茶碱的时辰给药系统及其在犬体内的药物动力学

目的 制备一种体外具有"慢速-快速"双相释药特征的茶碱时辰给药系统以用于哮喘的夜间治疗,并考察其在犬体内的药动学.方法 分别以磷酸钠和氯化钠为内外层渗透推动剂,制备双层片片芯,以CA-PEG400-DEP(54.5:36.4:9.1,)为包衣膜组成给药系统.考察包衣膜厚度对茶碱释放的影响,及经口送服后时辰给药系统和缓释片在犬体内的药动学.结果 时辰给药系统包衣增重不影响其双相释药特征,系统体外的累积释放量随包衣的增重而减小.犬体内药动学研究表明较之缓释片,时辰给药系统的Tmax延长,Cmax减小.包衣增重影响时辰给药系统的生物利用度,每片包衣增重19、9 mg时,其相对生物利用度约为50%,每片包衣增重6 mg时,其相对生物利用度约为100%.结论 成功制备了双相释药特征的茶碱时辰给药系统.较之缓释片,可提前至晚9:30服药在清晨达峰浓度,且达峰后可长时间维持较高的血药浓度.     

盐酸文拉法辛缓释片的制备及其家犬体内药动学初步研究

 　目的：研制盐酸文拉法辛(venlafaxine hydrochloride,VH)缓释片,并评价其家犬药动学特性及生物利用度。方法：以Kollidon SR为基本骨架材料制备缓释片芯,用Kollicoat SR 30D包衣混悬液包衣,采用单因素考察法优化VH缓释片。以RP-HPLC测定VH血药浓度,对6只家犬进行药动学和生物利用度初步研究。结果：VH缓释片优化处方中片芯骨架材料为Kollidon SR 80%,以Kollicoat SR 30D包衣混悬液包衣增重为1%时,具有良好的缓释特征;单剂量口服自制VH缓释片与市售VH缓释胶囊的AUC0~36 h分别为(1 107.25±202.85)和(1 172.54±276.05) ng?h?mL-1;Tmax为(7.2±0.8)和(6.7±0.8) h;Cmax为(106.57±19.40)和(102.00±34.00) ng?mL-1;缓释片的相对生物利用度为(96.04±13.20)%。结论：盐酸文拉法辛缓释片具有缓释特征,同市售缓释胶囊生物等效。     

Theophylline colon specific tablets for chronotherapeutic treatment of nocturnal asthma

The ultimate goal is to design a new chronotherapeutic system for theophylline (TPH) with high potential benefits in treating nocturnal asthma. TPH core tablets were prepared by wet granulation using a developed formula. Compression coating over core tablets containing 200?mg TPH was done using granulated chitosan with 10% PVP K30. Different formulae F1, F2 and F3 were prepared using coat weights 260, 300 and 360?mg, respectively. The in vitro release characteristics in both variant pH media mimicking the gastrointestinal media and in media containing rat cecal content were monitored. The in vivo performance of the optimum formula was compared with Avolen(?) SR in Beagle dogs. F3 with high coat thickness exhibited a minimal release after 5-h release study. Both F2 and F3 showed more than 50% drug release after 4?h in the rat cecal medium. This reflects the colon selectivity of the system. The C(max) values were found to be 5.49?±?0.46 and 5.12?±?0.85?μg/mL for F3 and Avolen(?) SR, respectively, F3 showed higher mean plasma concentration than Avolen(?) SR from the beginning and continued till 7?h post administration indicating high potential as chronotherapeutic treatment of nocturnal asthma.     

Relative bioavailability and bioequivalence study of theophylline sustained release formulations

The objective of this study was to determine the bioequivalence of two theophylline (CAS 58-55-9) sustained release formulations containing 400 mg (Theophyllin 400 retard Heumann, formulation A) and 375 mg (formulation C) theophylline, respectively. In addition, the relative bioavailability of the sustained release formulations in comparison to an oral solution (formulation B) was investigated. Twenty-four healthy male volunteers participated in the open randomized three-way crossover study. Multiple doses of the formulations were administered during three study periods of four days each (A: 400 mg once daily; B: 133 mg t.i.d.; C: 375 mg once daily). The absorption kinetics and the bioavailability of theophylline were investigated by model-independent and deconvolution methods. The relative bioavailability of formulation A as compared to the solution was 72%. The oral sustained release capsules did not exhibit any differences with respect to AUCss, tau and Css, max whereas differences were detected regarding tss, max and peak trough fluctuation indicating minor deviations of the plasma profiles of both formulations. However, 90% confidence intervals of the ratios of AUCss, tau and Css, max were within the respective acceptance limits. Thus, both formulations are bioequivalent considering rate and extent of absorption.     

