用于骨质疏松治疗的雷洛昔芬纳米粒透皮制剂的设计。

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 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.

目的：在临床环境中，雷洛昔芬是一种第二代选择性雌激素受体调节剂，通过口服给药；然而，由于其在水性流体中的溶解度差和广泛的首过代谢，生物利用度（BA）仅为 2%。因此，预计开发透皮制剂可以在不影响其治疗效果的情况下减少所需剂量。在这项研究中，我们设计了包含雷洛昔芬纳米颗粒的透皮制剂，并评估了它们在骨质疏松症治疗中的用途。

方法：通过珠磨机法将雷洛昔芬与甲基纤维素粉碎，将研磨后的雷洛昔芬与或不与薄荷醇（渗透增强剂）用 Carbopol 934 凝胶化（不含薄荷醇的雷洛昔芬纳米颗粒，Ral-NPs；含薄荷醇的 mRal-NPs）。使用 Franz 扩散池测量药物释放和透皮渗透，并用去卵巢大鼠模型进行骨质疏松治疗的疗效评价。

结果：透皮制剂（Ral-NPs）中雷洛昔芬的平均粒径为 173.7nm。尽管 Ral-NPs 中释放的雷洛昔芬仍处于纳米颗粒状态，但在大鼠皮肤中，雷洛昔芬纳米颗粒的皮肤穿透被角质层阻止。另一方面，制剂中包含薄荷醇会减弱角质层的屏障功能，并允许雷洛昔芬纳米颗粒穿透皮肤。此外，巨胞饮作用与包含薄荷醇的制剂的皮肤穿透有关（mRal-NPs），因为巨胞饮抑制剂 rottlerin 的处理抑制了渗透。此外，应用 0.3%mRal-NPs（每天一次）可减轻去卵巢大鼠骨钙水平和硬度的降低。

结论：我们通过珠磨机法制备了雷洛昔芬固体纳米颗粒，并设计了一种包含纳米颗粒和渗透增强剂的新型透皮制剂。这些透皮制剂克服了皮肤的屏障特性，并通过透皮途径显示出高药物渗透（BA8.5%）。此外，我们发现雷洛昔芬透皮制剂可用于治疗去卵巢大鼠的骨质疏松症。