Soluble Class Research Articles

Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma.

Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non-alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti-tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA/B-NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane-bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA-mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA/B-NKG2D-based or NK cell-based immunotherapy for HCC.

Nanostructured dendrimer improves the solubility of carvedilol, furosemide and nimodipine

Essential hypertension has been treated for over 30 years using both diuretics and beta-blockers. When it comes to treating heart failure, there are three different generations of beta-blockers that are now in use. Carvedilol is a blocker from the third generation. Nimodipine is a common L-type calcium channel blocker. The hypertension medication furosemide is a loop diuretic. This class of medications' low solubility in water has emerged as a serious obstacle in the pharmaceutical industry's pursuit of better treatments. A novel class of polymers called dendrimers has recently gained a lot of interest due to its impressive solubility-enhancing characteristics. Results from hemolysis studies and cytotoxicity tests using the novel nanostructure dendrimer shown here demonstrate superior performance of synthetic dendritic macromolecules compared to commercially available PAMAM dendrimer. Dendrimers are used to enhance the solubility of nimodipine, furosemide, and carvedilol up to 38.08µg/ml, 70.999µg/ml and 147.065µg/ml respectively. The enhancement of dendrimer-mediated solubility is primarily determined by factors such as dendrimer concentration and generation size. Drugs containing dendrimers may be studied using Fourier-transform infrared spectroscopy. Based on the results of this investigation, nanostructured dendrimer technology may help with hydrophobic medication dispersion.

Fabrication and In-Vivo Evaluation of Polyvinyl pyrrolidone/Poloxamer 188 Hybrid Nanofibers of Deflazacort

The superior flexibility, efficient drug loading, high surface-to-volume ratio, ease of formulation, and cost-controlled production are considered exceptional advantages of nanofibers (NFs) as a smart delivery system. Deflazacort (DEF) is an anti-inflammatory and immunosuppressant agent. It is categorized as a poorly soluble class II drug. In this study, DEF-loaded polymeric nanofibrous using the electrospinning technique mats, Polyvinyl pyrrolidone (PVP) with or without Poloxamer 188 (PX) were used as mat-forming polymers. Microscopical imaging, drug content (%), and in vitro dissolution studies were conducted for all NFs formulae (F1-F7). All NFs improved the DEF dissolution compared to the unprocessed form, with the superiority of the PVP/PX hybrid. The optimized formula (F7) exhibited an average diameter of 655.46 ± 90.4 nm and % drug content of 84.33 ± 5.58. The dissolution parameters of DEF loaded in PVP/PX NFs (F7) reflected a release of 95.3 % ± 3.1 and 102.6 % ± 1.7 after 5 and 60 min, respectively. NFs (F7) was investigated for drug-polymer compatibility using Fourier-Transform Infrared Spectroscopy (FTIR), Powder X-ray diffraction analysis (PXRD), and Differential Scanning Calorimetry (DSC). In vivo anti-inflammatory study employing male Sprague-Dawley rats showed a significant reduction of rat paw edema for F7 (p < 0.05) compared with unprocessed DEF with a normal epidermal and dermal skin structure comparable to the healthy negative control. Immunohistochemical and morphometric data displayed similarities between the immune reaction of F7 and the negative healthy control. The finding of this work emphasized that DEF loaded in PVP/PX NFs could be considered a useful strategy for enhancing the therapeutic performance of DEF.

Expression of concern: “High levels of soluble Major Histocompatibility Complex class I related chain A (MICA) are associated with biliary cast syndrome after liver transplantation” [Transplant Immunology 2009, volume 21, pages 210–214]

Expression of concern: “High levels of soluble Major Histocompatibility Complex class I related chain A (MICA) are associated with biliary cast syndrome after liver transplantation” [Transplant Immunology 2009, volume 21, pages 210–214]

Investigating the impact of x‐ray computed tomography imaging on soluble organic matter in the Murchison meteorite: Implications for Bennu sample analyses

