Comparative pharmacokinetics of ketoprofen derived from single oral doses of ketoprofen capsules or a novel sustained-release pellet formulation

Nine healthy male volunteers took part in a crossover study to compare the pharmacokinetics of ketoprofen after administration of a single oral dose (200 mg) of ketoprofen as 'Orudis' capsules or encapsulated sustained-release pellets, 'Oruvail'. The mean +/- standard deviation values for highest observed plasma ketoprofen concentrations were determined by high performance liquid chromatography to be 23 +/- 11 micrograms ml-1 at 0.82 +/- 0.18 h after dosing with ketoprofen capsules and 3.5 +/- 1.0 micrograms ml-1 at 4.9 +/- 1.0 h after dosing with sustained-release pellets. The apparent ketoprofen elimination half-lives after these treatments were 3.3 +/- 1.2 h and 8.4 +/- 3.4 h, respectively. The systemic availability of ketoprofen was essentially the same after each treatment. Administration of sustained-release pellets (containing 200 mg ketoprofen) once every 24 h is predicted to produce similar average and markedly higher minimum plasma ketoprofen concentrations than are produced by ketoprofen capsules (100 mg) every 12 h, and similar minimum plasma ketoprofen concentrations to those achieved by dosing ketoprofen capsules (50 mg) every 6 h. Once-daily administration of a non-steroidal anti-inflammatory agent has an obvious therapeutic advantage over more frequent dosing. This study suggests that the sustained-release pellet formulation described herein is a suitable formulation for once-daily administration of ketoprofen.     

口服缓释制剂的研究进展

缓释制剂作为一种前沿的药物剂型在制药行业得到广泛的研究和应用.缓释制剂具有释药平稳、药效持久、副作用小等优点,不仅可以有效控制血药浓度,减少用药副反应,而且可以大大延长药物作用时间,减少服药次数,提高患者的顺应性,在药品实际生产应用中占据重要地位.目前,缓释制剂多用于传统药物的剂型改进和新药的开发.本文通过查阅相关文献,综述了口服缓释制剂的应用研究进展.     

氟化钠缓释片人体药动学与体内外相关性研究

目的 :研究氟化钠缓释片在人体内药动学和体内外的相关性。方法 :采用氟离子选择电极 ,测定10名自愿者单剂量口服25mg氟化钠缓释片后的血清氟离子浓度 ,计算药动学参数 ;按照Wagner-Nelson法计算的药物吸收分数与体外释放度进行相关性研究。结果 :体内过程符合一室开放模型 ,AUC0→r为1216 03ng·h -1·ml -1,Ka为0 72h ,Tlag 为0 55h ,Ke为0 19h ,t12,Ke为3.75h ;药物体外释放与体内吸收具良好相关性。结论 :该研究可为氟化钠缓释片的内在质量评价和制剂开发提供一定科学依据。     

阿司匹林壳聚糖缓释片兔体内药物动力学研究

目的　研究阿司匹林壳聚糖缓释片的体内药物动力学。方法　采用随机分组自身对照实验 ,分别给予家兔口服阿司匹林壳聚糖缓释片和阿司匹林肠溶片 ,定时收集血样 ,以分光光度法测定血药浓度 ,用 3P97药动学程序进行处理。结果　缓释片和肠溶片的 Tmax分别为 (6 .90± 0 .5 2 ) h和 (4.6 6± 0 .4 0 ) h;Cmax分别为 (5 .33±0 .38)和 (9.39± 0 .5 3) mg· L-1;AUC0→ 2 4h分别为 (6 3.4 5± 1.19)和 (6 4.85± 1.96 ) mg·h· L-1;相对生物利用度为 (97.92± 0 .0 3) %。结论　阿司匹林壳聚糖缓释片在家兔体内有缓释特征 ,可望为预防和治疗血栓形成提供一个新的剂型。     

