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The instability of various small molecules, vaccines and peptides in the human stomach is a complex challenge for oral drug delivery. Recently, a novel gastro-resistant capsule - the enTRinsic™ Drug Delivery Technology capsule - has been developed. In this work, the salivary tracer technique based on caffeine has been applied to study the in vivo disintegration of enTRinsic™ capsules in 16 healthy volunteers. In addition, magnetic resonance imaging (MRI) was used to visualize GI transit and to verify the disintegration times determined by using the salivary tracer technique. The enTRinsic™ capsules filled with 50mg of caffeine and 5mg of black iron oxide were administered in the fed state, i.e. 30min after a light meal (500kcal). In the first hour after capsule intake, the subjects were placed in supine position in the MRI scanner and scans were performed in short time intervals. After 1h, the subjects could leave the MRI scanner in between the MRI measurements, which were performed every 15min until disintegration of the capsule was confirmed (maximum observation time: 8h). Saliva samples were obtained simultaneously with MR imaging. Caffeine concentrations in saliva were determined by LC/MS-MS. The starting point of capsule disintegration was determined visually by inspection of the MR images as well as by the onset of salivary caffeine concentrations. In 14 out of 16 subjects, the capsule disintegrated in the small intestine. In one subject, the enTRinsic™ capsule was not emptied from the stomach within the observation time. In another subject, disintegration occurred during gastric emptying in the antropyloric region. In this study, we demonstrated that the enTRinsic™ capsules are also gastro resistant when taken under fed state conditions. Furthermore, we demonstrated the feasibility of using low dose caffeine as a salivary tracer for the determination of the disintegration of an enteric formulation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The process of disintegration is a crucial step in oral drug delivery with immediate release dosage forms. In this work, the salivary tracer technique was applied as a simple and inexpensive method for the investigation of the in vivo disintegration time of hard gelatin capsules filled with caffeine. The disintegration times observed with the salivary tracer technique were verified by magnetic resonance imaging (MRI). After an overnight fast of at least 10 h and caffeine abstinence of minimum 72 h, conventional hard gelatin capsules containing 50 mg caffeine and 5 mg iron oxide were administered to 8 healthy volunteers. For the period of 1 h after capsule intake, subjects were placed in supine position in the MRI scanner, and scans were performed in short time intervals. Each MRI measurement was directly followed by saliva sampling by drooling. Salivary caffeine concentrations were determined by high performance liquid chromatography followed by mass spectrometric detection (LC/MS-MS). The time point of capsule disintegration was determined by visual inspection of the MR images as well as by an increase in the salivary caffeine concentration. The results indicated that the difference in mean disintegration times of the capsules as determined by the two in vivo methods was around 4 min (8.8 min for MRI vs 12.5 min for saliva). All disintegration times determined by the salivary tracer technique were slightly higher. This delay could be explained by the fact that the appearance of caffeine in saliva required drug absorption in the small intestine. Because capsule disintegration happened mainly in the stomach, the exact site of disintegration as well as the processes of gastric mixing and gastric emptying contributed to the delay between the two methods. This work demonstrated the feasibility of the salivary tracer technique to investigate the in vivo disintegration of immediate release dosage forms in a simple and reliable manner.