AbstractX‐ray computed tomography (XCT) is a valuable reconnaissance tool for three‐dimensional imaging and identification of distinct lithologies in extraterrestrial samples. It will be used as part of the preliminary examination of samples returned from asteroid (101955) Bennu by the Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer (OSIRIS‐REx) mission. However, it must first be established whether x‐rays generated during XCT could degrade or alter the organic composition of the returned samples by radiolysis. To test this, we split a crushed sample of the Murchison CM2 meteorite, kept one portion as a control, and irradiated the other portion up to the maximum x‐ray dosage (~180 Gy) that a Bennu sample would experience during an XCT imaging experiment. We then extracted organic compounds from both splits and conducted (i) nontargeted soluble organic analyses to compare the chemical distributions of C‐, H‐, O‐, N‐, and S‐bearing species and (ii) targeted measurements to quantify the abundances of 96 individual soluble organic molecules that included protein amino acids, amines, carboxylic acids, hydroxy acids, carbonyl compounds, polycyclic aromatic hydrocarbons, alcohols, sugars, and N‐heterocycles. We found that XCT imaging of the Murchison meteorite had no measurable impact on the relative abundances or enantiomeric compositions of most of the soluble organic compounds targeted in this study. Elevated total abundances of several soluble organic compound classes were observed in the XCT‐scanned Murchison sample relative to the control. This is likely related to particle size heterogeneity and specific surface area differences between the sample aliquots used for the extractions, rather than a result of the x‐ray exposure. Assuming the samples returned from asteroid Bennu by OSIRIS‐REx have a similar composition to carbonaceous chondrites, these data provide confidence that XCT will not significantly alter their soluble organic compositions.

Generating Novel and Soluble Class II Fructose-1,6-Bisphosphate Aldolase with ProteinGAN

Fructose-1,6-bisphosphate aldolase (FBA) is an important enzyme involved in central carbon metabolism (CCM) with promising industrial applications. Artificial intelligence models like generative adversarial networks (GANs) can design novel sequences that differ from natural ones. To expand the sequence space of FBA, we applied the generative adversarial network (ProteinGAN) model for the de novo design of FBA in this study. First, we corroborated the viability of the ProteinGAN model through replicating the generation of functional MDH variants. The model was then applied to the design of class II FBA. Computational analysis showed that the model successfully captured features of natural class II FBA sequences while expanding sequence diversity. Experimental results validated soluble expression and activity for the generated FBAs. Among the 20 generated FBA sequences (identity ranging from 85% to 99% with the closest natural FBA sequences), 4 were successfully expressed as soluble proteins in E. coli, and 2 of these 4 were functional. We further proposed a filter based on sequence identity to the endogenous FBA of E. coli and reselected 10 sequences (sequence identity ranging from 85% to 95%). Among them, six were successfully expressed as soluble proteins, and five of these six were functional—a significant improvement compared to the previous results. Furthermore, one generated FBA exhibited activity that was 1.69fold the control FBA. This study demonstrates that enzyme design with GANs can generate functional protein variants with enhanced performance and unique sequences.

The impact of sMICA/sMICB on immunochemotherapy outcomes in newly diagnosed diffuse large B-cell lymphoma.

Soluble MHC class I-related chain A (sMICA) and B (sMICB) play a critical role tumor evolution and poor prognosis through an immune evasion mechanism. Thus, this study determines the interaction between sMICA/sMICB and the tumor immune environment in newly diagnosed diffuse large B-cell lymphoma (ND-DLBCL). We analyzed sMICA/sMICB, cytokine in serum, and macrophage polarization analysis in tissue samples before the first chemotherapy administration. This research was performed to investigate the correlation between sMICA/sMICB expression and treatment outcomes as well as their influence on the immune system within ND-DLBCL. Of the 262 patients, 47.3% (n = 124) presented stage III or IV at diagnosis and 50.8% (n = 133) had a high International Prognostic Index (IPI ≥ 3). The patients with high (p = 0.034 and 0.004), elevated lactate dehydrogenase (p = 0.002 and 0.030), advanced stage (p = 0.003 and 0.012), and higher IPI risk (p = 0.009, and 0.032) correlated with the detection of sMICA or sMICB. The median progression-free survival (PFS) of patients with sMICA (p = 0.006) or sMICB (p =0.032) was inferior. Among the patients with advanced-stage or high IPI, those with sMICA or sMICB presented an inferior PFS and OS compared to those without. TNF-a, a pro-inflammatory cytokine, showed statistical significance with detected sMICA (p = 0.035) or sMICB (p = 0.044). Among anti-inflammatory cytokines, IL-1RA (P-value = 0.013) and IL-10 (p = 0.005) were associated with detecting sMICB, but not sMICA. In tissue samples, sMICA or sMICB detection did not correlate with the CD68/CD163 ratio. Conclusively, the identification of sMICA/sMICB presented unfavorable immunochemotherapy outcomes, and it was assumed that sMICA or sMICB and various cytokines interact, but the relationship with macrophage differentiation is unclear. Therefore, further research is needed to determine the relationship between sMICA/sMICB and tumor microenvironment in DLBCL.

