Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34)

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Abstract

Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) for the treatment of osteoporosis. PTH-loaded MNs, with needle length 800 µm, were fabricated via a micro-molding method. The stability of PTH in MNs was found to be 6-fold higher than that of PTH solution when stored at room temperature (15–20 °C) for one month. Micron-scale pores were clearly visible in rat skin following application of PTH-loaded MNs. PTH-loaded MNs were completely dissolved by 60 min following application to rat skin. The bioavailability (BA) of PTH relative to subcutaneous injection was 100 ± 4% following application of PTH-loaded MNs in rats. In addition, PTH-loaded MNs were found to effectively suppress decreases in bone density in a rat model of osteoporosis. Furthermore, no skin irritation was observed at the site of application in rats. These findings indicate that our dissolving MNs have a potential use in formulations for the transdermal delivery of PTH and for the treatment of osteoporosis.

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Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery.

Jung-Hwan Park, Mark Allen, Mark Prausnitz (2005)

To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.

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Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits.

Hans Wulf, Karin T. Poulsen, J Möller (2002)

Epidermal thickness and its relationship to age, gender, skin type, pigmentation, blood content, smoking habits and body site is important in dermatologic research and was investigated in this study. Biopsies from three different body sites of 71 human volunteers were obtained, and thickness of the stratum corneum and cellular epidermis was measured microscopically using a preparation technique preventing tissue damage. Multiple regressions analysis was used to evaluate the effect of the various factors independently of each other. Mean (SD) thickness of the stratum corneum was 18.3 (4.9) microm at the dorsal aspect of the forearm, 11.0 (2.2) microm at the shoulder and 14.9 (3.4) microm at the buttock. Corresponding values for the cellular epidermis were 56.6 (11.5) microm, 70.3 (13.6) microm and 81.5 (15.7) microm, respectively. Body site largely explains the variation in epidermal thickness, but also a significant individual variation was observed. Thickness of the stratum corneum correlated positively to pigmentation (p = 0.0008) and negatively to the number of years of smoking (p < 0.0001). Thickness of the cellular epidermis correlated positively to blood content (P = 0.028) and was greater in males than in females (P < 0.0001). Epidermal thickness was not correlated to age or skin type.

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The 500 Dalton rule for the skin penetration of chemical compounds and drugs.

Lieuwe D J Bos, M T Meinardi (2000)

Human skin has unique properties of which functioning as a physicochemical barrier is one of the most apparent. The human integument is able to resist the penetration of many molecules. However, especially smaller molecules can surpass transcutaneously. They are able to go by the corneal layer, which is thought to form the main deterrent. We argue that the molecular weight (MW) of a compound must be under 500 Dalton to allow skin absorption. Larger molecules cannot pass the corneal layer. Arguments for this "500 Dalton rule" are; 1) virtually all common contact allergens are under 500 Dalton, larger molecules are not known as contact sensitizers. They cannot penetrate and thus cannot act as allergens in man; 2) the most commonly used pharmacological agents applied in topical dermatotherapy are all under 500 Dalton; 3) all known topical drugs used in transdermal drug-delivery systems are under 500 Dalton. In addition, clinical experience with topical agents such as cyclosporine, tacrolimus and ascomycins gives further arguments for the reality of the 500 Dalton rule. For pharmaceutical development purposes, it seems logical to restrict the development of new innovative compounds to a MW of under 500 Dalton, when topical dermatological therapy or percutaneous systemic therapy or vaccination is the objective.

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Author and article information

Journal

Journal ID (nlm-ta): Pharmaceutics

Journal ID (iso-abbrev): Pharmaceutics

Journal ID (publisher-id): pharmaceutics

Title: Pharmaceutics

Publisher: MDPI

ISSN (Electronic): 1999-4923

Publication date (Electronic): 04 November 2018

Publication date Collection: December 2018

Volume: 10

Issue: 4

Electronic Location Identifier: 215

Affiliations

[1 ]Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan; kd16008@ 123456poppy.kyoto-phu.ac.jp (C.N.); suzuki_t1130@ 123456yahoo.co.jp (Tom.S.); sakane@ 123456kobepharma-u.ac.jp (Tos.S.); yamamoto@ 123456mb.kyoto-phu.ac.jp (A.Y.)

[2 ]CosMED Pharmaceutical Co., Ltd., Minami-ku, Kyoto 601-8014, Japan; quan@ 123456cosmed-pharm.co.jp (Y.-s.Q.); kamiyama@ 123456cosmed-pharm.co.jp (F.K.)

[3 ]Department of Pharmaceutical Technology, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan

Author notes

[* ]Correspondence: hkatsumi@ 123456mb.kyoto-phu.ac.jp ; Tel.: +81-75-595-4662

[†]

These authors contributed equally to this work.

Article

Publisher ID: pharmaceutics-10-00215

DOI: 10.3390/pharmaceutics10040215

PMC ID: 6320955

PubMed ID: 30400376

SO-VID: 9881b618-2ff9-48f9-b776-f54eaf643de3

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34)

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Most cited references 41

Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery.

Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits.

The 500 Dalton rule for the skin penetration of chemical compounds and drugs.

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