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??OBJECTIVE To prepare atorvastatin-loaded tetracycline-PEG-PLGA(TC-PEG-PLGA/ATO) polymeric micelles, and investigate its pharmaceutical characteristics and targeting function in vitro. METHODS The amphiphilic TC-PEG-PLGA conjugate was synthesized via an esterification reaction and identified by the ¹H-NMR. Water insoluble atorvastatin was loaded on TC-PEG-PLGA conjugate micelles via dialysis method. The morphology of TC-PEG-PLGA/ATO micelles was observed under transmission electron microscope. The particle size distribution and Zeta potential of TC-PEG-PLGA/ATO micelles were determined by dynamic light scattering method. The drug loading and encapsulation efficiency were measured by HPLC, and in vitro release behavior was investigated via dialysis method. In vitro cytotoxicity was assessed via MTT assay, and bone-targeting activity was investigated via binding to the hydroxyapatite powder. RESULTS TC-PEG-PLGA/ATO micelle was prepared successfully, and its particle size and Zeta potential were (47.2??4.7) nm and (-14.25??0.31) mV. The encapsulation efficiency and drug loading rate were(98.2??1.51)% and (8.71??0.23)%, respectively. Moreover, the accumulative release of ATO in vitro was about 70% in 48 h, which indicated that the drug was released slowly from the micelles. In vitro cell evaluation showed that TC-PEG-PLGA conjugate micelles were great biocompatibility with MC3T3-E1 cells within the concentration range of 100-500 ??g??mL^-1. In vitro targeting performance indicated that the proportion of the TC-PLGA NPs bound to Hap(87.94%) was greater than the bound proportion of PLGA NPs(18.59%). CONCLUSION The TC-PEG-PLGA/ATO micelles exhibit small partical size and good stability, and significantly increased ATO content in aqueous solution. TC-PEG-PLGA/ATO micelles have good delayed release behavior, safety and binding efficacy to the hydroxyapatite powder.     

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??OBJECTIVE To prepare and optimize meloxicam nanosuspensions fast dissolving sublingual films (MLX-NS-FDSFs) and to evaluate its in vitro dissolution characteristics. METHODS Meloxicam nanosuspensions (MLX-NS) were prepared by pH-dependent dissolving-precipitating/high speed shearing method and then transformed into fast dissolving sublingual films (FDSFs). The formulations of MLX-NS-FDSFs were optimized by employing Box-Behnken design-response surface methodology with the amount of HPMC-E30, PEG-400 and MLX-NS as investigation factors, and particle size of reconstituted nanoparticles from MLX-NS-FDSFs, disintegration time and stretch length as indexes. The morphology, content uniformity and in vitro dissolution of the optimal formulation were also evaluated. RESULTS The MLX-NS-FDSFs prepared by optimized formulation (35 mg??mL^-1 HPMC-E30, 40 mg??mL^-1 PEG-400, 10 mL MLX-NS) could fast disintegrate in (26.08??1.76) s, the tensile length was (1.51??0.13) mm, and the particle size of reconstituted nanoparticles from MLX-NS-FDSFs was (186.4??6.3) nm. There was a little deviation between the theoretically predicted value and the measured value. It showed that this model had a good prediction. Morphological analysis showed that well-dispersed MLX nanoparticles embedded in MLX-NS-FDSFs. The conformity of drug content was up to standard. MLX could be released in vitro as much as (91.75??8.05)% within five minutes. CONCLUSION Using Box-Behnken design and response surface method to optimize MLX-NS-FDSFs is effective and feasible. MLX-NS-FDSFs can significantly increase the cumulative dissolution of MLX.     