Neural Network Models for Predicting Solubility and Metabolism Class of Drugs in the Biopharmaceutics Drug Disposition Classification System (BDDCS).

The biopharmaceutics drug disposition classification system (BDDCS) categorizes drugs into four classes on the basis of their solubility and metabolism. This framework allows for the study of the pharmacokinetics of transporters and enzymatic metabolization on biopharmaceuticals, as well as drug-drug interactions in the body. The objective of the present study was to develop computational models by neural network models and structural parameters and physicochemical properties to estimate the class of a drug in the BDDCS system. In this study, deep learning methods were utilized to explore the potential of artificial and convolutional neural networks (ANNs and CNNs) in predicting the BDDCS class of 721 substances. The structural parameters and physicochemical properties [Abraham solvation parameters, octanol-water partition (log P) and over the pH range 1-7.5 (log D), number of rotatable bonds, hydrogen bond acceptor numbers, as well as hydrogen bond donor count] are calculated with various software. These compounds were then split into a training set consisting of 602 molecules and a test set of 119 compounds to validate the models. The results of this study showed that neural network models using applied parameters of the drug, i.e., log D and Abraham solvation parameters, are able to predict the class of solubility and metabolism in the BDDCS system with good accuracy. Neural network models are well equipped to deal with the relations between the structural parameters and physicochemical properties of drugs and BDDCS classes. In addition, log D is a more suitable parameter compared with log P in predicting BDDCS.

Mechanism of PAX6 overexpression in inhibiting the growth of hepatocellular carcinoma cells and promoting the killing ability of the natural killer cells.

Paired box gene 6 (PAX6) plays a major role in the regulation of embryonic development. Abnormal expression of PAX6 is associated with the development of various tumors. PAX6 can play a role in promoting or suppressing cancer in different tumors. This study aim to observe the effect of overexpression of PAX6 on the growth of hepatocellular carcinoma cells, and the killing of hepatocellular carcinoma cells via natural killer (NK) cell and the possible mechanism. The protein levels of PAX6, soluble major histocompatibility complex class I-like protein A (sMICA) and soluble UL16 binding protein 2 (sULBP2) in peripheral blood from 68 cases of hepatocellular carcinoma (HCC) patients and 10 healthy volunteers were detected by ELISA. Hepatocellular carcinoma cell line (HepG2, LM3) and human normal liver cells (LO2) were cultured at 37 ℃ and 5% CO2 condition in vitro. The PAX6 overexpressed plasmid (PAX6-OE) and empty vector (NC) were transferred into HepG2 and LM3 cells to construct stable cell lines. The mRNA and protein expression levels of PAX6 in HepG2 and LM3 cells were detected by real-time PCR, Western blotting and immunofluorescence, respectively. PAX6 was overexpressed in HepG2 and LM3 cells, the cell growth and migration ability were detected by CCK-8 method and cell scratch assay, and the levels of sMICA and sULBP2 in the supernatant were detected by ELISA. Matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9) and disintegrin and metalloproteinase 10 (ADAM10) in HepG2 and LM3 cells were detected by Western blotting. The killing ability of NK cells against these 2 HCC cells was detected by flow cytometry. Compared with the healthy volunteers, the expressions of PAX6 in the HCC patients were significantly decreased (P=0.002), while the expression of sMICA and sULBP2 were significantly increased (P=0.004 and P<0.001, respectively). Real-time PCR and Western blotting results showed that compared with LO2 cells, mRNA and protein expressions of PAX6 in HepG2 and LM3 cells were significantly decreased (all P<0.05). Immunofluorescence results also showed that the expressions of PAX6 in HepG2 and LM3 were lower than those of LO2 cells. Compared with the NC group, the ability of proliferation and migration of HepG2 and LM3 cells were decreased (both P<0.05). The protein expressions of MMP2, MMP9 and ADAM10 in HepG2 and LM3 cells in the PAX6-OE group were significantly decreased, and the levels of sMICA and sULBP2 in superneant of HepG2 and LM3 cells in the PAX6-OE group were significantly lower than those in the NC group (all P<0.05). Flow cytometry results showed that compared with the NC group, the proportion of NK cells killing HepG2 and LM3 cells in PAX6-OE group was significantly increased (both P<0.05). The expression of PAX6 is decreased in serum of HCC patients and hepatocellular carcinoma cell lines. Overexpression of PAX6 can inhibit the growth of hepatocellular carcinoma cells, enhance the killing efficiency of NK cells against hepatoma cells. The mechanism is related to the inhibition of the expression of metalloproteinase via PAX6 and the decrease of the secretion levels of sMICA and sULBP2.

