Development of Sustained-Release Tablets Containing Sodium Valproate: In Vitro and In Vivo Correlation

ABSTRACT

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

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.     

Progress and Challenge for Magnesium Alloys as Biomaterials

Magnesium alloys are very biocompatiable and show promise for use in orthopaedic implant. Significant progress of research on bioabsorbable magnesium stents and orthopaedic bones has been achieved in recent years. The issues on degradation, hydrogen evolution, and corrosion fatigue and erosion corrosion of magnesium alloys and various influencing factors in simulated body fluid (SBF) are discussed. The research progress on magnesium and its alloys as biomaterials and miscellaneous approaches to enhancement in corrosion resistance is reviewed. Finally the challenges and strategy for their application as orthopaedic biomaterials are also proposed.     

A New Rapidly Absorbed Paracetamol Tablet Containing Sodium Bicarbonate. II. Dissolution Studies and In Vitro/In Vivo Correlation

ABSTRACT

The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH 5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel® worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro–in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH 5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r = 0.773; p<.00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro–in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration–time profiles.     

Production of an Extremly Low Dose Procaterol HCl Preparation by Fluidized-Bed Coating Method: In Vitro and In Vivo Evaluation

Abstract

A convenient and reliable method to prepare procaterol HCl oral dosage form at an extremely low dosage (25 µg/cap) is presented in this paper. Procaterol HCl was mixed with the film-forming agent hydroxypropyl methylcellulose in an aqueous solution, which was then spray-coated on sugar spheres (Nu-pareil PG 20/25) to produce procaterol HCl pellets. The IR spectra of coated and noncoated pellets indicated that procaterol HCl was coated on the sugar spheres successfully with a weight increment less than 1%. Most of the coated pellets were able to pass through an 18-mesh screen with no agglomeration. The average weights of coated pellets filled inside of capsules were monitored during the filling process. A simple liquid chromatographic method was developed and validated for the assay and uniformity test of procaterol HCl in different dosage forms. The results of assay and content uniformity test for both in-house product and a commercial product, i.e., Meptin®-mini tablet, were satisfied. The data of f₂ function and ANOVA analysis for the dissolution profiles of both procaterol HCl products suggested that they are pharmaceutical equivalent.

In an in vivo study (n = 24), a single dose of 75 µg procaterol HCl was administrated to each volunteer and the plasma concentration of procaterol was determined by a LC/MS/MS method, developed by the same authors. There were no significant differences (p > 0.05) in the data of AUC_0→16h, AUC_0→∞, C_max, and MRT for both preparations. It is confirmed that the pellets capsule produced in this study is bioequivalent with Meptin®-mini tablet.     

In Vitro and In Vivo Evaluation of Glibenclamide in Solid Dispersion Systems

The purpose of this work is to improve the dissolution and bioavailability characteristics of glibenclamide as compared to Daonil® tablets (Hoechst). Solid dispersions of glibenclamide in Gelucire 44/14 (Formula 1) and in polyethylene glycol 6000 (PEG 6000) (Formula 2) were prepared by fusion method. In vitro dissolution studies showed that the dispersing systems containing glibenclamide and Gelucire 44/14 or PEG 6000 gave faster dissolution rates than the reference product Daonil. The in vivo bioavailability study was assessed in six healthy male volunteers in crossover design with a 1‐week washout period. Both formulas were found to be significantly different from Daonil with regard to the extent of absorption as indicated by the area under serum concentration‐time curve. Both formulas are not significantly different from Daonil with respect to time of peak plasma concentration (T_max). It is concluded from this pilot study that the ranking of the in vitro dissolution is similar to the ranking of in vivo availability. The ranking of the three preparations in term of dissolution rate and extent of absorption is as follows: Formula 2?>?Formula 1?>?Daonil.     

