In regions where malaria is endemic, there is an unmet need for malaria vector control. Insecticide treated nets (ITN) have provided significant reduction in malaria transmission  but are only effective when users are physically confined in the nets. Oral ivermectin administration has been proposed as a method to provide vector control outside of nets.
Ivermectin, a drug commonly administered to treat onchocerciasis, also has mosquitocidal activity when mosquitoes consume a blood meal that contains the drug . Mass drug administration (MDA) of ivermectin may significantly reduce malaria transmission [3 - 4], and adherence to daily ivermectin treatment is critical in this goal .
A lab scale Thermofisher Haake MiniCTW hot melt extruder was used to blend ivermectin with hydrophobic structural polymers and hydrophilic excipients. Ivermectin content was held at 40 wt % Ivermectin and hydrophilic excipient content was varied from 30% to 5%, with the balance being hydrophobic base polymer. Extruded formulations were analyzed for drug release over 14 days by incubation in 0.01 M phosphate buffer (pH=7.0 with 0.5% of sodium dodecyl sulfate; USP Ivermectin tablet source). Drug concentration was quantified by HPLC. Formulation candidates were chosen for scale up and an in vivo study based on extent of Ivermectin release on day 14.
Drug arm scale up
Formulation components were blended using a twin screw compounder, pelletized, and then extruded through a triangular die to create rod stock with triangular cross sections. Extrudates then were cut to 15mm lengths and assembled into stellate dosage forms.
Dosage Form Component and Assembly
In vitro lead candidate IVM119 was chosen to undergo in vivo testing. Figure 1 depicted the IR welded/assembled dosage form in open configuration (top) and in pill form (bottom). Component A was either a drug loaded arm or placebo arm. For the in vivo study, 1 drug arm (~35mg Ivermectin load) and 5 placebo arms were used to complete a dosage form were assembled with cores and disintegrating matrices via IR welding. Steel beads were added to the ends of the drug arms (component A) for radiopacity for X-ray imaging. Dosage forms were folded in to capsules shown in figure 1D prior to in vivo dosing.
In vivo Study
Six beagles were dosed orally with the stellate dosage form. The position and intactness of the dosage form was monitored by X-rays. Blood was drawn to analyze the plasma Ivermectin concentration starting from hour 2 up to 240 hours (10 days).
In vitro Testing:
Figure 2 shows the relationship of IVM release with different percentages of hydrophilic excipients and hydrophobic base polymers. Formulation A with 30% excipient and 30% base polymer released >85% IVM on day 14. With decreasing excipient amounts and increasing base polymer amount, the extent of IVM release decreased on day 14. As ivermectin is very hydrophobic, hydrophilic components are needed to aid its elution from the hydrophobic polymeric matrix.
In vivo Pharmacokinetics (PK) and Gastric Residency
PK results showed that Ivermectin was present in plasma for up to 10 days (Figure 3). Plasma concentration over time was consistent with constant release of ivermectin for 10 days. X-ray images showed that Ivermectin dosage forms were retained in the stomach for greater than 14 days.
In this study, a prototype ultra-long acting Ivermectin oral dosage form was developed. In vitro screening showed that the drug release rate was tunable, and that higher ratio of hydrophilic excipient to hydrophobic base polymer increased Ivermectin release. In vivo data showed that Ivermectin dosage forms successfully stayed inside the gastric space for greater than 14 days. PK data revealed that the Ivermectin formulation was able to release the drug constantly for 10 days.
1. WHO. World Malaria Report 2017. ISBN 978 92 4 156552 3.
2. Pinilla et al. https://doi.org/10.1371/journal.pntd.0006221.
3. Chaccour et al. https://doi.org/10.1186/s12936-015-0618-2.
4. Bellinger et al. Sci Transl Med 2016 Nov 16; 8(365): 365ra157.
5. Newby et al. doi: 10.4269/ajtmh.14-0254.
Susan Low– VP of Pharmacology & Toxicology, Lyndra Inc.
Rosemary Kanasty– Associate Director, Exploratory Technologies, Lyndra Inc.
Tyler Grant– Associate Director of Engineering, Lyndra Inc.
David Altreuter– VP of Pharmaceutical Sciences, Lyndra Inc.
Deblina Biswas– Analytical Scientist, Lyndra Inc.
Claire Lee– Northeastern University
Craig Simses– Associate Process Development Engineer, Lyndra Inc., Watertown, Massachusetts
Sonia Holar– Associate Engineer, Lyndra Inc.
Nicholas De La Torre– Associate Scientist, Lyndra Inc.
David Dufour– Design Engineer, Lyndra Inc.
Robert Debenedictis– Process Development Engineer, Lyndra Inc., Cambridge, Massachusetts
Andrew Bellinger– Chief Scientific Officer, Lyndra Inc.