RESUMEN
In the postprandial stomach, processes such as secretion, digestion, and gastric emptying all occur simultaneously. Therefore, the system is highly heterogeneous and dynamically changing, for instance, in terms of various physicochemical parameters such as pH value or viscosity. Thus, the administration of a drug together with food can result in highly variable drug plasma concentrations, which may affect the efficacy and safety of the pharmacotherapy. In this work, the pharmacokinetic (PK) data obtained from two fed-state bioequivalence studies with the immediate release (IR) drug products Viagra (sildenafil) and Adenuric (febuxostat) have been analyzed. This evaluation revealed that basically three characteristic types of onset behaviors of drug plasma concentration can be distinguished. It was hypothesized that the different types of onset behaviors were mainly caused by the interplay between gastric drug dissolution and gastric emptying. To study this interplay in vitro, a biopredictive dissolution tool-GastroDuo-was developed and used for both drug products. Therefore, three different test programs have been applied to simulate certain aspects of the postprandial human stomach, which included dynamic pH changes, gastric peristalsis, and the kinetics of gastric emptying. Specifically, the behavior of noncaloric fluids by the so-called "Magenstrasse" was taken into deeper consideration. The experiments revealed that the dissolution and emptying behavior of the two drug products were affected in different ways by the three test programs. The in vitro data nicely explained the tendencies of the drug products for certain types of onset behaviors observed in the PK data. While Viagra was strongly affected by simulated peristalsis, Adenuric was more sensitive to the simulated emptying kinetics. This work clearly demonstrated the important role of gastric fluid emptying for the onset of drug plasma concentration after oral administration of IR formulations in the fed state. Moreover, this was the first study in which GastroDuo was applied as a biopredictive in vitro model which is able to simulate crucial parameters of the human stomach (e.g., pH profiles and gastric emptying) in a realistic manner.
Asunto(s)
Vaciamiento Gástrico/fisiología , Periodo Posprandial/fisiología , Estómago/fisiología , Administración Oral , Adolescente , Adulto , Anciano , Disponibilidad Biológica , Liberación de Fármacos/fisiología , Febuxostat/metabolismo , Humanos , Cinética , Masculino , Persona de Mediana Edad , Citrato de Sildenafil/metabolismo , Solubilidad , Adulto JovenRESUMEN
The characterization of intestinal dissolution of poorly soluble drugs represents a key task during the development of both new drug candidates and drug products. The bicarbonate buffer is considered as the most biorelevant buffer for simulating intestinal conditions. However, because of its complex nature, being the volatility of CO2, it has only been rarely used in the past. The aim of this study was to investigate the effect of a biorelevant bicarbonate buffer on intestinal supersaturation and precipitation of poorly soluble drugs using a gastrointestinal (GI) transfer model. Therefore, the results of ketoconazole, pazopanib, and lapatinib transfer model experiments using FaSSIFbicarbonate were compared with the results obtained using standard FaSSIFphosphate. Additionally, the effect of hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor was investigated in both buffer systems and compared to rat pharmacokinetic (PK) studies with and without coadministration of HPMCAS as a precipitation inhibitor. While HPMCAS was found to be an effective precipitation inhibitor for all drugs in FaSSIFphosphate, the effect in FaSSIFbicarbonate was much less pronounced. The PK studies revealed that HPMCAS did not increase the exposure of any of the model compounds significantly, indicating that the transfer model employing bicarbonate-buffered FaSSIF has a better predictive power compared to the model using phosphate-buffered FaSSIF. Hence, the application of a bicarbonate buffer in a transfer model set-up represents a promising approach to increase the predictive power of this in vitrotool and to contribute to the development of drug substances and drug products in a more biorelevant way.
Asunto(s)
Bicarbonatos/química , Bicarbonatos/farmacología , Precipitación Química/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos/fisiología , Absorción Gastrointestinal/fisiología , Modelos Biológicos , Administración Oral , Animales , Tampones (Química) , Femenino , Tracto Gastrointestinal , Concentración de Iones de Hidrógeno , Indazoles , Cetoconazol/administración & dosificación , Cetoconazol/sangre , Cetoconazol/química , Cetoconazol/farmacocinética , Lapatinib/administración & dosificación , Lapatinib/sangre , Lapatinib/química , Lapatinib/farmacocinética , Metilcelulosa/análogos & derivados , Metilcelulosa/farmacología , Fosfatos/química , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Pirimidinas/química , Pirimidinas/farmacocinética , Ratas , Ratas Wistar , Solubilidad , Sulfonamidas/administración & dosificación , Sulfonamidas/sangre , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
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.
