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Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. To foster the translation of PROTACs into the clinics it is of high importance to establish sensitive bioanalytical methods that enable the assessment of absorption, bioavailability, and disposition of PROTACs after oral dosing. In this study, two highly sensitive LC-MS/MS methods (LLOQ = 0.5â¯ng/mL) were developed and validated for the quantification of bavdeglutamide (ARV-110) and vepdegestrant (ARV-471) in rat plasma. Plasma samples were processed by protein precipitation and separated on a C18 column over a gradient of acetonitrile and water with 0.1â¯% formic acid. Selected reaction monitoring in positive ESI mode was applied to quantify ARV-110 and ARV-471. Both methods showed linearity, accuracy, and precision as well as matrix effects and carry-over within the predefined acceptance criteria. High stability of the compounds in plasma was demonstrated at long-term storage for seven weeks at -20 °C, three freeze-thaw cycles, up to 20â¯min at room temperature, and as extracts in the autosampler. The plasma concentration-time curves after intravenous and intraduodenal bolus single-dose administrations in rats could be successfully quantified at clinically relevant doses per body weight. The highly sensitive bioanalytical assays presented in this work enable the application of a broad spectrum of in vivo studies to elucidate the oral absorption, bioavailability, and disposition of PROTACs.
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Disponibilidad Biológica , Cromatografía Líquida con Espectrometría de Masas , Quimera Dirigida a la Proteólisis , Proteolisis , Espectrometría de Masas en Tándem , Animales , Masculino , Ratas , Administración Oral , Cromatografía Liquida/métodos , Estabilidad de Medicamentos , Cromatografía Líquida con Espectrometría de Masas/métodos , Quimera Dirigida a la Proteólisis/administración & dosificación , Quimera Dirigida a la Proteólisis/química , Quimera Dirigida a la Proteólisis/farmacocinética , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
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, tmax 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.
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Cafeína , Preparaciones de Acción Retardada , Comprimidos , Humanos , Cafeína/administración & dosificación , Cafeína/farmacocinética , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Masculino , Adulto , Adulto Joven , Femenino , Ayuno , Administración Oral , Saliva/metabolismo , Saliva/química , Voluntarios Sanos , Mucosa Gástrica/metabolismo , Estudios Cruzados , Estómago/efectos de los fármacosRESUMEN
Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed.
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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.
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Cafeína , Vaciamiento Gástrico , Humanos , Agua , Estómago , Imagen por Resonancia Magnética/métodosRESUMEN
Food-drug interactions frequently hamper oral drug development due to various physicochemical, physiological and formulation-dependent mechanisms. This has stimulated the development of a range of promising biopharmaceutical assessment tools which, however, lack standardized settings and protocols. Hence, this manuscript aims to provide an overview of the general approach and the methodology used in food effect assessment and prediction. For in vitro dissolution-based predictions, the expected food effect mechanism should be carefully considered when selecting the level of complexity of the model, together with its drawbacks and advantages. Typically, in vitro dissolution profiles are then incorporated into physiologically based pharmacokinetic models, which can estimate the impact of food-drug interactions on bioavailability within 2-fold prediction error, at least. Positive food effects related to drug solubilization in the GI tract are easier to predict than negative food effects. Preclinical animal models also provide a good level of food effect prediction, with beagle dogs remaining the gold standard. When solubility-related food-drug interactions have large clinical impact, advanced formulation approaches can be used to improve fasted state pharmacokinetics, hence decreasing the fasted/fed difference in oral bioavailability. Finally, the knowledge from all studies should be combined to secure regulatory approval of the labelling instructions.
