Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable drugs across the intestinal epithelium. To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository. Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be co-released in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. An advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C₁₀), a compound already approved as a food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level as well as in vitro and in vivo efficacy and safety studies. In specific clinical examples, we review how C₁₀-based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for antisense oligonucleotides (ISIS Pharmaceuticals, USA).     

Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications

Drug-drug, drug-formulation and drug-meal interactions are of clinical concern for orally administered drugs that possess a narrow therapeutic index. This review presents the current status of information regarding interactions which may influence the gastrointestinal (GI) absorption of orally administered drugs. Absorption interactions have been classified on the basis of rate-limiting processes. These processes are put in the context of drug and formulation physicochemical properties and oral input influences on variable GI physiology. Interaction categorisation makes use of a biopharmaceutical classification system based on drug aqueous solubility and membrane permeability and their contributions towards absorption variability. Overlaying this classification it is important to be aware of the effect that the magnitudes of drug dosage and volume of fluid administration can have on interactions involving a solubility rate limits. GI regional differences in membrane permeability are fundamental to the rational development of extended release dosage forms as well as to predicting interaction effects on absorption from immediate release dosage forms. The effect of meals on the regional-dependent intestinal elimination of drugs and their involvement in drug absorption interactions is also discussed. Although the clinical significance of such interactions is certainly dependent on the narrowness of the drug therapeutic index, clinical aspects of absorption delays and therapeutic failures resulting from various interactions are also important.     

Evaluation and prediction of oral drug absorption and bioequivalence with food-druginteraction

This article reviews the impacts on the in vivo prediction of oral bioavailability (BA) and bioequivalence (BE) based on Biopharmaceutical classification systems (BCS) by the food-drug interaction (food effect) and the gastrointestinal (GI) environmental change. Various in vitro and in silico predictive methodologies have been used to expect the BA and BE of the test oral formulation. Food intake changes the GI physiology and environment, which affect oral drug absorption and its BE evaluation. Even though the pHs and bile acids in the GI tract would have significant influence on drug dissolution and, hence, oral drug absorption, those impacts largely depend on the physicochemical properties of oral medicine, active pharmaceutical ingredients (APIs). BCS class I and III drugs are high soluble drugs in the physiological pH range, food-drug interaction may not affect their BA. On the other hand, BCS class II and IV drugs have pH-dependent solubility, and the more bile acid secretion and the pH changes by food intake might affect their BA. In this report, the GI physiological changes between the fasted and fed states are described and the prediction on the oral drug absorption by food-drug interaction have been introduced.     

Lipid-based formulations for oral administration of poorly water-soluble drugs

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving/dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on the biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. The aim of this review is to provide an overview of the different lipid-based dosage forms from a biopharmaceutical point of view and to describe effects of lipid dosage forms and lipid excipients on drug solubility, absorption and distribution.     

Simultaneous In Vivo Visualization and Localization of Solid Oral Dosage Forms in the Rat Gastrointestinal Tract by Magnetic Resonance Imaging (MRI)

Purpose. Bioavailability of orally administered drugs is much influenced by the behavior, performance and fate of the dosage form within the gastrointestinal (GI) tract. Therefore, MRI in vivo methods that allow for the simultaneous visualization of solid oral dosage forms and anatomical structures of the GI tract have been investigated. Methods. Oral contrast agents containing Gd-DTPA were used to depict the lumen of the digestive organs. Solid oral dosage forms were visualized in a rat model by a ¹H-MRI double contrast technique (magnetite-labelled microtablets) and a combination of ¹H- and ¹⁹F-MRI (fluorine-labelled minicapsules). Results. Simultaneous visualization of solid oral dosage forms and the GI environment in the rat was possible using MRI. Microtablets could reproducibly be monitored in the rat stomach and in the intestines using a ¹H-MRI double contrast technique. Fluorine-labelled minicapsules were detectable in the rat stomach by a combination of ¹H- and ¹⁹F-MRI in vivo. Conclusions. The in vivo ¹H-MRI double contrast technique described allows solid oral dosage forms in the rat GI tract to be depicted. Solid dosage forms can easily be labelled by incorporating trace amounts of non-toxic iron oxide (magnetite) particles. ¹H-MRI is a promising tool for observing such pharmaceutical dosage forms in humans. Combined ¹H- and ¹⁹F-MRI offer a means of unambiguously localizing solid oral dosage forms in more distal parts of the GI tract. Studies correlating MRI examinations with drug plasma levels could provide valuable information for the development of pharmaceutical dosage forms.     

Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part II: extension to describe performance of solid dosage forms

The physiological absorption model presented in part I of this work is now extended to account for dosage-form-dependent gastrointestinal (GI) transit as well as disintegration and dissolution processes of various immediate-release and modified-release dosage forms. Empirical functions of the Weibull type were fitted to experimental in vitro dissolution profiles of solid dosage forms for eight test compounds (aciclovir, caffeine, cimetidine, diclofenac, furosemide, paracetamol, phenobarbital, and theophylline). The Weibull functions were then implemented into the model to predict mean plasma concentration-time profiles of the various dosage forms. On the basis of these dissolution functions, pharmacokinetics (PK) of six model drugs was predicted well. In the case of diclofenac, deviations between predicted and observed plasma concentrations were attributable to the large variability in gastric emptying time of the enteric-coated tablets. Likewise, oral PK of furosemide was found to be predominantly governed by the gastric emptying patterns. It is concluded that the revised model for GI transit and absorption was successfully integrated with dissolution functions of the Weibull type, enabling prediction of in vivo PK profiles from in vitro dissolution data. It facilitates a comparative analysis of the parameters contributing to oral drug absorption and is thus a powerful tool for formulation design.     

Towards Virtual Bioequivalence Studies for Oral Dosage Forms Containing Poorly Water-Soluble Drugs: A Physiologically Based Biopharmaceutics Modeling (PBBM) Approach

The objective of the present study was to develop a physiologically based biopharmaceutics (PBBM) approach to predict the bioequivalence of dosage forms containing poorly soluble drugs. Aripiprazole and enzalutamide were used as model drugs. Variations in the gastrointestinal (GI) physiological parameters of fasted humans were taken into consideration in in vitro biorelevant dissolution testing and in an in silico PBBM simulations. To estimate bioequivalence between dosage forms, the inter-individual variabilities in their performance in virtual human subjects were predicted from the in vitro studies and variability in e.g. gastric emptying and fluid volume in the stomach was also taken into account. Formulations with different in vitro dissolution performance, a solution and a tablet formulation, were used in order to evaluate the accuracy of bioequivalence prediction using the PBBM approach. The bioequivalence parameters, i.e. geometric mean ratio and 90% confidence interval, for both drugs were predicted well in the virtual studies. In order to achieve even more precise predictions, it will be important to continue characterizing GI physiological parameters, along with their variabilities, on both an inter-subject and inter-occasion basis.     

A Toolbox for Mimicking Gastrointestinal Conditions in Children: Simulated Paediatric Breakfast Media (SPBM) for Addressing the Variability of Gastric Contents After Typical Paediatric Breakfasts

Since co-administration of dosage forms with food can impact drug exposure, food effect studies became an integral part of oral drug product development. Studies are usually performed in healthy adults and the dosage form is co-administered with a high-fat high-calorie standard breakfast meal to mimic worst-case dosing conditions. A corresponding study design for children is lacking but would be essential for a proper risk-assessment in this vulnerable patient group. To protect healthy children from unnecessary in vivo studies, it would be even more desirable to predict food effects based on other than in vivo studies in the target age group. In the present study, typical children's breakfasts in different parts of the world were identified, prepared and physicochemical properties were assessed. Subsequently, Simulated Paediatric Breakfast Media (SPBM) resembling breakfast composition and properties were designed and applied in in vitro dissolution experiments mimicking the initial composition of the postprandial stomach after breakfast ingestion. Study results indicate the impact of different simulated gastric conditions on drug release. SPBM enabled to better estimate the variability of in vivo drug release in fed dosing conditions and their use will aid in better assessing food effects in children in different parts of the world.     

