In this study, a system for oral delivery of recombinant human parathyroid hormone [rhPTH(1–34); teriparatide (TRP)] was developed to enhance oral absorption and to demonstrate an equivalent therapeutic effect to that of subcutaneous (SC) TRP injection. The solid oral formulation of TRP was prepared by electrostatic complexation with l-lysine-linked deoxycholic acid (LDA) and deoxycholic acid (DA) at a molar ratio of 1:5:7 in the aqueous dispersion of non-ionic n-dodecyl-β-d-maltoside (DM) at a 1:15 weight ratio, followed by freeze-drying the dispersal, yielding TRP(1:5:7)-15. As expected, TRP(1:5:7)-15 showed a 414% increase in permeability across the Caco-2/HT29-MTX-E12 cell monolayer, resulting in a 13.0-fold greater oral bioavailability compared with free TRP. In addition, the intestinal transport mechanisms in the presence of specific inhibitors of clathrin-mediated endocytosis, macropinocytosis, and bile acid transporters revealed 44.4%, 28.7%, and 51.2% decreases in transport, respectively, confirming that these routes play crucial roles in the permeation of TRP in TRP(1:5:7)-15. Notably, this formulation showed similar activation of the release of cyclic adenosine monophosphate (cAMP) compared with TRP, suggesting equivalent efficacy in the parathyroid hormone receptor–adenylate cyclase system of osteosarcoma cells. Furthermore, oral TRP(1:5:7)-15 (equivalent to 0.4 mg/kg TRP) demonstrated increases in bone mineral density (36.9%) and trabecular thickness (31.3%) compared with untreated glucocorticoid-induced osteoporotic mice. Moreover, the elevated levels of biomarkers of bone formation, including osteocalcin, were also comparable with those after SC injection of TRP (0.02 mg/kg). These findings suggest that TRP(1:5:7)-15 can be used as an effective oral therapy for the management of osteoporosis.

在这项研究中，一种用于口服递送重组人甲状旁腺激素 [rhPTH(1-34); 特立帕肽 (TRP)] 被开发用于增强口服吸收并证明与皮下 (SC) TRP 注射具有等效的治疗效果。TRP的固体口服制剂是通过在非离子正十二烷基-水分散体中以1:5:7的摩尔比与l-赖氨酸连接的脱氧胆酸（LDA）和脱氧胆酸（DA）进行静电络合制备的。 β- d-麦芽糖苷 (DM) 的重量比为 1:15，然后将分散体冷冻干燥，得到 TRP(1:5:7)-15。正如预期的那样，TRP(1:5:7)-15 的 Caco-2/HT29-MTX-E12 细胞单层的通透性增加了 414%，与游离 TRP 相比，口服生物利用度增加了 13.0 倍。此外，在存在网格蛋白介导的内吞作用、大胞饮作用和胆汁酸转运蛋白的特异性抑制剂的情况下，肠道转运机制分别显示转运减少 44.4%、28.7% 和 51.2%，证实这些途径在TRP 在 TRP(1:5:7)-15 中的渗透。值得注意的是，与 TRP 相比，该制剂显示出类似的环磷酸腺苷 (cAMP) 释放激活，表明在骨肉瘤细胞的甲状旁腺激素受体 - 腺苷酸环化酶系统中具有同等功效。此外，与未经治疗的糖皮质激素诱导的骨质疏松小鼠相比，口服 TRP(1:5:7)-15（相当于 0.4 mg/kg TRP）显示骨矿物质密度（36.9%）和骨小梁厚度（31.3%）增加。此外，骨形成生物标志物（包括骨钙素）的升高水平也与皮下注射 TRP（0.02 mg/kg）后的水平相当。这些发现表明，TRP(1:5:7)-15 可用作治疗骨质疏松症的有效口服疗法。骨形成生物标志物（包括骨钙素）的升高水平也与皮下注射 TRP（0.02 mg/kg）后的水平相当。这些发现表明，TRP(1:5:7)-15 可用作治疗骨质疏松症的有效口服疗法。骨形成生物标志物（包括骨钙素）的升高水平也与皮下注射 TRP（0.02 mg/kg）后的水平相当。这些发现表明，TRP(1:5:7)-15 可用作治疗骨质疏松症的有效口服疗法。