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A powder formulation for mucosal administration of mRNA-encapsulated lipid nanoparticles (mRNA-LNPs) is expected to be useful for respiratory diseases. Although freeze-drying is widely used to obtain solid formulations of mRNA-LNPs, highly hydrosoluble cryoprotectants, such as sucrose are necessary. However, sucrose is not a suitable excipient for inhalation powders because of its hygroscopic and deliquescence properties. Spray freeze-drying (SFD) is a method to produce inhalable powder formulation. In this study, we prepared inhalable powder formulations of mRNA-LNPs without deliquescence excipients using pH-modified SFD, which strengthens the interaction between mRNA and ionizable lipids of LNPs by acidic pH modifier, leading to retention of the encapsulated structure of mRNA-LNPs even after SFD. Powdered mRNA-LNPs were suitable for inhalation, and mRNA was encapsulated in LNPs after SFD. The mRNA encapsulation efficiency and mRNA transfection efficiency of pH-modified SFD-mediated powdered mRNA-LNPs were higher than those of conventional SFD, although they were significantly lower than those of liquid intact mRNA-LNPs. However, after long-term storage, the powdered formulation of the mRNA-LNPs exhibited higher mRNA transfection efficiency than liquid mRNA-LNP. Powdered mRNA-LNPs also exerted their function in air-liquid interface cultivation and in vivo intratracheal administration. Collectively, the powder formulation of mRNA-LNPs especially prepared by SFD is expected to be applied for dry powder inhalers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

An integrated strategy by combining cocrystallization with nanotechnology is developed to optimize in vitro/vivo performances of marine antitumor drug cytarabine (ARA) and further obtain innovative insights into the exploitation of cocrystal alloy nanoformulation. Therein, the optimization of properties and synergistic effects of ARA mainly depends on assembling with uracil (U) and antitumor drug 5-fluorouracil (FU) into the same crystal by cocrystallization technology, while the long-term efficacy is primarily maintained by playing the superiority of nanotechnology. Along this line, the first cocrystal alloy of ARA, viz. , ARA-FU-U (0.6:0.4), is successfully obtained and then transformed into a nanocrystal. Single-crystal X-ray diffraction analysis demonstrates that this cocrystal alloy consists of two isomorphic cocrystals of ARA, namely, ARA-FU and ARA-U, in 0.6:0.4 ratio. An R 2 2 (8) hydrogen-bonding cyclic system formed by a cytosine fragment of ARA with U or FU can protect and stabilize the amine group on ARA, laying the foundation for regulating its properties. The in vitro / in vivo properties of the cocrystal alloy and its nanocrystals are investigated by theoretical and experimental means. It reveals that both the alloy and nanocrystal can improve physicochemical properties and promote drug absorption, thus bringing to optimized pharmacokinetic behaviors. The nanocrystal produces superior effects than the alloy that helps to extend therapeutic time and action. Particularly, relative to the corresponding binary cocrystal, the synergistic antitumor activity of ARA and FU in the cocrystal alloy is heightened obviously. It may be that U contributes to reducing the degradation of FU, specifically increasing its concentration in tumors to enhance the synergistic effects of FU and ARA. These findings provide new thoughts for the application of cocrystal alloys in the marine drug field and break fresh ground for cocrystal alloy formulations to optimize drug properties.

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment. Adverse effects, poor water solubility, and inevitable susceptibility to drug resistance seriously limit its therapeutic efficacy in the clinic. Piplartine (PPT), an alkaloid extracted from Piper longum L., has been shown to inhibit cancer cell proliferation in several cell lines due to its pro-oxidant activity. However, PPT has low water solubility and bioavailability in vivo , and new strategies should be developed to optimize its use as a chemotherapeutic agent. In this context, the present study aimed to synthesize a series of acetalated dextran nanoparticles (Ac-Dex NPs) encapsulating PPT and PTX to overcome the limitations of PPT and PTX, maximizing their therapeutic efficacy and achieving prolonged and targeted codelivery of these anticancer compounds into BC cells. Biodegradable, pH-responsive, and biocompatible Ac-Dex NPs with diameters of 100-200 nm and spherical morphologies were formulated using a single emulsion method. Selected Ac-Dex NPs containing only PPT or PTX as well as those coloaded with PPT and PTX achieved excellent drug-loading capabilities (PPT, ca. 11-33%; PTX, ca. 2-14%) and high encapsulation efficiencies (PPT, ∼57-98%; PTX, ∼80-97%). Under physiological conditions (pH 7.4), these NPs exhibited excellent colloidal stability and were capable of protecting drug release, while under acidic conditions (pH 5.5) they showed structural collapse, releasing the therapeutics in an extended manner. Cytotoxicity results demonstrated that the encapsulation in Ac-Dex NPs had a positive effect on the activities of both PPT and PTX against the MCF-7 human breast cancer cell line after 48 h of treatment, as well as toward MDA-MB-231 triple-negative BC cells. PPT/PTX@Ac-Dex NPs were significantly more cytotoxic (IC 50/PPT = 0.25-1.77 μM and IC 50/PTX = 0.07-0.75 μM) and selective (SI = 2.9-6.7) against MCF-7 cells than all the control therapeutic agents: free PPT (IC 50 = 4.57 μM; SI = 1.2), free PTX (IC 50 = 0.97 μM; SI = 1.0), the single-drug-loaded Ac-Dex NPs, and the physical mixture of both free drugs. All combinations of PPT and PTX resulted in pronounced synergistic antiproliferative effects in MCF-7 cells, with an optimal molar ratio of PPT to PTX of 2.3:1. PPT/PTX-2@Ac-Dex NPs notably promoted apoptosis, cell cycle arrest at the G2/M, accumulation of intracellular reactive oxygen species (ROS), and combined effects from both PPT and PTX on the microtubule network of MCF-7 cells. Overall, the combination of PTX and PPT in pH-responsive Ac-Dex NPs may offer great potential to improve the therapeutic efficacy, overcome the limitations, and provide effective simultaneous delivery of these therapeutics for BC treatment.

Background: Viral pneumonia, a pressing global health issue, necessitates innovative therapeutic approaches. Acyclovir, a potent ring-opening antiviral agent with broad-spectrum activity, faces water solubility, oral bioavailability, and drug resistance challenges. The aim of this study was to increase the efficacy of acyclovir through respiratory delivery by encapsulating it within albumin-modified lipid nanoparticles and formulate it as a spray., Methods: Nanoparticles was synthesized via the reverse evaporation method; its physicochemical characteristics were rigorously evaluated, including particle size, zeta potential, morphology, encapsulation efficiency, drug loading, and release profile. Furthermore, the cytotoxicity of nanoparticles and its therapeutic potential against viral pneumonia were assessed through cellular and animal model experiments. Result s: Nanoparticles exhibited a spherical morphology, with a mean particle size of 97.48 ± 5.36 nm and a zeta potential of 30.28 ± 4.72 mv; they demonstrated high encapsulation efficiency (93.26 ± 3.27%), drug loading (11.36 ± 0.48%), and a sustained release profile of up to 92% under neutral conditions. Notably, nanoparticles showed low cytotoxicity and efficient intracellular delivery of acyclovir. In vitro studies revealed that nanoparticles significantly reduced interleukin-6 levels induced by influenza virus stimulation. In vivo , nanoparticles treatment markedly decreased mortality, attenuated the inflammatory markers interleukin-6 and tumor necrosis factor-α levels, and mitigated inflammatory lung injury in mice with viral pneumonia., Conclusions: In this study, albumin was modified with polyethylene glycol (PEG) containing cationic lipid nanoparticles (LN) to prepare albumin-modified lipid nanoparticles encapsulating acyclovir (ALN-Acy), which can effectively deliver Acy into tissues and cells, prolong the survival of mice, and reduce lung injury and inflammatory factors. White albumin LN can be used as efficient drug delivery carriers, and the delivery of Acy via albumin LN is expected to be a therapeutic strategy for treating inflammatory diseases., (© 2024 The Author(s). Published by IMR Press.)

