Transdermal Insulin Application System with Dissolving Microneedles

Ito, Yoshiaki; Nakahigashi, Takuya; Yoshimoto, Naoko; Ueda, Yuriko; Hamasaki, Noriyuki; Takada, Kanji

doi:10.1089/dia.2012.0096

Cited by 37 publications

(27 citation statements)

References 32 publications

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“…At the predetermined time, a DM array chip was applied to the rat skin using an applicator with a collision speed of 2.0 m/s following a second pressure of 2.5 N for 1-3 min. 19) After the DM array chip was removed from the skin, wet unwoven cloth, 15.0 mm×15.0 mm, to which 10, 20, and/or 30 µL of distilled water had been absorbed, was attached to the skin for 0.1, 1.0, 2.0, 3.0, and 5.0 min to collect ISF. ISF samples were obtained by centrifuging the unwoven cloth at 12000 rpm for 5 min at 4°C using the Kokusan H-201FR centrifuge (Kokusan Co., Ltd., Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Application of Dissolving Microneedles to Glucose Monitoring through Dermal Interstitial Fluid

Ito

Taniguchi

Hayashi

et al. 2014

Biological & Pharmaceutical Bulletin

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Dissolving microneedles (DMs) were applied to glucose monitoring in the dermal interstitial fluid (ISF) of rats and their potential as an alternative blood glucose monitoring device was evaluated. Sodium chondroitin sulfate was used to prepare DM array chips, which consisted of 300 DMs/cm 2 . The mean length of the DMs was 475 18 µm and the mean diameter of the basement was 278 8 µm. After DMs were inserted into the skin of the hair-removed rat abdomen, a wet unwoven cloth containing 10-30 µL of water was placed on the skin and ISF was extracted. By increasing the absorbed amount of water on the unwoven cloth from 10 to 30 µL, the extracted amount of glucose increased from 1. Approximately 250 million people in Japan have diabetes, which is associated with damage to the heart, kidneys, eyes and central nervous system. 1) Diabetic patients should frequently monitor their blood glucose levels, about six times a day, in order to maintain appropriate blood glucose levels. Patients use needles to obtain blood samples from their fingers and blood glucose levels are measured with an enzyme assay method. However, this method is invasive and causes pain. In addition, concerns regarding infectious diseases often reduce the frequency by which patients take blood samples. Therefore, the development of a non-invasive method for blood glucose monitoring is desired. Transcutaneous spectroscopic methods have been reported previously, 2,3) however, electromagnetic energy is almost entirely absorbed by skin tissue. Therefore, the reliability of these electronic technologies is insufficient. Although ultrasound, 4) reverse iontophoresis, 5) and electroporation 6) have also been examined as non-invasive methods to monitor glucose levels, they have not yet been clinically introduced because of skin damage, pain, and low accuracy.Microneedle technology is attracting attention as an alternative method for non-invasive glucose monitoring. 7,8) Microneedles (MNs) were originally designed to percutaneously deliver drugs into the systemic circulation and have been classified into four categories 9,10) : (i) hollow type MNs, extremely small needles through which drug solutions are injected into the skin, (ii) coating type MNs, made of metallic and/or silastic substances, on which surface drugs are coated, (iii) pierce type MNs, made of metallic and/or silastic microneedles, through which microconduits are made in the skin followed by the application of drug solutions and/or cream after removal of the MNs, and (iv) dissolving microneedles (DMs), made of soluble polymers such as sodium chondroitin sulfate, dextran, and sodium hyaluronic acid, on which drug molecules are formulated as a solid dispersion.11,12) Of these, pierce type MNs, made of glass and plastic, have been used to monitor blood glucose levels. An MN array was stamped on the skin and interstitial fluid (ISF) was obtained by applying negative pressure, 200-500 mmHg.13) Thus, ISF could be collected without pain using a microneedle array, and glucose monitoring was performed with...

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Section: Methodsmentioning

confidence: 99%

Application of Dissolving Microneedles to Glucose Monitoring through Dermal Interstitial Fluid

Ito

Taniguchi

Hayashi

et al. 2014

Biological & Pharmaceutical Bulletin

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“…The hair on the abdominal region was carefully removed with a shaver. DMs were administered to the skin with an applicator described in our previous report 24) and were pressed for 3.0 min. At 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, and 8.0 h after administration, 0.2 mL of blood samples was collected from the left jugular vein.…”

Section: Methodsmentioning

confidence: 99%

Method to Increase the Systemically Delivered Amount of Drug from Dissolving Microneedles

Ito

Hamasaki

Higashino

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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To increase the absorbed amount of a drug from dissolving microneedles (DMs), three DM array chips were prepared in which (1) the drug was localized at the acral portion of DMs, (2) the drug was loaded in each whole DM, and (3) the drug was loaded in DMs and the chip. Fluorescein free form (FL) and its sodium salt (FLNa) were used as model drugs. The DM array chip had 15-mm diameter with 225 DMs, each 500-µm long with a 300-µm diameter base. The respective FLNa contents in the three chips were (1) Key words systemic delivery; dissolving microneedle; percutaneous absorption; rat Transdermal drug delivery systems (TDDS) are attractive drug delivery systems (DDS) for the systemic delivery of drugs with high safety. 1) However, TDDS products of drugs are only nine compounds such as nicotine, fentanyl, and hormones. The main reason is the poor permeability of drugs through the human skin. Moreover, most drugs do not permeate through the skin at therapeutically relevant rates. Consequently, a therapeutic drug concentration is not maintained in systemic circulation. To increase the permeability of the drug through the skin, several methods such as chemical enhancers, electric fields, ultrasound, and thermal methods have been attempted.2-6) Nevertheless, those technologies have not been applied to drugs as TDDS, because they often show skinrelated side-effects, skin damage, etc. To overcome the limitations of those technologies, microneedles (MNs) are being studied 7) : small needles by which microconduits are formed on the skin surface and through which drugs are absorbed into the skin. Human skin comprises three layers. The outermost one is the stratum corneum that is dead tissue with thickness of 10-15 µm. The stratum corneum has a strong primary barrier function against exogenous compounds, including drugs. MNs physically destroy the stratum corneum. Consequently, the drug permeates through the skin. MNs do not cause pain. Now, MNs of four kinds are used [8][9][10] : (1) extremely small needles through which the drug solution can be injected into the skin; (2) metallic and/or silastic MNs onto which surface drug is coated; (3) metallic and/or silastic MNs by which microconduits are made on the skin, after which a drug solution or cream is applied following removal of the microneedle; and (4) dissolving microneedles (DMs).11) DMs are made of watersoluble biopolymers such as chondroitin sulfate, hyaluronic acid and dextran, in which drug molecules are formulated as a solid dispersion or suspension.12) An important advantage of DMs over other MNs is that DMs have high biocompatibility, because the base polymer is made of water-soluble biopolymers and is more compatible with the human body than metal and silastic MNs. We have been studying on DMs for use as a delivery system for hydrophilic drugs such as peptide protein drugs. Results of those studies have improved the bioavailability (BA) of macromolecular drugs having poor permeability through the skin, for example 91.3-97.7% for insulin in mice 13) and of 81.5-102.3...

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“…Recent focus has shifted from making metal-based microneedles to developing microneedles made of bio- [11] Parathyroid hormone (1-34) 4 Coated microneedles [12], [13] Insulin 6 Hollow microneedles [3,[14][15][16][17] Dissolvable microneedles Solid microneedles Lysozyme 14.3 Dissolvable (polymer) microneedles [18] Human growth hormone 22 Hollow microneedles [19][20][21] Dissolvable (polymer) microneedles Bovine serum albumin 66 Dissolvable (polymer) microneedles [22] Human immunoglobulin 1500 Dissolvable (sugar) microneedles [23] Solid (metal-based) microneedles [18]. Simple modifications of drug loading and patch design allowed these microneedles to deliver a bolus dose or controlled release of the drug.…”

Section: Dissolving Microneedlesmentioning

confidence: 99%

“…The extent of bioavailability was reported to be ∼70% for the dextran-based system and 90% for the chondroitin system. Dissolvable microneedles were also made with insulin by incorporating it into the needle tip [15]. The relative pharmacological availability of insulin was found to be nearly 98%.…”

Section: Dissolving Microneedlesmentioning

confidence: 99%

Transdermal Delivery of biopharmaceuticals: Dream or reality?

Katikaneni

2015

Ther. Deliv.

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The skin being the largest organ of the body presents a potential route for administration of drugs. Passive transdermal products such as gels, creams and patches deliver drugs effectively across the skin. However, this approach is limited to lipophilic molecules with low molecular weights. Passive transdermal delivery of proteins and peptides which are hydrophilic with high molecular weights is negligible. This led to the development of various ways of surmounting the skin barrier so as to make this route feasible for peptide and protein delivery. The current article reviews various active transdermal technologies with special emphasis on microneedle mediated delivery. Microneedles, especially dissolvable microneedles present an excellent platform for protein and peptide delivery. Significant advances have been made in the past decade in this area. Published literature shows a broad spectrum of molecules being delivered successfully via microneedles. However, success in clinic will give a boost to all the efforts and advances made in this field so far.

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Transdermal Insulin Application System with Dissolving Microneedles

Abstract: These results suggest the usefulness of the two-layered DM application system for the transdermal delivery of insulin.

Cited by 37 publications

References 32 publications

Application of Dissolving Microneedles to Glucose Monitoring through Dermal Interstitial Fluid

Application of Dissolving Microneedles to Glucose Monitoring through Dermal Interstitial Fluid

Method to Increase the Systemically Delivered Amount of Drug from Dissolving Microneedles

Transdermal Delivery of biopharmaceuticals: Dream or reality?

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