Novel polymer series for pharmaceutical applications: alpha-hydroxycarboxylic acid modified polymethacrylates

Abstract

Enteric-coated dosage forms often suffer from sluggish post-gastric emptying drug release. This work focuses on developing novel enteric polymers as an approach to overcome this problem. The well-known polymer structures of Eudragit® L 100 and L 100-55 were esterified with the α-hydroxycarboxylic acids l-lactic, d,l-lactic and glycolic acid. A resulting partial positive charge arises within the ester linkage, reducing the pK_a value of the polymer. This translates to more facile deprotonation of the carboxylic acid moieties, which enables more rapid polymer dissolution and consequently faster drug release. The dissolution pH threshold was reduced from pH 5.5 for the established Eudragit® L 100-55 to around 5, while the valuable acid-resistant properties of the polymethacrylates were preserved. Capsules filled with paracetamol were coated with the modified polymers as well as with the commercially available materials Eudragit® L 100 and L 100-55. In 0.01 M hydrochloric acid all coated capsules remained intact without any significant drug release. However, in 15 mM phosphate buffer (pH 6.5) the drug release from the formulations based on the novel polymers was significantly enhanced compared to formulations with Eudragit® L 100 and L 100-55. The increased release rate was connected to the faster dissolution of the modified polymers. This novel series of enteric polymers could help to overcome clinical problems associated with the currently used enteric polymers.

Introduction

Enteric coatings are frequently used in the formulation of oral dosage forms to delay drug release until the dosage form is emptied from the stomach and reaches the small intestine. (Agyilirah and Banker, 1990) The rationale behind the use of pH-dependent coatings is e.g., to protect the drug from degradation in the stomach or to protect the stomach from irritation by drugs (Agyilirah and Banker, 1990). Usually, enteric coatings consist of acidic polymers that are protonated in the gastric fluid and therefore insoluble. When the coated dosage form reaches the small intestine with an increased pH value, the polymer gets deprotonated and thus soluble. As a result, the enteric coating begins to dissolve and the active pharmaceutical ingredient (API) is released from the dosage form and can be absorbed from the proximal small intestine. The most frequently used enteric polymer is the methacrylic acid-ethyl acrylate 1:1 copolymer (P[MA-co-EA]) with the trade name Eudragit® L30-D55 / Eudragit® L100-55 or Kollicoat® MAE (Breitkreutz, 2000). The manufacturer states that the polymer has a dissolution pH threshold of 5.5 and therefore targets the drug release in the duodenum (Evonik Nutrition & Care GmbH, 2026e).

However, recent studies indicate too slow post-gastric disintegration of enteric-coated (EC) dosage forms and consequently drug release in a lower part of the small intestine, missing their targeted release destination (Al-Gousous et al., 2017). A slow in vivo release of the API can sometimes lead to serious bioavailability problems of drugs with a major absorption site in the upper small intestine. Rudinskas et al. reported cases where poor bioavailability of iron sulfate from EC formulations is due to drug release taking place after the dosage form has passed the duodenum and jejunum, the preferential absorption site of iron salts (Rudinskas et al., 1989). Mössner and Keim proposed that the insufficient treatment of gastrointestinal distress symptoms associated with an exocrine pancreatic insufficiency is related to the delayed onset of pancreatin release from EC dosage forms (Mössner and Keim, 2010). A more recent study showed that low-doses of EC aspirin have no benefit in lowering the risk of cardiovascular diseases compared to placebo (McNeil et al., 2018). On the other hand, it is well known that low-dose aspirin decreases the risk of cardiovascular events (Antithrombotic Trialists’ Collaboration, 2002). The studies indicate that the failure of EC low-dose aspirin is related to a dissolution failure of the enteric coating. Cox et al. performed a bioequivalence study on five different aspirin preparations (three 75 mg EC dosage forms, one 75 mg dispersible form and one combination of 25 mg immediate release (IR) aspirin plus 200 mg modified release dipyridamole). They found that the EC aspirin showed a lower bioavailability compared to the IR formulation and concluded that the lower absorption from the EC dosage form is due to the enteric coating (Cox et al., 2006). The authors proposed that an increase in the dose of the EC formulation could overcome the clinical failure of the EC products (Cox et al., 2006). However, Cox et al. also stated that this could increase the risk for bleeding events (Cox et al., 2006, Serebruany et al., 2005). This observation is consistent with findings from Grosser et al. and Haastrup et al., who reported reduced efficacy of acetylsalicylic acid when formulated with enteric coatings (Grosser et al., 2013, Haastrup et al., 2015). Consequently, there is a need for novel formulation strategies to enhance the drug release from EC formulations, thus overcoming the low bioavailability and treatment failure of these products.

There has been progress in the development of EC dosage forms with enhanced post gastric dissolution rates. Liu et al. introduced a double-coating approach of pellets. The coating consists of two different coating layers, namely an inner film with partially neutralized Eudragit® L30 D-55 with addition of a buffer system (e.g., citrate and citric acid or adipate and adipic acid) and an outer coat with a standard Eudragit® L30D-55 formulation. Through the high local buffer concentrations, they could show an improved release of the API even at a decreased bulk pH of 5.6 (Liu et al., 2010, Liu et al., 2009, Liu and Basit, 2010). However, this approach includes two coating steps and is therefore more time-consuming and may be costlier in comparison to a single coat approach. Other recent approaches to improve the release from EC formulation were the use of amorphous solid dispersions inside EC capsules, which could improve the release of poorly soluble drug (Nguyen et al., 2023). On the commercial side Evonik (Eudracap®) as well as Lonza (Capsugel® Enprotect®) have brought precoated capsules to the market which have shown to be an alternative to traditionally coated capsules in vitro (Afonso Urich et al., 2023, Knopp et al., 2026) and in vivo (Rump et al., 2022).

In this study, we propose a novel strategy to enhance the post gastric disintegration and dissolution using modified methacrylic polymers. In our registered patent (DE 10 2018 129 419 A1) the successful synthesis of a novel type of methacrylic acid-based polymers is described (Frey et al., 2018). In brief, the well-known and established structure of P[MA-co-EA] and methacrylic acid-methyl methacrylate 1:1 copolymer P[MA-co-MMA] (corresponding the Eudragit® L 100-55 and Eudragit® L 100 polymer, respectively) were modified by esterification of the functional carboxylic group with the α-hydroxycarboxylic acids lactic acid (d,l-Lac or l-Lac) and glycolic acid (Gly)(Fig. 1). Both of these organic acids are expected to be unharmful as degradation products (Dubar et al., 2021).

The novel structure exhibits resonance creating a partial positive charge at the oxygen atom in the ester bond. The resulting strong electron withdrawing effect lowers the pKa of the carboxylic acid group. As described in literature, the pKa of carboxylic acid groups has a strong effect on the dissolution rate, and with a lower pKa value of the dissolving acid the dissolution rate is usually enhanced (Al-Gousous et al., 2019, Mooney et al., 1981a, Mooney et al., 1981b). Consequently, the drug release after gastric emptying from EC dosage forms with the proposed polymer should be more rapid compared to the commercially available polymers (P[MA-co-EA] and P[MA-co-MMA]). The aim of this work was to evaluate the newly synthesized polymers regarding their suitability for enteric coatings, to assess the drug release from coated formulations using the new material, and compare their performance to coated formulations employing commercially available polymers. In addition, the most promising candidates were further characterized with regards to stability and toxicity of the novel polymer.

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Materials

Size 0 hydroxypropyl methylcellulose (HPMC) capsules (ACG Nature Caps Plus) were received from ACG Associated Capsules Pvt Ltd (Ashagadh, Maharashtra, India). Paracetamol was brought from Caesar & Loretz GmbH (Hilden, Germany) and triethyl citrate (TEC) from Merck Schuchardt OHG (Hohenbrunn, Germany) Mannitol, fumed silica and talcum were pharmacopeial quality and purchased from Fagron GmbH (Glinde, Germany). 3-(4,5-di methyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), dimethyl sulfoxide (DMSO) and sodium dodecyl sulfate (SDS) were bought form Thermo Fischer Scientific (Waltham, USA), Eudragit® L 100 and L 100-55 were received as free samples from Evonik Röhm GmbH (Darmstadt, Germany).

Felix Claussen, Johannes Andreas Blechar, Jozef Al-Gousous, Dominik Albrecht Hugo Fuchs, Erik Kersten, Marko Jörg, Kristina Friedland, Holger Frey, Peter Langguth, Novel polymer series for pharmaceutical applications: alpha-hydroxycarboxylic acid modified polymethacrylates, International Journal of Pharmaceutics, Volume 695, 2026, 126782, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126782.

Read also our introduction article on Mannitol here: