头孢氨苄缓释小丸的初步研究

用膜控法制备头孢氨苄缓释小丸制剂,其体外溶出符合零级动力学过程(k_r=13.5mg/h)。在不同介质中其释药速率不同;释药速率与小丸的衣膜增重百分率的倒数成线性关系;体内动力学过程符合一室开放模型,血药浓度数据经 PKBP—Nl 计算机程序处理,求得 k_α=0.845h~(-1),k_e=0.641h~(-1),tmax=2.338h,Cmax=6.648μg/ml。体内外数据具有显著的相关性。     

阿司匹林缓冲片的生物利用度

本文对本室研制阿司匹林缓冲片的体外溶出速度,体外酸中和能力,单剂量和多剂量po服后的血药浓度、稳态血浓,生物利用度和对胃粘膜的刺激作用与阿司匹林普通片剂进行了比较研究。体外溶出采用转篮法,测得溶出50％所需时间分别为0.74min和3.76min。单剂量po后,缓 冲片的峰时和对照片剂有极显著差异,分别为1.23h和3.08h,峰浓分别为15μg/ml和133μg/ml,浓时曲线下面积分别为1454μg·ml~(-1)·h~(-1)和1343μg·m1~(-1)·h~(-1)。多剂量po达稳态后其最大血浓分别为297.5μg/ml和270.8μg/ml,尿液pH无明显差异。两种片剂大白鼠灌胃后2h的胃体解剖镜窥检,比较胃粘膜下水肿、充血、瘀血、特别是胃粘膜腐蚀糜烂程度,清楚地显示了缓冲片对胃刺激性轻于对照片。说明本室研制的阿司匹林缓冲片溶出迅速,吸收迅速、完全,对胃粘膜刺激性减轻,不影响尿液pH不降低稳态血浓。而且该片剂制备简单,明显优于普通片。     

盐酸青藤碱渗透泵控释片的体内外相关性研究

制备了盐酸青藤碱渗透泵控释片.以正清风痛宁缓释片为参比制剂,考察其体外释放度和Beagle犬体内吸收情况.自制控释片与参比制剂的主要药动学系数:AUCo-1(11.01±3.2)和(13.06±3.5)μg·ml-1·h,t1/2(27.8±2.6)和(8.6±1.9)h,cmax(790.8±126.3)和(1334.5±150.5)ng/ml.结果表明,自制控释片的体外释放符合零级动力学方程.采用HPLC法测定血药浓度,照Wagner-Nelson法计算药物的体内吸收分数,对响应时间的体外累积释放率线性回归,所得方程的相关系数为0.98.     

控释制剂的新技术——地形测绘溶出特征

对于大多数口服控释制剂而言,溶出是药物释放的主速过程。它们与一般制剂不同,吸收速率常慢于消除速率,因之药物在体内从片剂、包衣颗粒或骨架等的溶出和释放,成为关键的主速过程,体外模拟较为困难。由于控释制剂要通过一系列不同pH的环境(从pH接近1的胃到pH7的小肠远端),在制剂的设计和研究中,pH是必须考虑的主     

岩白菜素包合物渗透泵片制备工艺研究

目的利用β-环糊精（β-CD）包合技术改善微溶性药物岩白菜素的体外溶出行为,进而考察片芯及包衣处方对岩白菜素包合物渗透泵片体外释药性质的影响,并优选最佳片芯及包衣处方。方法采用饱和水溶液法制备岩白菜素β-CD包合物,并测定其溶出速率和溶解度;根据不同时间的累积释放度,考察药物的释放情况,通过单因素考察及正交试验设计优化片芯及包衣处方。结果聚氧乙烯的分子量和用量及甘露醇的用量,对岩白菜素包合物渗透泵片体外释药行为有影响。最后所得处方可在12h内稳定释药且累积释放度可达到90%以上。结论以岩白菜素β-CD包合物为中间体,可以制成零级释药特征显著的单室单层渗透泵片。     

盐酸强力霉素缓释微丸的制备及药物动力学研究

本文采用膜控法制备盐酸强力霉素缓释微丸。实验表明,本品的体外溶出符合零级动力学过程(K_r~0=20.5 mg/h);贮存期为两年,胃刺激性明显低于普通片剂(p<0.001),体内动力学过程符合表观零级吸收与一级消除的单室模型。体内数据经NONLIN计算机程序处理,求得各项参数如下:K_a=58.08 mg/h,K=0.032 h-1,V_d=82.211,t_(max)=3.94 h,c_(max)=2.30μg/ml。按强力霉素的常规用药方案给药,本品与市售普通片生物等效。本品的体内外数据具有显著的相关性(p<0.001)。     

