The new MIT method promises painful drug injections with small crystals

MIT engineers have devised a new method of delivering specific drugs at high doses that are less painful, by injecting them as suspensions of small crystals. Once under the skin, the crystals gather at the drug “depot” that can last for months or years, eliminating the need for frequent drug injections.

This approach may prove useful in providing long-term contraceptives or other medications that need to be administered over a long period of time. The drug is distributed during stop before injection, allowing it to be administered through a narrow needle that is easy for patients to withstand.

We have shown that we can make a very controlled and sustainable delivery for months and even through small needles. ”

Giovanni Traverso, Associate Professor of Mechanical Engineering at MIT, Gastroenterologist at Brigham and Women's Hospital (BWH), Associate Member of the Broad Institute, Senior Author of the Study

Chief author of today's paper Natural Chemical Engineeringformer MIT and BWH Postdoc Vivian Feig, and is currently an assistant professor of mechanical engineering at Stanford University. MIT graduate student Sanghyun Park; Pier Rivano, a former visiting research scholar in Traverso's lab.

Ejection is easy

The project began as part of an effort funded by the Gates Foundation to expand contraceptive options, particularly in developing countries.

“The overarching goal is to allow women to access many different forms of contraception. Contraception is compatible with being used in developing countries and has a range of behaviors across different time frames,” says Feig. “Our specific projects were interested in combining the benefits of long-acting implants with the ease of non-self-controlled injections.”

Although available injectable suspensions are available in the US and other countries, these drugs only function for about three months as they are distributed throughout the tissue after injection. Other injectable products have been developed that can form long-term depots under the skin, but these usually require the addition of a precipitating polymer that can comprise 23-98% of the solution by weight.

The MIT and BWH teams wanted to create a formulation that could be injected through a small gauge needle for at least six months to up to two years. They began using contraceptives called levonorgestrel, a hydrophobic molecule that can form crystals. The team discovered that suspending these crystals in a specific organic solvent led to the crystals gathering in very compact implants after injection. This depot can be formed without the need for large amounts of polymer, allowing drug formulations to be easily injected through a narrow gauge needle.

The solvent, benzylbenzoic acid, is biocompatible and has previously been used as an additive to injectables. The team discovered that the low ability of the solvent to mix with the biological fluid allows solid drug crystals to self-assemble into the depot under the skin after injection.

“The solvent is important because the solvent can inject liquid through a small needle, but once it's in place, the crystals self-assemble into the drug warehouse,” says Traverso.

By changing the density of the depot, researchers can adjust the rate at which drug molecules are released into the body. In this study, the researchers showed that density can be altered by adding small amounts of polymers, such as polycaprolactone, a biodegradable polyester.

“By incorporating very small amounts of polymer, we can regulate the rate of drug release, and extend its duration while maintaining infusion, indicating the adjustability of a system that can be designed to accommodate a more tailored administration area as well as a wider contraceptive needs for other therapeutic applications.

Stable drug depot

The researchers tested the approach by injecting rats with a drug solution subcutaneously and showed that the drug depot was able to release the drug gradually for three months with stable release of the drug. After the 3-month study is finished, approximately 85% of the drug remains at the depot, suggesting that the drug can continue to be released for a much longer period of time.

“We expect the depot to last for more than a year based on post-analysis of preclinical data. Follow-up research is underway and is currently underway to further validate them. Effectiveness Beyond this initial proof of concept,” says Park.

Once drug depots are formed, they are compact enough to be resilient, allowing surgical removal if treatment needs to be stopped before the drug is fully released.

The approach could also help with neuropsychiatric conditions and the supply of drugs to treat HIV and tuberculosis, researchers say. They are now heading towards the evaluation of translation into humans by conducting advanced preclinical studies to assess self-organization in a more clinically relevant skin environment. “This is a very simple system in that it's basically a solvent, a drug. And you can add a little bit of an absorbent polymer. Now we're looking at what signs we'll expel. Is it birth control?

This research was funded in part by the Gates Foundation, Professor of Carlvan Tassel Career Development, MIT Faculty of Mechanical Engineering, Schmidt Science Postdoctoral Fellowship, Rhodestrast, Takeda Fellowship, Warren M. Rossene Fellowship, and Kwanjong Education Foundation Fellowship.