Improved Pharmaceutical Properties of Honokiol via Salification with Meglumine: an Exception to Oft-quoted ∆pKa Rule.

Honokiol (HK), a BCS class II drug with a wide range of pharmacological activities, has poor solubility and low oral bioavailability, severely limiting its clinical application. In the current study, incorporating a water-soluble meglumine (MEG) into the crystal lattice of HK molecule was performed to improve its physicochemical properties. The binary mixture of HK and MEG was obtained by anti-solvent method and characterized by TGA, DSC, FTIR, and PXRD. The SCXRD analysis showed that two HK- molecules and two MEG+ molecules were coupled in each unit cell via the ionic interaction along with intermolecular hydrogen bonds, suggesting the formation of a salt, which was further confirmed by the XPS measurements. However, the ∆pKa value between HK and MEG was found to be less than 1, which did not follow the oft-quoted ∆pKa rule for salt formation. After salification with MEG, the solubility and dissolution rate of HK exhibited 3.50 and 25.33 times improvement than crystalline HK, respectively. Simultaneously, the powder flowability, tabletability and stability of HK-MEG salt was also significantly enhanced, and the salt was not more hygroscopic, and that salt formation did not compromise processability in that regard. Further, in vivo pharmacokinetic study showed that Cmax and AUC0-t of HK-MEG salt were enhanced by 2.92-fold and 2.01-fold compared to those of HK, respectively, indicating a considerable improvement in HK oral bioavailability.

Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging.

Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.

Meglumine Antimoniate-Loaded Aqueous-Core PLA Nanocapsules: Old Drug, New Formulation against Leishmania-Related Diseases.

Leishmaniasis is a human and animal disease endemic in tropical and subtropical areas treated by means of pentavalent antimony as first-line approach. Unfortunately, the formulations available on the market are characterized by significant side effects and a total remission of the disease is difficult to be obtained. The aim of this investigation is to describe the development and characterization of aqueous-core poly-l-lactide (PLA) nanocapsules containing glucantime (meglumine antimoniate, MA) with the aim of increasing the pharmacological efficacy of the active compound. The polymeric systems characterized by a mean diameter of ≈300 nm exert a great interaction with murine macrophages. MA-loaded PLA nanocapsules show a great antileishmanial activity on mice infected with Leishmania infantum with respect to the free drug, favoring a decrease of the administration times. The biodistribution profiles demonstrate a lower renal accumulation of MA after its nanoencapsulation and a significant increase of its plasmatic half-life. The parasite load evaluated by immunohistochemistry shows a significant decrease in liver, spleen, and kidneys when mice are treated with MA-loaded PLA nanocapsules especially after 45 days. The obtained results demonstrate the potential application of MA-loaded PLA nanocapsules as novel nanomedicine for the treatment of leishmaniasis.

Genetically and pharmacologically limiting RyR2 open time prevents neuronal hyperactivity of hippocampal CA1 neurons in brain slices of 5xFAD mice.

Neuronal hyperactivity is an early, common manifestation of Alzheimer's disease (AD), and is believed to drive AD progression. Neuronal hyperactivity in the form of baseline activity (or spontaneous Ca2+ transients) has consistently been demonstrated in mouse models of AD using two-photon in vivo Ca2+ imaging of cortical or hippocampal neurons in anesthetized animals. Notably, these AD-related spontaneous Ca2+ transients were hardly detected in acute hippocampal slices, probably due to neuronal damage during brain slicing. To better preserve neuronal activity, we employed the N-methyl-D-glucamine (NMDG) protective brain slicing protocol. We performed confocal in vitro Ca2+ imaging of hippocampal CA1 neurons in optimized hippocampal slices. Consistent with previous in vivo studies, our in vitro studies using optimized brain slices also showed that limiting the open duration of the ryanodine receptor 2 (RyR2) by the RyR2 mutation E4872Q or by the R-carvedilol enantiomer prevented and rescued neuronal hyperactivity of hippocampal CA1 neurons from 5xFAD mice. Thus, genetically and pharmacologically limiting RyR2 open time prevented and rescued AD-related neuronal hyperactivity in vitro in optimized brain slices in the absence of anesthetics' influence. Our data also suggest that the NMDG protective brain slicing preparation offers an alternative means to study neuronal hyperactivity of various cell types in different brain regions, especially in regions that are not readily accessible to two-photon in vivo Ca2+ imaging.

High-resolution T1 MRI via renally clearable dextran nanoparticles with an iron oxide shell.

