Box-Behnken响应面法优化吲哚美辛口服自微乳剂的处方

目的 采用Box-Behnken响应面分析法优化吲哚美辛口服自微乳剂的处方.方法 考察吲哚美辛在各种油相、乳化剂、助乳化剂中的溶解度,根据结果绘制伪三元相图,寻找自微乳区域;以油相、乳化剂、助乳化剂为自变量,透光率为因变量,通过对自变量中各种溶媒筛选的多元线性回归及多项式拟合,采用Box-Behnken响应面法优化处方,并进行预测分析.结果 处方中吲哚美辛、桉叶油、吐温20、二乙二醇单乙醚占自微乳处方的含量分别为3.1％、15.6％、56.3％、25％;透光率为98.8％±0.17％,平均粒径为14.57±0.77 nm;处方的实际值与预测值偏差为0.20％.结论 应用Box-Behnken响应面法能快速、方便地得到吲哚美辛自微乳剂的处方,所建模型预测性良好.     

甲苯达唑在不同介质中的溶解度研究

目的 研究甲苯达唑在几种油相和水相介质中的溶解度,通过观察溶解度的变化情况,为药物生物利用度的提高奠定基础.方法 将甲苯达唑分散于大豆油、甘油三油酸酯以及油酸等9种油相介质中,并以1％西黄耆胶和去离子水作为对照,于25℃或37℃的恒温水浴中以100 r/min的速度机械振荡24 h后离心,取上清液采用高效液相色谱法(HPLC)测定甲苯达唑在上述介质中的浓度.结果 在25℃时甲苯达唑在大豆油、甘油三油酸酯以及油酸中的溶解度分别为(2.1±0.2)μg/ml、(54.1±1 9)μg/ml以及(329.4 +9.7) μg/ml,均高于在去离子水(1.0±0.1) μg/ml和1％西黄芪胶(5.5±0.7) μg/ml的溶解度.当介质温度升高到37℃,甲苯达唑在上述溶剂中的溶解度均随着介质温度的升高而增加,其中在3种油相中的溶解度为(34.1 ± 1.9) ～(900.7±57.1)μg/ml,而在1％西黄耆胶和去离子水中增加到(7.2±0.7)μg/ml和(3.7±1.2)μg/ml.结论 与传统的水相给药介质相比,将甲苯达唑分散于油相溶剂中,可显著增加其溶解度.     

辛伐他汀对介入手术后急性冠状动脉综合征患者血清炎症因子的影响

目的:观察不同剂量辛伐他汀对ACS患者经冠状动脉介入治疗(PCI)术后炎症因子可溶性细胞黏附分子-1(sICAM-1)、血浆基质金属蛋白酶-9(MMP-9)、C-反应蛋白(CRP)水平的影响及其临床意义。方法:选择住院已行PCI术的ACS单支病变患者97例,随机将97例ACS病人分为辛伐他汀40mg治疗组、辛伐他汀20mg治疗组和对照组，另选健康成人20名为正常对照；测定治疗前、治疗4周后sICAM-1、MMP-9及CRP水平。结果:服用4周后，sICAM-1、MMP-9及CRP水平辛伐他汀40mg组及辛伐他汀20mg组均较对照组低(P<0.01)，而辛伐他汀40mg组较辛伐他汀20mg组更低(P<0.05)。结论:辛伐他汀可减轻ACS介入治疗患者炎症反应；与低剂量辛伐他汀比高剂量辛伐他汀具有更强的抗炎效果，从而有利益于改善内皮功能，稳定动脉粥样斑块。     

Development of Sr and CO3 co-substituted hydroxyapatites for biomedical applications

Sr and CO₃ co-substituted hydroxyapatite (SrCHA) nanopowder was synthesized by neutralization. The powder was characterized. The improved solubility in Hanks’ balanced solution of SrCHA granules (400–600 μm of dimensional range), potentially usable as bone filler, was assessed and compared with that of an analogous carbonate free granulate. SrCHA porous bodies with interconnected micro- and macro-porosity, which mimic the morphology of spongy bone, were prepared by the impregnation of cellulose sponges with suspensions of the SrCHA powder and controlled sintering. SrCHA porous scaffolds sintered at 850 °C, in flowing CO₂ atmosphere, showed satisfying compressive strength (4.58 ± 0.75 MPa) for a porosity value of 45 vol.% and retained the desired ionic substitutions (Sr/Ca = 0.11 and CO₃ = 6.8 wt.%). The possibility of widely modulating, by acting on the chemical–physical–geometrical features of the material, the prolonged in situ release of therapeutic Sr, together with the fundamental (Ca, PO₄) and main substituting (CO₃) ions that constitute the bone mineral phase, makes the use of SrCHA as resorbable bone filler or bone substitute scaffolds promising, especially when pathologies related with Sr deficiency are present. In vitro and in vivo tests are in progress.     

