Forecasting the Oral Absorption Behavior of Poorly Soluble Weak Bases Using Solubility and Dissolution Studies in Biorelevant Media

Pharmaceutical Research -     

Effect of Sodium Lauryl Sulfate in Dissolution Media on Dissolution of Hard Gelatin Capsule Shells

PURPOSE: Sodium lauryl sulfate (SLS) is a commonly used surfactant in dissolution media for poorly water soluble drugs. However, it has occasionally been observed that SLS negatively impacts the dissolution of drug products formulated in gelatin capsules. This study investigated the effect of SLS on the dissolution of hard gelatin capsule shells. METHODS: The USP paddle method was used with online UV monitoring at 214 nm (peptide bond). Empty size #0 capsule shells were held to the bottom of the dissolution vessel by magnetic three-prong sinkers. RESULTS: SLS significantly slowed down the dissolution of gelatin shells at pH < 5. Visually, the gelatin shells transformed into some less-soluble precipitate under these conditions. This precipitate was found to contain a higher sulfur content than the gelatin control sample by elemental analysis, indicating that SLS is part of the precipitate. Additionally, the slowdown of capsule shell dissolution was shown to be dependent on the SLS concentration and the ionic strength of the media. CONCLUSIONS: SLS interacts with gelatin to form a less-soluble precipitate at pH < 5. The use of SLS in dissolution media at acidic pH should be carefully evaluated for gelatin capsule products.     

Estimation of intragastric drug solubility in the fed state: comparison of various media with data in aspirates

The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake‐flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus^® to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk‐based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5–27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconazole (within 20%) but overestimated the intragastric values of dipyridamole by a factor of 2–19. For both drugs, the solubility in milk digested with pepsin and lipase predicted the solubility in aspirates collected 60 min after meal administration, whereas at other times it overestimated the intragastric solubility (by a factor of <5). Both the use of biorelevant media and simulation of intragastric digestion are necessary for the prediction of drug solubility in the fed stomach. Milk digested with pepsin and lipase enabled the estimation of the intragastric solubility of dipyridamole and ketoconazole at 1 h after meal intake. Simulation of vesicle/micellar structures seems to be key for the prediction of intragastric solubility in the fed stomach. Copyright © 2009 John Wiley & Sons, Ltd.     

Colloidal Structures in Media Simulating Intestinal Fed State Conditions with and Without Lipolysis Products

Purpose  To study the ultrastructure of biorelevant media and digestion products of self-nanoemulsifying drug delivery system (SNEDDS) at high level BS/PL conditions. Methods  Cryogenic transmission electron microscopy (Cryo-TEM) was employed to visualize the colloid structures in the biorelevant media and lipolytic products generated during hydrolysis of a SNEDDS formulation. Their electrical properties were investigated by measuring their ζ-potential values. Results  In the biorelevant media, vesicles (either unilamellar or multilamellar) and bilayer fragments are visualized. Occasionally, vesicles with an internal deformed structure are recognized, suggesting surface tension or uneven lateral stress. Visualization studies of the intermediate colloidal phases produced during digestion of a SNEDDS using the in vitro lipolysis model revealed the formation of similar structures as previously reported. The ζ-potential of the media was negatively charged and decreased from −23 to −35 mV with increasing surfactant/lipid load. Lower ζ-potential values (−16 mV) obtained for the structures formed during the lipid hydrolysis of the SNEDDS were probably due to the presence of calcium, which shields the surface, thereby reducing the charge. Conclusions  The diversity of these vesicles in terms of size, lamellarity, and internal organization advocate their important role during lipid digestion in the gastrointestinal milieu.     

Theoretical Analysis of Drug Dissolution in Micellar Media

A new theoretical approach combining convective diffusion and surface dissolution kinetics has been applied to micellar systems and tested on experimental data available for both rotating disk apparatus and particles. The micelles are shown to be in the state of dynamic equilibrium with solution for most systems but nanoparticles. For ionizable molecules, the variation of partition coefficient across diffusion boundary layer may affect the diffusivity. The intrinsic dissolution rate is generally a nonlinear function of the equilibrium concentration, c₀, in which the diffusion kinetic coefficient, β_D, surface kinetic coefficient, β₀, and total kinetic coefficient of dissolution, β, all typically decrease as functions of c₀ (or increasing micellar concentration, M_c). The observed absolute values of β₀ are usually in the order of 10^?3-10^?2 cm/s and strongly dependent on the nature of surfactant and solute molecules. For dissolution of particles, the surface kinetics tend to become the rate-limiting step.     

