Advancing ophthalmic delivery of flurbiprofen via synergistic chiral resolution and ion-pairing strategies.

Flurbiprofen (FB), a nonsteroidal anti-inflammatory drug, is widely employed in treating ocular inflammation owing to its remarkable anti-inflammatory effects. However, the racemic nature of its commercially available formulation (Ocufen®) limits the full potential of its therapeutic activity, as the (S)-enantiomer is responsible for the desired anti-inflammatory effects. Additionally, the limited corneal permeability of FB significantly restricts its bioavailability. In this study, we successfully separated the chiral isomers of FB to obtain the highly active (S)-FB. Subsequently, utilizing ion-pairing technology, we coupled (S)-FB with various counter-ions, such as sodium, diethylamine, trimethamine (TMA), and l-arginine, to enhance its ocular bioavailability. A comprehensive evaluation encompassed balanced solubility, octanol-water partition coefficient, corneal permeability, ocular pharmacokinetics, tissue distribution, and in vivo ocular anti-inflammatory activity of each chiral isomer salt. Among the various formulations, S-FBTMA exhibited superior water solubility (about 1-12 mg/ml), lipid solubility (1< lg Pow < 3) and corneal permeability. In comparison to Ocufen®, S-FBTMA demonstrated significantly higher in vivo anti-inflammatory activity and lower ocular irritability (such as conjunctival congestion and tingling). The findings from this research highlight the potential of chiral separation and ion-pair enhanced permeation techniques in providing pharmaceutical enterprises focused on drug development with a valuable avenue for improving therapeutic outcomes.

A simple and low-energy method to prepare loratadine nanosuspensions for oral bioavailability improvement: preparation, characterization, and in vivo evaluation.

The effervescent method, as a simple and effective technology to prepare nanosuspensions, has gained great attention. In this present research, loratadine (LTD) nanosuspensions were successfully prepared by the effervescent method using Soluplus as stabilizer to improve the bioavailability of LTD in vivo. The mean particle size was about 100 nm. And the LTD nanosuspensions were lyophilized for further study. The freeze-dried powders could be dissolved quickly, and the mean particle size remained almost unchanged after powders were re-dissolved. By transmission electron microscope (TEM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (X-RD), the characterizations of LTD nanosuspensions and freeze-dried powders were studied. Commercial tablets were used as the reference to investigate the dissolution behaviors in different release media and of bioavailability in vivo of LTD freeze-dried powders. The cumulative dissolution of the LTD freeze-dried powders was superior in different release media compared with commercial tables. In addition, for the evaluation of the bioavailability of LTD nanosuspensions, the LTD concentration in rat plasma was determined using LC-MS/MS method. The results showed that the AUC0-24 and Cmax of LTD freeze-dried powders were about 2.14- and 2.01-fold higher than those of commercial tablets. In short, the effervescent method has been successfully applied to the preparation of LTD nanosuspensions to improve the bioavailability of LTD in vivo with the advantage of low energy consumption. This simple technology also provides an idea for the preparation of the other nanosuspensions.

Functional black phosphorus nanosheets for cancer therapy.

Black phosphorus nanosheets (BP NSs), a kind of attractive two-dimensional materials, have been widely used in optoelectronics, transistors and photocatalysis. Recently, growing interest has been attracted to explore the application of BP NSs for cancer therapy in view of their unique properties. BP NSs have high surface area and negative charge, which can load drug, targeting molecules, photosensitizer, magnetic nanoparticles etc. They are also potential candidates for cancer phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) by virtue of extensive near-infrared absorbance. Furthermore, BP NSs exhibit biodegradable and compatible nature to avoid toxicity in vivo. In this review, the preparation and properties of BP NSs are firstly summarized. More importantly, multifunctional platform based on BP NSs for cancer therapy such as photothermal therapy, photodynamic therapy, chemotherapy, antibacterial therapy, chemo-/photothermal combined therapy, photothermal/gene- combined therapy, chemo-/photothermal/gene- combined therapy and chemo-/photothermal/photodynamic combined therapy is reviewed in detail. And the future perspectives of BP NSs is finally discussed.

Preparation and evaluation of self-assembly Soluplus®-sodium cholate-phospholipid ternary mixed micelles of docetaxel.

Ternary mixed micelles constituted of Soluplus®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36 ± 2.45 nm, polydispersity index (PDI) was 0.138 ± 0.039, and the zeta potential was -8.46 ± 0.55 mv. The encapsulation efficiency was 94.24 ± 4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.

Black phosphorus nanosheets and gemcitabine encapsulated thermo-sensitive hydrogel for synergistic photothermal-chemotherapy.

The purpose of this study was to propose a thermosensitive hydrogel incorporating black phosphorus (BP) nanosheets and gemcitabine for chemo-photothermal combination therapy against cancer. The BP nanosheets were prepared by liquid exfoliation method and the thermo-sensitive hydrogel was prepared by "cold method" with Pluronic F127 as hydrogel matrix for intratumoral injection. BP nanosheets and the hydrogel were characterized by particle size, morphology, phase transition feature, near infrared photothermal conversion performance, photothermal stability and biodegradation. The in vitro release behaviors of gemcitabine were assessed. Moreover, the photothermal efficacy, and photothermal-chemotherapy combination were evaluated in mice bearing tumors. The BP nanosheets displayed uniform 2D sheet-like morphology with a diameter of about 200 nm. The hydrogel showed phase translation at near body temperature, great photothermal efficacy in vitro and good biodegradability. The hydrogel exhibited good photothermal effect in BALB/c mice bearing 4T1 xenograft tumors. The combination of photothermal therapy and chemotherapy displayed superior antitumor effect compared to chemotherapy alone.

pH/near infrared dual-triggered drug delivery system based black phosphorus nanosheets for targeted cancer chemo-photothermal therapy.

Recently, chemo-photothermal has been developed as a promising strategy for cancer therapy. However, as a novel photothermal material, black phosphorus nanosheet (BP NSs) has the disadvantages of complicated preparation procedures, high purchase price and poor drug selectivity, which limits its application. Herein, BP NSs have been successfully prepared by self-made ultrasonic method, which was a simple and rapid laboratory preparation. Then, BP NSs based co-delivery system, which coated with mitoxantrone hydrochloride (MTX) and hyaluronic acid (HA) on the surface of BP NSs has been firstly developed via electrostatic interaction. The resulted BP@MTX-HA NSs not only have good physical stability and photothermal conversion efficiency, but also exhibit the unique pH/NIR laser triggered release abilities. Besides, the temperature both in vitro and vivo could rise up to 45 °C or more within 3 min under 808 nm near infrared (NIR) irradiation (1.0 W/cm2). Additionally, through the antitumor phototherapy efficacy investigation in 4T1 tumor-bearing BALB/c mice, BP@MTX-HA NSs exhibited significant inhibition on tumor growth and obvious superiorities over the single treatment of MTX chemotherapy or NIR photothermal therapy in terms of chemo-photothermal synergistic treatment and targeted co-delivery system. In conclusion, pH/NIR dual-triggered drug delivery system based BP NSs would be a prospective strategy in the chemo-photothermal medical fields through our preliminary assessments.

Cooperative effect of polyvinylpyrrolidone and HPMC E5 on dissolution and bioavailability of nimodipine solid dispersions and tablets.

Solid dispersion (SD) systems have been extensively used to increase the dissolution and bioavailability of poorly water-soluble drugs. To circumvent the limitations of polyvinylpyrrolidone (PVP) dispersions, HPMC E5 was applied in the formulation process and scaling-up techniques, simultaneously. In this study, SD of nimodipine (NMP) and corresponding tablets were prepared through solvent method and fluid bed granulating one step technique, respectively. Discriminatory dissolution media were used to obtain reliable dissolution results. Meanwhile, the stability study of SDs was investigated with storage under high temperature and humidity conditions. Moreover, the solubility of SDs was measured to explore the effect of carriers. The preparations were characterized by DSC, PXRD, and FTIR. Dramatical improvements in the dissolution rate of NMP were achieved by the ingenious combination of the two polymers. Binary NMP/PVP/HPMC-SDs released steadily, while the dissolution of single NMP/PVP-SDs decreased rapidly in water. The fluid-bed tablets (FB-T) possessed a similar dissolution behavior to the commercial Nimotop™ tablets. The characterization patterns implied that NMP existed in an amorphous state in our SDs. Furthermore, the results of stability tests suggested a better stability of the binary SDs. A special cooperative effect of PVP and HPMC was discovered on dissolution characteristics of NMP SDs and tablets, which could be extended to other drugs henceforth. Finally, the bioavailability of FB-T was evaluated in beagle dogs with Nimotop™ as the reference, and the results showed a higher AUC 0-12hvalue for FB-T.

Multifunctional micelle delivery system for overcoming multidrug resistance of doxorubicin.

Doxorubicin (DOX), as an anthracycline, plays an important role in chemotherapy. But multidrug resistance (MDR) tremendously retards the anticancer effect of DOX and results in the failure of chemotherapy. Multifunctional micelles emerge as a valid strategy to load DOX by physical encapsulation or chemical binding to be delivered to cancer cells against MDR. In this review, mechanism of MDR of DOX is simply described. Multifunctional co-delivery micelles of DOX and main MDR modulators have been summarised in detail. DOX-loaded multifunctional polymeric micelles are also introduced to alleviate MDR of DOX, in which polymers act as MDR modulators.

Current Delivery Strategies to Improve the Target of Cell Penetrating Peptides Used for Tumor-Related Therapeutics.

Cell Penetrating Peptides (CPPs) equipped with a high penetrating ability are used as a promising tool to gain access to the cell interior, cross the cell membrane and deliver bioactive small or macromolecular cargos into the cytoplasm or nucleus. The superiority of wide range of applications, high transport efficiency and low biological toxicity make them particularly desirable in laboratory or clinical studies. Previous studies have shown that their non-selectivity and reaction with proteins in plasma hamper their application for tumor therapy, which might adversely affect the treatment effect and even induce some side effects. However, several recent studies have found that various kinds of modifiers of CPPs can effectively increase the target selectivity, reduce cytotoxicity to normal cells and produce multiple antitumor functions due to the different cleavable bonds which are sensitive to the tumor microenvironment or other novel designs. Apparently, these designs of 'smart' CPPs appear to be promising in the field of antitumor drug delivery. Here, we review these current improved approaches which mainly involve strategies of physical, chemical as well as biological pathways and we also explain the possible uptake mechanisms of direct penetration, internalization and escape which have been discussed in some publications with specific attention. In addition, some possible problems needed to be considered in the process of improving CPPs are discussed at the end of this review. This study aims to present an overview of the latest progress of CPPs, and provides a comprehensive theoretical background and reference guidance for future laboratory research and clinical application.