葛根素聚氰基丙烯酸丁基酯纳米粒的制备及质量评价

目的：制备葛根素聚氰基丙烯酸正丁酯纳米粒（P-PBCA）,并对其进行质量评价.方法：以包封率和载药量为指标,采用正交设计综合评分法优化P-PBCA处方.结果：最佳工艺为葛根素质量20 mg、氰基丙烯酸正丁酯体积分数0.6％,pH为2.0,优化所得P-PBCA为球状,包封率为（78.13±7.42）％,载药量为（15.05±2.38）％;粒径（145.2±22.4） nm,Zeta电位（-28.7±1.1）mV.结论：正交设计综合评分法可用于P-PBCA的制备.     

注射用丝裂霉素C聚氰基丙烯酸正丁酯纳米粒的制备

采用乳化聚合法新鲜制备的注射用丝裂霉素C聚氰基丙烯酸正丁酯纳米粒平均粒径为(106.8±7.2)nm,平均包封率(92.1±2.3)%,载药量(7.3±0.2)%.半数致死剂量(LD50)本品为54.3mg/kg,注射用丝裂霉素为13.6mg/kg.     

聚氰基丙烯酸烷基酯纳米载体制备工艺的研究进展

综述了聚氰基丙烯酸烷基酯纳米载药系统的制备工艺、载药方式、纯化、灭菌、表面修饰等方面的研究进展.     

替莫唑胺聚氰基丙烯酸正丁酯纳米粒的制备

目的:优化工艺制备替莫唑胺聚氰基丙烯酸正丁酯纳米粒(TMZ-PBCA-NP)。方法:以α-氰基丙烯酸正丁酯(BCA)为载体,采用乳化聚合法制备TMZ-PBCA-NP,并以PluronicF-68作为表面活性剂,通过考察粒径大小和包封率2个指标,在单因素实验初选的基础上,正交设计法优化处方和制备工艺。结果:制备TMZ-PBCA-NP的优化条件为反应体系pH2.5,用1%PluronicF-68作为表面活性剂,TMZ用量5 mg,BCA单体用量0.1 mL,按优化条件所制备的TMZ-PBCA-NP平均粒径(135.8±11.3)nm,多分散系数为0.19,表面电位(-24.8±2.2)mV,包封率(44.23±2.04)%,载药量(2.80±0.05)%。结论:通过优化处方和制备工艺,采用乳化聚合法可制备出TMZ-PBCA-NP,对拓展TMZ临床给药新剂型提供一定的参考。     

大蒜素聚氰基丙烯酸正丁酯纳米粒的制备工艺研究

目的：研制大蒜素聚氰基丙烯酸正丁酯纳米粒并对处方与制备工艺进行优化筛选。方法：以生物降解型聚氰基丙烯酸正丁酯为载体材料，采用乳化聚合法制备大蒜素聚氰基丙烯酸正丁酯纳米粒；以载药量、包封率、形态和粒径分布为评价指标，通过单因素试验考查、均匀设计法优化制备工艺。结果：按优化处方与制各工艺条件，制得纳米粒球形圆整、分散良好，算术平均粒径为113．4nm，粒径分布范围为11．7—146．8nm，载药量为18．57％，包封率为92．87％。结论：经优化筛选出的工艺是大蒜素聚氰基丙烯酸正丁酯纳米粒的最佳制备工艺。     

正交设计优选阿糖胞苷聚氰基丙烯酸正丁酯纳米粒制备工艺

目的:制备阿糖胞苷聚氰基丙烯酸正丁酯(Ara-C-PBCA-NP)纳米粒.方法:在单因素考察的基础上,通过正交设计优选处方和制备工艺,并对优化条件下制备的Afa-C-PBCA-NP胶体溶液进行质量评价.结果:制备的Ara-C-PBCA-NP平均粒径为56 nm,平均粒径跨度为1.226,载药量为11.77%,包封率为53.38%.结论:所制备的稳定的纳米粒给药系统,为阿糖胞苷的临床应用提供了更广阔的前景.     

聚氰基丙烯酸正丁酯纳米粒载福莫司汀的制备工艺

目的优化工艺制备福莫司汀聚氰基丙烯酸正丁酯纳米粒（FCNU-PBCA—NP）。方法以α-氰基丙烯酸正丁酯（BCA）为载体,采用乳化聚合法制备FCNU-PBCA—NP,并加以聚乙二醇20000（PEG20000）进行表面修饰,通过考察粒径和包封率两个指标,在单因素实验初选的基础上,正交设计法优化处方和制备工艺。结果制备FCNU-PBCA—NP的优化条件为BCA单体体积分数0．8％（V/V）、FCNU20mg、PEG20000浓度2．0％,按优化条件所制备的FCNU-PBCA-NP的粒径为（124．6±5．2）nm,多分散系数（PDI）范围为0．07—0．16,包封率（64．12±2．36）％,载药量（7．28±0．76）％。结论通过优化处方和制备工艺,采用乳化聚合法可制备出FCNU—PBCA—NP,对拓展FCNU临床给药新剂型提供一定的参考。     