Phytoconstituent based therapies have the potential to reduce the adverse effects and enhance overall patient compliance for different diseased conditions. Embelin (EMB) is a natural compound extracted from Embelia ribes that has demonstrated high therapeutic potential, particularly as anti-inflammatory and anticancer therapeutic applications. However, its poor water solubility and low oral bioavailability limitations make it challenging to use in biomedical applications. Nanostructure-based novel formulations have shown the potential to improve physicochemical and biological characteristics of active pharmaceutical ingredients obtained from plants. Different nanoformulations that have been utilized to encapsulate/entrap EMB for various therapeutic applications are nanoliposomes, nanostructured lipid carriers, niosomes, polymeric nanoparticles, nanosuspensions, phytosomes, self nanoemulsifying drug delivery system, silver nanoparticles, microparticles, solid lipid nanoparticle, gold nanoparticles and nanomicelles. The common methods reported for the preparation of EMB nanoformulations are thin film hydration, nanoprecipitation, ethanol injection, emulsification followed by sonication. The size of nanoformulations ranged in between 50 and 345 nm. In this review, the mentioned EMB loaded nanocarriers are methodically discussed for size, shape, drug entrapment, zeta potential, in vitro release & permeation and in vivo studies. Potential of EMB with other drugs (dual drug approach) incorporated in nanocarriers are also discussed (physicochemical and preclinical characteristics). Patents related to EMB nanoformulations are also presented which showed the clinical translation of this bioactive for future utilization in different indications., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Microfluidic technology has not been extensively utilized in nanocrystals manufacture, although it has been used in the production of liposomes and LNPs. This is mainly due to concerns including blockage of narrow pipes and corrosion of organic solvents on chips. In this study, a detachable stainless steel microfluidic chip with split-and-recombine (SAR) structure was engraved and used to prepare curcumin nanocrystal suspensions by a microfluidic-antisolvent precipitation method. A simulation study of the mixing activities of three chip structures was conducted by COMSOL Multiphysics software. Then the curcumin nanocrystals preparation was optimized by Box-Behnken design to screen different stabilizers and solvents. Two curcumin nanocrystals formulations with an average particle size of 59.29 nm and 168.40 nm were obtained with PDIs of 0.131 and 0.058, respectively. Compared to curcumin powder, the formulation showed an increase in dissolution rate in 0.1 M HCL while pharmacokinetic study indicated that C max was increased by 4.47 and 3.14 times and AUC 0-∞ were 4.26 and 3.14 times greater. No clogging or deformation of the chip was observed after long usage. The results demonstrate that the stainless steel microfluidic chips with SAR structure have excellent robustness and controllability. It has the potential to be applied in GMP manufacturing of nanocrystals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The nanoparticle albumin bound™ (nab™) technology generally offers great potential for the formulation of poorly water-soluble drugs as albumin-stabilized nanosuspensions for intravenous use while avoiding solubilizers and cross-linking agents. The nab™ technology is a three-step process consisting of emulsification, high-pressure homogenization and solvent evaporation. Within this work, a screening approach was developed to predict whether active pharmaceutical ingredients are suitable for nab™ formulations. A design of experiments approach was used to investigate the effects of ultrasonic homogenization on an albumin-stabilized itraconazole nanosuspension. Based on this, a screening platform was developed, and subsequently evaluated and applied to a selection of poorly water-soluble drugs. The screening process to produce albumin-stabilized nanosuspensions consists of two process steps: Ultrasonic treatment, which combined emulsification and homogenization, followed by solvent evaporation. The results of the screening process were fully transferable to the standard three-step process of nab™ technology. In addition, based on drug screening, drug properties were highlighted that are important for the development of nab™ formulations. All in all, the nab™ technology is a promising but not universal formulation platform for poorly water-soluble drugs. Nevertheless, for some poorly soluble drugs it offers a valuable approach for the formulation of nanosuspensions for intravenous use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Repaglinide (RPG) belongs to the class of drugs known as meglitinides and is used for improving and maintaining glycemic control in the treatment of patients with Type 2 diabetes. RPG is a Class II drug (BCS) because of its high permeability and low water solubility. It also undergoes hepatic first-pass metabolism. The oral bioavailability of RPG is low (about 56 %) due to these drawbacks. Our aim in this study is to prepare two different nano-sized drug carrier systems containing RPG (nanoparticle: RPG-PLGA-Zein-NPs or nanoemulsion: RPG-NE) and to carry out a pharmacokinetic study for these formulations. We prepared NPs using PLGA and Zein. In addition, a single NE formulation was developed using Tween 80 and Pluronic F68 as surfactants and Labrasol as co-surfactant. The droplet size values of the blank-NE and RPG-NE formulations were found to be less than 120 nm. The mean particle sizes of blank-Zein-PLGA-NPs and RPG-Zein-PLGA-NPs were less than 260 nm. The C max and t max values of RPG-Zein-PLGA-NPs and RPG-NE (523 ± 65 ng/mL and 770 ± 91 ng/mL; 1.41 ± 0.46 h and 1.61 ± 0.37 h, respectively) were meaningfully higher than those of free RPG (280 ± 33 ng/mL; 0.72 ± 0.28 h) (p < 0.05). The AUC 0-∞ values calculated for RPG-Zein-PLGA-NPs and RPG-NE were approximately 4.04 and 5.05 times higher than that calculated for free RPG. These nanosized drug delivery systems were useful in increasing the oral bioavailability of RPG. Moreover, the NE formulation was more effective than the NP formulation in improving the oral bioavailability of RPG (p < 0.05)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To improve phytol bioavailability, a novel method of magnetic stirring and high-pressure homogenization (HPH) combination was used to prepare zein/fucoidan-coated phytol nanoliposomes (P-NL-ZF). The characterization, the simulated in vitro digestion, and the antioxidant activity of these phytol nanoliposomes from the different processes have been studied., Results: Based on the results of dynamic light scattering (DLS) and gas chromatography-mass spectrometer (GC-MS) analysis, P-NL-ZF prepared through the combination of magnetic stirring and HPH exhibited superior encapsulation efficiency at 76.19% and demonstrated exceptional physicochemical stability under a series of conditions, including storage, pH, and ionic in comparison to single method. It was further confirmed that P-NL-ZF by magnetic stirring and HPH displayed a uniform distribution and regular shape through transmission electron microscopy (TEM). Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) analysis showed that electrostatic interactions and hydrogen bonding were the primary driving forces for the formation of composite nanoliposomes. Additionally, an in vitro digestion study revealed that multilayer composite nanoliposomes displayed significant and favorable slow-release properties (58.21%) under gastrointestinal conditions compared with traditional nanoliposomes (82.36%) and free phytol (89.73%). The assessments of chemical and cell-based antioxidant activities demonstrated that the coating of zein/fucoidan on phytol nanoliposomes resulted in enhanced effectiveness in scavenging activity of ABTS free radical and hydroxyl radical and mitigating oxidative damage to HepG2 cells., Conclusion: Based on our studies, the promising delivery carrier of zein/fucoidan-coated nanoliposomes is contributed to the encapsulation of hydrophobic natural products and enhancement of their biological activity. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Introduction: Lipid-based nanoparticles (LNPs) is increasingly recognized for their potential in drug delivery, offering protection to hydrophobic drugs from degradation. Industrial synthesis of LNPs, exemplified by Pfizer-BioNTech and Moderna mRNA vaccines, utilizes flow chemistry or microfluidics, showcasing its scalability. This study explores the utilization of a novel design reactor, the vortex tube reactor, within flow chemistry for LNPs synthesis, aiming to optimize its conditions and compare them with batch synthesis., Methods: LNPs were synthesized using the vortex tube reactor, incorporating bovine serum albumin (BSA) as a model drug in the aqueous phase, alongside 1.2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol in the organic phase. Design of experiments (DoE), specifically Box-Behnken design, was employed to optimize parameters, including X 1 : the flow rate ratio (10-100 mL/min), X 2 : the aqueous-to-organic volumetric ratio (1:1-10:1), and X 3 : the number of reactor units (1-5 units). Responses evaluated encompassed physical properties and productivity. Optimized conditions were determined by minimizing particle size (Y 1 ), polydispersity index (Y 2 ), and zeta potential (Y 3 ), while maximizing entrapment efficiency (Y 4 ), drug loading (Y 5 ), and productivity (Y 5 )., Results: Results indicated that optimal conditions were achieved at X 1 of 100 mL/min, X 2 of 5.278, and X 3 of 1 unit. LNPs synthesized under these conditions exhibited favorable physical properties and productivity, with uniformity maintained across batches. The vortex tube reactor demonstrated superiority over batch synthesis, yielding smaller particles (166.23 ± 0.98 nm), more uniform nanoparticles (PDI 0.17 ± 0.01), and higher entrapment (67.75 ± 1.55%) and loading capacities (36.39 ± 0.83%), indicative of enhanced productivity (313.4 ± 12.88 mg/min)., Conclusion: This study elucidates the potential of flow chemistry, particularly utilizing the vortex tube reactor, for large-scale LNPs formulation, offering insights into parameter relationships and advancing nanoparticle synthesis for drug delivery applications., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Suwanpitak et al.)