Contrast agents for magnetic resonance imaging (MRI) improve anatomical visualizations. However, owing to poor image resolution in whole-body MRI, resolving fine structures is challenging. Here, we report that a nanoparticle with a polysaccharide supramolecular core and a shell of amorphous-like hydrous ferric oxide generating strong T1 MRI contrast (with a relaxivity coefficient ratio of ~1.2) facilitates the imaging, at resolutions of the order of a few hundred micrometres, of cerebral, coronary and peripheral microvessels in rodents and of lower-extremity vessels in rabbits. The nanoparticle can be synthesized at room temperature in aqueous solution and in the absence of surfactants, has blood circulation and renal clearance profiles that prevent opsonization, and leads to better imaging performance than Dotarem (gadoterate meglumine), a clinically approved gadolinium-based MRI contrast agent. The nanoparticle's biocompatibility and imaging performance may prove advantageous in a broad range of preclinical and clinical applications of MRI.

Expanding amphiphilic architectures by ring-opening of epoxides and polyepoxides with N-methyl-d-glucamine: Structure, chiral bias and gelation.

The facile reaction of a readily available aminopolyol from the chiral pool, N-methyl-d-glucamine, which avoids the side reactions usually associated to anomers of amino sugars, with epoxide and polyepoxide derivatives, enables the preparation of new non-ionic surfactant-like structures combining hydrophilic and hydrophobic moieties. The molecular architectures thus obtained range from linear to tripodal and pyramidal structures. The resulting substances containing multiple chiral centers exist as diastereomeric mixtures, for which various conformations are likewise possible by virtue of inter-chain interactions. The stability and chirality preferences of all possible stereoisomers have been evaluated in detail by DFT methods. Given the amphiphilic structure of both protected and O-protected derivatives obtained by acetylation, self-aggregation could eventually lead to solvent entrapment. Unfortunately, only one compound behaves as efficient hydrogelator and DMSO-gelator at low concentrations. The issue is also discussed in terms of the different molecular arrangements.

Evaluating survival in subjects with astrocytic brain tumors by dynamic susceptibility-weighted perfusion MR imaging.

PURPOSE: Studies have evaluated the application of perfusion MR for predicting survival in patients with astrocytic brain tumors, but few of them statistically adjust their results to reflect the impact of the variability of treatment administered in the patients. Our aim was to analyze the association between the perfusion values and overall survival time, with adjustment for various clinical factors, including initial treatments and follow-up treatments. MATERIALS AND METHODS: This study consisted of 51 patients with astrocytic brain tumors who underwent perfusion-weighted MRI with MultiHance® at a dose of 0.1 mmol/kg prior to initial surgery. We measured the mean rCBV, the 5% & 10% maximum rCBV, and the variation of rCBV in the tumors. Comparisons were made between patients with and without 2-year survival using two-sample t-test or Wilcoxon rank-sum test for the continuous data, or chi-square and Fisher exact tests for categorical data. The multivariate cox-proportional hazard regression was fit to evaluate the association between rCBV and overall survival time, with adjustment for clinical factors. RESULTS: Patients who survived less than 2 years after diagnosis had a higher mean and maximum rCBV and a larger variation of rCBV. After adjusting for clinical factors including therapeutic measures, we found no significant association of overall survival time within 2 years with any of these rCBV values. CONCLUSIONS: Although patients who survived less than 2 years had a higher mean and maximum rCBV and a larger variation of rCBV, rCBV itself may not be used independently for predicting 2-year survival of patients with astrocytic brain tumors.

Nebulised Gadolinium-Based Nanoparticles for a Multimodal Approach: Quantitative and Qualitative Lung Distribution Using Magnetic Resonance and Scintigraphy Imaging in Isolated Ventilated Porcine Lungs.