Suitability of κ-carrageenan pellets for the formulation of multiparticulate tablets with modified release

κ-Carrageenan is a novel pelletisation aid with high formulation robustness and quick disintegration leading to fast drug release unlike the matrix-like release from non-disintegrating microcrystalline cellulose pellets. Compression of pellets into tablets is cost effective. The feasibility of formulating multiparticulate tablets with coated κ-carrageenan pellets was investigated. Pellets containing a highly soluble drug in acid, namely bisacodyl and κ-carrageenan or MCC as pelletisation aid were prepared, enteric coated with a mixture of Kollicoat(?) MAE 30 DP and Eudragit(?) NE 30 D and compressed using silicified microcrystalline cellulose as embedding powder. The effect of coating level, type of pellet core, compression force and punch configurations on drug release were studied. A sufficient coating thickness for κ-carrageenan pellets was necessary to obtain multiparticulate tablets with adequate resistance in the acid stage regardless of the compression pressure used. While κ-carrageenan pellets and their tablets released over 80% of the drug during the neutral stage only about 20-24% was released from MCC pellets and their tablets. The type of punches used (oblong or round) did not significantly influence the drug release from the prepared tablets. Moreover, sufficient prolonged release properties were obtained with κ-carrageenan pellets containing theophylline as a model drug and coated with Kollicoat(?) SR 30 D using Kollicoat(?) IR as pore former. A lower coating level and higher amount of pore former were needed in case of theophylline pellets formulated with MCC as pelletisation aid. The sustained release properties of both coated pellet formulations were maintained after compression at different compression pressures.     

Development of sustained release gastroretentive drug delivery system for ofloxacin: in vitro and in vivo evaluation

Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new strategy is proposed for the development of gastroretentive dosage forms for ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in 24 healthy human volunteers and the pharmacokinetic parameters of developed formulations were compared with the marketed once daily (Zanocin) formulation. Based on the in vivo performance in a parallel study design in healthy subjects, the developed formulation shows promise to be bioequivalent to the marketed product (Zanocin). The percent relative bioavailability of developed formulation was found to be 97.55%.     

Time-release compression-coated core tablet containing nifedipine for chronopharmacotherapy

Compression-coated time-release tablets (CC tablets) containing nifedipine, dihydropyridine Ca channel blocker, in the core tablet were prepared by dry coating with different polyethylene oxide-polyethylene glycol mixtures. Each formulation showed a clear lag period before nifedipine release initiation, followed by sustained drug release lasting up to 24 h. The lag time of nifedipine release increased as the amount of polyethylene oxide in the outer layer increased. To investigate the applicability of such CC-tablets for chronopharmacotherapy, the pharmacokinetics of CC-1 and CC-2 tablets, with different in vitro lag times before drug release, were compared with the pharmacokinetics of a sustained-release (SR) tablet in dogs. The times of first nifedipine appearance (TFA) in plasma were 0.7 ± 0.3 h for SR, 2.5 ± 1.2 h for CC-1, and 5.3 ± 1.0 h for CC-2. These data show a significant difference in in vivo lag time (P < 0.01) among the three formulations that correlates with the in vitro lag times. Thus, the in vivo lag time could be predicted from the in vitro lag time. Additionally, higher plasma nifedipine concentrations were observed at 8 h after administration of the CC-2 than that observed for the SR-tablet. These results indicate that a CC-tablet with a lag time before drug release is a potentially useful formulation for chronopharmacotherapy that can control the time and duration of plasma drug concentration better than existing SR technologies.     

The physicodynamic properties of mucoadhesive polymeric films developed as female controlled drug delivery system

Phenoporlamine hydrochloride is a novel compound that is used for the treatment of hypertension. The purpose of this study was to develop a sustained release tablet for phenoporlamine hydrochloride because of its short biological half-life. Three floating matrix formulations of phenoporlamine hydrochloride based on gas forming agent were prepared. Hydroxypropyl methylcellulose K4M and Carbopol 971P NF were used in formulating the hydrogel drug delivery system. Incorporation sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 6 h. The dissolution profiles of all tablets showed non-Fickian diffusion in simulated gastric fluid. Moreover, release of the drug from these tablets was pH-dependent. In vivo evaluations of these formulations of phenoporlamine hydrochloride were conducted in six healthy male human volunteers to compare the sustained release tablets with immediate release tablets. Data obtained in these studies demonstrated that the floating matrix tablet containing more Carbopol was capable of sustained delivery of the drug for longer periods with increased bioavailability and the relative bioavailability of formulation (containing 25% Carbopol 971P NF, 8.3% HPMC K4M) showed the best bioequivalency to the reference tablet (the relative bioavailability was 1.11 ± 0.19).     

