(T1330-01-06) Scaled-Up Production of High Drug Loading and Dissolution Enabling Lumefantrine Granules

Purpose: Lumefantrine is an anti-malaria drug developed in the 1960s in China to address the increasing resistance of falciparum malaria to chloroquine and other previously used malaria drugs. The drug became available to the market in 2009 under the tradename Coartem where Lumefantrine is co-formulated with Artemether. However, due to the hydrophobic nature of Lumefantrine, it suffers from low bioavailability, and therefore a high number and frequency of dosages is required, increasing the risk of patient non-compliance. Patient non-compliance can lead to the development of anti-malarial drug resistance. Nanoparticles serve as promising solutions to improve drug dissolution and bioavailability of poorly soluble compounds. Given the above concerns, a scaled-up manufacturing process for Lumefantrine nanoparticles has been developed (based on the polymer-directed, rapid precipitation technique, Flash NanoPrecipitation). Lumefantrine nanoparticles produced were then formulated into Lumefantrine granules which have been shown to demonstrate enhanced bioavailability compared with the commercial counterpart and, therefore, serve as a potential new anti-malaria formulation to address the limitations of the current Lumefantrine drugs.

Methods: A schematic process flow diagram for the manufacturing process is presented in Figure 1. Five unit operations are included in the manufacturing process, which are flash nanoprecipitation (FNP), tangential flow filtration (TFF), spray drying (SD), tumble blending (TB) and dry granulation (DG). The FNP step was carried out by mixing four streams of liquid at a total Reynolds number (greater than 30,000) in a multi-inlet vortex mixer (MIVM) designed in-house (Feng, 2019). Two of the four streams were anti-solvent (1.017 mM NaOH solution) to the drug molecule while the other two streams were solvent (tetrahydrofuran, THF) to it, containing 22.5 mg/mL of Lumefantrine and 2.5 mg/mL of HPMCAS-126 (which acts as a stabiliser). An in-line water was introduced to dilute the flash nanoprecipitation. A flow ratio between the anti-solvent streams, the solvent streams and the in-line water of 1:1:1:1:16 was employed. The FNP suspension was then passed through a TFF unit to separate the excess water from the suspension, resulting in a concentrated FNP suspension. Afterwards, the concentrated FNP suspension was mixed with a cryoprotectant (HPMC E3) at a mass ratio of 1:1 between nanoparticles and HPMC E3 before the suspension was finally spray dried to obtain Lumefantrine nanoparticles. The Lumefantrine nanoparticles obtained were further formulated into granules of Lumefantrine nanoparticles through a TB and DG process. The excipients selected include microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silica, and talc. The granules were then packed in sachet for stressed stability studies at 40ºC/75%RH.

Results: The rapid mixing process of solvent and anti-solvent streams in the MIVM (5 L) reduced the timeframe in which nanoparticles formed could grow; therefore, d₅₀ particle size of 265.8 nm was obtained. The residual organic content in the nanoparticle suspension will result in instability of nanoparticles due to the Ostwald ripening effect. In-line water was then added to further dilute the nanoparticle suspension to prolong the stability. The TFF step was necessary; otherwise, there would be a tremendous volume of suspension to be spray dried, making the manufacturing process uneconomical. A concentration factor of 17 was aimed for in the TFF step. After TFF, the concentration of Lumefantrine in the suspension was determined to be 12.75 mg/mL. Although there was an increase in the size of nanoparticles in the TFF step which was caused by the intensive stress environment in the membrane, the spray dried nanoparticles from the concentrated FNP suspension still demonstrated superior in-vivo dissolution results. The nanoparticles were then formulated into a granule-in-sachet dosage form at a drug loading of 26%, via a TB and DG process. An accelerated stability programme was conducted on the final dosage form. In this study, the granular samples were found to generate consistent in-vitro dissolution behaviour (the formulated nanoparticles were noted to be far more soluble than the crystalline counterpart) and stable assay results, can be seen in Figure 2.

Conclusion: In conclusion, a scaled-up manufacturing process to produce sachet dosage for formulated granules of Lumefantrine nanoparticles has been built. The prototype formulation demonstrated enhanced in-vitro dissolution kinetics and consistent assay results in a 3M accelerated stability programme. A potential route to address growing concerns associated with low bioavailability of Lumefantrine can therefore be proposed.

References: Feng, J., Zhang, Y., McManus, S.A., Qian, R., Ristroph, K.D., Ramachandruni, H., Gong, K., White, C.E., Rawal, A. and Prud'homme, R.K., 2019. Amorphous nanoparticles by self-assembly: processing for controlled release of hydrophobic molecules. Soft matter, 15(11), pp.2400-2410.

Acknowledgments: The authors would like to thank for Bill Melinda Gates Foundation for providing generous financial support to this project.

Process parameters and characterisation of process streams



Stability results of formulated granules of Lumefantrine nanoparticles



Schematic process flow sheet for the manufacturing process