Gastric retentive dosage forms: a review

Gastric retentive dosage forms have been investigated to provide controlled release therapy for drugs with reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the stomach or upper GI tract. Gastric retentive dosage forms rely on either natural GI physiology, such as floating or large tablets that depend on delayed emptying from the fed stomach, or those dosage forms that are designed to fight the physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or without flotation or bioadhesion. To understand the behavior of the dosage forms, an introduction to GI motility and its measurement is provided. Because the fed mode underlies the successful development of dosage forms that rely on size or flotation, the emptying of these dosage forms in the fed mode and identification of the key factors influencing the variability of gastric retention are discussed. The design and limitations of size or density-based fed mode, and mucoadhesive and expandable fasting-state gastric retentive systems are presented.     

Influence of food and diet on gastrointestinal drug absorption: A review

The literature concerning the influence of food, and also fluid volumes, on drug absorption is reviewed. In most cases, the absorption of drugs from the gastrointestinal tract is reduced or delayed by food. However, some drugs are unaffected by food, while the absorption of a small number of drugs is increased. Observed effects of food on drug absorption are the net result of various factors, including the influence of food on gastrointestinal physiology and also physicochemical interactions between drugs, drug dosage forms, and dietary components. The intensity of food-drug interactions may be influenced by the type of food and by the time interval between eating and drug administration. Large coadministered fluid volumes tend to promote drug absorption. The clinical significance of changes in drug bioavailability due to these factors is discussed.     

Gastroretentive floating drug-delivery systems: a critical review

The oral delivery of drugs with a narrow absorption window in the gastrointestinal tract (GIT) is often limited by poor bioavailability with conventional dosage forms due to incomplete drug release and short residence time at the site of absorption. To overcome this drawback and to maximize the oral absorption of these drugs, gastroretentive systems such as mucoadhesive, high-density, expandable, and floating systems have been developed. These systems provide controlled delivery of drugs with prolonged gastric residence time. However, in humans, differences in various physiological and biological factors can affect the gastric residence time and drug-delivery behavior from gastroretentive systems. Some floating drug-delivery systems (FDDS) have shown the capability to accommodate these variations without affecting drug release. This review mainly focuses on various physiological considerations for development of FDDS, and highlights recent technological developments including new dosage forms and their production techniques (e.g., holt-melt extrusion, melt pelletization, and pulsed plasma-irradiation processes). Alternatives to the existing in vitro compendial methods for evaluating floating dosage forms will be discussed, and a critical analysis of the existing literature on FDDS, identifying the potential areas for future research, is provided.     

IV-IVC considerations in the development of immediate-release oral dosage form

Predictive scientific principles and methods to assess in vivo performance of pharmaceutical dosage forms based on in vitro studies are important in order to minimize costly animal and human experiments during drug development. Because of issues related to poor solubility and low permeability of newer drug candidates, there has in recent years been a special focus on in vitro-in vivo correlation (IV-IVC) of drug products, particularly those used orally. Various physicochemical, biopharmaceutical, and physiological factors that need to be considered in successful IV-IVC of immediate-release oral dosage forms are reviewed in this article. The physicochemical factors include drug solubility in water and physiologically relevant aqueous media, pK(a) and drug ionization characteristics, salt formation, drug diffusion-layer pH, particle size, polymorphism of drug substance, and so forth. The biopharmaceutical factors that need to be considered include effects of drug ionization, partition coefficient, polar surface area, etc., on drug permeability, and some of the physiological factors are gastrointestinal (GI) content, GI pH, GI transit time, etc. Various in silico, in vitro, and in vivo methods of estimating drug permeability and absorption are discussed. Additionally, how IV-IVC may be applied to immediate-release oral dosage form design are presented.     