Numerous literature reports describe the liquefaction of the vitreous body with increasing age. It must be expected that this process also influences drug distribution and elimination following intravitreal application of active pharmaceutical ingredients (APIs). To better understand the impact and extent of the liquefaction a magnetic resonance imaging (MRI) study was performed examining human donor eyes post mortem. For comparison, eyes of juvenile pigs were also examined representing a fully gelled vitreous. 7.1Tesla ultra-high field MRI and T2 mapping of the vitreous body were used in this study since it must be expected that age-induced degradation processes and structural changes of the vitreous gel to a liquid state will result in changes of the T2 relaxation time of water proton spins. The vitreous bodies were imaged in 12 axial slices and within each image the T2 relaxation times of water proton spins were determined. It was found that T2 relaxation time increased with increasing age of the donor. Whilst the mean T2 relaxation time (±standard deviation) of water proton spins within the central vitreous body of a juvenile porcine eye was 210.1 ± 31.1 ms, the mean T2 relaxation time within the central vitreous body of the 88-year-old and therefore oldest human donor was 528.0 ± 79.3 ms. Within the vitreous body of a single donor, the T2 relaxation time increased from the anterior to the posterior segment, for example in the vitreous body of the oldest human donor from 388.0 ± 31.1 ms on average in the anterior to 631.7 ± 42.8 ms in the posterior segment, indicating an increase in intravitreal liquefaction respectively inhomogeneity from anterior to posterior regions. Additionally, physicochemical parameters were determined yielding averages of 7.54 ± 0.34 for pH, 1.33629 ± 0.00044 for refractive index, 368.99 ± 26.87 mosmol/kg for osmolality, 97.56 ± 0.43% for drying mass loss and 0.73 ± 0.18 mg/mL for total protein content. The aging process and the liquefaction of the vitreous body are expected to affect the pharmacokinetic profile of intravitreally injected APIs, which is of high relevance to drug release from intravitreal drug delivery systems and the therapeutic concept in the treatment of posterior segment diseases. Our data indicate that such processes are not reflected in animal models. Since there is still a need for valid pharmacokinetic data, invitro test systems for the characterization of intraocular drug delivery systems have to be improved according to the current state of knowledge about the vitreous structure and intravitreal transport phenomena., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ready-to-fill enteric hard capsule shells are an evolving field of oral drug and nutraceutical products. Lonza Capsugel® Enprotect® capsules were recently proven to provide reliable release in the small intestine after fasted intake, but robustness against postprandial intake needed to be proven. In this study, the capsules were administered to 16 healthy young subjects after intake of a light meal. The Enprotect® capsules were labelled with 5 mg black iron oxide and 25 mg 13C3-caffeine. Magnetic Resonance Imaging was used to identify the localization and visual dispersion of the capsule filling. The salivary appearance of caffeine was considered a second independent and sensitive marker for the initial release. Whereas the fasted gastric residence time of the capsules amounted to 43 ± 32 min, it was increased to 158 ± 36 min after postprandial intake. Therefore, the mean dispersion time according to MRI and the mean caffeine appearance time were increased to 196 ± 37 min and 189 ± 37 min, respectively. But, similar to fasted administration, no capsule disintegration or leakage was observed in the stomach and 38% of the capsules disintegrated in the jejunum and 62% in the ileum. The mean dispersion time after gastric emptying and the mean caffeine appearance time after gastric emptying amounted to 38 ± 21 min and 31 ± 17 min, respectively. Both did not relevantly change compared to the fasted intake. Only the absolute dispersion time and caffeine appearance were prolonged due to the increased gastric residence and no relevant influence of the light meal was observed on the disintegration or release behavior of Enprotect® capsules after gastric emptying. The capsules also showed robust enteric properties after postprandial administration. [ABSTRACT FROM AUTHOR]

[Display omitted] Gastrointestinal fluid volumes are a crucial parameter for dissolution and absorption of orally taken medications. Most often 240 mL are used in clinical standard setups. Nonetheless, surveys in patient populations revealed dramatically lower volumes for intake of oral medications in real life and even in some clinical studies reduced fluid volumes are common. These reductions might have serious impact on pharmacokinetics. Thus, it was the aim of this study to compare the gastric emptying of 240 mL and 20 mL of water in 8 healthy volunteers. For investigation of gastric fluid volumes Magnetic Resonance Imaging with strongly T2 weighted sequences was used. Gastric emptying was additionally quantified via caffeine pharmacokinetics measured in saliva. The absolute gastric volumes after intake of 240 mL or 20 mL obviously differed by factor 10 but relative gastric emptying expressed as fraction per time was nearly comparable. Only slighter slower emptying after intake of 20 mL was observed. Salivary caffeine pharmacokinetics representing mass transfer from stomach to small intestine after intake of different volumes did not differ. The absorbed caffeine fraction and emptied gastric volume fraction correlated well after intake of 240 mL, but not after intake of 20 mL, indicating a higher influence of secretion on gastric volume measurements after intake of smaller volumes. Relative gastric emptying as measured with MRI and salivary caffeine method was only slightly delayed, thus transfer of orally administered drug fraction could be comparable even with lower fluid intake as can be seen by comparable caffeine pharmacokinetics. Nonetheless, the considerably reduced volumes might interfere with dissolution and absorption. [ABSTRACT FROM AUTHOR]

