Fasted State Simulated Intestinal Fluid Research Articles

Impact of components of biorelevant media on solubilization of methotrexate and sulfasalazine by Pluronic F127

Pluronics are micelle-based solubilizers, improving the therapeutic potential of orally administrated drugs. In this connection, solubilizing action of Pluronics is being intensively studied in standard buffers simulating gastrointestinal fluids and consisting of inorganic components. However, human gastrointestinal fluids have more complicate composition due to the presence of organic compounds such as enzymes, mucus, and bile, which are able to form supramolecular aggregates and influence the solubilizing effect of Pluronics. Therefore, the use of specially designed biorelevant media is a promising approach to assessing the effectiveness of solubilizing activity of Pluronics in vitro.Based on this, we studied the solubilization of poorly soluble methotrexate and sulfasalazine, which are used in the treatment of autoimmune and oncological diseases, by Pluronic F127 in Fasted State Simulated Gastric Fluid and Fasted State Simulated Intestinal Fluid. Taurocholic acid and lecithin being the main components of these biorelevant media form micelles and thereby enhance the solubility of drugs that are insoluble or sparingly soluble in water. The affinity of drugs under consideration to the micelles of different nature, which are present in the dissolution medium, is examined in this work. The possible competing interactions of drug-micelle and drug-unimer are discussed in terms of the ionization state of drug molecules and the nature of surfactants.

Development of polymer-encapsulated microparticles of a lipophilic API-IL and its lipid based formulations for enhanced solubilisation

Active Pharmaceutical Ingredient-Ionic liquids (API-ILs) have the potential to improve the bioavailability of BCS Class IV Drugs. However, the problematic physical handling properties of room temperature API-ILs have impaired clinical and commercial exploitation to date. Lipid-based formulations (LBFs) are used to improve the absorption of drugs with limited bioavailability. Nonetheless, LBFs face limitations such as low drug loading capacity and sub-par physical stability. A platform for transforming API-ILs into solid forms at high loadings via spray encapsulation with polymers has been developed and previously demonstrated for hydrophilic API-ILs. The current work demonstrates that this platform technology can be applied to a lipophilic API-IL of the BCS Class IV API, chlorpromazine, and to multi-component solutions comprising API-IL and a LBF. Furthermore, solidification of a type IIIB, liquid LBF was achieved via spray encapsulation with cellulose- and methacrylate- based polymers for the first time. The spray-encapsulated formulations had excellent physical handling properties, and successfully eluted the API-IL in aqueous media. The chlorpromazine release profiles from the API-IL, the API-IL containing LBF, and the solidified formulations, were evaluated in vitro using phosphate buffer (pH 6.8) and fasted state simulated intestinal fluid (FaSSIF). Spray-encapsulated formulations exhibited improved release profiles compared to the liquid formulations. Overall, these findings indicate that phase-separated, polymeric, solid formulations of liquid API forms represent a promising platform technology for developing oral solid dosage forms of poorly bioavailable drugs.

Characterization of macrocyclic peptide drug interactions with bile salts and biorelevant colloids via single amino acid mutations and 1H nuclear magnetic resonance (NMR) spectroscopy

There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e. bile salt micelles and bile salt-phospholipid mixed micelles, via dialysis membrane flux experiments and proton nuclear magnetic resonance (1H NMR) spectroscopy. A modified alanine scan was employed to generate eight mutated octreotide analogs; the impact of individual amino acid mutations on peptide dialysis membrane flux rates in micellar (trihydroxy and dihydroxy) bile salt solutions as well as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) was evaluated and compared against the parent peptide, octreotide. We show that octreotide interacts more strongly with dihydroxy bile salt micelles than trihydroxy bile salt micelles in solution, and in FaSSIF/FeSSIF media, octreotide mainly interacts with the phospholipid component. These interactions are largely mediated by hydrophobic interactions of octreotide's aromatic residues as well as electrostatic interactions between octreotide's basic Lys residue and terminal amine.