PURPOSE: This study aims at determining lung distribution of gadolinium-based polysiloxane nanoparticles, AGuIX® (small rigid platform - SRP), as a potential theranostic approach by the pulmonary route. METHODS: First, the aerodynamic size distribution and the aerosol output rate were thoroughly characterized. Then, a multimodal approach using magnetic resonance (MR) and gamma-camera (GC) imaging allows to assess the deposition of the aerosolised nanoparticles in the respiratory tract using isolated ventilated porcine lungs. RESULTS: The SRP has proven to be radiolabelled by radioisotope with a good yield. Crude SRP or radiolabelled ones showed the same aerodynamic size distribution and output as a conventional molecular tracer, as sodium fluoride. With MR and GC imaging approaches, the nebulised dose represented about 50% of the initial dose of nanoparticles placed in the nebuliser. Results expressed as proportions of the deposited aerosol showed approximately a regional aerosol deposition of 50% of the deposited dose in the lungs and 50% in the upper airways. Each technique assessed a homogeneous pattern of deposited nanoparticles in Lungs. MR observed a strong signal enhancement with the SRP, similar to the one obtained with a commonly used MRI contrast agent, gadoterate meglumine. CONCLUSION: As a known theranostic approach by intravenous administration, SRP appeared to be easily aerosolised with a conventional nebuliser. The present work proves that pulmonary administration of SRP is feasible in a human-like model and allows multimodal imaging with MR and GC imaging. This work presents the proof of concept of SRP nebulisation and aims to generate preclinical data for the potential clinical transfer of SRP for pulmonary delivery.

Interaction of macrocyclic gadolinium-based MR contrast agents with Type I collagen. Equilibrium and kinetic studies.

The interactions of gadoterate meglumine, gadobutrol, gadoteridol and Gd(HB-DO3A) with bovine Type I collagen were investigated by ultrafiltration and dialysis. The affinity of the four agents to collagen is similar. However, the maximum adsorbed amount of GdIII-complexes decreases in the following order: gadoterate meglumine > gadobutrol > gadoteridol > Gd(HB-DO3A). Calculations with the open three-compartment model reveal that the structural homologs gadoteridol and Gd(HB-DO3A) have a lower adsorption onto collagen, which may explain the less prolonged in vivo retention of gadoteridol observed in soft tissues of rats.

Effects of gadolinium-based magnetic resonance imaging contrast media on red blood cells and K562 cancer cells.

BACKGROUND: Gadolinium-based contrast media (GBCM) are commonly used in diagnostic magnetic resonance imaging (MRI) in clinical applications. The objective of this study is to evaluate the antioxidant properties and effects on red blood cells (RBCs) and K562 cancer cells of three GBCMs (i.e.; gadoterate meglumine, gadopentetate dimeglumine, and gadobenate dimeglumine) inin vitro levels. METHODS: For determiningin vitro antioxidant properties, the di (phenyl)-(2,4,6-trinitrophenyl) iminoazanium (DPPH) and ferric reducing ability of plasma (FRAP) assay were used. For determining effect on red blood cells, hemolysis, morphology and reactive oxygen species (ROS) were used. For determining effect on K562 cancer cells, cytotoxicity and ROS were used. The GBCM -exposed cells were compared to corresponding non-exposed control groups at various harvest times. RESULTS: The results show no changes occurring in the DPPH data. However, there were significant increases based on FRAP data in three GBCMs compared to the corresponding control at all concentrations. The ROS, morphology, and percentage of hemolysis in red blood cells indicated that no change had occurred in three GBCMs-exposed red blood cells compared to the corresponding non-exposed control groups at all harvest times. The percentage of cell viability in K562 cancer cells showed decreases in gadoterate meglumine- and gadobenate dimeglumine- in a concentration dependent manner, but did not show same in gadopentetate dimeglumine-exposed K562 cancer cells. The percentage of ROS in K562 cancer cells indicated that no change in three GBCMs-exposed cells had occurred when compared to the corresponding non-exposed control groups at all harvest times. CONCLUSION: These findings suggests thatin vitro antioxidant properties exhibited by those three GBCMs depends on their concentration and species of radical in testing assay. There were no toxic effects from those GBCMs when red blood cells were exposed in an in vitro condition. In addition, some of those GBCMs could induce cell death in cancer cells.

Natural polymeric nanoparticles as a non-invasive probe for mesenchymal stem cell labelling.

Non-invasive tracking of stem cells after transplant is necessary for cell therapy and tissue engineering field. Herein, we introduce natural and biodegradable nanoparticle to develop a highly efficient nanoprobe with the ability to penetrate the stem cell for tracking. Based on the use of (Gd3+) to label stem cells for magnetic resonance imaging (MRI) we synthesized nanoparticle-containing Gd3+. Gd3+ could be used as t1-weighted MRI contrast agents. In this study, chitosan-alginate nanoparticles were synthesized as a clinical Dotarem® carrier for decreased t1-weighted. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), and Fourier-transform infrared spectroscopy (FTIR) were utilized for nanoprobe characterization and ICP analysis was performed for Gd3+ concentration measurement. The results illustrate that nanoprobes with spherical shape and with a size of 80 nm without any aggregation were obtained. Relaxivity results suggest that r1 in the phantom was 12.8 mM-1s-1 per Gd3+ ion, which is 3.5 times larger than that for Dotarem® (r1 ∼3.6 mM-1s-1 per Gd3+ ion) and this result for synthesized nanoprobe in stem cells 3.56 mM-1s-1 per Gd3+ ion with 2.16 times larger than that for Dotarem® was reported and also enhanced signal in in-vivo imaging was observed. Chitosan-alginate nanoparticles as a novel biocompatible probe for stem cell tracking can be utilized in tissue engineering approach.