岩白菜素包合物渗透泵片制备工艺研究

目的　利用β-环糊精(β-CD)包合技术改善微溶性药物岩白菜素的体外溶出行为,进而考察片芯及包衣处方对岩白菜素包合物渗透泵片体外释药性质的影响,并优选最佳片芯及包衣处方。方法 采用饱和水溶液法制备岩白菜素β-CD包合物,并测定其溶出速率和溶解度;根据不同时间的累积释放度,考察药物的释放情况,通过单因素考察及正交试验设计优化片芯及包衣处方。结果 聚氧乙烯的分子量和用量及甘露醇的用量,对岩白菜素包合物渗透泵片体外释药行为有影响。最后所得处方可在12 h内稳定释药且累积释放度可达到90%以上。结论 以岩白菜素β-CD包合物为中间体,可以制成零级释药特征显著的单室单层渗透泵片。     

消炎痛缓释胶囊的生物利用度研究

消炎痛普通制剂口服吸收迅速,可出现不必要的高血药浓度,导致不良反应。为此我们对三种消炎痛缓释胶囊(A,B,C)和一种常用片剂(D)作了体外溶出试验和体内生物利用度比较。胶囊制剂由丙烯酸类树脂材料E_(30)D包衣的药物小丸制成,其体外溶出行为显示缓慢释放图象。在8名成年男性交叉实验中,不同胶囊制剂和普通片剂之间的Tmax,Cmax和AUC_(0～124)经方差分析无统计学差异,但是在给药后4至12小时的血清浓度—时间曲线,均比普通片剂高而平滑。在第12小时,三种胶囊产生的血清浓度显著高于普通片剂(P<0.1)。根据体外溶出行为和体内生物利用度发现T_(50)或Tmax和包衣厚度呈良好线性关系。     

流化床制备胃漂浮型控释甲硝唑微丸

为治疗胃内幽门螺旋菌感染,需制备胃漂浮型控释制剂。采用流化床制备甲硝唑控释微丸,以NaHCO_3作产气介质,产生浮力,以EC为主要成膜材料,控制药物释放。根据体外溶出对时间的曲线筛选处方。所得微丸以近似零级动力学进行释药,其溶出速率常数为0.15(t≤6h),释放持续时间达10h以上。约80％的微丸可稳定飘浮8h以上,达到了控释与漂浮的双重要求。     

甲壳素对双氯灭痛缓释片溶出的影响

以pH 6.8磷酸盐缓冲液为释放介质,采用转蓝法测定了不同甲壳素含量的双氯灭痛缓释片的体外累体释放度。结果表明,随着片剂中壳素含量的增高、片剂溶出变慢,且溶出越符合零级释放。     

Pharmacokinetics of ketanserin in patients with essential hypertension

Summary The pharmacokinetics of ketanserin and its main metabolite ketanserin-ol, and the antihypertensive effects of intravenous, single oral and chronic oral (40 mg once daily) administration of ketanserin, have been investigated in a single blind study of 10 patients with uncomplicated mild hypertension. Ketanserin had a terminal half-life of 29.2 h, a plasma clearance of 518 ml/min and a volume of distribution of 18.0 l/kg. Chronic oral intake of 40 mg ketanserin (tablet formulation) gave a peak concentration of unchanged ketanserin of 88 ng/ml after 1.1 h. Its absolute bioavailability was 48%.During chronic therapy the maximal concentration of ketanserin-ol was 208 ng/ml and its half-life of elimination was 35.0 h. As this metabolite can be oxidized back to ketanserin, it contributes to the prolonged half-life of unchanged ketanserin seen during chronic therapy.The blood pressure was reduced by approximately 15% by oral ketanserin. The maximal reduction in blood pressure coincided with the peak concentration of unchanged ketanserin. During chronic therapy with 40 mg once daily blood pressure was reduced over 24 h. The heart rate was slightly reduced and the cardiovascular responses and the plasma noradrenaline concentrations during isometric exercise were only slightly influenced by ketanserin therapy.Thus, unchanged ketanserin has a relatively long half-life during chronic oral therapy and its pharmacokinetics in middle-aged hypertensive patients is similar to that in normal young volunteers.     