Dissolution, phase behavior and mass transport of amorphous solid dispersions in aspirated human intestinal fluids

Amorphous solid dispersions (ASDs) typically show improved dissolution and generate supersaturated solutions, enhancing the oral bioavailability of poorly soluble drugs. To gain insights into intraluminal ASD behavior, we utilized two poorly soluble drugs with different crystallization tendencies, atazanavir and posaconazole, prepared as ASDs at a 10% drug loading with hydroxypropyl methylcellulose acetyl succinate (HPMCAS). We evaluated their release in aspirated fasted-state human intestinal fluid (FaHIF), and multi-component fasted-state simulated intestinal fluid (composite-FaSSIF), characterizing the supersaturation profiles and drug-rich nanodroplets that formed. Complete release was observed for atazanavir ASDs over a 90 min period. Flux for dissolved atazanavir ASDs remained high over the experimental time period of 3 h. In contrast, posaconazole solution concentrations were initially high and then decreased. Likewise, flux was initially high and then decreased where these changes are attributed to crystallization of the drug. Generation of spherical nano-sized amorphous droplets of ∼100-150 nm was found to occur in ex vivo FaHIF media for both ASDs, maximizing the diffusive flux during the supersaturation window. Moreover, buffer capacity differences were postulated to influence release rates of ASDs in simulated vs aspirated fluids. Importantly, the solution phase phenomena observed during ASD release in simulated fluids, namely amorphous nanodroplet formation and drug crystallization, were also found to occur in aspirated luminal fluids.

Characterisation of colloidal structures and their solubilising potential for BCS class II drugs in fasted state simulated intestinal fluid

A suite of fasted state simulated intestinal fluid (SIF), based on variability observed in a range of fasted state human intestinal fluid (HIF) samples was used to study the solubility of eight poorly soluble drugs (three acidic drugs (naproxen, indomethacin and phenytoin), two basic drugs (carvedilol and tadalafil) and three neutral drugs (felodipine, fenofibrate, griseofulvin)). Particle size of the colloidal structures formed in these SIF in the presence and absence of drugs was measured using dynamic light scattering and nanoparticle tracking analysis.Results indicate that drug solubility tends to increase with increasing total amphiphile concentration (TAC) in SIF with acidic drugs proving to be more soluble than basic or neutral drug in the media evaluated. Dynamic light scattering showed that as the amphiphile concentration increased, the hydrodynamic diameters of the structures decreased. The scattering distribution confirmed the polydispersity of the simulated intestinal fluids compared to the monodisperse distribution observed for FaSSIF v1). There was a large difference in the size of the structures found based on the composition of the SIF, for example, the diameter of the structures measured in felodipine in the minimum TAC media was measured to be 170 ± 5 nm which decreased to 5.1 ± 0.2 nm in the maximum TAC media point. The size measured of the colloidal structures of felodipine in the FaSSIF v1 was 86 ± 1 nm. However, there was no simple correlation between solubility and colloidal size.Nanoparticle tracking analysis was used for the first time to characterise colloidal structures within SIF and the results were compared to those obtained by dynamic light scattering. The particle size measured by dynamic light scattering was generally greater in media with a lower concentration of amphiphiles and smaller in media of a higher concentration of amphiphiles, compared to that of the data yielded by nanoparticle tracking analysis.This work shows that the colloidal structures formed vary depending on the composition of SIF which affects the solubility. Work is ongoing to determine the relationship between colloidal structure and solubility.

Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras.

PROTACs, proteolysis targeting chimeras, are bifunctional molecules inducing protein degradation through a unique proximity-based mode of action. While offering several advantages unachievable by classical drugs, PROTACs have unfavorable physicochemical properties that pose challenges in application and formulation. In this study, we show the solubility enhancement of two PROTACs, ARV-110 and SelDeg51, using Poly(vinyl alcohol). Hereby, we apply a three-fluid nozzle spray drying set-up to generate an amorphous solid dispersion with a 30% w/w drug loading with the respective PROTACs and the hydrophilic polymer. Dissolution enhancement was achieved and demonstrated for t = 0 and t = 4 weeks at 5 °C using a phosphate buffer with a pH of 6.8. A pH shift study on ARV-110-PVA is shown, covering transfer from simulated gastric fluid (SGF) at pH 2.0 to fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5. Additionally, activity studies and binding assays of the pure SelDeg51 versus the spray-dried SelDeg51-PVA indicate no difference between both samples. Our results show how modern enabling formulation technologies can partially alleviate challenging physicochemical properties, such as the poor solubility of increasingly large 'small' molecules.