硝苯地平缓释片人体药代动力学研究

目的建立HPLC-MS法硝苯地平血浓度测定方法,评价硝苯地平缓释片的药动学特点。方法固定相XB-C18（5μm,150mm×4.6mm,Agilent1100SeriesLC/MSD高效液相色谱/质谱仪;流动相甲醇：0.01mol·L^–1醋酸铵溶液（60：40,V/V）,0.40μm微孔滤膜过滤,在线脱气;流速1.0mL·min^–1;柱温25℃;进样量10L。离子源：AP-ESI,正离子模式,雾化电压50psi,保护气13.0L·min^–1 N2,毛细管电压4000V,碎片电压为110V。SIM离子采集方式,采集离子（m/z）硝苯地平314.9[M＋H]^＋,内标劳拉西泮320.8[M＋H]^＋。结果硝苯地平线性范围0.3～80ng·mL^–1,最低检出浓度为0.3ng·mL^–1。硝苯地平试验制剂和参比制剂t1/2分别为6.73±2.00h和7.04±2.18h,Tmax分别为4.28±0.70h和4.48±0.70h,Cmax分别为39.66±10.58ng·mL^–1和40.19±10.97ng·mL^–1,AUC0～36分别为391.63±108.55ng·mL^–1·h和387.57±121.51ng·mL^–1·h,AUC0–∞分别为408.28±121.16ng·mL^–1·h和406.15±133.13ng·mL^–1·h,试验制剂硝苯地平缓释片相对生物利用度F为103.02±13.93%。结论HPLC-MS法测定硝苯地平血浓度实用、可行,适用于常规硝苯地平药代动力学研究。     

Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin

Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan). Thirteen healthy female volunteers received three 5 mg OROS oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect).     

Pharmacokinetic evaluation of novel sustained-release dosage forms of valproic acid in humans

Five new sustained-release dosage forms of valproic acid (VPA) were developed. The new sustained-release formulations were administered to six healthy subjects for comparison with a standard tablet and an i.v. preparation of the drug. Three of the formulations exhibited a more prolonged and uniform absorption rate and yielded more sustained serum levels after ingestion. These three formulations maintained serum therapeutic levels of VPA for 24 h after a single oral administration of 1 g, and were bioequivalent to a marketed standard tablet of VPA. The absorption profile of the various oral formulations was analysed pharmacokinetically, using the Loo-Riegelman procedure.     

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)。     

Preparation and evaluation of sustained-release azithromycin tablets in vitro and in vivo

The objective of this study was to prepare azithromycin (AZI) sustained-release products in order to allow for a high dose to be administered, reduce gastrointestinal side-effects and increase the compliance of patients. AZI sustained-release tablets with different release performance (F-I: T_100% = 3 h and F-II: T_100% = 8 h in pH 6.0 phosphate buffer) were successfully prepared by wet granulation. The in vitro release rate and drug release mechanism were studied. The release rate of F-I was affected by dissolution media with different pH, but not for F-II. Hixson–Crowell model was the best regression fitting model for F-I and F-II. Additionally, F-I and F-II both belonged to non-Fick diffusion. Oral pharmacokinetics of the two tablets and one AZI dispersible tablet as reference were studied in six healthy beagle dogs after oral administration. Compared with the reference, the C_max of F-I and F-II were decreased, and the T_max were prolonged, in that case which meet the requirement of sustained-release tablets. The relative bioavailability of F-I and F-II were 79.12% and 64.09%. T-test of AUC_0–144, and AUC_0–∞ for F-I and F-II indicated there was no significant difference between F-I and F-II. These mean that the extended release rate did not induce different pharmacokinetics in vivo.     

Pharmacokinetic analysis of sustained-release dosage forms of theophylline in humans: comparison of single and multiple dose studies

A pharmacokinetic analysis of two sustained-release dosage forms of theophylline (Theo-Dur and Theotrim) was carried out following single and multiple dose administrations of the two formulations in five healthy subjects. Despite the prolonged absorption after administration of the two sustained-release formulations, theoretical predictions of theophylline steady-state levels following multiple dosages based upon data obtained from the single dose study, correlated with the data of the multiple dose study. This study shows that the recommended dose and dosage regimen of new sustained-release formulations of theophylline can be based upon single dose studies. In the population studied, repetitive doses of 450 mg b.i.d. of Theo-Dur and Theotrim maintain steady-state concentrations of theophylline within the drug's therapeutic window.     

Clinical assessment of theophylline absorption from Theolair-SR and two other sustained-release formulations relative to a conventional formulation

In this single dose study with 8 subjects, the rate and extent of theophylline absorption from 3 sustained-release formulations (Theolair-SR tablet, Slo-phyllin Gyrocaps, and an experimental SR tablet) were compared to absorption from a conventional formulation (Theolair tablet) that has been shown to provide both prompt and complete absorption. Plasma theophylline level versus time profiles show that the rate of absorption from all 3 sustained-release formulations is slower than from the conventional tablet. In addition, the higher plasma levels at later times and the slower apparent plasma elimination rate of theophylline following the Theolair-SR tablet as compared to the conventional Theolair tablet indicate that drug absorption continues over a more prolonged period of time. Plasma AUC data indicate, with good assurance, that the extent of theophylline absorption is essentially complete from all 3 sustained-release formulations when compared to data for the conventional tablet. Statistical analyses with plasma AUC data indicate that the Theolair-SR tablet should provide both reliable and complete drug absorption. Projected plasma drug levels for multiple dosage regimens (simulated on the basis of the single dose data from this study) demonstrate that, even with a twice daily dosage regimen, the Theolair-SR tablet has acceptable sustained-release characteristics relative to the conventional Theolair tablet with 4 daily doses, and that the sustained-release properties compare favorably with those of Slo-phyllin Gyrocaps.     

Bioequivalency of oral suspension formulations of cefixime

A study was performed in 24 healthy male subjects to establish that two suspension formulations of cefixime were bioequivalent to each other and to a reference oral solution. A single 400 mg oral dose of the drug was given in a randomized three-way crossover design as two suspensions (a research suspension (RS) used during clinical trials and a suspension intended for marketing (MS] and a reference oral solution (SOL). Each dose was separated from the other by a 3-day washout period. Mean peak serum concentrations (Cmax) were 4.67, 4.10, and 4.27 micrograms ml-1 after the MS, RS, and SOL, respectively. Although comparison (ANOVA) of the mean pharmacokinetic parameters for cefixime found significant differences (p less than 0.05) in Cmax, the time to Cmax, and area under the serum concentration time curve (AUC 0----infinity) values among the three formulations, the mean differences were less than 20 per cent. No significant differences (p greater than 0.05) were found in either the elimination half-life or renal clearance of unchanged drug. Overall, with a 98 per cent power to detect a 20 per cent difference in AUC0----infinity or urinary recovery values between the formulations tested, the results show that the MS was bioequivalent to the RS and that both suspensions were bioequivalent to the SOL.     

Evaluation of sustained-release granules of chlorphenesin carbamate in dogs and humans

The bioavailability and pharmacokinetic properties of two sustained-release (SR) formulations of chlorphenesin carbamate (CPC) with different in vitro release rates were compared to those of an immediate-release (IR) formulation in beagle dogs and humans. Plasma levels of CPC were determined by HPLC assay. In humans, both SR formulations (SR-1 and SR-2), which have a difference in the rates of in vitro release, showed satisfactory maintenance of plasma concentrations with sufficient bioavailability as compared with the IR formulation, and their bioavailabilities relative to IR (relative bioavailability) were 1.00 and 0.86 for SR-1 and SR-2, respectively. Satisfactory maintenance of plasma concentration was also obtained in dogs, although the gastrointestinal transit time was shorter than that in humans. The relative bioavailabilities under fasting conditions in dogs were 1.05 and 0.90, respectively, and were almost the same in humans. The absorption from the small intestine and colon was almost complete for CPC in rats. It is suggested that the bioavailability of CPC was little affected by the gastrointestinal transit time. The reason that the bioavailability and pharmacokinetic properties of CPC in dogs were similar to those in humans might be due to the continuous absorption of CPC from these SR formulations after arrival in the colon. In this study, the dog was found to be a useful animal model for primary screening of SR formulations containing a drug which can be absorbed from the entire intestine, such as CPC.     

硝酸异山梨酯缓释微丸处方及工艺优化

目的制备硝酸异山梨酯缓释微丸,优化处方及制备过程。方法采用粉末层积法和流化床喷雾法制备膜控缓释微丸,用单因素考察实验优化处方及工艺,采用HPLC法测定缓释微丸的累积释放度。结果确定以Eudragit RS30D和Eudragit RL30D混合分散体为包衣材料,Eudragit RS30D与Eudragit RL30D的比例是4∶1,包衣增重为5%,热处理温度、时间为40℃、24小时,抗静电剂、增塑剂分别占包衣聚合物量的0.5%、20%。在体外释放度实验中,微丸累积释放硝酸异山梨酯百分率,0.5小时为10.71%,2小时为45.80%,8小时90.79%,24小时为99.14%。结论体外释放度实验中,Eudragit RS30D与Eudragit RL30D的比例对微丸累积释放度的影响较大,随着包衣量增加,释放度略有降低。本制剂为膜控制剂。     

Multiple dose comparison of a whole 240 mg verapamil sustained-release tablet with two half tablets

