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??OBJECTIVE To optimize the preparation process of osthole microcapsules-temperature-sensitive gel and set up its quality standard.METHODS Using gelling temperature as the indicator,P407, P188 and the concentration of propylene glycol were investigated by single factor test,and orthogonal experiment was conducted to optimize the preparation process of osthole microcapsules-temperature-sensitive gel.Osthole content was determined by HPLC.The quality standard of osthole microcapsules-temperature-sensitive gel was established.RESULTS The optimal formulation of osthole microcapsules-temperature-sensitive gel was as followsP407-P188-propylene glycol=18%??1%??15%.Osthole contentin the osthole microcapsules-temperature-sensitive gel should not be less than 31.77 ??g??mL^-1, and the gelling temperature should be 36-37 ??.CONCLUSION Osthole microcapsules-temperature-sensitive gel prepared in this study has reasonable composition,simple preparation process, and stable quality standards,indicating a hopeful application prospect.     

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??OBJECTIVE To evaluate the physical stability of glycyrrhetinic acid derivatives-mediated coumarin 6(Cou6) liposomes and confirm the applicability of different stability tests on liposomes. METHODS Film dispersion-ultrasonic method was used to prepare Cou6 liposomes, PEG-modified liposomes and glycyrrhetinic acid-mediated liposomes. The stability constants, membrane stability, serum stability and leakages of the six kinds of liposomes were studied. RESULTS The physical stability of the liposomes without modification was poor. As for the glycyrrhetinic acid-mediated liposomes, the stability constants at 15 min were 5.37-7.32 and the concentrations of Triton X-100 were 0.207??-0.380?? when half liposome membranes were destroyed. The serum stability in 24 h and leakages in 7 or 14 d showed good stability with little change. CONCLUSION The physical stability is one of the key pharmaceutical properties of liposomes. The stability constant, serum stability and leakage tests and the method of membrane stability we have established can be used to study the stability of liposomes.     

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??Polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) are two kinds of multi-modular enzymes, which biosynthesize highly complex polyketides and nonribosonmal peptides, respectively. Both of these two secondary metabolites are of considerable pharmaceutical relevance and are thought to cover diverse biological functions. With the development of sequencing and bioinformatics, data about PKS/NRPS are increasing rapidly. New PKS/NRPS databases are created to analyze gene sequence and predict the functions and structures of natural products. In this article, we introduce five newest databases including PKMiner, NRPSsp, NaPDoS, ClusterMine360, and IMG-ABC, with the goal to help researchers choose databases.     

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??OBJECTIVE To provide a reference for enhancing the level of research and development investment of the large-scale enterprises of pharmaceutical industry by identifying what kind of internal factors influence the the research and development investment and how they do with it. METHODS The thesis empirically analyzed the relationship between research and development personnel,firm sizes,profitability, research and development knowledge outputs and the research and development investment of pharmaceutical manufacturing ,based on 1995-2014 survey data of research and development conditions and economic conditions of large enterprises of pharmaceutical manufacturing and with the use of factor regression analysis method.RESULTS R& D personnel , firm size, profitability, research and development knowledge outputs are positively correlated with R& D expenditure of pharmaceutical manufacturing,but they have little effect on research and development intensity.CONCLUSION Increasing research and development personnel ,expanding firm sizes , enhancing profitability, and promoting research and development knowledge outputs can significantly improve the R & D investment of pharmaceutical manufacturing . Government and businesses can take the appropriate incentives for different aspects ,stimulating the investment in research and innovation.     

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??OBJECTIVE To develop a supercritical fluid chromatography method for the separation of atorvastatin calcium and its enantiomer, meanwhile assaying the enantiomer. METHODS Atorvastatin calcium and its enantiomer were separated on a ACQUITY UPC² Trefoil CEL2 column(3.0 mm??150 mm, 2.5 ??m) maintained at 45 ?? with the mobile phase containing a mixture of CO₂ and methanol with 0.1% TFA(78??22, V/V) at 1.5 mL??min^-1, and the detection wavelength was set at 244 nm. The back pressure was set at 13.8 MPa. RESULTS The enantiomer and atorvastatin calcium were separated successfully in 5 min with a resolution factor of 4.1. Good linear relationship was established between the peak response and the concentration in the range of 2.5-50 ??g??mL^-1 for enantiomer(r²=0.999 9, n=6), the quantitative limit(S/N=10) was 2.5 ??g??mL^-1, and the detection limit(S/N=3) was 1.0 ??g??mL^-1. The spiked recovery of the enantiomer was 100.40%(n=9). CONCLUSION The proposed method shows high accuracy, repeatability and stability. It can be employed for the quality control and stability research of the enantiomer of atorvastatin calcium.     

