Low Bioavailability Research Articles

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in HealthyMale Volunteers.

Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞], half-life (T½) and time to reach Cmax (Tmax)were calculated. The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Preclinical pharmacokinetic studies of villocarine A, an active Uncaria alkaloid.

Villocarine A is a bioactive indole alkaloid isolated from the Uncaria genus. It has demonstrated vasorelaxation activity and potential to protect the central nervous system. To identify the pharmacokinetic properties of villocarine A, a series of in vitro and in vivo studies have been performed. Villocarine A was found to be highly permeable (15.6 ± 1.6*10-6cm/s) across human colorectal adenocarcinoma cell monolayer with high protein binding (>91%) in both rat and human plasma. Hepatic extraction ratio of villocarine A was 0.1 in pooled rat liver and 0.2 in human liver microsomes and was found stable in rat plasma at 37°C. Due to the high permeability and low rate of metabolism properties, villocarine A was initially considered suitable for preclinical development and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification (linearity: 1-150 ng/ml) in rat plasma was developed and validated for in vivo studies. Essential pharmacokinetic parameters included the volume of distribution and clearance of villocarine A, which were found to be 100.3 ± 15.6L/kg and 8.2 ± 1.1L/h/kg, respectively, after intravenous administration in rats. Following oral dosing, villocarine A exhibited rapid absorption as the maximum plasma concentration (53.2 ± 10.4ng/ml) occurred at 0.3 ± 0.1h, post-dose. The absolute oral bioavailability of villocarine A was 16.8 ± 0.1%. To our knowledge, this was the first pharmacokinetic study of villocarine A, which demonstrated the essential pharmacokinetic properties of villocarine A: large volume distribution, high clearance, and low oral bioavailability in rats.

A Hemoglobin Bionics-based System for Combating Antibiotic Resistance in Chronic Diabetic Wounds via Iron Homeostasis Regulation.

Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, we aim to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred "iron cargo" was synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and was delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB down-regulated the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrated insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (> 90%) against resistant strains of both S. aureus and E. coli, and accelerated tissue recovery (< 20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity. This article is protected by copyright. All rights reserved.

Optimization of gluten-free cake formulation by replacement of rice flour and baking powder with different levels of eggshell powder using response surface methodology

AbstractThe shell and membrane of the egg constitute approximately 11% of the whole egg and is an important food industry waste. Eggshells can be used as an additional source of calcium to the diet because of their low cost and high bioavailability. This study aimed to design and produce the optimum formulation for the gluten-free cake using eggshell powder as rice flour and baking powder replacer by Face-Centered Composite Design. According to the results, it was determined that the optimized formulation should contain 9.85% eggshell powder as a rice flour replacer and 32.78% eggshell powder as a baking powder replacer to obtain a gluten-free cake with a desirable profile in terms of hardness, specific volume, color ($${\text{L}}_{{{\text{crust}}}}^{*}$$ L crust ∗ and $${\text{L}}_{{{\text{crumb}}}}^{*}$$ L crumb ∗ values), ash content, calcium content, and overall acceptability. The gluten-free cake with eggshell powder obtained was characterized as a product rich in calcium, high in ash content, high in specific volume, with a brighter colour and good sensory acceptability. Also, the proximate properties of the gluten-free cake produced with the optimum formulation were also reported. These findings show for the first time that eggshell powder can be used as a rice flour and a baking powder replacer for the formulation of gluten-free cake.

Evaluation of poly(2-hydroxyethyl methacrylate) and poly(N-hydroxyethyl acrylamide) cryogels as potential quercetin release matrices

Fabrication of a suitable drug delivery system forms an attractive strategy to overcome the low bioavailability of quercetin. Poly(2-hydroxyethyl methacrylate–co-N-hydroxyethyl acrylamide), P(HEMA-co-HEAA) copolymer samples, and homopolymers of 2-hydroxyethyl methacrylate (PHEMA) and N-hydroxyethyl acrylamide (PHEAA) offer potential as quercetin delivery matrices owing to their favorable properties rendered in this study. Free radical polymerization applied under cryogenic conditions produced the polymer gels. The homopolymers and copolymers are noncytotoxic, porous, soft cryogels with surfaces resistant to protein and HCT-116 cancer cell adhesion. In vitro, quercetin release studies from samples reveal swelling-controlled, zero-order drug release at pH = 7.4 and 37 °C with high cumulative release percentages ranging from 92.03% to 94.82%. The durability of the cryogels and limited quercetin release at pH = 2.0 indicate that these cryogels are promising matrices for successfully delivering quercetin to the small intestine, where its primary absorption occurs.

