(M1330-09-61) Demonstration of MicroCoat^TM Scalability: A Fixed Dose Combination of Taste Masked Artesunate-Amodiaquine Micropellets for Malaria Treatment in Paediatrics

Purpose: A fixed dose combination (FDC) of Artesunate (AS) and Amodiaquine (AQ) is amongst the currently recommended Artemesinin based combination therapies (ACTs) by the World Health Organisation (WHO) in the treatment of malaria and is available as a bilayer tablet. These tablets are crushed for paediatric administration, however, AQ is bitter in taste and crushing leads to noncompliance among paediatric populations due to the poor palatability. Furthermore, AS is unstable and the two compounds are chemically incompatible posing challenges in formulation development. A FDC of taste masked AS/AQ micropellets with improved palatability and mouthfeel (diameter < 250 µm) has been developed for oral administration in young children (2 months to 5 years old) using fluidized bed coating at the benchtop scale. This process involved an excipient safety evaluation to ensure product suitability for the target population. A novel coating technology, MicroCoat™, was critical in the manufacturing process and the aim of this work is to scale up the coating process whilst maintaining product performance and quality.

Methods: Bitterness taste detection thresholds for AS and AQ base were established at the UCL School of Pharmacy sing a swirl and spit method in a human adult panel ^1,2 following ethics approval (n=15) (UCL REC (4612/030) & WHO ERC (ERC.0003733)). Due to its susceptibility to degradation, AS-excipient compatibility was tested. AS was mixed with each/all excipients in 1:1 ratio. The influence of trapped humidity was also investigated by sealing half of the samples with the remainder being left open. The two sets were placed in an oven set at 55 degrees for 14 days. Samples were then analysed using HPLC (Pursuit C18 column (4.6 mm X 150 mm, 3 µm) held at 30 °C was used with an isocratic mobile phase of phosphate buffer (pH 3): acetonitrile (34:66) (flow rate 0.4 mL/min, injection volume 20 µL, wavelength 216 nm). AS and AQ (micronised) were separately spray layered onto 1-2 kg microcrystalline cellulose (MCC) micropellets (Cellets^® 100) using ethanolic and aqueous-based formulations, respectively, in a pilot scale fluidized bed coater (GPCG2^®, Glatt GmbH) with 6” Wurster. AS layered micropellets were seal coated with an organic solution of polyvinyl pyrrolidone (PVP K30) and 70 % talc (w/w based on polymer) as anti-tacking agent. This was done to overcome the stability challenges associated with AS. AQ layered micropellets were taste mask coated using 77.5/22.5 ratios of ethyl cellulose and hypromellose (Ethocel^™ and Methocel^™ E5, respectively) with 40% talc (w/w based on polymer) to a 22 % coating level (CL). MicroCoat^™ technology was applied during coating whereby magnesium stearate was periodically added as a dry powder glidant into the coating chamber via an external feeding port. Coating processes were assessed for agglomeration, determined by sieve analysis, and practical yield calculated using the weight of the final product. Drug release was measured in vitro using 900 mL pH 5.5 acetate buffer in USP I & II apparatus for testing AS and AQ, respectively. Taste masking effectiveness was determined in vitro in 10 mL of deionised water. Concentrations of AQ and AS were quantified using UV and HPLC analysis, respectively.

Results: Taste evaluation revealed that AS and AQ had bitterness thresholds of 0.02 mg/mL and 0.0069 mg/mL, respectively. AS showed little to no signs of degradation in its pure form or with excipients used for AS and AQ micropellet manufacturing. Degradation was higher in closed vials (6.8 %) than the open vials (2.5 %) which could be attributed to the entrapped moisture within the closed samples. AS and AQ were successfully layered onto MCC micropellets with no agglomeration and yields of 95 and 89 %, respectively. AQ layered micropellets were successfully seal coated with a yield of 96 % and low agglomeration ( < 5 %). Taste mask coating of AQ layered micropellets was also successful with < 1 % agglomeration and 100 % yield. Results of in vitro drug release testing showed that effective taste masking of AQ was achieved with drug release in the simulated oral environment below the established bitterness threshold (0.0005±0.00 after 1 min). Release of both AS and AQ in the simulated gastric environment (99 % in 10 min) was also shown to meet the requirements of immediate release formulations ( >75 % in 45 min).

Conclusion: Drug layering and seal coating/taste masking in the development of AS/AQ micropellets was successfully scaled up from benchtop to pilot scale with the application of the MicroCoat™ technology. Low agglomeration and high product yields were obtained following all coating processes and product performance in terms of in vitro release was maintained. This is a breakthrough for malaria treatment in the paediatric population with the next steps including final packaging, stability, bioequivalence, and product commercialization.

References: 1. Quality control methods for herbal materials (2011) World Health Organization; 11 Determination of bitterness value pp 41-42Available at: https://apps.who.int/iris/handle/10665/44479
2. European Pharmacopoeia 10.0, (2021) Bitterness value (Method 2.8.15). Council of Europe, Strasbourg

Acknowledgements: The authors would like to thank Unitaid for awarding Fluid Pharma with a UnitaidExplore grant to carry out this project.