Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole-cyclodextrin formulations

The current research evaluated and compared the efficacy of hydroxybutenyl-beta-cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17-fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form.     

When Interactions Between Bile Salts and Cyclodextrin Cause a Negative Food Effect: Dynamic Dissolution/Permeation Studies with Itraconazole (Sporanox®) and Biomimetic Media

The marketed oral solution of itraconazole (Sporanox®) contains 40% (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption.In this study, we investigated the biorelevance of in vitro experiments by the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-β-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1).Both FaSSIF_V1 and HP-β-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effects were not additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-β-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and the duration of supersaturation depend on the concentrations of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact correlates well with what earlier had been observed in clinical studies for Sporanox® solution.In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of the latter on cyclodextrin-based drug formulations like Sporanox® Oral Solution and, at the same time, provide a deeper mechanistic insight.     

Design and evaluation of Lumefantrine – Oleic acid self nanoemulsifying ionic complex for enhanced dissolution

Background

Lumefantrine, an antimalarial molecule has very low and variable bioavailability owing to its extremely poor solubility in water. It is recommended to be taken with milk to enhance its solubility and bioavailability. The aim of present study was to develop a Self Nanoemulsifying Delivery system (SNEDs) of lumefantrine (LF) to achieve rapid and complete dissolution independent of food-fat and surfactant in dissolution media.

Methods

Solubility of LF in oil, co-solvent/co-surfactant and surfactant solution and emulsification efficiency of surfactant were analyzed to optimize the LF loaded self nanoemulsifying preconcentrate. Effect of LF-oleic acid complexation on emulsification, droplet size, zeta potential and dissolution were investigated. Effect of milk concentration and fat content on saturation solubility and dissolution of LF was investigated. Dissolution of marketed formulation and LF-SNEDs was carried out in pH 1.2 and pH 6.8 phosphate buffer.

Results

LF exhibited very high solubility in oleic acid owing to complexation between tertiary amine of LF and carboxyl group of oleic acid (OA). Cremophore EL and medium chain monoglyceride were selected surfactant and co-surfactant, respectively. Significantly smaller droplet size (37 nm), shift in zeta potential from negative to positive value, very high drug loading in lipid based system (> 10%), no precipitation after dissolution are the major distinguish characteristics contributed by LF-OA complex in the SNED system. Saturation solubility and dissolution study in milk containing media pointed the significant increment in solubility of LF in the presence of milk-food fat. LF-SNEDs showed > 90% LF release within 30 min in pH 1.2 while marketed tablet showed almost 0% drug release.

Conclusion

Self nanoemulsification promoting ionic complexation between basic drug and oleic acid hold great promise in enhancing solubility of hydrophobic drugs.     

Characterization of itraconazole semisolid dosage forms prepared by hot melt technique

The objective of this study was to formulate itraconazole semisolid dosage forms and characterize their physicochemical properties. Itraconazole and excipients such as polysorbate 80, fatty acids, fatty alcohols, oils and organic acids were melted at 160 degrees C. The fused solution was then cooled immediately at -10 degrees C to make wax-like semisolid preparations. Their physicochemical attributes were first characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectrometry. The solubility of itraconazole in semisolid preparations and their dispersability in the simulated gastric fluid were also determined. Our semisolid preparations did not show any distinct endothermic peak of a crystalline form of itraconazole around 160-163 degrees C. This suggested that it was changed into amorphous one, when it was formulated into semisolid preparations. In addition, the distinctive functional peaks and chemical shifts of itraconazole were well retained after processing into semisolid preparations. It could be inferred from the data that itraconazole was stable during incorporation into semisolid preparations by the hot melt technique. In particular, itraconazole semisolid preparations composed of polysorbate 80, fatty acids and organic acids showed good solubility and dissolution when dispersed in an aqueous medium. It was anticipated that the semisolid dosage forms would be industrially applicable to improving the bioavailability of poorly water-soluble drugs.     