HLA-A23/HLA-A24 serotypes and dementia interaction in the elderly: Association with increased soluble HLA class I molecules in plasma.

MHC class I molecules regulate brain development and plasticity in mice and HLA class I molecules are associated with brain disorders in humans. We investigated the relationship between plasma-derived soluble human HLA class I molecules (sHLA class I), HLA class I serotypes and dementia. A cohort of HLA class I serotyped elderly subjects with no dementia/pre-dementia (NpD, n = 28), or with dementia (D, n = 28) was studied. Multivariate analysis was used to examine the influence of dementia and HLA class I serotype on sHLA class I levels, and to compare sHLA class I within four groups according to the presence or absence of HLA-A23/A24 and dementia. HLA-A23/A24 and dementia, but not age, significantly influenced the level of sHLA class I. Importantly, the concurrent presence of HLA-A23/A24 and dementia was associated with higher levels of sHLA class I (p < 0.001). This study has shown that the simultaneous presence of HLA-A23/HLA-A24 and dementia is associated with high levels of serum sHLA class I molecules. Thus, sHLA class I could be considered a biomarker of neurodegeneration in certain HLA class I carriers.

Conjunction of semi-mechanistic in vitro-in vivo modeling and population pharmacokinetics as a tool for virtual bioequivalence analysis - a case study for a BCS class II drug

Virtual bioequivalence trial (VBE) simulations based on (semi)mechanistic in vitro-in vivo (IVIV) modeling have gained a huge interest in the pharmaceutical industry. Sophisticated commercially available software allows modeling variable drug fates in the gastrointestinal tract (GIT). Surprisingly, the between-subject and inter-occasion variability (IOV) of the distribution volumes and clearances are ignored or simplified, despite substantially contributing to varied plasma drug concentrations. The paper describes a novel approach for IVIV-based VBE by using population pharmacokinetics (popPK). The data from two bioequivalence trials with a poorly soluble BCS class II drug were analyzed retrospectively. In the first trial, the test drug product (biobatch 1) did not meet the bioequivalence criteria, but after a reformulation, the second trial succeeded (biobatch 2). The popPK model was developed in the Monolix software (Lixoft SAS, Simulation Plus) based on the originator’s plasma concentrations. The modified Noyes-Whitney model was fitted to the results of discriminative biorelevant dissolution tests of the two biobatches and seven other reformulations. Then, the IVIV model was constructed by joining the popPK model with fixed drug disposition parameters, the drug dissolution model, and mechanistic approximation of the GIT transit. It was used to simulate the drug concentrations at different IOV levels of the primary pharmacokinetic parameters and perform the VBE. Estimated VBE success rates for both biobatches well reflected the outcomes of the bioequivalence trials. The predicted 90% confidence intervals for the area under the time-concentration curves were comparable with the observed values, and the 10% IOV allowed the closest approximation to the clinical results. Simulations confirmed that a significantly lower maximum drug concentration for biobatch 1 was responsible for the first clinical trial’s failure. In conclusion, the proposed workflow might aid formulation screening in generic drug development.

