叔丁醇-水共溶剂体系冻干脂质体

目的考察用叔丁醇水共溶剂体系冻干脂质体的可行性。方法以钙黄绿素脂质体为模型,考察了糖脂比、磷脂组成以及叔丁醇含量对钙黄绿素滞留率的影响。采用LS230粒度分析仪对冻干前后脂质体的粒径进行了测定。采用DSC分析和低温显微技术考察了样品的冻结行为。通过绘制升华曲线,确定叔丁醇的存在是否可以缩短冻干周期。结果与结论用叔丁醇水共溶剂体系冻干脂质体,最好使用HSPC脂质体。冻干前后,钙黄绿素在HSPC脂质体中的滞留率和以水为溶剂冻干脂质体时基本相同,并且脂质体的粒径没有显著变化。叔丁醇的存在可以加快升华速度,缩短冻干周期。     

地高辛环糊精包合物的制备与鉴定

目的:研究地高辛环糊精包合物制备的方法.方法:用搅拌法制备地高辛环糊精包合物,UV、HPLC法测定其含量,结果:地高辛及其包合物的紫外吸收光谱完全一致.包合后地高辛的晶体衍射峰消失,差热分析检测同样说明包合后图谱的变化.结论:地高辛与环糊精包合成功.     

岩白菜素β-环糊精包合物的制备

目的 采用正交实验法研究岩白菜素β-环糊精包合物制备的最佳工艺. 方法运用饱和水溶液法制备岩白菜素β-环糊精包合物,并采用紫外分光光度法测定岩白菜素包合率,紫外光谱、红外光谱验证包合物. 结果 通过正交实验得到最佳制备工艺：岩白菜素与β-环糊精投料比为 1：1,包合时间为1 h,包合温度为80 ℃,包合率可达92.19%. 结论 饱和水溶液法制备岩白菜素β-环糊精包合物工艺简单可行,适用于岩白菜素口服制剂的改进.     

依普黄酮β-环糊精包合物的制备

目的优选依普黄酮β-环糊精包合物的包合工艺。方法采用正交试验法,考察药物的比例、包合温度、包合时间和搅拌速度对包合结果的影响。结果依普黄酮β-环糊精包合物的最佳包合条件为β-环糊精与药物配比为1∶1,包合温度为80℃,包合时间为4 h,搅拌速度为300 r.m in-1。结论该方法对设备能耗条件要求较低、包合物收率和实际包合率均较高。     

恩诺沙星β-环糊精包合物的制备

目的:探讨恩诺沙星β-环糊精包合物的制备工艺并对制剂进行质量考察.方法:采用饱和水溶液法制备恩诺沙星β-环糊精包合物,通过L9(34)正交试验设计,以药物的包封率为考察指标,综合评定后确定最佳制备工艺.结果:最佳包合条件恩诺沙星与β-环糊精比例为1:3、包合时间为1.5h、包合温度为60℃,平均包封率为50.01%.经...     

氯霉素-β-环糊精包合物的制备工艺

目的：氯霉素-β-环糊精包合物的制备。方法：以氯霉素为模型药物,通过正交实验筛选制备氯霉素-β-环糊精包合物的最佳条件。结果：制备包合物的最佳条件为60℃（包合温度）、2h（包合时间）、1．5：1（包合比例）。结论：氯霉素-β-环糊精包合物,可显著增加氯霉素的溶解度和生物利用度,增强氯霉素稳定性,减少氯霉素的刺激性,掩盖氯霉素的不良臭味,加快药物的吸收。     

双氯芬酸钠β-环糊精包合物滴眼液的制备

目的 :建立双氯芬酸钠 (DS)环糊精包合物滴眼液的制备方法。方法 :用搅拌法制备DS环糊精包合物 ,用仪器法鉴别其包合物 ,UV、HPLC法测定其含量。结果 :DS包合物的包合率为 (67 48±2 96) %。DS及其包合物的紫外吸收光谱完全一致。包合后DS的晶体衍射峰消失。结论 :DS/β-环糊精包合物可作为滴眼剂在临床上应用。     

酮洛芬β-环糊精包合物制备及质量评价

目的：介绍了酮洛芬β-环糊精包合物的制备方法及质量评价方法。方法：通过溶出性能测定、稳定性。研究及动物体内试验来评价β-环糊精包合物质量。结果：实验证明,酮洛芬β-环糊精包合物有利于增加药物的溶出度,提高药物的稳定性,增加药物生物利用度（在动物体内）。结论：酮洛芬β-CYD包合物制备可迭设计目的。     

