Engineers at MIT have developed an innovative method to administer specific medications in greater quantities with reduced discomfort, by injecting them as a mixture of minute crystals. Once beneath the skin, the crystals form a drug “reservoir” that could persist for several months or even years, thereby reducing the necessity for frequent drug injections.
This technique may prove advantageous for administering long-lasting contraceptives or other medications that require extended administration periods. Since the drugs are mixed in a suspension prior to injection, they can be delivered through a small needle that is more tolerable for patients.
“We demonstrated that we can achieve highly controlled, prolonged delivery, likely for several months and even years through a tiny needle,” states Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital (BWH), an associate member of the Broad Institute, and the lead author of the research.
The main authors of the paper, published today in Nature Chemical Engineering, include former MIT and BWH postdoc Vivian Feig, who is now an assistant professor of mechanical engineering at Stanford University; MIT graduate student Sanghyun Park; and Pier Rivano, a former visiting research scholar in Traverso’s laboratory.
Simplified injections
This initiative originated as part of a project funded by the Gates Foundation aimed at broadening contraceptive choices, especially in developing countries.
“The primary objective is to provide women with access to various forms of contraception that are easy to use, suitable for developing regions, and offer a diverse range of durations of effectiveness,” Feig explains. “In our specific project, we aimed to merge the advantages of long-acting implants with the convenience of self-administerable injectables.”
There are commercially available injectable suspensions in the United States and other nations, but these drugs are dispersed within the tissue after injection, limiting their effectiveness to approximately three months. Other injectable formulations have emerged that can create longer-lasting reservoirs beneath the skin, yet these usually necessitate the addition of precipitating polymers, which can account for 23 to 98 percent of the solution by weight and may complicate the injection process.
The MIT and BWH team sought to develop a formulation that could be injected using a small-gauge needle and last for at least six months, potentially extending up to two years. They focused on a contraceptive drug called levonorgestrel, a hydrophobic molecule capable of forming crystals. The team discovered that suspending these crystals in a specific organic solvent prompted them to consolidate into a highly compact implant post-injection. Since this reservoir could form without the requirement for substantial quantities of polymer, the drug formulation remained easily injectable through a narrow-gauge needle.
The solvent, benzyl benzoate, is biocompatible and has previously been utilized as an additive in injectable drugs. The team identified that the solvent’s limited miscibility with biological fluids is what enables the solid drug crystals to self-organize into a depot beneath the skin after being injected.
“The solvent is essential as it allows for fluid injection through a narrow needle; however, once in position, the crystals form a drug depot,” Traverso notes.
By modifying the density of the depot, the researchers can adjust the speed at which drug molecules are released into the body. In this study, the investigators demonstrated that they could alter the density by incorporating small amounts of a polymer like polycaprolactone, a biodegradable polyester.
“By integrating a minimal quantity of polymers — less than 1.6 percent by weight — we can fine-tune the drug release rate, prolonging its effect while preserving its injectability. This showcases the adaptability of our system, which can be optimized to meet a wider range of contraceptive requirements and customized dosing schedules for additional therapeutic applications,” Park remarks.
Durable drug reservoirs
The researchers assessed their approach by injecting the drug solution subcutaneously in rats and demonstrated that the drug reservoirs could remain stable and release the medication gradually over three months. At the conclusion of the three-month study, approximately 85 percent of the drug was retained in the reservoirs, indicating the potential for continued drug release over a significantly extended duration.
“We expect that the reservoirs could persist for more than a year, based on our post-analysis of preclinical data. Ongoing studies are aimed at further confirming their effectiveness beyond this initial proof-of-concept,” Park notes.
Once the drug reservoirs are established, they are compact enough to be retrieved, offering the possibility of surgical removal if treatment needs to be interrupted before the drug is entirely released.
This method could also be beneficial for delivering medications to address neuropsychiatric disorders as well as HIV and tuberculosis, the researchers indicate. They are currently advancing towards evaluating its application in humans by conducting thorough preclinical assessments to test self-assembly in a context more pertinent to clinical practice. “This system is quite straightforward in that it primarily consists of a solvent, the drug, and a small amount of bioresorbable polymer. We are now contemplating which indications to pursue: contraception or others? These are some of the factors we are beginning to explore in the next steps towards human translation,” Traverso states.
The research received funding from various sources including the Gates Foundation, the Karl van Tassel Career Development Professorship, the MIT Department of Mechanical Engineering, a Schmidt Science Fellows postdoctoral fellowship, the Rhodes Trust, a Takeda Fellowship, a Warren M. Rohsenow Fellowship, and a Kwangjeong Educational Foundation Fellowship.