通过胃传递胰岛素的药物胶囊问世

来源：麻省理工学院【 2019-02-12 发布】　美迪医讯

麻省理工学院领导的一个研究小组开发了一种药物胶囊，可用于输送口服剂量的胰岛素，可能取代2型糖尿病患者每天必须给自己注射的药物。

关于蓝莓的大小，胶囊包含由压缩胰岛素制成的小针，其在胶囊到达胃后注射。在动物试验中，研究人员表明，它们可以提供足够的胰岛素，使血糖降低到与通过皮肤注射产生的水平相当的水平。他们还证明该装置可以适应其他蛋白质药物。

“我们真的希望这种新型胶囊有朝一日可以帮助糖尿病患者，也许任何需要治疗的人，现在只能通过注射或输液给药，”麻省理工学院会员David H. Koch研究所教授Robert Langer说。科赫综合癌症研究所，该研究的高级作者之一。

Giovanni Traverso是哈佛医学院布莱根妇女医院的助理教授，也是麻省理工学院机械工程系的访问科学家，他在2019年开始担任教职员工，也是该研究的高级作者。这篇论文的第一作者出现在2月8日出版的“ 科学”杂志上，是麻省理工学院的研究生亚历克斯艾布拉姆森。该研究团队还包括制药公司Novo Nordisk的科学家。

几年前，Traverso，Langer和他们的同事开发了一种涂有许多小针头的药丸，可以用来将药物注射到胃或小肠的内层。对于新的胶囊，研究人员将设计改为只有一根针，这样他们就可以避免将药物注射到胃内部，在这些药物会产生任何影响之前它们会被胃酸分解。

针的尖端由几乎100％压缩的冷冻干燥的胰岛素制成，使用与形成药片相同的方法。不进入胃壁的针的轴由另一种可生物降解的材料制成。

在胶囊内，针头连接到压缩弹簧上，压缩弹簧由糖制成的圆盘固定就位。当吞咽胶囊时，胃中的水溶解糖盘，释放弹簧并将针注射到胃壁中。

胃壁没有疼痛感受器，因此研究人员认为患者无法感受到注射。为了确保将药物注入胃壁，研究人员设计了他们的系统，这样无论胶囊如何落入胃中，它都可以自我定向，使针头与胃的内层接触。

“一旦你接受它，你就希望系统能够自行调整，这样你才能确保与组织接触，”Traverso说。

研究人员从被称为豹龟的乌龟的自我定位特征中汲取灵感。这种乌龟是在非洲发现的，它的外壳有一个高而陡峭的圆顶，如果它翻到它的背上，它就会自行调整。研究人员利用计算机建模为其胶囊提供了这种形状的变体，即使在胃的动态环境中也可以重新定位。

“重要的是我们在注射针头时会将针头与组织接触，”艾布拉姆森说。“此外，如果一个人要四处走动或者肚子会咆哮，那么该设备就不会从其首选方向移动。”

一旦将针尖注入胃壁，胰岛素就会以制备胶囊时可由研究人员控制的速率溶解。在这项研究中，所有胰岛素需要大约一个小时才能完全释放到血液中。

对患者来说更容易

在猪的测试中，研究人员表明，他们可以成功地提供高达300微克的胰岛素。最近，他们已经能够将剂量增加到5毫克，这与患有2型糖尿病的患者需要注射的量相当。

胶囊释放其内容物后，可以无害地通过消化系统。研究人员发现胶囊没有任何副作用，胶囊由可生物降解的聚合物和不锈钢成分制成。

麻省理工学院的团队现在继续与诺和诺德合作，进一步开发技术并优化胶囊的制造工艺。他们认为这种类型的药物递送可用于通常必须注射的任何蛋白质药物，例如用于治疗类风湿性关节炎或炎性肠病的免疫抑制剂。它也可用于核酸，如DNA和RNA。

“我们的动机是让患者更容易服用药物，特别是需要注射的药物，”Traverso说。“经典的是胰岛素，但还有很多其他药物。”

该研究由Novo Nordisk，国立卫生研究院，国家科学基金会研究生研究奖学金，布莱根妇女医院，维京奥拉夫比约克研究奖学金和麻省理工学院本科研究机会计划资助。

New pill can deliver insulin through the stomach

An MIT-led research team has developed a drug capsule that could be used to deliver oral doses of insulin, potentially replacing the injections that people with type 2 diabetes have to give themselves every day.