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Absorción Intestinal , Modelos Biológicos , Animales , Perros , Absorción Intestinal/fisiología , Disponibilidad Biológica , Modelos Animales , Desarrollo de Medicamentos , Administración Oral , Solubilidad , Interacciones Alimento-DrogaRESUMEN
Amorphous solid dispersions (ASD) have been a successful formulation strategy to overcome the poor aqueous solubility of many novel drugs, but the development of pediatric formulations presents a special challenge due to variable gastrointestinal conditions in children. It was the aim of this work to design and apply a staged biopharmaceutical test protocol for the in vitro assessment of ASD-based pediatric formulations. Ritonavir was used as a model drug with poor aqueous solubility. Based on the commercial ASD powder formulation, a mini-tablet and a conventional tablet formulation were prepared. Drug release from the three formulations was studied in different biorelevant in vitro assays (i.e. MicroDiss, two-stage, transfer model, tiny-TIM) to consider different aspects of human GI physiology. Data from the two-stage and transfer model tests indicated that by controlled disintegration and dissolution excessive primary precipitation can be prevented. However, this advantage of the mini-tablet and tablet formulation did not translate into better performance in tiny-TIM. Here, the in vitro bioaccessibility was comparable for all three formulations. In the future, the staged biopharmaceutical action plan established herein will support the development of ASD-based pediatric formulations by improving the mechanistic understanding so that formulations are developed for which drug release is robust against variable physiological conditions.
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Ritonavir , Humanos , Niño , Liberación de Fármacos , Solubilidad , Comprimidos , Administración OralRESUMEN
The poor solubility and permeability of compounds beyond Lipinski's Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established a robust mucin-protected Caco-2 assay to allow the assessment of drug permeation in complex biorelevant media. To do that, the assay conditions were first optimized with dependence of the concentration of porcine mucin added to the cells. Mucin-specific effects on drug permeability were evaluated by analyzing cell permeability values for 15 reference drugs (BCS class I-IV). Secondly, a sigmoidal relationship between mucin-dependent permeability and fraction absorbed in human (fa) was established. A case study with venetoclax (BCS class IV) was performed to investigate the impact of medium complexity and the prandial state on drug permeation. Luminal fluids obtained from the tiny-TIM system showed a higher solubilization capacity for venetoclax, and a better read-out for the drug permeability, as compared to FaSSIF or FeSSIF media. In conclusion, the mucin-protected Caco-2 assay combined with biorelevant media improves the mechanistic understanding of drug permeation and addresses complex biopharmaceutical questions, such as food effects on oral drug absorption.
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Drug absorption following oral administration is determined by complex and dynamic interactions between gastrointestinal (GI) physiology, the drug, and its formulation. Since many of these interactions are not fully understood, the COST action on "Understanding Gastrointestinal Absorption-related Processes (UNGAP)" was initiated in 2017, with the aim to improve the current comprehension of intestinal drug absorption and foster future developments in this field. In this regard, in vivo techniques used for the characterization of human GI physiology and the intraluminal behavior of orally administered dosage forms in the GI tract are fundamental to gaining deeper mechanistic understanding of the interplay between human GI physiology and drug product performance. In this review, the potential applications, advantages, and limitations of the most important in vivo techniques relevant to oral biopharmaceutics are presented from the perspectives of different research fields.
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The increasing number of poorly water-soluble compounds in drug development is one of the major challenges in oral drug delivery nowadays. For rational formulation development, biopharmaceutical tools are needed that closely simulate the conditions present within the human gastrointestinal (GI) tract in order to early predict the potential effect of important factors like meal intake or acid-reducing agents on oral bioavailability. The tiny-TIM system equipped with the advanced gastric compartment is one of the most realistic in vitro models for the simulation of the physiological processes occurring in human stomach and small intestine. In the present study, this model was applied to study the in vitro performance of an ASD-based formulation of itraconazole under different clinically relevant conditions. Apart from the assessment of the bioaccessible fraction (i.e., the fraction available for drug absorption), the implementation of two additional sampling ports enabled the measurement of intraluminal concentration profiles. Along with solubility experiments in biorelevant media, deeper mechanistic insights into drug product performance in different prandial states as well as in case of gastric pH modification could be generated. The comparison of the in vitro data with published in vivo data revealed that the model successfully predicted the effect of food intake as well as of modified gastric pH conditions on the bioavailability of itraconazole from this formulation. In contrast, the negative food effect observed for an oral solution formulation could not be predicted. For this cyclodextrin-based formulation, the formulation effect on permeation needs to be considered. Nonetheless, the data presented in this study showed that tiny-TIM is an interesting tool to mechanistically study the impact of different physiological conditions on drug release from oral drug products.