The aim of this study was to rapidly develop a sufficiently robust andrographolide nanosuspension (AG-NS) system using hummer acoustic resonance (HAR) technology. The system can effectively improve the dissolution properties of AG, while having high stability and scale-up adaptability. The formulation of AG-NS was optimized in a high-throughput manner using HAR technology and the preparation process was optimized stepwise. Optimal AG-NS with Z-Ave = 223.99 ± 3.16 nm, PDI=0.095 ± 0.007 and zeta potential = -33.20 ± 0.58 mV was successfully prepared with Polyvinylpyrrolidone K30 and Sodium dodecyl sulfate. The optimal prescription was successfully scaled up 100 and 150 times using HAR technology, which was the initial exploration of its commercial scale production. AG-NS was solidified using freeze drying and fluid bed technology, respectively. The optimal AG-NS and its solidified products were exhaustively characterized using various analytical techniques. The high energy input of HAR technology and drying process converted part of the drug into the amorphous state. The in-vitro drug dissolution studies demonstrated relatively higher drug dissolution for AG-NS and its solidified products compared to controls at both the dissolution media (pH 1.2 buffer and pH 6.8 buffer). AG-NS and its solidified products successfully maintained their physical stability in short-term stability and accelerated stability experiments, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Resveratrol (RSV) has powerful antioxidant activities. However, the bioavailability is still limited due to low solubility and transport issues. Nanocrystal technology has been introduced to address these issues; however, the bulky formulation of the nanocrystal process through nanosuspension faces a big challenge in terms of stability and scale-up ability. This work aimed to enhance the bioavailability of RSV through nanocrystal formulation incorporated into soluble mesoporous carriers for superior solid-state stability and feasibility. This formulation was designed and developed rationally through scientific justification in the nanocrystal formulation along with quality by design paradigm. Box-Behnken design was applied to determine the optimized formulation based on the particle size and distribution, drug loading, zeta potential, and supersaturation parameters. The nanocrystal was formed through evaporation of drug, polymer, and surfactant in the solvent incorporated into mesoporous material. The nanocrystal was evaluated by vibrational spectroscopy, thermal analyses, and SEM and TEM photographs, followed by crystallinity evaluation. The results indicated that the factors only affected the particle size variation, zeta potential, drug loading, and the time to reach the supersaturation peak level. The optimized formulation was achieved by 68 % desirability value, producing 133.3 ± 1.2 nm particle size and -24.6 mV zeta potential. The physical and chemical evaluation characterization indicated no interaction between RSV and carrier. In addition, there was no difference in crystallinity between the RSV nanocrystal and native RSV. Moreover, the RSV nanocrystal improved the bioavailability nearly twice compared to the RSV suspension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study employed a Quality by Design (QbD) approach to spray dry amorphousclotrimazole nanosuspension (CLT-NS) consisting of Soluplus ® and microcrystallinecellulose. Using the Box-Behnken Design, a systematic evaluation was conducted toanalyze the impact of inlet temperature, % aspiration, and feed rate on the criticalquality attributes (CQAs) of the clotrimazole spray-dried nanosuspension (CLT-SDNS). In this study, regression analysis and ANOVA were employed to detect significantfactors and interactions, enabling the development of a predictive model for the spraydrying process. Following optimization, the CLT-SD-NS underwent analysis using Xraypowder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), Dynamic Scanning Calorimetry (DSC), and in vitro dissolution studies. The resultsshowed significant variables, including inlet temperature, feed rate, and aspiration rate,affecting yield, redispersibility index (RDI), and moisture content of the final product. The models created for critical quality attributes (CQAs) showed statistical significanceat a p-value of 0.05. XRPD and DSC confirmed the amorphous state of CLT in theCLT-SD-NS, and FTIR indicated no interactions between CLT and excipients. In vitrodissolution studies showed improved dissolution rates for the CLT-SD-NS (3.12-foldincrease in DI water and 5.88-fold increase at pH 7.2 dissolution media), attributed torapidly redispersing nanosized amorphous CLT particles. The well-designed studyutilizing the Design of Experiments (DoE) methodology., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Drug solubility and dissolution remain a significant challenge in pharmaceutical formulations. This study aimed to formulate and evaluate repanglinide (RPG) nanosuspension-based buccal fast-dissolving films (BDFs) for dissolution enhancement. RPG nanosuspension was prepared by the antisolvent-precipitation method using multiple hydrophilic polymers, including soluplus®, polyvinyl alcohol, polyvinyl pyrrolidine, poloxamers, and hydroxyl propyl methyl cellulose. The nanosuspension was then directly loaded into BDFs using the solvent casting technique. Twelve formulas were prepared with a particle size range of 81.6-1389 nm and PDI 0.002-1 for the different polymers. Nanosuspensions prepared with soluplus showed a favored mean particle size of 82.6 ± 3.2 nm. The particles were spherical and non-aggregating, as demonstrated by SEM imaging. FTIR showed no interaction between soluplus and RPG. Faster dissolution occurred for the nanosuspension in comparison with pure RPG (complete release vs 60% within 30 min). The nanosuspension was successfully incorporated into BDFs. The optimum film formula showed 28 s disintegration time, and 97.3% RPG released within 10 min. Ex-vivo permeation profiles revealed improved RPG nanosuspension permeation with the cumulative amount of RPG permeated is103.4% ± 10.1 and a flux of 0.00275 mg/cm 2 /min compared to 39.3% ± 9.57 and a flux of 0.001058 mg/cm 2 /min for pure RPG. RPG was successfully formulated into nanosuspension that boosted drug dissolution and permeation. The selection of the ultimate NP formula was driven by optimal particle size, distribution, and drug content. Soluplus NPs were shown to be the successful formulations, which were further incorporated into a buccal film. The film was evaluated for ex-vivo permeation, confirming successful RPG formulation with improved performance compared to pure drugs., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Tazarotene is a widely prescribed topical retinoid for acne vulgaris and plaque psoriasis and is associated with skin irritation, dryness, flaking, and photosensitivity. In vitro permeation of tazarotene was studied across the dermatomed human and full-thickness porcine skin. The conversion of tazarotene to the active form tazarotenic acid was studied in various skin models. Tazarotene-loaded PLGA nanoparticles were prepared using the nanoprecipitation technique to target skin and hair follicles effectively. The effect of formulation and processing variables on nanoparticle properties, such as particle size and drug loading, was investigated. The optimized nanoparticle batches with particle size <500 µm were characterized further for FT-IR analysis, which indicated no interactions between tazarotene and PLGA. Scanning electron microscopy analysis showed uniform, spherical, and non-agglomerated nanoparticles. In vitro release study using a dialysis membrane indicated a sustained release of 40-70 % for different batches over 36 h, following a diffusion-based release mechanism based on the Higuchi model. In vitro permeation testing (IVPT) in full-thickness porcine skin showed significantly enhanced follicular and skin delivery from nanoparticles compared to solution. The presence of tazarotenic acid in the skin from tazarotene nanoparticles indicated the effectiveness of nanoparticle formulations in retaining bioconversion ability and targeting follicular delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this work, novel erythrocyte-shaped electrosprayed nanoparticles (EENPs) were designed and constructed by tri-axial electrospraying technique with PEG as the outer layer, PLGA as the middle drugs (paclitaxel [PTX] and osimertinib [OSI]) carrier layer and air as the inner layer. The prepared EENP were characterized and evaluated based on their spectral and morphological attributes. After the PTX/OSI ratio and process optimization, the EENP has inspiring features, including nanoscale size, erythrocyte morphology with a concave disk shape, and satisfactory drug loading (DL) and encapsulation efficiency (EE). In vitro drug release showed that PTX and OSI in the formulation were released in the same ratio, and the cumulative release percentage at 24 h was close to 80 %. Furthermore, the TGIR in the EENP formulation group exceeded 90 %, approximately 3.8-fold higher than that in the free drug group. In summary, we developed an erythrocyte three-core-shell nanoparticle for the co-delivery of PTX and OSI, providing a potential chemotherapeutic delivery system for the treatment of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Resistance to antibiotics such as Ciprofloxacin (CIP) is becoming a critical issue and needs to be addressed globally. CIP is widely used because of manifold uses; however, the long-term therapy poses serious health risks including FDA black box warnings such as tendinitis and peripheral neuropathy. Therefore, nanotechnology-based products can be an effective measure to improve therapeutic outcomes by maintaining the dose at the target site while reducing the dose-dependent toxicity. Biodegradable and biocompatible polymers, Chitosan (CS) and Hyaluronic acid (HA) were used in this work due to their diverse biological characteristics. A simple yet economical ionic gelation method was employed to synthesize nanoparticles with a plexus-like network; nanoplexes, followed by spray-drying to obtain the dry powders to improve stability. Quality by Design (QbD) approach was utilized during the study for robustness and standardization followed by Design of Experiment (DoE) for optimization in a holistic way. The mean particle size of the optimized powder sample was found to be 301.1 nm with a percentage encapsulation efficiency (% EE) of 78.8%. In-vitro dissolution studies corroborated the controlled release of CIP over 48 h. Also, mathematical kinetic modeling was applied to obtain thorough insight into the mechanism of drug release. Moreover, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were presented to be lower in the case of prepared dry powder as compared to CIP, stating that nanotechnology can improve antimicrobial activity., Competing Interests: Deceleration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Bedaquiline (BQ) solid lipid nanoparticles (SLNs), which have previously been formulated for parenteral administration, have a risk of patient non-compliance in treating tuberculosis. This research presents a strategy to develop BQ SLNs for oral delivery to improve patient adherence, The upper and lower levels for the formulation excipients were generated from screening experiments. Using 4 input factors (BQ, lecithin, Tween 80, and PEG), a full factorial design from 3 × 2x2 × 2 experiments was randomly arranged to investigate 3 response variables: Particle size distribution (PSD), polydispersity index (PdI), and zeta potential (ZP). High shear homogenization was used to mix the solvent and aqueous phases, with 15% sucrose as a cryoprotectant. The response variables were assessed using a zeta sizer while TEM micrographs confirmed the PSD data. Solid-state assessments were conducted using powdered X-ray diffraction and scanning electron microscopy (SEM) imaging. A comparative invitro assessment was used to determine drug release from an equivalent dose of BQ free base powder and BQ-SLN, both packed in hard gelatin capsules. The sonicated formulations obtained significant effects for PSD, PdI, and ZP. The p-values (0.0001 for PdI, 0.0091 for PSD) for BQ as an independent variable in the sonicated formulation were notably higher than those in the unsonicated formulation (0.1336 for PdI, 0.0117 for PSD). The SEM images were between 100 - 400 nm and delineated nanocrystals of BQ embedded in the lipid matrix. The SLN formulation provides higher drug levels over the drug's free base; a similarity factor (f2 = 18.3) was estimated from the dissolution profiles., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The size of the drug particles is one of the essential factors for the proper absorption of the drug compared to the dose of the drug. When particle size is decreased, drug uptake into the body increases. Recent studies have revealed that the rapid expansion of supercritical solution with cosolvent plays a significant role in preparing micron and submicron particles. This paper examines the preparation of Erlotinib hydrochloride nanoparticles using a supercritical solution through the cosolvent method for the first time. An examination of the parameters of temperature (318-338 K), pressures (15-25 MPa) and nozzle diameter (300-700 μm) was investigated by Box-Behnken design, and their respective effects on particle size revealed that the nozzle diameter has a more significant impact on particle size than the other parameters. The smallest particles were produced at temperature 338 K, pressure 20 MPa, and nozzle diameter 700 μm. Besides, the ERL nanoparticles were characterized using SEM, DLS, XRD, FTIR, and DSC analyses. Finally, the results showed that the average size of the ERL particles decreased from 31.6 μm to 200-1100 nm., (© 2024. The Author(s).)

