ADMET and DMPK最新文献

Introduction: Olanzapine (OLZ) is a psychotropic class drug commonly used to treat schizophrenia, bipolar disorder, and acute manic episodes. It has less water solubility, resulting in a slow dissolution rate and oral bioavailability. Therefore, the development in oral dosage forms is required to enhance the drug solubility.

Method: The solid dispersion of olanzapine is prepared by spray drying technique. The solution of polyvinylpyrrolidone K-30 (PVP K-30), mono amino glycyrrhizinate pentahydrate (GLY), OLZ and silicon dioxide were dissolved in distilled water and ethanol and spray dried to get the solid dispersion. Solid dispersion was characterized for surface morphology, solubility, encapsulation efficiency (EE), X-ray diffraction (X-RD), Differential Scanning Calorimeter (DSC) and drug-polymer interaction by Fourier transforms infrared spectroscopy.

Results: The amorphous nature of the drug's incorporation in solid dispersion was confirmed by X-RD analysis. Prepared solid dispersion showed higher solubility, 11.51 mg, than pure OLZ (0.983 mg ml^-1), while the range of EE was found to be between 64 to 90 %.

Conclusions: The solubility and dissolution rate of the OLZ can effectively increase by spray-dried solid dispersion. Plackett-Burman screening design plays a vital role in understanding the effect of independent variables on EE and solubility.

Background and purpose: The reciprocal translocation of the ABL gene from chromosome 9 to chromosome 22 near the BCR gene gives rise to chronic myelogenous leukemia (CML). The translocation results in forming the Philadelphia chromosome (BCR-ABL) tyrosine kinase. CML results in an increase in the number of white blood cells and alteration in tyrosine kinase expression. CML prognosis includes three stages, namely chronic, accelerated, and blast. The diagnosis method involves a CT scan, biopsy, and complete blood count. However, due to certain disadvantages, early diagnosis of CML is not possible by traditional methods. Nanotechnology offers many advantages in diagnosing and treating cancer.

Experimental approach: We searched PubMed, Scopus and Google Scholar using the keywords Philadelphia chromosome, bionanotechnology, tyrosine kinase pathway, half-life, passive targeting, and organic and inorganic nanoparticles. The relevant papers and the classical papers in this field were selected to write about in this review.

Key results: The sensitivity and specificity of an assay can be improved by nanoparticles. Utilizing this property, peptides, antibodies, aptamers, etc., in the form of nanoparticles, can be used to detect cancer at a much earlier stage. The half-life of the drug is also increased by nanoformulation. The nanoparticle-coated drugs can easily escape from the immune system.

Conclusion: Depending on their type, nanoparticles can be categorized into organic, inorganic and hybrid. Each type has its advantages. Organic nanoparticles have good biocompatibility, inorganic nanoparticles increase the half-life of the drugs. In this review, we highlight the nanoparticles involved in treating CML.

Background and purpose: Chitosan, a chitin deacetylation product, has been applied in nanoparticle or nano-chitosan for medical applications. However, the chitin extraction from crustacean shells and other natural resources, chitin deacetylation, and crosslinking of the chitosan forming the nano-chitosan mostly involve hazardous chemical and physical processes. The risks of these processes to human health and the environment attract the attention of scientists to develop safer and greener techniques. This review aims to describe the progress of harmless chitosan synthesis.

Experimental approach: All strongly related publications to each section, which were found on scientific search engines (Google Scholar, Scopus, and Pubmed), were studied, selected, and then used as references in writing this review. No limitation for the publication year was applied. The publications were searched from April 2022 - June 2023.

Key results: Nano-chitosan could be synthesized in harmless techniques, including the preparation of the chitosan raw materials and crosslinking the chitosan polymer. Enzymatic processes in shell deproteination in the chitin extraction and deacetylation are preferable to reduce the negative effects of conventional chemical-physical processes. Mild alkalines and deep eutectic solvents also provide similar benefits. In the nano-chitosan synthesis, naturally derived compounds (carrageenan, genipin, and valinin) show potency as safer crosslinkers, besides tripolyphosphate, the most common safe crosslinker.