Oral delivery of nanomedicine for genetic kidney disease

Abstract Chronic and genetic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD) have few therapeutic options, and clinical trials testing small molecule drugs have been unfavorable due to low kidney bioavailability and adverse side effects. Although nanoparticles can be designed to deliver drugs directly to the diseased site, there are no kidney-targeted nanomedicines clinically available, and most FDA-approved nanoparticles are administered intravenously which is not ideal for chronic diseases. To meet these challenges of chronic diseases, we developed a biomaterials-based strategy using chitosan particles (CP) for oral delivery of therapeutic, kidney-targeting peptide amphiphile micelles (KMs). We hypothesized that encapsuling KMs into CP would enhance the bioavailability of KMs upon oral administration given the high stability of chitosan in acidic conditions and mucoadhesive properties enabling absorption within the intestines. To test this, we evaluated the mechanism of KM access to the kidneys via intravital imaging and investigated the KM biodistribution in a porcine model. Next, we loaded KMs carrying the ADPKD drug metformin into CP (KM-CP-met) and measured in vitro therapeutic effect. Upon oral administration in vivo, KM-CP-met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM only or free drug. As such, KM-CP-met treatment in ADPKD mice (Pkd1fl/fl; Pax8-rtTA; Tet-O-Cre which develops the disease over 120 days and mimics the slow development of ADPKD) showed enhanced therapeutic efficacy without affecting safety despite repeated treatment. Herein, we demonstrate the potential of KM-CP as a nanomedicine strategy for oral delivery for the long-term treatment of chronic kidney diseases.

Erythrocyte-Membrane-Camouflaged Magnetic Nanocapsules With Photothermal/Magnetothermal Effects for Thrombolysis.

Venous/arterial thrombosis poses significant threats to human health. However, drug-enabled thrombolysis treatment often encounters challenges such as short half-life and low bioavailability. To address these issues, the design of erythrocyte-membrane (EM) camouflaged nanocapsules (USIO/UK@EM) incorporating ultra-small iron oxide (USIO) and urokinase (UK) drug, which exhibits remarkable photothermal/magnetothermal effects and drug delivery ability for venous/arterial thrombolysis, is reported. USIO, UK, and EM are coextruded to fabricate USIO/UK@EM with average sizes of 103.7nm. As USIO/UK@EM possesses wide photoabsorption and good magnetic properties, its solution demonstrates a temperature increase to 41.8-42.9°C within 5min when exposed to an 808nm laser (0.33mW cm-2) or alternating magnetic field (AMF). Such photothermal/magnetothermal effect along with UK confers impressive thrombolytic rates of 82.4% and 74.2%, higher than that (≈15%) achieved by UK alone. Further, the EM coating extends the circulating half-life (t1/2 = 3.28h). When USIO/UK@EM is administered to mice and rabbits, tail vein thrombus in mice and femoral artery thrombus in rabbits can be dissolved by the synergetic effect of thermothrombolysis and UK. Therefore, this study not only offers insights into the rational design of multifunctional biomimetic nanocapsules but also showcases a promising thrombolysis strategy utilizing nanomedicine.

Quercetin loaded polymeric dissolving microarray patches: fabrication, characterisation and evaluation

AbstractQuercetin, a natural compound, shows promising potential in wound healing by reducing fibrosis, limiting scar formation, and boosting fibroblast proliferation. However, its effectiveness is hindered by poor solubility, resulting in low bioavailability and necessitating high doses for therapeutic efficacy. This study presents a novel approach, fabricating quercetin-loaded microarray patches (MAPs) using widely employed solubility enhancement strategies. Fabricated MAPs exhibited favourable mechanical strength and could be inserted into excised porcine skin to a depth of 650 μm. Furthermore, formulations containing Soluplus® significantly increased the drug loading capacity, achieving up to 2.5 mg per patch and complete dissolution within an hour of application on excised porcine skin. In vitro studies on full-thickness neonatal porcine skin demonstrated that Soluplus®-enhanced MAPs effectively delivered quercetin across various skin layers, achieving a delivery efficiency exceeding 80% over 24 h. Additionally, these prototype MAPs displayed anti-inflammatory properties and demonstrated biocompatibility with human keratinocyte skin cells. Therefore, quercetin-loaded MAPs employing Soluplus® as a solubility enhancer present a promising alternative strategy for wound healing and anti-inflammatory therapy applications. Graphical abstract