The Effects of Bile Salts and Lipids on the Physicochemical Behavior of Gemfibrozil

Physicochemical effects caused by intestinal fluids on drugs in the gastrointestinal (GI) tract can be a contributing factor in food induced changes in bioavailability. To identify physicochemical properties of gemfibrozil that may be altered by endogenous and dietary lipids, in vitro studies were conducted in model systems approximating the conditions of the upper GI tract. Factors examined include pH, solubility in bile salt micellar and mixed micellar systems with monoolein and lecithin, effect of fatty acids, dissolution, wetting, and partitioning in triglyceride dispersions. Gemfibrozil was solubilized by glycocholate solutions in a manner typical of other lipids and a three-fold increase in solubility was observed over physiologic concentrations. Addition of increasing amounts of swelling amphiphiles (monoolein, lecithin) to glycocholate solutions resulted in a linear increase in solubility. Fatty acid salts had no effect on gemfibrozil solubilization by micellar solutions. The dissolution rate of gemfibrozil increased slightly in the presence of glycocholate relative to buffer, however, addition of monoolein increased the dissolution rate three-fold. In triglyceride dispersions of mixtures of lipids, monoolein increased the fraction of drug in the micellar sub-phase, whereas fatty acid reduced it. The results indicate that in the conditions of the fed state gemfibrozil solubility and dissolution could be substantially increased relative to the conditions in the fasted state.Presented in the part at the 8th Annual Meeting of the American Association of Pharmaceutical Scientists, Lake Buena Vista, Florida, November 14–18, 1993.     

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.     

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.     

Improved understanding of the effect of food on drug absorption and bioavailability for lipophilic compounds using an intestinal pig perfusion model

The purpose of this study was to investigate the relative importance of mechanisms behind the effect of food on the intestinal absorption and bioavailability for low solubility compounds by applying a porcine single-pass perfusion model. Nanoparticle suspensions of the model compounds, danazol and cyclosporine were perfused through the jejunum in isotonic fluid alone (control) and isotonic fluid with a P-glycoprotein (P-gp) inhibitor (verapamil) or dietary and endogenous lipids added. The drugs were also administered as saturated solutions in the isotonic fluid containing lipids. Administration of cyclosporine together with verapamil increased the absorption compared to the control (1.6 times) suggesting an effect on jejunal permeability. However, addition of dietary lipids to the media led to a 50% reduction in the absorption of cyclosporine indicating lack of major effects by P-gp inhibition by lipids in vivo. The absorption of danazol was increased (2.6 times) when administered as a nanosuspension in lipid containing media compared to the control, but decreased (60%) when administered as a solution in the same media. This shows how important dissolution of the drug nanoparticles is in drug absorption. The difference in the effect of lipids in the absorption of cyclosporine and danazol when administered as nanosuspensions may be due to different distribution to the colloidal structures present in the media, thereby rendering the drugs’ different diffusion rates in the perfused segment. In conclusion, solubilisation seems to be a more important factor than P-gp inhibition as an explanation for the food–drug interaction observed for several low solubility drugs. In addition, the partition into different colloidal structures seems to play a major role in the dissolution and absorption of poorly soluble drugs.     

In vitro characterization of some biopharmaceutical properties of praziquantel

In several studies of patients with neurocysticercosis under treatment with praziquantel (PZQ), the pharmacokinetic data were difficult to interpret probably because of the low solubility as well as its variable oral bioavailability. Because there is limited information available regarding the biopharmaceutical properties of PZQ, the aim of this work was to evaluate the absorption characteristics of the drug and its dissolution behaviour in simulated media. Additionally, its in vitro protein binding and displacement by highly bound drugs was evaluated. Permeability evaluation was carried out by using Caco-2 cells. Dissolution release profiles were evaluated using the USP apparatus and the following dissolution media: HCl containing 2mg of sodium laurylsulfate per milliliter, milk, FeSSIF and FaSSIF. Protein binding of PZQ was carried out by equilibrium dialysis. Results showed that praziquantel was absorbed by passive diffusion. The apparent permeability constant value was 4.4x10(-5) cm/s. Binding was not influenced by the addition of highly bound drugs. Dissolution from a tablet formulation showed that the rate of praziquantel was dependent on the components of the media. Although the simulated media could explain the influence of the lipids on praziquantel absorption, they were not able to forecast the influence of carbohydrates. Further refinements are required to explain the in vivo data.     

