Sorafenib delivery nanoplatform based on superparamagnetic iron oxide nanoparticles magnetically targets hepatocellular carcinoma

Currently,sorafenib is the only systemic therapy capable of increasing overall survival of hepatocellular carcinoma patients.Unfortunately,its side effects,particularly its overall toxicity,limit the therapeutic response that can be achieved.Superparamagnetic iron oxide nanoparticles (SPIONs) are very attractive for drug delivery because they can be targeted to specific sites in the body through application of a magnetic field,thus improving intratumoral accumulation and reducing adverse effects.Here,nanoformulations based on polyethylene glycol modified phospholipid micelles,loaded with both SPIONs and sorafenib,were successfully prepared and thoroughly investigated by complementary techniques.This nanovector system provided effective drug delivery,had an average hydrodynamic diameter of about 125 nm,had good stability in aqueous medium,and allowed controlled drug loading.Magnetic analysis allowed accurate determination of the amount of SPIONs embedded in each micelle.An in vitro system was designed to test whether the SPION micelles can be efficiently held using a magnetic field under typical flow conditions found in the human liver.Human hepatocellular carcinoma (HepG2) cells were selected as an in vitro system to evaluate tumor cell targeting efficacy of the superparamagnetic micelles loaded with sorafenib.These experiments demonstrated that this delivery platform is able to enhance sorafenib's antitumor effectiveness by magnetic targeting.The magnetic nanovectors described here represent promising candidates for targeting specific hepatic tumor sites,where selective release of sorafenib can improve its efficacy and safety profile.     

Online hot selling period and its impact on e-retailer’s pricing strategies

The express delivery industry is often overloaded in some hot online selling seasons, which causes consumers’ dissatisfaction. Under such a circumstance, the e-retailer can utilise two opposite strategies, i.e. to set-up either a low price with a pre-announced markdown pricing (PMDP) strategy, or a high price with a pre-announced markup pricing (PMUP) strategy for the hot selling period. As both the prices and the express service quality are different between the regular period and the hot selling period, consumers can strategically choose their purchase time, which will in turn influences the e-retailer’s pricing strategy. To investigate under what condition one pricing strategy will dominate the other, we propose a two period pricing model in which the selling season are divided into regular and hot selling period, and all consumers are assumed to be strategic. The e-retailer determines the prices over the two kinds of periods to maximise its profit. The comparison shows that a PMUP (resp. PMDP) strategy is preferred when the overloading degree in the hot selling period is slight (resp. heavy). Furthermore, we extend our model by incorporating the competition of traditional retailers.     

The influence of bile salts on the distribution of simvastatin in the octanol/buffer system

Abstract

Introduction: Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability.

Methods: LogD values of SVA and SVL with or without bile salts were measured by liquid–liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes.

Results: Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results.

Conclusions: Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.     

Engineered microparticles based on drug–polymer coprecipitates for ocular-controlled delivery of Ciprofloxacin: influence of technological parameters

Abstract

Ciprofloxacin is a drug active against a broad spectrum of aerobic Gram-positive and Gram-negative bacteria, for the therapy of ocular infections. It requires frequent administrations owing to rapid ocular clearance and it is a good candidate for ocular controlled release formulations. The preparation of such drug release systems is still a challenge. Ionic interactions between ciprofloxacin and the polyelectrolytes chondroitin sulfate or lambda carrageenan result in coprecipitates that can act as microparticulate controlled release systems from which the drug is released after being displaced by the medium’s ions. In some formulations, Carbopol was added to improve the mucoadhesive properties. The aim of this research was the study of the influence of the technological parameters of the preparation method of coprecipitates on their particle size, with the goal of achieving particles engineered with a size suitable for the ocular administration. Technological parameters taken into account were: concentration of drug and polymer solutions utilized for the preparation of interaction products, possible use of surfactants (kind and concentration), temperature of the solutions and stirring during the process of preparation of the coprecipitates. Preliminary stability study tests were carried out to further characterize the leader formulation. Particle size in suspensions for ocular drug delivery is a critical parameter influencing the quality of the formulation. The results obtained from this study show that chondroitin sulfate coprecipitates present the best characteristics in terms of particle size suitable for ocular administration. A further improvement of the particle size characteristics has been obtained with the addition of surfactants.     

Anti prostate cancer using PEGylated bombesin containing,cabazitaxel loading nano-sized drug delivery system

Context: Prostate cancer (PCa) is the second most-frequently diagnosed cancer in men. Cabazitaxel was approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Objective: In this study, bombesin (BN), a ligand reported to specifically target GRP overexpressing prostate tumor, was applied for the construction of lipid-polymer hybrid nanoparticles (LPNs), and used for the targeted delivery of cabazitaxel (CAB) to prostate cancer.