Oral Delivery of Liraglutide-Loaded Zein/Eudragit-Chitosan Nanoparticles Provides Pharmacokinetic and Glycemic Outcomes Comparable to Its Subcutaneous Injection in Rats

Liraglutide (LIRA) is a glucagon-like peptide-1 (GLP-1) receptor agonist renowned for its efficacy in treating type 2 diabetes mellitus (T2DM) and is typically administered via subcutaneous injections. Oral delivery, although more desirable for being painless and potentially enhancing patient adherence, is challenged by the peptide’s low bioavailability and vulnerability to digestive enzymes. This study aimed to develop LIRA-containing zein-based nanoparticles stabilized with eudragit RS100 and chitosan for oral use (Z-ERS-CS/LIRA). These nanoparticles demonstrated a spherical shape, with a mean diameter of 238.6 nm, a polydispersity index of 0.099, a zeta potential of +40.9 mV, and an encapsulation efficiency of 41%. In vitro release studies indicated a prolonged release, with up to 61% of LIRA released over 24 h. Notably, the nanoparticles showed considerable resistance and stability in simulated gastric and intestinal fluids, suggesting protection from pH and enzymatic degradation. Pharmacokinetic analysis revealed that orally administered Z-ERS-CS/LIRA paralleled the pharmacokinetic profile seen with subcutaneously delivered LIRA. Furthermore, in vivo tests on a diabetic rat model showed that Z-ERS-CS/LIRA significantly controlled glucose levels, comparable to the results observed with free LIRA. The findings underscore Z-ERS-CS/LIRA nanoparticles as a promising approach for oral LIRA delivery in T2DM management.

Formulation and Evaluation of Immediate-Release Oral Tablets Containing Magnesium Aluminum Silicate-Loaded Simvastatin

Background: Simvastatin (SIM) is a lipid-lowering agent to prevent disorders caused by clogged blood vessels. Because of its low solubility, it has low bioavailability. The adsorption technique is effective in improving drug solubility and dissolution rate. Objective: To use magnesium aluminum silicate (MAS) as an adsorbent in combination with Soluplus® as a hydrophilic polymer to formulate SIM as immediate-release tablets (IRTs). Methods: We used the solvent evaporation method to make MAS-loaded SIM in the presence of Soluplus®, making sure that the ratio of SIM to MAS to SOLU was 1:6:3. We then used this mixture to make IRTs. Using the direct compression method, we made all of the SIM-IRT formulas. We used diluents like Avicel®PH102, Avicel®PH101, and starch, as well as super disintegrants like Crospovidone (CP), Croscarmellose sodium (CCS), and sodium starch glycolate (SSG). We evaluated these formulas for their weight variation, hardness, friability, disintegration time, drug content, and dissolution profile. Results: We prepared the tablet formula (T5) using MAS-loaded SIM, Avicel®PH102 as a diluent, and CCS 3% as a super disintegrant. This formula showed the shortest disintegration time (0.61 min) and best drug release in phosphate buffer pH 7.0, releasing more than 80% of the drug within 30 minutes. Conclusion: Using suitable excipients, adsorption was an efficient method to enhance the solubility of SIM for preparation as IRTs.

PVP/aprepitant microcapsules produced by supercritical antisolvent process

The supercritical antisolvent (SAS) process was a green alternative to improve the low bioavailability of insoluble drugs. However, it is difficult for SAS process to industrialize with limited production capacity. A coaxial annular nozzle was used to prepare the microcapsules of aprepitant (APR) and polyvinylpyrrolidone (PVP) by SAS with N, N-Dimethylformamide (DMF) as solvent. Meanwhile, the effects of polymer/drug ratio, operating pressure, operating temperature and overall concentration on particles morphology, mean particle diameter and size distribution were analyzed. Microcapsules with mean diameters ranging from 2.04 μm and 9.84 μm were successfully produced. The morphology, particle size, thermal behavior, crystallinity, drug content, drug dissolution and residual amount of DMF of samples were analyzed. The results revealed that the APR drug dissolution of the microcapsules by SAS process was faster than the unprocessed APR. Furthermore, the drug powder collected every hour is in the kilogram level, verifying the possibility to scale up the production of pharmaceuticals employing the SAS process from an industrial point of view.