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??OBJECTIVE To investigate the influence of tripterygium glucoside tablet on the pharmacokinetics of atorvastatin in rats. METHODS Twelve rats were equally randomized to two groups (six rats in each group), including the atorvastatin-only group (A) and the tripterygium glucoside tablet and atorvastatin group (B). Animals in group A were administered according the oral dose of 2 mg??kg^-1; and animals in group B were administered at an oral dose of atorvastatin (2 mg??kg^-1)and tripterygium glucoside tablet (2 mg??kg^-1). Blood samples were collected into a heparinized tube via the oculi chorioideae vein at different time points after drug administration, and the plasma concentration of atorvastatin were determined using HPLC-UV. Finally, the pharmacokinetic profiles of atorvastatin were calculated and compared. RESULTS Compared with the atorvastatin-only group(A), the pharmacokinetic parameters of the tripterygium glucoside tablet and atorvastatin group(B) have changed greatly. ??_max of atorvastatin increased from (4.77??0.64) to (7.79??0.61) mg??L^-1, and AUC_0-t increased from (12.82?? 3.50) to (27.39??5.76) mg??h??L^-1, at the same time, t_max was extended from (0.25??0.03) to (0.52??0.07) h, t_1/2 was prolonged from (2.39??0.19) to (5.09??1.35) h, MRT was extended from (2.93??0.23) to (4.36??0.44)h. It indicates that the metabolism of atorvastatin may be suppressed. CONCLUSION The RESULTS indicate that tripterygium glucoside tablet could influence the pharmacokinetics of atorvastatin when atorvastatin and tripterygium glucoside tablet are used concomitantly. This study could be used for clinical medication guidance of tripterygium glucoside tablet and atorvastatin to avoid the occurrence of adverse reactions.     

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??OBJECTIVE To introduce and compare research support for rare disease and orphan drug innovation in China and United States, and provide reference for relevant policies in China.METHODS Data of main source of funding for rare disease research in two countries ie. National Institutes of Health, Food and Drug Administration in the United States and National Natural Science Foundation of China were analyzed and compared. RESULTS US NIH gives substantial support for rare disease research every year with funded capital growing. FDA Orphan Products Grants program provides incentives for sponsors to develop products for rare diseases. In China, however, there is no specific support project for rare disease research, and there is a huge gap in funding efforts for rare disease research between China and the United States. CONCLUSION China should establish rare disease research center to promote rare disease research and set up specific funding for rare diseases research, increase efforts to support research and innovation for rare diseases and orphan drugs, in order to protect the health interests of patients with rare diseases.     

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??OBJECTIVE To observe whether low concentration (1??10^-8 mol??L^-1) of ouabain (OUA)can increase the contractility in rat cardiocytes and investigate the Na/K pump signal transduction pathways related to positive inotropic action following the low concentration of OUA. METHODS On enzymatic isolation of rats ventricular myocytes, the Na⁺/K⁺ pump current (Ip) was by whole-cell patch-clamp, in order to observe the low concentration of OUA on Ip. The contraction of a single myocyte was assessed by a video-based motion edge-detection system. ??To detect and compare the potentiations of 1??10^-8-1??10^-3 mol??L^-1 OUA on the contractility in rat cardiocytes. ??The cardiocytes were pre-treated with PP2(1 ??mol??L^-1), NAC(100 ??mol??L^-1), PD98059(50 ??mol??L^-1)for 5 min, and the effects of the signals transduction inhibitors on the positive inotropic effect of 1??10^-8 mol??L^-1 OUA was recorded. RESULTS The 1??10^-8-1??10^-3 mol??L^-1 OUA increased the contractility of rat cardiocytes (P<0.01). Compared 1 ??mol??L^-1 PP2 +1??10^-8 mol??L^-1 OUA group with 1??10^-8 mol??L^-1 OUA group, the contraction amplitude decreased (P<0.05), and compared 100 ??mol??L^-1 NAC +1??10^-8 mol??L^-1 OUA group with 1??10^-8 mol??L^-1 OUA group, the contraction amplitude also decreased (P<0.01), no significant difference in contraction amplitudes between 50 ??mol??L^-1 PD98059+1??10^-8 mol??L^-1 OUA group and 1??10^-8 mol??L^-1 OUA group (P>0.05). CONCLUSION The 1??10^-8-1??10^-3 mol??L^-1 OUA could increase the contraction amplitude of cardiocytes in rats in concentration-dependent manner. Positive inotropic effect of OUA in low concentration is related to Na/K pump signal transduction. Multiple signal pathways regulate the positive inotropic effect of 1??10^-8 mol??L^-1 of OUA, including the Src/ROS signal pathway.     

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??OBJECTIVE To establish an HPLC method for the simultaneous determination of butorphanol tartrate, dextroisomer and benzethonium chloride which works as the bacteriostatic agent in butorphanol tartrate injection on a cyclodextrin chiral column. METHODS The HPLC analysis was performed on an Astec Cyclobond ?? cyclodextrin chiral column (4.6 mm??250 mm,5 ??m), with mobile phase consisting of 0.05 mol??L^-1 ammonium acetate solution (pH was adjusted to 4.1 by acetic acid) and acetonitrile using gradient elution at a flow rate of 1.0 mL??min^-1. The detection wavelength was set at 280 nm. RESULTS The method showed good linearity for the three components to be measured. The linear ranges were 0.04-2.0 mg??mL^-1 for butorphanol tartrate (r=0.999 9), 0.01-2.0 mg??mL^-1 for dextroisomer (r=1.000 0), and 0.02-1.0 mg??mL^-1 for benzethonium chloride (r=0.999 9), respectively. The average recoveries were 100.2%, 100.7%, and 99.4%, respectively. CONCLUSION The method is simple, accurate and reproducible. It can be used for the quality control of butorphanol tartrate injection.     

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??OBJECTIVE To prepare and characterize hyaluronic acid-sinomenine conjugate. METHODS The tetrabutylammonium salt of hyaluronic acid(HA), HA-TBA, was prepared using ion-exchange resins, then HA-TBA and sinomenine were covalently bound to generate conjugate with glycine as a spacer. The drug-releasing characteristics of the conjugates was investigated in vitro. RESULTS The conjugate was characterized by IR, NMR, UV and TLC, and its chemical structure was confirmed,wherein the binding rate of sinomenine was 26.5%.The results of in vitro release test showed that the conjugate had significant sustained-release effect and the drug release patterns followed first-order, Higuchi and Ritger-Peppas equation.CONCLUSION The preparation process is feasible with high drug binding rate, and the conjugate has significant delayed-release effect.     

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??OBJECTIVE To prepare heparan sulfate-vitamin E succinate (HDV) amphipathic copolymers and explore the pharmaceutical properties of doxorubicin (DOX)-loaded HDV copolymer micelles (DOX/HDV). METHODS HDV copolymers were prepared by amide reaction and its structure was confirmed by ¹H-NMR. DOX/HDV micelles were prepared by ultrasonic method. The particle size, morphology, Zeta potential, drug loading, entrapment efficiency, and in vitro drug release and cytotoxicity were evaluated. RESULTS HDV amphipathic copolymers were synthesized successfully. The particle size, PDI value and Zeta potential of drug-loaded micelles were (105.0??7.3) nm, (0.239??0.484) and (-21.4??2.6) mV, respectively. The encapsulation and drug loading rate were (76.22??0.76)% and (9.53?? 0.58)%, respectively. The results of drug release test in vitro showed that DOX was released slowly from the micelles. Cytotoxicity experiments indicated that blank micelles had no apparent toxicity against both tumor cells and normal cells. However, DOX/HDV micelles could inhibit the tumor cells growth obviously. CONCLUSION HDV copolymers can effectively load DOX with properties of drug sustained release and enhanced cytotoxicity against tumor cells in vitro, which indicates that HDV may be a potential candidate for cancer therapy.     

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??OBJECTIVE To synthesize hyaluronic acid-octadecene (HOY) copolymers by terminal thiolation modification of hyaluronic acid (HA), prepare doxorubicin-loaded micelles and investigate its pharmaceutical characteristics. METHODS HOY copolymers were synthesized through Michael addition reaction. The doxorubicin-loaded copolymer micelles were prepared with ultrasonic method, then the particle size, Zeta potential, encapsulation efficiency, drug loading efficiency and in vitro release behavior were studied. RESULTS HOY copolymers were synthesized successfully. The particle size and Zeta potential of the drug-loaded micelles were (237.2??2.7) nm and (-22.37??0.38) mV, and the encapsulation efficiency and drug loading rate were (89.8??0.011)% and (5.4??0.007)%, respectively. Moreover, the accumulative release of doxorubicin in vitro was about 70% in 48 h, indicating that the drug was released slowly from the micelles. CONCLUSION This study develops a new micellar system based on terminal modified HA, and provides a reference for the study of HA nanocarrier.
     