壳聚糖及其衍生物包覆脂质体对胰岛素肠道吸收的影响

目的考察壳聚糖及其衍生物包覆脂质体对胰岛素肠道吸收的影响。方法采用逆相蒸发制备胰岛素脂质体；采用在体肠灌流法研究壳聚糖及其衍生物包覆胰岛素脂质体的肠道吸收；用酶-苯酚法测定血糖值；用放射免疫法测定血清和肠组织中胰岛素含量。结果壳聚糖(CH)、壳聚糖-EDTA轭合物(CEC)包覆胰岛素脂质体和CH-CEC双层包覆胰岛素脂质体的最佳吸收部位均集中在十二指肠，胰岛素溶液的最佳吸收部位在结肠，而未包覆胰岛素脂质体和N-三甲基壳聚糖盐酸盐(TMC)包覆胰岛素脂质体的最佳吸收部位尚不能确定。在各肠段中，以CH-CEC双层包覆胰岛素脂质体的吸收最佳。结论壳聚糖及其衍生物包覆脂质体能促进胰岛素经肠道吸收，并可提高其在肠道中的稳定性。     

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration–time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1–4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound’s BCS/BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions.     

Estimation of Agitation Intensity in the GI Tract in Humans and Dogs Based on in Vitro/in Vivo Correlation

In this study, we assessed the hydrodynamic flow around a dosage form in the GI tract in humans by comparing the characteristics of in vitro and in vivo release of two different types of controlled release acetaminophen (paracetamol) tablets, A and B. The former tablet showed an agitation speed-dependent release at a high speed range (50–100 rpm), whereas the latter showed this characteristic at a low speed range (10–50 rpm). The mean release amount-time profiles of tablets A and B in humans showed biphasic characteristics, and the first phase of the absorption profiles of A and B was close to their in vitro profiles at a paddle speed of 10 rpm. The in vivo profiles were also superimposable on in vitro dissolution curves obtained by the flow-through cell method at a flow rate of 1 mL/min (velocity 0.89 cm/min) or less. These results indicate that the hydrodynamic flow around the dosage forms in the human GI tract could be extremely low. The in vivo release rate of these tablets in dogs was greater than in humans, and was estimated to be equivalent to the release rate determined by the paddle method at 100 rpm. This indicates that a higher agitation intensity in the GI tract in dogs than in humans may be one cause of the discrepancies between humans and dogs in drug absorption studies.     

In vivo performance of time-controlled explosion system (TES) in GI physiology regulated dogs

In vivo oral absorption study of time-controlled explosion system (TES), using gastrointestinal (GI) physiology regulated dogs, was carried out to predict the feasibility in humans. TES is characterized by rapid drug release with a pre-programmed lag time, which can provide a programmed release system synchronized with circadian rhythm (e.g. asthma attack in the morning), a colon targeting system and a sustained release system with different lag times. In this study, TES containing diclofenac sodium with different lag times of 3 and 6 h (TES-3h and TES-6h) were prepared. TES-3h exhibited good performance in all six GI physiology regulated dogs without remarkable reduction of AUC. In the case of TES-6h, drug absorption was observed ∼6 h after administration in four of six dogs, but plasma level was low. Further, the location of the dosage forms after oral administration was estimated from the gastric emptying time (GET) and the small intestinal transit time (SITT) using a double marker method. As a result, in vivo performance of TES correlated with the intestinal location. It was concluded that TES-3h would perform well in humans and that the environmental water content in the GI tract affected the in vivo dissolution profile of TES when the drug release was initiated after entering the colon.     

Drug absorption in gastrointestinal disease and surgery. Clinical pharmacokinetic and therapeutic implications.