This research aimed to encapsulate the Capparis spinosa fruit extract to increase its stability for incorporation into food products such as jelly or jelly powder. After extraction, the nanoliposomes containing the extract were prepared in ratios of 60-0, 50-10, 40-20, and 30-30 lecithin-to-cholesterol. The effects of lecithin-to-cholesterol concentrations on the related parameters were then evaluated. The results showed that the average particle size was in the range of 95.05 to 164.25 nm, and with an increasing cholesterol concentration, the particle size of the nanoliposomes increased. The addition of cholesterol increased the zeta potential from -60.40 to -68.55 millivolt. Furthermore, cholesterol led to an increase in encapsulation efficiency, and even improved the stability of phenolic compounds loaded in nanoliposomes during storage time. Fourier transform infrared (FTIR) spectroscopy confirmed the successful loading of the extract. Field emission scanning electron microscopy (FE-SEM) analysis revealed nano-sized spherical and almost-elliptical liposomes. For jelly powders, the water solubility index ranged from 39.5 to 43.7% ( p > 0.05), and the hygroscopicity values ranged between 1.22 and 9.36 g/100 g ( p < 0.05). In conclusion, nanoencapsulated Capparis spinosa extract displayed improved stability and can be used in jelly preparation without any challenge or unfavorable perception.

