甲硝唑注射液共聚焦显微拉曼光谱法定性与定量分析

目的 研究拉曼光谱在甲硝唑注射液定性、定量分析中的应用.方法 分析甲硝唑注射液在酸性至碱性条件下(pH 1～12)拉曼光谱的变化,并检测甲硝唑注射液中的有关物质2-甲基-5-硝基咪唑的含量.采用偏最小二乘法(PLS)和主成分回归法(PCR)对甲硝唑注射液进行定量,并将检测结果与紫外分光光度法进行比较.结果 酸性条件下甲硝唑注射液在拉曼光谱图上有明显差别,碱性条件下,差异不明显,但在pH 12以上甲硝唑注射液变为暗红色.由于2-甲基-5-硝基咪唑在甲硝唑注射液中的浓度过低(1 mg/L),因此拉曼光谱图中无法检测到它的存在.结论 PLS和PCR两种方法在甲硝唑注射液的定量上都能得到满意的结果.拉曼光谱与紫外分光光度法得出的含量测定结果,根据t检验,没有显著差异(α=0.05).     

柱前衍生RP-HPLC-DAD法测定氨茶碱片及注射液中乙二胺的含量

目的：建立柱前衍生反相高效液相色谱法测定氨茶碱片及氨茶碱注射液中乙二胺的含量方法。方法：采用Agilent 5 TC-C18（2）色谱柱（4.6 mm × 250 mm,5 μm）,水（A）-乙腈（B）为流动相,梯度洗脱（0~12 min,60%→45% A,12~13.2 min,45%→25% A,13.2~18 min,25%→60% A,18~20 min,60%→60% A）,柱温30 ℃,流速1.0 mL·mL-1,紫外检测波长为228 nm,进样量10 μL。结果：主成分与其他成分能达到良好的分离;乙二胺的线性范围为1.076~10.757 μg·mL-1,线性方程为Y =228.073 1X + 24.177 5（r =0.999 9）;理论板数大于50 000,各相邻峰分离度均大于3,检测限为3.404 ng·mL-1,定量限为11.346 ng·mL-1;片剂的平均加标回收率为100.95%,RSD为0.34%（n=9）;注射剂的平均加标回收率为100.45%,RSD为0.21%（n=9）。3批氨茶碱片剂中乙二胺的含量测定结果分别为16.7%、16.9%、16.4%;3批注射剂中乙二胺的平均含量分别为16.9%、16.8%、16.6%。结论：该法可用于氨茶碱片及氨茶碱注射液中乙二胺的质量控制。     

便携式拉曼光谱法快速检测盐酸罗哌卡因注射液

摘要：目的:利用便携式拉曼光谱仪,建立快速检测盐酸罗哌卡因注射液的方法。方法:将便携式拉曼光谱仪与化学计量学方法相结合,建立盐酸罗哌卡因注射液定性和定量模型。其中,定性模型用相关系数法进行建立;定量模型用PLS算法（包装为玻璃安瓿瓶）以及通过不同浓度的盐酸罗哌卡因拉曼光谱特征峰(680.908 1 cm-1)结合标准曲线法（包装为玻璃以及聚丙烯安瓿瓶）进行建立。结果:9个厂家的24批样品定性结果均为“YES”;两种定量方法测定的盐酸罗哌卡因注射液含量均在95%～105%之间,与HPLC值相比较,相对偏差均在5%以内。结论:本方法测定简单,操作方便,可用于盐酸罗哌卡因注射液定性和定量检测。     

盐酸去甲万古霉素及其注射剂效价的浊度法研究

目的：建立浊度法测定盐酸去甲万古霉素及注射剂效价的方法。方法：以金黄色葡萄球菌为试验菌,加菌量2．0％～3．0％（V／V）,（37．0±0．5）℃培养4h左右测定。结果：抗生素线性浓度为1．6～4．8U／ml,一剂量法原料的平均回收率为101．2％,RSD为1．8％（n=9）;一剂量法注射用盐酸去甲万古霉素的平均回收率为100．8％,RSD为1．7％（n=9）。结论：本方法灵敏,快速,影响因素较少,可作为测定盐酸去甲万古霉素及注射剂的效价的方法。     

高效液相色谱法测定迪银片中无水茶碱的含量

目的:采用高效液相色谱法(HPLC法)测定迪银片中无水茶碱含量.方法:采用Nava-pak C18柱(5μm,150 mm×4.6 mm),以0.55%庚烷磺酸钠甲醇溶液-水(1:4)为流动相(以冰醋酸调节pH值为2.9±0.1),检测波长为254 nm,按外标法以峰面积定量.结果:无水茶碱的线性范围为40～200μg/mL,r=0.999 9,平均回收率为101.4%,RSD为0.4%.结论:高效液相色谱法灵敏、准确,可用于该制剂的质量控制.     

