(T1530-02-13) Scalability of EUDRATEC ^® Fasteric, an Advanced Technology to Target the Duodenum for Improved Absorption

Purpose: Drugs with a narrow absorption window are usually best absorbed in the duodenum and jejunum due to the large surface area or because the drug shows better solubility in the upper than in the lower part of the GIT¹. After passing the absorption window the released drug can no longer be absorbed in the remaining part of the GIT. This phenomenon decreases the absorption of such drugs when administered orally via immediate release drug delivery systems resulting in poor bioavailability. EUDRATEC^® Fasteric rapidly releases the drug, at pre-defined pH levels between 3.0 and 5.5 to precisely match the release profile requirements of drugs which have a narrow absorption window. EUDRATEC^® Fasteric is an advanced bilayer technology that provides enteric protection followed by rapid, homogeneous release for drug products targeting proximal regions of the small intestine such as the duodenum². It is fast and easy to process using standard equipment, and suitable for use with a range of oral dosage forms including multi-particulates, tablets, and capsules. This technology is based on a bilayer coating concept which consists of a modifying agent in the inner coating and enteric EUDRAGIT^® polymers in the outer layer, and was evaluated on different model drugs i.e., Benazepril HCl, Sotalol HCl, Caffeine, Metformin HCl in different dosage forms like tablets, capsules, and pellets. The aim of this study was to evaluate scalability of this technology using a pellet formulation in a fluidized bed processor.

Methods: Drug layered pellets were used for bilayer coating i.e, intermediate and enteric coating. Neutral pellets 700 - 841 μm (Sugar spheres, Hanns G. Werner GmbH, Tornesch, Germany) were used for drug layering coating. For drug layering process, the water suspension composed of 12.37% w/w model drug, Sotalol hydrochloride (Panchsheel organics, India), 1.43% w/w AEROSIL^® 200 (Evonik Industries AG, Darmstadt, Germany) and 3.08% w/w hydroxypropyl methylcellulose (JRS PHARMA GmbH & Co. Rosenberg, Germany) was used. For intermediate coating, a water suspension composed of 5.82% w/w modifying agent and 5.82% hydroxypropyl methylcellulose was used. For enteric coating, an aqueous dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate i.e., EUDRAGIT^® L 30 D 55 (18.88% w/w) (Evonik Industries AG, Darmstadt, Germany), with 1.90% w/w triethyl citrate (Vertellus LLC, Indianapolis, IN, USA) and 9.44% w/w of talc (Imerys Talc S.p.A., Porte, Italy) was used. All other materials used for dissolution tests were of analytical grade. Drug layering as well as functional coatings were done in a fluidized bed processor (ACG 125C). Analytical method: The coated formulation was analyzed for dissolution studies in 0.1 N HCl for 2 hours followed by drug release in pH 3.0 to 5.5 buffer for 1 hour at 50 rpm using a USP II (paddle) apparatus.

Results: Process observation: The intermediate coating process was carried out using 28.7 KG load of drug layered pellets in an ACG 125C fluid bed coater and it was scaled up to approx. 48.0 KG of enteric coated pellets. No additional excipients or change in concentration of excipients was required in coating dispersions for the scale-up batch. Both the coating processes were carried out without any issues like gun blocking, filter choking or other bottle necks. The pellets were monitored in free fall, which allowed the system to detect agglomeration of pellets in the process. Neither in the lab-scale nor in the pilot-scale process agglomeration of pellets was observed. The coated surface of the pellets was found smooth and uniform. Spraying at max. 250 g/min was achieved in both coatings as estimated earlier, and hence processing time was same as for the lab batch (image 2). The coating process was found uninterrupted, parameters were found satisfactory and comparable to the lab-scale batch. Analytical results: Enteric protection was obtained with more than 85% release in 45 min at pH 5.5, more than 85% release in 60 min and 120 min at pH 4.5 & 3.0, respectively. Scale-up results were comparable to the results of the lab batch. The process parameters and functionality were found satisfactory in first scale-up batch. Enteric protection followed by drug release was found comparable at pH 5.5, pH 4.5 & pH 3.0 in both aqueous and non-aqueous (organic) coating process.

Conclusion: The EUDRATEC^® Fasteric technology in a pellet formulation was successfully scaled-up from a 1.5 KG lab batch to a 48.0 KG scale-up batch. Processing and performance of the scale-up batch was found to be comparable to the lab batch. This successful scale-up shows that EUDRATEC^® Fasteric can be considered for commercial manufacturing.

References: 1 Shaha, S., et al., An overview of a gastro-retentive floating drug delivery system. Asian journal of pharmaceutical sciences, 2009. 4(1): p. 65-80.
2 Evonik Industries AG, Darmstadt, Germany, https://healthcare.evonik.com, press released on October 6, 2020

Acknowledgements: The authors would like to address sincere thanks to ACG Pharma Technologies Pvt. Ltd, for providing their facility to complete this scale-up activity.

Image 1: Rapid duodenal release as a demonstration of functionality

Image 2: Coating process parameters

Image 3: Comparative dissolution profile of enteric coated sotalol hydrochloride pellets