Objective: Posaconazole (PCZ) is an antifungal drug, which acts by inhibiting the lanosterol-14α-demethylase enzyme. It is a biopharmaceutical classification system class II drug with its bioavailability being limited by poor aqueous solubility. The aim of this study was to improve the oral bioavailability of PCZ by preparing nanocrystalline solid dispersion (NCS)., Methods: PCZ-NCS was prepared by a combination of precipitation and high-pressure homogenization followed by freeze-drying. Several different surfactants and polymers were screened to produce NCS with smaller particle size and higher stability., Results: The optimized NCS formulation containing 0.2% Eudragit S100 and 0.2% SLS was found to provide the average particle size of 73.31 ± 4.7 nm with a polydispersity index of 0.23 ± 0.03. Scanning electron microscopy revealed the preparation of homogeneous and rounded particles. Differential scanning calorimetry and X-ray diffraction confirmed crystalline nature of NCS. Nanonization increased the saturation solubility of PCZ by about 18-fold in comparison with the neat drug. Intrinsic dissolution study showed 93% dissolution of PCZ within the first 10 min. In vivo pharmacokinetic study in Wistar rats showed that C max and AUC total of PCZ-NCS increased by 2.58- and 2.64-fold compared to the marketed formulation., Conclusion: PCZ-NCS formulation presents a viable approach for enhancing the oral bioavailability of PCZ.

Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges., Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated., Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX., Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Du et al.)

The goal of this investigation is to develop stable ophthalmic nanoformulations containing cannabidiol (CBD) and its analog cannabidiol-valine-hemisuccinate (CBD-VHS) for improved ocular delivery. Two nanoformulations, nanoemulsion (NE) and nanomicelles (NMC), were developed and evaluated for physicochemical characteristics, drug-excipient compatibility, sterilization, thermal analysis, surface morphology, ex-vivo transcorneal permeation, corneal deposition, and stability. The saturation solubility studies revealed that among the surfactants tested, Cremophor EL had the highest solubilizing capacity for CBD (23.3 ± 0.1 mg/mL) and CBD-VHS (11.2 ± 0.2 mg/mL). The globule size for the lead CBD formulations (NE and NMC) ranged between 205 and 270 nm while CBD-VHS-NMC formulation had a particle size of about 78 nm. The sterilized formulations, except for CBD-VHS-NMC at 40 °C, were stable for three months of storage (last time point tested). Release, in terms of CBD, in the in-vitro release/diffusion studies over 18 h, were faster from the CBD-VHS nanomicelles (38 %) compared to that from the CBD nanoemulsion (16 %) and nanomicelles (33 %). Transcorneal permeation studies revealed improvement in CBD permeability and flux with both formulations; however, a greater improvement was observed with the NMC formulation compared to the NE formulation. In conclusion, the nanoformulations prepared could serve as efficient topical ocular drug delivery platforms for CBD and its analog., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of -33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Amorphous solid dispersion (ASD) is an enabling approach utilized to deliver poorly soluble compounds. ASDs can spontaneously generate drug-rich amorphous nanoparticles upon dissolution, which can act as a reservoir for maintaining supersaturation during oral absorption. But, conventional ASDs are often limited in drug loadings to < 20 %. For indications where the dose is high, this can translate into a significant pill burden. The aim of this research was to develop a high drug loading (DL) amorphous nanoparticle (ANP) formulation that can release the drug-rich nanoparticles into solution upon contact with aqueous environment. Nanoparticles were directly engineered using solvent/anti-solvent precipitation. The obtained nanoparticle suspension was then concentrated followed by solidification to a re-dispersible amorphous dosage form using spray drying or lyophilization. The impact of process variables was studied using dynamic light scattering (DLS), scanning electron microscopy (SEM), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). It was observed that spray drying led to a non-re-dispersible formulation. Sucrose and trehalose containing lyocakes resulted in re-dispersible formulations. The trehalose containing lyocakes, in a dog study, gave comparable performance to the reference tablet in the fasted state but lower area under the curve (AUC) in fed state., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AbbVie sponsored and funded the study; contributed to the design; participated in collection, analysis, and interpretation of data; and in writing, reviewing, and approval of the final version. Hitesh S. Purohit, Mengqi Yu, Hardeep Oberoi, Angélica de L Rodríguez López, Manish Kelkar, Yan He, Bradley Gates, Nandkishor Nere, Devalina Law are AbbVie employees and may own AbbVie stock. Maryam Zaroudi contributed to the research during her summer internship at AbbVie. Deliang Zhou contributed to the research during his employment at AbbVie., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The oral bioavailability of poorly soluble drugs has always been the focus of pharmaceutical researchers. We innovatively combined nanocrystal technology and solid dispersion technology to prepare novel nanocrystalline solid dispersions (NCSDs), which enable both the solidification and redispersion of nanocrystals, offering a promising new pathway for oral delivery of insoluble Chinese medicine ingredients. The rubusoside (Rub) was first used as the multifunctional stabilizer of novel apigenin nanocrystal-based solid dispersions (AP-NSD), improving the in vitro solubilization rate of the insoluble drug apigenin(AP). AP-NSD has been produced using a combination of homogenisation and spray-drying technology. The effects of stabilizer type and concentration on AP nanosuspensions (AP-NS) particles, span, and zeta potential were studied. And the effects of different types of protective agents on the yield and redispersibility of AP-NSD were also studied. Furthermore, AP-NSD was characterized by infrared spectroscopy (IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Solubility was used to assess the in vitro dissolution of AP-NSD relative to APIs and amorphous solid dispersions (AP-ASD), and AP-ASD was prepared by the solvent method. The results showed that 20% Rub stabilized AP-NSD exhibited high drug-loading and good redispersibility and stability, and higher in vitro dissolution rate, which may be related to the presence of Rub on surface of drug. Therefore provides a natural and safe option for the development of formulations for insoluble drugs., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interests., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Long-acting injectables have shown to offer a prolonged release of a drug compound up to several months, providing the opportunity to increase patient compliance for treatment of long-term and chronic conditions. Different formulation technologies have already been utilized for long-acting injectables, and especially aqueous suspensions with crystalline drug particles in the sub-micron range have sparked an interest for future development of long-acting injectables. Wet bead milling is a common top-down process used to prepare nano- and microsuspensions of crystalline drug particles with the addition of surfactants in the dispersion medium, which are working as stabilizers to prevent agglomeration or crystal growth that ultimately may influence the physical stability of nano- and microsuspensions. To examine the reproducibility of the suspensions manufactured and the behavior of their physical stability, i.e., changes in particle sizes over time, low-energy roller mill was utilized for the manufacturing of nano- and microsuspensions in the present study. Investigated formulation parameters was stabilizer type and concentration and milling parameters varied in bead size and duration of milling. The obtained results demonstrated that the physical stability of suspensions containing the two model compounds, cinnarizine and indomethacin, was highly affected by the constitution of surfactant and processing. Various size classes were obtained and accompanied by high variations between the individual samples that indicated uneven and unpredictable milling by the low-energy roller mill, limiting the possibility to prepare reproducible and physical stable suspensions. Short-term stability studies revealed clear tendencies towards reversed Ostwald ripening of suspensions stabilized with poloxamer 188 that contained cinnarizine as the drug compound, and to a smaller extent suspensions containing indomethacin. Furthermore, X-ray Powder Diffraction confirmed no alteration of the drug compounds crystal structure after roller milling for multiple days., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives : Nowadays, the development of enabled pharmaceutical nanoparticles of solid lipid type is continuously growing, because they have the potential to be used for targeted drug release leading to an increased effect of chemotherapy, being used in lung cancer nano-diagnosis and nano-therapy. The current study reports the preliminary results obtained regarding the biological effect of a new nano-enabled pharmaceutical formulation in terms of its cytotoxic and biosafety profile. Materials and Methods : The pharmaceutical formulations consist of solid lipid nanoparticles (SLN) obtained via the emulsification-diffusion method by loading green iron oxide nanoparticles (green-IONPs) with a pentacyclic triterpene (oleanolic acid-OA). Further, a complex biological assessment was performed, employing three-dimensional (3D) bronchial microtissues (EpiAirway TM ) to determine the biosafety profile of the SLN samples. The cytotoxic potential of the samples was evaluated on human lung carcinoma, using an in vitro model (A549 human lung carcinoma monolayer). Results : The data revealed that the A549 cell line was strongly affected after treatment with SLN samples, especially those that contained OA-loaded green-IONPs obtained with Ocimum basilicum extract (under 30% viability rates). The biosafety profile investigation of the 3D normal in vitro bronchial model showed that all the SLN samples negatively affected the viability of the bronchial microtissues (below 50%). As regards the morphological changes, all the samples induce major changes such as loss of the surface epithelium integrity, loss of epithelial junctions, loss of cilia, hyperkeratosis, and cell death caused by apoptosis. Conclusions : In summary, the culprit for the negative impact on viability and morphology of 3D normal bronchial microtissues could be the too-high dose (500 µg/mL) of the SLN sample used. Nevertheless, further adjustments in the SLN synthesis process and another complex in vitro evaluation will be considered for future research.