拉曼光谱快速检测利巴韦林注射液

目的:建立一种运用拉曼光谱技术快速鉴别测定利巴韦林注射液的方法。方法:以利巴韦林原料以及注射液为研究对象,应用拉曼光谱方法快速鉴别利巴韦林注射液和测定其含量。结果:拉曼光谱方法可以鉴别利巴韦林注射液,并进行含量测定。结论:本方法操作简便、快速、可发展成为注射剂快速检测的分析方法。     

拉曼光谱快速检测氨甲环酸注射液

目的 运用拉曼光谱技术快速鉴别、检查和测定氨甲环酸注射液.方法 以氨甲环酸原料及注射液为研究对象,应用拉曼光谱方法快速检测氨甲环酸.结果 拉曼光谱方法可以鉴别氨甲环酸注射液,并进行pH值检查和含量测定.结论 所用方法操作简便、快速,可发展成为注射剂快速检测的分析方法.     

基于拉曼光谱技术快速测定石膏中二水硫酸钙含量

目的:建立一种拉曼光谱技术快速测定石膏中二水硫酸钙含量的方法。方法:将不同产地的40批石膏样品做为训练集,以EDTA滴定法测定值为参考,利用OPUS软件建立二水硫酸钙拉曼光谱定量分析模型。结果:石膏中二水硫酸钙含量在97.93%~99.81%范围内的样品,所建立的拉曼光谱定量模型能快速准确测定。结论:本方法操作简便,快速,可以作为快速检测石膏主要成分含量的方法。     

近红外漫反射光谱法快速测定头孢氨苄胶囊含量

目的：利用近红外漫反射光谱（NIRDRS）分析技术对头孢氨苄胶囊进行快速定量分析。方法：以22个企业的98批头孢氨苄胶囊为分析对象,用光纤探头测定近红外漫反射光谱;定量模型的预处理方法为一阶导数与矢量归一化,波长范围11995．6～6098．1cm,回归方法为偏最小二乘法（PLS）。结果：80个样品经内部交叉验证建立预测模型,浓度范围为42．46％～92．32％,内部交叉验证均方差（RMSECV）为1．53％,相关系数为0．9871。用18个样品进行外部验证,外部验证均方差（RMSEP）为1．18％,平均回收率为100．1％,RSD为1．79％。结论：该法快速、准确、简便、无损,可用于药品的快速检验。     

近红外光谱法测定藿香正气水中乙醇含量

目的:利用近红外光谱建立快速测定藿香正气水中乙醇含量的方法.方法:用GC法测定藿香正气水中乙醇含量,采用偏最小二乘法(PLS)建立NIR光谱与GC测定值之间的多元校正模型,预测藿香正气水中乙醇含量.结果:所建立的校正模型内部交叉验证的决定系数R2为99.88,内部交叉验证方差(RMSECV)为0.347;验证预测值与理论值的相关系数为0.998 5,预测值平均回收率为99.92％(RSD=1.02％,n=9).结论:本方法简便精确、快速环保,可用于藿香正气水中乙醇含量的快速检测.     

