Researchers from the University of North Carolina at Chapel Hill have developed a unique new multi-drug delivery system that could p-rove to be useful for persons who need to take several drugs in a day as part of a regimen. The system is not only removable and effective up to a year but is also biodegradable say the scientists. Lead author Rahima Benhabbour from UNC explained that more than one drug could be administered using this system in the form of an implant.
The results of their findings were published in the latest issue of Nature Communications titled, “Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery.” It was a collaborative effort between UNC_NCSU Joint Department of Biomedical Engineering, UNC School of Medicine, UNC Eshelman School of Pharmacy, UNC Center for AIDS Research, and Merck Research Laboratories.
SEM cross-section images of implants after drug release for 30 days.
The UNC researchers targeted HIV positive persons who need a multi-drug regimen that has to be taken daily. They developed the system on lab animals studying them for seven years. The team explained that HIV patients are often put on a multi-drug regimen for treatment as well as prevention of full blown AIDS. These drugs need to be taken for years, they wrote.
Benhabbour, who is also an assistant professor in the UNC_NCSU Joint Department of Biomedical Engineering explained, “There is no FDA-approved or marketed technology for long-acting prevention of HIV, and we are the first to use this delivery method with multiple antiretroviral drugs. To have an HIV prevention treatment that consists of an injection once or twice a year would make an incredible impact for patients.” She added, “This technology is not only promising for HIV, but for any kind of condition that requires a daily intake of medication. We’re talking about a safe, removable, long-lasting injection that takes away the burden of adhering to a daily medication regimen.”
Benhabbour said that due to the long term use of these drugs there is often a decline in adherence of these patients to the medications. Healthy people who are put on anti-retroviral drugs to prevent them from contracting HIV are termed as Pre-exposure prophylaxis. This is usually prescribed for those who have steady and monogamous relationships with HIV positive partners but are themselves not HIV positive. Pre exposure prophylaxis is also a challenge for treating healthcare providers because need for multiple drugs to be taken each day deters these healthy individuals from taking the medications, explain the researchers. If these patients were to be given a drug delivery system that requires once or twice yearly administration, the adherence to the regimen might improve, they explain. Benhabbour added, “In sub-Saharan Africa where prevalence of HIV is highest, accessibility to these medications can be difficult, and there is much stigma associated with the virus. It is a very big deal for someone who doesn’t have HIV to go out of their way to not only access the drugs, but then associate themselves with HIV by taking a pill every day.”
Senior author J. Victor Garcia, professor of medicine at UNC School of Medicine, director of the International Center for the Advancement of Translational Science and member of the UNC Center for AIDS Research, in a statement said, “Because one of the biggest difficulties associated with HIV prevention is lack of adherence to drug treatment, we wanted to create a drug delivery system that essentially solved this problem.”
The authors emphasize that daily pill burden could be a reason behind missed pills as well. The implication when it comes to anti-retroviral drugs could be grave they added. Missing anti retroviral pills or even taking them later when one remembers having missed the pill could make them less effective, they wrote.
Describing their new system of drug delivery, the team wrote that it contained three elements;
- An organic solvent (N-methyl-2-pyrrolidone NMP)
- A polymer (poly DL-lactide-co-glycolide or PLGA)
- Drug or drugs that need to be delivered (Antiretrovirals MK-2048, Dolutegravir, Darunavir, Atazanavir, Rilpivirine and Ritonavir were tested).
When mixed the three form a honey-like mixture that turns into solid form when injected into the body and placed under the skin. This occurs because the solvent diffuses into the body and what remain are the polymer and the drug(s). The composition of this solid form determines the duration that would be required until the entire drug has been released into the bloodstream. In a next step the team used up to six antiretroviral drugs in the delivery system. Each of the drugs retained their original chemical form and therapeutic efficacy and the release was sustained over a period of up to one year depending on the formulation.
Martina Kovarova, one of the authors of the study and associate professor of medicine at UNC SOM, in a statement said, “If a patient needs to withdraw from the treatment because they’ve had a bad reaction to the drug(s), or maybe a woman has become pregnant, our implant can be easily surgically removed.” This assures patients that the implant is permanent or irreversible, the team wrote. The implant in fact is one of the first that can be removed within a week of administration or even after months of use if need is felt. After around a year, when the drug has been fully absorbed, the implant biodegrades into lactic and glycolic acids. These components are normally found in the body and thus are easily absorbed without causing harm.
The team wrote in conclusion, “All drugs released with concentrations above their protein-adjusted inhibitory concentration and retained their physical and chemical properties within the formulation and upon release. The versatility of this formulation to integrate multiple drugs and provide sustained plasma concentrations from several weeks to up to one year, combined with its ability to be removed to terminate the treatment if necessary, makes it attractive as a drug delivery platform technology for a wide range of applications.”
At present the team is working on making models that could mimic the safety and effectiveness of the implant in vivo and then their next step would be to conduct clinical trials on humans.
The study was supported financially by National Institute of Allergy and Infectious Diseases and the International Center for Advancing Translational Science.
S. Rahima Benhabbour, Martina Kovarova, Clinton Jones, Daijha J. Copeland, Roopali Shrivastava, Michael D. Swanson, Craig Sykes, Phong T. Ho, Mackenzie L. Cottrell, Anush Sridharan, Samantha M. Fix, Orrin Thayer, Julie M. Long, Daria J. Hazuda, Paul A. Dayton, Russell J. Mumper, Angela D. M. Kashuba & J. Victor Garcia, Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery, Nature Communications, DOI: 10.1038/s41467-019-12141-5, https://www.nature.com/articles/s41467-019-12141-5