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??OBJECTIVE To discuss whether the difference in dissolution profile in vitro may cause different bioavailability in vivo and investigate the effects of the key quality parameters of leflunomide on bioavailability.METHODS Using SANOFI product as the reference preparation and domestic product as the test preparation, the disintegration solution of leflunomide tablets was analyze by Morphologi G3-ID automated measurement to get the paricile size and size distribution of the API; using pH 6.5 FaSSIF solution without adding ox-gall sulfonic acid sodium and lecithin as the dissolution medium, the dissolution and permeation profiles of the reference and test preparations and raw material were compared at 37 ?? with rotate speed of 150 r??min^-1. The influence of quality parameters on the process of API??s release and absorption was investigated, then the difference between the reference and test preparations were compared to preliminarily predict the bioavailability and bioequivalence.RESULTS The particle size Dv(50)of domestic leflunomide tablets was 79.80 ??m, while the particle size Dv(50)of the reference product was 17.60 ??m; the dissolution rate and penetration rate of the test preparation were about 70% of the the reference preparation, the t_max was basically identical,but the ??_max and AUC_0-t were lower than the reference preparation. The bioavailability of the test preparation was about 90% of the reference preparation.CONCLUSION Though the dissolution profile of domestic leflunomide tablets is not identical to the reference preparation, but the two products were predicted to be bioequivalent.     

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??OBJECTIVE To prepare lappaconitine(LA)-loaded chitosan/ sodium ??-glycerophosphate(CS/??-GP) thermosensitive hydrogels and investigate its phase transition mechanism of gel formation process and release properties in vitro. METHODS The injectable CS/??-GP thermosensitive hydrogels were prepared with biodegradable CS as carrier material and ??-GP as coagulation accelerator. The release behavior in vitro was studied by dynamic dialysis, and the phase transition mechanism of gel formation process was further investigated by rheological method. RESULTS The optimized process condition was as follows:the concentration of ??-GP and CS was 560 and 22 mg??mL^-1, respectively, CS was dissolved by 0.1 mol??L^-1 HOAc, and the valume ratio of CS to ??-GP was 8.75??1.25(V/V), the gelation time of CS/??-GP thermosensitive hydrogels with volume ratio of 8.75??1.25(V/V) at 37 ?? was 5 min 38 s. The in vitro release study showed that these injectable CS/??-GP thermosensitive hydrogels had sustained release effect for LA, and the release behavior could be well described by the Higuchi model and Korsmeyer-Peppas model. The mechanism of LA releasing from CS/??-GP thermosensitive hydrogels was attributed to drug dissolution and diffusion. Rheological studies showed that the CS/??-GP thermosensitive hydrogels belonged to thixotropic system and exhibited non-Newtonian and shear-thinning fluid behavior as well as ??solid-like?? gelatin behavior. CONCLUSION LA-Loaded CS/??-GP injectable thermosensitive hydrogels with good elasticity and gel strength properties are prepared successfully, and they show sustained release effect of LA in vitro.     

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??OBJECTIVE To prepare coenzyme Q₁₀-??-cyclodextrin nano-crystal suspension using high pressure homogeneous combining freeze-drying method, optimize the preparation technology, and evaluate the quality of the product. METHODS Encapsulation efficiency and mean particle size of inclusion complex were used as indicators, and response surface method was performed for optimizing preparation process and formulations. The stability and transdermal performance in vitro of the inclusion complexes were investigated. RESULTS The optimal technical parameters were as follows: the mass ratio of ??-cyclodextrin and drug, 7.76??1; ultrasonic temperature, 40 ??; ultrasonic time, 28.33 min; homogeneous pressure, 40MPa. Under such conditons, an average encapsulation efficiency of 48.39% and average particle size of 324nm were obtained for the nano-crystal suspension. The transdermal experiment in vitro showed that the infiltration rate of inclusion was 5.68 ??g??cm^-2??h^-1. CONCLUSION The preparation method is simple and feasible. The product quality is stable. Moreover, it is easy to manufacture.     