About the size of a blueberry, the capsule contains a small needle made of compressed insulin, which is injected after the capsule reaches the stomach. In tests in animals, the researchers showed that they could deliver enough insulin to lower blood sugar to levels comparable to those produced by injections given through skin. They also demonstrated that the device can be adapted to deliver other protein drugs.

"We are really hopeful that this new type of capsule could someday help diabetic patients and perhaps anyone who requires therapies that can now only be given by injection or infusion," says Robert Langer, the David H. Koch Institute Professor, a member of MIT's Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.

Giovanni Traverso, an assistant professor at Brigham and Women's Hospital, Harvard Medical School, and a visiting scientist in MIT's Department of Mechanical Engineering, where he is starting as a faculty member in 2019, is also a senior author of the study. The first author of the paper, which appears in the February 8 issue of Science, is MIT graduate student Alex Abramson. The research team also includes scientists from the pharmaceutical company Novo Nordisk.

Self-orientation

Several years ago, Traverso, Langer, and their colleagues developed a pill coated with many tiny needles that could be used to inject drugs into the lining of the stomach or the small intestine. For the new capsule, the researchers changed the design to have just one needle, allowing them to avoid injecting drugs into the interior of the stomach, where they would be broken down by stomach acids before having any effect.

The tip of the needle is made of nearly 100 percent compressed, freeze-dried insulin, using the same process used to form tablets of medicine. The shaft of the needle, which does not enter the stomach wall, is made from another biodegradable material.

Within the capsule, the needle is attached to a compressed spring that is held in place by a disk made of sugar. When the capsule is swallowed, water in the stomach dissolves the sugar disk, releasing the spring and injecting the needle into the stomach wall.

The stomach wall has no pain receptors, so the researchers believe that patients would not be able to feel the injection. To ensure that the drug is injected into the stomach wall, the researchers designed their system so that no matter how the capsule lands in the stomach, it can orient itself so the needle is in contact with the lining of the stomach.

"As soon as you take it, you want the system to self-right so that you can ensure contact with the tissue," Traverso says.

The researchers drew their inspiration for the self-orientation feature from a tortoise known as the leopard tortoise. This tortoise, which is found in Africa, has a shell with a high, steep dome, allowing it to right itself if it rolls onto its back. The researchers used computer modeling to come up with a variant of this shape for their capsule, which allows it to reorient itself even in the dynamic environment of the stomach.

"What's important is that we have the needle in contact with the tissue when it is injected," Abramson says. "Also, if a person were to move around or the stomach were to growl, the device would not move from its preferred orientation."

Once the tip of the needle is injected into the stomach wall, the insulin dissolves at a rate that can be controlled by the researchers as the capsule is prepared. In this study, it took about an hour for all of the insulin to be fully released into the bloodstream.

Easier for patients

In tests in pigs, the researchers showed that they could successfully deliver up to 300 micrograms of insulin. More recently, they have been able to increase the dose to 5 milligrams, which is comparable to the amount that a patient with type 2 diabetes would need to inject.

After the capsule releases its contents, it can pass harmlessly through the digestive system. The researchers found no adverse effects from the capsule, which is made from biodegradable polymer and stainless steel components.

The MIT team is now continuing to work with Novo Nordisk to further develop the technology and optimize the manufacturing process for the capsules. They believe this type of drug delivery could be useful for any protein drug that normally has to be injected, such as immunosuppressants used to treat rheumatoid arthritis or inflammatory bowel disease. It may also work for nucleic acids such as DNA and RNA.

"Our motivation is to make it easier for patients to take medication, particularly medications that require an injection," Traverso says. "The classic one is insulin, but there are many others."

The research was funded by Novo Nordisk, the National Institutes of Health, a National Science Foundation Graduate Research Fellowship, Brigham and Women's Hospital, a Viking Olaf Bjork Research Scholarship, and the MIT Undergraduate Research Opportunities Program.

Other authors of the paper include Ester Caffarel-Salvador, Minsoo Khang, David Dellal, David Silverstein, Yuan Gao, Morten Revsgaard Frederiksen, Andreas Vegge, Frantisek Hubalek, Jorrit Water, Anders Friderichsen, Johannes Fels, Rikke Kaae Kirk, Cody Cleveland, Joy Collins, Siddartha Tamang, Alison Hayward, Tomas Landh, Stephen Buckley, Niclas Roxhed, and Ulrik Rahbek.

Story Source:
Materials provided by Massachusetts Institute of Technology. Original written by Anne Trafton. Note: Content may be edited for style and length.

本文关键字: 胰岛素药物胶囊

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