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Itraconazol , Modelos Biológicos , Administración Oral , Humanos , Absorción Intestinal , Preparaciones Farmacéuticas/química , SolubilidadRESUMEN
This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.
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COVID-19 , Tracto Gastrointestinal , Administración Oral , Simulación por Computador , Absorción Gastrointestinal/fisiología , Tracto Gastrointestinal/metabolismo , Humanos , Absorción Intestinal , Masculino , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , SolubilidadRESUMEN
More than 50 years ago, the first gastroretentive dosage forms came up. Since then, no practical and at the same time reliable gastroretentive system is available on market. A major obstacle in the development of novel gastroretentive systems is the lack of proper predictive test methods. In the present work, we aimed at developing and fully characterizing an expandable gastroretentive system containing furosemide as model drug. On the one hand, we used well-established in vitro tests for drug dissolution and gastroretentive properties (paddle apparatus, swelling characteristics). On the other hand, we used two novel models (dissolution stress test device, mechanical antrum model) to assess these properties under biorelevant conditions. Moreover, we performed an in vivo study under fed and fasted conditions that combined blood sampling and a high-resolution imaging technique (magnetic marker monitoring) to determine gastrointestinal location with the assessment of a pharmacodynamic endpoint (urinary sodium excretion). In vitro dissolution tests confirmed prolonged drug release over more than 8 h independent from pH and with slight pressure sensitivity. Swelling studies indicated good swelling behavior within 4 h along with medium gastroretentive properties as determined with the mechanical antrum model. In vivo imaging showed prolonged gastric residence time after fed compared to fasted administration (481 min vs 38 min). Comparison of geometric means of AUCo-tlast of the model drug confirmed this observation with 10 times higher value after fed administration. Urinary excretion of sodium well reflected the increased sodium-reuptake inhibition due to higher furosemide exposure under fed conditions. However, the poor performance after fasted intake of the system is in line with data from several other gastroretentive formulations. The present study highlighted the value of novel test methods during the development of gastroretentive formulations. Yet, a system with reproducible gastroretentive properties especially under fasted conditions has to be designed.
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Furosemida , Estómago , Liberación de Fármacos , Ayuno , Solubilidad , Estómago/diagnóstico por imagenRESUMEN
Ingestible sensor systems are unique tools for obtaining physiological data from an undisturbed gastrointestinal tract. Since their dimensions correspond to monolithic oral dosage forms, such as enteric coated tablets or hydrogel matrix tablets, they also allow insights into the physiological conditions experienced by non-disintegrating dosage forms on their way through the gastrointestinal tract. In this work, the different ingestible sensor systems which can be used for this purpose are described and their potential applications as well as difficulties and pitfalls with respect to their use are presented. It is also highlighted how the data on transit times, pH, temperature and pressure as well as the data from different animal models commonly used in drug product development such as dogs and pigs have contributed to a deeper mechanistic understanding of oral drug delivery.