In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media.

The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Müllertz, A. 2005. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug, Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiologically most relevant correlation with in vivo results was achieved with a medium containing 6.3 mM bile salts and 1.25 mM phospholipids (8 ml/min). A medium containing 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 ml/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissolution method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium composition were important for the dissolution of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.     

Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying

Purpose

The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation.

Methods

Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes.

Results

The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25–40 mg per g of solution at 25°C and 200 mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution.

Conclusions

A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.

     

Influence of Simulated Gastrointestinal Fluids on Polymorphic Behavior of Anhydrous Carbamazepine Form III and Biopharmaceutical Relevance

The dissolution behavior and bioavailability of carbamazepine (CBZ) is rate-limited by formation of carbamazepine dihydrate (CBZ-D) in dissolution fluids. The present investigation involves formation and biopharmaceutical evaluation of CBZ-D obtained from simulated gastrointestinal fluids. The results obtained from solubility studies revealed that formation of CBZ-D was pH-dependent. The minimum solubility of 115 ± 1.7 mg/L obtained with simulated gastric fluid without pepsin indicates that the strongly acidic pH favors formation of CBZ-D and it was confirmed by the powder X-ray diffractography. Differential scanning calorimetry thermograms of samples revealed formation of CBZ-D and subsequent transition of CBZ form I. The percentage relative crystallinty for dihydrate was found to be 77.51%. Triton X present in fasted-state simulated gastric fluid (FaSSGF) increased the extent of crystallinty in dissolution media upto 86.50%. However, CBZ-D obtained from FaSSGF showed highest solubility of 335.36 ± 4.813 mg/L and dissolution of 36.74% in 60 min. This may be due to presence of surfactant on the surface of CBZ-D. The linear correlation was established between pH of simulated gastrointestinal fluids and percentage relative crystallinty with a correlation coefficient of 0.9904. CBZ form I had a better dissolution profile than any of the other polymorphs. Stabilization of CBZ form I in in vitro and in vivo conditions using pharmaceutical polymers in dosage form may bring better clinical outcomes than present-day therapies.     

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.     

Preparation and evaluation of solid dispersion of meloxicam with skimmed milk

Meloxicam (MLX), a non-steroidal anti-inflammatory drug (NSAID) and a selective COX-2 inhibitor is a water insoluble drug (about 12 microg/ml). In order to improve the aqueous solubility of the drug and its dissolution rate, physical mixture and solid dispersions with skimmed milk were prepared and investigated. Enhancement of aqueous solubility of MLX was observed with solid dispersion of the drug with skimmed milk due to amino acids and surface active agents content in the milk, which can be used for the treatment of gastric disturbance. Rotary vacuum evaporation technique was used to prepare solid dispersion. Results showed that the solubility of solid dispersion of the drug was almost three times greater than the pure drug. Similarly, the solid dispersion of the drug indicated a significant improvement in the dissolution of the drug as compared to the physical mixture and the pure drug. Differential scanning calorimetry, X-ray diffraction and scanning electron microscopic analysis revealed the formation of solid dispersion of the drug with skimmed milk.     

Solubility and stability of dalcetrapib in vehicles and biological media

Dalcetrapib solubility was determined in aqueous and in non-aqueous vehicles and in biorelevant media. In a pure aqueous environment the solubility was low but could be increased by addition of surfactants or complexing agents. This was also reflected in the solubility seen in simulated gastrointestinal (GI) fluids, with almost no solubility in simulated gastric fluid, but reasonable solubilisation in simulated intestinal fluids containing lecithin and bile salt. Additionally, the stability of dalcetrapib was determined in simulated GI fluids with and without pancreatic lipase. In solutions without lipase, dalcetrapib was slowly hydrolysed, but in the presence of lipase the hydrolysis rate was significantly faster depending on pH and enzyme activity. In biological fluids, dissolved dalcetrapib appeared to behave similarly being rapidly hydrolysed in human intestinal fluids with a half-life below 20s with no degradation observed in human gastric fluids at low pH. The results provide supportive evidence that absorption is higher under fed conditions and indicate lipase inhibitors might interfere with oral absorption of dalcetrapib.     