Efficiency of single pharmaceutical surfactants to mimic intestinal biorelevant media solubilization and dissolution of etravirine: Comparison of intrinsic and film dissolution models

We understand that quality control dissolution media may best anticipate in vivo product performance by mimicking in vivo media, but preferably involve at most a single pharmaceutical surfactant for routine laboratory use. The objective here was to estimate the concentrations of six pharmaceutical surfactants to mimic etravirine solubility and intrinsic dissolution rate, as well as dissolution rate from a film model, in each Fed State Simulated Intestinal Fluid Version 2 (FeSSIF-V2) and Fasted State Simulated Intestinal Fluid Version 2 (FaSSIF-V2). Solubility studies and colloid sizing measurements were conducted. Results indicate that all six surfactants were more efficient than FeSSIF-V2 or FaSSIF-V2 at solubilizing drug, and also exhibited higher micelle diffusivities than FeSSIF-V2 and FaSSIF-V2 mixed-micelles. The rank-order potency (on mM basis) of the six pharmaceutical surfactants to mimic etravirine solubility in each FeSSIF-V2 and FaSSIF-V2 was: polysorbate 80 (PS80) > polysorbate 20 (PS20) > polyoxyethylene(23) lauryl ether (POE23) > POE10 > hexadecyltrimethylammonium bromide (HEX) > sodium lauryl sulfate (SLS). This rank-order potency was almost the same to mimic drug dissolution rate into each FeSSIF-V2 and FaSSIF-V2, except POE10 > POE23. For the most potent surfactant, PS80, 0.461 mM and 0.140 mM PS80 was estimated to mimic etravirine's solubility and dissolution rate into FeSSIF-V2, respectively, using the intrinsic dissolution model. The low PS80 concentration to mimic dissolution rate reflects the relatively high diffusivity of PS80 micelles, compared to FeSSIF-V2 mixed-micelle diffusivity, which was the case for all six pharmaceutical surfactants. Results are also presented in terms of a film dissolution model for surfactant-mediated dissolution, where dissolution enhancement was less than that in the intrinsic dissolution model, and the film model required lower surfactant concentration than in intrinsic dissolution model to mimic FeSSIF-V2-enhanced dissolution. Findings have promised to identify single pharmaceutical surfactant concentrations that mimic key performance attributes of biorelevant media.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs

PurposeThe purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles.MethodsMeloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles.ResultsThe solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation.ConclusionFor drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety.

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose-dependently induces PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC20 value of 15 μM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor. As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure-activity relationship (SAR), structure-metabolism relationship (SMR), and structure-solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j.

Drug solubility in biorelevant media in the context of an inhalation-based biopharmaceutics classification system (iBCS)

An inhalation-based Biopharmaceutics Classification System for pulmonary drugs (iBCS) holds the perspective to allow for scientifically sound prediction of differences in the in vivo performance of orally inhaled drug products (OIDPs).A set of nine drug substances were selected, that are administered via both the oral and pulmonary routes. Their solubility was determined in media representative for the oral (Fasted State Simulated Intestinal Fluid (FaSSIF)) and pulmonary (Alveofact medium and Simulated Lung Fluid (SLF)) routes of administration to confirm the need for a novel approach for inhaled drugs. The complexity of these media was then stepwise reduced with the purpose of understanding the contribution of their components to the solubilizing capacity of the media. A second reason for varying the complexity was to identify a medium that would allow robust but accurate dissolution testing. Hence, Hank’s balanced salt solution (HBSS) as a medium used in many in vitro biological tests, non-buffered saline solution, and water were included.For some drug substances (salbutamol sulfate, tobramycin, isoniazid, and tiotropium bromide), no significant differences were observed between the solubility in the media used. For other drugs, however, we observed either just small (rifampicin, budesonide, salmeterol) or unexpectedly large differences (beclomethasone dipropionate).Based on the minimum theoretical solubility required for their common pulmonary dose in 10 ml of lung lining fluid, drug solubility was classified as either high or low. Two high solubility and two low solubility compounds were then selected for refined solubility testing in pulmonary relevant media by varying their content of phospholipids, surfactant proteins and other proteins.The solubility of drug substances in simulated lung lining fluids was found to be dependent on the physicochemical properties of the drug substance and the composition of the media. While a pulmonary dissolution medium that would fit all drugs could not be established, our approach may provide guidance for finding the most suitable dissolution medium for a given drug substance and better designing in vitro tests for predicting the in vivo performance of inhalable drug products.

Green Tea Catechins Decrease Solubility of Raloxifene In Vitro and Its Systemic Exposure in Mice.