Development of Monolithic Osmotic Pump Tablet System for Isosorbide-5-Mononitrate Delivery and Evaluation of it In Vitro and In Vivo

The objective of this study is to develop the monolithic osmotic pump tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN), and to evaluate its in vitro and in vivo properties. The influences of tablet formulation variables, size and location of the delivery orifice, membrane variables, and pH value of the dissolution medium on 5-ISMN release from MOTS have been investigated. These results demonstrated that the tablet core played an important role in MOTS, and membrane variables could affect the 5-ISMN release rate. The optimal formulation of 5-ISMN MOTS was determined by uniform design. Furthermore, the dog pharmacokinetics and relative bioavailability of the test formulation (5-ISMN MOTS) have been compared with the reference formulation (Imdur^®: 60 mg/tablet, a sustained release, SR, tablet system) following an oral single dose of 60 mg given to each of six Beagle dogs. The mean drug fraction absorbed by the dog was calculated by the Wagner–Nelson technique. The results showed that drug concentration in plasma could be maintained more stable and longer after the administration of 5-ISMN MOTS compared with the matrix tablets of Imdur^®, and a level A “in vitro–in vivo correlation” was observed between the percentage released in vitro and percentage absorbed in vivo. It is concluded that 5-ISMN MOTS is more feasible for a long-acting preparation than 5-ISMN SR tablet system as once-a-day treatment, and it is very simple in preparation, and can release 5-ISMN at the rate of approximately zero order for the combination of hydroxypropylmethyl cellulose as retarder and NaCl as osmogent.     

Cytotoxicity of BSA‐Stabilized Gold Nanoclusters: In Vitro and In Vivo Study

Gold nanoclusters (Au NCs) are one of the most promising fluorescent nanomaterials for bioimaging, targeting, and cancer therapy due to their tunable optical properties, yet their biocompatibility still remains unclear. Herein, the cytotoxicity of bovine serum albumin (BSA)‐stabilized Au NCs is studied by using three tumor cell lines and two normal cell lines. The results indicate that Au NCs induce the decline of cell viabilities of different cell lines to varying degrees in a dose‐ and time‐dependent manner, and umbilical vein endothelial cells which had a higher intake of Au NCs than melanoma cells show more toxicity. Addition of free BSA to BSA‐Au NCs solutions can relieve the cytotoxicity, implying that BSA can prevent cell damage. Moreover, Au NCs increase intracellular reactive oxygen species (ROS) production, further causing cell apoptosis. Furthermore, N‐acetylcysteine, a ROS scavenger, partially reverses Au NCs‐induced cell apoptosis and cytotoxicity, indicating that ROS might be one of the primary reasons for the toxicity of BSA‐Au NCs. Surprisingly, Au NCs with concentrations of 5 and 20 nM significantly inhibit tumor growth in the xenograft mice model of human liver cancer, which might provide a new avenue for the design of anti‐cancer drug delivery vehicles.     

In Vitro and In Vivo Release of Naltrexone from Biodegradable Depot Systems

ABSTRACT

The aim of this study was to prepare poly(d, l-lactide) (PLA) microspheres containing naltrexone (NTX) by a solvent evaporation method, and to evaluate both in vitro and in vivo release characteristics and histopathological findings of tissue surrounding an implant formulation in rats.

This method enabled the preparation of microspheres of regular shape and relatively narrow particle size distribution. The in vitro release profiles of NTX from PLA microspheres showed the release of NTX did not follow zero-order kinetics. An initial burst release was observed, subsequently followed by a nearly constant rate of 0.4% per day after ten days. The cumulative amount of NTX released at the end of 60 days was 80%. Compressed microspheres showed near zero-order sustained release of NTX for 360 days. The plasma NTX levels in rats showed that for compressed microspheres NTX concentrations were constant and exceeded 2 ng/mL for 28 days. Throughout the 28 days of study, the implantations cause a minor inflammatory response, which can be regarded as a normal defence mechanism. The sustained release performance of NTX from the biodegradable depot systems may provide a reliable, convenient, and safe mechanism for the administration of NTX for the long-term treatment of opioid dependence.     