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Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos/métodos , Tracto Gastrointestinal/metabolismo , Administración Oral , Animales , Biofarmacia , Perros , Diseño de Equipo , Tránsito Gastrointestinal/fisiología , Humanos , Concentración de Iones de Hidrógeno , Porcinos , Comprimidos , TemperaturaRESUMEN
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
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Absorción Intestinal , Preparaciones Farmacéuticas , Administración Oral , Anciano , Niño , Femenino , Interacciones Alimento-Droga , Tracto Gastrointestinal/metabolismo , Humanos , Masculino , Preparaciones Farmacéuticas/metabolismo , FarmacocinéticaRESUMEN
Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
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Tracto Gastrointestinal/metabolismo , Absorción Intestinal , Administración Oral , Animales , Simulación por Computador , Composición de Medicamentos , Interacciones Alimento-Droga , Humanos , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismoRESUMEN
Infections with Helicobacter pylori are a global challenge. Currently, H. pylori infections are treated systemically, but the eradication rates of the different therapy regimens are declining due to the growing number of bacterial strains resistant to major antibiotics. Here, we present a strategy for the local eradication of H. pylori by the use of Penicillin G sodium (PGS). In vitro experiments revealed that PGS shows high antibiotic activity against resistant strains of Helicobacter pylori with a minimum inhibitory concentration (MIC) of 0.125 µg/ml. In order to provide luminal concentrations above the MIC for longer periods of time, an extended release tablet was developed. Alkalizers were included to prevent acidic degradation of PGS within the tablet matrix. Out of the tested alkalizers MgO, l-Lysine, NaHCO3, and Na2CO3 NaHCO3 provided the strongest rise in pH inside the hydrated matrix when tested in simulated gastric fluid. Better PGS stability can mainly reasoned from that, addition of MgO resulted in high pH values within the matrix, causing basic degradation of PGS. This work is a first step towards the use of extended release tablets containing PGS for the local treatment of H. pylori as a safe and cost-effective alternative to common systemic treatment regimens.
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Infecciones por Helicobacter , Helicobacter pylori , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
Within preclinical research, the pig has become an important model in regulatory toxicology and pharmacokinetics, to assess oral dosage forms and to compare different formulation strategies. In addition, there are emerging application of the pig model to asses clinical dosing conditions in the fasted and fed state. In this study, the gastrointestinal transit conditions in male landrace pigs were studied with a telemetric motility capsule under fasted and postprandial conditions. The whole gut transit time (WGTT) was determined by administering a SmartPill® capsule to four landrace pigs, under both fasted and fed state conditions in a cross-over study design. Overall, this study found that small intestinal transit in landrace pigs ranged from 2.3 - 4.0 h, and was broadly similar to reported human estimates and was not affected by the intake conditions. Gastric emptying was highly variable and prolonged in landrace pigs ranging from 20 - 233 h and up to 264 h in one specific case. Under dynamic conditions pigs have a low gastric pH comparable to humans, however a high variability under fasted conditions could be observed. The comparison of the data from this study with a recent similar study in beagle dogs revealed major differences between gastric maximum pressures observed in landrace pigs and dogs. In the porcine stomach maximum pressures of up to 402 mbar were observed, which are comparable to reported human data. Intestinal maximum pressures in landrace pigs were in the same range as in humans. Overall, the study provides new insights of gastrointestinal conditions in landrace pigs, which can lead to more accurate interpretation of in vivo results obtained of pharmacokinetic studies in preclinical models. While small intestinal transit conditions, GI pH and pressures were similar to humans, the prolonged gastric emptying observed in pigs need to be considered in assessing the suitability of the pig model for assessing in vivo performance of large non-disintegrated oral drug products.
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Vaciamiento Gástrico , Tránsito Gastrointestinal , Animales , Estudios Cruzados , Digestión , Perros , Motilidad Gastrointestinal , Masculino , Porcinos , TelemetríaRESUMEN
This workshop report summarizes the proceedings of Day 1 of a three-day workshop on "Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls". Physiologically based biopharmaceutics models (PBBM) are tools which enable the drug product quality attributes to be linked to the in vivo performance. These tools rely on key quality inputs in order to provide reliable predictions. After introducing the objectives of the workshop and the expectations from the breakout sessions, Day 1 of the workshop focused on the best practices and challenges in measuring in vitro inputs needed for modeling, such as the drug solubility, the dissolution rate of the drug product, potential precipitation of the drug and drug permeability. This paper reports the podium presentations and summarizes breakout session discussions related to A) the best strategies for determining solubility, supersaturation and critical supersaturation; B) the best strategies for the development of biopredictive (clinically relevant) dissolution methods; C) the challenges associated with describing gastro-intestinal systems parameters such as mucus, liquid volume and motility; and D) the challenges with translating biopharmaceutical measures of drug permeability along the gastrointestinal tract to a meaningful model parameter.
