Comprehensive insights into herbal P-glycoprotein inhibitors and nanoformulations for improving anti-retroviral therapy efficacy.

The worldwide HIV cases were 39.0 million (33.1-45.7 million) in 2022. Due to genetic variations, HIV-1 is more easily transmitted than HIV-2 and favours CD4 + T cells and macrophages, producing AIDS. Conventional HIV drug therapy has many drawbacks, including adherence issues leading to resistance, side effects that lower life quality, drug interactions, high costs limiting global access, inability to eliminate viral reservoirs, chronicity requiring lifelong treatment, emerging toxicities, and a focus on managing infections. Conventional dosage forms have bioavailability issues due to intestinal P-glycoprotein (P-gp) efflux, which can reduce anti-retroviral drug efficacy and lead to resistance. Use of phyto-constituents with P-gp regulating actions has great benefits for semi-synthetic modification to create formulations with greater bioavailability and reduced toxicity, which improves drug effectiveness. Lipid-based nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, polymer-based nanocarriers, and inorganic nanoparticles may inhibit P-gp efflux. Employing potent P-gp inhibitors within nanocarriers as a Trojan horse approach can enhance the intracellular accumulation of anti-retroviral drugs (ARDs), which are substrates for efflux transporters. This technique increases oral bioavailability and offers lower-dose options, boosting HIV patient compliance and lowering costs. Molecular docking of the inhibitor with P-gp may anticipate optimum binding and function, allowing drug efflux to be minimised.

Exploring the potential of P-glycoprotein inhibitors in the targeted delivery of anti-cancer drugs: A comprehensive review.

Due to the high prevalence of cancer, progress in the management of cancer is the need of the hour. Most cancer patients develop chemotherapeutic drug resistance, and many remain insidious due to overexpression of Multidrug Resistance Protein 1 (MDR1), also known as Permeability-glycoprotein (P-gp) or ABCB1 transporter (ATP-binding cassette subfamily B member 1). P-gp, a transmembrane protein that protects vital organs from outside chemicals, expels medications from malignant cells. The blood-brain barrier (BBB), gastrointestinal tract (GIT), kidneys, liver, pancreas, and cancer cells overexpress P-gp on their apical surfaces, making treatment inefficient and resistant. Compounds that compete with anticancer medicines for transportation or directly inhibit P-gp may overcome biological barriers. Developing nanotechnology-based formulations may help overcome P-gp-mediated efflux and improve bioavailability and cell chemotherapeutic agent accumulation. Nanocarriers transport pharmaceuticals via receptor-mediated endocytosis, unlike passive diffusion, which bypasses ABCB1. Anticancer drugs and P-gp inhibitors in nanocarriers may synergistically increase drug accumulation and chemotherapeutic agent toxicity. The projection of desirable binding and effect may be procured initially by molecular docking of the inhibitor with P-gp, enabling the reduction of preliminary trials in formulation development. Here, P-gp-mediated efflux and several possible outcomes to overcome the problems associated with currently prevalent cancer treatments are highlighted.

A novel Posaconazole oral formulation using spray dried solid dispersion technology: in-vitro and in-vivo study.

