Preparation, Characterization, and Hepatoprotective Activity Evaluation of Quercetin-loaded Pluronic® F127/Chitosan-Myristic Acid Mixed Micelles.

BACKGROUND: Quercetin (QTN) is a flavonol antioxidant found in foods, medicinal plants, fruits, vegetables, and beverages. QTN oral consumption produces several biological effects, including antioxidant, cardioprotective, anti-apoptotic, anti-cancer, neuroprotection, anti-hypertensive, and chemo preventive. OBJECTIVE: The study aimed to prepare Pluronic®F127/chitosan-myristic acid copolymer (PF127/C-MAc)-based mixed micelles (QTN MM) to improve the biopharmaceutical and hepatoprotective potential of QTN. METHODS: QTN MM was developed employing thin-film hydration and optimized using full factorial design (FFD). Optimized QTN MM was analyzed using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), powder x-ray diffractometry (PXRD), in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCL4)-induced albino rats. RESULTS: PF127/C-MAc ratio (1:1) with CMC value ~ 5 µg/mL showed the suitability for MM. Characterization supported the formation of MM. QTN MM revealed prominent encapsulation efficiency and drug loading of about ~ 95.10% and ~ 12.28% w/w, respectively. MM spherical shape of QTN with a smaller particle size of ~ 34.08 nm and a higher zeta potential of ~ 36.24 nm indicated excellent physical stability. Dissolution and ex vivo permeation results revealed higher dissolution and permeation of QTN MM compared to QTN and PM. In vivo antioxidant activity suggested that QTN MM at (~ 20 mg/kg, p.o.) restored the enhanced marker enzyme level compared to QTN. CONCLUSION: The findings demonstrate that developed QTN MM could be used as an alternative nanocarrier to increase the biopharmaceutical and hepatoprotective potential of QTN and other flavonoids.

Development and Characterization of Pentaerythritol-EudragitRS100 Co-processed Excipients as Solid Dispersion Carriers for Enhanced Aqueous Solubility, In Vitro Dissolution, and Ex Vivo Permeation of Atorvastatin.

Atorvastatin (ATV), a lipid-lowering agent, has low oral bioavailability due to its poor water solubility, permeability, and low dissolution rate. Therefore, pentaerythritol-EudragitRS100 co-processed excipients (PECE) were synthesized, and their feasibility as solid dispersion carriers (ATV-PECE-SD) for improving the solubility, permeability, and dissolution rate of ATV was explored. Solid dispersions were assessed in terms of particle size and zeta potential, and solubility, in vitro dissolution, and ex vivo permeation studies were studied. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) were used as characterization tools. ATV-PECE-SD3 (1:4) formulations exhibited a small particle size with high stability. Physicochemical evaluation evidenced the formation of solid dispersion due to the involvement of weak electrostatic interaction between the polar functional groups of ATV and PECE carriers. ATV-PECE-SD3 (1:4) significantly enhanced the water solubility by ∼43-fold compared to pure ATV. In vitro dissolution studies showed that optimized formulation enhanced the dissolution rate of ATV compared to pure ATV. Ex vivo permeation results revealed that ATV-PECE-SD3 (1:4) enhanced the permeation rate of ATV compared to pure ATV. The optimized formulations significantly improved the dissolution rate of ATV in the fed state due to the food effect and micelle formation mechanism compared to the fasted state. The study concludes that co-processed excipients could be used as promising solid dispersion carriers to enhance the aqueous solubility, permeability, and dissolution rate of ATV.

Tailoring Deep Eutectic Solvents to Provoke Solubility and Bioavailability of Naringin: Implications of a Computational Approach.