氨茶碱缓释片的人体生物等效性研究

目的：研究氨茶碱缓释片试验制剂和市售参比制剂在20名健康男性志愿者体内的药动学和相对生物利用度,并进行生物等效性评价。方法：根据双交叉试验方法口服单剂量200mg的两种氨茶碱缓释片,采用HPLC法测定血浆中茶碱的浓度。结果：口服单剂量200mg试验制剂后,t1/2、tmax、cmax、AUC0～36、AUC0～∞分别为（9.13±1.94）h、（3.95±0.56）h、（3.66±0.70）μg/ml、（41.01±7.33）μg.h.ml-1和（44.29±8.60）μg.h.ml-1;参比制剂为（9.85±1.79）h、（4.10±0.53）h、（2.69±0.37）μg/ml、（39.36±6.24）μg.h.ml-1和（43.32±7.36）μg.h.ml-1。氨茶碱缓释片试验制剂相对生物利用度为（105±16.7）%。结论：试验制剂和参比制剂具有生物等效性。     

Comparative plasma pharmacokinetics of theophylline and ethylenediamine after the administration of aminophylline to man

Plasma concentrations of theophylline and ethylenediamine have been examined after the oral and intravenous administration of aminophylline to three healthy male volunteers who received on separate occasions 250 mg aminophylline i.v. or 300 mg aminophylline by mouth. Blood samples were taken at regular intervals and the plasma levels of theophylline and ethylenediamine were assayed by h.p.l.c. After i.v. injection, plasma concentrations of theophylline were described by a two-compartment open model, with t1/2α 6 min, V_c 191 ml kg^?1, t1/2β 6·0 h and V_p 217 ml kg^?1. The plasma concentrations of ethylenediamine also exhibited a biphasic decline, the parameters of the two-compartment open model being t1/2α 7 min, V_c 214 ml kg^?1, t1/2β 32 min and V_p 133 ml kg^?1 (all values given are means of three subjects). The ratio of theophylline/ethylenediamine in plasma rose rapidly from the initial value of 6·2 (the ratio of the two compounds in aminophylline) over the first 10 min post injection to 47 at 120 min. After this time, ethylenediamine was not measurable in plasma, although theophylline was present for at least 6 h after dosing. Upon oral administration of aminophylline, plasma concentrations of theophylline rose to a peak value of 7·4 μg ml^?1 at 1 h, falling thereafter with a t1/2 of 8·0 h. Ethylenediamine, by contrast, could only be detected over the first 2 h after dosing, in amounts below 0·4 μg ml^?1. Comparison of oral and i.v. data showed the bioavailability of ethylenediamine was approximately 34% in comparison with a value of 88% for theophylline. These data indicate that the two components of aminophylline are handled independently by the body and that there is no molecular association between theophylline and ethylenediamine in biological media.     

HPLC法测定氨茶碱片中无水茶碱的含量

采用HPLC法测定氨茶碱片中无水茶碱的含量。色谱柱：天津兰博C18,流动相：甲醇-水（30：70）,流速为1.0mL.min-1,检测波长：275nm。线性范围5.6～44.5μg.mL-1,r=1.0000,平均回收率为97.91%（n=6）,RSD为0.94%。本法操作简便、方法准确、重现性好,可用于该制剂的质量控制。     

大豆苷元对氨茶碱在大鼠体内药动学的影响

摘 要 目的:研究大豆苷元对氨茶碱在大鼠体内药动学的影响。方法: 采用HPLC方法测定大豆苷元和氨茶碱合并给药组与氨茶碱单独给药组茶碱在大鼠体内的血药浓度,比较两者的药动学参数。结果:①茶碱在0.2～20.0 μg·ml^-1浓度范围内线性关系良好,定量下限为0.2μg·ml^-1,低中高3个浓度的绝对回收率分别为（86.7±4.2）%、（90.5±3.4）%和（92.4±4.6）%,相对回收率均大于90%,日间和日内精密度RSD分别小于8.94%、9.01%;②大豆苷元和氨茶碱合并给药组和单独给药组药动学参数分别为：半衰期（t_{1/2）为(123.63±18.23)和(133.94±11.20)min,曲线下面积（AUC(0-∞)）为(1 861.03±511.23)和(2 075.41±720.96) μg·min·ml^-1,AUC(0-8)为（1 749.71±376.68）和（1 963.34±475.84）μg·min·ml^-1,达峰浓度Cmax为(10.35±0.95)和(10.23±0.82)μg·ml^-1;③合并给药组较单独给药组的主要药动学参数峰值Cmax相似,t1/2、AUC有一定降低,但差异无统计学意义。结论:大豆苷元对氨茶碱在大鼠体内的药动学无明显影响。}     

Pharmacokinetic study of theophylline in dogs after intravenous administration with and without ethylenediamine