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??OBJECTIVE To prepare aziditaxel-loaded mPEG-PLA polymeric micelles, investigate its pharmaceutical characteristics and study its anti-tumor effects in vitro. METHODS Aziditaxel-loaded polymeric micelles were prepared by thin-film dispersion method. The morphology of aziditaxel-loaded micelles was observed under transmission electron microscope. The particle size distribution and Zeta potential of aziditaxel-loaded micelles were determined by dynamic light scattering method using a Malvern Zetasizer Nano ZS90 analyzer. The technical reproducibility and reconstitution stability of aziditaxel-loaded micelles were also checked. The drug loading and encapsulation efficiency were measured by HPLC. Dialysis method was used to investigate the in vitro release of aziditaxel-loaded micelles, and the release manner was fitted using the mathematic models. The in vitro anti-tumor activities were evaluated by proliferation inhibition and cycle block experiment. RESULTS Aziditaxel-loaded polymeric micelles were prepared successfully. Aziditaxel-loaded polymeric micelles showed spherical shape with a mean particle size of 24.50 nm, polydispersity index of 0.117 and Zeta potential of -10.06 mV. The mean drug loading and entrapment efficiency were (16.00??0.15)% and (95.80??0.10)%, respectively. The preparation reproducibility was fine, and the reconstitution solution of lyophilized preparation of aziditaxel-loaded polymeric micelles maintained stable within 6 h. The release behavior of aziditaxel-loaded micelles conformed to the ambiexponent model. Drug-loaded micelles could obviously inhibit the proliferation of MCF-7 breast cancer cell lines in vitro, and induce significant G₂/M cycle arrest and apoptosis on MCF-7 cancer cells. CONCLUSION Aziditaxel-loaded mPEG-PLA polymeric micelles are successfully prepared. The preparation method is simple, and the pharmaceutical properties of the products conform to the requirements of the subsequent study. The prepared aziditaxel-loaded polymeric micelles exhibit good application prospect with favourable in vitro anti-tumor activities.     

聚合物胶束载药制备方法研究进展

聚合物胶束作为给药系统具有药物增溶、肿瘤靶向性、增效减毒的作用,在药物传递系统中显示出良好的应用前景。对近几年国内外胶束制备方法的研究进展加以综述。     

大黄素soluplus聚合物胶束的制备及质量评价

目的:制备大黄素的soluplus聚合物胶束并对其进行质量评价。方法:采用薄膜分散法制备大黄素聚合物胶束(Emo-PMs)。利用粒径测定仪、透射电镜、X-射线衍射对其进行表征;采用HPLC测定Emo-PMs的包封率和载药量,流动相甲醇-0.1%磷酸(75∶25),检测波长437 nm;采用动态膜透析法考察载药胶束的体外释药特性。结果:Emo-PMs呈球形或类球形,平均粒径(65±3.8)nm,多分散系数0.099±0.022,Zeta电位-(12.7±0.19)mV,平均包封率(88.25±3.51)%,平均载药量(4.51±0.72)%;大黄素以无定形状态或分子状态包载在聚合物胶束中;Emo-PMs具有缓释作用,释放机制符合Higuchi方程。结论:制备的Emo-PMs粒径、包封率、载药量可控,具有缓释作用。     

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??OBJECTIVE To prepare luteolin-loaded Solutol hs15/Poloxamer188 mixed micelles, evaluate their pharmaceutical property and study their anti-tumor activity. METHODS The luteolin-loaded mixed micelles were prepared by thin-film hydration method. The particle size was measured by laser granulometry, and the morphology was observed under transmission electron microscope (TEM). The in vitro release behavior was determined by the dialysis method. Cell toxicity and uptake assays were employed to evaluate the anti-tumor activity. The targeting effect was studied by fluorescence labeling. RESULTS The prepared luteolin-loaded mixed micelles showed spherical and regular shape with an average particle size of 66.43 nm and its entrapment efficiency was more than 80%. The 12 h-accumulated release ratio in vitro was up to 97.42%. The cytotoxicity of luteolin-loaded mixed micelles on human lung adenocarcinoma cell line A549 was significantly stronger than that of free luteolin and the uptake rate was improved. After injecting DiR-loaded mixed micelles into nude mouse, the drug begun to accumulate in tumors after 2 h and reached the highest concentration at 6 h which was significantly higher than that in other tissues. There remained strong drug distribution in the tumors after 12 h. CONCLUSION The Solutol hs15/ Poloxamer188 mixed micelles have small particle size and high entrapment efficiency and can enhance cell toxicity and uptake with certain passive targeting effect. It is a promising delivery system for anti-tumor drug.     