Recently, the applications of deep eutectic solvents (DESs) as green and sustainable solvents for the solubilization of functional foods and phytophenols have dramatically risen concerning global issues on the utilization of organic solvents. Nevertheless, developing a suitable DES system for phytocomponents to enhance its solubility and bioavailability is complex and requires a sound experimental setup. Herein, we have attempted to develop DES encompassing the choline chloride (ChCl) along with oxalic acid (OA), l-glutamine (l-Glu), urea (U), and glycerol (Gro) at different ratios to elicit the solubility and bioavailability of naringin (NAR). Several DES systems were designed and tested for solubility, kinematic viscosity, and pH. Among these, DES-NAR encompassing ChCl/Gro in a 1:3 ratio exhibited the maximum solubility of NAR (232.56 ± 7.1 mg/mL) and neutral characteristic and thus considered suitable for NAR. Further, the conductor-like screening model for real solvents (COSMO-RS) has been employed to estimate the molecular and electrostatic interactions. DES-NAR was evaluated by polarized optical microscopy, Fourier-transform infrared (FTIR), differential scanning calorimetry (DSC), and 1H NMR to investigate the molecular transition and interaction. Further, diffusion and permeability studies were performed, which suggest significant improvements in DES-NAR. Likewise, the pharmacokinetic studies revealed a two times increase in the oral bioavailability of NAR in a designed DES system. Thus, the work represents a systematic and efficient development of the DES system for a potential phytocomponent considering the biosafety impact, which may widen the interest in pharmaceutical and food sciences.

Banana Peel Waste: An Emerging Cellulosic Material to Extract Nanocrystalline Cellulose.

Nanocrystalline cellulose (NCC) has gained attention due to its versatile properties such as biocompatibility, sustainability, high aspect ratio, and abundance of -OH groups that favor modifications of NCC. The objective of this paper is to develop NCC by extracting and characterizing NCC prepared from banana peel powder (BPP). BPP was subjected to alkali and bleaching treatment to remove lignin and hemicellulose and then subjected to acid hydrolysis to prepare NCC. Under optimal conditions (200 mL of sulfuric acid 55% v/v at 50 °C for 60 min), the NCC yield was found to be 29.9%. The particle size and zeta potential of the NCC were found to be 209 nm and -43 mV, respectively. Attenuated total reflectance Fourier transform infrared spectroscopy showed successful removal of lignin and hemicellulose from BPP after the alkali treatment, bleaching, and acid hydrolysis. Field emission scanning electron microscopy showed needle-shaped crystals and transmission electron microscopy showed particles in the nano range. X-ray diffraction analysis showed that the crystallinity index of NCC was 64.12% while keeping the cellulose I crystal structure intact. Thermogravimetric analysis showed good stability which paves way for NCC to be explored for various applications. All the parameters evaluated indicated that NCC was successfully prepared from BPP using alkali treatment, bleaching, and acid hydrolysis.

Development of phospholipon®90H complex nanocarrier with enhanced oral bioavailability and anti-inflammatory potential of genistein.

Genistein (GEN), an isoflavonoid, offers multifunctional biological activities. However, its poor oral bioavailability, aqueous solubility, extensive metabolism, and short half-life restricted its clinical use. Therefore, the Phospholipon®90H complex of genistein (GPLC) was prepared to enhance its biopharmaceutical properties and anti-inflammatory activity. GPLC was characterized by employing particle size and zeta potential, Fourier transforms infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry, proton nuclear magnetic resonance, aqueous solubility, in vitro dissolution, ex vivo permeation, oral bioavailability and in vivo anti-inflammatory activity. The complex showed high entrapment of GEN (∼97.88% w/w) within the Phospholipon®90H matrix. Particle size and zeta potential studies confirmed the small particle size with the modest stability of GPLC. The characterization analysis supported the formation of GPLC through the participation of hydrogen bonding between GEN and Phospholipon®90H. GPLC significantly enhanced the aqueous solubility (∼2-fold) compared to GEN. Dissolution studies revealed that GPLC drastically improved the GEN dissolution rate compared to GEN. Likewise, the complex improved the permeation rate across the membrane compared to GEN. GPLC formulation significantly enhanced the oral bioavailability of GEN via improving its Cmax, tmax, AUC, half-life and mean residence time within the blood circulation compared to GEN. The GPLC (∼20 mg/kg, p.o.) remarkably inhibited the increase in paw edema up to 5 h, compared to GEN and diclofenac. Results suggest that the Phospholipon®90 complex is a superior and promising carrier for enhancing the biopharmaceutical parameters of GEN and other bioactive with similar properties.

Deep Eutectic Solvents: Fundamental Aspect, Characterizations and Applications.

