Tyagi Puneet, Patel Chandresh, Gibson Kimberly, MacDougall Fiona, Pechenov Sergei Y, Will Sarah, Revell Jefferson, Huang Yue, Rosenbaum Anton I, Balic Kemal, Maharoof Umar, Grimsby Joseph, Subramony J Anand
Dosage Form Design and Development, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA.
BDD Pharma, Glasgow G4 0SF, UK.
Pharmaceutics. 2023 Oct 9;15(10):2436. doi: 10.3390/pharmaceutics15102436.
Oral delivery of peptides and biological molecules promises significant benefits to patients as an alternative to daily injections, but the development of these formulations is challenging due to their low bioavailability and high pharmacokinetic variability. Our earlier work focused on the discovery of MEDI7219, a stabilized, lipidated, glucagon-like peptide 1 agonist peptide, and the selection of sodium chenodeoxycholate (Na CDC) and propyl gallate (PG) as permeation enhancer combinations. We hereby describe the development of the MEDI7219 tablet formulations and composition optimization via in vivo studies in dogs. We designed the MEDI7219 immediate-release tablets with the permeation enhancers Na CDC and PG. Immediate-release tablets were coated with an enteric coating that dissolves at pH ≥ 5.5 to target the upper duodenal region of the gastrointestinal tract and sustained-release tablets with a Carbopol bioadhesive polymer were coated with an enteric coating that dissolves at pH ≥ 7.0 to provide a longer presence at the absorption site in the gastrointestinal tract. In addition to immediate- and enteric-coated formulations, we also tested a proprietary delayed release erodible barrier layer tablet (OralogiK) to deliver the payload to the target site in the gastrointestinal tract. The design of tablet dosage forms based on the optimization of formulations resulted in up to 10.1% absolute oral bioavailability in dogs with variability as low as 26% for MEDI7219, paving the way for its clinical development.
肽和生物分子的口服给药有望为患者带来显著益处，成为每日注射的替代方式，但由于其生物利用度低和药代动力学变异性高，这些制剂的开发具有挑战性。我们早期的工作重点是发现MEDI7219，一种稳定的、脂质化的胰高血糖素样肽1激动剂肽，并选择鹅去氧胆酸钠（Na CDC）和没食子酸丙酯（PG）作为渗透促进剂组合。在此，我们描述了通过在犬体内进行的研究来开发MEDI7219片剂制剂并优化其组成。我们设计了含有渗透促进剂Na CDC和PG的MEDI7219速释片。速释片用肠溶衣包衣，该肠溶衣在pH≥5.5时溶解，以靶向胃肠道的十二指肠上部区域；含有卡波姆生物粘附聚合物的缓释片用肠溶衣包衣，该肠溶衣在pH≥7.0时溶解，以便在胃肠道的吸收部位停留更长时间。除了速释和肠溶包衣制剂外，我们还测试了一种专有的延迟释放可蚀屏障层片剂（OralogiK），以将药物有效载荷递送至胃肠道的靶部位。基于制剂优化设计的片剂剂型在犬体内实现了高达10.1%的绝对口服生物利用度，MEDI7219的变异性低至26%，为其临床开发铺平了道路。