Asunto(s)
Cafeína/metabolismo , Cápsulas/metabolismo , Liberación de Fármacos , Gelatina/química , Imagen por Resonancia Magnética/métodos , Saliva/metabolismo , Administración Oral , Adulto , Cafeína/administración & dosificación , Femenino , Voluntarios Sanos , Humanos , Masculino , Adulto JovenRESUMEN
Grapefruit juice (GFJ) is known to affect the bioavailability of drugs in different ways. Despite the influence on gastrointestinal enzymes and transporters, the influence on gastrointestinal fluid kinetics is regarded to be relevant for the absorption of several drugs. Thus, it was the aim of this pilot study to investigate the gastric and intestinal volumes after intake of GFJ compared to isocaloric fructose and glucose solutions and water. The gastric and small intestinal volume kinetics after intake of 240 mL of GFJ, 10.6% fructose solution, 10.6% glucose solution, and water were investigated with magnetic resonance imaging in a four-way crossover study in six healthy human volunteers. The carbohydrate content of the administered beverages was quantified by high-performance liquid chromatography. Even with the small sample size of this pilot study, the gastric emptying of GFJ and the glucose solution was significantly slower than that of water. The fructose solution had only a slightly delayed gastric emptying. Small bowel water content was increased by administration of GFJ and fructose solution, whereas it was decreased by glucose compared to the administration of pure water. At 80 min the small bowel water content after GFJ was twice as high as the small bowel water content after administration of water. The observed influence of GFJ on gastrointestinal fluid kinetics may explain certain phenomena in drugs pharmacokinetics. The effect is double edged, as the slower gastric emptying and increased intestinal filling can lead to enhanced or altered absorption. Due to the comparability of fruit juices, a general effect of fruit juices on gastrointestinal volumes is likely.
Asunto(s)
Citrus paradisi , Interacciones Alimento-Droga , Jugos de Frutas y Vegetales , Vaciamiento Gástrico , Secreciones Intestinales/química , Adulto , Disponibilidad Biológica , Estudios Cruzados , Femenino , Fructosa/administración & dosificación , Glucosa/administración & dosificación , Voluntarios Sanos , Humanos , Intestino Delgado , Imagen por Resonancia Magnética , Masculino , Proyectos Piloto , Estómago/diagnóstico por imagen , Agua , Adulto JovenRESUMEN
Food effects on oral drug bioavailability can have significant impact on the provision of safe and reliable oral pharmacotherapy. A mechanistic understanding of the events that contribute to the occurrence of food effects is therefore critical. An increased oral bioavailability is often seen for poorly water-soluble drugs after co-administration with lipids, including lipids in food, and is commonly explained by the ability of lipids to enhance drug solubility in intestinal luminal fluids. In contrast, the impact of lipids on drug solubilisation in the stomach has received less attention. This is in spite of the fact that lipid digestion is initiated in the stomach by human gastric lipase and that gastric events also initiate emulsification of lipids in the gastrointestinal tract. The stomach therefore acts to 'pre-process' lipids for subsequent events in the intestine and may significantly affect downstream events at intestinal drug absorption sites. In this article, the mechanisms by which lipids are processed in the stomach are reviewed and the potential impact of these processes on drug absorption discussed. Attention is also focused on in vitro methods that are used to assess gastric processing of lipids and their application to better understand food effects on drug release and absorption.
Asunto(s)
Grasas de la Dieta/farmacología , Liberación de Fármacos/efectos de los fármacos , Interacciones Alimento-Droga , Absorción Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Administración Oral , Disponibilidad Biológica , Jugo Gástrico/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Lipasa/metabolismoRESUMEN
Food effects on oral drug bioavailability are a consequence of the complex interplay between drug, formulation and human gastrointestinal (GI) physiology. Accordingly, the prediction of the direction and the extent of food effects is often difficult. With respect to novel formulations, biorelevant in vitro methods can be extremely powerful tools to simulate the effect of food-induced changes on the physiological GI conditions on drug release and absorption. However, the selection of suitable in vitro methods should be based on a thorough understanding not only of human GI physiology but also of the drug and formulation properties. This review focuses on in vitro methods that can be applied to evaluate the effect of food intake on drug release from extended release (ER) products during preclinical formulation development. With the aid of different examples, it will be demonstrated that the combined and targeted use of various biorelevant in vitro methods can be extremely useful for understanding drug release from ER products in the fed state and to be able to forecast formulation-associated risks such as dose dumping in early stages of formulation development.