Aims: Desvenlafaxine (DES) in conventional dosage forms shows initial burst release after oral administration, leading to exaggeration of its side effects. These side effects can be overcome by a sustained-release dosage form using the chemically inert, low-melting-point lipid Compritol ® 888 ATO, as it reduces initial burst release. Materials & methods: The potential of DES-loaded solid lipid nanoparticles (DES-SLNs) synthesized by ultrasonication-assisted hot-melt encapsulation to modify the release of DES was investigated. Results: The entrapment efficiency of DES-SLNs was 65.90% with the in vitro release profile showing a sustained-release behavior achieving 81% cumulative release within 16 h without initial burst release. Conclusion: DES-SLNs are a potential carrier for sustained release of water-soluble antidepressant drugs such as DES.

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low T g (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant. Ternary ASDs were successfully produced with high weight ratios of PVP and P407. A hydrogen bond between the PBC hydroxyl proton and PVP carbonyl oxygen in the ternary ASD was detected using solid-state NMR spectroscopy, suggesting that amorphous PBC was stabilized mainly by PVP. Stable colloidal dispersions of amorphous PBC nanoparticles were obtained from the PBC/PVP/P407 ASD at a weight ratio of 1:4:2. The mean particle size was below 200 nm and the amorphous state of PBC remained stable upon storage at 25 °C for 14 d. Solution-state 1 H NMR and zeta-potential measurements suggested that P407 mainly stabilized the colloidal dispersion of amorphous PBC nanoparticles by steric hindrance at the solid/liquid interface. The findings of this study demonstrate that hot-melt extrusion can form practical ternary ASDs that provide colloidal dispersion of amorphous drug nanoparticles. Thus, this study advocates for the use of hot-melt extrusion in the design of an amorphous formulation for a variety of poorly water-soluble drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Solid lipid nanoparticles (SLNs) are lipid-based colloidal systems used for the delivery of active compounds. Although SLNs have many benefits, they show important issues due to physical and chemical instability phenomena during storage. For these reasons, it is highly desirable to have a dried SLN formulation available. Therefore, the aim of the project was to identify suitable methods to obtain a dry powder formulation from an SLN suspension. The nanoparticle suspension was dried using both freeze- and spray-drying techniques. The suitability of these methods in obtaining SLN dry powders was evaluated from the analyses of nanotechnological parameters, system morphology and thermal behavior using differential scanning calorimetry. Results pointed out that both drying techniques, although at different yields, were able to produce an SLN dry powder suitable for pharmaceutical applications. Noteworthily, the freeze-drying of SLNs under optimized conditions led to a dry powder endowed with good reconstitution properties and technological parameters similar to the starting conditions. Moreover, freeze-thaw cycles were carried out as a pretest to study the protective effect of different cryoprotectants (e.g., glucose and mannitol with a concentration ranging from 1% to 10% w / v ). Glucose proved to be the most effective in preventing particle growth during freezing, thawing, and freeze-drying processes; in particular, the optimum concentration of glucose was 1% w / v .

In recent years, polymorphic transformation involved in media milling has become a key factor in inducing the instability of nanosuspensions (NSs). The variation trend of microhydrodynamic parameters, including milling intensity factor (F), can be observed under different milling conditions. Therefore, this study first referenced the microhydrodynamic model to explore how formulations and process parameters affect Irbesartan (IRB) form A crystallinity during wet media milling. As a result, the crystallinity of form A was affected by the intermolecular interactions between drug particles and stabilizers. The crystallinity of form A decreased with decreasing drug loading, increasing stirrer speed and bead loading, which depended on the role of F. Milling could promote the transformation from a 1H to 2H tetrazole ring with stabilizers containing -OH, and form B was changed to form A and finally to an amorphous state. Molecular modelling shows that forms A and B are ductile and fragile materials, respectively, and both present anisotropy. When milling beads hit both polymorphs paralleling to the (010) surface, the bead-bead collisions are more helpful in fracturing IRB particles. The results of this study may provide a foundation for controlling crystal transformation and obtaining ideal crystal forms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: To develop quercetin nanocrystals by a simple approach and to evaluate their in vivo antifibrotic efficacy. Materials & methods: Nanosuspensions were fabricated by a thin-film hydration technique and ultrasonication. The influence of process variables on the average diameter of quercetin nanoparticles was investigated. Moreover, in vivo efficacy was investigated in an established murine CCl 4 -induced fibrosis model. Results: Nanocrystals showed a particle size of <400 nm. The optimized formulations showed an increase in dissolution rate and solubility. Quercetin nanocrystals markedly prevented fibrotic changes in the liver, as evidenced by mitigated histopathological changes and diminished aminotransferase levels and collagen accumulation. Conclusion: The findings reflect the promising potential of quercetin nanocrystals for liver fibrosis prevention.

Hospital-acquired pneumonia is an important infectious disease that requires special management and therapy for patients with compromised immunity, as opportunistic infections with microorganisms such as Pseudomonas aeruginosa can be fatal. Nanoparticle-based drug delivery to lung tissue provides several advantages in the treatment of respiratory diseases. In the current study, inhalable nanocomposite particles consisting of microparticles containing solid-state arbekacin (ABK) nanoparticles coated with hydrophobic surfactant (ABK-SD nanoparticles) were prepared using a spray dryer equipped with a two-solution mixing-type spray nozzle we previously developed. ABK-SD/mannitol (MAN) nanocomposite particles were obtained from ABK-SD nanoparticles by varying the amounts of hydrophobic surfactant and ABK. The aerosol performance of ABK-SD/MAN nanocomposite particles was superior to that of ABK-MAN microparticles in terms of the fine particle fraction (28.4 ± 5.4%, ABK-SD/MAN nanocomposite particles; 11.4 ± 7.6%, ABK-MAN microparticles). These results suggest that ABK-SD/MAN nanocomposite particles are suitable for use in inhalation drug formulations and useful for the treatment of lung infections involving Pseudomonas aeruginosa.

Although heat is generated during the wet stirred media milling of drug suspensions, leading to notable temperature rise, a comprehensive analysis of heat generation does not exist. Hence, we investigated the impact of stirrer speed, bead loading, and bead size at three levels on the evolution of suspension temperature at the mill outlet during the milling of fenofibrate. The particle sizes and viscosities of the milled suspensions and power were measured. Our results suggest that stirrer speed had the most significant impact on the temperature increase, followed by bead loading and bead size. Both the time when the temperature reached 22 °C and the temperature at 5 min of milling were strongly correlated with the power. Assessing the impacts of the process parameters on the temperature rise, cycle time, power, and median particle size holistically, an optimal milling process was identified: 3000 rpm with 50% loading of 200 or 400 µm beads. A power number correlation was established to calculate power at any milling condition which determines the heat generation rate. Overall, this study indicated the importance of developing a good understanding of heat generation during nanomilling for development of a robust milling process especially for thermally labile drugs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Wet media milling is a popular technology used to prepare nanosuspensions. However, the theories and methods to guide the research on the formulation and process affecting wet media milling remain limited. The research on wet media milling follows a "black box" approach to a certain extent. This review focuses on exploring the formulation and process parameters factors in wet media milling. The formulation factors include the concentration, hydrophilicity/hydrophobicity, and structure of the drug and stabilizer, whereas the milling process parameters include the milling speed, milling time, and material, size, and filling volume of milling beads. Contrary to other reviews, this review attempts to quantify and visualize these factors by combining a microhydrodynamic model with emerging characterization methods to provide a scientific basis for the selection of nanosuspension formulations and process parameters, as opposed to the conventional trial-and-error approach., (Copyright © 2022. Published by Elsevier B.V.)

Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre-few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations., (© 2022. The Author(s).)

Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Coronary artery disease (CAD) is currently a leading cause of death worldwide. In the history of percutaneous coronary intervention for the treatment of CAD, a drug-eluting stent (DES) is recognized as a revolutionary technology that has the unique ability to significantly reduce restenosis and provide both mechanical and biological solutions simultaneously to the target lesion. The aim of the research work was to design and fabricate DES coated with a nanoparticulate drug formulation. Sirolimus, an inhibitor of the smooth muscle cell (SMC) proliferation and migration, was encapsulated in polymeric nanoparticles (NPs). The NP formulation was characterized for various physicochemical parameters. Cell viability and cell uptake studies were performed using human coronary artery smooth muscle cells (HCASMCs). The developed NP formulation showed enhanced efficacy compared to plain drug solution and exhibited time-dependent uptake into the HCASMCs. The developed NP formulation was coated on the Flexinnium™ ultra-thin cobalt-chromium alloy coronary stent platform. The NP-coated stents were characterized for morphology and residual solvent analysis. In vitro drug release was also evaluated. Ex vivo arterial permeation was carried out to evaluate the NP uptake from the surface of the stents. The characterization studies together corroborated that the developed NP coated stent can be a promising replacement of the current DESs.

Wear-resistant polymers and ceramics-based media have been used to pulverize the bulk powder of poorly water-soluble drugs to nanoscale size in conventional milling; however, contamination of such media is still an issue in the context of drug formulation manufacturing. In the present study, we developed a novel method for pulverizing the particles of a poorly water-soluble drug, ketoprofen, to nanoscale size by mixing mannitol and polypropylene glycol as a safe pulverizing medium. The ketoprofen nanoparticles were prepared using a Hoover automatic muller, equipment that traditionally has been used for the mixing of paint and ink. This process represents a novel application of this machine for the on-demand preparation of nanoparticulate formulations for use in the clinical setting. The optimal composition of the drug formulation was determined by designing an experiment consisting of the central composite design and responsive surface method. We obtained a design space that yielded ketoprofen nanoparticles with targeted particle size, poly-dispersity index, and drug release properties. We validated the manufacturing conditions by preparing ketoprofen nanoparticles in four compositions. Thus, the present study provided useful information regarding not only simple and effective contamination-free milling but also the experimental conditions need to produce nanoparticles of a poorly water-soluble drug.

Piribedil (PBD) is a compound that has shown efficacy in clinical trials to treat motor and non-motor symptoms of Parkinson's disease. However, drug delivery issues like low oral bioavailability, high dosing frequency (3-5 tablets/day), gastrointestinal side-effects reduced the clinical use of PBD. In this work, we have developed lecithin-chitosan hybrid nanoparticles (PBD-LCNs) to improve the direct nose to brain uptake of PBD. PBD-LCNs were optimized using hybrid design approach based on DoE. The mean particle size and drug loading of PBD-LCNs were 147 nm, and 12%, respectively. The PBD-LCNs showed good stability and were found to be nearly spherical in shape. Further, the optimized LCNs were loaded in methylcellulose thermo-responsive in situ gel (PBD-LCN-ISG) to overcome rapid mucociliary clearance upon intranasal administration. Plasma and brain pharmacokinetic studies in rats showed that PBD-LCN-ISG increased the relative bioavailability of PBD in brain (AUC brain ) by about 6.4-folds and reduced the (C max ) plasma by 3.7-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with DTP values less than 0, while the optimized PBD-LCNs showed DTP value of 56% indicating efficient direct nose to brain uptake. Overall, the development of nanoformulations significantly improved the direct nose to brain uptake of PBD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with ∼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with ̴ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration., (Copyright © 2021. Published by Elsevier B.V.)

Nanosuspensions can effectively increase saturation solubility and improve the bioavailability of poorly water-soluble drugs attributed to high loading and surface-to-volume ratio. Wet media milling has been regarded as a scalable method to prepare nanosuspensions because of its simple operation and easy scale-up. In recent years, besides particle aggregation and Ostwald ripening, polymorphic transformation induced by processing has become a critical factor leading to the instability of nanosuspensions. Therefore, this review aims to discuss the influence factors comprehensively and put forward the corresponding improvement strategies of polymorphic transformation during the formation of nanosuspensions. In addition, this review also demonstrates the implication of molecular simulation in polymorphic transformation. The competition between shear-induced amorphization and thermally activated crystallization is the global mechanism of polymorphic transformation during media milling. The factors affecting the polymorphic transformation and corresponding improvement strategies are summarized from formulation and process parameters perspectives during the formation of nanosuspensions. The development of analytical techniques has promoted the qualitative and quantitative characterization of polymorphic transformation, and some techniques can in situ monitor dynamic transformation. The microhydrodynamic model can be referenced to study the stress intensities by analyzing formulation and process parameters during wet media milling. Molecular simulation can be used to explore the possible polymorphic transformation based on the crystal structure and energy. This review is helpful to improve the stability of nanosuspensions by regulating polymorphic transformation, providing quality assurance for nanosuspension-based products.HighlightsPolymorphic transformation depends on the intensity and temperature of milling.Stress intensities of milling can be elucidated and improved by microhydrodynamics.Higher stress intensities of milling perhaps be accompanied by higher temperatures.Molecular simulation used in polymorphs is based on crystal structure and energy.Molecular dynamics simulations can demonstrate the stability of amorphous forms.

Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles' size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension's stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form.

The study aims at formulation and optimization of resveratrol and humic acid co-encapsulated colloidal polymeric nanocarriers to improve stability, oral bioavailability, and antiradical activity of water-insoluble, resveratrol. The eudragit E100 polymeric material was used to fabricate resveratrol and humic acid co-encapsulated oral colloidal polymeric nanocarriers ( Res -HA-co-CPNs) using emulsification-diffusion-evaporation method. Taguchi orthogonal array design was employed to check the effect of formulation factors on in vitro physicochemical characteristics. The optimized formulation was further evaluated for oral bioavailability as well as for antiradical potential. Optimized Res -HA-co-CPNs demonstrated spherical and smooth surface including mean particle size, 120.56 ± 18.8 nm; polydispersity index, 0.122; zeta potential, +38.25 mV; and entrapment efficiency, 82.37 ± 1.49%. Solid-state characterization confirmed the amorphous characteristic of optimized Res -HA-co-CPNs. In vitro release profile of Res -HA-co-CPNs showed sustained release behavior up to 48 h and CPNs were found to remain stable at the refrigerated condition for 6 months. In vivo pharmacokinetic studies revealed significant ( p  < 0.05) improvement of ∼62.76-fold in oral bioavailability. The radical-scavenging activity was found to be increased with time and after 72 h, it was analogous to pure Res . IC 50 values were reported to be decreased with time. Henceforth, developed Res -HA-co-CPNs was proven to be a proficient dosage form to increase stability, oral bioavailability, and antiradical activity of resveratrol.HighlightsResveratrol-humic acid co-encapsulated colloidal polymeric nanocarriers ( Res -HA-co-CPNs) were fabricated by emulsification-diffusion-evaporation method and optimized by Taguchi orthogonal array design.The Res -HA-co-CPNs revealed favorable mean particle size and percent encapsulation efficiency with a spherical and smooth surface.The Res -HA-co-CPNs showed diffusion-controlled release of Res and were found to be stable at the refrigerated condition for 6 months.The optimized Res -HA-co-CPNs demonstrated significantly ( p  < 0.05) higher oral bioavailability with respect to pure Res and PM.The optimized Res -HA-co-CPNs demonstrated higher radical-scavenging activity with respect to time.