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??OBJECTIVE To improve the dissolution rate of fenofibrate (FNB) by using starch source mesoporous carbon (SMC) as a carrier and achieve controlled release of the drug by utilizing double-layer osmotic pump technology to improve the oral bioavailability. METHODS FNB was loaded into the mesoporous of NMS by adsorption method to prepare the drug loading system (FNB-SMC). Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXDR) were used to characterize the present state of the drug before and after being loaded. The dissolution rate of FNB-SMC was investigated by in vitro dissolution test, and the formulation of the double-layer osmotic pump tablets of FNB-SMC was optimized. The oral bioavailability of the self-made tablet was investigated by in vivo experiment in rabbits. RESULTS FNB existed in the mesoporous of SMC in an amorphous state. The in vitro dissolution test showed that NMS could significantly increase the dissolution rate of FNB, and the double-layer osmotic pump technology could achieve Zero-order release of the drug. The in vivo experiments showed that the oral bioavailability of the self-made tablets was significantly improved. CONCLUSION The combination of starch source mesoporous carbon carrier and double-layer osmotic pump technology prevente the burst effect and significantly improve the oral absorption of FNB.     

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??OBJECTIVE To prepare the tulobuterol crystal reservoir patch, and to evaluate morphology, stability and crystallization factors of the crystal in the patch, adhesive force, dissolution, transdermal properties in vitro and the pharmacokinetics in rabbits. METHODS The transdermal patch was prepared on the basis of drug recrystallization and characterized by morphology, stability and crystallization factors using microscope and adhesive force using initial adhesion tester, adhesion tester and peel tester. The dissolution and transdermal properties were evaluated by using the dissolution tester and transdermal tester. In addition, pharmacokinetics was studied using New Zealand rabbits as experimental animals. RESULTS The drug crystals were evenly distributed in the form of filaments, which had average width of (4.4??1.8)??m and kept stable at 2-40 ??. The crystallization in patches is affected by tulobuterol supersaturation and temperature. The adhesive force of patch was suitable and its dissolution matched standard which can be fitted by the Higuchi equation. In the diffusion cell in vitro, the drug penetrated through the skin in a Zero-order kinetic equation, and the cumulative penetration percentage and skin retention concentration were 92.04% and 10.36 ??g??cm^-2 with in 24 h. The pharmaceutic parameters showed that the tulobuterol blood concentration can be maintained within 24 h, whose t_max and ??_max were (6.67??3.06)h and (3.08??1.32) ng??mL^-1, respectively. CONCLUSION The tulobuterol crystal reservoir patch can be established by control of recrystallization conditions. The patch has good adhesive properties and sustained release characteristics in vitro and in vivo, which has the practical significance for further study.     

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??OBJECTIVE To study the preparation of carboxylated multi-walled carbon nanotubes loaded with podophyllotoxin (PPT-CNTs-COOH) as well as the characteristics of the in vitro transdermal penetration.METHODS PPT-CNTs-COOH was prepared by freezing milling method; IR, UV, XRD, and TGA were used to characterize the PPT-CNTs-COOH; HPLC method was used for determination of the content of podophyllotoxin loaded in the carboxylated multi-walled carbon nanotubes; franze diffusion cells method was used to determine the drug transdermal penetration rate.RESULTS The IR spectrum of PPT-CNTs-COOH showed the main absorption peaks of PPT and CNTs-COOH and the peaks changed obviously. Compared with free PPT, the UV absorption peaks of PPT-CNTs-COOH changed obviously. The PPT content in the CNTs-COOH gel was 58.0 ??g??mg^-1; the transdermal penetration rate of PPT gel was 7.08 ??g??cm^-2??h^-1 and that of the PPT-CNTs-COOH gel was 3.03 ??g??cm^-2??h^-1; the skin retention of PPT-CNTs-COOH gel was 3.04 ??g??cm^-2, far less than the 1.52 ??g??cm^-2 of PPT gel. Mild irritation developed within 24 h following removal of the PPT-CNTs-COOH gel, and disappears after 72 h.CONCLUSION Podophyllotoxin can successfully be loaded into the carboxylated multi-wall carbon nanotubes by using the frozen ball milling method. The product has remarkable sustained release effect in vitro and high retention in skin, which is beneficial to transdermal delivery.