SD (solid dispersion) technology is one of the well-recognized solubility enhancement methods; but the use of versatile carriers in ASD (amorphous SD) to achieve the added advantage of modified release along with solubility improvement is an emerging area of exploration. Spray drying is a widely used technology with excellent scalability and product attributes. The SD carriers explored were Soluplus®, possessing excellent solubilization properties that may enhance bioavailability and is suitable for innovative processing, and Gelucire 43/01, a lipid polymer utilized in a non-effervescent-based floating gastro-retentive DDS for the modified release of API. The CPPs of spray drying were screened during preliminary trials, and the formulation variables were optimized using a 32 Full Factorial Design. All nine batches were evaluated for % yield, % drug content, flow properties, floating behavior, saturation solubility, and in-vitro drug release in 0.1 N HCl. The optimized batch characterized based on DSC (differential scanning calorimetry) and PXRD (powder X-ray diffraction) confirmed the amorphous nature of entrapped drug in SDD (spray-dried dispersion). Particle size analysis and SEM (scanning electron microscopy) demonstrated micron size irregular shaped particles. Residual solvent analysis by GCMS-HS confirmed the elimination of organic solvents from SDD. The optimized batch was found stable after 6 months stability study as per ICH guidelines. In-vivo roentgenography study in New Zealand white rabbit showed the residence of SDD in gastric environment for sufficient time. The pharmacokinetic study was performed in male Sprague-Dawley rats to determine the bioavailability of developed SDD based product in fasting and fed conditions, and to compare the data with marketed Noxafil formulation. The current research is focused on the development of a novel ternary SDD (spray-dried dispersion)-based gastro-retentive formulation for an anti-fungal drug Posaconazole.

Quality by Design Approach for Optimization of Microbial and pH-Triggered Colon-Targeted Tablet Formulation Using Carboxymethyl Tamarind Gum.

ABSTRACT The purpose of this study was to apply the quality by design (QbD) approach in the development of a microbial and pH-triggered colon-targeted budesonide tablet. A retrospective research strategy was used to select various polysaccharide-based natural gums such as tamarind gum, gellan gum, karaya gum, gum ghutti, and khaya gum, which were then evaluated for their effectiveness in microbial degradation and targeting the colon. Viscosity profiles were generated in the presence of a prebiotic culture medium prepared by using the Velgut capsule that mimicked the impact of 4% rat cecal content and helpful in screening of natural polymer. Based on the cumulative drug release data of preliminary batches, carboxymethyl (CM) tamarind gum was identified as a superior and an excellent polymer over the tamarind gum for formulation development. The presence of water as a bridging agent in wet granulation also played an important role in the retardation of drug release. Tablets were supercoated with the enteric polymer, Eudragit S100. The Box-Behnken design was utilized, where the selected independent variables were the proportion of CM tamarind gum, % water proportion, and % weight gain of Eudragit S 100 to optimize the formulation. The optimized design space was generated with the criteria that a drug release should be of less than 5% within the first 2 h, less than 10% within the first 5 h, and more than 70% within the first 8 h, to achieve colon targeting. The optimized batch F3 was found stable as per International Council for Harmonisation guidelines. The roentgenography study for optimized formulation demonstrated that it remained intact for 5 h and, at 7 h, was disseminated completely. CM tamarind gum is efficient for colon targeting, and its proportion in 100 mg along with an enteric coating of 6% led to the optimized formulation.

Advances in AI-Driven Retention Prediction for Different Chromatographic Techniques: Unraveling the Complexity.

Retention prediction through Artificial intelligence (AI)-based techniques has gained exponential growth due to their abilities to process complex sets of data and ease the crucial task of identification and separation of compounds in most employed chromatographic techniques. Numerous approaches were reported for retention prediction in different chromatographic techniques, and consistent results demonstrated that the accuracy and effectiveness of deep learning models outclassed the linear machine learning models, mainly in liquid and gas chromatography, as ML algorithms use fewer complex data to train and predict information. Support Vector machine-based neural networks were found to be most utilized for the prediction of retention factors of different compounds in thin-layer chromatography. Cheminformatics, chemometrics, and hybrid approaches were also employed for the modeling and were more reliable in retention prediction over conventional models. Quantitative Structure Retention Relationship (QSRR) was also a potential method for predicting retention in different chromatographic techniques and determining the separation method for analytes. These techniques demonstrated the aids of incorporating QSRR with AI-driven techniques acquiring more precise retention predictions. This review aims at recent exploration of different AI-driven approaches employed for retention prediction in different chromatographic techniques, and due to the lack of summarized literature, it also aims at providing a comprehensive literature that will be highly useful for the society of scientists exploring the field of AI in analytical chemistry.