Green tea is a widely consumed beverage. A recent clinical study reported green tea decreased systemic exposure of raloxifene and its glucuronide metabolites by 34-43%. However, the underlying mechanism(s) remains unknown. This study investigated a change in raloxifene's solubility as the responsible mechanism. The effects of green tea extract, (-)-epigallocatechin gallate (EGCG), and (-)-epigallocatechin (EGC) on raloxifene's solubility were assessed in fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF). EGCG and EGC represent green tea's main bioactive constituents, flavan-3-gallate and flavan-3-ol catechins respectively, and the tested concentrations (mM) match the µg/mg of each compound in the extract. Our mouse study (n = 5/time point) evaluated the effect of green tea extract and EGCG on the systemic exposure of raloxifene. EGCG (1mM) and EGC (1.27mM) decreased raloxifene's solubility in FaSSIF by 78% and 13%, respectively. Micelle size in FaSSIF increased with increasing EGCG concentrations (> 1000% at 1mM), whereas EGC (1.27mM) did not change micelle size. We observed 3.4-fold higher raloxifene solubility in FeSSIF compared to FaSSIF, and neither green tea extract nor EGCG significantly affected raloxifene solubility or micelle size in FeSSIF. The mice study showed that green tea extract significantly decreased raloxifene Cmax by 44%, whereas EGCG had no effect. Green tea extract and EGCG did not affect the AUC0-24h of raloxifene or the metabolite-to-parent AUC ratio. This study demonstrated flavan-3-gallate catechins may decrease solubility of poorly water-soluble drugs such as raloxifene, particularly in the fasted state.

Study of in vitro poorly soluble drug solubility into fasted state simulated intestinal fluid reflective of in vivo gastrointestinal variability

Solubilityand dynamic light scattering (DLS) studies of three poorly soluble drugs(naproxen, indomethacin and phenytoin) in simulated intestinal fluid (SIF) werecarried out in order to calculate the number of drug molecules per micelle basedon the assumption of monodisperse spherical micelles. As the total amphiphileconcentration increased in the SIF the solubility of the drug also increased.The size of the micelles formed decreased with increasing amphiphileconcentration in combination with drug and the number of drug molecules permicelle decreased. Further work is planned to provide more information of theparticle size and geometry of the drug loaded micelles.

A novel formulation of ketoconazole entrapped in alginate with anionic polymer beads for solubility enhancement: Preparation and characterization

Ketoconazole has low solubility in intestinal pH, whereas drug absorption is largest in the small intestine, which can reduce the bioavailability of the drug. Alginate can be combined with a suitable polymer and cross-linked with divalent ions and another polymer to enhance the solubility of the drug. Ketoconazole could be loaded into a matrix polymer consisting of alginate and anionic polymer through hydrogen bonds formed with the N atom of the ketoconazole. The method employed to produce ketoconazole beads involved ionic gelation with CaCl2 as a cross- linking agent, and various polymer combinations were used: alginate 100:0 (AL100), alginate:pectin 75:25 (AP75) and 50:50 (AP50), alginate:gum acacia 75:25 (AG75) and 50:50 (AG50), and alginate:carrageenan 75:25 (AK75) and 50:50 (AK50). The beads were characterized by using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), swelling study, in vitro drug release study, and solubility determination. The incorporation of ketoconazole into combination matrices of AL100, AG75, AP75, AP50, and AK75 resulted in significantly higher solubility in FaSSIF-2X (Fasted State Simulated Intestinal Fluid) at pH 6.5 compared to pure ketoconazole.

Cocrystals Enhance Biopharmaceutical and Antimicrobial Properties of Norfloxacin.

A solvate cocrystal of the antimicrobial norfloxacin (NFX) was formed by using isonicotinamide (INA) as a coformer with the solvent evaporation technique. The cocrystal formation was confirmed by performing solid-state characterization techniques. We evaluated the dissolution under supersaturated conditions and also the solubility at the vertex of triphasic domain of cocrystal and NFX in both water and Fasted-State Simulated Intestinal Fluid (FaSSIF). The antimicrobial activity was evaluated using the microdilution technique. The cocrystal showed 1.8 times higher dissolution than NFX in water at 60 min and 1.3 times higher in FaSSIF at 180 min in the kinetic study. The cocrystal also had an increase in solubility of 8.38 times in water and 6.41 times in FaSSIF. The biopharmaceutical properties of NFX with cocrystallization improved antimicrobial action, as shown in the results of minimum inhibitory concentration (MIC) and inhibitory concentrations of 50% (IC50%) and 90% (IC90%). This paper presents, for the first time, a more in-depth analysis of the cocrystal of NFX-INA concerning its dissolution, solubility, and antimicrobial activity. In all these criteria, the cocrystal obtained better results compared to the pure drug.

A Combined In-Vitro and GastroPlus® Modeling to Study the Effect of Intestinal Precipitation on Cinnarizine Plasma Profile in a Fasted State.