紫杉醇聚氰基丙烯酸正丁酯纳米粒对人卵巢癌细胞的毒性

目的:评价制备紫杉醇聚氰基丙烯酸正丁酯纳米粒(PTX-PBCA-NPs)的原料的生物安全性以及PTX-PBCA-NPs的细胞毒性。方法:采用四噻唑蓝法(MTT法)和检测乳酸脱氢酶(LDH)活性的方法考察空白PBCA-NPs及其聚合的原料、PTX-PBCA-NPs对L-02人正常肝细胞、卵巢癌敏感株(A2780)和卵巢癌耐紫杉醇肿瘤细胞株(A2780/T)的细胞毒性。结果:制备的空白PBCA-NPs只有在大于608 ng·mL-1时,对于L-02细胞具有明显的毒性(P<0.05);在质量浓度304～608 ng·mL-1,空白PBCA-NPs对A2780和A2780/T细胞有明显毒性(P<0.05)。与同一浓度PTX溶液比较,PTX-PBCA-NPs对A2780和A2780/T细胞的毒性作用明显(P<0.05)。结论:空白PBCA-NPs有一定的生物安全性,PTX-PBCA-NPs在对卵巢癌肿瘤细胞有一定的杀伤能力。     

吉西他滨聚氰基丙烯酸正丁酯纳米粒在小鼠脑内的靶向分布

目的:研究聚山梨酯-80包衣吉西他滨聚氰基丙烯酸正丁酯纳米粒(CCTB-PBCA-NP)在正常小鼠脑内靶向分布.方法:建立生物样品中GCTB的高效液相色谱(HPLC)测定法,并测定了小鼠给药后的血浆及脑组织中GCTB浓度.结果:与GCTB溶液组、GCTB-PBCA-NP胶体溶液组以及1%聚山梨酯-80 空白PBCA-NP GCTB混合液组相比,1%聚山梨酯-80包衣GCTB-PBCA-NP能大大地增加脑组织内浓度,差异有显著性(P＜0.05).结论:1%聚山梨酯-80包衣GCTB-PBCA-NP有一定的脑靶向作用.     

盐酸环丙沙星-聚氰基丙烯酸正丁酯纳米溶胶的制备

目的:制备盐酸环丙沙星-聚氰基丙烯酸正丁酯纳米溶胶,并对其处方因素进行考察。方法:以氰基丙烯酸正丁酯为载体材料,采用乳化聚合法制备盐酸环丙沙星-聚氰基丙烯酸正丁酯纳米溶胶,以粒径、外观为主要指标,用单因素方法优化处方,得到二步法制备纳米溶胶的条件和工艺。结果:制备的纳米溶胶的平均粒径为(82.6±15)nm,包封率为61.9%,载药量为34.2%(g/g),平均Zeta电位为(-25.1±9.92)mV。结论:本实验制备的盐酸环丙沙星-聚氰基丙烯酸正丁酯纳米溶胶的粒径小,分布窄,稳定性好。     

载羟基喜树碱纳米粒的制备和体外评价

目的:制备壳寡糖接枝布洛芬(COS-g-IBU)纳米粒负载羟基喜树碱(HCPT)纳米粒,并考察其体外释药性能。方法:以1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)为偶联剂,制备壳寡糖接枝布洛芬纳米粒(COS-g-IBU NPs)。以COS-g-IBU NPs为载体,使用超声振荡技术制备负载HCPT的壳寡糖接枝布洛芬纳米粒(HCPT-COS-g-IBU NPs)。结果:透射电镜照片显示COS-g-IBU NPs和HCPT-COS-g-IBU NPs为球形,平均粒径分别为(116±2)nm和(146±5)nm,测得药物包封率为(79.24±1.18)%,载药量为(3.62±0.05)%,体外药物释放试验表明HCPT-COS-g-IBU NPs具有明显的缓释作用。结论:COS-g-IBU可作为HCPT缓释载体材料。     

布洛芬微球的制备及影响因素考察

目的研究乳化溶剂扩散法制备布洛芬微球的工艺。方法采用乳化溶剂扩散法制备布洛芬微球,以粒度分布、载药量以及包封率为指标,对处方及工艺进行单因素考察,选出较佳的处方和工艺条件,并对所得微球的外观及体外释放度进行研究。结果该法所制微球外观圆整,流动性好,粒径分布集中在2~20μm,包封率为69.74%,载药量为68.37%。结论布洛芬微球的制备工艺简单,所制微球粒径小,分布窄。体外释药试验表明所得布洛芬微球在人工肠液中有明显的缓释作用。     