Development of Delayed Release Oral Formulation Comprising Esomeprazole Spray Dried Dispersion Utilizing Design of Experiment As An Optimization Strategy.

Solid dispersion (SD) technology is one of the most widely preferred solubility enhancement methods, especially for Biopharmaceutics classification system class II and IV drugs. Since the last decade, its application for the dual purpose of solubility hike and modified release using novel carriers has been in demand for its added advantages. Spray drying is a commercially accepted technique with high aspects of scalability and product characteristics. The current study used spray-dried dispersion to design delayed release capsule for the proton pump inhibitor esomeprazole. The SD carrier hydroxypropyl methylcellulose acetate succinate-medium grade (HPMCAS-MF) enhanced solubility, inhibited precipitation of saturated drug solutions, and allowed enteric release owing to its solubility above pH 6. The proposed approach avoided compression, coating with enteric polymers, and the development of multi-particulate pellet-based formulations, improving manufacturing feasibility. The formulation was optimized using Box-Behnken design, considering significant formulation variables like HPMCAS-MF proportion and critical process parameters like feed flow rate and inlet temperature. The optimized spray-dried dispersion were characterized based on Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) and also evaluated for solubility, in vitro drug release, residual solvent content, and stability testing. Response surface methodology optimization anticipated that formulation variables affected solubility and release profile, whereas CPPs affected yield. The design space was developed via overlay plot based on constraints specified to attain the desired response and validated using three checkpoint batches with desirability 1. FTIR showed active pharmaceutical ingredient-polymer compatibility. Particle size and SEM studies showed spherical particles with an average Z-value of 1.8 µ. DSC and PXRD confirmed SD's amorphous nature. The drug release investigation and release kinetics prediction utilizing DD-solver software showed a 2-h lag time with > 90% cumulative drug release up to 4 h for the DR formulation. ESM SDD were prepared by spray drying technique using the novel solid dispersion carrier HPMCAS-MF to serve the dual purpose of solubility enhancement and delayed release. The ratio of API:carrier and process variables like feed flow rate and inlet temperature were varied using the Box-Behnken Design to determine the design space of optimized product to procure the desired characteristics of solubility improvement compared to crystalline API and delayed release of PPI to avoid the degradation in the gastric environment. The developed formulation represents several benefits over the already existing marketed products.

Current trends in chromatographic prediction using artificial intelligence and machine learning.

Artificial intelligence (AI) and machine learning (ML) gained tremendous growth and are rapidly becoming popular in various fields of prediction due to their potential abilities, accuracy, and speed. Machine learning algorithms employ historical data to analyze or predict information using patterns or trends. AI and ML were most employed in chromatographic predictions and particularly attractive options for liquid chromatography method development, as they can help achieve desired results faster, more accurately, and more efficiently. This review aims at exploring various AI and ML models employed in the determination of chromatographic characteristics. This review also aims to provide deep insight into reported artificial neural network (ANN) associated techniques which maintained better accuracy and significant possibilities for chromatographic characteristics prediction in liquid chromatography over classical linear models and also emphasizes the integration of a fuzzy system with an ANN, as this integrated study provides more efficient and accurate methods in chromatographic prediction than other linear models. This study also focuses on the retention prediction of a target molecule employing QSRR methodology combined with an ANN, highlighting a more effective technique than the QSRR alone. This approach showed the benefits of combining AI or ML algorithms with the QSRR to obtain more accurate retention predictions, emphasizing the potential of artificial intelligence and machine learning for overcoming adversities in analytical chemistry.

Development and evaluation of novel krill oil-based clomiphene microemulsion as a therapeutic strategy for PCOS treatment.

