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Starring our way to once weekly orally delivered HIV antiretroviral therapy

Go to the profile of Omar Abouzid
Jan 09, 2018
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By Omar Abouzid and Giovanni Traverso

Behind the paper: Ameya R. Kirtane*, Omar Abouzid*, Daniel Minahan, Taylor Bensel, Alison L. Hill, Christian Selinger, Anna Bershteyn, Morgan Craig, Shirley S. Mo, Hormoz Mazdiyasni, Cody Cleveland, Jaimie Rogner, Young-Ah Lucy Lee, Lucas Booth, Farhad Javid, Sarah J. Wu, Tyler Grant, Andrew M. Bellinger, Boris Nikolic, Alison Hayward, Lowell Wood, Philip A. Eckhoff, Martin A. Nowak, Robert Langer & Giovanni Traverso. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nature Communications. 2018 Jan 9; doi:10.1038/s41467-017-02294-6.

Below is the link for the paper:

https://www.nature.com/articles/s41467-017-02294-6

Youtube video:

https://youtu.be/tiGIWyE_GcA


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If we were to rank epidemics in terms of number of people affected and treatment costs, then non-adherence to prescribed medications would rank near the top. Staggeringly, non-adherence affects half of all patients who are on prescription drugs, resulting in significant morbidity and mortality as well as financial burden on healthcare systems estimated in hundreds of billions of dollars each year in the US alone (1).

It is a complex issue but at the heart of the matter, it’s simply tough sometimes to remember to take one’s medication.

Having taken pills ourselves, we recognize the ease of administration in daily versus twice or three times a day dosing. Daily dosing has been shown to manifest in significant improvements in adherence over more frequent dosing regimens.  This observation can be extended further, and specifically the improvement in adherence for weekly-dosage regimens over daily ones (2) is one that we recognized.  We set out to develop oral sustained drug delivery systems for patients receiving treatments for HIV/AIDS or for those potentially at risk of contracting the infection.

To achieve this, we developed a new capsule system that remains in the stomach for a week after being swallowed, gradually releasing its drug-content over time. We selected three anti-HIV drugs (dolutegravir, cabotegravir and rilpivirine) which were sufficiently potent to potentially allow for a week’s worth of drug to fit inside of a capsule.

The dosage form looks like a star that basically has 2 different components: arms that are loaded with the drug, and an elastic central portion (central elastomer) that enables the folding of the star into a capsule.  The 2 segments are bonded with linkers that can provide control over the time the system remains intact and therefore resident in the stomach as well as safety to ensure the system can break up should it leave the stomach.

Once swallowed, acid in the stomach dissolves the outer layer of the capsule allowing the star’s six arms to unfold thanks to the central elastomer. The star’s shape, size and material properties enable it to remain housed in the stomach for a week, preventing it from normally transiting down the digestive tract, while causing no obstructions or adverse effects. The polymers in the arms are then able to deliver the full course of antiretroviral medications in a controlled-manner for the week-period.

Simulations of viral dynamics on a patient level showed that implementing such systems would considerably reduce therapeutic failures and improve patient outcomes. The potential of long-acting antiretrovirals in prophylactic regimens in uninfected individuals was gauged by epidemiological modelling and was estimated to be able to avert hundreds of thousands of new HIV cases over 20 years.

This new platform is a modular system that provides gastric resident capacity and drug release from two separate aspects of the dosage form. Thus, it employs two different polymers in the star arms: a structural rigid polymer constituting the arms’ backbone in which a pocket is milled and filled with a second polymer matrix that is loaded with drug and that controls its release rate in the stomach.  

We believe that our dosage form could be applied broadly to many diseases including infectious disease, psychiatric illness and others. Settings that are resource-constrained and with limited access to healthcare in Sub-Saharan Africa for example will also typically benefit from such technologies.

Figure 1: Structure of the gastric-resident star-shaped dosage form.

References

1. Shorter, H. "Noncompliance with medications: an economic tragedy with important implications for health care reform." Task Force for Compliance Report (1993).

2. Kishimoto, H. & Maehara, M. Compliance and persistence with daily, weekly, and monthly bisphosphonates for osteoporosis in Japan: analysis of data from the CISA. Arch. Osteoporos. 10, 27 (2015).


Go to the profile of Omar Abouzid

Omar Abouzid

Master's student, Massachusetts Institute of Technology

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