Characterization of the Human Upper Gastrointestinal Contents Under Conditions Simulating Bioavailability/Bioequivalence Studies

Purpose This study was conducted to compare the luminal composition of the upper gastrointestinal tract in the fasted and fed states in humans, with a view toward designing in vitro studies to explain/predict food effects on dosage form performance. Methods Twenty healthy human subjects received 250 mL water or 500 mL Ensure plus^? (a complete nutrient drink) through a nasogastric tube and samples were aspirated from the gastric antrum or duodenum for a period up to 3.5 h, depending on location/fluid combination. Samples were analyzed for polyethylene glycol, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, and bile salts. Results Following Ensure plus^? administration, gastric pH was elevated, buffer capacity ranged from 14 to 28 mmoL L⁻¹ ΔpH⁻¹ (vs. 7–18 mmol L⁻¹ ΔpH⁻¹), contents were hyperosmolar, gastric pepsin levels doubled, and surface tension was 30% lower than after administration of water. Post- and preprandial duodenal pH values were initially similar, but slowly decreased to 5.2 postprandially, whereas buffer capacity increased from 5.6 mmol L⁻¹ ΔpH⁻¹ (fasted) to 18–30 mmol L⁻¹ ΔpH⁻¹ (p< 0.05). Postprandial surface tension in the duodenum decreased by >30%, bile salt levels were two to four times higher, luminal contents were hyperosmotic, and the presence of peptides and sugars was confirmed. Conclusions This work shows that, in addition to already well characterized parameters (e.g., pH, and bile salt levels), significant differences in buffer capacity, surface tension, osmolality, and food components are observed pre-/postprandially. These differences should be reflected in test media to predict food effects on intralumenal performance of dosage forms.     

Solute Absorption from the Airways of the Isolated Rat Lung. I. The Use of Absorption Data to Quantify Drug Dissolution or Release in the Respiratory Tract

Coprecipitates of fluorescein and magnesium hydroxide demonstrate delayed absorption relative to fluorescein solutions when administered to the airways of the isolated perfused rat lung (IPRL). Perfusate concentration vs time profiles showed that dissolution and not epithelial permeability was the rate-controlling factor in the airway-to-perfusate transfer process. A simple data deconvolution method was developed to determine the fluorescein release from the microparticulate coprecipitates in the airways. The deconvolution technique is generally applicable and provides values for undissolved solute remaining in the airways as a function of time provided that (a) significant binding and/or metabolism does not occur, (b) absorption from solution is apparent first order, and (c) all solid or dissolved material reaching perfused regions is absorbed within the lifetime of the preparation. Increased release rates of fluorescein occurred from precipitates containing greater starting concentrations of the dye. Dissolution profiles were similar to those that occur for log-normally distributed powders. The analysis of two unusual time profiles implied that the regional distribution of solid and dissolved material, between perfused areas and nonperfused areas, could be nonhomogeneous despite the use of a standardized dosing technique. The studies describe a method of using the IPRL with the potential to screen aerosol formulations for extended dissolution in the respiratory tract.     

The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids

Purpose This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF). Methods Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents. Results Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%). Conclusions Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.     

Drugs in the Brazilian Print Media: An Exploratory Survey of Newspaper and Magazine Stories in the Year 2000

Print media is one of the key factors for defining public opinion and setting public policies regarding drugs. Therefore, surveying its content should provide us with a better understanding of the situation. The few existing surveys on this issue in Brazil point out discrepancies between print media and public health. The objective of the present survey is to enhance the analysis of drug-related stories in the Brazilian print media, based on a new time frame, in the year 2000. Major newspapers and magazines of all Brazilian state capitals have been surveyed throughout year 2000, with 4,669 stories presenting drugs as their main topic. A random sample of 964 stories underwent content analysis. Approximately half the stories (49.6%) dealt with smuggling- and repression-related issues. The remainder of the stories (50.4%) approached health, legislation, and public policy issues. Tobacco was the most widely discussed drug, with stories focusing mainly on damage caused by use and on measures for reducing consumption rates among the population. Articles about cocaine, also featured frequently in the print media, dealt mainly with the issues of drug dealing and of damage caused by cocaine use. Regarding marijuana, in addition to the law enforcement repressive approach, some articles dealt with decriminalization and therapeutic use. Articles about alcoholic beverages, featured less frequently in the print media, approached the subject matter from various angles. The number of stories on solvents and psychotropic medication was negligible. The results confirm discrepancies between print media coverage and epidemiology. They also indicate that each drug is approached differently, allowing for a better understanding of the “social climate” in Brazil regarding each drug. Of all possible social interventions for dealing with the issue repression stands out, whereas stories about treatment and damage reduction are relatively scarce. These findings suggest the need for improved communication between journalists and health professionals.     