Pharmacokinetic studies with atenolol in the dog

The pharmacokinetics of the cardioselective β-adrenoreceptor blocking agent atenolol have been determined following intravenous and oral dosing to the dog. After intravenous administration at 200 mg the blood levels of parent drug were found to decay tri-exponentially with a final elimination phase half-life of about 4–5 h. The volume of distribution for the central compartment was 40 per cent body weight and the whole body volume of distribution was 160 per cent body weight. The percentage urinary recovery of parent drug was 83 per cent. Following oral dosing at 400 mg (as a solution and as a clinical trial tablet) the percentage urinary recovery was 65 per cent and the half-life extended slightly to between 5 and 6h. The peak blood levels were however very similar for the two formulations (17 and 15μg/ml for the solution and tablet respectively) and occurred at the same time (l–2h after dosing). The total areas under the blood concentration time curves were similar and the values (100 and 104ugml^?1h respectively) agreed well with that anticipated on the basis of the intravenous data. It was concluded that the two formulations were bioequivalent and that following oral dosing atenolol was almost completely absorbed with little metabolism or biliary excretion. Following chronic oral dosing at 50, 100, and 200mg/kg/day the systemic blood levels were found to increase with dose at all time points throughout the study. There was no sex or dose dependency of the half-life and its value on chronic dosing was very similar to that on acute dosing. The dose dependency of the area under the blood concentration time curves was reflected in the plateau blood levels and there was very good agreement between the experimental values and the theoretical relationship based on the acute pharmacokinetic data. In accordance with the half-life there was no accumulation at any of the dose levels studied. Thus it can be concluded that atenolol obeys linear pharmacokinetics over the dose range studied.     

Tissue time course and bioavailability of the pyrethroid insecticide bifenthrin in the Long-Evans rat

1.?Pyrethroids are neurotoxic and parent pyrethroid appears to be toxic entity. This study evaluated the oral disposition and bioavailability of bifenthrin in the adult male Long-Evans rat.

2.?In the disposition study, rats were administered bifenthrin (0.3 or 3?mg/kg) by oral gavage and serially sacrificed (0.25?h to 21 days). Blood, liver, brain and adipose tissue were removed. In the bioavailability study, blood was collected serially from jugular vein cannulated rats (0.25 to 24?h) following oral (0.3 or 3?mg/kg) or intravenous (0.3?mg/kg) administration of bifenthrin. Tissues were extracted and analyzed for bifenthrin by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

3.?Bifenthrin concentration in blood and liver peaked 1–2-h postoral administration and were approximately 90?ng/ml (or g) and 1000?ng/ml (or g) for both tissues at 0.3 and 3?mg/kg, respectively. Bifenthrin was rapidly cleared from both blood and liver. Brain concentrations peaked at 4–6?h and were lower than in blood at both doses (12 and 143?ng/g). Bifenthrin in adipose tissue peaked at the collected time points of 8 (157?ng/g) and 24 (1145?ng/g) h for the 0.3 and 3?mg/kg doses, respectively and was retained 21 days postoral administration. Following intravenous administration, the blood bifenthrin concentration decreased bi-exponentially, with a distribution half-life of 0.2?h and an elimination half-life of 8?h. Bifenthrin bioavailability was approximately 30%. These disposition and kinetic bifenthrin data may decrease uncertainties in the risk assessment for this pyrethroid insecticide.     

Pharmacokinetics and side-effects of clonidine

Summary A single oral dose of clonidine 300 µg was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17±0.12 ng/ml at about 2 h: the absorption half-life was 0.6±0.2 h. Elimination followed first order kinetics with a half-life of 7.7±2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p<0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 µg t.i.d.) for one week a steady state serum level of 0.30–0.35 ng/ml was achieved. One 75 µg tablet of clonidine raised the serum level to about 0.69±0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5±1.5 h. The urinary excretion of unchanged clonidine was found to be about onethird of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.     

Pharmacokinetics of haloperidol in psychotic patients

Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5–5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79±0.03. The blood clearance was then calculated to be 550±133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9±2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60±0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3±1.1 h and a longer absorption half-life (1.9±1.4 h) was found in the patients compared with healthy volunteers.     

