Self-Dissolving Micropiles for the Percutaneous Absorption of Recombinant Human Growth Hormone in Rats

Ito, Yoshiaki; Ohashi, Yoshinori; Shiroyama, K; Sugioka, Nobuyuki; Takada, Kanji

doi:10.1248/bpb.31.1631

Cited by 33 publications

(15 citation statements)

References 24 publications

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“…The high physiological availabilities (PA) of insulin, 91.3-97.7%, 14) and low molecular weight heparin (LMWH), 81.5-102.3%, were previously reported in rats. 15) In addition, high bioavailabilities (BA) were obtained for recombinant human growth hormone (rhGH), 87.5%, in rats 16) and for erythropoietin (EPO), 82.1-99.4%, in mice. 17) The relative BA of interferon (IFN) against a subcutaneous injection of IFN solution was 79.9-117.8% in rats.…”

Section: Application Of Dissolving Microneedles To Glucose Monitoringmentioning

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: Application Of Dissolving Microneedles To Glucose Monitoringmentioning

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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“…66 After mixing dextran solution with rhGH, SDMPs were prepared by pulling the mixture with polypropylene tips. SDMPs were inserted into the rat skin at a dose of 200 μg/kg, and by comparing with IV injection of rhGH solution (5 μg/kg), bioavailability of rhGH from SDMP was calculated to be 87.5%.…”

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confidence: 99%

Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

Cai¹,

Xu²,

Yuan³

et al. 2014

IJN

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Since the availability of recombinant human growth hormone (rhGH) enabled the application of human growth hormone both in clinical and research use in the 1980s, millions of patients were prescribed a daily injection of rhGH, but noncompliance rates were high. To address the problem of noncompliance, numerous studies have been carried out, involving: sustained-release preparations, prolonged half-life derivatives, new injectors that cause less pain, and other noninvasive delivery methods such as intranasal, pulmonary and transdermal deliveries. Some accomplishments have been made and launched already, such as the Nutropin Depot ® microsphere and injectors (Zomajet ® , Serojet ® , and NordiFlex ® ). Here, we provide a review of the different technologies and illustrate the key points of these studies to achieve an improved rhGH product.

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“…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% for low molecular weight heparin (LMWH) in rats, 14) 87.5% for recombinant human growth hormone (rhGH) in rats 15) and of 82.1-99.4% for erythropoietin (EPO) in mice.16) The relative BA of interferon (IFN) against subcutaneous injection of IFN solution was 79.9-117.8% in rats.17) The relative physiological availability (PA) of insulin was 90-99% in dogs.18) The secondary stage of our DM study used a twolayered DM array chip of 1.0×1.0 cm, on which 100 DMs with 10 lines and 10 columns were designed and prepared.19) Each DM had 500 µm length and 300 µm diameter at its base. The drug was formulated at the acral portion of the DMs, which was inserted into the region of the epidermis and/or epidermal/dermal junctions by pressing with fingers.…”

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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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Self-Dissolving Micropiles for the Percutaneous Absorption of Recombinant Human Growth Hormone in Rats

Cited by 33 publications

References 24 publications

Application of Dissolving Microneedles to Glucose Monitoring through Dermal Interstitial Fluid

Application of Dissolving Microneedles to Glucose Monitoring through Dermal Interstitial Fluid

Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

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

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