共查询到20条相似文献,搜索用时 15 毫秒
1.
Gaynor C Dunne A Costello C Davis J 《Journal of pharmacokinetics and pharmacodynamics》2011,38(3):317-332
Developing an In Vitro–In Vivo Correlation (IVIVC) model is becoming an important part of the drug development process. Traditional
methods such as deconvolution and convolution make the assumption of linearity of the system being studied and are, therefore,
unsuitable for use with compounds exhibiting nonlinear kinetics. This study proposes the use of a compartmental approach which
may be based on systems of differential equations, a method which can comfortably accommodate nonlinearity. This technique
can easily be implemented using existing NONMEM libraries and is an accurate, fast and straightforward method of developing
an IVIVC model. 相似文献
2.
《Yao wu shi pin fen xi = Journal of food and drug analysis.》2014,22(2):257-263
The objective of this study was to develop an in vitro–in vivo correlation (IVIVC) model for hydrophilic matrix extended-release (ER) propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8). In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR) commercial products. The similarity factor f2 was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE) values of Cmax and AUC0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for Cmax and AUC0–∞ demonstrated that the propranolol IVIVC model was valid. 相似文献
3.
Lin Zhou Yuan-Bo Li Yu Yuan Mei Dai Bo Huang 《Journal of Asian natural products research》2013,15(4):391-402
A two-step release system (TSRS) for the compound Danshen, which has drug-release behavior that is in accordance with the circadian rhythms of cardiovascular disease, was developed by combining an effervescent osmotic pump tablet and a pulsed-released tablet into one hard capsule by our lab. An in vivo study indicated that after oral administration of TSRS, two peaks of the plasma concentration of both Danshensu (DS) and protocatechuic aldehyde (PA) were observed, which suggested that the drug plasma concentration–time curve could meet the requirements for chronotherapy of cardiovascular disease after the bed-time administration of such a device. High performance liquid chromatography using an ultraviolet (UV) detector was used to simultaneously determine the concentrations of DS and PA in plasma. This method was simple, convenient, and appropriate for the quality control of DS and PA. A linear correlation model was established based on the percent absorbant data and percent in vitro dissolution data. Because the drugs were released from the device in an osmotic pressure-dependent manner and absorbed rapidly, a reasonable linear regression relationship was observed between the in vitro and in vivo performances. The current study highlights the potential use of such a device for chronopharmaceutical drug delivery. 相似文献
4.
Sam T. Mathew S. Gayathri Devi V. V. Prasanth B. Vinod 《Journal of microencapsulation》2013,30(5):456-469
AbstractThe objective of this work was to prepare and evaluate ketoprofen-loaded albumin microspheres for intramuscular administration. Microspheres were prepared by emulsion cross-linking method using a 23 factorial design and the effect of different factors on entrapment efficiency was determined. Microspheres were evaluated for entrapment efficiency, percentage yield, particle size and release behaviour. Selected formulations were then tested by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Further they were analysed for residual solvents, syringeability and stability. Microspheres were then sterilized and bioavailability studies were carried out in New Zealand white rabbits. The physical characteristics of microspheres showed that they were suitable for IM administration. The sterilization technique adopted was adequate to maintain sterility. In vivo studies showed increase in Cmax, AUC, t1/2 and MRT (p < 0.05) administered in the form of microspheres. MRT of ketoprofen was almost 3.2-times in the form of microspheres. From these results it was concluded that the developed albumin microspheres of ketoprofen is a potential delivery system for once-a-day intramuscular administration. 相似文献
5.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(10-11):1090-1109
The importance of hepatic uptake transporters in drug clearance is well recognized. The subject is reviewed with the intention of providing an overview of the concepts in order to link the increasing knowledge of transporter-mediated uptake into established models of hepatic clearance. In order to understand and quantify their impact, models of hepatic elimination that incorporate permeability barriers are required. Models that include both active and passive uptake into hepatocytes are discussed and simulations of the influence of active uptake and passive diffusion on hepatic clearance are presented. The advantages and weaknesses of a number of in vitro assays of hepatic uptake are described, and their ability to predict hepatic clearance is reviewed. 相似文献
6.
《Drug delivery》2013,20(3):152-157
The objective of this study was to enhance the solubility, dissolution rate, and oral bioavailability of a very poorly water-soluble anti-fungal agent, ketoconazole (KET), by inclusion complexation with a highly-soluble cyclodextrin derivative, hydroxypropyl-β cyclodextrin (HP-β-CD). Two groups of tablets containing KET alone and KET:HP-β-CD (1:2) kneaded product (KP) including magnesium stearate and lactopress (anhydrous and spray-dried) as excipients were prepared by direct compression method. After the characterization studies, the in vitro dissolution studies of these tablets in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out. To evaluate the in vivo bioavailability, the tablets were administered orally to rabbits and drug levels in serum were determined by HPLC. Tablets containing the cyclodextrin complex showed a higher in vitro dissolution rate and bioavailability compared to the tablets containing KET alone. 相似文献
7.