Preparation of Biodegradable Insulin Nanocapsules from Biocompatible Microemulsions

Purpose. To prepare poly(ethyl 2-cyanoacrylate) nanocapsulescontaining insulin by interfacial polymerization of spontaneously forming,biocompatible microemulsions. Methods. A pseudo-ternary phase diagram of a mixture of mediumchain glycerides (caprylic/capric triglycerides and mono-/diglycerides),a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) andwater was constructed. Polarizing light microscopy was used to identifycombinations forming microemulsions. Microemulsions werecharacterized by conductivity and viscosity to select systems suitable for thepreparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacialpolymerization. Nanocapsules were prepared by addition of 100 mgof ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsioncontaining 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. Thenanocapsules formed were characterized by photon correlation spectroscopy,freeze fracture transmission and scanning electron microscopy. Insulinnanocapsules were prepared by using an aqueous solution of insulin(100 units/ml) as the dispersed phase of the microemulsion. Theentrapment and the release of insulin from the nanocapsules were determined. Results. Three regions were identified in the pseudo-ternary phasediagram; a microemulsion region, a region in which liquid crystallinestructures were present and a coarse emulsion region. All systems inthe microemulsion region were water-in-oil dispersions.Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nmwere formed upon interfacial polymerization of the microemulsion.Nanocapsules were found to have a central cavity surrounded by apolymer wall. In excess of 80;pc of the insulin present in themicroemulsion was encapsulated upon interfacial polymerization. Conclusions. Interfacial polymerization of spontaneously formingwater-in-oil microemulsions represents a convenient method for thepreparation of poly(alkylcyanoacrylate) nanocapsules suitable for theentrapment of bioactive peptides.     

Acute Renal Toxicity of Doxorubicin (Adriamycin)-Loaded Cyanoacrylate Nanoparticles

Acute doxorubicin-loaded nanoparticle (DXNP) renal toxicity was explored in both normal rats and rats with experimental glomerulo-nephritis. In normal rats, 2/6 rats given free doxorubicin (DX) (5 mg / kg) died within one week, whereas all control animals and all rats having received free NP or DXNP survived. A 3 times higher proteinuria appeared in animals treated with DXNP than in those treated with DX. Free NP did not provoke any proteinuria. Two hr post-injection, DXNP was 2.7 times more concentrated in kidneys than free DX (p<0.025). In rats with immune experimental glomerulonephritis, 5/6 rats given DX died within 7 days, in contrast to animals treated by DXNP, NP, or untreated, which all survived. Proteinuria appeared in all series, but was 2-5 times more intense (p>0.001) and prolonged after doxorubicin treatment (400-700 mg / day), without significant difference between DXNP and DX. Rats treated by unloaded NP behaved as controls. These results demonstrate that, in these experimental conditions, DXNP killed less animals than free DX, despite of an enhanced renal toxicity of the former. Both effects (better survival and nephrosis) are most probably related to an enhanced capture of DXNP by cells of the mono-nuclear phagocyte system, including mesangial cells.     

Uptake of Nanoparticles by Rat Glomerular Mesangial Cells in Vivo and in Vitro

Glomerular mesangial cells play a major role in the structure of capillary loops, generation of mediators of inflammation, and uptake of macromolecules. We demonstrate here that isobutylcyanoacrylate nanoparticles loaded with actinomycin D (ADNP) concentrate in rat mesangial cells in vitro and in vivo, as compared to the free drug (AD). In normal rats injected with 20 µg of ³H-ADNP or ³H-AD, the uptake ratios ³H-ADNP/³H-AD measured in whole kidneys at 30 and 120 min were 2.2 ± 1.0 and 2.3 ± 0.9, respectively. The same ratios calculated for isolated rat glomeruli and tubules, were 4.1 ± 0.5 and 0.8 ± 0.2 at 30 min, and 2.6 ± 0.5 and 0.6 ± 0.3 at 120 min, respectively. In the glomeruli, the absolute uptake of ³H-ADNP corresponded to 7.5 (30 min) and 1.8 (120 min) % I.D./100 mg of protein. In rats with experimental glomerulonephritis, the uptakes of ³H-ADNP and ³H-AD by the glomeruli were 6.9 and 4.0 times higher than in normal rats, respectively. In vitro experiments demonstrated up to 5 times higher uptake by glomerular mesangial cells than by epithelial cells. Uptake was maximum after 60 min, higher at 37°C than at 4°C, dependent on the presence of fresh serum and inhibited by cytochalasin-B. Drug targeting by nanoparticles is thus possible to renal cells involved in inflammatory processes, especially mesangial cells and macrophages. Nanoparticles could also be useful for lowering drug concentration in tubular cells, to reduce any tubular toxicity. Targetting of the mesangial cells is of particular interest for drugs such as corticosteroids capable of reducing glomerular inflammation in various pathological conditions.     