Polycystic ovary syndrome (PCOS) is frequently diagnosed hormonal disorder with reproductive and metabolic complications. The most common symptoms include cyst in ovaries, anovulation, insulin resistance, and obesity. Clomiphene citrate, an ovulating agent, is the first-line drug used to treat PCOS. We hypothesized that clomiphene citrate, by stimulating ovarian function, with krill oil used as an oil phase to improve solubility, by addressing PCOS-associated symptoms might be effective in PCOS. Hence, our goal was to target hormonal imbalance along with PCOS-associated symptoms using a single formulation. The concentration of water (X1), oil (X2), and Smix (surfactant-cosurfactant mixture) (X3) were selected as independent variables, in a simplex lattice design, from microemulsion area derived from a pseuodoternary phase diagram while the globule size (Y1) was selected as a dependent parameter. The optimized microemulsion showed good sphericity having 41 nm globule size, 0.32 poly dispersibility index and + 31 mV zeta potential. The optimized microemulsion was further evaluated in-vivo using letrozole-induced PCOS rats. Formulation treated group reversed the effect of letrozole on body weight and estrus cycle in comparison to the disease control group (p < 0.001). The formulation was also effective in reducing insulin resistance, cholesterol and serum testosterone level (p < 0.001). The in vivo results were supported by histopathological studies where the formulation-treated group showed a marked decrease in the number of cystic follicles and a remarkable increase in the number of growing follicles at variable stages, similar to the normal control group. Thus, the results confirmed that novel krill oil-based clomiphene microemulsion may become a promising therapeutic choice for the treatment of PCOS.

Nano-vaccination Strategies: Applications and Challenges for Intranasal Immunization.

The nasal route, a subgroup of mucosal delivery systems, constitutes a lucrative and encouraging substitute for administering drugs and vaccines. Over the years, a lot of research has been done in this area, and scientists have successfully explored this pathway using novel formulations to combat several infections. This review article aims to address the pathways of mucosal immunization, the dominance of the nasal route over other mucosal routes for immunization, and the mechanism of generation of immunogenic response via nasal route and nanotechnology-based approaches for intranasal vaccination. The immunotherapeutic and vaccinations for intranasal administration available in the market are also discussed, along with a brief overview of the products in the pipeline. It can also be assumed that such an approach can prove to be favorable in designing vaccinations for the current uncertain times. In spite of some dubious views on this.

Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review.

Solubility limited bioavailability is one of the crucial parameters that affect the formulation development of the new chemical entities. Thus the major constraint in the pharmaceutical product development is the suitable solubility enhancement technique for Active Pharmaceutical Ingredient. Solid dispersion (SD) is an established and preferred method for improving the solubility which ultimately may be helpful to enhance bioavailability. For long period of time Amorphous solid dispersion (ASD) have been preferred for improving solubility, but since last two decades, ASD approach have been combined with different modified release approaches to improvise the stability and site specificity of SD to grasp a hold over the specific advantages associated with such dosage forms. It is an established fact now that the SD technique not only improves solubility limited bioavailability, but it may be combined with other approaches to modify the drug release profile from the formulation as per the requirement based on the apt selection of SD carriers and suitable technology. This review covers the comprehensive overview of all such formulations where SD technology is used to serve dual purpose rather than only the sole purpose of solubility enhancement. The SD approach has been successfully implemented for some of the poorly soluble herbal drugs and still there is a vast scope of advancement in that area. The current review will provide a broad outcome in the area of SD technology for modified release formulations along with the description of current status and future prospective of SD. The SD formed by dispersing drug within the conventional carrier to form ASD increases solubility, dissolution rate and bioavailability; whereas fourth generation hydrophobic carriers provide added advantage of controlled release (CR) or sustained release (SR) profile along with enhanced stability of SD. On the other frontier, pH dependant carriers enable the SD to achieve site specificity or delayed release (DR) profile.

Formulation development, optimization, and evaluation of sustained release tablet of valacyclovir hydrochloride by combined approach of floating and swelling for better gastric retention.

The present study is intended to enhance gastric retention of sustained release tablet of valacyclovir hydrochloride by combined approach of floating and swelling. The tablets are prepared by direct compression method. Polyethylene oxide (Polyox WSR 303) is selected as the swelling matrix agent. Sodium starch glycolate (SSG) is used as swelling enhancer, and sodium bicarbonate is used as an effervescent agent for floating. A 3(2) full factorial design is applied to systematically optimize the formulation. The concentration of Polyox WSR 303 (X 1) and concentration of SSG (X 2) are selected as independent variables. The percentage drug release at 12 h, floating lag time, and maximum percentage swelling are selected as dependent variables. Formulations are evaluated for hardness, friability, floating lag time, total floating time, percentage swelling, in vitro drug release, and in vivo floating study. The results indicated that X 1 and X 2 significantly affected the drug release properties, floating lag times, and maximum percentage swelling. Release rate decreases as the concentration of Polyox increased. Regression analysis and numerical optimization are performed to identify the best formulation. Formulation F5 prepared with Polyox WSR 303 (15 %) and SSG (10 %) is found to be the best formulation. F5 followed zero-order release mechanism. Swelling and floating gastroretentive tablets of valacyclovir HCl are successfully formulated with controlled delivery to stomach with an aim of increasing the mean residence time in the upper part of GIT where the drug has its absorption window.

Central composite design for the formulation and optimization of a multi-unit potential colonic drug delivery system of budesonide for ulcerative colitis.

Budesonide is a potent glucocorticoid with high affinity for the glucocorticoid receptor, which is used for the treatment of inflammatory bowel diseases. Current oral formulations of budesonide present low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. The objective of this study was to develop a colon specific delivery system for budesonide to increase the efficacy in the treatment of ulcerative colitis using a statistical procedure. Pellets were prepared by powder layering of budesonide on nonpareils (0.5-0.6 mm) in a coating pan. Drug-layered pellets were coated with an inner layer of a combination of Eudragit RL PO and RS PO and an outer layer of Eudragit FS in a fluidized-bed apparatus. Central composite design was used to study the effect of three independent variables. The independent variables selected were amount of Eudragit FS outer coating (X1), proportion of Eudragit RL PO in the inner coating (X2), amount of Eudragit RL PO-RS PO inner coating (X3). Fifteen batches were prepared and evaluated for amount of drug released in 6 h (Y1), amount of drug released in 12h (Y2). The proportion of the more hydrophilic polymer Eudragit RL PO had the most significant effect on drug release - higher proportion gave faster release; the amount of inner and outer coat did not have a significant effect on the rate of drug release at either 6 or 12 h in the range studied. The computer optimization process and contour plots predicted the levels of independent variables X1, X2, and X3 (0.79, 0.69 and 0.35 respectively), for colon targeting.

Box-Behnken experimental design in the development of pectin-compritol ATO 888 compression coated colon targeted drug delivery of mesalamine.

The aim of this study was to investigate the combined influence of 3 independent variables in the compression coated tablet of mesalamine for ulcerative colitis. A 3-factor, 3-level Box-Behnken design was used to derive a second order polynomial equation and construct contour plots to predict responses. The independent variables selected were: percentage of polymers (pectin and compritol ATO 888) in compression coating (X(1)), coating mass (X(2)) and coating force (X(3)). Fifteen batches were prepared and evaluated for percent of drug released in 5 h (Y(5)), time required for 50 % mesalamine to dissolve (t(50)) with rat cecal (RC) content and without rat cecal content (t(50)), percent of drug released in 24 h in the presence of rat cecal content (Y(24) with RC). Transformed values of independent and dependent variables were subjected to multiple regressions to establish a full-model second-order polynomial equation. F was calculated to confirm the omission of insignificant terms from the full-model equation. The computer optimization process and contour plots predicted the levels of independent variables X(1), X(2), and X(3) (0, 0.2 and -0.15, respectively) for colon targeting and total percent of drug released up to 24 h.