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced. In this work, we investigated if the in vitro effective approach of viscosity enhancement of the vehicle used to prepare suspensions of amorphous solid dispersions could reduce the pharmacobezoar formation potential following repeated daily oral dosing to rats as well. The dose level of 2400 mg/kg/day used in the main study was determined in a dose finding study carried out in advance. In the dose finding study, MRI investigations were carried out at short time intervals to gain insights into the process of pharmacobezoar formation. Whereas MRI investigations underlined the importance of the forestomach for the formation of pharmacobezoars, viscosity enhancement of the vehicle reduced the incidence of pharmacobezoars, delayed the onset of pharmacobezoar formation and reduced the overall mass of pharmacobezoars found at necropsy. [ABSTRACT FROM AUTHOR]

The characterization of intravitreal dosage forms with regard to their behavior in vivo is usually explored in preclinical development through animal studies. In vitro vitreous substitutes (VS) to simulate the vitreous body for preclinical investigations have so far been insufficiently studied. To determine a distribution or concentration in the mostly gel-like VS, extraction of the gels is required in many cases. This destroys the gels, which makes a continuous investigation of the distribution impossible. In this work, the distribution of a contrast agent in hyaluronic acid agar gels and polyacrylamide gels was studied by magnetic resonance imaging and compared with the distribution in ex vivo porcine vitreous. The porcine vitreous served as a surrogate for human vitreous since both are similar in their physicochemical properties. It was shown that both gels do not completely represent the porcine vitreous body, but the distribution in the polyacrylamide gel is similar to that in the porcine vitreous body. In contrast, the distribution throughout the hyaluronic acid agar gel is much faster. It was also shown that anatomical features such as the lens and the interfacial tension to the anterior eye chamber could have an influence on the distribution that is difficult to reproduce using in vitro VS. However, with the presented method, new in vitro VS can be investigated continuously without destruction in the future, and thus their suitability as a substitute for the human vitreous can be verified. [ABSTRACT FROM AUTHOR]

Gastric water emptying as a critical parameter for oral drug absorption can be investigated by several imaging techniques or by the interpretation of pharmacokinetics of appropriate substances. Recently introduced salivary caffeine kinetics is a valuable tool, but the required caffeine abstinence limits its applicability. To avoid the caffeine abstinence, stable isotope-labeled caffeine might be used, but the representability and transferability of kinetics for evaluation of gastric emptying must be demonstrated. Thus, salivary caffeine pharmacokinetics were compared for naturally occurring 12C-caffeine and 13C3-caffeine after the administration of water under fasting conditions in six healthy young subjects. For this purpose, an ice capsule containing the two caffeine species was administered with 50 mL tap water. Gastric water emptying was simultaneously quantified using magnetic resonance imaging (MRI). Gastric emptying of 50 mL of water could be successfully evaluated. The salivary caffeine kinetics of 13C3- and 12C-caffeine were nearly congruent and showed good linear correlations in all subjects, with a mean correlation coefficient of 0.96 in pooled data. Thus, the substitution of natural 12C caffeine with stable isotope-labeled 13C3-caffeine offers the opportunity for broader application of the salivary caffeine gastric emptying technique and increases the robustness of the method against environmental contamination with caffeine. [ABSTRACT FROM AUTHOR]

