Development of a furosemide-containing expandable system for gastric retention.

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.

Anestesia para reparación antenatal de mielomeningocele: Presentación de un caso / Anesthesia for myelomenigocele antenatal repair: Case report

INTRODUCTION: The advance in the methods of prenatal diagnosis and surgical techniques have allowed the development of fetal surgery, achieving identification and early treatment of anomalies invalidating extrauterine life. Myelomeningocele (MMC) is the most frequent neural tube defect and its intrauterine correction has demonstrated benefits. OBJECTIVE: To publicize the anesthetic management of a prenatal correction of MMC performed in a public hospital in Chile. CASE REPORT: 31-year-old woman, pregnancy of 25 weeks of gestational age, fetus carrying MMC lumbosacral, who underwent open correction. Procedure performed with incidents under general anesthesia with remifentanil and sevoflorane MAC in 2 and tocolytic prophylaxis. At 48 hours post operative, he presented an acute pulmonary edema compatible (EPA), which was successfully resolved with depletive therapy for 24 hours in the Intensive Care Unit, without the need for mechanical ventilation or use of vasoactive drugs. Discharged one week later in good condition, with interruption of pregnancy by elective caesarean section at 37 weeks, with a newborn without stigmas of neurological sequelae. CONCLUSIONS: The mother-fetus binomial is a challenge for the anesthetist. In intrauterine surgery the need for knowledge about the pharmacology of tocolytics, placental uterine physiology and the complications of the procedure are added.

INTRODUCCIÓN: El avance en los métodos de diagnóstico prenatal y las técnicas quirúrgicas han permitido el desarrollo de la cirugía fetal, logrando identificación y tratamiento precoz de anomalías invalidantes para la vida extrauterina. El mielomeningocele (MMC) es el defecto del tubo neural más frecuente y su corrección intrauterina tiene beneficios demostrados. OBJETIVO: Dar a conocer el manejo anestésico de una corrección prenatal de MMC realizada en un hospital público de Chile. CASO CLÍNICO: Mujer de 31 años, embarazo de 25 semanas de edad gestacional, feto portador de MMC lumbosacro, que se sometió a una corrección por vía abierta. Procedimiento realizado con incidentes bajo anestesia general con remifentanilo y sevoflorano MAC en 2 y profilaxis tocolítica. A las 48 horas postoperatorias presentó cuadro compatible con edema pulmonar agudo (EPA), que se resolvió exitosamente con terapia depletiva por 24 horas en Unidad de Cuidados Intensivos, sin necesidad de ventilación mecánica ni uso de drogas vasoactivas. Dada de alta una semana después en buenas condiciones. El embarazo se interrumpió por cesárea electiva a las 37 semanas, con un recién nacido sin estigmas de secuela neurológica. CONCLUSIONES: El binomio madre-feto es un reto para el anestesista. En cirugía intraútero se suma la necesidad de conocimientos sobre la farmacología de los tocolíticos, fisiología útero placentaria y las complicaciones propias del procedimiento.

A novel mechanical antrum model for the prediction of the gastroretentive potential of dosage forms.

The development of gastroretentive dosage forms can be significantly enhanced by the reliable estimation of gastroretentive properties in vitro. In this context, it is mandatory to consider the propulsive contraction waves that occur in the antral region of the stomach, since they are regarded as the major physiological hurdle to overcome. Therefore, the aim of this study was to develop an in vitro model that allowed the evaluation of the gastroretentive potential of objects with different properties (e.g. size, shape and elasticity). The model enabled a realistic simulation of the human antrum and occurring contraction waves. We could demonstrate that larger objects made of elastic polyurethane foam were more rapidly emptied by the model than smaller objects having the same shape. Compared to this, rigid as well as slippery objects showed decreased gastroretentive properties. In contrast, a self-formed trichobezoar - an indigestible object known to remain in the stomach - showed the highest gastroretentive potential. We suggest that the gastroretentive potential of objects of a certain size increases if they exhibit compressible and elastic properties along with certain dimensions. The data showed that the development of novel gastroretentive dosage forms may be facilitated with the aid of the mechanical antrum model.

Development of a bio-relevant dissolution test device simulating mechanical aspects present in the fed stomach.

A novel bio-relevant in vitro dissolution device was designed to mimic intragastric conditions after food intake paying particular consideration to mechanical aspects: the Fed Stomach Model (FSM). The FSM represents a fully computer-controlled dynamic flow-through system, in which dosage forms are hosted in so-called gastric vessels. Dosage form movement profiles as well as pressures can be simulated in a physiologically relevant manner. This proof-of-concept study aimed at the investigation of the effects of individual parameters and complex test programs on the drug delivery behavior of diclofenac sodium bilayer extended release tablets. Magnetic marker monitoring experiments demonstrated the applicability of the FSM to simulate intragastric movement velocities of solid oral dosage forms equivalent to in vivo data. Dissolution experiments revealed the relevance of all simulated parameters (i.e. pressure, dosage form movement and pump rate). Moreover, three different test scenarios with test programs specific for fundus, antrum and gastric emptying considered the variability of intragastric transit of solid oral dosage forms after food intake and were confirmed to be reasonable. Dissolution rates were low under conditions specific for fundus owing to low shear stresses. In contrast, higher amounts of the drug were released under high stress conditions simulating antral transit and gastric emptying. Concluding, the FSM can be a valuable tool for bio-relevant dissolution testing due to its potential of precise and reproducible simulation of mechanical parameters characteristic for the fed stomach.

Simulating the postprandial stomach: biorelevant test methods for the estimation of intragastric drug dissolution.

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.

Simulating the postprandial stomach: physiological considerations for dissolution and release testing.

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.