Development of Robust Tablet Formulations with Enhanced Drug Dissolution Profiles from Centrifugally-Spun Micro-Fibrous Solid Dispersions of Itraconazole, a BCS Class II Drug

Fibre-based oral drug delivery systems are an attractive approach to addressing low drug solubility, although clear strategies for incorporating such systems into viable dosage forms have not yet been demonstrated. The present study extends our previous work on drug-loaded sucrose microfibres produced by centrifugal melt spinning to examine systems with high drug loading and investigates their incorporation into realistic tablet formulations. Itraconazole, a model BCS Class II hydrophobic drug, was incorporated into sucrose microfibres at 10, 20, 30, and 50% w/w. Microfibres were exposed to high relative humidity conditions (25 °C/75% RH) for 30 days to deliberately induce sucrose recrystallisation and collapse of the fibrous structure into powdery particles. The collapsed particles were successfully processed into pharmaceutically acceptable tablets using a dry mixing and direct compression approach. The dissolution advantage of the fresh microfibres was maintained and even enhanced after humidity treatment for drug loadings up to 30% w/w and, importantly, retained after compression into tablets. Variations in excipient content and compression force allowed manipulation of the disintegration rate and drug content of the tablets. This then permitted control of the rate of supersaturation generation, allowing the optimisation of the formulation in terms of its dissolution profile. In conclusion, the microfibre-tablet approach has been shown to be a viable method for formulating poorly soluble BCS Class II drugs with improved dissolution performance.

Role of CD4+NKG2D+ T cells in the disease activity of juvenile idiopathic arthritis

To study the expression levels of CD4+NKG2D+ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4+NKG2D+ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4+NKG2D+ T cells, sMICA and sMICB in the disease activity of JIA. The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4+NKG2D+ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. The percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4+NKG2D+ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.

Improving the Bioactivity of Norfloxacin with Tablets Made from Paper.

(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for oral administration to improve the solubility and bioactivity of a poorly soluble BSC class IV antibiotic. (2) Methods: Norfloxacin was used as the model drug and loaded into commercially available paper. The resulting norfloxacin-loaded smartFilms were transformed into smartFilm granules via wet granulation and the resulting norfloxacin-loaded smartFilm granules were transformed into norfloxacin-loaded tablets made from paper, i.e., smartFilm tablets. The crystalline state of norfloxacin was investigated, as well as the pharmaceutical properties of the granules and the tablets. The bioactivity of the smartFilm tablets was assessed in vitro and ex vivo to determine the antibacterial activity of norfloxacin. The results were compared to a physical mixture tablet that contained non-loaded paper granules and equal amounts of norfloxacin as a crystalline powder. (3) Results: Norfloxacin-loaded smartFilm granules and norfloxacin-loaded smartFilm tablets contained norfloxacin in an amorphous state, which resulted in an improved and faster release of norfloxacin when compared to the physical mixture tablet. The bioactivity was up to three times higher when compared to the physical mixture tablet. The ex vivo model was demonstrated to be a useful tool that allows for a fast and cost-effective discrimination between "good" and "bad" formulations. It provides realistic physiological conditions and can therefore yield meaningful, additional biopharmaceutical information that cannot be assessed in classical in vitro experiments. (4) Conclusions: smartFilm tablets are a promising, universal, industrially feasible and cost-effective formulation strategy for improved solubility and enhanced bioactivity of poorly soluble drugs.

RPPSP: A Robust and Precise Protein Solubility Predictor by Utilizing Novel Protein Sequence Encoder

Protein solubility prediction is essential to understand diverse types of biological processes and to explore the impact of different factors (ionic strength, temperature, PH of medium and electrostatic repulsion) on the productivity of proteins. It also plays an important role in disease analysis and drug development processes. Protein solubility prediction through experimental approaches is time-consuming, labour intensive and error-prone. To empower the process of protein solubility prediction and facilitate large scale analysis, 16 different computational predictors have been proposed. However, these predictors have low predictive performance mainly due to extraction of less semantic and discriminative features from raw protein sequences. Existing predictors either extract sequence order information or positional information, while both types of information are important to discriminate soluble and insoluble proteins. This paper presents a novel encoder CTAPAAC capable of generating statistical representations of protein sequences by extracting 4 different types of information correlation, distribution, composition and transition. Over 4 benchmark datasets a comprehensive intrinsic and extrinsic performance analysis of proposed and 14 most widely used existing protein sequence encoders reveals that proposed encoder has more potential in transforming soluble and insoluble protein sequences into statistical vectors having discriminative patterns among soluble and insoluble classes. Proposed encoder along with random forest classifier outperforms existing best performing protein solubility predictors with a significant margin of 6%, 7%, 25% and 10% over PSI:Biology, E.coli, price and Esol datasets in terms of accuracy. Source code of proposed predictor is publicly available at <uri xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">https://github.com/Faiza-Mehmood/RPPSP</uri> .