Abstract The application areas of hard capsules are currently widened by the introduction of acid-resistant capsule shells. In this study, the gastrointestinal behavior of acid-resistant hard capsule formulations as well as the influence of their density on the gastric residence time were characterized using magnetic resonance imaging (MRI). As labeling material for a reliable identification of the capsules in the MR images, small pieces of dried pineapple were used as they provide a high T1 signal. Tested products were DRcaps™ as capsule in capsule (Cap-in-Cap) system (outer capsule size 00). For the investigation of the influence of the capsule density on the gastric residence time, a floating low-density Cap-in-Cap capsule formulation and a sinking high-density Cap-in-Cap capsule formulation were investigated. The study was performed in eight healthy human subjects under fasting conditions. Besides the transit data of the capsule systems, the intraluminal fluid volume kinetics were determined using T2 weighted sequences. The gastric emptying times of the systems did not differ, with mean values of 45 ± 35 min for floating DRcaps™ and 36 ± 18 min for the sinking DRcaps™. The difference in density had no remarkable influence on gastric emptying. Thus, the concept of floating capabilities for gastroretentive dosage forms seems rather implausible. Furthermore, this assures transferability of common knowledge about dosage form transit for estimation of the performance of acid-resistant capsule shells, which most typically float. The mean disintegration times amounted to 139 ± 35 min for the floating DRcaps™ Cap-in-Cap and 163 ± 55 min for the sinking DRcaps™ Cap-in-Cap. In only one case, a sinking DRcaps™ Cap-in-Cap system disintegrated during gastric emptying, but all other capsules disintegrated in the small intestine, irrespective of their gastric residence time. The use of dried pineapple as labeling material could be successfully demonstrated as a reliable and easy method for the tracking of the transit and disintegration behavior of orally administered drug delivery systems, leading to a thorough understanding of their in vivo performance. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The amount and composition of gastrointestinal media are crucial parameters in oral drug delivery. In fasted state, variable residual gastric volumes and gastric emptying behavior often cause variable drug release and absorption from oral drug products. Unfortunately, interindividual and intraindividual variability of the gastric conditions in fasted state are currently insufficiently mapped. In this work, datasets from 5 MRI studies with 16 treatments in total were pooled. The interindividual and intraindividual variability of residual gastric volumes after 10 h overnight fasting and the subsequent emptying of 240 mL of water were compared in healthy human subjects under conditions mimicking clinical studies. This work shows that even under standardized clinical conditions, residual gastric volumes and water emptying are highly variable. Interestingly, interindividual and intraindividual variabilities of both parameters were comparable, suggesting that the variability within the studies was mainly resulting from intraindividual day-to-day variations. The mean resting volumes in all conducted investigations amounted to 25 ± 18 mL (n = 120). Furthermore, 85 ± 13% (n = 22) of initially available gastric volume (resting volume plus 240 mL) was emptied after 30 min. The findings of this work will hopefully contribute to a better comprehension of the variability of oral drug release and absorption. [ABSTRACT FROM AUTHOR]

Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions. [ABSTRACT FROM AUTHOR]

[Display omitted] The transit and distribution pattern of fluids in the small intestine is a key parameter for the dissolution and absorption of drugs. Although some information is known about the small intestinal water content after administration of fluid volumes and meals, the intestinal transit of orally ingested fluids and solutions has been barely investigated. The aim of this three-arm, cross-over, 9-subject human study was to investigate the transit of orally ingested water in the small intestine under fasting and postprandial conditions using MRI. To identify the ingested water, manganese gluconate, which can be identified with T1-weighted MRI sequences, was added as a marker. Using Horos (DICOM software), quantification of the distribution of Mn2+ ions in the gastrointestinal tract in fasted versus fed state (standard meal by FDA guidance and a light meal) was possible. The distribution and approximate wetted intestinal length was very similar in the fasting and postprandial states, suggesting rapid transport of water ingested after a meal through the chyme-filled small intestine in continuation of the "Magenstrasse" (stomach road). In some subjects, manganese gluconate reached deeper parts of the small intestine even more quickly in the postprandial state than in the fasting arm of the study. A deeper understanding of the behaviour of solutes in the gastrointestinal tract is fundamental to a mechanistic explanation for the kinetic interaction between food and drug intake (food effects). [ABSTRACT FROM AUTHOR]