Changes in the Solid State of Nicergoline,a Poorly Soluble Drug,Under Different Grinding and Environmental Conditions: Effect on Polymorphism and Dissolution

Nicergoline native crystals (Form I) were subjected to different grinding methods for 15, 30, 45, and 60 min: Method A, grinding at 20°C under air atmosphere; Method B, grinding in presence of liquid nitrogen under air atmosphere; Method C, grinding at 20°C under nitrogen atmosphere; and Method D, grinding in presence of liquid nitrogen under nitrogen atmosphere. Scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, thermogravimetry, and infrared spectroscopy were used to follow changes in the particle size and in crystalline structures. Batches from Methods A and C underwent partial amorphization immediately after grinding; Form II was obtained by heating these partially amorphous forms or after spontaneous crystallization after 1 and 5 months storage. Method B promoted the hydration of nicergoline to a monohydrate form. Batch D was stable under grinding and neither amorphization nor hydration were observed. The best intrinsic dissolution rate was that of metastable Form II, followed by Form I, while the worst was that of the Method B monohydrate form. The slowest particle dissolution was observed for hydrated particles, because of the lowest IDR, while the most rapid was exhibited by batch D, because of the very small particle size.     

A Clinical Single-Pass Perfusion Investigation of the Dynamic in Vivo Secretory Response to a Dietary Meal in Human Proximal Small Intestine

Purpose To investigate the gastrointestinal secretory and enzymatic responses to a liquid meal during in vivo perfusion of the proximal human jejunum. Methods Human intestinal fluid was collected from the proximal jejunum by single-pass in vivo perfusion (Loc-I-Gut). The fluid was quantitatively collected at 10-min intervals during 90 min while perfusing a nutritional drink at 2 mL/min. Quantification of lipids in the fluid leaving the segment was performed by using novel chromatographic methods. Results The overall bile acid concentration varied between 0.5 and 8.6 mM with a peak level 40 min after the start of the liquid meal perfusion. The total concentration of phospholipids was between 0.1 and 3.9 mM and there was a rapid degradation of phosphatidylcholine to lysophosphatidylcholine. The tri-, di-, monoglycerides and free fatty acid levels increased sharply in the beginning and reached steady-state levels between 7 and 9.5 mM. Conclusions There is a rapid secretion of bile in response to food. Most of the dietary lipids are found in the form of their degradation products in vivo in human jejunum. This novel in vivo characterization, based on direct and high-recovery sampling of intestinal fluids, forms a basis for further development of improved in vitro drug dissolution test media.     

Dissolution of lonizable Drugs into Unbuffered Solution: A Comprehensive Model for Mass Transport and Reaction in the Rotating Disk Geometry

A model has been developed to describe the mass transport and reaction of ionizable compounds where mass transfer is caused by convection and diffusion from a rotating disk. Dissolution rates of benzoic acid, 2-naphthoic acid, and indomethacin in aqueous solutions of high ionic strength (I = 0.5 with potassium chloride) at 25°C were investigated. The model includes the effects of diffusion, convection, and simultaneous acid/base reaction at all points in the region adjacent to the dissolving solid. The solution of the transport equations is obtained numerically with an iterative algorithm which uses (a) closure of all material balances and (b) equilibria at the solid/liquid surface as constraints. The model solution yields both the flux of the dissolving acid and the concentration profile of each component. Reduced values of all reaction rate constants are used in the region adjacent to the dissolving surface to allow convergence of the computation. Although nonequilibrium concentration values are calculated, it is shown that the theoretical dissolution rate determined as the solution of the model is insensitive to the magnitude of the rate constants as their maximum useable values are approached. Comparisons of the model results with experimentally determined fluxes show close agreement and confirm that the transport mechanisms in the model formulation are consistent with the measured values. Further, the inclusion of convection allows accurate calculations without utilization of an arbitrary boundary layer thickness. Accurate dissolution rates can be determined using this technique under a wide range of conditions, except at low pH.     