Asunto(s)
Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos/fisiología , Interacciones Alimento-Droga/fisiología , Tránsito Gastrointestinal/fisiología , Administración Oral , Animales , Disponibilidad Biológica , Preparaciones de Acción Retardada/administración & dosificación , Alimentos , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/fisiología , Tránsito Gastrointestinal/efectos de los fármacos , Humanos , SolubilidadRESUMEN
Despite extensive research in the field of gastroretentive dosage forms, this "holy grail" of oral drug delivery yet remained an unmet goal. Especially under fasting conditions, the reproducible retention of dosage forms in the stomach seems to be an impossible task. This is why such systems are often advised to be taken together with food. But also the postprandial motility can contribute significantly to the failure of gastroretentive dosage forms. To investigate the influence of postprandial pressure conditions on drug release from such systems, we used a novel in vitro dissolution tool, the dissolution stress test device. With the aid of this device, we simulated three different intragastric pressure profiles that may occur after postprandial intake. These transit scenarios were based on recently obtained, postprandial SmartPill® data. The tested systems, Glumetza® 1000 and Madopar® HBS 125, are marketed dosage forms that are based on different approaches to achieve proper gastric retention. All three transit scenarios revealed a highly pressure-sensitive drug release behavior, for both drugs. For Madopar® HBS 125, nearly complete drug release was observed even after early occurring pressures. Glumetza® 1000 seemed to be more resistant to these, most likely due to incomplete wetting of the system. On the contrary to these findings, data from standard dissolution tests using the paddle apparatus displayed controlled drug release for both systems for about 6 h. Based on these results, it can be doubted that established gastroretentive systems stay intact over a longer period of time, even under postprandial conditions.
Asunto(s)
Benserazida/farmacocinética , Liberación de Fármacos/fisiología , Levodopa/farmacocinética , Periodo Posprandial/fisiología , Estómago/fisiología , Benserazida/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/metabolismo , Formas de Dosificación , Combinación de Medicamentos , Sistemas de Liberación de Medicamentos/métodos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Ayuno/metabolismo , Humanos , Levodopa/administración & dosificación , Periodo Posprandial/efectos de los fármacos , Presión , Estómago/efectos de los fármacosRESUMEN
The Magenstrasse (stomach road) describes the fast emptying of ingested liquids from the postprandial stomach. The occurrence of the Magenstrasse has great importance for drugs administered together with food as it represents a shortcut through the fed stomach and allows rapid onset of plasma levels. In this study, we investigated the effect of different meals and their texture and fat content on the occurrence of the Magenstrasse. Since the administration of water is common 60 min after drug intake in clinical trials, we also investigated the effect of time point of water administration on the Magenstrasse by a second water administration. The texture of solid meals and a higher amount of solid food components turned out to favor the presence of the Magenstrasse. On the other hand, the effect of fat content of the meals was negligible. Additionally, the gastric emptying of water was comparable between the first and the second (60 min later) fluid administration, which could lead to an entrainment of drug substance. So far, the Magenstrasse is proven for water; an investigation of other liquid vehicles might be interesting for further mechanistic understanding and utilization. It turned out that the phenomenon of the Magenstrasse can also occur at later time points in clinical studies and may have great impact on the pharmacokinetic profiles obtained in these studies.
Asunto(s)
Ayuno/fisiología , Vaciamiento Gástrico/fisiología , Periodo Posprandial/fisiología , Estómago/fisiología , Agua/fisiología , Absorción Fisiológica , Adulto , Ensayos Clínicos como Asunto , Ingestión de Alimentos/fisiología , Femenino , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Estómago/diagnóstico por imagen , Factores de TiempoRESUMEN
The drug plasma profile after oral administration of immediate release dosage forms can be affected by the human gastrointestinal physiology, the formulation, and the drug itself. In this work, we investigated the in vivo and in vitro performance of two formulations (granules vs. tablet) containing the highly soluble drug N-Acetylcysteine (BCS class I). Thereby, special attention was paid to the effect of the dosage form and the coadministration of water on drug release. Interestingly, the in vivo results from a pharmacokinetic study with 11 healthy volunteers indicated that the drug plasma concentrations were comparable for the tablet given with water as well as for the granules given with and without water. In order to mechanistically understand this outcome, we used a biorelevant dissolution test device, the dynamic open flow-through test apparatus. With the aid of this test apparatus, we were able to simulate biorelevant parameters, such as gastric emptying, hydrodynamic flow as well as physical stress. By this, it was possible to mimic the intake conditions of the clinical trial (i.e., drug intake with and without water). Whereas the experiments in the USP paddle apparatus revealed differences between the two formulations, we could not observe significant differences in the release profiles of the two formulations by using the dynamic open flow-through test apparatus. Even by considering the different intake conditions, drug release was slow and amounted to around 30% until simulated gastric emptying. These results suggest that dissolution was irrespective of coadministered water and the formulation. Despite the high aqueous solubility of N-Acetylcysteine, the limiting factor for drug release was the slow dissolution rate in relation to the gastric emptying rate under simulated gastric conditions. Thus, in case of administration together with water, large amounts of the drug are still present in the stomach even after complete gastric emptying of the water. Consequently, the absorption of the drug is largely controlled by the nature of gastric emptying of the remaining drug. The data of this study indicated that the water emptying kinetics are only determining drug absorption if drug release is rapid enough. If this is not the case, physiological mechanisms, such as the migrating motor complex, play an important role for oral drug delivery.
