Formulation, characterization, pharmacokinetics and antioxidant activity of phloretin oral granules.

Phloretin (PHL), a flavonoid of the dihydrogen chalcone class, is reported to have low oral bioavailability due to its poor solubility and absorption. A common approach to enhance the solubility of such flavonoids is solubilization in a polymeric or lipidic matrix which would help in enhance dissolution rate and solubility. Accordingly, in the current study PHL was dissolved in Gelucire® 44/14 by melt-fusion technique and the viscous semisolid melt was adsorbed on a solid carrier to obtain free flowing granules. SeDeM-SLA (Solid-Liquid Adsorption) expert system was employed to select the most suitable carrier. This study achieved positive outcomes through the successful development of formulated oral PHL granules. The granules exhibited good stability, and favourable pharmacokinetic properties. In addition, the selected carrier effectively retained the antioxidant properties of PHL.

Contact line motion in dewetted polymer droplets on anisotropic nanopatterned surfaces.

Thin polymer films can become unstable and dewet on a non-wettable substrate leading to the formation of an array of droplets. This instability-mediated drop formation lacks spatial order on flat substrates, but it can be ordered for better combinatorial studies using patterned substrates. In this work, we studied the process of dewetting polystyrene (PS) films on grating patterned substrates upon solvent vapor exposure. The PS film thickness was commensurate with the grating pattern height (hP). Our findings show that the initial dewetting stages follow the direction of the underlying grating pattern with the formation of directional holes in the film. During the later stages of dewetting, there was a lateral coalescence of polymer threads across the grating stripes. The final morphology comprised smaller droplets or threads confined within the pattern grooves and anisotropic large drops covering several pattern stripes. Furthermore, the larger drops show a unique behavior of shape change from anisotropic to isotropic as a function of solvent vapor concentration (Cn) inside the dewetting chamber. The drop regained its anisotropic shape with an increase in Cn, and this transition continued, with the movement of the three-phase contact line (TPCL). While the capillary flow of the polymer causes anisotropy during high Cn, the local orientation of the contact line and a mismatch in the value of the equilibrium contact angle can drive the drop back into an isotropic shape as Cn reduces and capillary forces weaken. We also observed that the extent of anisotropy quantified as droplet distortion ratio (Dr) not only depends on the Cn during dewetting but also on solvent type and hP. This new-found dynamic behavior of dewetted polymeric drops can be studied in greater detail and potentially leveraged for applications in sensing and microfluidics.

PP/Jute Fiber Composites: Effect of Biological Route of Surface Treatment and Content of Jute on Composites.

Jute as a fiber has many applications. It is also used in polymers as reinforcement due to its good tensile properties. However, when it is used in polymer matrices, there is a lack of adhesion between the polymer and jute fiber. Surface treatment of fiber using chemicals has been found to improve the properties. However, the use of chemicals causes environmental pollution, when these chemicals are discharged into the environment. In this paper, an attempt has been made to study the effect of the biological route to surface treat the jute fiber. The effect of surface treatment on the morphology of jute was examined. A comparative study was on the crystalline, thermal, and tensile fracture morphology of the composites to understand the effect of the incorporation of untreated and treated jute fibers in polypropylene (PP).

A concise summary of powder processing methodologies for flow enhancement.

The knowledge of powder properties has been highlighted since the 19th century since most formulations focus on solid dosage forms, and powder flow is essential for various manufacturing operations. A poor powder flow may generate problems in the manufacturing processes and cause the plant's malfunction. Hence these problems should be studied and rectified beforehand by various powder flow techniques to improve and enhance powder flowability. The powder's physical properties can be determined using compendial and non-compendial methods. The non-compendial practices generally describe the powder response under the stress and shear experienced during their processing. The primary interest of the current report is to summarize the flow problems and enlist the techniques to eliminate the issues associated with the powder's flow properties, thereby increasing plant output and minimizing the production process inconvenience with excellent efficiency. In this review, we discuss powder flow and its measurement techniques and mainly focus on various approaches to improve the cohesive powder flow property.

Hot-melt extruded in situ gelling systems (MeltDrops Technology): Formulation development, in silico modelling and in vivo studies.