Deep eutectic solvents (DESs) containing bioactive have been explored as potential choices for therapeutic efficiency enhancement. DESs are regarded as superior compared to established solvents owing to accessibility, storage conditions, synthesis, and low cost. As such, intensive research has taken place in different disciplines, especially nutraceuticals, foods and pharmaceuticals. The applications of DESs, especially in nutraceuticals and pharmaceutical delivery, have shown great promise. Despite these different successes, the safety issues of these DESs need to be properly identified. A safe mixture of DESs must be developed to take its broad range of advantages to the nutraceutical industry, and, therefore, its nutraceutical applications can only be introduced if DESs are known to have profiles of negligible or minimal toxicity. This review emphasizes the fundamental aspects needed to have a better understanding of DESs. It covers the current prospects of DES, including types, properties, formulation components and characterization methods. The several characterization methods, viz., pH, density, refractive index, viscosity, surface tension, solubility, polarized optical microscopy, x-ray diffraction studies, Fourier transforms infrared spectroscopy, and nuclear magnetic resonance spectroscopy are also mentioned. Further, the promising applications of DESs in different nutraceutical and pharmaceutical domains are highlighted.

Calcium Ion-Sodium Alginate-Piperine-Based Microspheres: Evidence of Enhanced Encapsulation Efficiency, Bio-Adhesion, Controlled Delivery, and Oral Bioavailability of Isoniazid.

Isoniazid (INH) is a first-line chemotherapeutic drug employed in the management of tuberculosis. However, its extensive first-pass metabolism, short-life life, and low oral bioavailability confined its medical application. Therefore, the calcium ion-alginate-piperine microspheres (INH-CaSP Ms) was prepared to enhance encapsulation efficiency, controlled delivery, and oral bioavailability of INH. The INH-CaSP Ms was developed using a modified emulsification method and optimized via Box-Behnken design (BBD). Optimized INH-CaSP Ms were characterized for encapsulation efficiency, differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), bio-adhesion, in vitro dissolution, ex vivo permeation, and oral bioavailability studies. Characterization studies confirmed the formation of microspheres. The INH-CaSP Ms showed spherical microspheres with enhanced encapsulation efficiency (~ 93.03 ± 1.54% w/w). The optimized INH-CaSP Ms exhibited higher bio-adhesion around (~ 81.41 ± 1.31%). The INH-CaSP Ms enhanced the dissolution rate of INH (~ 57%) compared to pure INH (~ 57%) and INH-SA Ms (~ 81%) in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.4). The same formulations improved the permeation rate of INH (~ 90%) compared to pure INH (~ 55%) and INH-SA Ms (~ 80%). The oral bioavailability results indicated that INH-CaSP Ms appreciably improved the oral bioavailability of INH via increasing the Cmax, Tmax, t1/2, and AUC parameters compared to pure INH. The study demonstrates that the development of INH-CaSP Ms via cross-linked coordinate bond interaction between divalent cation calcium ion-alginate complex and anion piperine bio-enhancer is an effective approach for enhancing the encapsulation efficiency, bio-adhesion, controlled release, and oral bioavailability of INH.

Egg White Protein Carrier-Assisted Development of Solid Dispersion for Improved Aqueous Solubility and Permeability of Poorly Water Soluble Hydrochlorothiazide.

Hydrochlorothiazide (HTZ) is a first-line drug used in the treatment of hypertension suffered from low oral bioavailability due to poor aqueous solubility and permeability. Hence, lyophilized egg white protein-based solid dispersion (HTZ-EWP SD) was developed to explore its feasibility as a solid dispersion carrier for enhanced aqueous solubility and permeability of HTZ. The HTZ-EWP SD was prepared using the kneading method. HTZ-EWP SD was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), solubility, in vitro dissolution, and ex vivo permeation studies. The physico-chemical evaluation suggested the formation of the solid dispersion. Optimized HTZ-EWP SD4 drastically enhanced (~32-fold) aqueous solubility (~16.12 ± 0.08 mg/mL) over to pure HTZ (~ 0.51 ± 0.03 mg/mL). The dissolution study in phosphate buffer media (pH 6.8) revealed that HTZ-EWP SD4 significantly enhanced the release rate of HTZ (~ 87 %) over to HTZ (~ 25 %). The permeation rate of HTZ from optimized HTZ-EWP SD4 was enhanced significantly (~ 84 %) compared to pure HTZ (~ 24 %). Optimized HTZ-EWP-SD4 enhanced the rate of HTZ dissolution (~ 86 %) in FeSSIF (fed state simulated intestinal fluid), compared to a low dissolution rate (~ 72 %) in FaSSIF (fasted state simulated intestinal fluid) state after 2-h study. Obtained results conclude that lyophilized egg white protein can be utilized as an alternative solid dispersion carrier for enhancing the solubility and permeability of HTZ.