Asunto(s)
Acetilcisteína/farmacocinética , Liberación de Fármacos , Vaciamiento Gástrico/fisiología , Técnicas In Vitro/instrumentación , Agua/fisiología , Absorción Fisiológica/fisiología , Acetilcisteína/administración & dosificación , Administración Oral , Adulto , Biofarmacia/instrumentación , Biofarmacia/métodos , Química Farmacéutica , Estudios Cruzados , Sistemas de Liberación de Medicamentos , Femenino , Interacciones Alimento-Droga/fisiología , Voluntarios Sanos , Humanos , Técnicas In Vitro/métodos , Masculino , Persona de Mediana Edad , Solubilidad , Comprimidos , Adulto JovenRESUMEN
The aim of this magnetic resonance imaging (MRI) study was to investigate gastric emptying after intake of a high-caloric and high-fat standard meal as recommended by FDA and EMA for food-effect bioavailability and fed bioequivalence studies. Twelve healthy human subjects (7 male, 5 female) received the standard meal after an overnight fast. MRI was performed before as well as 15, 25, 35, 45, 55, 65, 105, 195, 275, and 375 min after meal intake using strong T2-weighted sequences and chemical shift imaging. In addition, 30 min after the beginning of meal intake subjects ingested 240 mL of water representing the recommended coadministration of water during drug intake. Gastric content volume was assessed using T2-weighted images, and fat fraction was estimated using a calculation of fat fraction in chemical shift imaging. In addition, the existence of a mechanism allowing fast gastric emptying of water in the fed state was investigated. After a lag phase of 50-90 min, gastric content volume decreased constantly with a rate of 1.7 mL/min. The water ingested 30 min after the start of the meal intake directly reached the antrum and subsequently was emptied quickly from the human stomach. Complete gastric emptying within 6 h was observed in only one out of 12 subjects. The fat fraction of the intragastric chyme decreased from 9.5% directly after meal intake to 6.3% at the end of the experiments. Moreover, the fat fraction in fundus was significantly higher compared to the antrum. This study contributes fundamental data for the assessment of food effects of solid oral dosage forms.
Asunto(s)
Desayuno , Dieta Alta en Grasa , Estómago/fisiología , Adulto , Femenino , Vaciamiento Gástrico/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The aim of the present work was the investigation of robustness and reliability of drug release from 50 to 400 mg quetiapine extended release HPMC matrix tablets towards mechanical stresses of biorelevant intensity. The tests were performed under standard conditions (USP apparatus II) as well as under simulated gastrointestinal stress conditions. Mechanical stresses including pressure and agitation were applied by using the biorelevant dissolution stress test apparatus as it has been introduced recently. Test algorithms already established in previous studies were applied to simulate fasting gastrointestinal conditions. The dissolution experiments demonstrated striking differences in the product performance among standard and stress test conditions as well as dose strengths. In USP apparatus II, dissolution profiles were affected mainly by media pH. The dissolution experiments performed in biorelevant dissolution stress test device demonstrated that stress events of biorelevant intensity provoked accelerated drug release from the tablets.
Asunto(s)
Preparaciones de Acción Retardada/química , Dibenzotiazepinas/química , Comprimidos/química , Concentración de Iones de Hidrógeno , Fumarato de Quetiapina , Solubilidad , Estrés MecánicoRESUMEN
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.
Asunto(s)
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.