Aims: Previous studies suggested that Salvianolic acid B (SalB) has strong protective effect against cerebral ischemia. Recently, Sal B has been reported to enhance angiogenesis in vitro. Based on the information above, in this study we are interested in the effect of SalB on neurogenesis and angiogenesis. Methods:In vitro study, we used embryonic mouse (El6) primary cortical neural cultures. Neuron was recognized by anti-MAP2 with immunocytochemistry. Neurogenesis was tested with BrdU incorporation by ELSA method. SalB( 10 -6 -10 -8M) or vehicle was added to the culture medium 24 hrs before BrdU addition. In vivo, middle cerebral artery occlusion (MCAO) rats were used as focal cerebral ischemia model. 相似文献
8.
Mutagenicity tests on epristeride in vitro and in vivo 总被引:1,自引:0,他引:1
目的:评价治疗良性前列腺肥大的新药依立雄胺(Epr)的遗传影响.方法:1)鼠沙门氏菌体外回复突变试验测试能否诱发基因突变;2)CHL细胞染色体的损伤和畸变实验;3)ICR小鼠一次igEpr后测试是否导致骨髓嗜多染红细胞染色体的损伤;4)昆明种小鼠连续igEpr5d,30d后统计精子头部异常情况.结果:1)Epr不诱导细菌回复突变.2)CHL细胞染色体畸变低于3%不造成细胞染色体损伤.3)Epr不诱导小鼠嗜多染红细胞微核的形成.4)Epr高、中、低剂量组引起的头部畸形率分别为5.3%±2.7%,5.3%±1.9%,5.2%±1.2%,与对照组相比不引起显著的精子头部异常.结论:Epr在体内外实验中没有表现出遗传毒性. 相似文献
9.
《Journal of drug targeting》2013,21(4):389-406
AbstractLow molecular weight heparin (LMWH) and standard heparin are widely used anticoagulants. However, they have very poor oral bioavailability and have to be administered by the parenteral route. Alginates are biodegradable, biocompatible and mucoadhesive polymers which can be used for advantage for the oral administration of LMWH. The aim of the study was to develop LMWH–alginate beads for oral delivery. Alginate beads were prepared based on the 23 factorial design. In vitro characterization studies of the beads were carried out. In vivo studies were performed on rabbits. The LMWH solutions (5000?IU/kg, with and without 5% dimethyl-β-cyclodextrin), as well as the LMWH–alginate beads were administered to rabbits. The IV solution was also administered (100?IU/kg). The anti-Xa activity was measured in plasma. Area under curve (AUC) and Cmax values were determined. Histological investigations were also carried out. The formulation consisting of a 1:2 drug/alginate ratio and cured using 0.5?M CaCl2 for 15?min gave the best result in terms of encapsulation efficiency and the time for 50% of the drug to be released (t50%). A significantly higher bioavailability was observed for LMWH–alginate beads than for LMWH solutions. It was concluded that, anticoagulant effectiveness was achieved using alginate beads containing LMWH after oral administration to the rabbits. 相似文献
10.
Lin Sun Dongmei Cun B.o. Yuan Hongxia Cui Honglei Xi Liwei Mu Yang Chen Chao Liu Zhongyan Wang Liang Fang 《Journal of pharmaceutical sciences》2012,101(12):4540-4548
The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012 相似文献
11.
This study investigated cholesterol–polyethylene glycol (PEG) comodified poly (ethyleneglycol)-poly (lactide) nanoparticles (CLS-PEG NPs) as a novel, biodegradable brain drug delivery system and included an evaluation of its in vitro and in vivo properties. To this end, coumarin-6 (C6), a fluorescent probe, was encapsulated into CLS-PEG NPs by an emulsion polymerization method. We reported that the use of CLS-PEG NPs led to a sustained drug release in vitro. Additionally, cell viability experiments confirmed their safety. The uptake and transport of CLS-PEG NPs, by bEnd.3 cells (an immortalized mouse brain endothelial cell line), was significantly higher than that of a control C6 solution. An investigation of the uptake mechanisms of different NP formulations demonstrated that cholesterol modifications may be the primary way to improve the efficiency of cellular uptake, wherein macropinocytosis may be the most important endocytic pathway in this process. An investigation of the transport mechanisms of CLS-PEG NPs also implicated macropinocytosis, energy and cholesterol in bEnd.3 cells lines. Following an intravenous (IV) administration to rats, pharmacokinetic experiments indicated that C6-loaded CLS-PEG NPs achieved sustained release for up to 12?h. In addition, IV delivery of CLS-PEG NPs appeared to significantly improve the ability of C6 to pass through the blood–brain barrier: the concentration of C6 found in the brain increased nearly 14.2-fold when C6 CLS-PEG NPs were used rather than a C6 solution. These in vitro and in vivo results strongly suggest that CLS-PEG NPs are a promising drug delivery system for targeting the brain, with low toxicity. 相似文献
12.
Nigel J Waters 《British journal of clinical pharmacology》2015,79(6):946-958
Aims
Understanding drug–drug interactions (DDI) is a critical part of the drug development process as polypharmacy has become commonplace in many therapeutic areas including the cancer patient population. The objectives of this study were to investigate cytochrome P450 (CYP)-mediated DDI profiles available for therapies used in the oncology setting and evaluate how models based on in vitro–in vivo extrapolation performed in predicting CYP-mediated DDI risk.Methods
A dataset of 125 oncology therapies was collated using drug label and approval history information, incorporating in vitro and clinical PK data. The predictive accuracy of the basic and net effect mechanistic static models was assessed using this oncology drug dataset, for both victim and perpetrator potential of CYP3A-mediated DDI.Results
The incidence of CYP3A-mediated interaction potential was 47%, 22% and 11% for substrates, inhibitors and inducers, respectively. The basic models for precipitants gave conservative predictions with no false negatives, whilst the mechanistic static models provided reasonable quantitative predictions (2.3–3-fold error). Further analysis revealed that incorporating DDI at the level of the intestine was in most cases over-predicting interaction magnitude due to overestimates of the rate and extent of oral absorption of the precipitant. Quantifying victim DDI potential was also demonstrated using fmCYP3A estimates from ketoconazole clinical DDI studies to predict the magnitude of interaction on co-administration with the CYP3A inducer, rifampicin (1.6–3.3 fold error).Conclusions
This work illustrates the utility and limitations of current DDI risk assessment approaches applied to a range of contemporary anti-cancer agents, and discusses the implications for therapeutic combination strategies. 相似文献13.
Nishimura H Hayashi C Aiba T Okamoto I Miyamoto Y Nakade S Takeda K Kurosaki Y 《Biological & pharmaceutical bulletin》2007,30(11):2221-2225
Plasma concentration profiles of arundic acid ((R)-(-)-2-propyloctanoic acid), an oil-like medicine, administered as soft-gel capsules in human clinical tests were predicted from the dissolution test data of the soft-gel capsules with different storage terms (short- and long-term stored drugs) by applying the in vitro-in vivo correlation (IVIVC). We established two linear-regression IVIVCs, which were characterized by either the in vitro dissolution behaviors against the pH 8.0 dissolution medium or the pH 6.8 dissolution medium containing 2% sodium dodecyl sulfate (SDS), in this study. Also, the prediction accuracies for the in vivo plasma profiles in humans for these two IVIVCs were compared. Regarding dissolution from the long-term stored capsule in pH 8.0 dissolution medium without surfactant, the prediction accuracies of the in vivo plasma profiles in humans were not satisfactory for the obtained IVIVC. The use of pH 6.8 dissolution medium containing 2% SDS, according to the Japanese guideline, improved the dissolution of the long-term stored capsule. Furthermore, the prediction accuracies for the in vivo plasma profiles in humans for these two IVIVCs were compared. The IVIVC established by the in vitro dissolution data obtained with the dissolution medium containing surfactant more effectively predicted the plasma drug concentration profiles following oral administrations of the soft-gel capsules under both storage conditions. 相似文献
14.
15.
The transporting kinetics and metabolic kinetics of ursolic acid were studied in transgenic cell models. Then, the pharmacokinetics features of ursolic acid and the expression of ATP-binding cassette transporters (ABC transporter) and cytochrome P450 (CYP) enzymes in tissues after pregnane X receptor (PXR) activation by 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN) were investigated in rats. After silencing of PXR in Caco2–siRNA–PXR cells, there was a decrease in the protein abundance of P-glycoprotein, breast cancer-resistant protein, multidrug resistance-associated protein 2 (MRP2), and CYP2C9. The apparent permeability (PDR) values of 10, 20, and 50 µM ursolic acid in Caco2 cells were 2.19 ± 0.44, 1.40 ± 0.17, and 1.25 ± 0.07, respectively, whereas in Caco2–siRNA–PXR cells, they were 1.85 ± 0.36, 1.24 ± 0.11, and 1.19 ± 0.04, respectively. PXR–RXRα would significantly activate ABC transporter expression in Caco2 cells. Compared with Caco2 cells, when the concentrations of ursolic acid were 10, 20, and 50 µM, the PDR values increased in Caco2–PXR–RXRα cells after PXR activation: 1.60 ± 0.31 versus 1.97 ± 0.21, 1.46 ± 0.08 versus 2.01 ± 0.19, and 1.32 ± 0.26 versus 2.09 ± 0.22, respectively. Simultaneously, PXR–RXRα would activate the expression of CYP2C9; metabolic kinetics of ursolic acid in CYP metabolizing enzyme lysate of Caco2 cells and Caco2–PXR–RXR cells was studied and it was found that the Km values were 81.99 ± 44.32 and 60.05 ± 29.62 µg/ml, and Vmax values were 3.77 ± 0.86 and 3.41 ± 0.96 µg · ml−1 · min−1, respectively. However, in human CYP metabolizing recombinase, we found that both CYP2C9 and CYP34A were involved in the metabolism of ursolic acid. Vm and Km values for CYP3A4 and CYP2C9 were 3.57 ± 1.12 µg · ml−1 · min−1 and 81.71 ± 18.38 µg/ml, 3.85 ± 1.46 µg · ml−1 · min−1 and 62.18 ± 14.56 µg/ml, respectively. As a strong agonist for mouse pxr, PCN could significantly affect pharmacokinetics of ursolic acid in rats, and it showed discrepant effects on messenger RNA expression of cyp and transporters in tissues. 相似文献
16.
Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and th... 相似文献
17.
Jingjing Tang Jiayin Bao Xiangjun Shi Xiaoxia Sheng 《Journal of microencapsulation》2013,30(5):454-466
AbstractThe research aimed to prepare febuxostat (FEB) solid dispersion through solvent evaporation. Optimised solid dispersion composed of FEB, polyvinylpyrrolidone (PVP K30) and poloxamer at a ratio of 1:3:3 was characterised. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) indicated FEB was transformed from crystalline into the amorphous state in solid dispersion and scanning electron microscopy (SEM) revealed the morphology. Fourier transform infrared spectroscopy (FT-IR) suggested the interactions formed between FEB and polymers. A remarkable increase was observed of the optimised formulation in saturation solubility, dissolution studies (96.17?±?0.79% in pH 6.0), and bioavailability (Cmax 18.25?±?2.44 vs. 7.72?±?0.48?μg/mL and AUC0–∞ 53.62?±?7.63 vs. 34.76?±?2.45?μg·h/mL). Besides, the FEB solid dispersion showed great stability after 90 days storage. Thus, the present study supports the rationality of PVP K30 and poloxamer188 as co-carriers for the preparation of FEB solid dispersion. 相似文献
18.
The present investigation was designed with the intention to formulate a versatile 5-fluorouracil(5-FU) matrix tablet surpassing issues associated with current conventional chemotherapeutic drug delivery systems. The novel 5-FU matrix tablet fulfills therapeutic needs by engineering matrix tablets utilizing chitosan–sodium alginate interpolyelectrolyte complex (IPEC). IPEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The matrix tablets were formulated utilizing IPEC alone and in combination with chitosan, sodium alginate and sodium deoxycholate as permeation enhancer. Pharmaceutical properties, swelling studies, in vitro dissolution and diffusion studies, mucoadhesive studies and in vivo studies were performed for formulated 5-FU. The selected chitosan–sodium alginate IPEC offers pH independent 5-FU release in comparison to alone or physical mixture of chitosan and sodium alginate. Furthermore, novel matrix tablets demonstrated significantly higher bioadhesive properties with controlled 5-FU release without the initial burst effect and also demonstrated a higher permeation of 5-FU. To conclude, the developed novel 5-FU matrix tablets pave way as an excellent alternative for cancer treatment which could potentially minimize the dose dependent side effects and provide better patient compliance. 相似文献
19.
Costello C Rossenu S Vermeulen A Cleton A Dunne A 《Journal of pharmacokinetics and pharmacodynamics》2011,38(5):519-539
In vitro–in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution
specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing
an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical
concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop
an IVIVC model for a drug with quite different in vitro and in vivo time scales. The in vitro and the in vivo data were longitudinal
in nature with considerable between subject variation in the in vivo data. The model was successfully developed and fitted
to the data using the NONMEM package. Model utility was assessed by comparing model-predicted plasma concentration-time profiles
with the observed in vivo profiles. This comparison met validation criteria for both internal and external predictability
as set out by the regulatory authorities. This study demonstrates that a time-scaling approach may prove useful when attempting
to develop an IVIVC for data with the aforementioned properties. It also demonstrates that the convolution-based population
approach is quite versatile and that it is capable of producing an IVIVC model with a big difference between the in vitro
and in vivo time scales. 相似文献
20.
Chang J Schul W Butters TD Yip A Liu B Goh A Lakshminarayana SB Alonzi D Reinkensmeier G Pan X Qu X Weidner JM Wang L Yu W Borune N Kinch MA Rayahin JE Moriarty R Xu X Shi PY Guo JT Block TM 《Antiviral research》2011,89(1):26-34
Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection. 相似文献