Dynamic, Simultaneous Concentration Mapping of Multiple MRI Contrast Agents with Dual Contrast - Magnetic Resonance Fingerprinting.

Synchronous assessment of multiple MRI contrast agents in a single scanning session would provide a new "multi-color" imaging capability similar to fluorescence imaging but with high spatiotemporal resolution and unlimited imaging depth. This multi-agent MRI technology would enable a whole new class of basic science and clinical MRI experiments that simultaneously explore multiple physiologic/molecular events in vivo. Unfortunately, conventional MRI acquisition techniques are only capable of detecting and quantifying one paramagnetic MRI contrast agent at a time. Herein, the Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF) methodology was extended for in vivo application and evaluated by simultaneously and dynamically mapping the intra-tumoral concentration of two MRI contrast agents (Gd-BOPTA and Dy-DOTA-azide) in a mouse glioma model. Co-registered gadolinium and dysprosium concentration maps were generated with sub-millimeter spatial resolution and acquired dynamically with just over 2-minute temporal resolution. Mean tumor Gd and Dy concentration measurements from both single agent and dual agent DC-MRF studies demonstrated significant correlations with ex vivo mass spectrometry elemental analyses. This initial in vivo study demonstrates the potential for DC-MRF to provide a useful dual-agent MRI platform.

Meglumine-based supra-amphiphile self-assembled in water as a skin drug delivery system: Influence of unfrozen bound water in the system bioadhesiveness.

Hexagonal liquid crystals and supramolecular polymers from meglumine-based supra-amphiphiles were developed as drug delivery systems to be applied on the skin. The influence of fatty acid unsaturation on the structure and mechanical properties was evaluated. Moreover, we have investigated the system biocompatibility and how the type of water could influence its bioadhesive properties. Meglumine-oleic acid (MEG-OA) was arranged as hexagonal liquid crystals at 30-70 wt% water content, probably due to its curvature and increased water solubility. Meglumine-stearic acid (MEG-SA) at 10-80 wt% water content self-assembled as a lamellar polymeric network, which can be explained by the low mobility of MEG-SA in water due to hydrophobic interactions between fatty acid chains and H-bonds between meglumine and water molecules. Both systems have shown suitable mechanical parameters and biocompatibility, making them potential candidates to encapsulate therapeutic molecules for skin delivery. Moreover, a strong positive correlation between the amount of unfrozen bound water in meglumine-based systems and the bioadhesion properties was observed. This work shows that a better understanding of the physicochemical properties of a drug delivery system is extremely important for the correlation with the desired biological response and, thus, improve the product performance for biomedical applications.

A New Method for Classification of Salts and Cocrystals Using Solid-State UV Spectrophotometry.

Salt and cocrystal formulations are widely used as techniques to improve physicochemical properties of compounds. Some spectrometric techniques to distinguish cocrystals from salts have been reported; however, it has not been possible to adapt these formulations with many compounds, because of limitations, high difficulty, and exceptions. Therefore, we focused on the possibility of UV spectrometry, which had not been reported as a classification technique for salts and cocrystals. The integration values of solid-state UV/visible (Vis) spectra of indomethacin salts were larger than those of physical mixtures of indomethacin and counter molecules, while that of indomethacin cocrystal was not large compared with that of the physical mixture. From these results, differences between a salt and a cocrystal were observed in their solid-state UV/Vis absorption spectra for indomethacin complexes. Therefore, it is suggested that solid-state UV/Vis absorption spectra can be used as a new technique to classify salts and cocrystals.

Meglumine as a green, efficient and reusable catalyst for synthesis and molecular docking studies of bis(indolyl)methanes as antioxidant agents.

