通過胃傳遞胰島素的藥物膠囊問世

來源：麻省理工學院【?2019-02-12 發(fā)布?】　美迪醫(yī)訊

麻省理工學院領導的一個研究小組開發(fā)了一種藥物膠囊，可用于輸送口服劑量的胰島素，可能取代2型糖尿病患者每天必須給自己注射的藥物。

關(guān)于藍莓的大小，膠囊包含由壓縮胰島素制成的小針，其在膠囊到達胃后注射。在動物試驗中，研究人員表明，它們可以提供足夠的胰島素，使血糖降低到與通過皮膚注射產(chǎn)生的水平相當?shù)乃?。他們還證明該裝置可以適應其他蛋白質(zhì)藥物。

“我們真的希望這種新型膠囊有朝一日可以幫助糖尿病患者，也許任何需要治療的人，現(xiàn)在只能通過注射或輸液給藥，”麻省理工學院會員David H. Koch研究所教授Robert Langer說?？坪站C合癌癥研究所，該研究的高級作者之一。

Giovanni Traverso是哈佛醫(yī)學院布萊根婦女醫(yī)院的助理教授，也是麻省理工學院機械工程系的訪問科學家，他在2019年開始擔任教職員工，也是該研究的高級作者。這篇論文的第一作者出現(xiàn)在2月8日出版的“ 科學”雜志上，是麻省理工學院的研究生亞歷克斯艾布拉姆森。該研究團隊還包括制藥公司Novo Nordisk的科學家。

幾年前，Traverso，Langer和他們的同事開發(fā)了一種涂有許多小針頭的藥丸，可以用來將藥物注射到胃或小腸的內(nèi)層。對于新的膠囊，研究人員將設計改為只有一根針，這樣他們就可以避免將藥物注射到胃內(nèi)部，在這些藥物會產(chǎn)生任何影響之前它們會被胃酸分解。

針的尖端由幾乎100％壓縮的冷凍干燥的胰島素制成，使用與形成藥片相同的方法。不進入胃壁的針的軸由另一種可生物降解的材料制成。

在膠囊內(nèi)，針頭連接到壓縮彈簧上，壓縮彈簧由糖制成的圓盤固定就位。當吞咽膠囊時，胃中的水溶解糖盤，釋放彈簧并將針注射到胃壁中。

胃壁沒有疼痛感受器，因此研究人員認為患者無法感受到注射。為了確保將藥物注入胃壁，研究人員設計了他們的系統(tǒng)，這樣無論膠囊如何落入胃中，它都可以自我定向，使針頭與胃的內(nèi)層接觸。

“一旦你接受它，你就希望系統(tǒng)能夠自行調(diào)整，這樣你才能確保與組織接觸，”Traverso說。

研究人員從被稱為豹龜?shù)臑觚數(shù)淖晕叶ㄎ惶卣髦屑橙§`感。這種烏龜是在非洲發(fā)現(xiàn)的，它的外殼有一個高而陡峭的圓頂，如果它翻到它的背上，它就會自行調(diào)整。研究人員利用計算機建模為其膠囊提供了這種形狀的變體，即使在胃的動態(tài)環(huán)境中也可以重新定位。

“重要的是我們在注射針頭時會將針頭與組織接觸，”艾布拉姆森說?！按送?，如果一個人要四處走動或者肚子會咆哮，那么該設備就不會從其首選方向移動?！?/span>

一旦將針尖注入胃壁，胰島素就會以制備膠囊時可由研究人員控制的速率溶解。在這項研究中，所有胰島素需要大約一個小時才能完全釋放到血液中。

對患者來說更容易

在豬的測試中，研究人員表明，他們可以成功地提供高達300微克的胰島素。最近，他們已經(jīng)能夠?qū)┝吭黾拥?毫克，這與患有2型糖尿病的患者需要注射的量相當。

膠囊釋放其內(nèi)容物后，可以無害地通過消化系統(tǒng)。研究人員發(fā)現(xiàn)膠囊沒有任何副作用，膠囊由可生物降解的聚合物和不銹鋼成分制成。

麻省理工學院的團隊現(xiàn)在繼續(xù)與諾和諾德合作，進一步開發(fā)技術(shù)并優(yōu)化膠囊的制造工藝。他們認為這種類型的藥物遞送可用于通常必須注射的任何蛋白質(zhì)藥物，例如用于治療類風濕性關(guān)節(jié)炎或炎性腸病的免疫抑制劑。它也可用于核酸，如DNA和RNA。

“我們的動機是讓患者更容易服用藥物，特別是需要注射的藥物，”Traverso說。“經(jīng)典的是胰島素，但還有很多其他藥物?！?/span>

該研究由Novo Nordisk，國立衛(wèi)生研究院，國家科學基金會研究生研究獎學金，布萊根婦女醫(yī)院，維京奧拉夫比約克研究獎學金和麻省理工學院本科研究機會計劃資助。

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.

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