Methods: BN-polyethylene glycol-1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (BN-PEG-DSPE) was synthesized. CAB loaded, BN-PEG-DSPE contained LPNs (BN-CAB-LPNs) were prepared. Their particle size, zeta potential and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study of BN-CAB-LPNs was tested in LNCaP human prostatic cancer cell line (LNCaP cells). In vivo anti-tumor efficacy of the carriers was evaluated on mice bearing prostate cancer model.

Results: The optimum BN-CAB-LPNs formulations had a particle size of 184.9?nm and a 26.5?mV positive surface charge. The growth of LNCaP cells in vitro was obviously inhibited. BN-CAB-LPNs also displayed better anti-tumor activity than the other formulations in vivo.

Conclusion: The results demonstrated that BN-CAB-LPNs can sufficiently deliver CAB to the cancer cells and enhance the anti-tumor capacity. Thus, BN-CAB-LPNs can be proved to be a superior nanomedicine which can achieve better therapeutic efficacy of prostate tumor.     

Modulation of the wettability of excipients by surfactant and its impacts on the disintegration and release of tablets

Objective: To investigate the modulation of the wettability of excipients by different types of surfactants and its impacts on the disintegration of tablets and drug release.

Materials and methods: The critical micelle concentration (CMC) of surfactants, including sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS), dodecyl trimethyl ammonium bromide (DTAB), cetyltrimethyl ammonium bromide (CTAB) and polysorbate (Tween-20 and Tween-80), was obtained using the platinum ring method. Contact angles of surfactant solutions on the excipient compacts and double-distilled water on the mixture of surfactant and the other excipient (magnesium stearate (MgSt) or sodium alginate (SA)) were measured by the sessile drop technique. Besides, surface free energy of excipients was calculated by the Owens method. Finally, the disintegration of tablets and in vitro dissolution testing were performed according to the method described in USP.

Results and discussion: The wettability of excipients could be enhanced to different extent with low concentration of surfactant solutions and maintained stable basically after CMC. For MgSt (hydrophobic excipient), the shorter the hydrophobic chain (C₁₂, including SDS and DTAB), the better the wettability with the addition of surfactant in the formulation, leading to the shorter disintegration time of tablets and higher drug release rate. In contrast, the wettability of SA (hydrophilic excipient) was reduced by adding surfactant, resulting in the longer disintegration time of tablets and lower release rate.

Conclusion: The modulation of the wetting of pharmaceutical excipients by surfactant had changed the disintegration time of tablets and drug release rate to a greater extent.     

Formulation design,in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles

Context: Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability.

Objective: To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability.

Materials and methods: Rational blends of Softisan^®154 and Phospholipon^®90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice.

Results: Stable, smooth and spherical particles with sizes ranging from 4.2?±?0.02 to 9.3?±?0.8?µm were formed. EE% of 92.2–97.3% and 30.2–84.7% and pH of 3.0?±?0.02 to 4.9?±?0.12 and 3.0?±?0.02 to 5.8?±?0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p?Conclusion: Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.     

Fabrication of novel GMO/Eudragit E100 nanostructures for enhancing oral bioavailability of carvedilol

In the present work, novel nanostructures comprising of glyceryl monooleate (GMO) and Eudragit E100 were prepared using high intensity ultrasonic homogenization. 3² Factorial design approach was used for optimization of nanostructures. Results of regression analysis revealed that the amount of GMO and Eudragit E100 had a drastic effect on particle size and percent entrapment efficiency. Optimized carvedilol-loaded nanostructures (Car-NS) were characterized by FTIR, TEM, DSC, in vitro drug release study. Pharmacokinetic parameters such as C_max, T_max, Ke, Ka, V_d and AUC were estimated for Car-NS upon its oral administration in Sprague-Dawley rats. Particle size of Car-NS was found to be 183?±?2.43?nm with an entrapment efficiency of 81.4?±?0.512%. FTIR studies revealed loading and chemical compatibility of carvedilol with the components of nanostructures. DSC thermograms did not show endothermic peak for melting of carvedilol which could be attributed to solubilization of carvedilol in molten GMO during DSC run. The prepared Car-NS released carvedilol in sustained manner over a period of 10 h as suggested by in vitro drug release study. The pharmacokinetic study of Car-NS showed significant improvement in C_max (two fold, p?p?相似文献