In situ gelling systems (ISGS) can prolong retention time and bioavailability of ophthalmic solutions. The complexity and cost of ISGS avert their industrial scale-up and clinical implementation. In this study, we demonstrate novel application of hot-melt extrusion (HME) technology for continuous manufacturing of ISGS (MeltDrops Technology). Timolol maleate (TIM) and dorzolamide hydrochloride (DRZ) loaded MeltDrops were successfully developed using HME for glaucoma management, thereby resolving issues with batch manufacturing of ISGS, prolonging retention time thus improving bioavailability. The MeltDrops technology involves one-step, i.e., passing all the ingredients through an extruder at a screw speed between 20 and 50 rpm and barrel temperature of 80 °C. The comparative evaluation of MeltDrops and batch-processed ISGS demonstrated that MeltDrops exhibited better physical and chemical content uniformity. The extrusion temperature and screw speed were critical factors influencing content uniformity and properties of the MeltDrops. MeltDrops showed sustained drug release for > 12 h in vitro (TIM = 83.07%; DRZ = 60.43%, 12 h) versus marketed eyedrops. The developed MeltDrops followed Peppas-Sahlin model, combining Fickian diffusion and swelling processes. The in vivo study in New Zealand rabbits revealed superior effectiveness and safety of the MeltDrops as compared to the marketed eyedrops. Herein we conclude, MeltDrops would serve as a cutting-edge platform technology that can be used to manufacture various ISGS with one-step processability, cost-effectiveness, and improved product quality, which are otherwise processed by batch manufacturing that involves numerous complex processing steps.

Green Surfactants (Biosurfactants): A Petroleum-Free Substitute for Sustainability-Comparison, Applications, Market, and Future Prospects.

Surfactants are a group of amphiphilic molecules (i.e., having both hydrophobic and hydrophilic domains) that are a vital part of nearly every contemporary industrial process such as in agriculture, medicine, personal care, food, and petroleum. In general surfactants can be derived from (i) petroleum-based sources or (ii) microbial/plant origins. Petroleum-based surfactants are obvious results from petroleum products, which lead to petroleum pollution and thus pose severe problems to the environment leading to various ecological damages. Thus, newer techniques have been suggested for deriving surfactant molecules and maintaining environmental sustainability. Biosurfactants are surfactants of microbial or plant origins and offer much added advantages such as high biodegradability, lesser toxicity, ease of raw material availability, and easy applicability. Thus, they are also termed "green surfactants". In this regard, this review focused on the advantages of biosurfactants over the synthetic surfactants produced from petroleum-based products along with their potential applications in different industries. We also provided their market aspects and future directions that can be considered with selections of biosurfactants. This would open up new avenues for surfactant research by overcoming the existing bottlenecks in this field.

Neuroprotective potential of cannabidiol: Molecular mechanisms and clinical implications.

Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer's disease, Parkinson's disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection. Please cite this article as: Tambe SM, Mali S, Amin PD, Oliveira M. Neuroprotective potential of Cannabidiol: Molecular mechanisms and clinical implications. J Integr Med. 2023; 21(3): 236-244.

Nebulizer systems: a new frontier for therapeutics and targeted delivery.

Drug delivery via the pulmonary route is a cornerstone in the pharmaceutical sector as an alternative to oral and parenteral administration. Nebulizer inhalation treatment offers multiple drug administration, easily employed with tidal breathing, suitable for children and elderly, can be adapted for severe patients and visible spray ensures patient satisfaction. This review discusses the operational and mechanical characteristics of nebulizer delivery devices in terms of aerosol production processes, their usage, benefits and drawbacks that are currently shaping the contemporary landscape of inhaled drug delivery. With the advent of particle engineering, novel inhaled nanosystems can be successfully developed to increase lung deposition and decrease pulmonary clearance. The above-mentioned advances might pave the path for treating a life-threatening disorder like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is also discussed in the current state of the art.

Determination of Microstructural Impact on the Release of Drug from Hydroxypropyl Cellulose Gel by Validated In Vitro Release Test Method.

Microstructure of a semisolid system is greatly influenced by the formulation composition and the processing parameters. Different polymers exhibit different three-dimensional structure and these have a great impact on the drug release properties. The current research focuses on studying the impact of hydroxypropyl cellulose gel microstructure on the release properties of chlorhexidine gluconate (CHX G). The two main investigating methods of microstructure were used namely, rheology and texture analysis to determine the differences in the formulations studied. The CHX G drug release study was performed using a developed and validated in vitro release test method, which is reproducible, discriminative, and robust to detect the formulation differences. The drug release results showed that there was appreciable difference in the release rates of the different formulations. The rheology and texture analysis data correlated well with the difference in the release rates. The formulations differences were further confirmed by a statistical approach using analysis of variance.