New Frontiers in Gut Nutrient Sensor Research: Free Fatty Acid Sensing in the Gastrointestinal Tract

Utilizing the human genome database, the recently developed G-protein–coupled receptors (GPCRs) deorphanizing strategy successfully identified multiple receptors of free fatty acids (FFAs). FFAs have been demonstrated to act as ligands of several GPCRs (FFAR1, FFAR2, FFAR3, and GPR120). These fatty acid receptors are proposed to play critical roles in various types of physiological homeostases. FFAR1 and GPR120 are activated by medium- and long-chain FFAs. In contrast, FFAR2 and FFAR3 are activated by short-chain FFAs. It has been elucidated that these four receptors are expressed in the gastrointestinal tract and have many essential roles as sensors of FFA. In this review, we summarize the physiological and pharmacological function of the receptors in the gastrointestinal tract.     

Zinc Uptake in Five Sectors of the Rat Gastrointestinal Tract: Kinetic Study in the Whole Colon

Purpose. The uptake of zinc as acexamic acid salt in the rat gastrointestinal tract, using an in situ static technique, was studied. Our aim was to investigate an absorption window for zinc and the uptake kinetics in the colon. Methods. To detect selectivity phenomena in zinc absorption, buffered saline solutions of zinc (50 µg/ ml) were perfused in stomach, whole colon and three 33-cm fractions of the small intestine (proximal, middle and distal segments). To characterize zinc uptake kinetics in whole colon, five different zinc concentrations (5, 25, 50, 150 y 250 µg/ml) were assayed. Zinc secreted into the gastrointestinal tract during the experiments was deducted from the uptake. Results. Zinc secretion was characterized as an apparent zero-order process for all the studied segments (mean secretion rate = 0.10 ± 0.03 µg/(ml × min)). The stomach exhibited little ability to absorb zinc (apparent first order rate constant = 0.17 ± 0.07 h^–1), whereas the highest transport rates were found in the last two thirds of the small intestine and colon (first order constants: 0.66 ± 0.13 h^–1, 1.00 ± 0.06 h^–1,0.97 ± 0.14 h^–1, 0.96 ± 0.19h^–l for proximal, middle, distal and colon segments, respectively). Zinc uptake in the colon was characterized by means of a Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 0.36 ± 0.02 µg/(ml × min), Km = 18.01 ± 0.40 µg/ ml and Ka = 0.40 ± 0.01 h^–l. Conclusions. Zinc is preferably absorbed in the middle and distal parts of the rat gastrointestinal tract. In the colon a saturable mechanism may be involved in apparent absorption.     

Use of biorelevant media for assessment of a poorly soluble weakly basic drug in the form of liquisolid compacts: in vitro and in vivo study

The purpose of this work is to use biorelevant media to evaluate the robustness of a poorly water soluble weakly basic drug to variations along the gastrointestinal tract (GIT) after incorporation in liquisolid compacts and to assess the success of these models in predicting the in vivo performance. Liquisolid tablets were prepared using mosapride citrate as a model drug. A factorial design experiment was used to study the effect of three factors, namely: drug concentration at two levels (5% and 10%), carriers at three levels (avicel, mannitol and lactose) and powder excipients ratio (R) of the coating material at two levels (25 and 30). The in vitro dissolution media utilized were 0.1?N HCl, hypoacidic stomach model and a transfer model simulating the transfer from the stomach to the intestine. All compacts released above 95% of drug after 10?min in 0.1?N HCl. In the hypoacidic model, the compacts with R 30 were superior compared to R 25, where they released >90% of drug after 10?min compared to 80% for R 25. After the transfer of the optimum compacts from Simulated gastric fluid fast (SGFfast) to fasted state simulated intestinal fluid, slight turbidity appeared after 30?min, and the amount of drug dissolved slightly decreased from 96.91% to 90.59%. However, after the transfer from SGFfast to fed state simulated intestinal fluid, no turbidity or precipitation occurred throughout time of the test (60?min). In vivo pharmacokinetic study in human volunteers proved the success of the in vitro models with enhancement of the oral bioavailability (121.20%) compared to the commercial product.     

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.     

