Fabrication of novel GMO/Eudragit E100 nanostructures for enhancing oral bioavailability of carvedilol

In the present work, novel nanostructures comprising of glyceryl monooleate (GMO) and Eudragit E100 were prepared using high intensity ultrasonic homogenization. 3² Factorial design approach was used for optimization of nanostructures. Results of regression analysis revealed that the amount of GMO and Eudragit E100 had a drastic effect on particle size and percent entrapment efficiency. Optimized carvedilol-loaded nanostructures (Car-NS) were characterized by FTIR, TEM, DSC, in vitro drug release study. Pharmacokinetic parameters such as C_max, T_max, Ke, Ka, V_d and AUC were estimated for Car-NS upon its oral administration in Sprague-Dawley rats. Particle size of Car-NS was found to be 183?±?2.43?nm with an entrapment efficiency of 81.4?±?0.512%. FTIR studies revealed loading and chemical compatibility of carvedilol with the components of nanostructures. DSC thermograms did not show endothermic peak for melting of carvedilol which could be attributed to solubilization of carvedilol in molten GMO during DSC run. The prepared Car-NS released carvedilol in sustained manner over a period of 10 h as suggested by in vitro drug release study. The pharmacokinetic study of Car-NS showed significant improvement in C_max (two fold, p?p?相似文献   

Development, characterization and stabilization of amorphous form of a low Tg drug

The objective of the present study was to develop a stable amorphous form of model drug carvedilol (CAR). The amorphous material produced by melt quench technique was subjected to physico-chemical characterization. Chemical stability of the drug during preparation of glass was tested by HPLC and IR spectroscopy and presence of amorphous form was confirmed by DSC and XRPD. The rate of dissolution and magnitude of the apparent solubility were found to be significantly higher for amorphous CAR than for crystalline CAR, at 25 °C. However at 37 °C, it was observed that dissolution of the amorphous form did not show a noticeable improvement over pure CAR over the period of 60 min, due to formation of cohesive supercooled liquid state. This observation was supported by enthalpy relaxation study, which indicated increase in enthalpy recovery and structural relaxation of amorphous form towards the supercooled liquid region. This indicated the functional inability of amorphous CAR from stability point of view and suggested the need for elevation of T_g. Hence combination of solid dispersion (SD) and surface adsorption techniques was attempted to overcome the functional limitations of amorphous CAR. SD in the ratio of 1:2:2 parts by weight of CAR, PVP (for elevation of T_g) and Aerosil^® 200 (as adsorbent) respectively presented dramatic improvement in rate and extent of drug dissolution. During accelerated stability studies with SD 1:2:2 the dissolution characteristics were slightly decreased over the period of 3 months and no crystallization events were observed. Thus, to exploit the functional advantage of amorphous form of low T_g drugs, formation of ternary SD system is recommended.     

Development of novel interpenetrating network gellan gum-poly(vinyl alcohol) hydrogel microspheres for the controlled release of carvedilol

Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 µm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.     

Inhibitory effect of ketoconazole and voriconazole on the pharmacokinetics of carvedilol in rats

The aim of this study was to investigate the effect of orally administered ketoconazole and voriconazole on the pharmacokinetics of carvedilol and its metabolites in rats. Fifteen healthy male Sprague–Dawley (SD) rats were randomly divided into three groups: A group (30?mg/kg ketoconazole), B group (30?mg/kg voriconazole) and C group (control group). A single dose of carvedilol was administered orally 30?min after administration of ketoconazole and voriconazole. Carvedilol and its metabolites plasma levels were measured by ultra-high performance liquid chromatography-mass spectrometry method (UPLC–MS/MS), and pharmacokinetic parameters were calculated by DAS 3.0 software. The co-administrated with ketoconazole could significantly increase the maximal plasma concentration (C_max) and area under the curve (AUC) of carvedilol (p?C_max of its three metabolites 4′-hydroxyphenyl carvedilol (4′-HPC), 5′-hydroxyphenyl carvedilol (5′-HPC) and o-desmethyl carvedilol (o-DMC) decreased drastically by 39.4% (p?p?p?T_max of carvedilol and o-DMC increased, and the C_max of 5′-HPC decreased by 27.7% (p?相似文献   

Development of Novel Interpenetrating Network Gellan Gum-Poly(vinyl alcohol) Hydrogel Microspheres for the Controlled Release of Carvedilol

Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 µm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.     

卡维地洛对柯萨奇病毒B3感染小鼠儿茶酚胺及IL-6表达水平的影响

目的: 研究卡维地洛对急性柯萨奇B3(CVB3)病毒性心肌炎小鼠的儿茶酚胺及炎症因子IL-6表达水平的影响。方法: 随机将80只雄性BALB/C小鼠分为3组:正常对照组(n=20),心肌炎组(n=30),卡维地洛组(n=30)。后两组经腹腔接种CVB3诱发急性病毒性心肌炎,感染 24 h 后卡维地洛组每日灌胃给予卡维地洛 10 mg/kg,连续 14 d。于接种第7和14天随机从各组抽取8只小鼠取血后处死并留取心脏等标本。比较干预组与对照组心肌病理改变,采用高效液相色谱-电化学法检测去甲肾上腺素含量,采用RT-PCR法检测心肌IL-6 mRNA的表达,采用酶联免疫吸附实验方法检测心肌IL-6蛋白的表达。结果: 与心肌炎组比较,卡维地洛组心肌病理损伤明显减轻。与正常组比较,病毒性心肌炎小鼠血浆去甲肾上腺素明显升高,卡维地洛干预后小鼠血浆去甲肾上腺素明显下降(P<0.05)。与正常组比较,心肌炎组心肌IL-6表达明显上调(P<0.05)。与心肌炎组比较,卡维地洛组IL-6表达明显下调(P<0.05)。结论: 卡维地洛通过抑制儿茶酚胺对心肌的毒性作用以及下调心肌IL-6表达水平,减轻心肌炎小鼠的心肌损害。     