An efficient and convenient Meglumine catalyzed procedure for the synthesis of bis(indolyl) methanes at ambient temperature under aqueous conditions in high yields. The catalytic reaction proceeds very smoothly. Clean reaction, ease of product isolation/purification, easily available reactants, metal free and environmentally friendly reaction conditions are the notable advantages of the present methodology. All the entitled compounds were characterized by IR, 1H, 13C NMR, mass spectra and evaluated for their antioxidant (DPPH, H2O2 and NO scavenging methods). They exhibited potent in vitro antioxidant activity dose-dependently. The binding interactions and molecular docking studies for entitled compounds were studied against 3MNG protein. 4d exhibited marked binding affinity with excellent docking score of -7.6 K.cal/mol and emerged as a lead compound.

Diffusion-weighted imaging of the dentate nucleus after repeated application of gadolinium-based contrast agents in multiple sclerosis.

OBJECTIVE: Over the last years several studies reported an increased signal intensity (SI) of the dentate nucleus (DN) on unenhanced T1-weighted images after repeated application of gadolinium-based contrast agents (GBCAs), suggesting gadolinium deposition. The aim of this study was to investigate with diffusion-weighted MRI possible tissue abnormalities of the DN in multiple sclerosis (MS) patients. MATERIAL AND METHODS: We retrospectively identified seventeen patients with at least six contrast-enhanced MRI examinations by using the linear GBCA gadopentate dimeglumine and twenty-three patients with the exclusive use of the macrocyclic contrast agent gadoterate meglumine followed by another 3 Tesla MRI scan including unenhanced T1-weighted and diffusion-weighted images. RESULTS: In the linear GBCA group, we found significant differences of the DN-to-pons SI ratio on unenhanced T1-weighted images (1.13 ±â€¯0.05) when compared to the macrocyclic GBCA group (0.97 ±â€¯0.03; p < 0.001). However, we found no significant differences between apparent diffusion coefficient (ADC) values of the DN in both groups (linear GBCA group: 0.82 ±â€¯0.04 × 10-3 mm/s2; marcocyclic GBCA group: 0.79 ±â€¯0.04 × 10-3 mm/s2; p = 0.15). CONCLUSIONS: Our results do not suggest that there is any difference in ADC values in the T1-hyperintense DN, which does not indicate a difference in tissue integrity between patients exposed to macrocyclic or linear GBCAs.

FTIR and TG analyses coupled with factor analysis in a compatibility study of acetazolamide with excipients.

A compatibility study of drug substance with excipients is a crucial step in the drug development process in order to generate potent final drug formulations for efficient and safe therapy for various diseases. Thus, the development of new methods for compatibility studies is a great challenge. For this reason, a new approach based on improvement of FTIR spectra and TG curves interpretation using factor analysis (FA) was developed as a screening technique for assessing the compatibility of acetazolamide with selected excipients. This multivariate method demonstrates that in some cases acetazolamide and mixtures with high acetazolamide content formed one cluster, while a second cluster consisted of excipient and mixtures with high excipient content. Such clustering of the analyzed samples (drug substance, excipient and their mixtures) demonstrates the compatibility between ingredients. This in turn means that the FTIR spectra and TG curves of mixtures are the sum of absorption bands or of the thermal profiles of ingredients. In the case of incompatibility, the FTIR spectra and TG curves of mixtures differ from those of ingredients. The FA score scatter plot shows that clusters consist of mixtures which differ with respect to ingredient content. In conclusion, FA proved the incompatibility of acetazolamide mixtures with ß-cyclodextrin, chitosan, lactose, mannitol, meglumine and starch. This was also confirmed by complementary techniques such as DSC and PXRD. Hence, the application of FA can be helpful for better comprehension of data obtained from FTIR spectra and TG curves.

Intrapatient Comparison of the Hepatobiliary Phase of Gd-BOPTA and Gd-EOB-DTPA in the Differentiation of Hepatocellular Adenoma From Focal Nodular Hyperplasia.