桉叶油β-环糊精包合物的制备

目的研究β-环糊精包合桉叶油的最佳制备工艺。方法采用正交实验法,以包合物的包合率和收得率为评价指标,优化桉叶油β-环糊精包合物的制备工艺。结果最佳包合工艺条件为挥发油与β-CD的比例为1∶8（mL∶g）,包合温度为55℃,搅拌时间为3h,β-CD与水的比例为1∶10（g∶mL）。结论该工艺合理可行,可用于桉叶油β-环糊精包合物的制备。     

密封控温技术制备β-环糊精包合物及影响工艺的因素

目的以苯甲酸为模型药物采用新的密封控温技术制备包合物,考察制备工艺中的各种影响因素。方法将主、客分子密封于容器内,通过控制加热温度、时间等因素使主、客分子形成包合物。结果加热温度、时间及载体的晶型等因素对包合过程都会产生影响。结论对苯甲酸-β-环糊精系统采用密封控温技术制备包合物的条件为控温90℃密封加热3 h为最佳;无定形性β-环糊精系统的包合率高于结晶性β-环糊精。     

Solid state studies of drug–cyclodextrin inclusion complexes in PEG 6000 prepared by a new method

The melting method was investigated as a possible method for producing drug–cyclodextrin (CD) inclusion compounds in a carrier. Various solid dispersions of -, β- and γ-CD in polyethylene glycol (PEG) 6000 with and without the addition of 5% w/w indomethacin or griseofulvin were prepared using the original components. Characterisations of the samples included X-ray powder diffraction, modulated-temperature differential scanning calorimetry and dissolution tests by the paddle method according to USP XXI standard. Evidence of a complex between indomethacin and β-CD in PEG 6000 was found. An indomethacin–γ-CD complex formed a well defined phase in the PEG carrier, with tetragonal structure and unit cell parameters a=23.885(35) Å and c=23.181(64) Å. No complexation of indomethacin with -CD, or with griseofulvin and β-CD could be detected. It is suggested that competition between PEG and the drug for the binding to different CDs along with varying patterns of water loss from the CDs influence the inclusion reaction. The formation of complexes was accompanied by a decrease in the relative crystallinity of the dispersions. Dissolution tests showed that the CDs have a delaying effect on the release of indomethacin from PEG 6000 in the order -CD<γ-CD≤β-CD.     

Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase the absorption of perphenazine in rabbits

Objectives The sublingual administration route as well as solid dispersion formation with macrogol 8000 and complexation with β‐cyclodextrin (β‐CyD) were investigated as ways for improving the absorption of perphenazine, a poorly water‐soluble drug subjected to substantial first‐pass metabolism. Methods The absorption of perphenazine was studied in rabbits after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/β‐CyD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze‐drying (perphenazine/macrogol solid dispersion) or spray‐drying (perphenazine/β‐CyD complex). Key findings The value for area under the curve from 0 to 360 min (AUC_{0–360 min}) of perphenazine after peroral administration was only 8% of the AUC_{0–360 min} value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/β‐CyD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first‐pass metabolism; good sublingual absorption of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations. Conclusions With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo.     

The effects of methyl tert-butyl ether (MTBE) on the male rat reproductive system

Methyl tert-butyl ether (MTBE) is an oxygenated compound, which has been widely used in Asia, Europe and North America. Although numerous in vitro and in vivo studies have demonstrated the carcinogenicity and the toxicity of MTBE, there is still a lack of data on reproductive system exposure of MTBE in male rodent animals. We studied subacute exposure of MTBE on the reproductive systems of male Sprague-Dawley rats. MTBE was administered to rats at dose levels of 0, 400, 800 and 1600 mg/kg/day. After 2 or 4 weeks of treatments, the rats were euthanized, and their serum, epididymis and testes were collected. Significant adverse effects in their reproductive system were observed including: a significant increase in the percentage of abnormal sperm; an irregular and disordered arrangement of the seminiferous epithelium indicated by a histopathological examination; changed serum levels of testosterone (T), luteinizing hormone (LH) and follicle stimulating hormone (FSH); and decreased levels of mRNA and of androgen binding protein (ABP). In the oxidative stress study, results indicated an increased maleic dialdehyde (MDA) content, implying a raised peroxide level, and that the total antioxidant ability in serum was significantly increased. This finding was especially strong at 1600 mg/kg/day MTBE. In the 2-week treatment, at 1600 mg/kg/day, the mRNA level of 8-oxoguanine DNA glycosidase (OGG1) was significantly decreased, and the mRNA level of the extra-cellular form of superoxide dismutase (SOD(EX)) was significantly increased. Our experiments suggest that relatively high doses of MTBE can exert reproductive system toxicity of male rats and disturb the secretions of T, LH and FSH, possibly due to oxidative stress induced by MTBE.     

