查看更多>>摘要：Treatment of posterior uveitis via topical route is desirable but cannot be achieved by conventional drug delivery strategies. Therefore, the aim of this study is to develop a topical nanomicellar formulation of an immunosuppressant drug, everolimus using Soluplus?, a grafted copolymer of polyvinyl caprolactam-polyvinylalcoholpolyethyleneglycol (PVCL-PVA-PEG) for improved permeation through ocular epithelia with minimal or no irritation resulting in enhanced ocular bioavailability at the posterior segments of the eye for the treatment of uveitis. Soluplus-everolimus nano micelles were found to have a low CMC (7.2 ?g/ml) and 65.55 nm in size. The prepared nanomicelles were characterized for surface morphology by TEM, SEM, and AFM and found to have spherical particles with a smooth surface. The nanomicelles were found to have high encapsulation efficiency and result in sustained release of everolimus when compared with everolimus suspension. The everolimus nanomicelles showed significantly higher permeation across goat cornea than everolimus suspension (p<0.001). CLSM of prepared nanomicelles confirmed the deeper permeation through the goat cornea. These results indicated the significantly higher accessibility and improved drug bioavailability thus, everolimus nanomicelles could be considered a promising topical drug delivery nanocarrier for treating uveitis.
查看更多>>摘要：The present research work was aimed to explore the ability of nanostructured lipid carriers (NLCs) to improve oral bioavailability of Nintedanib esylate (NE) via lymphatic uptake. The NE loaded NLCs (NE-NLCs) were fabricated using high speed homogenization followed by probe sonication method and physiochemically characterized. The NE-NLCs had particle size of 125.7 +/- 5.5 nm, entrapment efficiency of 88.5 +/- 2.5% and zeta potential of -17.3 +/- 3.5 mV. DSC and XRD studies indicated that NE was converted to amorphous form. TEM images showed uniformly distributed spherical shaped particles. In vitro release study of NE-NLCs showed drug release of 6.87 +/- 2.72% in pH 1.2 and 92.72 +/- 3.40% in phosphate buffer pH 6.8 and obeyed higuchi model. Lipolysis study showed higher amount of drug in aqueous layer in NE-NLCs compared to NE-suspension. Tissue distribution study showed deeper penetration of FITC loaded NLCs compared to FITC solution. The cellular uptake across Caco-2 cells exhibited more uptake of FITC loaded NLCs. Cytotoxicity study using A549 cell line revealed higher potential of NE-NLCs in inhibiting tumor cell growth in comparison to that of suspension. The oral bioavailability of NE was ameliorated over 26.31 folds after inclusion into NLCs in contrast to NE-suspension. Intestinal lymphatic uptake of NE-NLCs in cycloheximide treated mice was lower as compared to control without cycloheximide treatment. Thus, the developed NE-NLCs can be an encouraging delivery strategy for increasing oral bioavailability of NE via lymphatic uptake.
查看更多>>摘要：Objective: Pyrotinib, a new oral irreversible pan-ErbB tyrosine kinase inhibitor (TKI), has been approved in China for the treatment of HER2-positive advanced or metastatic breast cancer. This study aimed to conduct a population pharmacokinetics (PK) analysis of pyrotinib and to evaluate the impact of patient characteristics on pyrotinib's PK.
查看更多>>摘要：The safety problem of injections caused by clarity has lately become a widely shared concern. Due to the synthesis process, polysorbate 80 had a wide molecular weight distribution, which is also related to the clinical anaphylaxis. In this paper, ultrasonic-assisted ultrafiltration (UAU) technology was firstly applied to regulate colloidal structure and remove macromolecules from polysorbate 80 to improve injection clarity. In the separation process, ultrafiltration molecular weight cut off (MWCO), ultrasonic power and polysorbate 80 concentraion were selected as variables to adjust the separation efficiency. The ultrasonic frequency and power were provided by KQ-700DE ultrasonic system, based on the data analysis by response surface methodology (RSM), the optimal UAU parameters were as follows: ultrafiltration MWCO of 50,000, ultrasonic power of 900 W and polysorbate 80 concentration of 15.00 mg/mL. The experimental transmittance of polysorbate 80 was 87.6% and the qualification rate of clarity was 94.5%, which solved the separation contradiction among yield, clarity and safety. As an innovation in colloidal separation fields, UAU had a vast range of prospects for making use in pharmaceutical area.
查看更多>>摘要：Purpose: The objective of this study was to describe the pulmonary targeting of beclomethasone dipropionate (BDP) and its active metabolite beclomethasone 17-monopropionate (BMP) in rats using a semi-mechanistic PK/PD model.
查看更多>>摘要：The interaction between anticancer drugs and HSA may have a significant impact on the pharmacology and efficacy of drugs. Drugs change the binding properties of HSA by regulating the quenching mechanism, binding mode and binding affinity. In this study, the interactions of cisplatin (cDDP), HSA, and daphnoretin were elucidated by multi-spectroscopic analyses and docking simulation. Fluorescence quenching showed that cDDP could not change the static quenching mechanism of HSA-daphnoretin, but could enhance their binding affinity. Site competition experiments revealed that daphnoretin and cDDP both bound to site I, which was consistent with the results of molecular docking. Thermodynamic date indicated that cDDP and daphnoretin formed a more stable complex with HSA via hydrophobic, van der Waals interaction and hydrogen bond. Three-dimensional fluorescence and circular dichroism spectra showed that cDDP changed the conformation and micro-environment of HSA induced by daphnoretin. This work could provide valuable information for the binding properties and interaction among cDDP, daphnoretin and HSA, and put forward the possibility of using HSA as a multidrug carrier.
Matarazzo, Ananda PuliniElisei, Livia Maria SilvestreCarvalho, Flavia ChivaBonfilio, Rudy...
11页
查看更多>>摘要：The therapeutic potential of cannabidiol (CBD) has been explored to treat several pathologies, including those in which pain is prevalent. However, the oral bioavailability of CBD is low owing to its high lipophilicity and extensive first-pass metabolism. Considering the ability of the nasal route to prevent liver metabolism and increase brain bioavailability, we developed nanostructured lipid carriers (NLCs) for the nasal administration of CBD. We prepared particles with a positively charged surface, employing stearic acid, oleic acid, Span 20 (R), and cetylpyridinium chloride to obtain mucoadhesive formulations. Characterisation of the CBD-NLC dispersions showed uniform nano-sized particles with diameters smaller than 200 nm, and high drug encapsulation. The mucoadhesion of cationic particles has been related to interactions with negatively charged mucin. Next, we added in-situ gelling polymers to the CBD-NLC dispersion to obtain a CBD-NLC-gel. A thermo-reversible in-situ forming gel was prepared by the addition of Pluronics (R). CBD-NLC-gel was characterised by its gelation temperature, rheological behaviour, and mucoadhesion. Both formulations, CBD-NLC and CBD-NLC-gel, showed high mucoadhesion, as assessed by the flow-through method and similar in vitro drug release profiles. The in vivo evaluation showed that CBD-NLC dispersion (without gel), administered intranasally, produced a more significant and lasting antinociceptive effect in animals with neuropathic pain than the oral or nasal administration of CBD solution. However, the nasal administration of CBD-NLC-gel did not lessen mechanical allodynia. These findings demonstrate that in-situ gelling hydrogels are not suitable vehicles for highly lipophilic drugs such as CBD, while cationic CBD-NLC dispersions are promising formulations for the nasal administration of CBD.
查看更多>>摘要：Among drugs in development and/or in market, there are poorly water-soluble and poorly lipid-soluble compounds. Rebamipide, classified into BCS class IV, is one of those drugs which provide very low bioavailability and/or the difficulty of formulation for oral administration. Because of its low solubility in available lipoidal excipients, it was impossible to prepare an adequate SNEDDS formulation of rebamipide. Then, we tried to increase the solubility of rebamipide in lipoidal excipients for preparing a more practical SNEDDS formulation by making the complex with its counter ion, tetrabutylphosphonium hydroxide (TBPOH) or NaOH. Rebamipide concentration in ethanol was proportionally increased with the increment of TBPOH or NaOH added, indicating that the formation of complex with a counter ion should contribute to the solubilization of rebamipide in ethanol. Both Rebamipide-TBPOH complex (Reb-TBPOH) and Rebamipide-NaOH complex (Reb-NaOH) obtained by lyophilization showed no endothermic peak in DSC and no diffraction peak in XRPD, suggesting that the solid state of both complexes should be amorphous. Reb-TBPOH maintained the dissolution of rebamipide in SNEDDS vehicle (Capryol 90:Cremophor EL:Transcutol P = 4:3:3) at 20 mg/g at least for 28 days, while Reb-NaOH did it at 10 mg/g. In vitro dissolution study showed that Reb-TBPOH SNEDDS and Reb-NaOH SNEDDS containing rebamipide at 10 mg/g maintained the complete dissolution of rebamipide in FaSSIF (intestinal luminal condition). In the gastric luminal condition (pH3.9 acetate buffer), the high concentration, close to the complete dissolution, was transiently observed and quickly decreased to one-sixth of the maximum, but it was still around 70 times higher than that of the crystalline powder. The additional utilization of Eudragit EPO for SNEDDS preparations of both complexes successfully maintained the high concentrations of rebamipide in the gastric luminal condition. In vivo oral absorption studies clearly indicated that SNEDDS preparations utilizing Rebcounter ion complex successfully improved rebamipide absorption.
Shiels, Ryan G.Hewage, WenuVidimce, JosifPearson, Andrew G....
10页
查看更多>>摘要：Background and purpose: Biliverdin (BV) administration induces antioxidant and anti-inflammatory effects, with previous reports also identifying anti-anaphylactic potential. Interestingly however, intra-duodenal administration of BV in rats leads to the formation of bilirubin-10-sulfonate (BRS), which might be responsible for BV's purported effects.
查看更多>>摘要：An increasing resistance of human pathogenic bacteria and fungi has become a global health problem. Based on previous reports of 4-(salicylideneamino)benzoic acids, we designed, synthesised and evaluated their me-too analogues as potential antimicrobial agents. Forty imines derived from substituted salicylaldehydes and aminobenzoic acids, 4-aminobenzoic acid esters and 4-amino-N-phenylbenzamide were designed using molecular hybridization and prodrug strategies. The target compounds were synthesized with high yields and characterized by spectral methods. They were investigated against a panel of Gram-positive and Gram-negative bacteria, mycobacteria, yeasts and moulds. The most active imines were tested to determine their cytotoxicity and selectivity in HepG2 cells. Dihalogenosalicylaldehydes-based derivatives showed potent broad-spectrum antimicrobial properties, particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 7.81 mu M) and Enterococcus faecalis (MIC of >= 15.62 mu M), yeasts (MIC from 7.81 mu M) and Trichophyton interdigitale mould (MIC of >= 3.90 mu M). Methyl 4-[(2-hydroxy-3,5-diiodobenzylidene)amino] benzoate 4h exhibited excellent in vitro activity along with low toxicity to mammalian cells. This compound is selective for staphylococci, Candida spp. and Trichophyton interdigitale. In addition, this imine was evaluated as a potential inhibitor of Gram-positive biofilms. The successful approach used provided some promising derivatives with more advantageous properties than the parent 4-(salicylideneamino) benzoic acids.
NSTL
Elsevier