutaneously administered to dogs. BA of EPO delivered from p-SDMA was 65.9-69.0%. These results suggest the usefulness of p-SDMA as a percutaneous drug delivery system (DDS) for EPO.

AbstractBackground:This study tested the hypothesis that dissolving microneedles are a useful transdermal drug delivery system (TDDS) for insulin.Methods:Insulin was loaded on a patch (1.0 cm2) that had 100 dissolving microneedles with chondroitin sulfate by microfabrication technology. Pharmacodynamic evaluation was performed by applying two or four patches to the shaved abdominal skin of dogs, and blood samples were collected for 360 min to measure plasma glucose and insulin levels. In diffusion experiment, microneedles containing fluorescein isothiocyanate-insulin and/or Evans blue were administered to the rat skin, and the diffusion rates of tracers were recorded.Results:The mean length, diameter of basement, and drug-loaded space from the top of the microneedles were 492.6 ± 2.4, 290.0 ± 3.6, and 316.0 ± 7.3 μm, respectively. The insulin content was 1.67 ± 0.17 IU per patch. The time when the minimum plasma glucose level was obtained was 50.0 ± 8.7 min for two-patch and 82.5 ± 14.4 min for four-patch studies. A dose-dependent hypoglycemic effect was observed. By comparing the cumulative percentage change in the plasma glucose level between insulin microneedles and solution, the relative physiological availabilities were calculated to be 71.1 ± 17.8% (for two patches) and 59.3 ± 4.4% (for four patches). Bioavailabilities of insulin from microneedles were 72.1 ± 11.6% (for two patches) and 72.4 ± 8.3% (for four patches). High diffusion rates of fluorescein isothiocyanate-insulin and Evans blue were observed at the administered skin site and correlated well with the high absorption rate of insulin into the systemic circulation. Insulin was stable in dissolving microneedles for 1 month at 4°C; the recovered percentage was 99.2 ± 13.9%.Conclusions:Dissolving microneedles were demonstrated to be a useful TDDS as an immediate-acting insulin preparation. [ABSTRACT FROM AUTHOR]