BACKGROUND: Current imaging guidelines do not specify the preferred hepatobiliary contrast agent when differentiating hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH) on MRI. PURPOSE: To analyze intrapatient differences in the hepatobiliary phase (HBP) after use of both gadobenate dimeglumine (Gd-BOPTA) and gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI to differentiate HCA from FNH. STUDY TYPE: Retrospective. POPULATION: Patients who underwent both Gd-BOPTA and Gd-EOB-DTPA-enhanced MRI, including 33 patients with 82 lesions (67 HCA; 15 FNH), with a step-down reference standard of pathology, 20% regression, identical appearance to earlier biopsied lesions, and stringent imaging findings. FIELD STRENGTH/SEQUENCE: 1.5T and 3T HBP of Gd-BOPTA and Gd-EOB-DTPA-enhanced MRI, precontrast fat-suppressed T1 -weighted sequence. ASSESSMENT: Signal intensities relative to the surrounding liver in the HBP were assessed by two observers. STATISTICAL TESTS: Sensitivity and specificity of HCA diagnosis were calculated for both contrast agents. Interobserver agreement was evaluated using Cohen's kappa; differences in degree of certainty for scoring a lesion were calculated by means of the Wilcoxon signed rank test. Differences in signal intensity between Gd-BOPTA and Gd-EOB-DTPA were calculated using McNemar's test. RESULTS: Almost perfect agreement was found between observers for scored signal intensities with both contrast agents. In 30 of the 82 lesions (37%) a difference was observed between contrast agents in the HBP, with Gd-EOB-DTPA proving correct in all but one of the discordant lesions. When distinguishing HCA from FNH, Gd-BOPTA showed a sensitivity of 46% (31/67) and a specificity of 87% (13/15), while the sensitivity and specificity of Gd-EOB-DTPA was 85% (57/67) and 100% (15/15), respectively. A risk of misclassifying HCA as FNH typically occurs for Gd-BOPTA when lesions are intrinsically hyperintense (P < 0.005). DATA CONCLUSION: The HBP of Gd-EOB-DTPA shows superior accuracy in ruling out HCA in comparison with Gd-BOPTA, especially when the lesion is intrinsically hyperintense on T1 -weighted imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:700-710.

Application of a Novel 'Make and Test in Parallel' Strategy to Investigate the Effect of Formulation on the Pharmacokinetics of GDC-0810 in Healthy Subjects.

PURPOSE: GDC-0810, administered orally, was used in Phase I and II clinical studies to treat estrogen receptor positive breast cancers. It contains N-methyl-D-glucamine (NMG) salt of GDC-0810 with 10% sodium lauryl sulfate (SLS) as a surfactant and 15% sodium bicarbonate (NaHCO3) as an alkalizing agent to aid dissolution. To improve the processability of the formulation and reduce potential mucosal irritation in future Phase III clinical studies, the salt form and the amount of excipient required further optimization. To achieve this, we employed a novel "Make and Test in Parallel" strategy that facilitated selecting formulation in a rapid timeframe. METHODS: RapidFACT®, a streamlined, data-driven drug product optimization platform was used to bridge Phase I/II and Phase III formulations of GDC-0810. Five prototype formulations, varying in either the form of active pharmaceutical ingredient and/or the levels of the excipients SLS and NaHCO3 were assessed. Uniquely, the specific compositions of formulations manufactured and dosed were selected in real-time from emerging clinical data. RESULTS: The study successfully identified a Phase III formulation with a reduced SLS content, which when administered following a low-fat meal, gave comparable pharmacokinetic exposure to the Phase I/II formulation administered under the same conditions. CONCLUSIONS: Our novel 'Make and Test in Parallel' approach enabled optimization of GDC-0810 formulation in a time- and cost-efficient fashion.

Synthesis of novel magnetic nano-sorbent functionalized with N-methyl-D-glucamine by click chemistry and removal of boron with magnetic separation method.

Click chemistry refers to a group of reactions that are fast, simple to use, easy to purify, versatile, regiospecific, and give high product yields. Therefore, a novel, efficient magnetic nano-sorbent based on N-methyl-D-glucamine attached to magnetic nanoparticles was prepared using click coupling method. Its boron sorption capacity was compared with N-methyl-D-glucamine direct attached nano-sorbent. The characterization of the magnetic sorbents was investigated by several techniques such as X-ray diffraction, scanning electron microscope, transmission electron microscope, dynamic light scattering, thermogravimetric analysis, Fourier transform infrared spectrophotometer, and vibrating sample magnetometer. The boron sorption capacity of sorbents was compared by studying various essential factors influencing the sorption, like sorbate concentration, sorbents dosage, pH of the solution, and contact time. Langmuir and Freundlich and Dubinin-Radushkevich adsorption isotherms models were applied. Percent removal and sorption capacities efficiencies of sorbents obtained with direct and click coupling are found to be 49.5%, 98.7% and 6.68 mg/g, 13.44 mg/g respectively. Both sorbents have been found to be compatible with Langmuir isotherm, and the boron sorption kinetics conforms to the pseudo second order kinetics. The reusability study of sorbents was carried out five times for boron sorption and desorption.