Release, absorption and elimination of theophylline from fast and slowly released oral formulations

Each 2 tablets of four tablet formulations with 150 mg theophylline were administered to 6 and 5 volunteers, respectively, as single oral dose. 8 volunteers received 256 mg theophylline as a solution and as a sustained released formulation, as well as 176 mg theophylline as short intravenous bolus infusion. The elimination was independent of the examined formulations, but differences occurred between the experiments with the different groups of volunteers. The invasion parameters (t1/2i) of the four fast released tablet formulations corresponded to the values (t1/2a) of the oral theophylline solution. Furthermore, no difference existed concerning the mean times (Tsys). The mean time (theophylline) for the body model, Tvss, is 9.9 h; the mean time, which is attributed to the absorption process (Tabs) is 0.7 h; the mean in vivo dissolution time (Tdiss-vivo) for the sustained release formulation is 6.3 h. The mean time after oral administration of the theophylline solution (Tbiol) is 10.6 h. General conditions for a comparison between the in vitro and the in vivo release data are reported.     

新型茶碱口服结肠靶向给药系统的体内动力学

目的研究以时间为释药开关的结肠靶向给药系统。方法以非pH依赖型聚丙烯酸树脂Eu dragit NE 3 0D为膜材 ,制备茶碱薄膜衣片 ;用HPLC法进行体内血药浓度分析 ;以γ 闪烁照相研究该制剂体内胃肠道的转运情况。结果本制剂与参比制剂主要药代动力学参数分别为 :tlag( 8 67± 1 0 4 )h、( 0 67± 1 1 5 )h ;Cmax( 5 2 5± 1 2 1 )mg/L、( 4 0 9± 1 2 5 )mg/L ;AUC0 2 6 ( 2 7 5 0±7 2 0 )mg·h/L、( 3 9 0 4± 1 0 4 3 )mg·h/L ;体内γ 闪烁照相研究表明 ,体外 6 5h释放的制剂口服8 0h后到达升结肠处开始释药 ,且体内释药与体外释药有一定的相关性。结论本制剂能达到结肠靶向释药的设计要求     

Formulation and Evaluation of Dextromethorphan Hydrobromide Sustained Release Tablets

Sustained release (SR) matrix tablets of dextromethorphan hydrobromide were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. A complete cross-over bioavailability study of the optimized formulation of the developed sustained tablets and marketed immediate release tablets was performed on six healthy male volunteers. The extent of absorption of drug from the SR tablets was significantly higher than that for the marketed dextromethorphan hydrobromide tablet because of lower elimination rate and longer half-life.     

Theophylline colon specific tablets for chronotherapeutic treatment of nocturnal asthma

The ultimate goal is to design a new chronotherapeutic system for theophylline (TPH) with high potential benefits in treating nocturnal asthma. TPH core tablets were prepared by wet granulation using a developed formula. Compression coating over core tablets containing 200?mg TPH was done using granulated chitosan with 10% PVP K30. Different formulae F1, F2 and F3 were prepared using coat weights 260, 300 and 360?mg, respectively. The in vitro release characteristics in both variant pH media mimicking the gastrointestinal media and in media containing rat cecal content were monitored. The in vivo performance of the optimum formula was compared with Avolen^® SR in Beagle dogs. F3 with high coat thickness exhibited a minimal release after 5-h release study. Both F2 and F3 showed more than 50% drug release after 4?h in the rat cecal medium. This reflects the colon selectivity of the system. The C_max values were found to be 5.49?±?0.46 and 5.12?±?0.85?μg/mL for F3 and Avolen^® SR, respectively, F3 showed higher mean plasma concentration than Avolen^® SR from the beginning and continued till 7?h post administration indicating high potential as chronotherapeutic treatment of nocturnal asthma.     

Formulation and evaluation of dextromethorphan hydrobromide sustained release tablets

Sustained release (SR) matrix tablets of dextromethorphan hydrobromide were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. A complete cross-over bioavailability study of the optimized formulation of the developed sustained tablets and marketed immediate release tablets was performed on six healthy male volunteers. The extent of absorption of drug from the SR tablets was significantly higher than that for the marketed dextromethorphan hydrobromide tablet because of lower elimination rate and longer half-life.     

Evaluating tamsulosin hydrochloride-released microparticles prepared using single-step matrix coating

The purpose of the present study was to prepare matrix extended release pellets of diclofenac potassium using low amount of release-modifying agents and, to compare its performance in vivo with coated pellets and matrix tablets. Coated pellets were prepared by extrusion-spheronization, followed by double layer coating using different polymers separately. Matrix pellets with different release rate in vitro were prepared by extrusion-spheronization with different kinds of retarding materials. Bioavailability study of different coated pellets revealed that the drug concentration in plasma of beagle dogs was too low to be detected and, implied that the drug was nearly not released from the preparations before reaching colon due to the appearance of lag time in the dissolution process. The phenomenon indicated that slow-release pellets of diclofenac potassium perhaps should not be developed as double membrane-controlled type. The AUC((0 → 24)) of the immediate release pellets, the two matrix pellets and the reference were 304.4, 87.7, 204.1 and 179.1 μg h/ml, respectively. The C(max) of the formulations mentioned above were 46.3, 13.0, 33.6 and 32.1 μg/ml, respectively. All the matrix formulations, including the reference, exhibited incomplete absorption due to the short small intestine transit time and termination of the drug release in the colon because of its limited solubility. The matrix pellets were bioequivalent with the commercially available tablet (Voltaren(?)) although the drug release in vitro of the former was much faster, while the bioavailability of the matrix pellets with similar in vitro drug release to the reference (Voltaren(?)) was much lower than the latter. The results perhaps was caused by lacking of physical robustness in the waxy tablet formulation, resulted in low wet strength and easily destroyed by the mechanical destructive forces and finally introduced faster drug release rate in vivo. It is apparent that preparations with similar performance in vitro may differ a lot in vivo because of the differences in drug release rate in vivo owing to various wet strengths of excipients contained, especially for sustained release products.     

Pharmacokinetics and bioavailability of four modified-release ursodeoxycholic acid preparations for once-a-day administration

Ursodeoxycholic acid (UDCA) is currently used for the treatment of cholestatic liver disease and for cholesterol gallstone dissolution. Various formulations have been designed to enhance its intestinal absorption or to improve patient compliance through once-a-day administration. The pharmacokinetics and bioavailability of four commercially available modified-release UDCA formulations (450 mg) were studied in 12 healthy subjects randomly receiving the four drugs under study. Serum samples were collected hourly for a 12-h period after administration and UDCA concentrations were measured using a specific enzyme immunoassay. For each formulation, Cmax, tmax, and the area under the curve (AUC) were determined and compared. Although all formulations were designed to provide sustained release, we observed different pharmacokinetics among the studied formulations. One of the formulations (sustained-release ursodeoxycholic acid Ratiopharm 450 mg tablets) showed high bioavailability, but failed to produce sustained release. In contrast, two other formulations (modified-release ursodeoxycholic acid Dorom 450 mg capsules and controlled-release Ursobil HT 450 mg capsules) provided sustained release, but did not offer efficient bioavailability. A fourth formulation (Ursilon retard 450 mg) exhibited gradual UDCA release lasting over 10 h, with efficient bioavailability, similar to that of conventional prompt-release formulations administered at the same dose. These data highlight the variability of commercially available sustained-release formulations. Manufacturers should be encouraged to provide drug kinetics and bioavailability data to further support the claimed pharmacokinetics.     

Preparation and evaluation of a novel delayed-onset sustained-release system of propranolol hydrochloride

The objective of this work was to prepare and evaluate a new delayed-onset sustained-release system, comprising a sustained-release core tablet with hydroxypropyl methylcellulose as polymer matrix and an ethylcellulose/Eudragit L coating capable of delaying the drug release. The sustained core containing propranolol hydrochloride as the model drug was prepared by granulate tableting and the polymer coating was applied in a computer-controlled coating pan. The dissolution tests demonstrated that the in-vitro drug release was pH-dependent with sufficient gastric resistance, and the lag time (t(10%)) could be controlled by adjusting the coating level. Three dosage forms including commercial tablet, sustained-release tablet and the delayed-onset sustained-release tablet were administrated to six beagle dogs and the plasma levels of propranolol hydrochloride were measured with high-performance liquid chromatography. The delayed-onset sustained-release tablet had a lag time of 3.0 h in-vitro and 3.5 h in-vivo, and a t(max) of 7.0 h. The relative bioavailability for delayed-onset sustained-release tablet was 96.98% compared with commercial tablets. The results indicate that the new propranolol delayed-onset sustained-release system could achieve a relatively constant drug release followed by a programmed lag time, and this may provide a promising drug delivery form for chronopharmacotherapy of certain cardiovascular diseases.     

Development of sustained release formulation of an antithrombotic drug and application of fuzzy logic

Clopidogrel bisulphate has quite low bioavailability (40–50%). It was aimed to increase its bioavailability by designing a controlled release dosage form of clopidogrel, which is different from available current dosage forms in the market. There are also some attempts to overcome patent protection of clopidogrel by combination of active substances or preparation of controlled release tablets. Therefore, it was also aimed to determine in vitro and in vivo properties of controlled release clopidogrel tablets. The amounts of releases from formulations were subjected computer program and effects of components in the formulation on release were investigated (INFORM v.3.7 and FORMRULES, Intelligensys Ltd). Two sustained release formulations and innovator product were selected and their effectiveness was compared by in vivo tests in rabbits. In conclusion, proposed controlled release formulations were found to be an alternative and to be more effective for longer periods than the commercial one.     

Development of sustained release formulation of an antithrombotic drug and application of Fuzzy logic

Clopidogrel bisulphate has quite low bioavailability (40-50%). It was aimed to increase its bioavailability by designing a controlled release dosage form of clopidogrel, which is different from available current dosage forms in the market. There are also some attempts to overcome patent protection of clopidogrel by combination of active substances or preparation of controlled release tablets. Therefore, it was also aimed to determine in vitro and in vivo properties of controlled release clopidogrel tablets. The amounts of releases from formulations were subjected computer program and effects of components in the formulation on release were investigated (INFORM v.3.7 and FORMRULES, Intelligensys Ltd). Two sustained release formulations and innovator product were selected and their effectiveness was compared by in vivo tests in rabbits. In conclusion, proposed controlled release formulations were found to be an alternative and to be more effective for longer periods than the commercial one.     

Analysis of formulation and food effect on the absorption of metoclopramide

OBJECTIVES: Assessment of the relative and absolute bioavailability of immediate release and sustained release formulations of metoclopramide. Assessment of the effect of a high-fat meal on the pharmacokinetics of sustained release metoclopramide. MATERIAL AND METHODS: In a balanced 4-way crossover study in 16 healthy male volunteers, a sustained release (SR) formulation of metoclopramide was compared with a solution for injection (A) and an immediate release tablet (B). The SR formulation was administered after a fasting period (C) as well as after a high-fat meal (D). A single dose of 30 mg metoclopramide was investigated in each treatment. Metoclopramide concentrations were determined by HPLC. RESULTS: The absolute bioavailability of the sustained release formulation (fasting state) was 58% and thus about 17% lower than the bioavailability of the immediate release formulation. Comparing the treatments C (sustained release, fasting state) and D (sustained release, high-fat meal) no significant influence of food on the absorption of sustained release metoclopramide could be detected.     

A method for the preparation of sustained release-coated Metoprolol Succinate pellet-containing tablets

The purpose of this study was to develop a method to prepare Metoprolol Succinate (MS) sustained release pellets and compress them into pellet-containing tablets without losing sustained release property. The drug layered pellets were coated with Eudragit NE 30D to obtain a sustained release (SR) property. The mechanical properties and permeability of the coating film were tailored by adjusting the proportion of talc in the coating dispersion and the weight gain of the coating film. Pellets with different MS release rates were tested and then mixed together by different ratios to optimize drug release rate. The mixed pellets were compressed into tablets with cushioning excipients. The results showed that when the ratio of talc and coating material was 1:4, the coating operation could be conducted successfully without pellet conglutination and the mechanical property of the coating film was enhanced to withstand the compress force during tableting. Blending SR-coated pellets of 20% weight gain with SR-coated pellets of 40% weight gain at the ratio of 1:5 could produce a constant and desired drug release rate. The formulation and the procedure developed in the study were suitable to prepare MS pellet-containing tablets with selected SR properties.