河豚毒素处方前初步研究

目的 考察河豚毒素（TTX）在不同溶剂中的溶解性及稳定性，以及温度和pH值对稳定性的影响。方法 配制TTX不同介质的溶液，采用高效液相色谱法（HPLC）测定其在不同温度、不同pH缓冲液中的浓度，分析计算其溶解度及稳定性。结果 TTX在pH值为3.5时溶解度最大，随着pH值增加其溶解度逐渐降低。TTX在强碱条件下降解最为迅速，在70 ℃条件下、0.1 mol/L的氢氧化钠溶液中，20 min即完全降解。稳定性试验结果同样证明TTX在碱性条件下的稳定性最差，在37 ℃、pH值=7.4的磷酸缓冲盐溶液（PBS）中，TTX浓度在1~10 h时开始持续降低，28天降解率为88.07±0.27%。结论 TTX易溶于pH值=3.5的酸性水溶液，几乎不溶于碱性水溶液。其稳定性与温度、介质pH值密切相关，在酸性水溶液中较为稳定，在碱性条件下易降解，温度升高会加速其降解过程。     

Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature

Recently trans-resveratrol (trans-RSV) has received great attention due to its prophylactic and therapeutic properties. Its limited bioavailability provides compelling evidence of the need for more suitable formulations in order to attain better clinical effectiveness. Some physicochemical properties of trans-RSV are still unknown or research findings are contradictory. Therefore, this paper presents newly determined trans-RSV solubility and stability at various pH and temperatures, and the importance of such data for the studies of novel trans-RSV-loaded nanofibers. In acidic pH trans-RSV was stable, whereas its degradation started to increase exponentially above pH 6.8. Consequently, it is worthwhile to note that special consideration has to be dedicated to long dissolution testing or biological assays on cell lines in order to obtain relevant data. Measurements were done by validated UV/VIS spectroscopy, HPLC, and newly developed UPLC methods. Specificity was confirmed for HPLC and UPLC method, whereas UV/VIS spectroscopy resulted in false higher trans-RSV concentrations in conditions under which it was not stable (alkaline pH, light, increased temperature). The study is of interest because it draws attention to the importance of careful selected experimental conditions, their influence on the trans-RSV stability and the implications this has for formulation development, storage, and maintenance of therapeutic doses.     

HPMA-based polymeric micelles for curcumin solubilization and inhibition of cancer cell growth

Curcumin (CM) has been reported as a potential anticancer agent. However, its pharmaceutical applications as therapeutic agent are hampered because of its poor aqueous solubility. The present study explores the advantages of polymeric micelles composed of block copolymers of methoxypoly(ethylene glycol) (mPEG) and N-(2-hydroxypropyl) methacrylamide (HPMA) modified with monolactate, dilactate and benzoyl side groups to enhance CM solubility and inhibitory activity against cancer cells. Amphiphilic block copolymers, ω-methoxypoly(ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide) (PEG-HPMA-Bz) were synthesized and characterized by ¹H NMR and GPC. One polymer with a molecular weight of 28,000 Da was used to formulate CM and compared with other aromatic substituted polymers. CM was loaded by a fast heating method (PEG-HPMA-DL and PEG-HPMA-Bz-L) and a nanoprecipitation method (PEG-HPMA-Bz). Physicochemical characteristics and cytotoxicity/cytocompatibility of the CM loaded polymeric micelles were evaluated. It was found that HPMA-based polymeric micelles significantly enhanced the solubility of CM. The PEG-HPMA-Bz micelles showed the best solubilization properties. CM loaded polymeric micelles showed sustained release of the loading CM for more than 20 days. All of CM loaded polymeric micelles formulations showed a significantly potent cytotoxic effect against three cancer cell lines. HPMA-based polymeric micelles are therefore promising nanodelivery systems of CM for cancer therapy.     

