Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

Abstract

PurposeIn 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.MethodsRaloxifene 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.ResultsThe 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.ConclusionWe prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal 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.

Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles

“…We have also reported the method for preparing solid nanoparticles using bead mill treatment and showed that the addition of HPβCD and MC enhances the dispersion stability and crushing force, respectively [15,[17][18][19]. In addition, our previous studies using indomethacin showed a hydrophilic gel base, such as carbopol, provides for a high drug release of solid nanoparticles from the gel [15,[17][18][19]. Based on these findings, HPβCD, MC and carbopol were selected as components of TL-NPs-Gel in this study.…”

“…Type SM-4 methylcellulose (MC) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) were provided by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan) and Nihon Shokuhin Kako Co., Ltd. (Tokyo, Japan), respectively. The HPβCD and MC were selected to enhance the dispersion stability and crushing force, respectively [15,[17][18][19]. Mixtures of these reagents (TL powder, MC and HPβCD) were dispersed in distilled water, and zirconia beads (0.1 mm in diameter) were added.…”

“…TL release from the TL formulations was evaluated as in previous studies using a Franz diffusion cell [15,[17][18][19]. Briefly, a 220 nm-pore size MF™-MEMBRANE FILTER (Merck Millipore, Tokyo, Japan) was set into a Franz diffusion cell and 0.3 g of 0.75% TL formulation was applied to the filter.…”

“…There are recent reports of systems to deliver drugs into skin tissue, such as in situ gels. Iontophoresis [7], nanostructured lipid carriers [8,9], liposomes [10], dendrimers [11], phonophoresis [12], patches [13], micro-needles [14], and such systems can help overcome the low skin penetration [15]. However, the eyelid is easily stimulated by these systems, since the eyelid is the thinnest skin on the body and is highly sensitive to stimulus [16].…”

Invasome: A Novel Nanocarrier for Transdermal Drug Delivery

“…The strategic mechanism for terpene penetration occurs through interaction with SC intercellular lipids [57]. Terpenes are applied alone or in combination with other drug delivery systems as permeation enhancers for therapeutic applications [58][59][60][61]. But beside the potency of terpenes in comparison to different penetration enhancers, the toxicities of terpenes should be considered.…”