Food-derived bioactive peptides--opportunities for designing future foods

Dietary proteins are known to carry a wide range of nutritional, functional and biological properties. Nutritionally, the proteins are a source of energy and amino acids, which are essential for growth and maintenance. Functionally, the proteins contribute to the physicochemical and sensory properties of various protein-rich foods. Furthermore, many dietary proteins possess specific biological properties which make these components potential ingredients of functional or health-promoting foods. Many of these properties are attributed to physiologically active peptides encrypted in protein molecules. Particularly rich sources of such peptides are milk and egg, but they are also found in meat of various kinds as well as many plants. These peptides are inactive within the sequence of parent protein and can be released during gastrointestinal digestion or food processing. Depending on the amino acid sequence, these peptides may exert a number of different activities in vivo, affecting, e.g., the cardiovascular, endocrine, immune and nervous systems in addition to nutrient utilization. There is increasing commercial interest in the production of bioactive peptides from various sources. Industrial-scale production of such peptides is, however, hampered by the lack of suitable technologies. Bioactive peptides can also be produced from milk proteins through fermentation of milk, by starters employed in the manufacture of fermented milks or cheese. In particular, antihypertensive peptides have been identified in fermented milk, whey and ripened cheese. A few of these peptides have been commercialised in the form of fermented milks. There is a need to develop technologies which retain or even enhance the activity of bioactive peptides in food systems. Also, it is essential to study the optimum utilization of such peptides during passage through the gastrointestinal tract.     

Study of the influence of sodium taurocholate (STC) and sodium glycocholate (SGC) on the mass transfer of certain drugs. Diethylstilbestrol

Diethylstilbestrol had a solubility of 1.05 mg/100 ml and a negligible dissolution efficiency in phosphate buffer. The presence of bile salts raised the solubility to a value as high as 219.5 and 218.25 mg/100 ml and the dissolution efficiency to 57.7 and 46.4% for STC and SGC systems, respectively. The addition of lecithin, cholesterol, lecithin plus cholesterol or fatty acids (lauric, myristic, palmitic) or monoglycerides (glyceryl monolaurate, glyceryl monomyristate or glyceryl monostearate) to STC or SGC aqueous solutions did not have any significant effect on the solubility or dissolution rate of the drug. However, the simultaneous presence of these additives in the medium enhanced the solubility but the dissolution rate remained practically unchanged.     

Dynamic Dissolution Testing To Establish <Emphasis Type="BoldItalic">In Vitro</Emphasis>/<Emphasis Type="BoldItalic">In Vivo</Emphasis> Correlations for Montelukast Sodium,a Poorly Soluble Drug

Purpose  The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations. Methods  Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus 2. Computer simulations were performed using GastroPlus™. Biorelevant dissolution media (BDM) prepared using bile salts and lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlus™ to simulate the in vivo profiles of the drug. Results  The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best. Conclusions  Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus.     

Effect of protein on the absorption of phenytoin through everted gut preparations

The transfer of phenytoin across everted gut membrane has been measured both from solutions and from media where the drug is dissolving at different pH. Introduction of protein into the mucosal medium caused varying effects. Protein binding in the mucosal solution causes a decrease in the apparent transfer rate. However, in accord with previous findings, at pH 4 both the solubility and dissolution rate of phenytoin increase in the presence of protein, and this can lead to increased transfer rates. Effects such as these may account for the effect of food on phenytoin bioavailability.     

Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media

This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g. simulated gastric fluid or dissolution media) can result in an underestimation of solubility of some weak bases. We systematically study this phenomenon and provide evidence (chromatography and pXRD) for the first time that the decrease in solubility is likely due to formation of a less soluble salt/complex between the protonated form of the weak base and lauryl sulfate anion.