Aminophylline (ethylenediamine salt of theophylline) and Theodrip, a new formulation of theophylline developed by Nikken Chemicals, are drugs for the treatment of acute bronchial asthma in injectable form. The present study was conducted using dogs to first confirm the bioequivalence of the two injectable forms containing theophylline and aminophylline and to secondly clarify the influence of the rate of venous infusion on the pharmacokinetics of theophylline in plasma. The following results were obtained: 1) Pharmacokinetic parameters of plasma theophylline after an intravenous bolus injection were close to those after the dosing of aminophylline in dogs by a crossover method. Thus, the 95% confidence limits of mean value differences of Cmax, t1/2 and AUC between the two injection forms were in the range of -3.16-4.28%, -6.19-7.28% and -7.23-5.28%, respectively. These results indicate the bioequivalence between theophylline and aminophylline in dogs from a pharmacokinetic point of view as well as the lack of influence of ethylenediamine on the pharmacokinetics of theophylline. 2) After the intravenous bolus injection (30 sec) and the 15-min constant rate infusion of theophylline to dogs, the plasma concentrations of theophylline were 27.37 +/- 3.67 micrograms/ml and 18.34 +/- 2.32 micrograms/ml immediately after the completion of administration, respectively. It is notable that in humans the former concentration level has been observed to frequently cause adverse effects, whereas the latter was in the safe range. Consequently, the 15-min constant rate infusion did not result in the rapid increase in the plasma theophylline concentrations and was superior to the bolus injection from the viewpoint of maintaining the safety plasma concentrations. In conclusion, to avoid hypersensitivity due to ethylenediamine and the adverse effects caused by high plasma concentrations of theophylline, it was considered that constant rate infusion of theophylline to the venous is preferable in the clinical setting.     

Usefulness and safety of theophylline injection form (Theodrip) for the treatment of acute asthma

The effects of the speed of intravenous infusion on the pharmacokinetics of theophylline were studied in 9 healthy volunteers (Ex I). Subjects were intravenously administered either six 4.8 mg/kg theophylline (Theodrip, Nikken Chemicals Co., Ltd., Japan) or three matching placebo injections (4.8 ml/kg physiological saline) for 30 min (Step I) or for 15 min (Step II). In Steps I and II, Cmax was 10.8 +/- 1.1 and 10.8 +/- 0.8 micrograms/ml, respectively. These Cmaxs were concentrations yielding therapeutic effects in patients with acute asthma. Next, comparative pharmacokinetics between theophylline (Theodrip) and aminophylline were examined by a crossover method in 16 healthy volunteers (Ex II). The 90% confidence limits of the differences of mean values were within 80-120% and were 92.8-100.1% for Cmax, 99.7-105.3% for t1/2 and 100.2-104.4% for AUC. Thus, we concluded that the pharmacokinetics of the plasma theophylline after intravenous administration of Theodrip (theophylline at 4.8 mg/kg) were bioequivalent to those of aminophylline (6.0 mg/kg) for 30 min. In Ex I and II, no subjects had adverse effects and in Ex I no influence on ECG was seen. In addition, the convenience of Theodrip was compared with that of ampules of aminophylline among nurse volunteers (Ex III). The times required for set-up of Theodrip were significantly shorter than those of aminophylline ampules. On the other hand, the adverse reactions to aminophylline resulting from hypersensitivity reactions to its ethylenediamine component have been reported. Theodrip consists of 200 mg theophylline and 200 ml physiological saline in a plastic bag. Therefore, Theodrip, which does not contain ethylenediamine, is expected to have less adverse effects and be easier to handle than aminophylline.     

Effects of intravenous theophylline, aminophylline and ethylenediamine on antigen-induced bronchoconstriction in guinea pigs

The antiasthmatic effect of i.v. injection of theophylline was compared with that of aminophylline by using an antigen-induced bronchoconstriction model in sensitized guinea pigs. Both theophylline and aminophylline showed dose-dependent inhibition of antigen-induced bronchoconstriction. Statistically significant differences were observed at theophylline doses of 20 and 40 mg/kg and at aminophylline doses of 25 and 50 mg/kg. Thus, antiasthmatic effects of both drugs appeared to be similar. In addition, intravenous ethylenediamine did not influence either airflow in normal guinea pigs or bronchoconstriction induced by antigen at doses up to 30 mg/kg. In conclusion, the ethylenediamine in aminophylline may not influence the antiasthmatic action of theophylline, and the therapeutic effects of theophylline and aminophylline are suggested to be similar.     