Drug absorption from the gastrointestinal (GI) tract and the impact of GI surgery and disease on drug absorption are discussed. Recommendations are made to manage problems of drug malabsorption. Absorption from the GI tract is a first-order process described by its rate and extent. GI surgery changes the anatomy of the GI tract and alters important variables in the absorption process. In the wake of procedures which diminish small bowel surface area, the extent of absorption of phenytoin, digoxin, cyclosporin, aciclovir, hydrochlorothiazide and certain oral contraceptives is reported to be reduced. The underlying cause of the reduction is unknown. When gastric emptying time or pH are altered by surgery, the rate of drug absorption appears to be reduced. However, it is not clear which variable is more important in determining therapeutic effects. The effects of coeliac and inflammatory bowel diseases on the distribution and clearance of drugs must be considered before attributing abnormal serum concentrations of drugs to malabsorption. GI disease may slow gastric emptying and delay the complete absorption of drugs when their rate of absorption depends on gastric emptying time. Other inflammatory GI diseases such as graft-versus-host disease (GVHD) of the gut, Beh?et's syndrome and scleroderma involving the GI tract may directly reduce absorption of drugs such as cyclosporin, amitriptyline, benzodiazepines, anticonvulsants, paracetamol (acetaminophen) and penicillamine. GI diseases which alter gut pH affect the absorption only of drugs with limited water solubility and pH-dependent dissolution such as ketoconazole. Clinicians should be aware of the variable absorption seen after GI disease and surgery and monitor their patients accordingly.     

In Vitro System to Evaluate Oral Absorption of Poorly Water-Soluble Drugs: Simultaneous Analysis on Dissolution and Permeation of Drugs

Purpose. The aim of the present work was to develop a new in vitro system to evaluate oral absorption of poorly water-soluble drugs by utilizing Caco-2 monolayers. Methods. Caco-2 monolayer was mounted between side-by-side chambers, which enabled the simultaneous assay of dissolution and permeation of drugs (dissolution/permeation system; D/P system). Apical and basal sides of the chamber were filled with buffer solutions. Drugs were applied to the apical side as powder, suspension, or solution, and then, the permeated amounts into the basal side were monitored for 2 h. At the same time, dissolved amounts of drugs at the apical side were detected. The amount of drug applied to the D/P system was based on its in vivo clinical dose. Results. Sodium taurocholate (5 mM, apical side) and bovine serum albumin (4.5% w/v, basal side) increased the permeated amount of poorly water-soluble drugs. Both additives were considered to be effective at mimicking in vivo conditions of intestinal drug absorption. From the correlation between the permeated amount of 13 drugs (% dose/2 h) in the D/P system and their percentage dose absorbed in humans in vivo, this system was found to be useful in evaluating oral absorption of poorly water-soluble drugs. Conclusions. With attempts made to mimic the physiologic conditions of the human GI tract, in vivo oral absorption of drugs was quantitatively assessed in the D/P system in vitro. This system is quite useful to predict the oral absorption of poorly water-soluble drugs after administration as solid dosage forms.     

Utilizing Tiny-TIM to Assess the Effect of Acid-Reducing Agents on the Absorption of Orally Administered Drugs

Acid-reducing agents (ARAs) are the most commonly used medicines to treat patients with gastric acid-related disorders. ARA administration results in an elevation of intragastric pH and eases symptoms such as acid reflux. However, this effect could also lead to a reduction in the absorption of some co-administered oral medications (i.e. weakly basic drugs) by decreasing their gastric solubility. This in turn can result in a significant reduction of the efficacy of the co-administered oral medications. In order to address this problem, substantial efforts in translational modeling and the development of predictive in-vitro assays to better forecast the effect of ARA on oral absorption are conducted in the pharmaceutical industry. Despite these efforts, it remains challenging to predict the impact of ARAs on co-administered drugs. In this study, we evaluated the utility of Triskelion's Gastro-Intestinal Model (Tiny-TIM) in predicting ARA effect on twelve model drugs whose in-vivo data are available. The Tiny-TIM prediction of the ARA effect matched the observed effect of ARA co-administration in humans for the 12 model compounds. In summary, Tiny-TIM is a very reliable and promising GI model to successfully predict the nature of DDI when ARAs are co-administered with the drug of interest.