紫杉醇聚合物胶束的制备及其pH响应性能

目的:制备以具有p H响应性能的聚乙二醇-聚乳酸[poly(ethylene glycol)-poly(lactic acid),PELA]-聚-β-氨基酯(PBAE)为载体的纳米胶束,提高紫杉醇在水中溶解度。方法:Michael加成合成PBAE共聚物,通过核磁共振波谱法表征其结构,酸碱滴定法测定碱解离常数(dissociation contant of a base,p Kb),荧光法测定临界胶束浓度(criticle micelle concentration,CMC)。采用薄膜水化法制备载紫杉醇纳米胶束,HPLC测定载药量和包封率,激光粒度仪测定粒径及分布,透射电镜表征其形态,透析袋透析法测定纳米胶束在不同p H条件下的释放特性。结果:PELA和PBAE的p Kb分别为7.1和6.5,CMC分别为3.31,4.79 mg·L-1,载药量分别为12.37%和12.05%,包封率分别为70.55%和68.53%,且紫杉醇胶束1周内稳定。体外释放试验表明非p H响应材料随介质p H降低,药物释放略微增加;而p H敏感材料在弱酸性条件下药物释放明显加快。结论:PBAE作为纳米载体能明显提高紫杉醇的水溶性,载药量较高且稳定,具有明显的p H敏感性。     

维甲酸/聚乙二醇磷脂酰乙醇胺胶束的制备及优化

 目的 制备甲氧基聚乙二醇磷脂酰乙醇胺（mPEG-DSPE）两亲线型聚合物及其载全反式维甲酸（ATRA）的胶束,通过考察胶束的电位、粒径、包封率进行制备工艺的优化。方法 选择多种制备方法及不同药物/聚合物比例制备ATRA胶束。用荧光探针技术测定临界胶束浓度（CMC）,动态光散射（DLS）法测定其粒径及电位,紫外分光光度法对胶束的载药等性质进行表征,Sulforhodamine B（SRB）法考察载药聚合物胶束及游离ATRA对Balb/c脑内皮细胞的抑制作用。结果 药物/聚合物比例对胶束粒径及包封率的影响显著,在药物/聚合物的比例为1∶20时,胶束的粒径约为100 nm,包封率为17.47%。mPEG-DSPE聚合物载ATRA胶束可以明显增加ATRA在水中的溶解度,抑制细胞生长的能力约为游离ATRA 的29倍。结论 两亲性聚合物mPEG-DSPE的胶束对疏水药物ATRA有良好的装载能力,可以显著增加ATRA的溶解度,聚合物胶束能增强ATRA体外细胞毒作用。     

载紫杉醇的大黄酸偶联物纳米胶束的制备及初步评价

目的制备载紫杉醇的D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopheryl polyethylene glycol 1000 succinate,TPGS)修饰的羧甲基壳聚糖-大黄酸偶联物(PTX/TPGS-CR)纳米胶束,并对其进行初步评价。方法采用透析法,以载药量、包封率及粒径为指标,通过单因素考察优化PTX/TPGS-CR纳米胶束的制备工艺并进行验证。以溶血实验及血管刺激性实验初步考察PTX/TPGS-CR纳米胶束的安全性。四甲基偶氮唑盐微量酶反应比色法(MTT)法考察PTX/TPGS-CR纳米胶束对Hela细胞的毒性。通过激光扫描共聚焦显微镜定性和流式细胞仪定量考察Hela细胞对PTX/TPGS-CR纳米胶束的摄取情况。结果制备工艺优化后制得的PTX/TPGS-CR纳米胶束粒径为(197.3±4.4)nm,PDI为(0.131±0.021),电位为(-31.8±0.5)mV,载药量为(48.20±3.03)%,包封率为(87.26±4.91)%。溶血实验结果表明,其溶血率低于1.71%;血管静脉注射无明显刺激性。其对Hela细胞的杀伤作用具有浓度和时间依赖性,能被Hela细胞高效摄取。结论PTX/TPGS-CR纳米胶束载药量和包封率高,安全性好,其体外抗肿瘤活性稍优于Taxol?。