Optimization of acyclovir oral tablets based on gastroretention technology: factorial design analysis and physicochemical characterization studies

The purpose of this research was to prepare a floating drug delivery system of acyclovir. Floating matrix tablets of acyclovir were developed to prolong gastric residence time and increase its bioavailability. The tablets were prepared by direct compression technique, using polymers such as hydroxypropylmethylcellulose 4000, Compritol 888. Sodium bicarbonate was used as a gas-generating agent. A 32 factorial design using the Design Expert Software (version 7.1.6) was applied to optimize the drug release profile systematically. The amounts of hydroxypropylmethylcellulose 4000 (X?) and Compritol 888 (X?) were selected as independent variables and the percentage drug released in 1 (Q?), 6 (Q?), and 12 (Q??) h as dependent variables. The results of factorial design indicated that a high level of both hydroxypropylmethylcellulose 4000 (X?) and Compritol 888 (X?) favors the preparation of floating controlled-release of acyclovir tablets. Also, a good correlation was observed between predicted and actual values of the dependent variables chosen for the study. By fitting the data into zero-order, first-order, and Higuchi models, we concluded that the release followed Higuchi diffusion kinetics. Storage of the prepared formulations at 40°C/75% relative humidity for 3 months showed no significant change in drug release profiles and buoyancy of the floating tablets. We can conclude that a combination of hydroxypropylmethylcellulose 4000, Compritol 888, and sodium bicarbonate can be used to increase the gastric residence time of the dosage form up to 12?h. These floating tablets seem to be a promising gastroretentive drug delivery system.     

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization,in vitro and in vivo pharmacokinetic studies

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).

Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3² factorial design was done using Polyox WSR 303 (X₁) and HPMC K₄M (X₂) as independent variables and cumulative percentage drug released at 6?h (Q6h) as dependent variable.

Results: Optimized formulation showed floating lag time of 4–5 s, floated for more than 12?h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6?h. In vivo pharmacokinetic studies in rabbits showed C_max of 189.96?±?13.04?ng/mL and T_max of 4?±?0.35?h for GFDDS. The difference for AUC_(0–T) and AUC_(0–∞) between the test and reference formulation was statistically significant (p > 0.05). AUC_(0–T) and AUC_(0–∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively.

Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.     

Preparation and pharmacokinetics study on gastro-floating sustained-release tablets of troxipide

The purpose of this research aimed at preparing gastro-floating sustained-release tablets of troxipide and a further study on in vitro release and in vivo bioavailability. Under the circumstances of direct powder compression, the floating tablets were successfully prepared with HPMC as main matrix material, Carbopol as assistant matrix material, octadecanol as floating agent and sodium bicarbonate as foaming agent to float by gas-forming. The floating time and accumulative release amount as evaluation indexes were utilized to perform pre-experiment screening and single-factor test, respectively, while central composite design response surface method was applied for formulation optimization, followed by in vivo pharmacokinetic study in beagles after oral administration for floating tablets and commercial tablets used as the control. The results indicated that the floating sustained-release tablets held a better capability for floating and drug release and more satisfactory pharmacokinetic parameters, such as a lower C_max, a prolonged T_max, but an equivalent bioavailability calculated by AUC_0–24 compared to commercial tablets. So a conclusion was finally drawn that the floating sustained-release tablets possessing a good release property could be suitable for demands of design.     

Design and optimization of gastric floating sustained-release mini-tablets of alfuzosin hydrochloride based on a factorial design: in vitro/in vivo evaluation

Abstract

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO₃) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO₃ were found to float immediately within 1?min and duration more than 9?h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67?h. Furthermore, the AUC_0?t of the floating mini-tablets (6849.83?±?753.80?h ng·mL^?1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16?±?924.60?h ng·mL^?1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.     

Buccal Bioadhesive Delivery System of 5-Fluorouracil: Optimization and Characterization

The objective of this work was to apply the response surface approach in the development of buccal bioadhesive tablets of 5-fluorouracil (5-FU). Experiments were performed according to a 3² factorial design to evaluate the effects of two polymers, Gantrez MS-955 (X₁) and hydroxypropylmethyl cellulose (HPMC) K15M (X₂) on the bioadhesive force, percentage drug release in 8 h (Rel_{8 h}), time taken for 50% drug release (t_50%), and diffusion coefficient (n). The effect of the two independent variables on the response variables was studied by response surface plots and contour plots generated by the Design Expert® software. The compatibility between 5-FU and the tablet excipients was confirmed by differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) studies. Both the polymers were found to have synergistic effect on bioadhesion but the effect of Gantrez was more pronounced. A nonlinear twisted relationship was obtained for Rel_{8 h} at the intermediate and high levels of the polymers, which indicated an interaction between them at the corresponding factor levels. Kinetic treatment to the dissolution profiles revealed that the drug release ranged from Fickian to anomalous transport, which was mainly dependent on both the independent variables. The desirability function was used to optimize the response variables, and the observed responses were in agreement with the experimental values.     

Gastrointestinal stability,physicochemical characterization and oral bioavailability of chitosan or its derivative-modified solid lipid nanoparticles loading docetaxel

Abstract

Objective: The purpose of this study was to prepare the positively charged chitosan (CS)- or hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) loading docetaxel (DTX), and to evaluate their properties in vitro and in vivo.

Methods: The DTX-loaded SLNs (DTX-SLNs) were prepared through an emulsion solvent evaporation method and further modified with CS or HACC (CS-DTX-SLNs or HACC-DTX-SLNs) via noncovalent interactions. The gastrointestinal (GI) stability, dissolution rate, physicochemical properties and cytotoxicities of SLNs were investigated. In addition, the GI mucosa irritation and oral bioavailability of SLNs were also evaluated in rats.

Results: The HACC-DTX-SLNs were highly stable in simulated gastric and intestinal fluids (SGF and SIF). By contrast, the CS-DTX-SLNs were less stable in SIF than in SGF. The drug dissolution remarkably increased when DTX was incorporated into the SLNs, which may be attributed to the change in the crystallinity of DTX and some molecular interactions that occurred between DTX and the carriers. The SLNs showed low toxicity in Caco-2 cells and no GI mucosa irritations were observed in rats. A 2.45-fold increase in the area under the curve of DTX was found in the HACC-DTX-SLN group compared with the DTX group after the modified SLNs were orally administered to rats. However, the oral absorption of DTX-SLN or CS-DTX-SLN group showed no significant difference compared with that of DTX group.

Conclusions: The positively charged HACC-DTX-SLNs with a stable particle size could provide the enhanced oral bioavailability of DTX in rats.     

Improved oral bioavailability of valsartan using proliposomes: design,characterization and in vivo pharmacokinetics

Abstract

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6?±?2.9% with a vesicle size of 364.1?±?14.9?nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12?h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.     

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.     

基于QFD理论的工业设计专业课程体系优化设计

为了有效减少高校培养出来的工业设计人才与社会实际需求之间的错配现象,利用KJ法将能力需求类聚为9类,课程类聚为6个模块,采用层次分析法(AHP)求取各能力需求项的重要度,将其与调研得到的能力需求满意度一起作为基础信息输入质量屋.在进行课程模块的质量设计时,以质量屋的信息为基础,根据本校的经验和竞争对手的信息确定能力需求的目标满意度,以此建立目标规划模型求出各课程模块的目标值,进而得到工业设计专业的课程体系.由此,从根本上保证工业设计专业人才满足社会需求．     

Effect of chitosan glutamate,carbomer 974P,and EDTA on the in vitro Caco-2 permeability and oral pharmacokinetic profile of acyclovir in rats

Background: Chitosan glutamate and polyacrylic acid (e.g., carbomer 974P) are known to modulate the tight junctions in the intestinal wall and increase permeability and blood exposure of drugs absorbed orally by the paracellular route. Aim: To assess the impact of chitosan glutamate and carbomer 974P on the absorption of paracellularly absorbed model drug, acyclovir, in vitro and in rat in vivo. Methods: The influence of chitosan glutamate and carbomer 974P (alone and in combination with EDTA–Na2) on the in vitro Caco-2 permeability and oral pharmacokinetic profile in the rat of acyclovir was investigated. Results: In the presence of chitosan glutamate, the apparent permeability of acyclovir across Caco2 monolayer increased 4.1 times relative to control. This increase was accompanied by a significant (～60%) decrease in transepithelial electrical resistance values indicating opening of the tight junctions in the cell monolayer. In rat, chitosan glutamate doubled oral bioavailability of acyclovir and tripled the amount of acyclovir excreted unchanged into urine. In contrast, the effect of carbomer 974P was not statistically significant at 5% level. Conclusions: In conclusion, chitosan glutamate (1–3%) and chitosan glutamate (1%)/EDTA–Na2 (0.01%) are effective excipients to increase permeability of acyclovir across Caco-2 cell monolayers and the oral absorption in the rat in vivo.     

Optimization of fluid bed formulations of metoprolol granules and tablets using an experimental design

Background: The granulation process of a metoprolol tartrate (very difficult to process active pharmaceutical ingredient) formulation in laboratory scale fluid bed equipment was studied. Aim: To study the influence of two formulation factors and three process parameters on the characteristics of the granules and subsequently of the tablets, in the case of fluid bed granulating of a powder mix containing metoprolol tartrate. Method: In order to study the influence of formulation factors (binder solution concentration and the silicon dioxide ratio) and process factors (atomizing pressure, the length of the final drying phase, and the inlet air temperature) on the technological and pharmaceutical properties of granules and tablets, a fractional factorial experimental design resolution V+ with five factors and two levels was used. Results: A high atomizing pressure allows us to obtain fine granules with large poly-dispersion index and granules with high tapped and untapped density, tablets with short disintegration time, short mean dissolution time, and a high percentage metoprolol tartrate release in the first 15 minutes. A lower concentration of binder solution allows us to obtain granules with very good flow properties, tablets which have no tendency to stick on the set punch of tabletting machine and no capping. The final drying time of granules has an influence only on the granule's relative humidity and tapped and untapped density, without any influence on the granules flow properties. Conclusions: The practical experimental results from the formulation processed in optimal working conditions were close to the predicted ones by Modde 6.0 software.     

Cubosomal based oral tablet for controlled drug delivery of telmisartan: formulation,in-vitro evaluation and in-vivo comparative pharmacokinetic study in rabbits

A nanoparticulate system; cubosomes has been suggested to support the controlled release of Telmisartan (TEL), a poorly water-soluble medication. Four distinctive formulae were selected according to the results of three estimated responses. The liquid cubosomes were successfully adsorbed onto Aerosil 380 to form granules. The formulae were evaluated for their flow properties. The best granules were compressed into tablets suitable for oral administration. The tablets were evaluated for its performance. The in vivo study of the best selected cubosomal tablets was checked after oral administration in the blood of albino rabbits utilizing an HPLC method. Results revealed that the highest EE was shown in formulae C5 (59.68?±?1.3). All the prepared formulae had particle size less than 500?nm with PDI < 0.5 and the highest zeta potential results were observed in C5, C7, C9, C11 and C12 (>30?mv). A7 and A9 prepared using Aerosil 380 showed a perfect flowability. After 1?h of dissolution testing, the commercial product showed a 66% drug release while the release of all cubosomal formulae didn’t exceed 35% during the first hour reaching a 85% of the drug released at the end of 24?h. A7 was selected for the in vivo study; T_max of TEL absorption is increased for cubosomal formula by three folds indicating sustained release pattern. The relative bioavailability is also increased by 2.6 fold. The investigation proposed the rationality of cubosome to figure an effective controlled release tablets to improve its bioavailability and expand its activity.     

基于面向对象技术的汽车模拟碰撞节制杆设计

 根据节制杆式模拟汽车碰撞台车试验系统的技术特点,分析了节制杆式碰撞吸能装置的工作原理和节制杆设计计算模型,利用面向对象编程技术设计了汽车模拟碰撞节制杆计算软件.经软件设计的节制杆碰撞吸能装置可以很好地再现实车碰撞动力学过程,具有较高的设计精度.     

Chitosan nanoparticles for the oral delivery of tenofovir disoproxil fumarate: formulation optimization,characterization and ex vivo and in vivo evaluation for uptake mechanism in rats

Objective: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption.

Significance: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption.

Methods: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles.

Results: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156?±?5?nm with an entrapment efficiency of 48.2?±?1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin-mediated uptake played a key role in increasing the oral absorption of tenofovir.

Conclusions: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways.     

Removal of boron from aqueous solution by adsorption on Al2O3 based materials using full factorial design

This paper aims the adsorption of boron from aqueous solution onto Siral 30 and Pural using 2³ full factorial design. The effect of individual variables and their interactional effects for boron adsorption were also determined. From the statistical analysis, it is inferred that as pH and temperature increased boron adsorption from aqueous solution decreased. Siral 30 was found to be more efficient adsorbent than Pural. The unimportant factor affecting boron adsorption from aqueous solution was also verified by using Fisher adequacy test. At the 90% confidence level, the type of adsorbent, temperature and type of adsorbent–temperature interaction was effective on boron adsorption from aqueous solution. The experimental results were fitted to the Langmuir, Freundlich and Dubinin–Radushkevich (DR) equations to find out adsorption capacities. In most cases, the results indicate that Freundlich and DR equations are well described with the sorption data. The adsorption capacity values of Siral 30 calculated from Freundlich and DR equation was greater than that of Pural. The thermodynamic parameters were also estimated and the adsorption process was not spontaneous nature.     

基于基因工程思想的产品族设计及其关键技术研究

通过分析型材断面的尺寸和形状特征的继承关系及型材模块的结构变异,将基因工程的思想用于产品族的开发设计中,并将"型材特征"看作是产品结构信息的"DNA"。借鉴生物学领域基因工程原理,揭示了"型材特征"这种信息流在产品树中的传播规律,在此基础上提出了一种基于基因工程思想的产品基因编码与重组方法。通过对产品族和产品基因DNA的概念以及产品族设计DNA的内涵和研究内容的探讨,指出了支持产品基因工程的关键技术,并以门体型材为例,说明产品族基因工程思想的设计效果。     

Macroscopic analysis of design processes based on a scheme for coding designers' cognitive actions

We have devised a new scheme for coding designers' cognitive actions from video/audio design protocols. Designers' actions are coded into four cognitive levels; physical, perceptual, functional and conceptual. Relations between actions belonging to different levels, such as dependencies and triggering relations, are also coded. The present scheme has two benefits. First, we found that design actions are definable in a systematic way using the vocabulary of the scheme, and thus a designer's cognitive behaviours in each of local design stages is represented as a structure composed of defined primitive actions. This is expected to lay the foundation for microscopic analyses of how particular types of actions contribute to the formation of key design ideas. Second, this scheme is suitable for macroscopic analyses of how designers cognitively interact with their own sketches. We examined, for a practising architect, the ways in which drawing, inspection of drawings, perception, and functional thoughts correlated with one another in his design process. The findings suggest that design sketches serve not only as external memory or as a provider of visual cues for association of non-visual information, but also as a physical setting in which design thoughts are constructed on the fly.     

Solid dispersion adsorbate technique for improved dissolution and flow properties of lurasidone hydrochloride: characterization using 32 factorial design

The aim of the present study was to improve the dissolution and flow properties of lurasidone hydrochloride (LH) by solid dispersion adsorbate (SDA) technique. Solid dispersions (SDs) of LH were prepared by fusion method using Poloxamer P188. The melt dispersion was adsorbed onto the porous carrier Florite (calcium silicate). A 3² factorial design was employed to quantify the effect of two independent variables, namely ratio of carrier (Poloxamer 188) and LH in SD and ratio of adsorbent (Florite) to SD. SDA granules of LH were studied for flow properties and characterized using differential scanning calorimetry, scanning electron microscopy, and X-ray diffraction. Tablets of optimized composition of SDA granules (equivalent to 20?mg of drug) and plain tablets were prepared by direct compression method. The dissolution studies were carried out in Mcllvaine buffer (pH 3.8) as per USFDA guidelines and characterized for parameters such as percent dissolution efficiency, t₅₀, and Q₃₀. Tablets prepared from SDA granules showed almost four-fold increase in cumulative percentage drug release as compared to tablets prepared from plain LH. The value of dissolution efficiency was enhanced from 49.60% for plain tablets to 94.15% for SDA tablets. SDA granules did not show any change in drug release and X-ray diffraction pattern after storage at 40?°C/75% of RH for 3?months, which confirms that Florite prevented conversion of drug from amorphous form to crystalline form improving physical stability of the amorphous state of LH.     

A survey of research and studies on design

This review is based on two hundred responses to a questionnaire designed by the Design Methodology Unit, Department of Praxiology, Polish Academy of Sciences. On the basis of the replies it shows the state of research in design and the applied sciences.     

基于虚拟样机技术的汽车操纵稳定性参数正交优化设计

以某型轿车底盘为研究对象,采用虚拟样机软件ADAMS建立整车多体动力学仿真模型;结合汽车操纵稳定性的客观定量评价标准,建立了直接生成操纵稳定性评价值的ADAMS函数;用ADAMS软件结合正交试验方法对整车操纵稳定性进行了虚拟正交优化设计.虚拟样机技术在车辆操纵稳定性参数正交优化中的应用,不仅使仿真模型与集中质量模型相比提高了精度,还分析出整车操纵稳定性的主要零部件影响因素,得到了最优的一组设计方案.由于是直接对具体零部件的优化,整个设计过程适于在企业中应用.