Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

Noriaki Nagai,1 Fumihiko Ogata,1 Hiroko Otake,1 Yosuke Nakazawa,2 Naohito Kawasaki1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan; 2Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan Purpose: In the clinical setting, raloxifene, a second-generation selective estro...

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Autores principales:	Nagai N, Ogata F, Otake H, Nakazawa Y, Kawasaki N
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	nanomedicine transdermal delivery system permeation enhancer endocytosis skin. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/43b34159ba3840e397cedcac9a13c3d7
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spelling	oai:doaj.org-article:43b34159ba3840e397cedcac9a13c3d72021-12-02T04:07:22ZDesign of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment1178-2013https://doaj.org/article/43b34159ba3840e397cedcac9a13c3d72018-09-01T00:00:00Zhttps://www.dovepress.com/design-of-a-transdermal-formulation-containing-raloxifene-nanoparticle-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Noriaki Nagai,1 Fumihiko Ogata,1 Hiroko Otake,1 Yosuke Nakazawa,2 Naohito Kawasaki1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan; 2Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan Purpose: In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Methods: Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Results: The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. Conclusion: We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These transdermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat. Keywords: nanomedicine, transdermal delivery system, permeation enhancer, endocytosis, skinNagai NOgata FOtake HNakazawa YKawasaki NDove Medical Pressarticlenanomedicinetransdermal delivery systempermeation enhancerendocytosisskin.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 5215-5229 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	nanomedicine transdermal delivery system permeation enhancer endocytosis skin. Medicine (General) R5-920
spellingShingle	nanomedicine transdermal delivery system permeation enhancer endocytosis skin. Medicine (General) R5-920 Nagai N Ogata F Otake H Nakazawa Y Kawasaki N Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
description	Noriaki Nagai,1 Fumihiko Ogata,1 Hiroko Otake,1 Yosuke Nakazawa,2 Naohito Kawasaki1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan; 2Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan Purpose: In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Methods: Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Results: The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. Conclusion: We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These transdermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat. Keywords: nanomedicine, transdermal delivery system, permeation enhancer, endocytosis, skin
format	article
author	Nagai N Ogata F Otake H Nakazawa Y Kawasaki N
author_facet	Nagai N Ogata F Otake H Nakazawa Y Kawasaki N
author_sort	Nagai N
title	Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
title_short	Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
title_full	Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
title_fullStr	Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
title_full_unstemmed	Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
title_sort	design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/43b34159ba3840e397cedcac9a13c3d7
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Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

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