Quantitative determination of diclofenac sodium and aminophylline in injection solutions by FT-Raman spectroscopy

The FT-Raman quantification of diclofenac sodium and aminophylline commercial injection solutions was performed. The efficiency of various spectra treatment procedures including classical univariate intensity ratio and multivariate partial least squares (PLS) and principal component regression (PCR) methods was compared. First, the calibration models were built using unnormalised spectra. Next, spectra normalised by the intensity of a selected band of CH₃CN added as an internal standard to the studied samples were utilised. To compare the predictive ability of the models constructed, the relative standard error of prediction (RSEP) was calculated. The errors found for multivariate calibrations were a few times smaller than those for the univariate ones. Usually, the most effective was the PLS method, for which RSEP values of the order of 1–2% for calibration and 2–3% for testing data sets were obtained.

Four commercial preparations of diclofenac sodium and one of aminophylline containing by weight, 2.4% of the active pharmaceutical ingredient (API) were quantified applying the developed models. Concentrations found from the Raman data analysis correlate with the declared values and the results of reference analyses. For the studied diclofenac sodium solutions they amount to 99.2–101.2% of the former and 101.2–102.4% of the latter quantities for the PLS models optimised for each medicine based on unnormalised spectra. These values for the aminophylline preparation were found to be 101.0 and 99.1%, respectively. It shows that the proposed procedure based on the chemometric treatment of FT-Raman spectra can be a fast and convenient alternative to the standard pharmacopoeial procedures of API quantification even in relatively diluted injection solutions.     

Intravenous theophylline?

Aminophylline (theophylline ethylenediamine) has been widely used orally, intravenously, and rectally as a bronchodilator of choice in patients with asthma or chronic obstructive pulmonary disease. Its popularity for chronic oral administration has declined in recent years due to the development of a multitude of conventional and sustained release anhydrous theophylline preparations. The availability of a premixed intravenous theophylline product may further reduce aminophylline usage. This article reviews the potential usefulness of premixed intravenous theophylline.     

3D打印氨茶碱分剂量片的辅料相容性研究

目的 制备性质稳定的3D打印氨茶碱分剂量片,通过考察其理化性质,对药物与辅料的相容性进行研究。方法 制备不同处方和工艺的3D打印氨茶碱分剂量片,根据中国药典2020年版方法进行检测,初步确定影响药物稳定性的因素。采用差式扫描量热法(differential scanning calorimetry,DSC)、X射线粉末衍射(X-ray powder diffraction,XRPD)、傅里叶变换红外光谱(Fourier transform infrared spectroscopy,FTIR)、HPLC等方法对3D打印氨茶碱分剂量片进行分析,揭示药物与辅料的相容性以及影响药物稳定性的机制。根据研究结果,制备性质稳定的3D打印氨茶碱分剂量片,并考察其质量。结果 根据中国药典2020年版方法检测无水茶碱和乙二胺含量,初步确定影响药物稳定性的因素为填充剂的添加。添加MCC或乳糖的2种3D打印氨茶碱分剂量片在DSC、XRPD检测均有药物特征峰的消失;FTIR检测结果表明反应产物的官能团吸收峰与药物的有重叠,使特征谱带变宽;HPLC在检测无水茶碱时有小的杂质峰出现,说明MCC中存在少量的糖类降解产物,而乳糖不适合作氨茶碱的辅料,会影响药物的稳定性,因此3D打印氨茶碱分剂量片处方采用非糖类无水磷酸氢钙做填充剂,并根据临床需求规格设计药物处方并打印药片。所得片剂的药物含量及溶出度均符合中国药典2020年版规定,在DSC、FTIR、XRPD图谱中,药物特征峰均未受辅料影响,药物与辅料相容性良好。结论 3D打印药品分剂量片添加辅料时,需考察药物与辅料的相容性,MCC中微量杂质还原糖会与氨茶碱中乙二胺发生Maillard反应,在制备3D打印分剂量片时,需选择不影响药物稳定性的辅料。