缬沙坦联合卡维地洛治疗慢性心力衰竭的临床疗效观察

目的探讨缬沙坦联合卡维地洛治疗慢性心力衰竭的临床疗效。方法选择我院2007年5月至2009年9月慢性心力衰竭患者112例,随机分为2组,观察组和对照组。对照组患者采用常规治疗,如低盐饮食、给予洋地黄强心、利尿剂等,患者有心绞痛的给予硝酸酯类药物,观察组在对照组用药基础上,给予缬沙坦和卡维地洛。2组患者疗程为2个月。结果 2组患者治疗后,总有效率比较,差异有统计学意义,P<0.05。结论缬沙坦联合卡维地洛治疗慢性心力衰竭临床治疗效果显著,值得借鉴。     

Upgrading of dissolution and anti-hypertensive effect of Carvedilol via two combined approaches: self-emulsification and liquisolid techniques

Objective: The aim of the study was to design a self-emulsifying drug delivery system (SEDDS) of the anti-hypertensive Carvedilol in liquid and liquisolid forms as a way to enhance its dissolution profile and anti-hypertensive effect.

Methods: Solubility studies of Carvedilol in various oils, surfactants and co-surfactants were conducted, followed by the construction of pseudo-ternary phase diagrams and other in vitro assessments. The selected SEDDS formulation (S1) was adsorbed onto solid powder excipients and compressed into tablets. The resulting liquisolid tablets were evaluated under British Pharmacopoeia (B.P.) specifications. Pre- and post-compression studies were performed to determine the flow properties and evaluate the liquisolid systems, followed by in vivo studies in hypertensive rats.

Results: Attempts of self-emulsification, droplet size, and thermodynamic stability studies showed acceptable results for the S1 formulation containing Capryol 90, Tween 20, and Transcutol HP (10:53.3:26.2%), respectively. Pre-compression studies showed adequate flowability and compatibility of liquid and solid excipients with Carvedilol. The selected liquisolid tablet (LS7) demonstrated the best disintegration and water absorption ratio in addition to satisfactory friability and hardness. A significantly (p?®. The in vivo study of LS7 formulation revealed a rapid significant (p?®.

Conclusion: Self-emulsifying liquisolid tablets expressed rapid onset of action with enhanced anti-hypertensive effect of Carvedilol.     

Preparation and evaluation of SEDDS and SMEDDS containing carvedilol

A new self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS) have been developed to increase the solubility, dissolution rate, and, ultimately, oral bioavailability of a poorly water soluble drug, carvedilol. Ternary phase diagrams were used to evaluate the self-emulsification and self-microemulsfication domains. The self-emulsification time following introduction into an aqueous medium under gentle agitation was evaluated. The minimum self-emulsification time was found at a Tween 80 content of 40%. The particle size distribution and ζ-potential were determined. Benzoic acid had a dual function, it improved the self-emulsification performance of SEDDS and SMEDDS in 0.1 N HCl and lead to a positively charged emulsion. The in vitro dissolution rate of carvedilol from SEDDS and SMEDDS was more than two-fold faster compared with that from tablets. The developed SEDDS formulations significantly improved the oral bioavailability of carvedilol significantly, and the relative oral bioavailability of SEDDS compared with commercially available tablets was 413%.     

Systematic development of pH-independent controlled release tablets of carvedilol using central composite design and artificial neural networks

The purpose of this study was to apply the optimization method incorporating artificial neural network (ANN) using pH-independent release of weakly basic drug, carvedilol from HPMC-based matrix formulation. Because of weakly basic nature of carvedilol, drug shows pH-dependent solubility. The enteric polymer EUDRAGIT L100 was added formulations to overcome pH-dependent solubility of carvedilol. Effects of the Hydroxypropylmethyl cellulose (HPMC) K4M and EUDRAGIT L100 amount on drug release were investigated. For this purpose 13 kinds of formulations were prepared at three different levels of each variables. The optimization of the formulation was evaluated by using ANN method. Two formulation parameters, the amounts of HPMC K4M and Eudragit L100 at three levels (?1, 0, 1) were selected as independent/input variables. In-vitro dissolution sampling times at twelve different time points were selected as dependent/output variables. By using experimental dissolution results and amount of HPMC K4M and EUDRAGIT L100, percentage of dissolved carvedilol was predicted by ANN. Similarity factor (f₂) between predicted and experimentally observed profile was calculated and f₂ value was found 76.33. This value showed that there was no difference between predicted and experimentally observed drug release profile. As a result of these experiments, it was found that ANNs can be successfully used to optimize controlled release drug delivery systems.