Pioglitazone-loaded nanostructured lipid carriers: In-vitro and in-vivo evaluation for improved bioavailability

Pioglitazone (PZ), a highly lipophilic Class II drug with poor aqueous solubility possesses low oral bioavailability. The oral bioavailability of pioglitazone can be improved by incorporating into nanostructured lipid carriers (NLCs). Pioglitazone-loaded nanostructured lipid carriers (PZ-loaded NLCs) were developed by using the solvent emulsification evaporation method. The lipid phase of the formulation consists of a solid and liquid lipid mixture (fatty acids and oils) and surfactants (Tween 20, Span 40) were used for the stability of the formulation. PZ-loaded NLCs were characterized for physicochemical characteristics including particle size, zeta potential, polydispersity index (PDI), fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM) and stability studies. Moreover, drug entrapment efficiency, drug loading capacity, drug release, toxicity studies, permeation studies, and in-vivo studies were performed to evaluate enhanced bioavailability. PZ-loaded NLCs have shown an average particle size of 152 nm, PDI of 0.19, and a negative value of zeta potential. Drug entrapment efficiency and loading capacity were about 83% and 5.8%, respectively. SEM results delineated the smooth homogenous surface in nano-sized range, whereas FTIR spectra demonstrated no interaction between components of PZ-loaded NLCs formulation. For drug release studies, the dialysis bag method confirmed a biphasic release behavior in beginning followed by slow, controlled release up to 24 h. Furthermore, permeation studies showed enhanced permeability and in-vivo studies confirmed the enhanced bioavailability of pioglitazone. Based on the above finding, it can be concluded that NLCs are a versatile tools for enhancing the bioavailability of poorly soluble Class II drugs.

Upgrading of Sharqy Baghdad Heavy Oil via N-Hexane Solvent

Asphaltenes are a solubility class described as a component of crude oil with undesired characteristics. In this study, Sharqy Baghdad heavy oil upgrading was achieved utilizing the solvent deasphalting approach as asphaltenes are insoluble in paraffinic solvents; they may be removed from heavy crude oil by adding N-Hexane as a solvent to create deasphalted oil (DAO)of higher quality. This method is known as Solvent De-asphalting (SDA). Different effects have been assessed for the SDA process, such as solvent to oil ratio (4-16/1 ml/g), the extraction temperature (23 ºC) room temperature and (68 ºC) reflux temperature at (0.5 h mixing time with 400 rpm mixing speed). The best solvent deasphalting results were obtained at room temperature and 12 ml/g solvents to oil ratio. As a result, the API of DAO was increased by 9.3º compared to the API of Sharqy Baghdad heavy oil. The asphaltene reduction was 61.56%. The Sulfur removal was 32.8%, the Vanadium removal was 36.48%, and the Nickel removal was 46.21%.

Solid self‑emulsifying pellets: Solubility enhancement for oral delivery of poorly soluble BCS Class II drug

The review focused on technique of solid self-emulsifying pellets (SEPs) for solubility enhancement of poorly water soluble drug. The oral route of administration has been and still is currently the primary route of drug delivery owing to its potential advantages compared to the other routes. The solubility enhancement process of hydrophobic drugs plays a key role in the formulation development to achieve the bioavailability and therapeutic action of the drug at the target site.1 Around 40% of probe new drugs are characterized as belonging to class II in the BCS classification (poorly water soluble and highly permeable), giving rise to poor and erratic oral bioavailability. The solid SEPs system combines the advantages of liquid Self emulsifying drug delivery system with those of solid dosage form, which can overcome the limitations of liquid formulations and improve the storage stability and patient compliance. To enhance the dissolution and oral absorption of water insoluble drug selfmicroemulsifying pellets develop and evaluated. SEPs pellets showed a significant quicker redispersion rate than the dissolution rate of commercial tablets. The solid SEPs pellets might be an encouraging strategy to improve the oral absorption of Poorly water soluble drug and the extrusion–spheronization method is a feasible technology for the solidification of liquid SMEPs. Self microemulsifying drug delivery system (SEPs) as an effective bioavailability enhancement pharmaceutical technology has been widely used during the recent years and have some successful products in the market (e.g. Neoral®, Norvir® and Fortovase®).&#x0D; Keywords: Self Emulsifying Pellets, Bioavailability, Solubility, extrusion–spheronization, Biopharmaceutical Classification.

Development, Characterization and In vitro Evaluation of Solid Dispersion Formulations of Low Aqueous Soluble BCS Class II Drug Pitavastatin with Poloxamer 407 and HPMC

This study was aimed to boost up the dissolution rate of a sparingly aqueous soluble BCS Class II drug pitavastatin (PTV) by solid dispersion (SD) techniques using two hydrophilic polymers poloxamer 407 and hydroxypropylmethylcellulose (HPMC). Low aqueous solubility of PTV is associated with less oral bioavailability, and a real challenge in preparing appropriate dosage form. To enhance the aqueous solubility, physical mixing and SD formulations of PTV were developed by fusion and solvent evaporation methods using two hydrophilic polymers, poloxamer 407 and HPMC. Scanning electron microscopy (SEM) investigation indicated that PTV molecules were homogeneously dispersed in carrier prepared by different formulation methods at 1:2 and 1:3 ratios of PTV: polymer assuming amorphous SD state. The thermogravimetric profiles demonstrated that PTV was stable up to 198°C and began to decompose rapidly with significant weight loss as the temperature was raised over 190°C. Formulations prepared by SD techniques were stable at high temperature. In vitro studies illustrated that cumulative drug release of PTV: HPMC/poloxamer 407 formulations prepared by physical mixing, fusion and solvent evaporation techniques were better compared to pure PTV powder (61.42±0.91%). Among all the approaches, formulations prepared by solvent evaporation and fusion methods displayed higher cumulative releases of PTV than physical mixing formulations. The results of current study clearly indicated that PTV: HPMC/poloxamer 407 (1:2) formulations (S3, S1) developed by solvent evaporation method possess enhanced dissolution profile (96.06%; 95.62%) than the fusion SD formulations (F3; 94.62%, F1; 87.05%). Whereas PTV physical mixing formulations (P2; 82.32%, P4; 80.28%) containing high amount of carrier polymers (ratio 1:3) exhibited superior in vitro dissolution rates than formulations (P3; 68.70%, P1; 71.52%) having less quantity (ratio 1:2) of HPMC/poloxamer 407. It is apparent from the findings of this study that SD formulations (S3, S1, F3, F1) of PTV with HPMC/poloxamer 407 is a very promising approach for improving the in vitro dissolution profile of the sparingly aqueous soluble PTV. Moreover, 1:2 ratio formulations prepared by fusion and solvent evaporation SD approaches were found more effective to upgrade the release rate of PTV than the 1:3 formulations. Dhaka Univ. J. Pharm. Sci. 20(3): 325-336, 2022 (June) Centennial Special Issue

Baseline soluble MICA levels act as a predictive biomarker for the efficacy of regorafenib treatment in colorectal cancer

BackgroundTo evaluate the effect of regorafenib on soluble MHC class I polypeptide-related sequence A (MICA) (sMICA) level in vitro. In addition, we clinically examined whether its plasma levels were associated with regorafenib activity in terms of progression-free survival (PFS) in patients with CRC.MethodsHuman CRC cell line HCT116 and HT29 cells were treated with regorafenib and its pharmacologically active metabolites, M2 or M5 at the same concentrations as those in sera of patients. We also examined the sMICA levels and the area under the plasma concentration–time curve of regorafenib, M2 and M5.ResultsRegorafenib, M2, and M5 significantly suppressed shedding of MICA in human CRC cells without toxicity. This resulted in the reduced production of sMICA. In the clinical examination, patients with CRC who showed long median PFS (3.7 months) had significantly lower sMICA levels than those with shorter median PFS (1.2 months) (p = 0.045).ConclusionsMICA is an attractive agent for manipulating the immunological control of CRC and baseline sMICA levels could be a predictive biomarker for the efficacy of regorafenib treatment.