Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, Maryland 20850.
Aesica Formulation Development, Biocity, Pennyfoot Street, Nottingham NG1 1GF, UK.
J Pharm Sci. 2018 Feb;107(2):662-671. doi: 10.1016/j.xphs.2017.09.028. Epub 2017 Oct 6.
There is growing evidence that methane production, predominantly by Methanobrevibacter smithii, in the intestines is a cause of constipation, pain, and bloating in irritable bowel syndrome with constipation (IBS-C). M smithii resides primarily in the large intestine but can also colonize the small intestine. In vitro studies found that the prodrug lactone form of lovastatin, found in cholesterol-lowering drugs, inhibited methane production in stool samples from patients with IBS-C. However, the cholesterol-lowering lovastatin β-hydroxyacid was ineffective at inhibiting methane production in this system. A considerable amount of lovastatin is converted to hydroxyacid in the stomach and is absorbed. It was hypothesized that galenic innovations could protect lovastatin from the stomach and allow release in 2 strategic locations, the duodenum and the ileocecal region, to reach M smithii. The desired release profile was achieved by developing an oral dosage form containing lovastatin and coated with 2 different enteric polymers that enabled a pH-dependent "dual pulse" drug release. Combinations of the 2 coated tablets were encapsulated together to deliver the desired amount of lovastatin to the targeted intestinal locations. The capsules have been tested in vitro and in vivo and show promise in treating IBS-C.
越来越多的证据表明，肠道中甲烷的产生（主要由 Methanobrevibacter smithii 产生）是导致便秘、腹痛和腹胀的原因之一，这些症状在便秘型肠易激综合征（IBS-C）中较为常见。M smithii 主要存在于大肠中，但也可以在小肠中定植。体外研究发现，降胆固醇药物中洛伐他汀的前药内酯形式可以抑制 IBS-C 患者粪便样本中的甲烷生成。然而，在该系统中，降胆固醇的洛伐他汀β-羟基酸对抑制甲烷生成无效。相当一部分洛伐他汀在胃中转化为羟基酸并被吸收。研究人员假设，药剂学创新可以保护洛伐他汀免受胃酸的影响，并使其在十二指肠和回盲肠部位 2 个战略位置释放，以达到 M smithii 所在的位置。通过开发一种含有洛伐他汀并涂有 2 种不同肠溶聚合物的口服剂型，实现了所需的释放曲线，这种剂型能够实现 pH 依赖性的“双重脉冲”药物释放。将两种涂层片剂组合封装在一起，将所需剂量的洛伐他汀递送到靶向肠道部位。这些胶囊已经在体外和体内进行了测试，有望用于治疗 IBS-C。
