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4.Studies with different patients using magnetic resonance imaging show that a dose of water with a volume varying between about 240 and 250 mL empties rapidly from the fasted human stomach, with a half emptying time (T50%) between approximately 13 and 18 min and complete gastric emptying in 45 min (Mudie et al. 2014, Steingoetter et al. 2006).Although the release results of our formulation were different, it is important to consider that gastrintestinal conditions (GI) can differ among patients and therefore a variety of inter- and intra-individual differences in GI physiology have been reported in the literature, such as variations in gastric emptying, intestinal transit times, composition and volume of fluid available in the different GI sections and in GI motility patterns in both fasted and fed state dosing conditions Table 3 Physicochemical characterization of the formulations before and after enteric coating.It is worth mentioning that in preliminary studies we tested larger concentrations of enteric coating polymer, however, it was observed that they reduced the EE of the drug and the decision was thereby made to use 0.03%, which was able to maintain the characteristics of the formulation.In vitro release The purpose of EL100-55 as an enteric coating is to delay the exposure of OME to an acidic environment, avoiding significant degradation of the drug as well as preventing the reduction of bioavailability (Tawfeek et al. 2017).The in vitro drug release test was carried out for the OERS/EL nanoparticles in simulated gastric fluid (pH 1.2) for 60 min based on the residence time of the formulation in the stomach (Mudie et al. 2014, Steingoetter et al. 2006).Taking into account that OME is administered fasted and at a half emptying time (T50%), in these conditions and with ranges from 13 to 18 min to be completed at a maximum of 45 min arises the suggestion that the nanoparticles proposed in this study arrive at the intestinal transit in less than 1 h, ensuring that less than 10% is released into the stomach. A study that developed nanoparticles of OME using the emulsion diffusion method and EL100-55 as an enteric coating polymer showed less than 10% drug degradation in 0.1 N HCl solution (Hao et al. 2013a).This release behavior can be explained by the pH influence on the EL100-55 polymer solubility and by the ionization of the methacrylic acid carboxylic groups in aqueous medium (pH >= 5.5) (Sauer et al. 2009).Sample D4,3 (nm) Span(v) z-average (nm) PDI EE (%) pH OERS 175 +- 3.51a 2.26 +- 0.20a 166 +- 7.21a 0.213 +- 5.00a 95.8 8.7 +- 0.22a OERS/EL 223 +- 13.05b 2.16 +- 0.20a 174 +- 17.00a 0.229 +- 0.01a 68.1 10.4 +- 0.36b Matching letters within a column indicate no statistical difference (p >= 0.05).Fig. 3). 3).In this study, 0.03% was used.1.

4. In vitro release
   The purpose of EL100-55 as an enteric coating is to delay the exposure of OME to an acidic environment, avoiding significant degradation of the drug as well as preventing the reduction of bioavailability (Tawfeek et al. 2017). The in vitro drug release test was carried
   out for the OERS/EL nanoparticles in simulated gastric fluid (pH 1.2)
   for 60 min based on the residence time of the formulation in the stomach (Mudie et al. 2014, Steingoetter et al. 2006). Following this, the
   drug release in the simulated intestinal fluid (pH 6.8) was also evaluated. The OME release curve of the OERS/EL nanoparticles was obtained at different time points and the results expressed in percentage of
   OME release versus time (Fig. 3).
   The OME release from the OERS/EL nanoparticles varied over time
   and seemed to be influenced by the simulated fluid medium (Fig. 3).
   The initial release of OME was slow in the simulated gastric medium
   (pH 1.2), with less than 11% of the drug released. The EL100-55, a
   polymer used as an enteric coating, is insoluble in an acid environment,
   preserving the integrity of the particles and delaying the release of the
   drug (Shen et al. 2011). Furthermore, the absence of a burst release
   indicates an efficient coating and entrapment of OME within the OERS/
   EL nanoparticles. Similar behavior was reported in other studies that
   also employed EL100-55 as an enteric coating for a variety of drugs
   (Jelvehgari et al. 2010, Tawfeek et al. 2017). The OME release was
   increased by the change in the pH from 1.2 to 6.8. This release behavior
   can be explained by the pH influence on the EL100-55 polymer solubility and by the ionization of the methacrylic acid carboxylic groups in
   aqueous medium (pH ≥ 5.5) (Sauer et al. 2009). The release of OME
   from OERS nanocapsules increased significantly when the pH of the
   medium changed to 6.8, showing sustained release due to the presence
   of ERS 100. This polymer has low permeability with pH independent
   swelling and is used for a controlled and customized release profile
   (Animesh et al. 2012, Patra et al. 2017).