Poorly water-soluble weak base molecules such as cinnarizine often exhibit pH-dependent solubility within the gastrointestinal tract. This means that their solubility can be influenced by the pH of the surrounding environment, and this can affect their oral absorption. The differential pH solubility between the fasted-state stomach and intestine is an important consideration when studying the oral absorption of cinnarizine. Cinnarizine has moderate permeability and is known to exhibit supersaturation and precipitation in fasted-state simulated intestinal fluid (FaSSIF), which can significantly impact its oral absorption. The present work is aimed at studying the precipitation behavior of cinnarizine in FaSSIF using biorelevant in vitro tools and GastroPlus® modeling, to identify the factors contributing to the observed variability in clinical plasma profiles. The study found that cinnarizine demonstrated variable precipitation rates under different bile salt concentrations, which could impact the concentration of the drug available for absorption. The results also showed that a precipitation-integrated modeling approach accurately predicted the mean plasma profiles from the clinical studies. The study concluded that intestinal precipitation may be one of the factors contributing to the observed variability in Cmax but not the AUC of cinnarizine. The study further suggests that the integration of experimental precipitation results representing a wider range of FaSSIF conditions would increase the probability of predicting some of the observed variability in clinical results. This is important for biopharmaceutics scientists, as it can help them evaluate the risk of in vivo precipitation impacting drug and/or drug product performance.

Amphotericin B and monoacyl-phosphatidylcholine form a stable amorphous complex

Amphotericin B (AmB) is a “life-saving” medicine for the treatment of invasive fungal infections and visceral leishmaniasis. To date, all marketed AmB formulations require parenteral administration, which causes high rates of acute infusion-related side effects and dose-dependent nephrotoxicity. The development of an oral AmB formulation will entail numerous advantages including increased patient compliance, eliminated infusion-related toxicities and reduced nephrotoxicity. Unfortunately, the gastrointestinal absorption of AmB is negligible due to its extremely low solubility in both aqueous and lipid solvents, and its poor gastrointestinal permeability. Drug-phospholipid complexation is an emerging strategy for oral delivery of poorly soluble drugs. In this study, monoacyl-phosphatidylcholine (MAPC) was complexed with AmB forming an AmB-MAPC complex (APC), to enhance the dissolution rate and aqueous solubility of AmB, in order to enable oral delivery of AmB. X-ray powder diffraction demonstrated that AmB was transformed to its amorphous form following complexation with MAPC, i.e. in the APC. Fourier-transform infrared spectroscopy suggested molecular interactions between AmB and MAPC. Dynamic light scattering indicated formation of colloidal structures after aqueous dispersion of APC; Cryogenic transmission electron microscopy showed that APC formed small round, “rod-like” and “worm-like” micellar structures and Small-angle neutron scattering provided three-dimensional micellar structures formed by APC upon aqueous dispersion, which indicated that AmB was inserted into the micellar mono-layer membrane formed by MAPC. Additionally, APC showed an increased dissolution rate and a higher amount of AmB solubilized in fasted state simulated intestinal fluid, compared to AmB/MAPC physical mixtures and crystalline AmB. In conclusion, an APC exhibiting amorphous properties was developed, the APC showed improved dissolution rate and increased apparent aqueous solubility compared to AmB, indicating that the application of APC could be a promising strategy to enable the oral delivery of AmB.

Synthesis and Characterization of Ezetimibe Pharmaceutical Cocrystal: A Reaction Crystallization Method to Improve Physicochemical Properties and Hypolipemic Activity Evaluation

Ezetimibe has significant lipid-lowering activity but presents low aqueous solubility. Co-crystallization techniques can be used to overcome this limitation. However, it is not yet clear whether the solubility of the cocrystal can be maintained after oral administration. In the present study, an ezetimi-imidazole cocrystal was synthetized by the reaction crystallization method, a promising strategy in cocrystal engineering. After conducting characterization tests, we determined the solubility and thermodynamic stability of the cocrystal. Also, the solubility advantage for both water and biorelevant fasted state simulated intestinal fluid (FaSSIF) was calculated. Dissolution was determined under supersaturated conditions, and the hypolipidemic activity of the cocrystal was assessed in vivo. The cocrystal exhibited high solubility and thermodynamic stability in FaSSIF. The solubility advantage was calculated as 22.4 in water and 11.8 in FaSSIF. The dissolution of the cocrystal resulted in supersaturation levels (σmax) of 1.3 in water and 3.3 in FaSSIF and the area under the curve (AUC) increased from 478.49 (ezetimibe) to 2963.62 µg min mL-1(cocrystal) in FaSSIF. The atherogenic index of the animals that received the cocrystal was similar to that of the control group. These results demonstrate that the inherent advantages of the co-crystallization process were maintained, enabling us to elucidate the behavior of the cocrystal.