Assessing the Association Between E-Cigarette Use and Exposure to Social Media in College Students: A Cross-Sectional Study

Background: Social media platforms provide an indirect medium for encouraging e-cigarette use between individuals and also serve as a direct marketing tool from e-cigarette brands to potential users. E-cigarette users share information via social media that often contains product details or health-related claims. Objective: Determine whether e-cigarette use is associated with exposure to e-cigarettes on social media in college students. Methods: Data from a sample of 258 college students was obtained via a clicker-response questionnaire (90% response rate). Demographic, lifetime and current e-cigarette/cigarette use, and e-cigarette exposure via social media (peer posts or advertisements) were examined. Logistic regression was used to assess the relationship between lifetime and current e-cigarette use and viewing peer posts or advertisements on social media while adjusting for cigarette use and self-posting about e-cigarettes. Results: Overall, 46% of participants reported lifetime e-cigarette use, 16% current e-cigarette use, and 7% were current dual users of e-cigarettes and cigarettes. There were positive and significant associations between lifetime e-cigarette use and viewing peer posts (aOR = 3.11; 95% CI = 1.25–7.76) as well as advertisements (aOR = 3.01; 95% CI = 1.19–7.65) on e-cigarettes via social media after adjusting for cigarette use. Current e-cigarette use was only significantly associated with viewing peer posts via social media (aOR = 7.58; 95% CI = 1.66–34.6) after adjusting for cigarette use. Conclusions/Importance: Almost half of college students view peer posts and advertisements on e-cigarettes via social media. This exposure is associated with individual e-cigarette use. Continued efforts to examine online e-cigarette content are needed to help future interventions decrease e-cigarette use.     

New Frontiers in Gut Nutrient Sensor Research: Nutrient Sensors in the Gastrointestinal Tract: Modulation of Sweet Taste Sensitivity by Leptin

The ability to perceive sweet compounds is important for animals to detect an external carbohydrate source of calories and has a critical role in the nutritional status of animals. In mice, a subset of sweet-sensitive taste cells possesses leptin receptors. Increase of plasma leptin with increasing internal energy storage in the adipose tissue suppresses sweet taste responses via this receptor. The data from recent studies indicate that leptin may also act as a modulator of sweet taste sensation in humans with a diurnal variation in sweet sensitivity. The plasma leptin level and sweet taste sensitivity are proposed to link with post-ingestive plasma glucose level. This leptin modulation of sweet taste sensitivity may influence an individual’s preference, ingestive behavior, and absorption of nutrients, thereby playing important roles in regulation of energy homeostasis.     

Mucus Gel Thickness and Turnover in the Gastrointestinal Tract of the Rat: Response to Cholinergic Stimulus and Implication for Mucoadhesion

The thickness of the mucus gel and its turnover rate were measured in the stomach, proximal jejunum, cecum and proximal colon of the rat, using microscopy and staining techniques. The specific mucus-secretory responses to carbachol-induced cholinergic stimulus in these locations were also studied. The mucus gel was found to be the thinnest (18 ±1 microns) in the cecum, and the thickest in the stomach (39 ±14 microns). The effect of carbachol on mucus secretion was profound and dose dependent in the stomach, and less profound, although still dose dependent, in the proximal jejunum. The least responsive organs were the cecum and the proximal colon, where no effect was observed after three doses of carbachol. Mucus secretion rate was significantly higher in the jejunum (1.1 ± 0.5 µg glucose equivalent min^–1 cm^–2) than in the colon (0.5 ± 0.2 µg glucose equivalent min^–l cm^–2). Also, the proximal jejunum was more responsive to the carbachol stimulus (mucus secretion rate of 5.4 ±2.2 µg glucose equivalent min^–1 cm^–2 after carbachol treatment) than the colon (mucus secretion rate of 1.0 ±0.4 µg glucose equivalent min^–l cm^–2 after carbachol treatment). In vitro mucoadhesion studies with Polycarbophil disks were performed in the mucosal tissues of the stomach, jejunum, cecum and proximal colon of the rat with and without cholinergic (carbachol) stimulus. The adhesion force in the cecum and the colon was significantly stronger than in the stomach and proximal jejunum when the studies were performed at pH 2. Carbachol treatment did not significantly change the mucoadhesion of Polycarbophil disks. It is concluded that in the gastrointestinal tract of the rat the colon and the cecum are more suitable locations for the mucoadhesion than the stomach and the jejunum because: (1) their mucus turnover is lower, (2) their sensitivity to mucus secretory stimulus is lower, and (3) their Polycarbophil adherence properties are stronger.