Saliva is an attractive sampling matrix for measuring various endogenous and exogeneous substances but requires sample treatment prior to chromatographic analysis. Exploiting supercritical CO2 for both extraction and chromatography simplifies sample preparation, reduces organic solvent consumption, and minimizes exposure to potentially infectious samples, but has not yet been applied to oral fluid. Here, we demonstrate the feasibility and benefits of online supercritical fluid extraction coupled to supercritical fluid chromatography and single‐quadrupole mass spectrometry for monitoring the model salivary tracer caffeine. A comparison of 13C‐ and 32S‐labeled internal standards with external standard calibration confirmed the superiority of stable isotope‐labeled caffeine over nonanalogous internal standards. As proof of concept, the validated method was applied to saliva from a magnetic resonance imaging study of gastric emptying. After administration of 35 mg caffeine via ice capsule, salivary levels correlated with magnetic resonance imaging data, corroborating caffeine's usefulness as tracer of gastric emptying (R2 = 0.945). In contrast to off‐line methods, online quantification required only minute amounts of organic solvents and a single manual operation prior to online bioanalysis of saliva, thus demonstrating the usefulness of CO2‐based extraction and separation techniques for potentially infective biomatrices. [ABSTRACT FROM AUTHOR]

Improving our knowledge about human gastrointestinal physiology and its impact on oral drug delivery is crucial for the development of new therapies and effective drug delivery systems. The aim of this study was to develop an in vivo tool to determine gastric emptying of water by administration of a caffeine as a tracer substance followed by subsequent saliva caffeine analysis. For this purpose, 35 mg of caffeine were given to six healthy volunteers after a 10 h overnight together with 240 mL of tap water either on a fasted stomach or 30 min after the high-caloric, high-fat breakfast recommended for bioavailability/bioequivalence (BA/BE) studies. Caffeine was administered in form of an ice capsule in order to omit the contamination of the oral cavity with caffeine. Parallel to saliva sampling, magnetic resonance imaging (MRI) was applied in order to validate this novel approach. After administration of the ice capsule, MRI measurements were performed every 2 min for the first 20 min followed by further measurements after 25, 30, 35, 40, 50 and 60 min. Saliva samples were collected always 1 min after the MRI measurement in supine position in the MRI scanner and continued for further 240 min. The caffeine concentration in saliva was quantified after liquid-liquid extraction by a validated HPLC/MS-MS method. The obtained MRI data revealed a fast emptying of the co-administered water within 10 to 50 min in the fasted state and likewise in the fed state. Salivary caffeine kinetics showed a C max from 150 to 400 ng/mL with a t max from 20 to 90 min. MRI data were normalized by setting the maximum emptied volume to 100% and the salivary caffeine kinetics were normalized by setting C max to 100%. In order to compare the results obtained by the MRI and the saliva method, the normalized data for each volunteer was correlated based on a linear regression. In the fasted state the mean slope for six comparisons was 0.9114 ± 0.1500 and the mean correlation coefficient was 0.912 ± 0.055. In the fed state, a mean slope of 0.8326 ± 0.1630 and a mean correlation coefficient of 0.887 ± 0.047 were obtained. Based on these results, we could show that salivary caffeine concentrations are suitable to describe the emptying of water as a non-caloric liquid from the fasted and the fed stomach. The presented technique provides a straight-forward, inexpensive and noninvasive method to assess gastric emptying of hydrophilic liquids, which can be broadly used in oral biopharmaceutics. Possible applications are the characterization of real-life conditions, specific populations (e.g. elderly people) and the better understanding of the contribution of gastric emptying to pharmacokinetic profiles of orally administered drugs. [ABSTRACT FROM AUTHOR]