Development of Gelucire® 48/16 and TPGS Mixed Micelles and Its Pellet Formulation by Extrusion Spheronization Technique for Dissolution Rate Enhancement of Curcumin.

The oral bioavailability of curcumin is limited, attributed to its low solubility or dissolution and poor absorption. Herein, the study describes formulation of curcumin-loaded mixed micelles of Gelucire® 48/16 and TPGS for its dissolution rate enhancement. Curcumin was dispersed in these molten lipidic surfactants which was then adsorbed on carrier and formulated as pellets by extrusion spheronization. Critical micelle concentration (CMC) of binary mixture of Gelucire® 48/16 and TPGS was lower than their individual CMC demonstrating the synergistic behavior of mixture. Thermodynamic parameters like partition coefficient and Gibbs free energy of solubilization indicated that mixed micelles were more efficient than micelles of its individual components in curcumin solubilization. Dynamic light scattering (DLS) suggested slight increase in micellar size of mixed micelles than its components suggesting curcumin loading in mixed micelles. Fourier transform infrared spectroscopy (FTIR) revealed that phenolic hydroxyl group interacts with lipids which contribute to its enhanced solubility. Furthermore, the differential scanning calorimetry (DSC) and X-ray diffraction (XRD) study indicated the conversion of crystalline curcumin into amorphous form. In the pellet formulation, Gelucire® 48/16 acted as a binder and eliminated the requirement of additional binder. Microcrystalline cellulose (MCC) forms wet mass and retards the release of curcumin from pellets. Increase in concentration of water-soluble diluent increased drug release. The optimized formulation released more than 90% drug and maintains supersaturation level of curcumin for 2 h. Thus, mixed micellar system was effective delivery system for curcumin while pellet formulation is an interesting formulation strategy consisting semi-solid lipids.

Insights on the Critical Parameters Affecting the Probiotic Viability During Stabilization Process and Formulation Development.

Probiotics have gained a lot of interest in recent years as an alternative as well as adjuvant therapy for several conditions owing to their health benefits. These live microorganisms have proven efficacy for treating gut disorders, inflammation, bacterial vaginosis, hepatic and depressive disorders, and many more. There are conventional as well as non-conventional formulations available for the delivery of probiotics with the latter having fewer regulatory guidelines. The conventional formulations include the pharmaceutical formulations specifically designed to deliver an efficacious number of viable microorganisms. Studies have indicated 108-109 CFU/g as an ideal dose of probiotics for achieving health benefits, and hence, all the formulations must at least contain the said number of viable bacteria to show a therapeutic effect. The most crucial feature of probiotic formulations is that the bacteria are prone to several environmental and processing factors which all together reduce the viability of the bacteria in the final formulation. These factors include processing parameters like temperature, humidity, pressure, and storage conditions. Thus, the present review primarily focuses on the critical process parameters affecting the probiotic viability during stabilization process and formulation development. Understanding these factors prior to processing helps in delivering probiotics in the required therapeutic numbers at the target site.

Thermodynamic aspects of the preparation of amorphous solid dispersions of Naringenin with enhanced dissolution rate.

Amorphous ternary solid dispersions of poorly water-soluble Naringenin (NRG) in Poloxamer 188 (POX) and Neusilin US2 (NSL) were prepared in a Hot- Melt Extruder (HME) using the principle of Low-Temperature Solubilization (LTS). Before HME, the NRG-POX solid-state interaction was investigated using Flory Huggins (F-H) theory. Construction of the composition-phase diagram showed Gibbs free energy to be negative close to the melting temperature of NRG, indicating a miscible system. The temperature-composition phase diagram provided insights on the phase behavior of the active-polymer solid dispersion system. The interactions and phase behavior predicted within the framework of the F-H theory were further investigated using Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), Hot Stage Microscopy (HSM) and Fourier-transform infrared spectroscopy (FT-IR). Based on the findings, amorphous solid dispersions of NRG were prepared via HME, which demonstrated a significant increase in the dissolution rate (p ≤ 0.05). The enhancement of the dissolution rate is due to conversion from crystalline to amorphous form, as confirmed by DSC and XRD. The amorphous NRG prepared in the current study exhibited a release of 77% at the end of 2 h, which is an increment of 250% from that of pure crystals.

Extended release delivery system of metoprolol succinate using hot-melt extrusion: effect of release modifier on methacrylic acid copolymer.