Preparation of a fluorinated dental resin system and its anti-adhesive properties against S. mutans

ObjectivesThe purpose of this study was to characterize physicochemical properties and investigate anti-bacterial adhesion effect of dental resins containing fluorinated monomers.MethodFluorinated dimethacrylate FDMA was mixed with commonly used reactive diluent triethylene- glycol dimethacrylate (TEGDMA) and fluorinated diluent 1 H,1 H-heptafluorobutyl methacrylate (FBMA) separately at a mass ratio of 60 wt./40 wt. to prepare fluorinated resin systems. Double bond conversion (DC), flexural strength (FS) and modulus (FM), water sorption (WS) and solubility (SL), contact angle and surface free energy, surface element concentration, and anti-adhesion effect against Streptococcus mutans (S. mutans) were investigated according to standard or referenced methods. 2,2-bis[4-(2-hydroxy-3-methacryloy-loxypropyl)-phenyl]propane (Bis-GMA)/TEGDMA (60/40, wt./wt.) was used as control.ResultsBoth fluorinated resin systems had higher DC than Bis-GMA based resin (p < 0.05); compared with Bis-GMA based resin (FS, FDMA/TEGDMA resin system had higher FS (p < 0.05) and comparable FM (p > 0.05), while FDMA/FBMA resins system had lower FS and FM (p < 0.05). Both fluorinated resin systems had lower WS and SL than Bis-GMA based resin (p < 0.05), and FDMA/TEGDMA resin system had the lowest WS (p < 0.05) in all experimental resin systems. Only FDMA/FBMA resin system showed lower surface free energy than Bis-GMA based resin (p < 0.05). When the surface was smooth, FDMA/FBMA resin system had lower amount of adherent S. mutans than Bis-GMA based resin (p < 0.05), while after the surface became roughness, FDMA/FBMA resin system had comparable amount of adherent S. mutans as Bis-GMA based resin (p > 0.05).SignificanceResin system prepared exclusively with fluorinated methacrylate monomers reduced the S. mutans adhesion due to their increased hydrophobicity and decreased surface energy., while flexural properties of it should be improved.     

Advances in the design of fasted state simulating intestinal fluids: FaSSIF-V3

Biorelevant media are commonly used to simulate the physiological composition of human intestinal fluids (HIF) in in vitro solubility and dissolution investigations. In comparison with the surfactant solutions or blank buffers, these media are able to better reflect the physiological solubility and dissolution behavior of poorly soluble active pharmaceutical ingredients (APIs). The aim of this investigation was to review the composition of FaSSIF and FaSSIF-V2 according to recently summarized data about the physiological composition of fasted state human intestinal fluid and propose an updated version, FaSSIF-V3. Furthermore the surface tension was considered as a possible surrogate parameter to gauge the physiological correctness of new versions of biorelevant media.Various prototypes of FaSSIF-V3 were prepared with each of the following five bile salts: taurocholate (TC), glycocholate (GC), tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and glycochenodeoxycholate (GCDC) as well as replacing lecithin with its hydrolysis products, lysolecithin and sodium oleate. Two additional media consisting of a mixture of glycocholate (GC) and taurocholate (TG), with or without 0.2 mM cholesterol, were also investigated.Solubilities of ten model compounds in various prototypes of FaSSIF-V3 were measured using HPLC-UV and compared to the solubilities in the existing biorelevant media (FaSSIF and FaSSIF-V2), fasted HIF, blank buffer and a 0.5% sodium dodecyl sulfate (SDS) solution. Additionally, the influence on the surface tension properties of various combinations of bile salts, phospholipids and their hydrolysis products and cholesterol in these media was investigated and an attempt was made to calculate the CMC of the various generations of FaSSIF.The results demonstrated that the amount and the type of phospholipids as well as the type of bile salt had a significant influence on the solubility and surface tension in the various FaSSIF-V3 prototypes and existing biorelevant media. In contrast to results with biorelevant media, it was demonstrated that blank buffers generally underestimate and SDS solutions highly overestimate the physiological relevant solubilities of all investigated APIs.The prototype containing FaSSIF-V3-GC/TC_Chol was able to better reflect the solubilities of the most investigated APIs in fasted HIF than the existing media, and it also matched the physiological surface tension reported for the fasted human gut, and was designated FaSSIF-V3.     

Drug delivery challenges and formulation aspects of proteolysis targeting chimera (PROTACs)

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