Prolongation of the gastric residence time of caffeine after administration in fed state: Comparison of effervescent granules with an extended release tablet

The aim of the present study was to investigate the gastroretentive capacity of different formulation principles. This was indirectly determined by the absorption behavior of caffeine from the dosage forms. A slow and continuous appearance of caffeine in the saliva of healthy volunteers was used as a parameter for a prolonged gastric retention time. For this purpose, a four-way study was conducted with twelve healthy volunteers using the following test procedures: (1) Effervescent granules with 240 mL of still water administered in fed state, (2) effervescent granules with 20 mL of still water in fed state, (3) extended release (ER) tablet with 240 mL of still water in fed state, and (4) effervescent granules with 240 mL of still water in fasted state. The initial rise of the caffeine concentrations was more pronounced after the intake of the effervescent granules in the fed state compared to that of the ER tablets. However, t_max tended to be shorter in the fed study arms following administration of the ER tablet compared to the granules. Overall, the application of active pharmaceutical ingredients formulated as effervescent granules seems to be a promising approach to increase their gastric residence time after intake in fed state.

Introduction

There are several reasons to increase the gastric residence time of drugs [1]. Often the primary goal is to improve the bioavailability of drug candidates, that either suffer from low solubility (e.g. cinnarizine [2]), instability at different pH values (e.g. verapamil [3]) or the candidates are only absorbed in certain regions of the intestine (e.g. pregabaline [4]). A common approach for this concept are gastroretentive drug delivery systems (GRDDS) [1]. For example, major efforts have been made to develop gastroretentive formulations of antibiotics for the local treatment of Helicobacter pylori infections to increase the chance of the therapeutic success and also to reduce side effects [4], [5], [6], [7], [8], [9]. Reducing the dosing interval and thus improving patient compliance is another possible advantage of this strategy researcher regularly aiming for [10].

Different aspects have to be considered, when local treatment of the stomach and due to that prolonged gastric residence time of a dosage form shall be achieved. The retention time in the stomach is mainly determined by the physiology of the stomach. In humans, gastric emptying of indigestible solids in the fasting state is controlled by the interdigestive migrating motor complex (IMMC) [11], [12]. This physiological phenomenon is characterized by phases of very different contractile activity in terms of frequency, duration and intensity. Especially in the third phase of the IMMC, pronounced antral contractions, also known as housekeeping waves, promote the emptying of even larger objects, such as non-disintegrating tablets, from the stomach. Accordingly, large monolithic dosage forms are also emptied from the human stomach under fasting conditions [13], [14]. Ingestion of food disrupts the course of the IMMC. In fed state, gastric emptying behavior changes and only small particles with a diameter below approximately 2 mm can pass the pylorus [15]. Large objects, such as monolithic non-disintegrating tablets, are usually retained in the postprandial stomach until the reoccurrence of the fasted state motility cycle [15], [16]. However, the physiological behavior of the human stomach represents a major challenge in terms of achieving therapeutic drug concentrations for local treatment. Established dosage forms may face challenges in ensuring effective concentration and transport to the site of the stomach due to the dynamic conditions inside the stomach and their influence on the dosage form, such as shear forces on a monolithic dosage form through food or placement of the dosage form in a full stomach [17]. Additionally, there are several other important factors to consider achieving an effective local therapy, e.g. the distribution of the meal components or the viscosity of the ingested food [18].

Another important factor to consider is the emptying of water from the stomach. Under postprandial conditions, administered water, together with dissolved or dispersed API, rapidly passes through the stomach by a mechanism called stomach road or “Magenstraße”. Due to that, the intake of medications after a meal in the hope of prolonged gastric residence time, may result in surprisingly fast emptying kinetics followed by rapid drug absorption. In clinical studies solid dosage forms are applied together with 240 mL of water and this volume is being emptied from the stomach within 15 to 45 min in fasted as well as fed state [18], [19], [20]. But not only the emptying rate of the co-administered water but also the amount of water is important, especially looking at real life dosing conditions. Several studies have shown that most patients take their mediactions with less than 240 mL water [18], [21]. Overall, the emptying of water can be an additional challenge achieving gastric retention.

As mentioned above, major efforts are being made to extend the gastric residence time of APIs. Regarding the first line therapy of Helicobacter pylori for example, prolonging the gastric residence time of antibiotics could result in a better eradication and an increased therapeutic success [22], [23], [24]. Especially the eradication with amoxicillin is time dependent [25]. Nowadays, the first line treatment recommends the triple-therapy for 7 days or the non-bismuth quadruple therapy for 10–14 days [24], [26]. The standard therapy always includes a proton-pump-inhibitor (PPI) and at least one antibiotic [24], [25]. Helicobacter pylori is a gram-negative bacteria with 4.4 billion individuals infected worldwide [25]. Therefore, Helicobacter pylori is one of the main factors causing gastric ulcers in addition to the widespread of use of non-steroidal anti-inflammatory drugs (NSAIDs) [27], [28].