Overview of Mycotic Keratitis

Abstract: Keratomycosis is a serious corneal infection associated with high ocular morbidity that can lead to severe vision loss. It is estimated to affect more than 1 million patients annually, most commonly occurring in tropical climates, and represents a growing threat to patients worldwide. Despite aggressive medical management, fungal infections have a higher rate of perforation requiring surgical intervention compared with other infectious etiologies. Early diagnosis and appropriate treatment are keys to preserving vision and saving patients' eyes. Timely diagnosis of fungal keratitis helps minimize corneal damage and scarring and increases the likelihood of a favorable outcome. Studies have shown that correct identification of fungal infections is often delayed up to 2 to 3 weeks after initial presentation. This leads to incorrect or ineffective treatment for many patients. Diagnostic techniques explored in this study include corneal scrapings with staining and culture, visualization with in vivo confocal microscopy, molecular diagnostic techniques including polymerase chain reaction, and recently developed omics-based technologies. Treatment of fungal keratitis begins with topical antifungals. Medical management has been proven to be effective, but with limitations including poor drug penetration and low bioavailability. Cases that do not respond to topical therapy require more invasive and novel treatments to control the infection. We review the clinical trials that have shaped current practice patterns, with focus on the efficacy of topical natamycin as the primary therapy for filamentous fungal keratitis. We explore additional management strategies such as localized intrastromal and intracameral injections of antifungal medications, photodynamic therapy, and surgical intervention.

Chitosan-based buccal mucoadhesive bilayer tablets enhance the bioavailability of tizanidine hydrochloride by bypassing the first-pass metabolism

Tizanidine hydrochloride (TZN) is an antimuscarinic agent used in the treatment of pain-related spasms, multiple sclerosis, and stroke-related spasticity. It has low oral bioavailability (40 %) due to excessive first-pass metabolism in the liver. The aim of this project was to enhance the systemic bioavailability of TZN by developing buccal mucoadhesive bilayer tablet formulations using chitosan salts with molecular weights of 136 kDa (7 cP) and 169 kDa (10 cP). Structural characterisation of chitosans and their salts was performed by FTIR, 1H NMR, DSC, TGA, and XRD analyses. Soluble chitosan salts, chitosan glutamate and chitosan chloride, for the adhesive layer, and insoluble ethyl cellulose for the impermeable backing layer were selected as polymers to fabricate the buccal tablets by direct compression method. The tablets containing TZN demonstrated high swelling and good mucoadhesion characteristics as well as released all the drug within 8 h. While TC10, formulated with 10 cP chitosan chloride, showed the highest swelling properties, TG10, prepared with 10 cP chitosan glutamate, exhibited the highest mucoadhesion. Chitosan glutamate tablets (TG7 and TG10) demonstrated better mucoadhesive characteristics and stability than chitosan chloride ones (TC7 and TC10) in the buccal medium based on the results of swelling and drug release studies. The permeability studies performed by Franz diffusion cell demonstrated that the amount of TZN passing through the bovine buccal mucosa was between 13.4 and 14.4 %. Stability studies conducted at 5 ± 2 °C, 25 ± 2 °C and 40 ± 2 °C for 6 months showed that no changes in the content uniformity and pH were observed. The in vivo comparative bioavailability studies in female New Zealand rabbits were performed and TZN-containing buccal mucoadhesive bilayer tablets fabricated with both chloride (TC10) and glutamate (TG10) salts of chitosan demonstrated three times higher bioavailability than the commercial TZN product (Sirdalud® oral tablet) administered by the gastrointestinal route.

Advancements and challenges in pharmacokinetic and pharmacodynamic research on the traditional Chinese medicine saponins: a comprehensive review

Recent research on traditional Chinese medicine (TCM) saponin pharmacokinetics has revealed transformative breakthroughs and challenges. The multicomponent nature of TCM makes it difficult to select representative indicators for pharmacokinetic studies. The clinical application of saponins is limited by their low bioavailability and short half-life, resulting in fluctuating plasma concentrations. Future directions should focus on novel saponin compounds utilizing colon-specific delivery and osmotic pump systems to enhance oral bioavailability. Optimizing drug combinations, such as ginsenosides with aspirin, shows therapeutic potential. Rigorous clinical validation is essential for practical applications. This review emphasizes a transformative era in saponin research, highlighting the need for clinical validation. TCM saponin pharmacokinetics, guided by traditional principles, are in development, utilizing multidisciplinary approaches for a comprehensive understanding. This research provides a theoretical basis for new clinical drugs and supports rational clinical medication.

Enhancing Curcumin’s therapeutic potential in cancer treatment through ultrasound mediated liposomal delivery

Improving the efficacy of chemotherapy remains a key challenge in cancer treatment, considering the low bioavailability, high cytotoxicity, and undesirable side effects of some clinical drugs. Targeted delivery and sustained release of therapeutic drugs to cancer cells can reduce the whole-body cytotoxicity of the agent and deliver a safe localized treatment to the patient. There is growing interest in herbal drugs, such as curcumin, which is highly noted as a promising anti-tumor drug, considering its wide range of bioactivities and therapeutic properties against various tumors. Conversely, the clinical efficacy of curcumin is limited because of poor oral bioavailability, low water solubility, instability in gastrointestinal fluids, and unsuitable pH stability. Drug-delivery colloid vehicles like liposomes and nanoparticles combined with microbubbles and ultrasound-mediated sustained release are currently being explored as effective delivery modes in such cases. This study aimed to synthesize and study the properties of curcumin liposomes (CLs) and optimize the high-frequency ultrasound release and uptake by a human breast cancer cell line (HCC 1954) through in vitro studies of culture viability and cytotoxicity. CLs were effectively prepared with particles sized at 81 ± 2 nm, demonstrating stability and controlled release of curcumin under ultrasound exposure. In vitro studies using HCC1954 cells, the combination of CLs, ultrasound, and Definity microbubbles significantly improved curcumin’s anti-tumor effects, particularly under specific conditions: 15 s of continuous ultrasound at 0.12 W/cm2 power density with 0.6 × 107 microbubbles/mL. Furthermore, the study delved into curcumin liposomes’ cytotoxic effects using an Annexin V/PI-based apoptosis assay. The treatment with CLs, particularly in conjunction with ultrasound and microbubbles, amplified cell apoptosis, mainly in the late apoptosis stage, which was attributed to heightened cellular uptake within cancer cells.

Whey protein nanoparticles: Enhancing solubility, environmental resistance, and bio-accessibility of pterostilbene

Pterostilbene (Pte) is a dietary phenolic compound derived from plants that offers numerous physiological advantages. Nonetheless, its low water solubility and limited oral bioavailability restrict its bioactivity. To address these limitations, nanoparticles were prepared using anti-solvent precipitation method. Optimal nanoparticles were achieved at a 10:1 mass ratio of whey protein isolate (WPI) to Pte, resulting in a particle size of 104.54 nm, a polydispersity index of 0.42, and an impressive encapsulation efficiency of Pte at 85.02%. The water solubility of Pte in the nanoparticles was found to be 53.14 times higher than that of free Pte and remained stable under various environmental conditions. Furthermore, the DPPH and ABTS+ free radical scavenging activities of the nanoparticles were maximized at 55.58% and 92.97%, respectively. Pte release from WPI-Pte nanoparticles was well-fitted to Korsmeyer-Peppas model and followed a non-Fickian mechanism controlled by both diffusion and erosion. This environmentally friendly, straightforward, and efficient approach shows promise for large-scale production of Pte products with amplified health benefits.

Preparation of valine-curcumin conjugate and its in vitro antibacterial and antitumor activity and in vivo biological effects on American eels (Anguilla rostrata)

Curcumin (Cur) exhibits diverse natural pharmacological activities, despite its limited water solubility (hydrophobicity) and low bioavailability. In this investigation, a valine-curcumin conjugate (Val-Cur) was synthesized through amino acid side chain modification, and its solubility increased to 1.78 mg/mL. In vitro experimental findings demonstrated that the antibacterial activity of Val-Cur against Escherichia coli, Staphylococcus aureus, Aeromonas hydrophila, and Vibrio parahaemolyticus was significantly superior to that of Cur. The inhibition rate of Val-Cur against HepG2 (human hepatocellular carcinoma) cells was higher than that of Cur at low concentrations (below 25 μmol/L), although the IC50 value of Val-Cur did not differ significantly from that of Cur. In vivo biological effects of Val-Cur were assessed by adding it into the feed (150 mg/kg) of American eels (Anguilla rostrata). Val-Cur significantly improved the growth performance (↑weight gain rate, ↑specific growth rate, and ↓feed conversion rate) and activities of intestinal digestive enzymes (amylase and lipase) and antioxidant enzymes (superoxide dismutase) in American eels. Additionally, Val-Cur significantly improved serum biochemical indices (↑high-density lipoprotein cholesterol, ↓low-density lipoprotein cholesterol, ↓aspartate and alanine aminotransferases). Furthermore, Val-Cur increased intestinal microbial diversity, reduced the abundance of potentially pathogenic bacteria (Spiroplasma, Clostridium, and Pseudomonas), and elevated the abundance of beneficial digestion-promoting bacteria (Romboutsia, Phyllobacterium, Romboutsia sedimentorum, and Clostridium butyricum) conducive to glucose metabolism (P < 0.05). To the best of our knowledge, this study is the first to explore water-soluble curcumin in aquaculture, and the findings will lay the groundwork for the potential application of water-soluble curcumin in the field of aquaculture.