Development of controlled release captopril granules coated with ethylcellulose and methylcellulose by fluid bed dryer

Captopril granules of controlled release with different polymers as ethylcellulose, ethyl/methylcellulose, and immediate release with polyvinylpyrrolidone (PVP) were developed by fluid bed dryer technique. The formulations were analyzed by scanning electron microscopy, X-ray powder diffraction, and dissolution profiles. To compare the formulations an in vivo setting rat blood pressure assay was performed, using angiotensin I as a vasoconstrictor agent. The scanning electron microscopy of granules showed differences in morphology, and X-ray powder diffraction technique presented some modification in crystalline structure of captopril in granules coated with PVP and ethyl/methylcellulose. The dissolution profile of granules coated with ethylcellulose showed a median time release of 4 hr whereas for granules coated with ethyl/methylcellulose, this time was 3.5 hr. The blockage of angiotensin I-induced hypertensive effect lasted 8 hr in granules coated with PVP and of more than 12 hr in the granules coated with ethylcellulose and ethyl/methylcellulose.     

Fraction of theophylline in sustained-release formulation which is absorbed from the large bowel

Summary In a cross-over study of six healthy male volunteers, 500 mg theophylline was administered either as plain tablets or in a sustained release preparation. On each occasion 2 g of non-enteric coated sulphasalazine was administered simultaneously as the time of appearance of sulphapyridine, the product of hydrolysis, in the blood provides an approximation of the oral — caecal transit time. The mean fraction absorbed — time profile was calculated from serial serum concentration measurements of theophylline by a modification of the Wagner-Nelson equation. The mean cumulative fraction of the dose absorbed following administration of the plain tablets was maximal at 3 h i.e. approximately 3 h ahead of the mean oral-caecal transit time, which was 5.9 h. Thus complete absorption occurred in the small intestine.With the sustained — release formulation, approximately only half of the dose was absorbed at the time the medication reached the large bowel i.e. at about 5.4 h. Absorption continued and at least 38% of the administered dose was additionally absorbed over the next 25 h.A reliable lengthened dosage interval is therefore possible with this particular sustained — release formulation.     

Prolonged action preparation of cefaclor

This study was conducted to develop a prolonged action preparation of cefaclor (CCL) which can offer, with the twice-a-day administration, as much effectiveness as its conventional preparation (Kefral capsule) with the 3 times-a-day administration. Absorption site of CCL in gastrointestinal tract, preparation form (enteric coated granules) which slowly release CCL, dissolution property of the form, and mixed ratio of the form and rapid release form (nonenteric coated granules) were studied and complex granules consisting of 40% of nonenteric coated granules and 60% of enteric coated granules which dissolve at pH 6 were chosen as a prolonged action preparation of CCL. Bactericidal activity of the prolonged action preparation (S6472) was confirmed to be the same as that of the conventional preparation by comparative viable cell count study in which concentrations of CCL simulated to plasma concentrations following the administration of S6472 at the dosage of 375 mg b.i.d. and the conventional preparation at the dosage of 250 mg t.i.d. were used. From the above, S6472 is considered to be a prolonged action preparation of CCL which serve our purpose. Since S6472 can be given with the twice-a-day administration, its daytime administration is not necessary. Therefore, S6472 is considered to be much useful preparation for the patients.     

Pharmacokinetics of N4-Octadecyl-1-β-d-Arabinofuranosylcytosine in Plasma and Whole Blood after Intravenous and Oral Administration to Mice

N⁴-octadecyl-1-β-d -arabinofuranosylcytosine (NOAC) is a new cytotoxic derivative of cytosine arabinoside with improved cytotoxic activity and stability against deamination. Its pharmacokinetics were studied in mice. The drug was administered intravenously and orally to ICR mice to assess its pharmacokinetic parameters in plasma and whole blood. The lipophilic drug was administered in small unilamellar liposomes 100–400 nm in diameter. The concentrations of NOAC in plasma and erythrocytes were determined by high-performance liquid chromatography (HPLC). When given orally a rather low amount of the delivered NOAC was absorbed as the unchanged drug, resulting in a bioavailability of 11% from the plasma and 12.9% from whole blood. As shown elsewhere, the amount of drug absorbed is sufficient to provide excellent cytotoxic activity in the L1210 leukemia and in human xenograft models after oral administration. The mean residence time of NOAC after intravenous administration was 3.5 h in plasma and 6 h in whole blood giving NOAC a terminal half-life in blood substantially longer than that of cytosine arabinoside. After oral administration the mean residence time was 18 h in plasma and whole blood. In summary, NOAC has a prolonged half-life after intravenous administration compared with cytosine arabinoside. The distribution of NOAC in blood is highly dependent on its mode of administration.     

Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects

Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (C_max) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels.