Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs.

The main purpose of this review is to provide a current and general overview of the existing self-dispersing formulations resulting from dilution into emulsions, microemulsions and surfactant dispersions. The systematic approach used and the presentation of the various physico-chemical and biopharmaceutical aspects should facilitate the comprehension of this interesting field and clarify the main considerations involved in designing and characterizing a specific self-dispersing drug delivery system. Studies have shown that the self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. It was suggested that the ease of emulsification could be associated with the ease by which water penetrates into the various liquid crystalline (LC) or gel phases formed on the surface of the droplet. Numerous bioavailability studies carried out in animals and humans, reviewed in the present study, suggest that hydrophobic drugs are better absorbed when administered in self-dispersing lipid formulations (SDLFs). Examples which illustrate the beneficial use of SDLFs for drug absorption enhancement are presented. This review outlines SDLFs as one of the most promising approaches to overcome the formulation difficulties of these hydrophobic/lipophilic drugs.     

脂质制剂体外动态肠吸收模型的建立及评价

根据脂质制剂肠消化吸收的特性,本文在体外脂解模型基础上,引入肠吸收评价方法,建立了一种用于筛选评价脂质制剂的新型体外动态肠吸收模型,包括肠消化和肠组织培养两大体系。探究模型重要参数(Ca2+、葡萄糖、K+)的影响,发现Ca2+浓度的增加能显著增强脂质制剂的肠消化;葡萄糖浓度的递增能显著减慢肠组织活性衰减;K+虽能维持肠组织的活性,但其浓度变化对肠组织活性衰减并无显著性影响;最终选择Ca2+10 mmol.L-1、葡萄糖15 mmol.L?1和K+5.5 mmol.L-1为模型参数。利用该模型评价TypeⅠ脂质制剂得到的体外吸收曲线与大鼠体内吸收曲线呈现极显著的点对点相关性(r=0.995 6,P<0.01)。本模型可望应用于脂质制剂的筛选、评价及预测。     

Lipid-itraconazole interaction in lipid model membranes.

Itraconazole, a lipophilic, fungal sterol-biosynthesis inhibitor, does not disturb membrane organization parameters measured by differential scanning calorimetry and infrared spectroscopy. Conformational analysis studies suggest that the molecular volume and the position of itraconazole in the lipid membrane is similar to that of dipalmitoyl phosphatidylcholine. The mean energy of interaction between itraconazole and the phospholipid is -60.6 kJ mol-1 whereas this energy in the pure lipid matrix is -54.3 kJ mol-1. The mean molecular area of itraconazole calculated by projecting the molecule on the lipid-water interface is equal to that occupied by the pure lipid (60 A2/molecule).     

Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs

The purpose of this study was to validate human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for predicting the oral drug absorption in humans with the main focus on moderately and poorly permeable compounds. The obtained apparent permeability coefficient (P(app)) of eleven test compounds was compared to their fraction absorbed (Fa) in humans taken from the literature. Beside the conventional P(app) a new parameter, the apparent permeability coefficient total (P(app,total)), involving both the apical-to-basolateral permeability and the time-dependent compound accumulation in the tissue was established. The permeability of lucifer yellow (LY), a fluorescent marker of the paracellular pathway and the test compounds showed no obvious differences between small intestine and colon. Furthermore, small intestinal and colonic tissue from a single donor showed similar permeability of both LY and a transcellularly transported compound metoprolol. All test compounds including low molecular weight hydrophilic compounds such as metformin, atenolol, sulpiride and famotidine showed adequate permeability reflecting human Fa values (R(2)=0.87). The P(app) values of digoxin, a P-glycoprotein (P-gp) substrate, were not significantly affected by the addition of verapamil, a P-gp inhibitor. In contrast, the P(app,total) values of digoxin increased approximately threefold in the presence of verapamil. In conclusion, both small intestinal and colonic tissue mounted in the Ussing chamber provide a good opportunity to predict the oral drug absorption rate in humans even for moderately and poorly absorbed compounds. The novel calculation of P(app,total) allows the study of the carrier-mediated drug-drug interactions in human intestine.     

Increasing intestinal absorption of drugs by formulation

The biological potency of steroid hormones was increased by formulation with cholesterol, or its esters, in proportions at which the drugs form a solid solution. Improved intestinal absorption was most likely achieved by increasing the contransport of the drugs with the lipid into the lymphatic system. Increases in blood concentrations were highest for hormones possessing a short biological half-life.     

药物的肠吸收与处置研究进展

对近几年药物肠吸收与处置方面的研究进展进行了综述。包括:特定部位吸收、代谢的认识和利用,与药物首过效应有关的肠壁外泌及代谢作用的介绍,促进药物肠道吸收的方法及常用研究模型的比较。     

Use of the unanesthetized rhesus monkey as a model for studying the gastrointestinal absorption of drugs

A model has been developed to study the gastrointestinal absorption of drugs and dosage forms in the unanesthetized rhesus monkey. Chronic vascular catheters were implanted in the iliac vein and the artery to enable the investigator to withdraw blood samples without disturbing the monkey. The vascular catheters also allow intravenous studies to be carried out so that the kinetic parameters of any drug can be determined. Plastic cannulae were implanted surgically in the stomach and in the duodenum very close to the pylorus. These cannulae provide a means of instilling a drug solution or a dosage form directly into the stomach or the duodenum. A technique was developed using Foley catheters to block the pylorus so that a drug solution or drug particles can be maintained in the stomach. With this setup, absorption of a drug specifically from the stomach can be studied. Sample data for salicylic acid absorption from the stomach and the intestine and for carbamazepine absorption following gastric administration of a solution or a broken tablet are presented.Supported in part by Grant GM 16496 from the National Institutes of Health.Presented, in part, at the APhA Academy of Pharmaceutical Sciences Symposium on Pharmacokinetics, Chicago, Illinois, November 1972.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process.     

Elucidation of intestinal absorption mechanism of carvedilol-loaded solid lipid nanoparticles using Caco-2 cell line as an in-vitro model

Abstract

Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanoparticles (SLNs) via lymphatic delivery has been documented. Since no in-vitro lymphoid tissue is currently available, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. Therefore, optimized carvedilol-loaded SLNs (FOPT-SLNs) were prepared, characterized, and evaluated using Caco-2 cell line as an in-vitro model. Physical mixture of components of FOPT-SLNs (FOPT-PM) and carvedilol solution were used as control groups. From the studies of effect of SLNs concentration and cells incubation time, suitable carvedilol concentration and incubation time were selected for the model in which cells were subjected to five pretreatments for 24?h or 1?h of cell incubation and then followed with treatment of FOPT-SLNs, FOPT-PM or 100?µg/mL solution of carvedilol, for additional 24?h of cell incubation. The results obtained in this model suggest that main absorption mechanism of FOPT-SLNs could be endocytosis and, more specifically, clathrin-mediated endocytosis. When Transwell® permeable supports were used for the cells, carrier-mediated mechanism for FOPT-SLNs and passive absorption mechanism (transcellular and paracellular) for FOPT-PM and drug solution were concluded.     

Everted rat intestinal sacs as an in vitro model for assessing absorptivity of new drugs.

An in vitro model that utilizes everted rat intestinal sacs was evaluated for assessing the absorptivity of several analogs of potential drug substances prior to formulation work and clinical trials. This model not only is a useful qualitative tool for assessing absorptivity of structurally related compounds but also yields some insight into the process involved in drug absorption. Notwithstanding the complexities involved in the absorption processes, the data support the hypothesis that the absorption of organic electrolytes mainly takes place by the partitioning of the unionized species into the lipoidal membranes and then diffusion.     

Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption.

Creatine is a nutraceutical that has gained popularity in both well-trained and casual athletes for its performance-enhancing or ergogenic properties. The major disadvantages of creatine monohydrate formulations are poor solubility and oral bioavailability. In the present study, creatine transport was examined using Caco-2 monolayers as an in vitro model for intestinal absorption. Confluent monolayers of Caco-2 cells (passage 25-35) were used for the permeability studies. Monolayers were placed in side-by-side diffusion chambers. (14)C-Creatine (0.1-0.5 microCi/mL) was added to either the apical or basolateral side, and the transport of the creatine across the Caco-2 monolayer was measured over a 90-min period. The apical to basolateral transport of (14)C-creatine was small, ranging from 0.2-3% of the original amount appearing on the receiver side in a 90-min period. Interestingly, the basolateral to apical permeability of radiolabeled creatine was substantially greater than that observed in the apical to basolateral direction. Studies with drug efflux transport inhibitors indicate that neither the P-glycoprotein nor multidrug resistance-associated protein is involved in the enhanced basolateral to apical transport of creatine.     

Mechanism for the inducement of the intestinal absorption of poorly absorbed drugs by mixed micelles I. Effects of various lipid—bile salt mixed micelles on the intestinal absorption of streptomycin in rat

The effects of various lipid—bile salt mixed micelles on the intestinal absorption of streptomycin were investigated using in situ closed-loop method in the rat. Lipids used were fatty acids, glycerides, oleyl alcohol and methyl oleate. Mixed micelles composed of monoolein or unsaturated fatty acids markedly enhanced the absorption of streptomycin in the large intestine. On the other hand, saturated fatty acids caused a small enhancement of the absorption. Triolein, diolein, oleyl alcohol and methyl oleate had no enhancing effect on the absorption.To clarify the difference in the enhancing effects of monoolein, unsaturated fatty acids and saturated fatty acids, the interaction of the drug with mixed micelles, the absorbability of lipids and the alteration of the mucosal membrane permeability induced by mixed micelles were investigated. The alteration of the mucosal membrane permeability was examined by an exsorption experiment. The difference in the enhancing effects was not attributed to the interaction or the absorbability of lipids, but a close correlation was found between the enhancing effects and the alteration of the mucosal membrane permeability. Monoolein or unsaturated fatty acids mixed micelles markedly increased the mucosal membrane permeability, while bile salt or saturated fatty acid mixed micelles caused small or no alteration of the permeability. The enhancement of the intestinal absorption by mixed micelles was mostly due to the alteration of the mucosal membrane permeability.     

Use of lipid microspheres as a drug carrier for antitumour drugs

9-Oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester (delta 7-PGA1), an antitumour drug was incorporated into lipid microspheres of 0.2 micron diameter (lipo-delta 7-PGA1). In in-vivo experiments, lipo-delta 7-PGA1 had a significantly greater antitumour activity than free delta 7-PGA1 against P388 leukaemia. Lipo-delta 7-PGA1 slightly, but significantly, prolonged the survival time of mice inoculated with L1210 leukaemia, whereas free delta 7-PGA1 did not. Against MM46 ascites tumour, the survival time after treatment with 10 mg kg-1 of lipo-delta 7-PGA1 was significantly greater than that after the same dose of free delta 7-PGA1. The results suggest that lipid microspheres can be used as drug delivery carriers for lipid soluble antitumour agents.     

Evaluation of permeation through polymeric membranes as a model for the release of drugs from gelatin-acacia walled microcapsules

The evaluation of gelatin-acacia membranes as suitable models for the release of various N-7-theophylline derivatives from similar walled microcapsules prepared by a coacervation technique has been studied. The dependence of transfer rate on partition coefficient and phase boundary resistance is discussed. The validity of the diffusional film model is tested. The rapid release of theophylline and caffeine from this type of microcapsule is shown to agree with predictable theory.     

Human intestinal absorption of imidacloprid with Caco-2 cells as enterocyte model

In order to assess the risk to mammals of a chronic exposure to imidacloprid (IMI), we investigated its absorption with the human intestinal Caco-2 cell line. Measurements of transepithelial transport revealed an apparent permeability coefficient of 21.6 x 10(-6) +/- 3.2 x 10(-6) cm/s reflecting a 100% absorption. The comparison of apical to basal (A-B) and basal to apical (B-A) transports showed that the monolayer presents a basal to apical polarized transport. Studies of apical uptake demonstrated that the transport was concentration-dependent and not saturable from 5 to 200 microM. Arrhenius plot analysis revealed two apparent activation energies, Ea(4-12 degrees C) = 63.8 kJ/mol and Ea(12-37 degrees C) = 18.2 kJ/mol, suggesting two temperature-dependent processes. IMI uptake was equivalent when it was performed at pH 6.0 or 7.4. Depletion of Na+ from the transport buffer did not affect the uptake, indicating that a sodium-dependent transporter was not involved. Decrease of uptake with sodium-azide or after cell surface trypsin (Ti) treatment suggested the involvement of a trypsin-sensitive ATP-dependent transporter. Investigations on apical efflux demonstrated that initial velocities paralleled the increase of loading concentrations. A cell surface trypsin treatment did not affect the apical efflux. The lack of effect when the efflux was performed against an IMI concentration gradient suggested that an energy-dependent transporter was involved. However, the inhibition of P-glycoproteins (P-gp) and multidrug resistance-associated proteins (MRP) by taxol, vincristine, and daunorubicine had no effect on IMI intracellular accumulation suggesting the involvement of transporters distinct from classical ATP binding cassette transport (ABC-transport) systems. All results suggest that IMI is strongly absorbed in vivo by inward and outward active transporters.     

Implementation of the caco-2 cell culture model as a predictive tool for the oral absorption of drugs. In-house evaluation procedures

The Caco-2 cell culture model is widely used during drug development and lead optimization as a predictive tool for the oral absorption of drugs. In order to improve the reliability and quality of the results of Caco-2 experiments and to ensure that the system being used is functionally and enzymatically representative for the intestinal mucosa, it is important to perform a validation of the implemented Caco-2 system. In this paper, we summarize evaluation techniques to guarantee the in-house validity of the model. Theophyllin and sodium fluorescein are used as model compounds to evaluate passive transcellular and passive paracellular transport, respectively. Phenylalanine serves as a substrate to demonstrate active carrier mechanisms. Aminopeptidase and dipeptidyl peptidase are two brush border enzymes present in an active form in the Caco-2 culture model. The presence of an active efflux carrier mechanism is demonstrated with cyclosporin A as a substrate.     

Theoretical model studies of intestinal drug absorption V. Non-steady-state fluid flow and absorption

A reasonably realistic physical model has been described for the simultaneous longitudinal spreading, fluid flow and absorption of drugs in solution under non-steady-state conditions m the small intestinal tract. Various input cases included first-order and zero-order stomach emptying and input from an infinite drug reservoir at constant infusion rate. The mathematical solutions were unique and rigorous. Theoretical simulations using reasonable physical parameter values illustrated the interrelationships of the longitudinal spreading diffusion coefficient, flow rate, apparent permeability coefficient and intestinal length on the change in concentration—distance profiles with time and the kinetics of appearance of unabsorbed drug at the end of the intestinal segment. The model is accessible to the design of intestinal absorption experiments and data interpretation on a quantitative mechanistic basis and also provides the way for studying intestinal absorption under more realistic situations.