Preparation and evaluation of silymarin nanosuspensions for protective effects on stress-induced liver injury

OBJECTIVE To fabricate Silymarin(SM) nanosuspensions(NSs) and evaluate their protective effect on stress-induced liver injury. METHODS SM nanosuspensions were tailored by combination of the anti-solvent precipitation and high pressure homogenization(HPH); the formulations were optimized by central composite design. The pharmacokinetics and pharmacodynamics of SM-NSs were also performed.RESULTS In light of the quadratic mathematical equations derived from the Design of Expert Software,the optimal formulation of SM-NSs consisted of PVP 0.34% and F188 0.36%. The morphology of NSs was found to be spherical with a diameter of about 150 nm using transmission electron microscope(TEM)observation. The pharmacokinetics experiment demonstrated that oral administration of SM-NSs significantly increased its bioavailability compared to the coarse powder(Cmax: 9.03 ± 2.39 mg · L^(-1);AUMC_(0→∞):3757.35±227.19 mg·L^(-1)·h; AUC_(0→∞):171.84±26.61 mg·L^(-1)·h). In pharmacodynamics,it was found that restraint stress produced oxidative effects and increased serum AST and ALT levels in mice,both of which were significantly inhibited by SM and SM-NSs; in addition,administration of SM-NSs showed more effective prevention against acute liver injury than SM coarse suspensions(r^2=0.986,0.984,P<0.05). CONCLUSION The results suggest that fabricated SM-NSs exert potent hepatoprotective effects and attenuate restraint stress-induced liver injury. The study provides an effective approach to improving the property of SM,which can be used for treatment of liver diseases.

Improved stability and oral bioavailability of Ganneng dropping pills following transforming lignans of herpeto- spermum caudigerum into nanosuspensions

The present study was designed to improve storage stability and oral bioavailability of Ganneng dropping pills(GNDP) by transforming lignans of Herpetospermum caudigerum(HL) composed of herpetrione(HPE) and herpetin(HPN) into nanosuspension(HL-NS), the main active ingredient of GNDP, HL-NS was prepared by high pressure homogenization and lyophilized to transform into solid nanoparticles(HL nanoparticles), and then the formulated HL nanoparticles were perfused into matrix to obtain NS-GNDP by melting method. For a period of 3 months, the content uniformity, storage stability and pharmacokinetics test in vivo of NS-GNDP were evaluated and compared with regular GNDP at room temperature. The results demonstrated that uniformity of dosage units of NS-GNDP was acceptable according to the criteria of Chinese Pharmacopoeia 2015 J. Physical stability of NS-GNDP was investigated systemically using photon correlation spectroscopy(PCS), zeta potential measurement, and scanning electron microscopy(SEM). There was a slight increase in particles and PI of HL-NS re-dispersed from NS-GNDP after storage for 3 months, compared with new formulated NS-GNDP, which indicated a good redispersibility of the NS-GNDP containing HL-NS after storage. Besides, chemical stability of NS-GNDP was studied and the results revealed that HPE and HPN degradation was less when compared with that of GNDP, providing more than 99% of drug residue after storage for 3 months. In the dissolution test in vitro, NS-GNDP remarkably exhibited an increased dissolution velocity compared with GNDP and no distinct dissolution difference existed within 3 months. The pharmacokinetic study showed that HPE and HPN in NS-GNDP exhibited a significant increase in AUC0–t, Cmax and decrease in Tmax when compared with regular GNDP. These results indicated that NS-GNDP possessed superiority with improved storage stability and increased dissolution rate and oral bioavailability.

Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma

Nanosuspensions,as a new drug delivery system for insoluble drugs,are only composed of a drug and a small amount of stabilizer,which is dispersed in an aqueous solution with high drug-loading,small particle size,high dispersion,and large specific surface area.It can significantly improve the dissolution,bioavailability,and efficacy of insoluble drugs.In this study,paclitaxel nanosuspensions((PTX)NS)were prepared by an ultrasonic precipitation method,with the characteristics of simple preparation and easy repetition.With the help of a homologous targeting mechanism,a kind of glioma C6 cancer cell membrane(CCM)-coated(PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting.The results showed that the cancer cell membrane could effectively camouflage the nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier(BBB)and selectively target tumor tissues.Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased.Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice.Finally,the cancer cell membrane coating endowed the nanosuspensions with the biological properties of homologous adhesion and immune escape.This study provides an integrated solution for improving the targeting of nanosuspensions and demonstrates the encouraging potential of biomimetic nanosuspensions applicable to tumor therapy.

Permeation into but not across the cornea:Bioimaging of intact nanoemulsions and nanosuspensions using aggregation-caused quenching probes

Nanoemulsions(NEs) and nanosuspensions(NSs) show great potential in enhancing the ocular bioavailability of therapeutics through topical delivery. However, transocular fate of intact NEs and NSs is still inconclusive. In this study, an aggregation-caused quenching fluorescent probe is used to track precorneal retention and transocular transportation of intact NEs and NSs, while coumarin 6 is used to mimick the cargo. NEs show superior precorneal retention to NSs. Both the two types of nanocarriers can permeate into but not across the cornea. The smaller NEs(100 nm) permeate better into the cornea than the bigger ones(210 nm). Nanocarriers in the cornea serves as depots. The released cargo molecules can penetrate across the cornea and diffuse into the lens. Moreover, the conjunctiva-scleral route may be potential to deliver drugs to the back of the eye, In conclusion, the study provides useful tools and information in the field of transocular transportation of nanoparticles.

Insight into the in vivo fate of intravenous herpetrione amorphous nanosuspensions by aggregation-caused quenching probes

Intravenous nanosuspensions are attracted growing attention as a viable strategy for development of intravenous formulations of poorly water-soluble drugs.However,only few information about the biological fate of intravenous nanosuspensions is currently known,especially amorphous nanosuspensions are not reported yet.In this study,the in vivo fate of herpetrione(HPE)amorphous nanosuspensions following intravenous administration was explored by using an aggregation-caused quenching(ACQ)probe and HPLC methods.The ACQ probe is physically embedded into HPE nanoparticles via anti-solvent method to form HPE hybrid nanosuspensions(HPE-HNSs)for bioimaging.HPE-HNSs emit strong and stable fluorescence,but fluorescence quenches immediately upon the dissolution of HPE-HNSs,confirming the selfdiscrimination of HPE-HNSs.Following intravenous administration of HPE-HNSs,integral HPE-HNSs and HPE show similar degradation and biodistribution,with rapid clearance from blood circulation and obvious accumulation in liver and lung.Due to the slower dissolution and enhanced recognition by reticuloendothelial system,450 nm HPE-HNSs accumulate more in liver,lung and spleen than that of 200 nm HPE-HNSs.These results demonstrate that integral HPE-HNSs determine the in vivo performance of HPEHNSs.This study provides insight into the in vivo fate of intravenous amorphous nanosuspensions.

Preparation and Characterization of Paclitaxel/Chitosan Nanosuspensions for Drug Delivery System and Cytotoxicity Evaluation In Vitro

In this study,we prepared paclitaxel/chitosan(PTX/CS)nanosuspensions(NSs)with different mass ratios of PTX and CS(1.5:2,2:2,and 2.5:2),for controlled drug delivery purposes.For attachment and dispersion in water medium,a simple ultrasonic disruption technique was employed.The water-dispersed PTX/CS NSs exhibited a rod-shape morphology with an average diameter of 170-210 nm and average length of about 1-10μm.Transmission electron microscopy,differential scan-ning calorimetry and X-ray diffraction indicated that the obtained PTX/CS NSs contain a nanocrystalline PTX phase.It was also inferred that presence of CS can promotes the crystalline nature of PTX up to 80%.In addition,efficiency of PTX loading reached over 85%in freeze-dried PTX/CS NSs,showing a slow rate of drug release in vitro for 8 days.The MTT and LDH assessments revealed that PTX/CS NSs significantly inhibit the growth of tumor cells(HeLa),while it is slightly toxic for the normal cells(NIH/3T3).Therefore,PTX/CS NSs is suggested as a potential nanodrug delivery system for cancer therapy.

Facile pathway to generate agrochemical nanosuspensions integrating super-high load, eco-friendly excipients, intensified preparation process, and enhanced potency

An aqueous nanosuspension of agrochemicals unlike pharmaceutics has to achieve massive production in an effective way,capable to ensure sufficient profits in commercialization.This work implements the flash nanoprecipitation(FNP)technique to effectively generate agrochemical nanosuspension,anticipatedly overcoming such an obstacle.Azoxystrobin,a broad spectrum fungicide,in either acetone or ethanol is used herein as a mode agrochemical.To ensure a green and practical utilization,three kinds of commercially available and eco-friendly surfactants,i.e.,poly(ethylene glycol)-block-poly(lactic-co-glycolic acid)(PEG-b-PLGA),Tween 80 and alkyl polyglucosides(APGs),are employed for stabilizing the nanoparticles.The results show that the polymeric stabilizer,PEG-b-PLGA,has the best stabilization efficiency,and can maintain the particles below 100 nm for at least three weeks.The azoxystrobin load of the nanoparticles reaches as high as 77 wt.%,beneficial to enhancing the biological potency.Moreover,the FNP brings the particles a much smaller size,narrower size distribution,better size stability,and higher biological efficacy than the ones made via a traditional method of the drop and stir(DS).The nanosuspensions present superior fungicidal performances over a prevailing counterpart from Syngenta.This study proves an enhanced biological potency and reduced dosage of agrochemical nanosuspension made via the FNP,indicating a remarkable advantage of the FNP over the conventional preparation.The integration of a super-high load,eco-friendly excipients,intensified preparation process,enhanced potency,and reduced dosage creates a promising pathway to generate a green aqueous nanosuspension of agrochemicals.

Combined nanosuspensions from two natural active ingredients for cancer therapy with reduced side effects

Tumor drug resistance and systemic side effects of chemotherapeutic drugs are the main reasons for the failure of cancer treatment.In recent years,it was found that some natural active ingredients can reverse MDR and regulate body immunity to enhance the efficacy and reduce toxicity of chemotherapeutic drugs.In this paper,a new nanosuspensions,HCPT and QUR hybrid nanosuspensions(HQ-NPs),was prepared by the microprecipitation-high pressure homogenization method to reverse tumor drug resistance,reduce toxicity,and increase therapeutic efficacy.The in vitro investigation results showed that HQ-NPs had a unique shape(particle size was about 216.3±5.9 nm),changed crystalline,and different dissolution rates compared with HCPT-NPs and QUR-NPs,which is attributed to the strong intermolecular forces between HCPT and QUR as indicated by the results of the molecule dock.It was verified that the HQ-NPs could double the retention of HCPT in cells and enhance the cytotoxicity to A549/PTX cells in vitro tests compared with HCPT-NPs.We also found that HQ-NPs can significantly enhance the accumulation of HCPT in tumor sites,improve the antitumor activity of HCPT,and protect the immune organs and other normal tissues(P<0.01),compared with HCPT-NPs.Therefore,hybrid nanosuspensions can offer promising potential as the drug delivery system for HCPT and QUR to increase the therapeutic efficacy and reduce the toxicity of HCPT.