OVA (ovalbumin)/CMC (sodium carboxymethylcellulose) nanoparticles are prepared by combining complex coacervation and thermal induction. The effect of different parameters on stability of OVA/CMC nanoparticles (different ratios, pH, temperature, salt concentration and storage time) is investigated. And then the loading and stabilizing mechanism of particles on curcumin are further analyzed. After heating, OVA and CMC in particle could further cross-linking and a highly salt-tolerant and ultra-long stable nanoparticle can be formed. OVA/CMC nanoparticle with the loose structure of wool ball could effectively load curcumin with the loading content and loading efficiency of 36.40 and 95.40%, 36.30 and 92.82%, 36.0 and 94.48% for the ratios of 1:2, 1:1 and 2:1, respectively. Curcumin-loaded of OVA/CMC nanoparticles show good DPPH· scavenging activity, Ferric-reducing ability and ABTS + scavenging activity compared with curcumin/water. The results can be useful for designing food and beverage particle with improving bioactive substances functional properties., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The efficient association and controlled release of hydrophilic and aromatic low molecular-weight drugs (HALMD) still remains a challenge due to their relatively weak interactions with excipients and strong affinity to water. Considering that a wide variety of drugs to treat chronic diseases are HALMD, their inclusion in polymeric nanoparticles (NPs) constitutes an attractive possibility by providing to these drugs with controllable physiochemical properties, preventing crisis episodes, decreasing dose-dependent side effects and promoting therapeutic adhesiveness. However, the strong interaction of HALMD with the aqueous medium jeopardizes their encapsulation and controlled release. In this work, the role of the self-assembly tendency of HALMD on their association with the aromatic excipient poly(sodium 4-styrensulfonate) (PSS) to form NPs is studied. For this aim, the widely used drugs amitriptyline (AMT), promethazine (PMZ), and chlorpheniramine (CPM) are selected due to their well described critical aggregation concentration (cac) (36 mM for AMT, 36 mM for PMZ, and 69.5 mM for CPM). These drugs undergo aromatic-aromatic interactions with the polymer, which stabilize their mutual binding, as seen by NMR. The simple mixing of solutions of opposite charged molecules (drug + PSS) allowed obtaining NPs. Importantly, comparing the three drugs, the formation of NPs occurred at significantly lower absolute concentration and significantly lower drug/polymer ratio as the cac takes lower values, indicating a stronger binding to the polymer, as also deduced from the respective drug/polymer dissociation constant values. In addition, the number of formed NPs is similar for all formulations, even though a much lower concentration of the drug and polymer is present in systems comprising lower cac. The obtained NPs are spheroidal and present size between 100 and 160 nm, low polydispersity (≤0.3) and negative zeta potential (from -30 to -60 mV). The association efficiency reaches values ≥ 83% and drug loading could achieve values up to 68% (never evidenced before for systems comprising HALMD). In addition, drug release studies are also significantly influenced by cac, providing more prolonged release for AMT and PMZ (lower cac), whose delivery profiles adjust to the Korsmeyer-Peppas equation. As a novelty of this work, a synergic contribution of drug self-association tendency and aromatic-aromatic interaction between the drug and polymers is highlighted, a fact that could be crucial for the rational design and development of efficient drug delivery systems., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The study of tropical diseases like leishmaniasis, a parasitic disease, has not received much attention even though it is the second-largest infectious disease after malaria. As per the WHO report, a total of 0.7-1.0 million new leishmaniasis cases, which are spread by 23 Leishmania species in more than 98 countries, are estimated with an alarming 26,000-65,000 death toll every year. Lack of potential vaccines along with the cost and toxicity of amphotericin B (AmB), the most common drug for the treatment of leishmaniasis, has raised the interest significantly for new formulations and drug delivery systems including nanoparticle-based delivery as anti-leishmanial agents. The size, shape, and high surface area to volume ratio of different NPs make them ideal for many biological applications. The delivery of drugs through liposome, polymeric, and solid-lipid NPs provides the advantage of high biocomatibilty of the carrier with reduced toxicity. Importantly, NP-based delivery has shown improved efficacy due to targeted delivery of the payload and synergistic action of NP and payload on the target. This review analyses the advantage of NP-based delivery over standard chemotherapy and natural product-based delivery system. The role of different physicochemical properties of a nanoscale delivery system is discussed. Further, different ways of nanoformulation delivery ranging from liposome, niosomes, polymeric, metallic, solid-lipid NPs were updated along with the possible mechanisms of action against the parasite. The status of current nano-vaccines and the future potential of NP-based vaccine are elaborated here., (Copyright © 2021. Published by Elsevier Masson SAS.)

The intersection of lipid-based nanoparticles and lyotropic liquid crystals has provided a novel type of nanocarrier system known as 'lipid-based lyotropic liquid crystals' or 'liquid crystalline nanoparticles' (LCNPs). The unique advantages and immense popularity of LCNPs can be exploited in a better way if the formulation of LCNPs is done using the approach of quality by design (QbD). QbD is a systematic method that can be utilized in formulation development. When QbD is applied to LCNPs formulation, it will proffer many unique advantages, such as better product and process understanding, the flexibility of process within the design space, implementation of more effective and efficient control strategies, easy transfer from bench to bedside, and more robust product. In this work, the application of QbD in the formulation of LCNPs has been explored. The elements of QbD, viz. quality target product profile, critical quality attributes, critical material attributes, critical process parameters, quality risk management, design of experiments, and control strategy for the development of LCNPs have been explained in-depth with case studies. The present work will help the reader to understand the nitty-gritties in the application of QbD in the formulation of LCNPs, and provide a base for QbD-driven formulation of LCNPs with a regulatory perspective., (Copyright © 2021. Published by Elsevier Masson SAS.)

Aqueous-based film coating suspensions are associated with reliance on alkalinising reagents and poor film formation. The impact of particle size in this process and resultant film properties remains unclear. This study offers the first direct comparison of film formation properties between aqueous micro- and nano-suspensions of the enteric polymer Eudragit S100. High-pressure homogenisation was employed to produce nano-suspensions of the enteric polymer. Formed enteric suspensions (micro- and nano-) were evaluated in terms of size, morphology, and ability to form film; with resultant films analysed in terms of; film thickness, mechanical and thermoplastic properties, water uptake, weight loss, and drug permeability in acidic medium. High-pressure homogenisation yielded particles within a submicron range (150-200 nm). Produced nano-suspensions formed significantly thinner films ( p  < 0.01), at lower plasticiser concentrations, than films cast from micro-suspensions (differences in thickness up to 100 µm); however, exhibited comparative gastro-resistant properties ( p  > 0.05) in terms of water uptake (∼25% w/w), weight loss (<16% w/w) and drug permeability (<0.1%). Interestingly, nano-suspension-based films exhibited lower glass transition temperatures (Tg) ( p  < 0.01), when compared to films cast from micro-suspensions (∼7-20 °C difference), indicating enhanced plasticisation. This was reflected in film mechanical properties; where nano-suspension-based films demonstrated significantly lower tensile strength ( p  < 0.01) and higher percentage elongation ( p  < 0.05), suggesting high elasticity. Thinner, highly elastic films were formed from nano-suspensions, compared to films cast from micro-suspensions, exhibiting comparative properties; obviating the need for alkalinising agents and high concentrations of plasticiser.