Separation of cis-β-lactam enantiomers by capillary electrophoresis using cyclodextrin derivatives

Chiral separation of 19 pairs of cis-β-lactam (BL) stereoisomers of pharmacological importance was examined by capillary electrophoresis using cyclodextrin (CD) derivatives. In order to select the most effective conditions separating the highest number of stereoisomers of BLs, single carboxymethyl α-, β- and γ-, as well as sulfobutyl β-CD derivatives were applied. Additionally, carboxymethyl and sulfobutyl β-CD derivatives complemented with neutral β-CD derivatives as dual CD systems were tested. Both the composition and concentration of applied selectors and the pH of background electrolyte were selected. In single systems the structural characteristics of BLs and the complex forming affinity were correlated. Most BLs provided optimal complexation with β-CD derivatives. In conclusion, the efficiency of combining sulfobutyl-β-CD and permethylated β-CD was superior to other single and dual CD systems applied. This method successfully separated each pair of stereoisomers investigated.     

Recent results of biotransformation of drugs: investigation of the in vitro biotransformation of thalidomide using a dual cyclodextrin system in capillary electrophoresis

A previously developed capillary electrophoresis method for the simultaneous separation and enantioseparation of thalidomide (TD) and its hydroxylated metabolites was extended to one additional biotransformation product. The dual chiral selector system using native beta-cyclodextrin (beta-CD) and the negatively charged sulfobutyl-beta-CD (SBE-beta-CD) was slightly modified up to a concentration of 12 mg/ml running buffer of each CD. The carrier mode in which these buffer additives transport the neutral compounds to the detector as well as the use of a polyacrylamide-coated capillary were necessary to achieve reproducible enantioseparations of all eight analytes.     

Selective induction of apoptosis in mouse and human lung epithelial cell lines by the tert-butyl hydroxylated metabolite of butylated hydroxytoluene: a proposed role in tumor promotion

Butylated hydroxytoluene (BHT) causes lung injury in mice and promotes tumor formation. Hydroxylation of a tert-butyl group on BHT to yield the metabolite, 6-tert-butyl-2-[2′-(2′-hydroxymethyl)-propyl]-4-methylphenol (BHTOH), may be required. BHTOH is more potent than BHT on an equimolar basis in causing lung damage, enhancing lung tumor development, killing isolated bronchiolar non-ciliated Clara cells, and inhibiting lung epithelial gap junctional intercellular communication. One mechanism proposed for tumor promoting agents is selective cytotoxicity; killing normal cells allows uninhibited clonal expansion of neighboring initiated cells. We compared the abilities of BHT, BHTOH, and other BHT metabolites to kill non-tumorigenic and tumorigenic mouse and human lung cell lines, and examined the contribution of apoptosis to this cytotoxicity. These cells lack the cytochrome P450 2B isozyme necessary for converting BHT to BHTOH. BHTOH and 4-hydroperoxy-4-methyl-2,6-di-tert-butyl-2,5-cyclohex-adienone (BHTOOH) were most toxic, BHT and 2,6-di-tert-butyl-1,4-benzoquinone (BHTQu) were less potent, and 4-methyl BHT metabolites that are not pneumotoxic were ineffective. BHTOH most strongly induced apoptosis, based on nuclear condensation and transmission electron microscopy. Non-tumorigenic cells were as susceptible to cell death as the neoplastic cell lines when apoptosis and necrosis are not distinguished, but more sensitive to BHTOH-induced apoptosis. An apoptotic mechanism may underlie the lung tumor promoting actions of BHTOH.     

Characterization and in vitro evaluation of the formoterol/cyclodextrin complex for pulmonary administration by nebulization

The aim of this work is to investigate the effect of cyclodextrin complexation on the pulmonary deposition of formoterol, a drug with a very poor aqueous solubility, after jet nebulization. Two types of cyclodextrins, a hydroxypropyl β cyclodextrin (Kleptose HP) and a polydispersed methyl β cyclodextrin (Crysmeb) were used. The interactions of formoterol with the cyclodextrins were studied by NMR. The aqueous cyclodextrin solutions containing formoterol were defined by their physicochemical properties in relation to nebulization capacity: density, surface tension and viscosity. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity nebulized and nebulization time. The NMR ROESY spectra suggest that formoterol or a part of it is included inside the cyclodextrins. Densities and viscosities of the solutions tested are close to those of water; the lower surface tensions compared to water (53.7 and 56.7 vs 70 mN/m) favour the formation of small droplets. The aqueous solutions of cyclodextrins and formoterol studied can generate aerosols with a particle size that is compatible with pulmonary deposition. Respirable fraction values between 57.5% and 88 % were obtained when nebulizing the solutions with four nebulizers that differ geometrically. Nebulization rates varied from 0.19 to 0.47 g/min. Large quantities of drug nebulized over acceptable delivery times were observed. β-cyclodextrin derivatives can be used to formulate nebulizable solutions of formoterol. It is indispensable to define the appropriate nebulizers and operating conditions associated with the solutions to obtain adapted and reproducible activity.     