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Modelos Biológicos , Informe de Investigación , Administración Oral , Biofarmacia , Desarrollo de Medicamentos , Absorción Intestinal , SolubilidadRESUMEN
The process of gastric emptying is of major importance for the in vivo performance of immediate release dosage forms. In the fed state, this process consists of two phases: the rapid emptying of water along the "Magenstrasse" and the continuous emptying of the chyme. The relevance of these phases for the pharmacokinetic (PK) profile of a drug depends on the release behavior from its dosage form. It was the aim of this study to investigate the role of gastric emptying for the pharmacokinetics of a fast disintegrating and dissolving Aspirin® tablet (FDDT). For this purpose, a three way pharmacokinetic study with 30 healthy volunteers was performed to investigate the performance of the FDDT under fasted and fed conditions and compare it to a regular Aspirin® tablet (RT) administered in the fed state. Plasma samples were taken at predetermined time points and analyzed by LC MS/MS. In the second part of this work, both products were tested in a biorelevant dissolution test device - the GastroDuo. To simulate the occurrence of the Magenstrasse at different time points, two test programs have been applied. The results of the PK study clearly demonstrated the superiority of the FDDT over the RT. We observed an earlier tmax (0.39 h vs. 2.00 h) and a higher Cmax (6.33 ± 2.37 µg/mL vs. 3.23 ± 1.28 µg/mL), whereas the AUC was only slightly different between both formulations. The administration of the FDDT together with food had no marked effect on tmax (0.34 h vs. 0.39 h), but caused a decrease in Cmax compared to fasted intake (14.76 ± 4.81 µg/mL vs. 6.33 ± 2.37 µg/mL). This effect could be explained by the in vitro data collected with the GastroDuo. The FDDT showed a faster drug release and improved emptying kinetics in the GastroDuo. In contrast, the RT showed incomplete emptying in both test programs. Thus, the early tmax observed for the FDDT under fed conditions could be related to the presence of the Magenstrasse. In contrast, drug release from the RT was insufficient to allow gastric emptying via the Magenstrasse, which resulted in later tmax. This study highlighted the importance of gastric emptying for immediate release dosage forms and illustrated that the application of suitable formulation techniques provides a strategy to generate a fast and reliable onset of drug plasma concentrations even in the fed state.
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Aspirina/farmacocinética , Liberación de Fármacos/fisiología , Vaciamiento Gástrico/fisiología , Estómago/fisiología , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Ayuno/metabolismo , Ayuno/fisiología , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad , Solubilidad , Comprimidos/farmacocinética , Equivalencia Terapéutica , Adulto JovenRESUMEN
The fasted state administration of immediate release (IR) dosage forms is often regarded as uncritical since physiological aspects seem to play a minor role for disintegration and drug release. However, recent in vivo studies in humans have highlighted that fasted state conditions are in fact highly dynamic. It was therefore the aim of this study to investigate the disintegration and drug release behavior of four different IR formulations of the probe drug caffeine under physiologically relevant conditions with the aid of the GastroDuo. One film-coated tablet and three different capsule formulations based on capsule shells either made from hard gelatin or hydroxypropylmethyl cellulose (HPMC) were tested in six different test programs. To evaluate the relevance of the data generated, the four IR formulations were also studied in a four-way cross-over study in 14 healthy volunteers by using the salivary tracer technique (STT). It could be shown that the IR formulations behaved differently in the in vitro test programs. Thereby, the simulated parameters affected the disintegration and dissolution behavior of the four IR formulations in different ways. Whereas drug release from the tablet started early and was barely affected by temperature, pH or motility, the different capsule formulations showed a longer lag time and were sensitive to specific parameters. However, once drug release was initiated, it typically progressed with a higher rate for the capsules compared to the tablet. Interestingly, the results obtained with the STT were not always in line with the in vitro data. This observation was due to the fact that the probability of the different test programs was not equal and that certain scenarios were rather unlikely to occur under the controlled and standardized conditions of clinical studies. Nonetheless, the in vitro data are still valuable as they allowed to discriminate between different formulations.
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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.