Asunto(s)
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
Food effects on drug release and absorption from solid oral dosage forms are a common biopharmaceutical problem. The fed state is characterized by different motility and secretory activity of the complete gastrointestinal (GI) tract compared to fasting conditions. Due to long gastric transit times, the postprandial stomach plays an essential role for drug release and the appearance of food effects. Therefore, a concise comprehension of the relationship between food intake and its effect on drug release from solid oral dosage forms is essential to understand their dissolution behavior under fed conditions. This review describes important aspects of stomach physiology occurring after meal ingestion with particular reference to the FDA standard breakfast. A brief overview of oral and gastric food processing and their potential influence on drug release is given. The key factors affecting the intragastric dissolution of solid oral dosage forms and their regional distribution in the stomach are discussed. Additionally, the effects of food properties on gastric emptying kinetics are presented. Mechanical aspects such as intragastric pressures and hydrodynamics caused by gastric peristalsis are defined. The initial state and the dynamic changes of the gastric content during digestion are characterized since the different physicochemical aspects such as pH value, buffer capacity, rheological properties or surface tension may be essential for the in vivo dissolution profiles of oral dosage forms. Possible effects of the discrete interplay of the physiological factors on the in vivo drug delivery behavior of solid oral dosage forms are discussed.
Asunto(s)
Periodo Posprandial/fisiología , Estómago/fisiología , Administración Oral , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos , Vaciamiento Gástrico , Tránsito Gastrointestinal , Humanos , Absorción Intestinal , Masticación , Modelos Biológicos , Preparaciones Farmacéuticas/administración & dosificación , SalivaciónRESUMEN
Intragastric drug release from solid oral dosage forms can be affected by altered physicochemical and mechanical conditions in the upper gastrointestinal (GI) tract. Food effects may lead to changes of one or more pharmacokinetic parameters and, hence, influence drug plasma levels. This can result in severe consequences such as adverse drug reactions or even therapy failure. This review highlights different examples of drug performance under fed conditions. Various reasons such as delayed gastric emptying and pH-dependent solubility of the API as well as intragastric location and movement profiles of solid dosage forms can account for changed drug dissolution. Over the past years, several biorelevant media (e.g., fed state simulated gastric fluid) have been developed with the aim to approach the physiological situation regarding parameters such as pH, buffer capacity, surface tension, and osmolality. It was shown in different in vitro experiments that all of these factors can have an impact on drug dissolution. Besides the application of complex media such as milk or nutritional drinks, the dynamic changes of the gastric content were depicted in recent studies. The capabilities, limitations, and applicability of newly established test setups for the biorelevant simulation of intragastric drug delivery behavior are discussed. Simple test devices (e.g., rotating beaker or dissolution stress test) are mainly used for the biopharmaceutical evaluation of certain problems such as the impact of pressure or shear forces. On the other hand, complex biorelevant test devices (e.g., TNO TIM-1, Dynamic Gastric Model) have recently been introduced aiming at the simulation of multiple parameters characteristic for the postprandial upper GI tract. The different test methods are reviewed with respect to the spectrum of the simulated physiological factors and the degree of complexity.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Preparaciones Farmacéuticas/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Modelos Biológicos , Periodo PosprandialRESUMEN
The bicarbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions. However, its use in dissolution testing of solid oral dosage forms is very limited. The reason for this is the thermodynamic instability of the solution containing hydrogen carbonate ions and carbonic acid. The spontaneous loss of carbon dioxide (CO(2)) from the solution results in an uncontrolled increase of the pH. In order to maintain the pH on the desired level, either a CO(2) loss must be completely avoided or the escaped CO(2) has to be replaced by quantitative substitution, i.e. feeding the solution with the respective amount of gas, which re-acidifies the buffer after dissociation. The present work aimed at the development of a device enabling an automatic pH monitoring and regulation of hydrogen carbonate buffers during dissolution tests.
Asunto(s)
Bicarbonatos/química , Microelectrodos , Tecnología Farmacéutica/instrumentación , Automatización de Laboratorios , Tampones (Química) , Dióxido de Carbono/química , Diseño de Equipo , Gases , Concentración de Iones de Hidrógeno , Microcomputadores , Modelos Químicos , Programas Informáticos , Solubilidad , Tecnología Farmacéutica/métodos , Factores de TiempoRESUMEN
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.
Asunto(s)
Absorción Intestinal , Modelos Biológicos , Animales , Perros , Absorción Intestinal/fisiología , Disponibilidad Biológica , Modelos Animales , Desarrollo de Medicamentos , Administración Oral , Solubilidad , Interacciones Alimento-DrogaRESUMEN
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.
Asunto(s)
Cafeína , Vaciamiento Gástrico , Humanos , Agua , Estómago , Imagen por Resonancia Magnética/métodosRESUMEN
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.
Asunto(s)
Ritonavir , Humanos , Niño , Liberación de Fármacos , Solubilidad , Comprimidos , Administración OralRESUMEN
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.