HPLC测定槲皮素自微乳中槲皮素的含量

目的测定槲皮素自微乳制剂的含量。方法采用HPLC法,C18色谱柱,甲醇-磷酸盐缓冲液(60:40)为流动相;流速1 m l.m in-1;检测波长373 nm。结果线性范围为7~70μg.m l-1(r=0.9998),回收率为98.4%,RSD=1.24%。结论本法简便、灵敏、准确。     

Preference for alcohol evoked by tetrahydropapaveroline (THP) chronically infused in the cerebral ventricle of the rat

The voluntary preference for ethyl alcohol in Sprague-Dawlet rats was determined over 12 days with water as the alternative fluid. The alcohol solutions offered to the animals were increased systematically in concentrations from 3 to 30%, according to a three-bottle, two-choice technique. Tetrahydropapaveroline (THP), a tetrahydroisoquinoline derivative, was infused repeatedly into the lateral cerebral ventricle of each rat through a guide tube implanted chronically. The metabolite was dissolved in a CSF vehicle, and infused in a volume of 1.0 μl every 15 min or 4.0 μl every 30 min around the clock, for the entire 12-day period of alcohol-water self-selection. Within 3 to 6 days of the start of infusion, extraordinary amounts of alcohol were consumed which ranged as high as 8 to 17 g per kg per day. Both the racemic mixture of THP and the S-(-)-THP isomer exerted this alcohol-inducing effect, when they were infused chronically in a range of doses from 100 picograms/μl to 1.0 mu;g/μl. Control intraventricular infusions of CSF according to the same regimen had no effect on alcohol preference. The excessive intake of alcohol during the intraventricular infusions of THP persisted long after the cessation of the infusion regimen, i.e., during retests carried out at one, six and nine months' intervals. Further, when THP-treated rats were offered a simultaneous choice of a palatable solution of saccharin together with alcohol, they continued to drink large volumes of alcohol. The 24 hr patterns of fluid intake, as registered continuously by a drinkometer, revealed that alcohol drinking was typically massed within two to four bouts during the night-time interval. During this period, the blood alcohol level reached concentrations as high as 0.2%. Withdrawal-like symptoms including wet-dog shakes, elevated tail, whisker twitching and occasional convulsive episodes, were also observed in the THP-infused rats. These findings provide support for the hypothesis that an alkaloid metabolite, which may be formed in both the brain and periphery, is involved in the mechanism underlying the pathological and sustained drinking which is characteristic of the disease state of alcoholism.     

Prenatal alcohol exposure causes the over-expression of DHAND and EHAND by increasing histone H3K14 acetylation in C57 BL/6 mice

Prenatal alcohol exposure leads to congenital heart abnormal development, its mechanisms are still unknown. Recent reports have associated alcohol exposure with histone H3 acetylation. In the present study, we have performed the experiments to test the hypothesis that histone H3K14 acetylation is the key role in the fetal heart leads to over-expression of cardiac specific genes DHAND and EHAND caused by prenatal alcohol exposure. Seventy pregnant C57BL/6 mice were divided randomly into seven groups (n = 10). They were the untreated group, dimethyl sulfoxide group, alcohol exposure group, curcumin treatment group, both alcohol and curcumin treatment group, SAHA treatment group, both alcohol and SAHA treatment group. Fetal mouse hearts were collected on embryonic day 14.5. The changes of HATs activities, the acetylation levels of histone H3K14 (H3K14ac), the expression levels of cardiac specific genes DHAND and EHAND, and structure of chromatin were determined. Our data indicates that curcumin and SAHA significantly reduces and increases the activities of HATs and the levels of histone H3K14ac in fetal hearts, respectively. The expression of DHAND and EHAND is significantly down-regulated and up-regulated in the groups treated with curcumin and SAHA. Furthermore, our results from ChIP assays have shown that the histone H3K14ac connects with the DHAND and EHAND genes are significantly inhibited by curcumin and simulated by SAHA. Our study suggests that prenatal alcohol exposure causes the over-expression of DHAND and EHAND by increasing H3K14ac in mice.