镁合金热裂行为研究的测试方法探讨

针对镁合金的特点，就合金热裂行为研究的测试方法进行了实验研究和分析。用热裂行为测试系统测量合金凝固过程中的温度、线收缩和收缩应力，用铸造热分析系统分析铸造凝固条件下的相析出，这为研究合金的热裂形成机理提供了重要的实验手段。采用热裂环法可以有效地评价合金的热裂倾向性，而等长度试棒法(无论金属型还是砂型)则不适于测试镁合金。     

In Vitro and In Vivo Interrogation of Bio-sprayed Cells

Bio-sprays can directly form pre-organized cell-bearing structures for applications ranging from engineering functional tissues to the forming of cultures, most useful for modeling disease, to the discovery and development of drugs. Bio-electrosprays and aerodynamically assisted bio-jets, are leading approaches that have been demonstrated as having far-reaching ramifications for regenerative biology and medicine.     

Water‐Dispersible,pH‐Stable and Highly‐Luminescent Organic Dye Nanoparticles with Amplified Emissions for In Vitro and In Vivo Bioimaging

A new strategy is presented for using doped small‐molecule organic nanoparticles (NPs) to achieve high‐performance fluorescent probes with strong brightness, large Stokes shifts and tunable emissions for in vitro and in vivo imaging. The host organic NPs are used not only as carriers to encapsulate different doped dyes, but also as fluorescence resonance energy transfer donors to couple with the doped dyes (as acceptors) to achieve multicolor luminescence with amplified emissions (AE). The resulting optimum green emitting NPs show high brightness with quantum yield (QY) of up to 45% and AE of 12 times; and the red emitting NPs show QY of 14% and AE of 10 times. These highly‐luminescent doped NPs can be further surface modified with poly(maleic anhydride‐alt‐1‐octadecene)‐polyethylene glycol (C18PMH‐PEG), endowing them with excellent water dispersibility and robust stability in various bio‐environments covering wide pH values from 2 to 10. In this study, cytotoxicity studies and folic acid targeted cellular imaging of these multicolor probes are carried out to demonstrate their potential for in vitro imaging. On this basis, applications of the NP probes in in vivo and ex vivo imaging are also investigated. Intense fluorescent signals of the doped NPs are distinctly, selectively and spatially resolved in tumor sites with high sensitivity, due to the preferential accumulation of the NPs in tumor sites through the passive enhanced permeability and retention effect. The results clearly indicate that these doped NPs are promising fluorescent probes for biomedical applications.     

超高强韧Mg-Gd-Y-Zn-Zr变形镁合金研究进展

超高强韧镁合金的研发对推广镁合金在高技术领域的应用具有重要意义。镁与稀土均是我国的优势资源,因此在我国发展超高强韧稀土镁合金具有得天独厚的优势,其中Mg-Gd-Y-Zn-Zr系变形镁合金因其接近高强铝合金的超高强度和塑性,近年来受到研究者的广泛关注。综述了超高强韧Mg-Gd-Y-Zn-Zr系变形镁合金的合金成分、常规塑性变形工艺、新型剧烈塑性变形工艺和热处理工艺对该合金显微组织和力学性能的影响规律,以及该超高强韧变形镁合金的显微组织特征和强韧化机理。T5峰时效态超高强韧Mg-8.2Gd-3.8Y-1Zn-0.4Zr(质量分数)挤压合金具有双峰分布的晶粒尺寸“软-硬”复合层片微结构,以及由高密度的基面γ′纳米片状析出相和棱柱面β′纳米析出相形成的近连续网状结构,该挤压合金室温拉伸屈服强度、拉伸强度和断裂延伸率分别为466 MPa、514 MPa和14.5%。介绍了哈尔滨工业大学等单位在超高强韧Mg-Gd-Y-Zn-Zr系变形镁合金的规模化制备和应用方面的研究进展,并展望了Mg-Gd-Y-Zn-Zr系变形镁合金的发展趋势。     

镁合金的腐蚀行为与表面防护方法

对镁合金的腐蚀行为，各种因素对镁合金腐蚀性能的影响进行了综述，介绍了几种镁合金表面防腐蚀处理方法及其发展趋势。     

Review on Hot Working Behavior and Strength of Calcium‐Containing Magnesium Alloys