Conclusion: A list of eco-friendly and safer processes in the synthesis of nano-chitosan has been reported in recent years. These findings are suggested for the nano-chitosan synthesis on an industrial scale in the near future.

Background and purpose: The aim of the work was to compare the interactions of three newly synthesized non-toxic starch derivatives, with varied anionic and non-ionic functional groups with methylene blue (MB) as a model cationic drug, and selection of starch derivative with highest affinity to the MB.

Experimental approach: The native potato starch (SN), modified via acetylation (SM1), esterification and crosslinking (SM2) and crosslinking (SM3), was evaluated in MB adsorption studies and assessed by FTIR, PXRD, and DSC.

Key results: The adsorption of MB on SM2 and SM3 matched the BET isotherm model, which confirmed physisorption on the low-porous surface. In the case of SM1, adsorption took place via electrostatic attraction between the heterogeneous adsorbent surface and the adsorbate, as demonstrated by the Freundlich plot. The FTIR confirmed vibrations assigned to N=C stretching bonds at 1600 cm^-1 in the case of MB adsorbed on the SN and SM2. The most intense PXRD peaks belonged to SN and the least to SM2. In the DSC study, the thermal stability via ΔT was assessed, with SM2 of lowest ΔT value (179.8 °C).

Conclusion: SM2 presented the best adsorption capacity, followed by SM3 and the weakest SM1. The interactions were confirmed in the adsorption studies and may reflect applications of the modified starches as drug carriers. In the FTIR study, a probable interaction between the OH^- groups of SM2 and N⁺ of MB was revealed. The most amorphous structure was shown for SM2, which was correlated with the lowest thermal stability provided by the DSC study.

Background and purpose: Physiologically-based biopharmaceutics modeling (PBBM) has been widely used to predict the oral absorption of drugs. However, the prediction of food effects on oral drug absorption is still challenging, especially for negative food effects. Marked negative food effects have been reported in most cases of quaternary ammonium compounds (QAC). However, the mechanism has remained unclear. The purpose of the present study was to investigate the bile micelle and food binding of QACs as a mechanism of the negative food effect.

Experimental approach: Trospium (TRS), propantheline (PPT), and ambenonium (AMB) were selected as model QAC drugs. The oral absorption of these QACs has been reported to be reduced by 77% (TRS), > 66% (PPT), and 79% (AMB), when taken with food. The fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) were used as the simulated intestinal fluid. The unbound fraction (f_u) of the QACs in these media was measured by dynamic dialysis.

Key results: The f_u ratios (FeSSIF/ FaSSIF) were 0.67 (TRS), 0.47 (PPT), and 0.76 (AMB). When BFH was added to FeSSIF, it was reduced to 0.39 (TRS), 0.28 (PPT), and 0.59 (AMB).

Conclusion: These results suggested that bile micelle and food binding play an important role in the negative food effect on the oral absorption of QACs.

Yalkowsky's General Solubility Equation (GSE), with its three fixed constants, is popular and easy to apply, but is not very accurate for polar, zwitterionic, or flexible molecules. This review examines the findings of a series of studies, where we have sought to come up with a better prediction model, by comparing the performances of the GSE to Abraham's Solvation Equation (ABSOLV), and Random Forest regression (RFR) machine-learning (ML) method. Large, well-curated aqueous intrinsic solubility databases are available. However, drugs may be sparsely distributed in chemical space, concentrated in clusters. Even a large database might overlook some regions. Test compounds from under-represented portions of space may be poorly predicted, as might be the case with the 'loose' set of 32 drugs in the Second Solubility Challenge (2020). There appears to be still a need for better coverage of drug space. Increasingly, current trends in predictions of solubility use calculated input descriptors, which may be an advantage for exploring properties of molecules yet to be synthesized. The risk may be that overall prediction approaches might be based on accumulated uncertainty. The increasing use of ML/AI methods can lead to accurate predictions, but such predictions may not readily suggest the strategies to pursue in selecting yet-to-be-synthesized compounds. Based on our latest findings, we recommend predictions based on both 'grouped' ABSOLV(GRP) and 'Flexible Acceptor' GSE(Φ,B) models with the provided best-fit parameters, where Φ is the Kier molecular flexibility index and B is the Abraham H-bond acceptor strength. For molecules with Φ < 11, the prudent choice is to pick the Consensus Model, the average of ABSOLV(GRP) and GSE(Φ,B). For more flexible molecules, GSE(Φ,B) is recommended.