Parenteral nanosuspensions:a brief review from solubility enhancement to more novel and specific applications

Advancements in in silico techniques of lead molecule selection have resulted in the failure of around 70% of new chemical entities(NCEs). Some of these molecules are getting rejected at final developmental stage resulting in wastage of money and resources. Unfavourable physicochemical properties affect ADME profile of any efficacious and potent molecule, which may ultimately lead to killing of NCE at final stage. Numerous techniques are being explored including nanocrystals for solubility enhancement purposes. Nanocrystals are the most successful and the ones which had a shorter gap between invention and subsequent commercialization of the first marketed product. Several nanocrystal-based products are commercially available and there is a paradigm shift in using approach from simply being solubility enhancement technique to more novel and specific applications. Some other aspects in relation to parenteral nanosuspensions are concentrations of surfactant to be used, scalability and in vivo fate. At present, there exists a wide gap due to poor understanding of these critical factors,which we have tried to address in this review. This review will focus on parenteral nanosuspensions,covering varied aspects especially stabilizers used, GRAS(Generally Recognized as Safe) status of stabilizers, scalability challenges, issues of physical and chemical stability, solidification techniques to combat stability problems and in vivo fate.

Viscosity of Nanofluids. Why It Is Not Described by the Classical Theories

Transport properties of nanofluids are extensively studied last decade. This has been motivated by the use of nanosized systems in various applications. The viscosity of nanofluids is of great significance as the application of nanofluids is always associated with their flow. However, despite the fairly large amount of available experimental information, there is a lack of systematic data on this issue and experimental results are often contradictory. The purpose of this review is to identify the typical parameters determining the viscosity of nanofluids. The dependence of the nanofluid viscosity on the particles concentration, their size and temperature is analyzed. It is explained why the viscosity of nanofluid does not described by the classical theories. It was shown that size of nanoparticles is the key characteristics of nanofluids. In addition the nanofluid is more structural liquid than the base one.

Improved dissolution and oral absorption by co-grinding active drug probucol and ternary stabilizers mixtures with planetary beads-milling method

The objective of this work is to construct a nanosuspension drug delivery system of probucol,a BCS II drug,in order to improve its dissolution and oral bioavailability.The wet milling procedure using planetary beads-milling equipment was utilized to grind the raw probucol to ultrafine nanoparticle/nanocrystal aqueous suspension that was further solidified by freeze-drying process.Cellulose derivatives of different substitution groups and molecular weights,including HPMC,HPC,and MC,were evaluated as the primary stabilizer of probucol nanosuspension.Ternary stabilizers system composed of a primary stabilizer(cellulose derivative,i.e.HPC),a nonionic surfactant(Pluronic R F68),and an anionic surfactant(SDS)was employed to obtain probucol nanosuspension of finer particle size and enhanced dissolution in aqueous media.The probucol nanosuspension with good physical stability showed no obvious change of particle size even after storing over 7 d at 4°C or 25°C.The solidified probucol nanosuspension with trehalose as the cryoprotectant showed the highest dissolution rate(>60%at 2 h)compared to other cryoprotectant.The in vivo pharmacokinetic evaluation indicated about 15-folds higher AUC value of the probucol nanosuspension compared to that of coarse probucol suspension after oral administration to rats.The probucol nanosuspension prepared by wet-milling and ternary stabilizers system may find wide applications for improving the dissolution and oral absorption of water-insoluble drugs.

Nanosuspension enhances dissolution rate and oral bioavailability of Terminalia arjuna bark extract in vivo and in vitro

Objective:To enhance the dissolution rate and oral bioavailability of Terminalia arjuna bark extract by formulating its nanosuspension.Methods:Nanoprecipitation approach was used for the formulation of nanosuspension using polysorbate-80 as a stabilizer.The formulated nanosuspension was assessed for particle size,polydispersity index,zeta potential value and for in vitro dissolution study.Oral bioavailability studies were carried out in Wistar male albino rats by administering a single dose(50 mg/kg.b.wt)of the formulated nanosuspension and coarse suspension.The storage stability of the formulated nanosuspension was determined after three months of storage at room temperature and under the refrigerated condition.Mutagenicity assay was carried out to evaluate the toxicity of the formulated nanosuspension using two mutant strains(Salmonella typhimurium TA100 and Salmonella typhimurium TA98).Results:The mean particle size of the formulated nanosuspension was 90.53 nm with polydispersity index and zeta potential values of 0.175 and-15.7 m V,respectively.Terminalia arjuna nanosuspension showed improved dissolution rate and 1.33-fold higher oral bioavailability than its coarse suspension.The formulated nanosuspension also showed better stability under the refrigerated condition and was non-mutagenic against both strains.Conclusions:Our study demonstrates that nanosuspension technology can effectively enhance the dissolution rate and oral bioavailability of Terminalia arjuna bark extract.

Comparison of solid dispersion and nanosuspension for improvement of drug absorption

Currently, drug discovery technology is heavily dependent oncombinatorial chemistry and high throughput screening, resultingin more and more poorly water-soluble drugs, eitherclass II (low solubility and high permeability) or IV (low solubilityand low permeability) in the standard biopharmaceuticalclassification system. Owing to the importance of solubility/dissolution for oral absorption, formulation scientists face agreat challenge.Thus, strategies have been proposed to improvethe solubility and dissolution rate. Among these approaches,solid dispersion [1] and nanosuspension [2] are the most usuallyused. However, which one is better for improving the in vitrodissolution and in vivo bioavailability?

Cytotoxic Effect of Propolis Nanoparticles on Ehrlich Ascites Carcinoma Bearing Mice

Background and objective Previous studies have demonstrated the anti-cancer effects of propolis. However, its use is limited because of its poor bioavailability. In the present study, the major objective was to improve propolis bioavailability using a nanosuspension formulation. The cytotoxic effect of propolis nanosuspension (PRO-NS) on the Ehrlich ascites carcinoma (EAC) in female Swiss albino mice was investigated in comparison to the free propolis. Materials and methods A propolis-loaded nanosuspension was formulated by applying solvent-antisolvent nano-precipitation technique. The prepared PRO-NS was characterized for average particle size, polydispersity index (PDI) and zeta potential. Also, the morphology of the nanosuspension particles was investigated using scanning electron microscopy (SEM). Moreover, PRO-NS cytotoxicity was tested using EAC bearing mice. The anticancer activity of Pro-NS was assessed by studying tumor volume, life span, viable and non-viable cell count, antioxidant, biochemical estimations and proliferation of EAC cells. Results The results revealed that propolis nanoparticles were relatively spherical in shape with rough surface. The tumor bearing mice treated with PRO-NS showed increased life span and inhibited tumor growth and the proliferation of EAC cells in comparison to the free propolis (p Conclusions Our results indicate that PRO-NS has a strong inhibitory activity against growth of tumors in comparison to free propolis. The anti-tumor mechanism may be mediated by preventing oxidative damage, immune-stimulation and induction of apoptosis.

Formulation of dried lignans nanosuspension with high redispersibility to enhance stability,dissolution,and oral bioavailability

Herpetospermum caudigerum lignans(HTL), one of the potential drugs with anti-hepatitis B virus and hepatoprotective effects, has limited clinical applications because of poor aqueous solubility and low bioavailability. Both herpetrione(HPE) and herpetin(HPN) are the most abundant ingredients in HTL and exhibit weak acidity. The purpose of the present study was to produce dried preparations of HTL(composed of HPE and HPN) nanosuspensions(HTL-NS) with high redispersibility using lyophilization technology. The HTL-NS was prepared by utilizing precipitation-combined homogenization technology based on acid-base neutralization reactions, and critical formulation and process parameters affecting the characteristics of HTL-NS were optimized. The resultant products were characterized by particle size analysis, SEM, XRD, stability, solubility, dissolution and in vivo bioavailability. HTL-NS showed near-spherical-shaped morphology and the size was 243 nm with a narrow PDI value of 0.187. The dried preparations with a relatively large particle size of 286 nm and a PDI of 0.215 were achieved by using 4%(W/V) mannitol as cryoprotectants, and had a better stability at 4 or 25 oC for 2 months, compared to HTL-NS. In the in vitro test, the dried preparations showed markedly increased solubility and dissolution velocity. Besides, in the in vivo evaluation, it exhibited significant increases in AUC0–t, C_(max), MRT and a decrease in T_(max), compared to the raw drug.. In conclusion, our results provide a basis for the development of a drug delivery system for poorly water-soluble ingredients with p H-dependent solubility.

Geometrical Deposits on Microstructured Surfaces

Research into evaporating droplets on patterned surfaces has grown exponentially,since the capacity to control droplet morphology has proven to have significant technological utility in emerging areas of fundamental research and industrial applications.Here,we incorporate two interest domains-complex wetting patterns of droplets on structured surfaces and the ubiquitous coffee-ring phenomenon of nanofluids containing dispersed aluminium oxide particles.We lay out the surface design criteria by quantifying the effect of pillar density and shape on the wetting footprint of droplets,yielding complex polygon droplet geometries.Our work is not constrained to pure liquids only,as we delve into the shape selection of particle-laden droplets of different concentrations.We visualise the deposition patterns through microscopy on surfaces exhibiting different features and further establish the ordering of particles on microscale surface asperities.At a high nanofluid concentration,we observe intriguing self-assembly of particles into highly ordered intricate structures.The collective findings of this work have the potential to enhance many industrial technologies,particularly attractive for high performance optical and electrical devices.

Preparation,characterization and pharmacokinetics of 10-hydroxycamptothecin nanosuspension

10-Hydroxycamptothecin （HCPT） is a broad-spectrum anticancer drug, while its low solubility and instability severely limit its application. In this study, HCPT nanosuspension （HCPT-NSP）, also known as nanocrystal, was prepared by micro-precipitation combined with high-pressure homogenization method. This nanosuspension was characterized by size, shape, zeta potential, drug loading efficiency and in vitro drug release behavior. Preferred formulation and process showed that particle size was （129.8±13.9） nm, PDI was 0.20±0.07, and drug loading efficiency was 36.5%±9.5%. Moreover, HCPT nanocrystal concentration reached （1.35±0.2） mg/mL in HCPT-NSP, which was more than 1000-fold higher than that of HCPT. Transmission electron microscopy （TEM） results showed that the nanosuspension was short rod in shape. X-ray powder diffraction （XRD）, thermogravimetric analysis （TGA）, derivative thermogravimetric analysis （DTA） and differential scanning calorimetry （DSC） further elaborated the crystal state of the HCPT. The drug concentration-time curve of HCPT-NSP in rats was in accordance with the three-compartment model, showing prolonged half-life. Taken together, our data suggested that HCPT-NSP was a promising drug delivery system.

Determination of dabigatran in dog plasma by LC-MS/MS and its application to a pharmacokinetic study of dabigatran etexilate nanosuspension

In this study, a sensitive and rapid LC-MS/MS method was developed and validated to determine dabigatran in plasma of beagle dogs after oral administration of dabigatran etexilate nanosuspension （DABE-NS）. The analytes （dabigatran） and sertraline hydrochloride （internal standard, IS） were separated on a Kromasil C18 column using gradient elution consisting of methanol and formate buffer at a flow rate of 0.4 mL/min in 20 min. Detection and quantitation were carded out by multiple reaction monitoring following the transitions： m/z 472.17→289.07 and 305.98→275.00 for dabigatran and IS at positive ion mode, respectively. The calibration curves were linear from 1.0 to 500.0 ng/mL for dabigatran with r = 0.9995. The accuracy of each analyte ranged from 94.8% to 107.1%, and the precision was within 6%. Besides, this method was successfully applied in the investigation of the pharmacokinetic profile of dabigatran in beagle dogs after oral administration of DABE-NS. The maximum concentration and the areas under curves of dabigatran for DABE-NS were significantly higher than those of control formulation, indicating improved oral absorption.