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.

Oral Delivery of Niclosamide as an Amorphous Solid Dispersion That Generates Amorphous Nanoparticles during Dissolution.

Niclosamide is an FDA-approved anthelmintic that is being studied in clinical trials as a chemotherapeutic and broad-spectrum antiviral. Additionally, several other applications are currently in the preclinical stage. Unfortunately, niclosamide is a poorly water soluble molecule, with reduced oral bioavailability, which hinders its use for new indications. Moreover, niclosamide is a poor glass former; in other words, the molecule has a high tendency to recrystallize, and it is virtually impossible to generate a stable amorphous solid employing the neat molecule. Previously, our group reported the development of an amorphous solid dispersion (ASD) of niclosamide (niclosamide ASD) that generates nanoparticles during its dissolution, not only increasing niclosamide's apparent solubility from 6.6 ± 0.4 to 481.7 ± 22.2 µg/mL in fasted state simulated intestinal fluid (FaSSIF) but also its oral bioavailability 2.6-fold in Sprague-Dawley rats after being administered as a suspension. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form is needed for its translation into the clinic. In this work, we further characterized the nanoparticles that generated during the dissolution of the niclosamide ASD. Cryogenic transmission electron microscopy (Cryo-TEM) and wide-angle X-ray scattering (WAXS) revealed that the nanoparticles were amorphous and had a particle size of ~150 nm. The oral dosage forms of niclosamide ASD were formulated using commercial enteric capsules (Capsuline® and EudracapTM) and as enteric-coated tablets. The enteric dosage forms were tested using pH-shift dissolution and acid-uptake tests, using the USP type II dissolution apparatus and the disintegration apparatus, respectively. The capsules exhibited a higher percentage of weight gain, and visual rupture of the Capsuline capsules was observed. Eudracap capsules protected the formulation from the acidic media, but polymer gelling and the formation of a nondispersible plug were noted during dissolution testing. In contrast, enteric-coated tablets protected the formulation from acid ingress and maintained the performance of niclosamide ASD granules during dissolution in FaSSIF media. These enteric-coated tablets were administered to beagle dogs at a niclosamide dose of 75 mg/kg, resulting in plasma concentrations of niclosamide higher than those reported in the literature using solubilized niclosamide at a higher dose (i.e., 100 mg/kg). In summary, an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide's apparent solubility. The enteric-coated tablets successfully increased the niclosamide plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents.

The effect of mucin on supersaturation of poorly water-soluble drugs with different crystallization behavior and in vitro-in vivo correlation

Drug delivery systems such as lipids, solid dispersions, or nanocrystals have been proposed to improve the absorption and bioavailability of poorly water-soluble drugs with different crystallization behavior by polymers in a spring-parachute model, which generate and stabilize the drug supersaturation. Mucins, synthesized by specialized epithelial cells, have characteristics of high molecular polymer and electrostatic or hydrophobic interactions with drugs. Our study aims to investigate the effect of mucin on supersaturation of poorly water-soluble drugs with different crystallization behavior in fasted state simulated intestinal fluid (FaSSIF) and in vitro-in vivo correlation (IVIVC). The solubility of poorly water-soluble drugs was tested. The experiment of supersaturation stability was performed by solvent-shift method. The experiment of crystallization was observed by polarized light microscope analysis. The animal pharmacokinetic experiment was conducted, and the IVIVC was analyzed by linear regression. There was no significant difference in solubility between FaSSIF without and with mucin. It showed significant differences in Tss or AUC of naproxen (nifedipine, itraconazole) between FaSSIF without and with mucin (p < 0.05, p < 0.01). There was no significant difference in Tss of ritonavir between FaSSIF without and with mucin, except for significant differences in AUC (p < 0.01). In the presence of mucin, crystallization time was prolonged in FaSSIF. The SSR of drugs in FaSSIF with mucin and Fa in rat showed a better level of IVIVC with a higher r value, compared with that between FaSSIF and rat. Mucin prolonged the supersaturation of poorly water-soluble drugs with different crystallization behavior, without the change of solubility, by inhibiting the drug nucleation (or crystal growth) or forming the mucin-drug interaction. It showed the role of mucin widely existed in poorly water-soluble drugs in vivo condition.