(M1230-09-59) Investigation of Poly(meth)Acrylate-Based Technology and Enteric Polymers for Fast Duodenal Release

Purpose: Poly(meth)acrylate-based technology 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 duodenum. This technology is based on a bilayer coating concept which consists of modifying agent in inner coating and enteric polymers in outer layer. The aim of this study was to compare this technology with different enteric polymers using model drug sotalol hydrochloride in the form of pellets. This technology (EUDRATEC^® Fasteric) is compatible with various solvent systems in bilayer coatings. The strategy involves assessing organic coating systems in this technology and comparing them to aqueous coating systems. This is crucial because many drugs ae vulnerable to aqueous environments, which can significantly diminish the therapeutic effects of solid pharmaceutical dosages. Active pharmaceutical ingredients that are sensitive to moisture necessitate the use of non-aqueous solvents in their formulations to avoid hydrolytic degradation during the manufacturing process. Therefore, employing non-aqueous solvents in coatings is the most effective method for enhancing the stability and efficacy of drug products.

Methods: Sotalol hydrochloride was used as a model drug. Drug layered pellets were coated with bilayer coatings i.e., intermediate and enteric coating. For aqueous coating, water suspension composed of modifying agent and hydroxypropyl methyl cellulose was used for intermediate coating process. Here 1:1 ratio was selected for modifying agent and binder. For enteric coating, aqueous dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate (EUDRAGIT^® L30D 55) with triethyl citrate and talc was used. For non-aqueous coating, ethanol was used for dissolving polyvinyl pyrrolidone as binder, glycerol anhydrous as plasticizer and modifying agent in intermediate coating process. Here 1:1 ratio was selected for binder and modifying agent. For enteric coating, an anionic copolymer based on methacrylic acid and ethyl acrylate (EUDRAGIT^® L100 55) with triethyl citrate and talc was dispersed into solvent mixture of isopropyl alcohol, acetone and water. Hypromellose acetate succinate and hypromellose phthalate (2 different grades, soluble at pH 5.0 and pH 5.5) were selected as alternative polymers for this study. These polymers were selected because they dissolve and provide drug releases at pH 5.0-5.5. For aqueous dispersion, hypromellose acetate succinate was dispersed into water. Triethyl citrate as a plasticizer, talc as anti-tacking agent, and sodium lauryl sulfate as a wetting agent were used. For hydroalcoholic coating system, hypromellose acetate succinate was dispersed into ethanol and water (80:20) with triethyl citrate as plasticizer. Maximum 6% solid contents were achieved with hydroalcoholic dispersions. Hydroalcoholic dispersions of hypromellose phthalate (of 2 different grades) were prepared with maximum solid content of 10%w/w. Here triethyl citrate was used as plasticizer. Intermediate and enteric coating was done on sotalol hydrochloride core pellets in fluidized bed processor (GPCG 1.1) (For process parameters see tables 1 and 2). The coated formulations were studied for enteric protection in 0.1 N HCl for 2 hours followed by drug release in pH 3.0 to 4.5 buffer for 1 hour. (Fig , 2)

Results: Enteric protection followed by rapid drug release was found comparable at pH 5.5, pH 4.5 and pH 3.0 in both aqueous and non-aqueous (organic) coating processes using poly(meth)acrylate-based technology. Complete enteric protection was observed at 20% coating weight gain with this technology and comparatively faster drug release was observed in pH 4.5 & pH 3.0 buffer than with cellulose-based polymers. Hypromellose acetate succinate aqueous dispersions were found to be heat sensitive and caused gun clogging several times during coating at room temperature hence coating could not be achieved. Hydroalcoholic dispersions of hypromellose acetate succinate also caused gun blocking at higher spray rate. A maximum 2-3g/min spray rate was achieved throughout the process. Enteric functionality was achieved at 10% build up, but very slow drug release was observed at pH 4.5 and pH 3.0 buffer. At 15% enteric coating weight gain, drug release was found on higher side in 0.1N HCl using hypromellose phthalate (soluble at pH 5.0) hydroalcoholic dispersions. Enteric functionality was achieved beyond 15% coating weight build up, but slow drug release was observed at pH 3.0 buffer. Enteric functionality was achieved at 25% coating weight build up using hypromellose phthalate (soluble at pH 5.5) hydroalcoholic dispersions, but no drug release was achieved at pH 4.5 & pH 3.0 buffer.

Conclusion: EUDRATEC^® Fasteric technology demonstrates comparable performance in both aqueous and non-aqueous coatings, making it more favorable than cellulose based enteric polymers that use only organic or organo-aqueous solvent systems. Additionally, coating time with cellulose based polymers was higher due to processability challenges even though a single layer process highlights the efficiency of this technology. This technology offers significant processing and performance advantages over cellulose based polymers, particularly for applications requiring enteric resistance and rapid drug release at pH 4.5 and below, outperforming others in faster drug release. It is particularly beneficial for moisture-sensitive drugs, utilizing a non-aqueous coating system.

Table 1: Coating process parameters for EUDRATEC® Fasteric technology in aqueous and organic coating system

Table 2: Coating process parameters for different polymers

Comparative dissolution profile (aqueous and non-aqueous coatings of EUDRATEC® Fasteric) and (EUDRATEC® Fasteric and cellulose based enteric polymers) of sotalol hydrochloride pellets in 0.1N HCl followed by buffer