QbD Enabled Development and Evaluation of Pazopanib Loaded Nanoliposomes for PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7nm and 182.0nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.

A Multifunctional Hydrogel Fabricated by Direct Self-Assembly of Natural Herbal Small Molecule Mangiferin for Treating Diabetic Wounds.

Clinical studies have continually referred to the involvement of drug carrier having dramatic negative influences on the biocompatibility, biodegradability, and loading efficacy of hydrogel. To overcome this deficiency, researchers have proposed to directly self-assemble natural herbal small molecules into a hydrogel without any structural modification. However, it is still a formidable challenge due to the high requirements on the structure of natural molecules, leading to a rarity of this type of hydrogel. Mangiferin (MF) is a natural polyphenol of C-glucoside xanthone with various positive health benefits, including the treatment of diabetic wounds, but its poor hydrosolubility and low bioavailability significantly restrict the clinical application. Inspired by these, with heating/cooling treatment, a carrier-free hydrogel (MF-gel) is developed by assembling the natural herbal molecule mangiferin, which is mainly governed through hydrogen bonds and intermolecular π-π stacking interactions. The as-prepared hydrogel has injectable and self-healing properties and shows excellent biocompatibility, continuous release ability, and reversible stimuli-responsive performances. All of the superiorities enable the MF-based hydrogel to serve as a potential wound dressing for treating diabetic wounds, which was further confirmed by both the vitro and vivo studies. In vitro, the MF-gel could promote the migration of healing-related cells from peripheral as well as the angiogenesis and displays the capacity of mediating inflammation response by scavenging the intracellular ROS. In vivo, the MF-gel accelerates wound contraction and healing via inflammatory adjustment, collagen deposition, and angiogenesis. This study provides a facile and effective method for diabetic wound management and emphasizes the direct self-assembly hydrogel from natural herbal small molecule.

Incorporation of efavirenz inclusion complex In Dissolvable Microneedle for enhanced effectiveness of intravaginal drug delivery: A proof of concept study

Efavirenz (EFV) is one of the first line treatments of HIV infection. EFV is one of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that can inhibit the responsible of reverse transcriptase enzyme for HIV replication. In oral administration, EFV exhibits low bioavailability (30–56 %) problem owing to its poor solubility (0.9 μg/mL). In this research, the poor solubility was overcome by formulating EFV as a complex inclusion (IC)with β-cyclodextrin (β-CD). Furthermore, considering the benefits of vaginal delivery, IC was further incorporated into dissolving microneedle systems (DMN) using polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) as biocompatible and biodegradable polymes. The results showed that EFV successfully formed IC by the change of the molecular shape with β-CD polymer, confirmed by FTIR and XRD. Importantly, the results showed that the formulation did not cause lysis and irritation on erythrocytes and blood vessels, showing the safety of this approach. Following its incorporation into DMN, IC-DMN could permeate the skin ex vivo as 78.70 ± 14.22 μg/cm3, which was about 3-times higher compared to DMN containing pure EFV and patch control. The in vivo pharmacokinetic study showed that the maximum plasma concentration of IC-DMN was 13.74 ± 2.48 μg/cm3, EFV-oral 6.27 ± 1,13 μg/cm3, vaginal gel 14.83 ± 3.65 μg/cm3. AUC values for each treatment was 147.33 ± 26.62 h μg/mL, 22.33 ± 4.03 h μg/mL, 63.33 ± 11.44 h μg/mL, respectively, indicating that the purpose of this study which was to increase the bioavailability of EFV was succefully achieved. Therefore, this combibation approach could be new alternative to HIV treatment using EFV in woman.