In recent years, calcium has been a chosen alloying element as an alternative to rare‐earth elements for developing creep‐resistant magnesium alloys, which find promising applications for components in automobile and aerospace industries, and as bio‐implants. In this paper, the research covering the influence of Ca additions to several magnesium alloy systems on their strength, microstructure, and hot workability is reviewed. During mechanical processing, the formation of basal texture is considerably weakened by Ca addition. Ca‐containing alloys have limited workability and can be processed only by choosing the right combination of temperature and strain rate that corresponds to the occurrence of dynamic recrystallization (DRX). This can be done without trial‐and‐error through the use of processing maps. The processing maps for hot working of low‐Ca containing alloys typically exhibit three DRX domains while the maps for high‐Ca alloys typically exhibit only two DRX domains. In particular, the high‐Ca alloys have to be processed at lower strain rates and higher temperatures since the high volume content of intermetallic particles prevents DRX at high strain rates. Flow instabilities occur rampantly in Ca‐containing alloys, particularly in high‐Ca alloys, at lower temperatures and higher strain rates that have to be avoided during their thermo‐mechanical processing.

     

In Vitro and In Vivo Evaluation of Two Extended Release Preparations of Combination Metformin and Glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.     

Systematic study of(MoTa)xNbTiZr medium-and high-entropy alloys for biomedical implants-In vivo biocompatibility examination

In this study,the application of medium-and high-entropy(MoTa)xNbTiZr alloys in biomedical implants was systematically analyzed.The alloy with the best combination of mechanical properties was selected and characterized for in vitro and in vivo response for the first time to examine its biomedical properties.A logarithmic increase in the hardness and the yield strength was observed as a function of the Mo and Ta content.Alloys with up to 0.4 mol fraction of Mo and Ta showed a plastic strain of more than 30％under compression.The nanoindentation results showed that the addition of Mo and Ta increased the elastic modulus of the system linearly.It was surmised that the addition of Ta and Mo above a critical concentra-tion(mole fraction=0.4)was unfavorable from a biomedical perspective as it increased the brittleness and elastic modulus and decreased the ductility of the system.Therefore,the(MoTa)0.2NbTiZr alloy is a potential structural material for biomedical implants because of its excellent strength and ductility.The developed alloy was investigated for its corrosion properties and compared with commercial biomedical alloys.Furthermore,the biocompatibility of the alloy was examined using an in vivo examination.The alloy was implanted in the skeletal muscles of mice for four weeks and the histology of the surround-ing tissue was studied.The alloy exhibited strong passive behavior in a phosphate buffer solution and non-toxic soft tissue response.     

In Vivo Study on Degradation Behavior and Histologic Response of Pure Magnesium in Muscles

When an orthopedics device is implanted into bone injury site, it will contact the soft tissue(skeletal muscle, fascia, ligament etc.) except for bone. Magnesium based biodegradable metals are becoming an important research object in orthopedics due to their bioactivity to promote bone healing. In this study,pure Mg rods with and without chemical conversion coating were implanted into the muscle tissue of rabbits. Implants and their surrounding tissues were taken out for weight loss measurement, crosssectional scanning electron microscopy observation, elemental distribution analysis and histological examination. The results showed that the chemical conversion coating would increase the in vivo corrosion resistance of pure Mg and decrease the accumulation of calcium(Ca) and phosphorus(P) elements around the implants. For the bare magnesium implant, both Ca and P contents in the surrounding tissues increased at the initial stage of implantation and then decreased at 12 weeks implantation, while for the magnesium with chemical conversion coating, Ca and P contents in the surrounding tissues decreased with the implantation time, but were not significant. The histological results demonstrated that there was no calcification in the muscle tissue with implantation of magnesium for up to 12 weeks. The chemical conversion coating not only increased the in vivo corrosion resistance of pure Mg, but also avoided the depositions of Ca and P in the surrounding tissues, meaning that pure magnesium should be biosafe when contacting with muscle tissues.