Twelve healthy male volunteers were studied in a balanced crossover comparison of an intact 240 mg verapamil sustained-release tablet (Securon SR, Isoptin Forte Retard) given once daily for 7 days, and the same dose given as two half tablets. One subject was withdrawn because of asymptomatic second degree heart block on day 3 of verapamil treatment. The mean Cmax after dosing with whole tablets, 143 (95 per cent confidence limits 91.6-223) ng ml-1 was lower than after dosing with half tablets, 160 (107-241) ng ml-1, but this was not significant (p = 0.49). The mean steady-state Cmin values after whole and half tablets were also similar: 22.2 (12.6-39.4) ng ml-1 and 22.0 (16.2-29.9) ng ml-1, respectively (p = 0.96). The mean (+/- S.D.) tmax, AUC0-24 and t 1/2 were not significantly different: whole tablet 3.5 +/- 1.2 h, 1733 +/- 1125 ng.h ml-1 and 10.5 +/- 3.4 h, respectively, and half tablets 3.6 +/- 1.0 h, 1780 +/- 1057 ng.h ml-1 and 9.6 +/- 2.3 h, respectively. The findings for plasma norverapamil were generally similar to those for the parent drug. This investigation indicates that the formulation is sufficiently robust to retain its sustained-release properties when the tablet is halved.     

Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes

Rationale Methylphenidate (MPH) is a dopamine and noradrenaline enhancing drug used to treat attentional deficits. Understanding of its cognition-enhancing effects and the neurobiological mechanisms involved, especially in elderly people, is currently incomplete. Objectives The aim of this study was to investigate the relationship between MPH plasma levels and brain activation during visuospatial attention and movement preparation. Methods Twelve healthy elderly volunteers were scanned twice using functional magnetic resonance imaging (fMRI) after oral administration of MPH 20 mg or placebo in a within-subject design. The cognitive paradigm was a four-choice reaction time task presented at two levels of difficulty (with and without spatial cue). Plasma MPH levels were measured at six time points between 30 and 205 min after dosing. FMRI data were analysed using a linear model to estimate physiological response to the task and nonparametric permutation tests for inference. Results Lateral premotor and medial posterior parietal cortical activation was increased by MPH, on average, over both levels of task difficulty. There was considerable intersubject variability in the pharmacokinetics of MPH. Greater area under the plasma concentration-time curve was positively correlated with strength of activation in motor and premotor cortex, temporoparietal cortex and caudate nucleus during the difficult version of the task. Conclusion This is the first pharmacokinetic/pharmacodynamic study to find an association between plasma levels of MPH and its modulatory effects on brain activation measured using fMRI. The results suggest that catecholaminergic mechanisms may be important in brain adaptivity to task difficulty and in task-specific recruitment of spatial attention systems.     

Sensitization of mice to methylphenidate

Mice that received five daily injection of methylphenidate HCl, 10–75 mg/kg, showed an increased running response to methylphenidate, cocaine, and amphetamine. Sensitization to methylphenidate persisted for at least 50 days. Repeated IP injections of methylphenidate into mice with unilateral striatal lesions increased ipsilateral turning in response to methylphenidate, but decreased contralateral turning after apomorphine. The climbing response to apomorphine in intact, methylphenidate-sensitized mice was also decreased. There was no change in either basal or dopamine-stimulated adenyl cyclase activity in the striata of sensitized mice, but there was a 36% increase in the specific binding of haloperidol. The rate of turnover of striatal dopamine was increased in sensitized mice. These results suggest that pretreatment with methylphenidate may alter the sensitivity of presynaptic dopamine receptors.     

单剂量头孢克洛缓释片与常释胶囊在健康人体药动学和生物等效性研究

目的了解单剂量头孢克洛缓释片和常释胶囊的药动学特点,评价其生物等效性。方法22名健康男性受试者随机口服头孢克洛缓释片或常释胶囊750m g,定时采集血标本,HPLC法测定血药浓度,按照最佳拟合的方法求算两种药物的药动学参数,评价生物等效性。结果头孢克洛缓释片和常释胶囊的Cm ax分别为(7.44±2.77)和(10.11±3.887)m g/L;tm ax分别为(3.80±0.87)和(1.42±0.53)h;t1/2β分别为(0.74±0.46)和(0.74±0.19)h;AUC0~n分别为(22.94±5.19)和(23.14±5.41)m g.h/L;AUC0~∞分别为(23.11±5.17)和(23.33±5.497)m g.h/L;CL/F分别为(4.4±1.98)和(6.05±7.49)L/h。F为(101±17.5)%。AUC的双向单侧t检验结果显示两药为生物等效制剂,Cm ax和tm ax的结果显示头孢克洛缓释片的达峰时间明显滞后于常释胶囊(P<0.05),血药浓度也明显低于常释胶囊(P<0.05)。结论头孢克洛缓释片和常释胶囊为生物等效制剂,且头孢克洛缓释片在体内确有缓慢释放的特点。     

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.