Design and in vitro testing of a floatable gastroretentive tablet of metformin hydrochloride

Metformin hydrochloride, which is better absorbed in the upper intestine, was formulated as a floating (buoyant) matrix tablet using a gas generating agent (sodium bicarbonate) and a gel forming hydrophilic polymer (hydroxypropyl methylcellulose). The formulation was optimized on the basis of floating ability and in vitro drug release. The resulting formulation produced robust tablets with optimum hardness, consistent weight uniformity and low tablet friability. All tablets but one exhibited satisfactory (gradual and near complete) drug release and buoyancy. In vitro drug release tests of these tablets indicated controlled sustained release of metformin hydrochloride and 96-99% released at the end of 8 h. Two formulations of fabricated tablets containing metformin hydrochloride (500 mg), sodium bicarbonate (75 mg), hydroxypropyl methylcellulose-K 4M (170-180 mg), citric acid (between 15 and 20 mg) and polyvinyl pyrrolidone K90 (32-40 mg) with hardness between 6.8 to 7.5 kg/cm2 showed a floating time of more than 8 h and promising drug release results. The release followed the Higuchi kinetic model, indicating diffusion dominated drug release.     

Floating matrix dosage form for propranolol hydrochloride based on gas formation technique: development and in vitro evaluation

Gastroretentive tablets of propranolol hydrochloride were developed by direct compression method using citric acid and sodium bicarbonate as the effervescent base. Hydroxypropyl methylcellulose; HPMC K15M was used to prepare the floating tablets to retard the drug release for 12h in stomach. Na-carboxymethyl cellulose (NaCMC) or carbopol 934P was added to alter the drug release profile or the dimensional stability of the formulation. Dicalcium phosphate (DCP) was used as filler. Formulations were evaluated for floating lag time, duration of floating, dimensional stability, drug content and in vitro drug release profile. The formulations were found to have floating lag time less than 1min. It was found that the dimensional stability of the formulations increase with increasing concentration of the swelling agent. The release mechanism of propranolol hydrochloride from floating tablets was evaluated on the basis of Peppas and Higuchi model. The ana value of the formulations ranged from 0.5201 to 0.7367 (0.5相似文献   

Formulation and evaluation of sustained release floating capsules of nicardipine hydrochloride

Nicardipine hydrochloride, a calcium channel blocker with significant vasodilating and antihypertensive activities, was formulated in this work as sustained release floating capsules. A hydrocolloid of high viscosity grade was used for the floating systems. The inclusion of sodium bicarbonate to allow evolution of CO2 to aid buoyancy was studied. Polymers that retard drug release were included as coprecipitates with the drug and/or as additives in the formulated capsules. Both simple powder mixing of the ingredients and granule preparation via wet granulation were used. Seven capsule formulae were prepared. The prepared capsules were evaluated in vitro by testing drug dissolution, floating time and the kinetics of drug release. In vitro evaluation of a commercially available conventional 20 mg capsule of nicardipine hydrochloride, "Micard", was carried out for comparison. The hydrocolloid used succeeded in effecting capsule buoyancy. Floating time increased with increasing the proportion of the hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. All of the seven floating capsule formulae prepared proved efficient in controlling drug release. The sustained release floating capsule formulation of choice was evaluated in vivo in comparison to "Micard" capsules using rabbits. Reversed phase HPLC with UV detection was used for drug determination in rabbit plasma. Plasma concentration time curves revealed a longer drug duration for administration in the sustained release formula than the conventional "Micard" capsule being 16 h in the former versus 8 h for the latter.     

Gastroretentive drug delivery system of metoclopramide hydrochloride: formulation and in vitro evaluation

The present investigation concerns the development of floating matrix tablets of metoclopramide hydrochloride (MHCl) for improving its bioavailability by prolonging gastric residence time. Floating matrix tablets (FMT) of MHCl were prepared using the polymers guar gum (GG), karaya gum (KG), HPMC E15 (HE) alone and in combination with HPMC K15M (HK) and gas generating agents such as calcium carbonate and citric acid. The fabricated tablets were evaluated for their physical characteristics such as hardness, drug content, buoyancy, swelling properties and in vitro release studies in 0.1N HCl. The tablets without gas generating agents and HK did not float at all whereas tablets with gas generating agents and without HK floated for 2.33-5.48 h then eroded completely and exhibited faster drug release. Tablets with gas generating agents and HK floated for 24 h without complete erosion and showed slower drug release. This indicates that gas generating agents contributes towards the initial floating of tablets and faster drug release and HK for maintaining the integrity of the FMT and sustaining the drug release. The increase in the concentration of HK in FMT from 10 mg to 40 mg resulted in decrease in release rate of drug. The possibility of drug polymer interaction was determined by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) spectrometer, and confirmed no interaction between drug and polymers. The release pattern of prepared tablets followed Higuchi kinetics which confirms release mechanism by diffusion.     

巴洛沙星胃漂浮缓释片的制备及体外释放

以体外漂浮性能和释放度为指标优化巴洛沙星胃漂浮缓释片的处方。结果表明,每片用量HPMCK100M为120mg、碳酸氢钠为200mg和羧甲淀粉钠为100mg的片剂能在1min内起漂,持续漂浮时间达8．2h,8h累积释放率达90％。按优化处方制备的片荆在高温（60℃）、强光（4500h）下贮存10d,均保持稳定,高温（相对湿度75％）条件下有吸湿现象。     

Formulation and evaluation of floating drug delivery system of famotidine

A multiple unit oral floating drug delivery system of famotidine was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. Drug and polymer compatibility was studied by subjecting physical mixtures of drug and polymers to differential scanning calorimetry. Cod liver oil entrapped calcium alginate beads containing famotidine, capable of floating in the gastric condition were formulated and evaluated. The gel beads were prepared by emulsion gelation method by employing sodium alginate alone and mixture of sodium alginate and hydrophilic copolymers such as carbopol 934P and hydroxypropylmethylcellulose K15M grade in three different ratios. The effect of selected factors, such as percentage of oil and amount of copolymers on floating properties was investigated. The beads were evaluated for percent drug loading, drug entrapment efficiency, buoyancy and in vitro drug release. The in vitro drug release study of the beads was carried out in simulated gastric media employing a modified Rosette-Rice test apparatus. Wherein, the apparatus was further modified by incorporating a water jacket to the apparatus to circulate hot water to maintain 37±2° for throughout the release study. All the oil entrapped calcium alginate beads floated if a sufficient amount of oil was used. Beads formulated employing sodium alginate alone could not sustain the drug release up to 8 h, whereas beads formulated with mixture of sodium alginate and copolymers demonstrated sustained release of famotidine up to 8 h. The results suggested that cod liver oil entrapped calcium alginate beads were promising as a carrier for intragastric floating drug delivery of famotidine.     

Design and optimization of floating drug delivery system of acyclovir

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 3(2) full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t(50%)) and 70% (t(70%)) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t(50%) and t(70%) indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix.     

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).     

法莫替丁单室单层渗透泵片的制备

目的:以法莫替丁(famotidine,FMT)为模型药物研究难溶性药物单层渗透泵片的制备。方法:以PEO,HPMC,NaCl和柠檬酸组成片芯,以醋酸纤维素为包衣材料制备FMT单层渗透泵片,并对片芯组成优化;用相似因子法考察了体外释放条件。结果:片芯最佳组成为:FMT40 mg,PEON1065 mg,HPMCK4M70 mg,NaCl 50 mg,柠檬酸20 mg。释放介质和转速对药物释放无显著影响。本渗透泵片24 h恒速释药,累积释药率93%。结论:本渗透泵片制备简便,能较好地控制FMT24 h匀速释药。     

Formulation and evaluation of effervescent floating tablets of tizanidine hydrochloride

Tizanidine hydrochloride is an orally administered prokinetic agent that facilitates or restores motility through-out the length of the gastrointestinal tract. The objective of the present investigation was to develop effervescent floating matrix tablets of tizanidine hydrochloride for prolongation of gastric residence time in order to overcome its low bioavailability (34-40 %) and short biological half life (4.2 h). Tablets were prepared by the direct compression method, using different viscosity grades of hydroxypropyl methylcellulose (HPMC K4M, K15M and K100M). Tablets were evaluated for various physical parameters and floating properties. Further, tablets were studied for in vitro drug release characteristics in 12 hours. Drug release from effervescent floating matrix tablets was sustained over 12 h with buoyant properties. DSC study revealed that there is no drug excipient interaction. Based on the release kinetics, all formulations best fitted the Higuchi, first-order model and non-Fickian as the mechanism of drug release. Optimized formulation (F9) was selected based on the similarity factor (f2) (74.2), dissolution efficiency at 2, 6 and 8 h, and t50 (5.4 h) and was used in radiographic studies by incorporating BaSO4. In vivo X-ray studies in human volunteers showed that the mean gastric residence time was 6.2 ± 0.2 h.     

Box-Behnken效应面法优化盐酸左氧氟沙星胃漂浮缓释片处方

目的：探讨Box-behnken效应面法在优化盐酸左氧氟沙星胃漂浮缓释片处方过程中的应用。方法：以盐酸左氧氟沙星为模型药物,采用湿法制粒压片法制备左氧氟沙星胃漂浮缓释片剂。利用Box-behnken实验设计,考察三种缓释材料HPMCK 4M、卡泊姆CP934P及海藻酸钠(SA)对不同时间点释药性能和对漂浮片漂浮性能的影响,通过二项式方程拟合建立因素与响应值之间的数学关系以优化处方,对体外释药数据进行方程拟合,探讨其释药机理。结果：通过优化后的最佳处方为HPMC K4M 30 %、卡泊姆CP934P 12.3 %、海藻酸钠(SA) 28.6%,优化处方的实测值与预测值之间的偏差较小;药物的释药机制为骨架溶蚀与药物扩散双重作用。结论：Box-behnken效应面法优化法建立的模型可以用于盐酸左氧氟沙星缓释片处方的优化。     

Effect of formulation parameters on the drug release and floating properties of gastric floating two-layer tablets with acetylsalicylic acid

Floating dosage forms of acetylsalicylic acid, used for its antithrombotic effect, were developed to prolong gastric residence time and increase bioavailability. In the two-layer tablet formulation, hydroxypropyl methylcellulose (HPMC) of high viscosity and an effervescent mixture of citric acid and sodium bicarbonate formed the floating layer. The release layer contained the drug, direct tableting agent and different types of matrix-forming polymers such as HPMC of low viscosity, sodium carboxymethylcellulose and chitosan. Tablets were prepared using a direct compression technique. The effect of formulation variables on physicochemical and floating properties and the drug release from tablets were investigated. Floating ability was dependent on the amount of effervescent agent and gel-forming polymer of the floating layer. Drug release was prolonged to 8 hours by changing the type and viscosity of the matrix-forming polymer in the drug-loading layer and all formulations showed a diffusion release mechanisms.     

左卡尼汀胃漂浮缓释片的制备及体外评价

目的:应用Box-behnken效应面法优化左卡尼汀胃漂浮缓释片处方,并评价其体外漂浮和释放特性.方法:以粉末直接压片法制备片剂.采用单因素法筛选出主要影响因素,即硬度、HPMC用量及碳酸氢钠用量,以漂浮性能和不同时间点释药性能为评价指标,通过Boxbehnken设计实验优化处方,对体外释药数据进行方程拟合,并结合扫描电子显微镜对溶出前后片剂表面形态的观察,探讨其释药机理.结果:优选处方为每片含HPMCK100M 29.7％,碳酸氢钠5.0％,十八烷醇15.0％,硬度为4 kg· mm-2.体外释药符合Makoid-Banakar模型,药物的释药机制为骨架溶蚀与药物扩散双重作用.结论:Box-behnken效应面法可用于左卡尼汀胃漂浮缓释片处方优化,且制备工艺简单,优化处方具漂浮缓释作用.     

诺氟沙星胃漂浮片处方及体外释放研究

目的通过对诺氟沙星胃漂浮片的制备处方研究,考察其漂浮性和体外释放性。方法对处方中辅料的因素水平进行逐一考察,并采用相似因子法比较药物释放曲线的差异。结果HPMC规格对胃漂浮片的释药和持漂时间有明显影响,HPMCK100M用量为120mg·片^-1碳酸氢钠用量为200mg·片^-1和羧甲基淀粉钠用量为100mg·片^-1时漂浮性能和释放度最佳。结论该处方研制的诺氟沙星胃漂浮片具有良好的漂浮特性和缓释特性。     

Formulation design and optimization of fast disintegrating Lorazepam tablets by effervescent method

Fast disintegrating tablets of lorazepam were prepared by effervescent method with a view to enhance patient compliance. A 3(2) full factorial design was applied to investigate the combined effect of two formulation variables: amount of crospovidone and mixture of sodium bicarbonate, citric acid and tartaric acid (effervescent material) on in vitro dispersion time. Crospovidone (2-8% w/w) was used as superdisintegrant and mixture of sodium bicarbonate, citric acid and tartaric acid (6-18% w/w) was used as effervescent material, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity and in vitro dispersion time. Based on in vitro dispersion time (approximately 13 s); the formulation containing 8% w/w crospovidone and 18% w/w mixture of sodium bicarbonate, citric acid and tartaric acid was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability and drug-excipient interaction. Surface response plots are presented to graphically represent the effect of independent variables (concentrations of crospovidone and effervescent material) on the in vitro dispersion time. The validity of the generated mathematical model was tested by preparing two extra-design check point formulations. The optimized tablet formulation was compared with conventional marketed tablet for drug release profiles. This formulation showed nearly eleven-fold faster drug release (t(50%) 2.8 min) compared to the conventional commercial tablet formulation (t(50%) >30 min). Short-term stability studies on the formulation indicated that there were no significant changes in drug content and in vitro dispersion time (P<0.05).     

Formualtion and evaluation of floating drug delivery system containing clarithromycin for Helicobacter pylori

Floating matrix tablets are designed to prolong the gastric residence time after oral administration, at a particular site and controlling the release of drug especially useful for achieving controlled plasma level as well as improving bioavailability. With this objective, floating dosage form containing clarithromycin as drug was designed for the treatment of Helicobacter pylori. Tablets containing hydroxypropylmethylcellulose (HPMC), drug and different additives were compressed using wet granulation and D-optimal design technique. The study shows that tablet composition and mechanical strength have great influence on the floating properties and drug release. Incorporation of gas-generating agent together with polymer improved drug release, besides optimal floating (floating lag time < 30 s; total floating time > 10 h). The drug release was sufficiently sustained (more than 8 h) and anomalous diffusion as well as zero-order was confirmed. Optimization of the evaluating parameters with 'design expert' software was employed to get final optimized formulation. The optimized formulation was obtained using 62.5% clarithromycin, 4.95% HPMC K15M, 18.09% HPMC K4M, 12.96% sodium bicarbonate which gave floating lag time < 30 s with a total floating time > 10 h, in vitro release profile very near to the target in vitro release profile and follows anomalous diffusion as well as zero order pattern of release.     

The synthesis and characterization of fatty acid salts of chitosan as novel matrices for prolonged intragastric drug delivery

The aim of this study was to prepare fatty acid salts of chitosan (CS) and to evaluate the salts as matrices for sustained drug release and prolonged gastric retention. CS-laurate and CS-palmitate were formed by mixing saturated CS solution and aqueous solutions of sodium laurate and sodium palmitate, respectively, and collected by centrifugation. They were characterized using Fourier-transform infrared spectroscopy and differential scanning calorimetry. Different matrices as effervescent tablets were prepared using each of these CS-salts, CS and the corresponding physical mixtures of CS and the fatty acids. Sodium bicarbonate as an effervescent agent and ranitidine HCl as a model drug were incorporated into these matrices. In vitro buoyancy and drug dissolution were studied for the matrices in 0.1 M HCl. Tablets with fatty acid salts of CS showed both rapid and prolonged buoyancy (> 8 h). Comparatively, CS tablets exhibited a short floatation period (< 2 h) and tablets were completely disintegrated within 1 h of soaking. In addition, slow and prolonged drug release was achieved from tablets of fatty acid salts of CS with average drug release of 80.1 and 71.8% for CS-laurate and CS-palmitate, respectively. Rapid drug release (> 80% at 1 h) was exhibited by tablets with CS or the physical mixtures.     

Carbopol 934-Sodium Alginate-Gelatin Mucoadhesive Ondansetron Tablets for Buccal Delivery: Effect of pH Modifiers

The present work aims at developing mucoahesive tablets of ondansetron hydrochloride using bioadhesive polymers like carbopol-934, sodium alginate and gelatin. Tablets prepared by direct compression using different polymer with varying ratio were evaluated for hardness, friability, uniformity of weight, disintegration time, microenvironmental pH, bioadhesion and in vitro release. Hardness, friability disintegration time and drug release were found within pharmacopoeial limit. Microenvironmental pH decreased whereas bioadhesive strength, water uptake, and in vitro release increased with increase in carbopol-934. Increasing sodium alginate and gelatin increased the microenviromental pH and decreased bioadhesive strength, water uptake and in vitro release. With a view to investigate the modulation of drug release from formulation by addition of pH modifiers viz. citric acid and sodium bicarbonate, the tablets with carbopol-934 (2.0), sodium alginate (0.5) and gelatin (6.5) were used and the effect of pH modifiers on microenvironmental pH, bioadhesion, water uptake, in vitro permeation and in vitro release was studied. Microenvironmental pH, bioadhesive strength, water uptake, in vitro release and permeation decreased with increasing concentration of citric acid whereas microenvironmental pH, water uptake and release were enhanced and bioadhesive strength was lowered with increase in sodium bicarbonate. Present study demonstrates carbopol-934, sodium alginate, gelatin polymer system with added pH modifier can be successfully formulated for buccal delivery of ondansetron with desired release profile.     

星点设计 -效应面法优化杜仲漂浮型脉冲释放片处方的研究

目的 采用星点设计-效应面法优化杜仲漂浮型脉冲释放片的处方.方法 在前期单因素试验的基础上,以包衣层材料中羟丙甲纤维素(HPMCK15M)、乳糖、碳酸氢钠的百分含量为考察因素,以释药时滞和起漂时间为考察指标,采用Design-Ex-pert 8.06软件进行试验设计,对指标与因素之间进行多元线性和二次多项式方程拟合,通过效应面法优化最佳处方为:HPMCK15M、乳糖、碳酸氢钠分别占包衣层质量的35％、20％、20％,并对其进行验证.结果 各指标与因素之间二次多项式方程拟合良好,相关系数R2分别为0.9655和0.9668,采用优化处方制备的杜仲漂浮型脉冲释放片具有脉冲释药和快速漂浮特性,各指标实测值与预测值偏差+1.94％和-3.77％.结论 星点设计-效应面法可用于本制剂处方的优化,所制得的杜仲漂浮型脉冲释放片具有体外定时脉冲释药特性.     

Design,Development and Optimization of S (-) Atenolol Floating Sustained Release Matrix Tablets Using Surface Response Methodology

The objective of this present investigation was to develop and formulate floating sustained release matrix tablets of s (-) atenolol, by using different polymer combinations and filler, to optimize by using surface response methodology for different drug release variables and to evaluate the drug release pattern of the optimized product. Floating sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: Hydroxypropyl methylcellulose, sodium bicarbonate as a gas generating agent, polyvinyl pyrrolidone as a binder and lactose monohydrate as filler. The 3² full factorial design was employed to investigate the effect of formulation variables on different properties of tablets applicable to floating lag time, buoyancy time, % drug release in 1 and 6 h (D_{1 h,}D_{6 h}) and time required to 90% drug release (t_90%). Significance of result was analyzed using analysis of non variance and P < 0.05 was considered statistically significant. S (-) atenolol floating sustained release matrix tablets followed the Higuchi drug release kinetics that indicates the release of drug follows anomalous (non-Fickian) diffusion mechanism. The developed floating sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.