   In addition, the release of the free drug carried out at pH 6.8
   showed, after 15, 30 and 60 min, diffusion of 66.0 ± 1.8%,
   80.6 ± 6.3% and 96 ± 7.8% of OME, respectively. At the same time,
   43.4 ± 2.14%, 56.7 ± 2.6% and 73 ± 3.1% were released in the
   OERS/EL nanoparticles, showing the ability of nanoparticles to control
   the release of the OME in this system.
   Pharmaceutical forms containing PPI have been developed using a
   variety of techniques to improve aspects related to acid degradation.
   Microparticles containing pantoprazole sodium and tablets containing
   the pantoprazole microparticles were prepared with Eudragit® S100.
   Drug dissolution profiles from the tablets demonstrated slower release
   than untabletted microparticles (Raffin et al. 2006).
   A study that developed nanoparticles of OME using the emulsion
   diffusion method and EL100-55 as an enteric coating polymer showed
   less than 10% drug degradation in 0.1 N HCl solution (Hao et al.
   2013a). However, it is worth mentioning that the concentration of
   EL100-55 used by the authors was 1 to 4%. In this study, 0.03% was
   used. In another study, using the electrospray nanoparticles preparation
   method and OME as a pH-sensitive model drug, it presented less than
   5% in gastric fluid (pH 1.2), and after 15 min in pH 6.8, 90% OME
   release. In this case, the authors used EL100-55 in the 0.8% concentration (Hao et al. 2013b).
   These results show that the concentration of sensitive pH polymer
   and the method of preparation of the nanoparticles may influence the
   release in a simulated gastric fluid (pH 1.2). It is worth mentioning that
   in preliminary studies we tested larger concentrations of enteric coating
   polymer, however, it was observed that they reduced the EE of the drug
   and the decision was thereby made to use 0.03%, which was able to
   maintain the characteristics of the formulation.
   Although the release results of our formulation were different, it is
   important to consider that gastrintestinal conditions (GI) can differ
   among patients and therefore a variety of inter- and intra-individual
   differences in GI physiology have been reported in the literature, such
   as variations in gastric emptying, intestinal transit times, composition
   and volume of fluid available in the different GI sections and in GI
   motility patterns in both fasted and fed state dosing conditions
   Table 3
   Physicochemical characterization of the formulations before and after enteric coating.
   Sample D4,3 (nm) Span(v) z-average (nm) PDI EE (%) pH
   OERS 175 ± 3.51a 2.26 ± 0.20a 166 ± 7.21a 0.213 ± 5.00a 95.8 8.7 ± 0.22a
   OERS/EL 223 ± 13.05b 2.16 ± 0.20a 174 ± 17.00a 0.229 ± 0.01a 68.1 10.4 ± 0.36b
   Matching letters within a column indicate no statistical difference (p ≥ 0.05).
   Fig. 1. (A) TEM image of OERS nanoparticles (scale bar, 200 nm) and (B) TEM image of OERS/EL nanoparticles (scale bar, 200 nm).
   H.S. Diefenthaeler, et al. International Journal of Pharmaceutics 589 (2020) 119818
   5
   (Karkossa and Klein 2019).
   Studies with different patients using magnetic resonance imaging
   show that a dose of water with a volume varying between about 240
   and 250 mL empties rapidly from the fasted human stomach, with a half
   emptying time (T50%) between approximately 13 and 18 min and
   complete gastric emptying in 45 min (Mudie et al. 2014, Steingoetter
   et al. 2006). Taking into account that OME is administered fasted and at
   a half emptying time (T50%), in these conditions and with ranges from
   13 to 18 min to be completed at a maximum of 45 min arises the
   suggestion that the nanoparticles proposed in this study arrive at the
   intestinal transit in less than 1 h, ensuring that less than 10% is released
   into the stomach.