These ulcers are small open wounds in the mucosa of the stomach that are larger than 5 mm. The standard therapy of these ulcers is usually based on PPIs, but these are associated with several side effects, including renal disorders, cardiovascular risks and micronutrient deficiencies [29], [30]. Local therapy could reduce these side effects, but has to deal with several challenges [31]. On the one hand, the drug has to be transported to the target site and more important, the drug must remain over a longer period of time at this site. This requires a homogenously mixing of the drug in the chymus in fed state. A constant and effective concentration has to be reached for a local treatment of the stomach walls. Due to the physiological behavior of the stomach, it is only possible to increase the gastric residence time of drugs in the fed state so far [17], [31]. For example, hydroxypropylmethylcellulose (HPMC)-based ER tablet represented a well established way to achieve a prolonged release of drugs inside the stomach after administration in fed state [32], [33]. This can dramatically increase the period of time in the stomach and thus the period of time at the target site of gastric diseases like gastric ulcers. Today’s established gastroretentive drug delivery systems have difficulties in meeting these mentioned requirements. For example, the transport to the target site or generating a homogeneous mixture as prerequisite for locally high concentrations, to ensure a local therapy is very challenging and can be difficult to achieve.

Increasing the gastric residence time of active pharmaceutical ingredients (API) can have other important benefits besides a local therapy especially for diseases that would benefit from a constant and steady drug emptying from the stomach, and thus a constant absorption in the small intestine, corresponding to constant plasma concentrations [31], [34]. For example, the pancreatic enzyme replacement therapy (PERT) requires a slow and constant emptying in the small intestine to ensure effective digestion and absorption [35]. These PERT enzymes are often administered in microgranules or minimicrospheres with a pH sensitive coating due to the possible inactivation by the gastric acid [36]. Due to the established dosage forms, inconsistent concentrations in the small intestine could occur after gastric emptying, as the mentioned microgranules or minimicrospheres are not homogenously contributed in the food content [37]. In this case, possibly a homogenous mixing in the co-administered food could result in a more constant drug emptying out of the stomach.

Another therapy that would benefit from a constant and slow drug emptying from the stomach is the treatment of bowel diseases such as Crohn’s disease or Ulcerative Colitis [37]. Actually, oral administration of drugs is preferred, and the characteristics of Crohn’s disease, especially the discontinuous inflammatory regions of the bowel, would make a continuous and steady concentration of effective anti-inflammatory agents desirable. The constant and slow emptying of homogeneous food content could provide a constant drug concentration in the following parts of the gastrointestinal tract (GIT). This would potentially increase the therapeutic success and reduce the risk of adverse effects.

In the present study, we investigated the potential of different formulations to achieve higher concentrations in stomach for a longer period of time. By generating and releasing the incorporated carbon dioxide, these granules should be mixed into the gastric content. The incorporated model drug caffeine should be distributed homogenously within the chyme. Moreover, we studied the impact of different amount of co-administered water on the magnitude of this mixing effect. Due to the emptying behavior in the fed state, the concentration of caffeine in the stomach should be increased over an extended period of time. Additionally, we compared the potential to increase the gastric residence time of these effervescent granules with that of a hydrogel forming extended release tablet based on HPMC. The extended release tablet represents a common approach of a large monolithic dosage form to continuously release drug into the stomach. Furthermore, the effervescent granules were also administered under fasted state conditions to investigate the absorption profile of the incorporated caffeine when intragastric chyme is not present prior to intake.

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Materials

Caffeine, citric acid (anhydrous), glycerol anhydrous, black iron oxide (E172) and blue food coloring (E131) were obtained from Caesar & Loretz GmbH (Hilden, Germany). Macrogol 4000, magnesium stearate and silicon dioxide have been purchased from Fagron GmbH & Co. KG (Barsbüttel, Germany). Mannitol (Mannogem EZ) as well as sodium hydrogencarbonate (EfferSoda 12) were obtained from SPI Pharma (Wilmington, USA) Microcrystalline Cellulose (VIVAPUR 101) was purchased from JRS PHARMA GmbH.

Constantin Foja, Stefan Senekowitsch, Fabian Winter, Michael Grimm, Christoph Rosenbaum, Mirko Koziolek, Maximilian Feldmüller, Marie-Luise Kromrey, Eberhard Scheuch, Mladen V. Tzvetkov, Werner Weitschies, Philipp Schick, Prolongation of the gastric residence time of caffeine after administration in fed state: Comparison of effervescent granules with an extended release tablet, European Journal of Pharmaceutics and Biopharmaceutics, Volume 199, 2024, 114313, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114313.

Read also our introduction article on Mannitol here: