Preparation and in vitro evaluation of albumin nanoparticles produced by thermal driven self-assembly / 中国药科大学学报

@#The aim of this study was to prepare albumin nanoparticles by thermal driven self-assembly, and to investigate the formation mechanism, cellular uptake, the kinetics of cellular uptake and intracellular degradation, etc. By measuring the concentrations of thiol, amino and carboxyl groups, the formation mechanism of albumin nanoparticles was revealed. CCK-8 assay was performed to detect the cytotoxicity; inverted fluorescence microscope was used to observe the cellular uptake of the nanoparticles; while the fluorescence resonance energy transfer(FRET)method was applied to investigate the cellular uptake and intracellular degradation kinetics. The drug-loading capacity was investigated using paclitaxel(PTX)as the model drug. The results showed that the albumin nanoparticles produced by thermal driven self-assembly were safe, nontoxic, biodegradable and stabilized by intermolecular disulfide and amide bonds. The drug-loading study indicates that PTX can be highly encapsulated in the nanoparticles. Hence, thermal driven self-assembly method is green and easy to operate, and the albumin nanoparticles can be applied as a new delivery platform for anticancer drugs.

Formulation and process optimization of doxorubicin-loaded PLGA nanoparticles and its in vitro release / 药学学报

Doxorubicin-loaded PLGA nanoparticles (DOX-PLGA NPs) was prepared by double emulsion (W/O/W) solvent evaporation method with the biodegradable materials-poly (lactic-co-glycolic acid) (PLGA) used as carrier materials. Single-factor test was used to investigate the influence of the type and ratio of the organic phase, the amount of surfactant, PLGA concentration, the ratio of external water phase and oil phase (W/O), the ratio of doxorubicin and PLGA, ultrasonic time and stirring time on the preparation of nanoparticles. The best formulation and preparation conditions were optimized by orthogonal test based on single-factor test, evaluation indicator as particle size and entrapment efficiency, and the results were analyzed by overall desirability. And the in vitro release behaviors of the nanoparticles were studied as well. The size distribution, zeta potential, morphology of DOX-PLGA NPs were characterized by laser light scattering and transmission electron microscopy; encapsulation efficiency and releasing behavior of DOX-PLGA NPs in vitro were investigated by ultraviolet spectrophotometry. The results show that the DOX-PLGA NPs are regularly spherical in shape with the mean size of (189.2 +/- 5.3) nm, and the zeta-potential of the NPs is about (-28.32 +/- 0.52) mV. Drug loading and encapsulation efficiency are estimated to be (73.16 +/- 0.43) % and (1.51 +/- 0.07) %, respectively. The cumulative percentage of the drug released is 90.34%, and the in vitro release behavior made up of initial burst release and sustained-release could be described by the bidirectional kinetic equation. The results indicate that hydrophilic small-molecule drugs could be successfully entrapped into PLGA-NPs. With optimization of the formulation and preparation conditions, we obtained uniform and stable DOX-PLGA NPs with sustained release character in vitro and pH-sensitive property, which could provide the experimental basis for the development of a new anti-tumor sustained-release formulation.

A new mathematical equation for the evaluation of the compression behavior of pharmaceutical materials / 药学学报

A new mathematical equation characterizing the compression of pharmaceutical materials is presented. This equation presumed that the rate of change of the compressible volume of powder with respect to the pressure is proportional to the compressible volume. The new model provided a good fit to several model substances employing non-linear regression techniques. The validity of the model had been verified with experimental results of various pharmaceutical powders according to the Akaikes informatics criterion (AIC) and the sum of squared deviations (SS). The parameter of the new model might reflect quantitatively the fundamental compression behaviors of the powders. It had demonstrated that the proposed model could well predict the compaction characteristics of solid particles like the Kawakita model.

Preparation of polyelectrolyte microcapsules containing ferrosoferric oxide nanoparticles / 药学学报

In this study, polyelectrolyte microcapsules have been fabricated by biocompatible ferrosoferric oxide nanoparticles (Fe3O4 NPs) and poly allyamine hydrochloride (PAH) using layer by layer assembly technique. The Fe3O4 NPs were prepared by chemical co-precipitation, and characterized by transmission electron microscopy (TEM) and infrared spectrum (IR). Quartz cell also was used as a substrate for building multilayer films to evaluate the capability of forming planar film. The result showed that Fe3O4 NPs were selectively deposited on the surface of quartz cell. Microcapsules containing Fe3O4 NPs were fabricated by Fe3O4 NPs and PAH alternately self-assembly on calcium carbonate microparticles firstly, then 0.2 molL(-1) EDTA was used to remove the calcium carbonate. Scanning electron microscopy (SEM), Zetasizer and vibrating sample magnetometer (VSM) were used to characterize the microcapsule's morphology, size and magnetic properties. The result revealed that Fe3O4 NPs and PAH were successfully deposited on the surface of CaCO3 microparticles, the microcapsule manifested superparamagnetism, size and saturation magnetization were 4.9 +/- 1.2 microm and 8.94 emu x g(-1), respectively. As a model drug, Rhodamin B isothiocyanate labeled bovine serum albumin (RBITC-BSA) was encapsulated in microcapsule depended on pH sensitive of the microcapsule film. When pH 5.0, drug add in was 2 mg, the encapsulation efficiency was (86.08 +/- 3.36) % and the drug loading was 8.01 +/- 0.30 mg x m(L-1).

Chitosan-coated ophthalmic submicro emulsion for pilocarpine nitrate / 药学学报

The study is to design chitosan-coated pilocarpine nitrate submicro emulsion (CS-PN/SE) for the development of a novel mucoadhesive submicro emulsion, aiming to prolong the precorneal retention time and improve the ocular absorption. CS-PN/SE was fabricated in two steps: firstly, pilocarpine nitrate submicro emulsion (PN/SE) was prepared by high-speed shear with medium chain triglycerides (MCT) as oil phase and Tween 80 as the main emulsifier, and then incubated with chitosan (CS) acetic solution. The preparation process was optimized by central composite design-response surface methodology. Besides the particle size, zeta potential, entrapment efficiency and micromorphology were investigated, CS-PN/SE's precorneal residence properties and miotic effect were especially studied using New Zealand rabbits as the animal model. When CS-PN/SE was administered topically to rabbit eyes, the ocular clearance and the mean resident time (MRT) of pilocarpine nitrate were found to be dramatically improved (P < 0.05) compared with PN/SE and pilocarpine nitrate solution (PNs), since the K(CS-PN/SE) was declined to 0.006 4 +/- 0.000 3 min(-1) while MRT was prolonged up to 155.4 min. Pharmacodynamics results showed that the maximum miosis of CS-PN/SE was as high as 46.3%, while the miotic response lasted 480 min which is 255 min and 105 min longer than that of PNs and PN/SE, respectively. A larger area under the miotic percentage vs time curve (AUC) of CS-PN/SE was exhibited which is 1.6 folds and 1.2 folds as much as that of PNs and PN/SE, respectively (P < 0.05). Therefore, CS-PN/SE could enhance the duration of action and ocular bioavailability by improving the precorneal residence and ocular absorption significantly.

Ion-sensitive nanoemulsion-in situ gel system for ophthalmic delivery of flurbiprofen axetil / 药学学报

The aim of the study is to prepare flurbiprofen axetil nanoemulsion-in situ gel system (FBA/NE- ISG) and observe its ocular pharmacokinetics, rheological behavior, TEM images, irritation and cornea retention. Production of nanoemulsion was based on high-speed shear and homogenization process, and then mixed with gellan gum to prepare FBA/NE-ISG. Rheological study showed that FBA/NE-ISG possesses strong gelation capacity and its viscosity and elastic modulus increases by 2 Pa?s and 5 Pa respectively when mixed with artificial tear at the ratio of 40∶7. TEM images suggested no significant changes in particle morphology of the pre and post gelation. Good ocular compatibility of FBA/NE-ISG was testified by the irritation test based on histological examination. In vivo fluorescence imaging system was applied to investigate the characteristics of cornea retention, and the results indicated that the nanoemulsion-in situ gel (NE-ISG) prolonged the cornea retention time significantly since KNE-ISG (0.008 5 min-1) was much lower compared with flurbiprofen sodium eye drops (FB-Na, 0.03% w/v) of which the KEye drops was 0.105 2 min-1, indicated that the cornea retention time of NE-ISG was prolonged significantly. Pharmacokinetics of FBA/NE-ISG in rabbit aqueous humor was studied by cornea puncture, the MRT (12.3 h) and AUC0→12 h (126.8 ?g?min?mL-1) of FBA/NE-ISG was 2.7 and 2.9 times higher than that of the flrubiprofen sodium eye drops respectively, which meant that the ocular bioavailabilitywas improved greatly by the novel preparation. Therefore, FBA/NE-ISG can enhance the ocular bioavailability by prolonging drug corneal retention significantly. What’s more, encapsulated by emulsion droplets prodrug flurbiprofen (FBA) instead of flurbiprofen (FB) can reduce the ocular irritation.

Preparation of cationic dextran microspheres loaded with tetanus toxoid and study on the mechanism of protein loading / 药学学报

The aim of this study is to prepare cationic biodegradable dextran microspheres loaded with tetanus toxoid (TT) and to investigate the mechanism of protein loading. Positively charged microspheres were prepared by polymerization of hydroxylethyl methacrylate derivatized dextran (dex-HEMA) and dimethyl aminoethyl methacrylate (DMAEMA) in an aqueous two-phase system. The loading of the microspheres with TT was based on electrostatic attraction. The net positive surface charge increased with increasing amounts of DMAEMA. Confocal images showed fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) could penetrate into cationic dextran microspheres but not natural dextran microspheres. TT loading efficiency by post-loading was higher compared with by pre-loading. Even though TT is incorporated in the hydrogel network based on electrostatic interaction, still a controlled release can be achieved by varying the initial network density of the microspheres.

Preparation of polyelectrolyte microcapsules contained gold nanoparticles / 药学学报

In this work, polyelectrolyte microcapsules containing gold nanoparticles were prepared via layer by layer assembly. Gold nanoparticles and poly (allyamine hydrochloride) (PAH) were coated on the CaCO3 microparticles. And then EDTA was used to remove the CaCO3 core. Scanning electron microscopy (SEM) was used to characterize the surface of microcapsules. SEM images indicate that the microcapsules and the polyelectrolyte multilayer were deposited on the surface of CaCO3 microparticles. FITC-bovine serum albumin (FITC-BSA, 2 mg) was incorporated in the CaCO3 microparticles by co-precipitation. Fluorescence microscopy was used to observe the fluorescence intensity of microcapsules. The encapsulation efficiency was (34.31 +/- 2.44) %. The drug loading was (43.75 +/- 3.12) mg g(-1).

Ion-sensitive nanoemulsion-in situ gel system for ophthalmic delivery of flurbiprofen axetil / 药学学报

The aim of the study is to prepare flurbiprofen axetil nanoemulsion-in situ gel system (FBA/NE-ISG) and observe its ocular pharmacokinetics, rheological behavior, TEM images, irritation and cornea retention. Production of nanoemulsion was based on high-speed shear and homogenization process, and then mixed with gellan gum to prepare FBA/NE-ISG. Rheological study showed that FBA/NE-ISG possesses strong gelation capacity and its viscosity and elastic modulus increases by 2 Pa*s and 5 Pa respectively when mixed with artificial tear at the ratio of 40 : 7. TEM images suggested no significant changes in particle morphology of the pre and post gelation. Good ocular compatibility of FBA/NE-ISG was testified by the irritation test based on histological examination. In vivo fluorescence imaging system was applied to investigate the characteristics of cornea retention, and the results indicated that the nanoemulsion-in situ gel (NE-ISG) prolonged the cornea retention time significantly since K(NE-ISG) (0.008 5 min(-1) was much lower compared with flurbiprofen sodium eye drops (FB-Na, 0.03% w/v) of which the K(Eye drops) was 0.105 2 min(-1), indicated that the cornea retention time of NE-ISG was prolonged significantly. Pharmacokinetics of FBA/NE-ISG in rabbit aqueous humor was studied by cornea puncture, the MRT (12.3 h) and AUC(0-12h) (126.8 microg x min x mL(-1)) of FBA/NE-ISG was 2.7 and 2.9 times higher than that of the flurbiprofen sodium eye drops respectively, which meant that the ocular bioavailability was improved greatly by the novel preparation. Therefore, FBA/NE-ISG can enhance the ocular bioavailability by prolonging drug corneal retention significantly. What's more, encapsulated by emulsion droplets prodrug flurbiprofen (FBA) instead of flurbiprofen (FB) can reduce the ocular irritation.

Synthesis of N-acyl chitosan derivatives and investigation of chitosan-modified docetaxel liposomes in vitro / 中国药科大学学报

Aim: Synthesized N-acylated chitosan(NAC) was used to anchor on the surface of plain docetaxel li-posomes( PDL) in order to to sustain drug release. Methods; NAC of low substitution degrees were prepared using hexanoic(C_6), lauric( C_(12)), and palmitic( C_(16)) anhydrides. W-palmitoyl chitosan was chosen to anchor the do-cetaxel liposomes. In vitro release profiles of conventional liposmes and the anchored liposomes was compared. Results: Hexanoic(C_6), lauric( C_(12)), and palmitic( C_(16)) -branched chitosans were synthesized. It was found that N-acylated chitosan-anchored DXL liposomes (NDL) increase stabilities of docetaxel liposomes. 70% of docetaxel was released from PDL in 24 hours but 39% from NDL Conclusion: Liposomes anchored by the low substituted N-acylated chitosan could decrease the drug release.

Preparation and characterization of aqueous polymer dispersions with high flexibility for coating / 中国药科大学学报

Aim: To prepare novel aqueous polymer dispersions with high flexibility for sustained-release coating and investigate their properties. Methods: The aqueous polymer dispersions were synthesized by the emulsion polymerization. The physico-chemical properties and film-forming potential of the dispersions were investigated while the mechanical properties of the formed film and the drug release behavior when atenolol pellets were coated with the aqueous polymer dispersions were evaluated. Results: The prepared aqueous polymer dispersions (methyl methacrylate/ethyl acrylate, 1:2) were found to have proper physico-chemical properties, excellent film-forming capability and satisfying mechanical properties. It could form free film with high flexibility and low viscosity in low temperature even in absence of the plasticizer. Sustained release of atenolol pellets was achieved when the pellets were coated the polymer dispersions. 4-h and 8-h cumulative releases were more than 50% and 80%, respectively. There was no significant difference in release between pellets prior to and post compression of the coated pellets. Conclusion: The resulting aqueous polymer dispersions could be used as sustained-release coating material with high flexibility suitable for tableting.

Ocular pharmacokinetics of dexamethasone cubosomes in rabbit aqueous humor / 中国药科大学学报