Background and purpose: Flavonoids are a group of phytochemicals found abundantly in various plants. Scientific evidence has revealed that flavonoids display potential biological activities, including their ability to alleviate inflammation. This activity is closely related to their action in blocking the inflammatory cascade and inhibiting the production of pro-inflammatory factors. However, as flavonoids typically have poor bioavailability and pharmacokinetic profile, it is quite challenging to establish these compounds as a drug. Nevertheless, progressive advancements in drug delivery systems, particularly in nanotechnology, have shown promising approaches to overcome such challenges.

Review approach: This narrative review provides an overview of scientific knowledge about the mechanism of action of flavonoids in the mitigation of inflammatory reaction prior to delivering a comprehensive discussion about the opportunity of the nanotechnology-based delivery system in the preparation of the flavonoid-based drug.

Key results: Various studies conducted in silico, in vitro, in vivo, and clinical trials have deciphered that the anti-inflammatory activities of flavonoids are closely linked to their ability to modulate various biochemical mediators, enzymes, and signalling pathways involved in the inflammatory processes. This compound could be encapsulated in nanotechnology platforms to increase the solubility, bioavailability, and pharmacological activity of flavonoids as well as reduce the toxic effects of these compounds.

Conclusion: In Summary, we conclude that flavonoids and their derivates have given promising results in their development as new anti-inflammatory drug candidates, especially if they formulate in nanoparticles.

Background and purpose: Sensitive analytical determination of folic acid is important in clinical laboratories due to its versatile biological functions.

Experimental approach: A simple folic acid sensor was successfully fabricated based on two-dimensional transition metal dichalcogenide MoS₂ modified carbon ionic liquid paste electrode (MoS₂-CILPE). The electrochemical properties of the fabricated electrode were investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and chronoamperometry.

Key results: The fabricated sensor displayed excellent electroactivity towards folic acid using CV. Under optimal conditions (0.1 M PBS (pH 7.0)), the DPV oxidation peak current was proportional to folic acid concentration in the range from 5.0 μM to 100.0 μM with an estimated limit of detection of 1.0 μM and limit of quantification of 5.0 μM.

Conclusion: The ability of the sensor for routine analyses was demonstrated by the detection of folic acid present in folic acid tablets and urine samples with appreciable recovery values.

Background and purpose: Physicochemical properties of an amorphous solid dispersion (ASD) comprising an experimental grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-MX) with lower glass transition temperature have been previously investigated. This study aimed to evaluate applicability of HPMCAS-MX to hot-melt extrusion (HME) and dissolution-permeation performance of prepared ASDs using MicroFLUX.

Review approach: A physical mixture of indomethacin (IMC) and HPMCAS-MX or -MG (a commercial grade with higher transition temperature) at 20:80 weight ratio was hot-melt extruded to prepare an ASD (IMC-MX and IMC-MG, respectively). The dissolution-permeation performance and the stability of the ASDs were measured.

Key results: A torque reduction at 120 °C implied that IMC-MX transformed into an amorphous state at this temperature, but IMC-MG required around 170 °C. This result was supported by Raman mapping of the the HME samples. IMC-MG and IMC-MX remained in an amorphous state at 40 °C for three months. The initial dissolution rate and solubility of the ASDs were higher than that of crystalline IMC. The apparent permeability of IMC from IMC-MX and IMC-MG was comparable but was approximately two-fold higher than that from crystalline IMC.

Conclusion: HPMCAS-MX enabled HME process at a lower temperature and improved the dissolution-permeation performance of indomethacin.