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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2018-09-01
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| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/design-of-a-transdermal-formulation-containing-raloxifene-nanoparticle-peer-reviewed-article-IJN |
| _version_ | 1818937297439031296 |
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| 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 |
| collection | DOAJ |
| 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 |
| first_indexed | 2024-12-20T05:49:43Z |
| format | Article |
| id | doaj.art-43b34159ba3840e397cedcac9a13c3d7 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-20T05:49:43Z |
| publishDate | 2018-09-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-43b34159ba3840e397cedcac9a13c3d72022-12-21T19:51:13ZengDove Medical PressInternational Journal of Nanomedicine1178-20132018-09-01Volume 135215522940404Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatmentNagai NOgata FOtake HNakazawa YKawasaki NNoriaki 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, skinhttps://www.dovepress.com/design-of-a-transdermal-formulation-containing-raloxifene-nanoparticle-peer-reviewed-article-IJNnanomedicinetransdermal delivery systempermeation enhancerendocytosisskin. |
| spellingShingle | Nagai N Ogata F Otake H Nakazawa Y Kawasaki N Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment International Journal of Nanomedicine nanomedicine transdermal delivery system permeation enhancer endocytosis skin. |
| title | 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_short | Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment |
| title_sort | design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment |
| topic | nanomedicine transdermal delivery system permeation enhancer endocytosis skin. |
| url | https://www.dovepress.com/design-of-a-transdermal-formulation-containing-raloxifene-nanoparticle-peer-reviewed-article-IJN |
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