Polyalkylcyanoacrylate Nanoparticles as Polymeric Carriers for Antisense Oligonucleotides

Adsorption of oligothymidylates on polyisobutyl- or polyisohexylcyanoacrylate nanoparticles was achieved in the presence of hydrophobic cations such as tetraphenylphosphonium chloride or quaternary ammonium salts. Results suggested that oligonucleotide adsorption on the nanoparticles was mediated by the formation of ion pairs between the negatively charged phosphate groups of the nucleic acid chain and the hydrophobic cations. The adsorption efficiency of oligonucleotide–cation complexes on nanoparticles was found to be highly dependent upon several parameters: oligonucleotide chain length, nature of the cyanoacrylic monomer, hydrophobicity of cations used as ion-pairing agents, and ionic concentration of the medium. Carrier capacity of polyisohexylcyanoacrylate nanoparticles for oligothymidylates (16 nucleotides) complexed with cetyltrimetylammonium bromide in the presence of 0.15 M NaCl was determined to be 5 µmol/g polymer. The in vitro protection of oligothymidylates adsorbed to nanoparticles against degradation by a 3-exonuclease (snake venom phosphodiesterase) was also demonstrated. These results showed that nanoparticles can be considered as convenient carriers for the protection and delivery of Oligonucleotides to cells in culture and for future applications in vivo.     

Ability of Doxorubicin-Loaded Nanoparticles to Overcome Multidrug Resistance of Tumor Cells After Their Capture by Macrophages

Purpose. Investigation of the ability of doxorubicin-loaded nanoparticles (NP/Dox) to overcome multidrug resistance (MDR) when they have first been taken up by macrophages. Methods. The growth inhibition of P388 sensitive (P388) and resistant (P388/ADR) tumor cells was evaluated in a coculture system consisting of wells with two compartments. The tumor cells were seeded into the lower compartment, the macrophages were introduced into the upper part in which the drug preparations were also added. Results. Doxorubicin exerted lower cytotoxicity on tumor cells in coculture compared with direct contact. In P388/ADR, NP/Dox cytotoxicity was far higher than that of free doxorubicin (Dox). Three different formulations of cyclosporin A (either free (CyA), loaded to nanoparticles (NP/CyA) or in a combined formulation with doxorubicin (NP/Dox-CyA)), were added to modulate doxorubicin efficacy. The addition of cyclosporin A to Dox increased drug cytotoxicity. Both CyA added to NP/Dox and NP/Dox-CyA were able to bypass drug resistance. Conclusions. Despite the barrier role of macrophages, NP/Dox remained far more cytotoxic than Dox against P388/ADR. Both NP/ Dox + CyA and NP/Dox-CyA allowed to overcome MDR, but the last one should present greater advantagein vivo by confining both drugs in the same compartment, hence reducing the adverse effects.     

布洛芬混悬液的研制及其生物利用度

通过处方、工艺筛选 ,以羧甲纤维素为助悬剂、蔗糖和甘露醇为矫味剂制备布洛芬混悬液 ,并在 10名健康志愿者中进行生物利用度研究。采用 HPL C法测定人血清中布洛芬浓度 ,并与市售布洛芬片进行比较。结果显示 ,单剂量口服 30 0 mg布洛芬混悬液和片剂的药动学参数分别为 tmax(0 .790± 0 .36 0 ) h和 (4.0 2 4± 0 .819) h;cmax(2 2 .2 8± 3.6 8) μg/m l和 (2 0 .0 4± 3.370 ) μg/ml;t1 / 2 (2 .0 2 6± 0 .2 70 ) h和 (2 .0 2 6± 0 .2 6 5 ) h。混悬液的相对生物利用度为(91.4 6± 10 .5 9) % ,与布洛芬片相比无显著性差异。     

熔融法制备布洛芬固体分散体

目的提高布洛芬的体外溶出速率。方法以亲水性Sylysia 730为载体,采用熔融法制备布洛芬-Sylysia 730固体分散体;利用体外溶出度实验确定熔融法制备固体分散体的制备条件;采用粉末X射线衍射法、差示扫描量热法、扫描电子显微镜分析法对制备的固体分散体进行物相鉴别。结果熔融法制备的布洛芬-Sylysia 730固体分散体中布洛芬均以非晶态存在于载体中。结论用Sylysia 730制备布洛芬固体分散体后显著提高了布洛芬的溶出速率,可进一步进行体内释药行为考察。