Aim: To prepare novel cubosome system for effective ocular drug delivery with dexamethasone(DEX) as model drug, and investigate its pharmacokinetic profile in rabbit aqueous humor. Methods: DEX cubosomes was prepared by the method of high-pressure homogenization, and its particle size was determined by the laser particle sizer, and the microstructure observed by cryo-TEM. In addition, Draize method was used to evaluate the ocular irritation of DEX cubosomes. Finally, aqueous humor microdialysis was utilized to evaluate its pharmacokinetics in rabbits. Results: Average diameter of DEX cubosomes was about 200 nm, and the cubic structure of the particles was evident under the cryo-TEM. It was indicated by Draize scores that this dosage form exhibited excellent ocular tolerance. Results of pharmacokinetic profiles in aqueous humor showed that AUC_(0→240) and c_(max) of the rabbit group administered with DEX cubosomes were significantly higher than those of the control group( DEX sodium phosphate eye drops), with AUC_(0→240) of the formulation Fl( 10% oil content) and F2(20% oil content) is being about 1. 8 and 2. 9 times higher than those of the control group, respectively( P <0. 05). Conclusion: The novel ocular drug delivery system of DEX cubosomes was capable of increasing significantly the drug concentration in aqueous humor, and improving the ocular bioavailability.

Effect of Nimodipine Liposomes for Injection on Focal Cerebral Ischemia/Reperfusion Injury in Rats / 国际脑血管病杂志

Objective:To investigate the effect of nimodipine liposomes for injection(NOLI)on focal cerebral ischemia/reperfusion(I/R)injury in rats.Methods:Seventy SD rats were divided into NDLI 1.00 mg/kg,NDLI 0.50 mg/kg,NDLI 0.25 mg/kg,nimodipine 1.00mg/kg,solvent 10 mL/kg,sham-operation and ischemic model groups.The model of middle cerelral artery occlusion in rat was replicated.The behavioral scores in rats were assessed in all groups.The infarct volume,brain water content,biochemical indices of brain homogenate and histology were detected.Results:1he NDLI 1.00mg/kg,0.50 mg/kg and 0.25 mg/kg groups could significantly improve the behavior scores in focal cerebral ischemic rats,reduce the volume of cerebral infarction,decrease the brain water content,improve the activities of Na+,K+-ATPase,Ca2+-ATPase,glutathione(GSH)and superoxide dismutazse(SOD)in brain tissues,reduce conteras of malondialdehyde(MDA),lactic acid(LA)and nitric oxide(NO),and improve histo logical injury.Conclusions:NDLI has the protective effect on focal cerebral ischemia/reperfusion injury in rats.

Deposition of insulin powders for inhalation in vitro and pharmacodynamic evaluation of absorption promoters in rats / 药学学报

Aim To prepare insulin powder for inhalation by spray-drying technology, determine the deposition of the insulin powder formulation in vitro and preliminarily investigate hypoglycemic response of the dry powder with/without absorption promoters. Methods The depositions of the insulin powder for inhalation were determined by the China Pharmacopoeia 2000 version addenda XH and hypoglycemic effects were evaluated by testing serum glucose with glucose oxidase-peroxidase (GOD-PAP) method.Results The depositions of the spray-dried insulin powder for inhalation were more than 40% under significantly greater decline in blood glucose levels, while coadministration with 1% sodium caprylate, 1%effect ( P ＞ 0. 05 ). Conclusion Insulin powder for inhalation was relatively stable under various humidity pulmonary route.

Protective effects of nimodipine liposomes for injection on injuries of total cerebral ischemia/reperfusion in rats and anoxia in mice / 中国临床药理学与治疗学

AIM: To study the protective effects of nimodipine liposomes for injection (NDLI) on injuries of total cerebral ischemia/reperfusion(I/R) in rats and anoxia in mice. METHODS: Acute anoxia in mice was produced by hypoxia under normal pressure and decapitation. In these two models the survival time and persistent time of gasping were observed. Ameliorated pulsinelli four-vessel occlusion method was used to make global brain ischemia model. The EEG, the time of righting reflex recovery and Evans blue content in the homogenate of the brain tissues were recorded. RESULTS: NDLI obviously prolonged the survival time and persistent time of gasping in mice subjected to acute anoxia, remarkably shortened the time of EEG recovery and righting reflex recovery, and reduced Evens blue content in the homogenate. CONCLUSION: NDLI has significantly protective effects on injuries of total cerebral I/R and anoxia.