The current study reports on the manufacturing of extended release dosage forms of metoprolol succinate via hot-melt extrusion (HME) technology. Either Eudragit®S100 and Eudragit®L100 alone or in combination with release modifying agent Polyox™ WSR 303 and Eudragit®L100-55 were processed to obtain complete and faster release. Metoprolol succinate with similar solubility parameters to polymer was dispersed in polymer matrix and was characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Stability of drug after extrusion was confirmed by thermogravimetric analysis and high-performance liquid chromatography. Physical characterization method exhibited that the drug was homogeneously dispersed in non-crystalline state in Eudragit®L100-55-based formulations whereas in semi-crystalline state in Polyox™ WSR 303. The drug release percentage was below 3 and 40% in 0.1 N HCL with Eudragit®L100-55- and Polyox™ WSR 303-containing formulations, respectively, and exhibited pH-dependent dissolution properties. The drug-release mechanism was anomalous with Polyox™ WSR 303 formulations whereas diffusion through pore formation was obtained with Eudragit®L100-55. Both Eudragit®L100-55 and Polyox™ WSR 303 changed the release mechanism and kinetics of drug release from thermally processed dosage forms. The optimized stable formulation is similar to the marketed formulation with F2 value of 72.36. Thus, it can be concluded that HME was exploited as an effective process for the preparation of controlled release matrix system based on pH-dependent polymer matrices Eudragit®S100 and Eudragit®L100.

Solid crystal suspension of Efavirenz using hot melt extrusion: Exploring the role of crystalline polyols in improving solubility and dissolution rate.

Poor aqueous solubility of drugs has emerged as a major issue for pharmaceutical scientists from many decades. The current study explores the manufacture and development of a thermodynamically stabilized solid crystal suspension (SCS) of poorly water soluble drug efavirenz via hot melt extrusion. Efavirenz is a non-nucleoside reverse transcriptase inhibitor and belongs to BCS class II. The SCS was prepared using pearlitol and xylitol as a crystalline carrier. The drug-excipient blend was processed by hot melt extrusion with up to 50% (w/w) drug loading. Physico-chemical characterization of the SCS conducted via a scanning electron microscopy, differential scanning calorimetry and hot stage microscopy confirmed that SCS are in crystalline state. Similarly, X-ray powder diffraction analysis revealed highly crystalline existence of pure drug, crystalline carriers and developed SCS. The FTIR chemical imaging analysis of SCS formulations showed a homogeneous drug distribution within respective crystalline carriers while an advanced chemical analysis via atomic force microscopy and Raman analysis complemented the foregoing findings. The developed SCS1 formulation showed up to 81 fold increase in the solubility and 4.1 fold increase in the dissolution rate of the drug compared to that of the bulk substance. Surprisingly, the developed SCS formulation remained stable for a period of more than one year at accelerated conditions inferred from dissolution studies. It can be concluded that the SCS approach can be used as an alternative contemporary technique to enhance the dissolution rates of many other poorly water-soluble drugs by means of thermal HME processing.

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire.

Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition.

Development and Validation of Stability-Indicating RP-HPLC Method for Simultaneous Determination of Metformin HCl and Glimepiride in Fixed-Dose Combination.

A simple reversed-phase high-performance liquid chromatography method was developed and validated for simultaneous determination of Metformin hydrochloride (MET) and Glimepiride (GLM) in combination and estimation of their principal degradation products. The separation was achieved using JASCO Finepak SIL (250 mm × 4.6 mm i.d. 5 µm) at ambient temperature. The optimized mobile phase composed of an aqueous phase (20 mM phosphate buffer, adjusted to pH 3.0) and an organic phase (methanol:acetonitrile; 62.5:37.5) in the ratio of 80:20. The flow rate was 1 mL/minute, and the analytes were detected at 230 nm. The developed method was validated for accuracy, precision, specificity, linearity, and sensitivity. The chromatographic analysis time was approximately six minutes with the complete resolution of MET (Rt = 2.75 minutes) and GLM (Rt = 5.87 minutes). The method exhibited good linearity over the range of 5-30 µg/mL for MET and 1-10 µg/mL for GLM. The drugs in combination were subjected to various stress degradation studies as per the International Conference Harmonization (ICH) guidelines. Results obtained from the stress degradation studies revealed that the developed method is applicable for stability studies.

Modified extrusion-spheronization as a technique of microencapsulation for stabilization of choline bitartrate using hydrogenated soya bean oil.