Use of combined nanocarrier system based on chitosan nanoparticles and phospholipids complex for improved delivery of ferulic acid.

A novel nanocarrier system of phospholipids complex loaded chitosan nanoparticles (FAPLC CNPs) was developed to improve the oral bioavailability and antioxidant potential of FA. FAPLC CNPs were optimized using a Box-Behnken Design (BBD). FAPLC CNPs were characterized using differential scanning calorimetry, Fourier transforms infrared spectroscopy, powder x-ray diffractometry, proton nuclear magnetic resonance, solubility, in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCl4)-induced albino rat model. The characterization studies indicated a formation of the complex as well as FAPLC CNPs. The FAPLC CNPs exhibited a lower particle size ~123.27 nm, PDI value ~0.31, and positive zeta potential ~32 mV respectively. Functional characterization studies revealed a significant improvement in the aqueous solubility, dissolution, and permeation rate of FAPLC and FAPLC CNPs compared to FA and FA CNPs. The FAPLC CNPs showed significant enhancement of in vivo antioxidant activity of FA by restoring the elevated marker enzymes in the CCl4-intoxicated rat model compared to FA CNPs. Moreover, the pharmacokinetic analysis demonstrated a significant enhancement of oral bioavailability of FA from FAPLC CNPs compared to FA CNPs. These findings show that FAPLC CNPs could be used as an effective nanocarrier for improving the oral delivery of FA.

Phospholipid complex-loaded self-assembled phytosomal soft nanoparticles: evidence of enhanced solubility, dissolution rate, ex vivo permeability, oral bioavailability, and antioxidant potential of mangiferin.

In this study, self-assembled phytosomal soft nanoparticles encapsulated with phospholipid complex (MPLC SNPs) using a combination of solvent evaporation and nanoprecipitation method were developed to enhance the biopharmaceutical and antioxidant potential of MGN. The mangiferin-Phospholipon® 90H complex (MPLC) was produced by the solvent evaporation method and optimized using central composite design (CCD). The optimized MPLC was converted into MPLC SNPs using the nanoprecipitation method. The physicochemical and functional characterization of MPLC and MPLC SNPs was carried out by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), proton nuclear magnetic resonance (1H-NMR), solubility, in vitro dissolution, oral bioavailability, and in vivo antioxidant studies. A CCD formed stable MPLC with the optimal values of 1:1.76, 50.55 °C, and 2.02 h, respectively. Characterization studies supported the formation of a complex. MPLC and MPLC SNPs both enhanced the aqueous solubility (~ 32-fold and ~ 39-fold), dissolution rate around ~ 98% via biphasic release pattern, and permeation rate of ~ 97%, respectively, compared with MGN and MGN SNPs. Liver function tests and in vivo antioxidant studies exhibited that MPLC SNPs significantly preserved the CCl4-intoxicated liver marker and antioxidant marker enzymes, compared with MGN SNPs. The oral bioavailability of MPLC SNPs was increased appreciably up to ~ 10-fold by increasing the main pharmacokinetic parameters such as Cmax, Tmax, and AUC. Thus, MPLC SNPs could be engaged as a nanovesicle delivery system for improving the biopharmaceutical and antioxidant potential of MGN. Graphical abstract.

Double-loaded liposomes encapsulating lycopene ß-cyclodextrin complexes: preparation, optimization, and evaluation.

In the present investigation, we attempted to develop a lycopene-in- ß-CD -in-phospholipid vesicles (LCPV) with the sole aim of combining the solubilizing power of ß-CD with the sustained-release pattern of phospholipid vesicles. Inclusion complexes of ß-CD and lycopene were formed and characterized by using DSC and FT-IR. Double-loaded liposomes encapsulating lycopene ß-CD complex were prepared using soy lecithin, cholesterol, and ß-CD by thin film hydration method. The LCPV formulation was optimized using a 33 full factorial design to understand the impact of independent variables on entrapment efficiency and particle size. The formulations were evaluated for particle size, entrapment efficiency, drug release, and in vivo activity. The particle size of the optimized formulation showed entrapment efficiency of 78.9 ± 4.8% with a size of 255.15 ± 3 nm and zeta potential of -32.6, indicated the formation of a stable formulation which sustained the release up to 49.5% in 12 h. The results of the in vivo study indicated significant cardio-protective activity in an experimental animal. From the above results, it can be concluded that, the LCPV could be effectively used for sustained release of the drug.

Enhanced transdermal permeation and anti-inflammatory potential of phospholipids complex-loaded matrix film of umbelliferone: Formulation development, physico-chemical and functional characterization.

In the present study, umbelliferone - phospholipids complex - loaded matrix film (UPLC - MF) was developed with a goal of improving transdermal permeation and anti-inflammatory potential of umbelliferone (UMB). Umbelliferone - phospholipids complex (UPLC) was prepared using solvent evaporation method. UPLC-MF was prepared by simple and reproducible solvent casting method. Prepared UPLC and UPLC-MF were both physico-chemically characterized by Fourier transforms infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), proton nuclear magnetic resonance spectroscopy (1H NMR), weight variation, thickness, tensile strength, folding endurance, % elongation, moisture content and uptake Functional characterization of UPLC and UPLC-MF was carried out by solubility analysis, in vitro dissolution, diffusion, and ex vivo permeation via dialysis and biological membrane. UPLC - MF was also evaluated for in vivo anti-inflammatory activity using carrageenan-induced Albino rat paw model. Design-based optimal values for formulation and process variables of UPLC were observed to be 1:1.78, 50 °C and 2 h, respectively. Physico-chemical characterization confirmed the formation of the complex and the film. UPLC demonstrated a higher aqueous solubility (~11-fold), compared to pure UMB. Rate and extent of dissolution of UMB from UPLC was enhanced significantly to that of pure UMB. Compared to UMB-MF, the diffusion and permeation rate of UMB from UPLC-MF enhanced significantly. The UPLC - MF improved the anti-inflammatory potential of UMB by significant enhancement of edema inhibition (%), compared to UMB-MF. The obtained results showed that the present combined formulation system could be employed as a promising strategy for improving transdermal permeation of UMB.

Polymers, responsiveness and cancer therapy.

A single outcome in a biological procedure at the time of cancer therapy is due to multiple changes happening simultaneously. Hence to mimic such complex biological processes, an understanding of stimuli responsiveness is needed to sense specific changes and respond in a predictable manner. Such responses due to polymers may take place either simultaneously at the site or in a sequential manner from preparation to transporting pathways to cellular compartments. The present review comprehends the stimuli-responsive polymers and multi-responsiveness with respect to cancer therapy. It focuses on the exploitation of different stimuli like temperature, pH and enzymes responsiveness in a multi-stimuli setting. Nanogels and micelles being two of the most commonly used responsive polymeric carriers have also been discussed. The role of multiple stimuli delivery system is significant due to multiple changes happening in the near surroundings of cancer cells. These responsive materials are able to mimic some biological processes and recognize at the molecular level itself to manipulate development of custom-designed molecules for targeting cancer cells.

Biomass and waste materials as potential sources of nanocrystalline cellulose: Comparative review of preparation methods (2016 - Till date).

Nanocrystalline cellulose (NCC) has gained much popularity over the last decade as a preferred nanomaterial in varied applications, despite its laborious industrial production and higher cost. Its production methods have undergone a great deal of metamorphosis lately. The main emphasis has been on the environment-friendly and green processes, in addition to the sustainable and renewable feedstock. Globally, the researchers have explored biomass and waste cellulosic materials as renewable sources for NCC extraction. Newer and/or improved process alternatives, e.g., ultrasonication, enzymatic hydrolysis and mechanical treatments have been applied successfully for producing high-quality material. Detailed investigations on optimizing the overall yield from cheaper feedstock have yielded obvious benefits. This is still work in progress. The present review majorly focuses on the advances made in the NCC preparation field from biomass and waste cellulosic materials in last three years (2016 - till date). Collaborative efforts between chemical engineers and research scientists are crucial for the success of this really amazing nanomaterial.

Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential.

The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility.