Design and Evaluation of a Two-Layer Floating Tablet for Gastric Retention Using Cisapride as a Model Drug

A new kind of two-layer floating tablet for gastric retention (TFTGR) with cisapride as a model drug was developed. The in vitro drug release was determined, and the resultant buoyancy and the time-buoyancy curve were plotted. Because of the sodium bicarbonate added to the floating layer, when immersed in simulated gastric fluid (SGF) the tablet expands and rises to the surface, where the drug is gradually released. The in vitro drug release of this kind of two-layer dosage was controlled by the amount of hydroxypropylmethylcellulose (HPMC) in the drug-loading layer. Generally, the more HPMC, the slower the drug releases. Because cisapride has greater solubility in SGF than simulated intestinal fluid (SIF), its in vitro drug dissolution in SGF is faster than in SIF. One of the distinguishing characteristics of this kind of tablet is the separate regulation of buoyancy and drug release. The idea developed in this experiment can be used as a general model for the design of other tablets for gastric retention.     

Formulation Design of an HPMC-Based Sustained Release Tablet for Pyridostigmine Bromide as a Highly Hygroscopic Model Drug and its In Vivo/In Vitro Dissolution Properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0–t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Channeling Agent and Drug Release from a Central Core Matrix Tablet

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance-polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.     

Channeling Agent and Drug Release from a Central Core Matrix Tablet

A new oral dosage form for controlled and complete release of drug after a predetermined lag time is described. The system, designed to exploit the relatively constant small intestine transit time, consists of a drug-containing core coated with a polymeric matrix formed by a channeling agent (NaCl, mannitol, and Emdex) and an inert polymer (Eudragit RS100). The lag time was found to be dependent on type and particle size of the channeling substances used. Also, rheological properties of the binary mixtures (channeling substance–polymer) can affect the lag time periods. On the other hand, the release kinetics were found to be influenced significantly by excipient type and particle size. Results obtained from in vitro dissolution testing demonstrated that this device potentially could be used to deliver drugs orally for up to once-a-day dosing at controllable rates.     

Mathematical Modeling and Optimization of Two-Layer Sintering Process for Sinter Quality and Fuel Efficiency Using Genetic Algorithm

Two-layer sintering by charging a green sinter mix with normal coke rate in the upper layer and reduced coke rate in the lower layer can substantially reduce the coke rate and improve the sinter quality by producing more uniform thermal profile throughout the bed height. The two-layer sintering process has been analyzed by numerical simulation using a detailed CFD-based model, considering all the important phenomena (i.e., gas-solid reaction, melting and solidification, flow through porous bed, heat, and mass transfer etc.). A genetic algorithm optimization technique is then applied to evaluate the optimum coke rate in the two layers of the bed to produce the ideal thermal profile and melting fraction in the sinter bed for optimum sinter quality. By this optimization method a high-quality sinter with minimum return fines can be achieved along with reduced coke rate. Application of genetic algorithm for this type of process optimization has several advantages over traditional optimization techniques, because it can identify the global optimum condition and perform multiobjective optimization very easily for a complex industrial process such as iron ore sintering.     

论探寻平板电脑设计机会的方法

从目前市场上平板电脑存在的定位模糊问题出发,指出在设计之初对特定人群开展针对其生活形态及行为等分析研究的必要性,并基于群体文化学理论,探讨其在模糊前期对寻找产品机会缺口的意义,提出了运用群体文化学原理在平板电脑开发设计前期的具体应用程序与方法,为相关新产品机会缺口的寻找及产品定位,提供了可操作的方法和步骤。     

Evaluation of Monolithic Osmotic Tablet System for Nifedipine Delivery In Vitro and In Vivo

Abstract

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5–1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

Design and Evaluation of Transdermal Drug Delivery System for Curcumin as an Anti-Inflammatory Drug

The purpose of this research was to develop a matrix-type transdermal therapeutic system containing herbal drug, curcumin (CUR), with different ratios of hydrophilic (hydroxyl propyl methyl cellulose K4M [HPMC K4M]) and hydrophobic (ethyl cellulose [EC]) polymeric systems by the solvent evaporation technique. Different concentrations of oleic acid (OA) were used to enhance the transdermal permeation of CUR. The physicochemical compatibility of the drug and the polymers was also studied by differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results suggested no physicochemical incompatibility between the drug and the polymers. Formulated transdermal films were physically evaluated with regard to drug content, tensile strength, folding endurance, thickness, and weight variation. All prepared formulations indicated good physical stability. In vitro permeation studies of formulations were performed by using Franz diffusion cells. The results followed Higuchi kinetics, and the mechanism of release was diffusion-mediated. Formulation prepared with hydrophilic polymer containing permeation enhancer showed best in vitro skin permeation through rat skin as compared with all other formulations. This formulation demonstrated good anti-inflammatory activity against carrageenan-induced oedema in Wistar albino rats similar to standard formulation.     

Using an Experimental Design to Identify and Quantify the Effects of Environment Related Test Parameters on the In Vitro Mucoadhesivity Testing of a Propanolol Buccal Tablet

ABSTRACT

This study sought to identify and quantify the effects of environmental test parameters on the mucoadhesivity of a propranolol tablet. Their effects on Maximum Detachment Force (MDF) measurements were evaluated using a Box-Behnken design matrix. Prehydration time (PT) had a statistically significant negative main effect while contact force (CF) had no significant effect on in vitro MDF measurements. While contact time (CT) had no significant main or quadratic effects, it had a positive interaction effect with PT. The mathematical model was statistically validated and a PT of 3.5 min and a CT of 5 min was proposed for mucoadhesion testing by the tensile method during formulation optimization.     

Robustness Testing of a Tablet Formulation Using Multivariate Design

ABSTRACT

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations—a product of two strengths—with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.     

Optimization of a Granulation Procedure for a Hydrophilic Matrix Tablet Using Experimental Design

An experimental design was used in order to optimize a granulation procedure in a high-shear mixer for a hydrophilic matrix tablet formulation. The parameters tested were the amount of water in the hydroalcoholic granulation liquid, the amount of granulation liquid, and the massing time. The amount of granulation liquid was the most important parameter, followed by the amount of water in the granulation liquid. The influence of the massing time was negligible. A granule with a friability below 20% was obtained.     

Evaluation and Floating Enhancement of Levodopa Sustained Release Floating Minitablets Coated with Insoluble Acrylic Polymer

This article describes the in vitro evaluation and the enhancement of the floating properties of coated sustained release (SR) minitablets (MTs). The evaluated system consisted of a 3-mm drug-containing gas-generating core prepared by melt granulation and subsequent compression, which was then coated with a flexible polymeric membrane. Eudragit® RL30D and acetyl triethylcitrate were used as a film former and a plasticizer, respectively. The coating level was fixed at 20% (wt/wt). The optimally coated floating MTs floated within 10 min and remained buoyant for more than 13 h, regardless of the pH of the test medium. By evaluating the dissolution profiles of levodopa at different pH, it was found that the release of levodopa was sustained for more than 12 h regardless of the pH, even if the coating did not cancel the effect of the pH-dependent solubility of the active drug. Finally, the robustness of the coated floating MTs was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.     

浮动凹模温精密成形圆柱斜齿轮变形规律分析

目的研究采用浮动凹模工艺温精密成形圆柱斜齿轮时,不同凹模运动速度下齿轮力能参数和各种场量变化规律。方法结合浮动凹模原理和圆柱斜齿轮结构特点,利用Defrom-3D软件建立变形-传热耦合有限元模型,模拟圆柱斜齿轮采用浮动凹模温精密成形过程,分析不同凹模运动速度下的变形规律。结果通过模拟分析,得到了凹模运动速度不同时的温成形斜齿轮成形载荷特点、坯料流动速度场分布、等效应力-应变分布、温度场分布等规律。结论采用浮动凹模工艺成形圆柱斜齿轮,可以减小成形力,当凹模运动速度大于凸模下行速度时,齿轮成形性更好。     

Formulation and In Vitro Studies of a Fixed-Dose Combination of a Bilayer Matrix Tablet Containing Metformin HCl as Sustained Release and Glipizide as Immediate Release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the . The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Power of Experimental Design Studies for the Validation of Pharmaceutical Processes: Case Study of a Multilayer Tablet Manufacturing Process

ABSTRACT

Experimental design studies (EDS) are already widely used in the pharmaceutical industry for drug formulation or process optimization. Rare are the situations in which this methodology is applied for validation purposes. The power of this statistical tool, key element of a global validation strategy, is demonstrated for a multilayer tablet manufacturing process. Applied to the Geomatrix® system generally composed of one compression and three granulation processes, time and strictness gains are non-negligible. Experimental design studies are not used in this work for modeling. Introduced at each important step of the process development, they allow for the evaluation of process ruggedness at pilot scale and specifications for full production. A demonstration of the complete control of key process parameters is given, identified throughout preliminary studies.     

An Evaluation of Smecta as a Tablet Disintegrant and Dissolution Aid

Abstract

Smecta is a nonfibrous Attapulgite (NFA), mostly composed of smectite. It was evaluated as a disintegrant in tablets made by direct compression as well as by wet granulation and using lactose and dicalcium phosphate as water soluble and water insoluble fillers, respectively. An inorganic clay, magnesium aluminum silicate (Veegum), a modified starch (Starch 1500), a cross-linked carboxymethyl cellulose (Ac-Di-Sol), and a cross-linked polyvinylpyrrolidone (Polyplasdone XL) were used for comparative evaluation. Smecta performed well as a disintegrant in tablets made by either method. It was superior to Veegum and Starch 1500, but inferior to Ac-Di-Sol and Polyplasdone XL. In tablets with Smecta, dissolution of hydrochlorothiazide (HCTZ) was superior to those with Ac-Di-Sol.     

An Evaluation of Smecta as a Tablet Disintegrant and Dissolution Aid

Smecta is a nonfibrous Attapulgite (NFA), mostly composed of smectite. It was evaluated as a disintegrant in tablets made by direct compression as well as by wet granulation and using lactose and dicalcium phosphate as water soluble and water insoluble fillers, respectively. An inorganic clay, magnesium aluminum silicate (Veegum), a modified starch (Starch 1500), a cross-linked carboxymethyl cellulose (Ac-Di-Sol), and a cross-linked polyvinylpyrrolidone (Polyplasdone XL) were used for comparative evaluation. Smecta performed well as a disintegrant in tablets made by either method. It was superior to Veegum and Starch 1500, but inferior to Ac-Di-Sol and Polyplasdone XL. In tablets with Smecta, dissolution of hydrochlorothiazide (HCTZ) was superior to those with Ac-Di-Sol.     

Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Optimization Design of TMD for Vibration Suppression of Offshore Floating Wind Turbine

In order to suppress the responses of the large vibration displacements and loads of the offshore floating wind turbine under the harsh marine environment,an effect method for restraining vibration,putting tuned mass dampers( TMD) in the cabin of wind turbine,is proposed in this paper.A dynamics model for offshore floating wind turbine with a fore-aft TMD is established based on Lagrange equation; Parameter identification of the wind turbine is performed by the non-linear least squares Levenberg-Marquardt( LM) algorithm; Parameter optimization of the TMD is researched when considering the standard deviation of the tower top longitudinal displacements as the objective function.Aiming at five typical combined wind and wave load cases under normal running state of the wind turbine,the dynamic responses of the wind turbine with / without TMD are simulated and the suppression effect of the TMD is investigated.The results show that:there exists the optimum TMD mass ratio1.8% when the damped free vibration of the wind turbine,and the standard deviation of the tower top longitudinal displacements is decreased 60% in 100 seconds by the optimized TMD.The standard deviation suppression rates of the longitudinal displacements and loads about the tower and blades increase with the increasing TMD mass ratio when the wind turbine vibration under the combined wind and wave load cases,and when the mass ratio changes from 0.5% to 2%,the maximum suppression rates are from 20% to 50%,which effectively reduce the vibration responses of the wind turbine.The research results of this paper preliminarily verify the feasibilities of using TMD for restraining vibration of the offshore floating wind turbine.     

聚乙二醇法测定超滤膜截留率的不确定度评定

截留率和切割分子量是表征超滤膜截留性能的主要技术参数。以聚乙二醇-20000为标准物质,建立截留率测试结果的不确定度评定数学模型,分析不确定度来源,评定超滤膜截留率测试结果的不确定度。结果表明,PEG-20000的多分散系数(Mw/Mn)为1.005,优于标准中对截留测试标准物质的分子量分布系数小于1.8的要求,GPC谱图呈现单峰形式,符合PEG结构明确、分子量分布窄的特点,完全满足测试需要,标准测试曲线线性好、相关系数R2大于0.999;通过重复性实验,测定了超滤膜对PEG-20000的截留率为93.04%,对该结果进行了A类和B类不确定度评定,当包含因子k=2、置信水平为95%时,扩展不确定度为2.90%。