INTRODUCTION: Choline bitartrate (CBT) is a vital nutrient for fetal brain development and memory function. It is hygroscopic in nature which is associated with stability related problem during storage such as development of fishy odor and discoloration. AIM: Microencapsulation method was adopted to resolve the stability problem and for this hydrogenated soya bean oil (HSO) was used as encapsulating agent. MATERIALS AND METHODS: Industrially feasible modified extrusion-spheronization technique was selected for microencapsulation. HSO was used as encapsulating agent, hydroxypropyl methyl cellulose E5/E15 as binder and microcrystalline cellulose as spheronization aid. Formulated pellets were evaluated for parameters such as flow property, morphological characteristics, hardness-friability index (HFI), drug content, encapsulation efficiency, and in vitro drug release. The optimized formulations were also characterized for particle size (by laser diffractometry), differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy, and scanning electron microscopy. RESULTS AND DISCUSSIONS: The results from the study showed that coating of 90% and 60% CBT was successful with respect to all desired evaluation parameters. Optimized formulation was kept for 6 months stability study as per ICH guidelines, and there was no change in color, moisture content, drug content, and no fishy odor was observed. CONCLUSION: Microencapsulated pellets of CBT using HSO as encapsulating agent were developed using modified extrusion spheronization technique. Optimized formulations, CBT 90% (F5), and CBT 60% (F10), were found to be stable for 4M and 6M, respectively, at accelerated conditions.

Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis.

In multiple sclerosis (MS), lymphocyte--in particular B cell--transit between the central nervous system (CNS) and periphery may contribute to the maintenance of active disease. Clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MS patients; however, it remains unclear which subpopulations of the highly diverse peripheral B cell compartment share antigen specificity with intrathecal B cell repertoires and whether their antigen stimulation occurs on both sides of the blood-brain barrier. To address these questions, we combined flow cytometric sorting of PB B cell subsets with deep immune repertoire sequencing of CSF and PB B cells. Immunoglobulin (IgM and IgG) heavy chain variable (VH) region repertoires of five PB B cell subsets from MS patients were compared with their CSF Ig-VH transcriptomes. In six of eight patients, we identified peripheral CD27(+)IgD(-) memory B cells, CD27(hi)CD38(hi) plasma cells/plasmablasts, or CD27(-)IgD(-) B cells that had an immune connection to the CNS compartment. Pinpointing Ig class-switched B cells as key component of the immune axis thought to contribute to ongoing MS disease activity strengthens the rationale of current B cell-targeting therapeutic strategies and may lead to more targeted approaches.

Study of doxofylline and its degradation products in bulk drug by a newly developed stability-indicating HPLC method.

The purpose of this work was to study the stability behavior of doxofylline under different stress conditions and to develop a sensitive stability-indicating HPLC assay method. The stress conditions applied included heat, moisture, acid-base hydrolysis, oxidation, and UV light. The drug was particularly labile under oxidative and thermal stress conditions, with 58.40 and 53.90% degradation, respectively. Good resolution of drug from degradation products formed under stress conditions was achieved on a C18 column using 10 mM KH2PO4 buffer solution (pH 6) methanol (40 + 60, v/v) as the mobile phase (pH 7.2). The flow rate was 1 mLlmin, and the detection wavelength was 273 nm. The method was validated for linearity, range, precision, accuracy, LOD, and LOQ. The RSD was found to be <2%. Since the method effectively separates the drug from its degradation products, it can be used as a stability-indicating method.

Artemether-Soluplus Hot-Melt Extrudate Solid Dispersion Systems for Solubility and Dissolution Rate Enhancement with Amorphous State Characteristics.

This work studied artemether (ARTM) solid dispersion (SD) formulation using mixture of polymer excipient Soluplus, PEG 400, Lutrol F127, and Lutrol F68 melts at temperatures lower than the melting point of ARTM using a laboratory-size, single-screw rotating batch extruder. The effects of three surfactants PEG 400, Lutrol F127, and Lutrol F68 and parameters like mixing temperature, screw rotating speed, and residence time were systematically studied. SEM, XRD, and FT-IR were employed to investigate the evolution of ARTM's dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the ratio of polymer and surfactant to that of drug. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process and that laminar distributive mixing can significantly enhance the dissolution rate. The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced. In vitro antimalarial studies revealed marked improvement in IC50 values. Thus hot-melt extrusion (HME) is a promising technology for improving solubility and dissolution profile of ARTM.