Modulation and Optimization of Drug Release from Uncoated Low Density Porous Carrier Based Delivery System

The purpose of this research work was to explore an application of uncoated porous drug carrier prepared by single-step drug adsorption for a delivery system based on integration of floating and pulsatile principles intended for chronotherapy. This objective was achieved by utilizing 3² factorial design, solvent volume (X ₁) and drug amount (X ₂) as selected variables, for drug adsorption using solvents, methanol, and dichloromethane (DCM), of varying polarity. Nitrogen adsorption (N₂), scanning electron microscopy of cross-sections, and atomic force microscopy were done to study adsorption patterns and their effect on release pattern. Drug release study was customized by performing for 6 h in acidic environment to mimic gastroretention followed by basic environment akin to transit phase. Correlation between porous data from mercury and N₂ adsorption was probably studied for the first time. Observed regression analysis values for pore volume, surface area, and drug release indicated the influence of selected variables. Total release range in acidic medium was 12.77–24.57% for methanol, 8.79–15.26% for DCM, and final release of 69.45–92.23% for methanol, and 60.16–99.99% for DCM influenced by varying internal geometries was observed. Present form of drug delivery system devoid of any additives/excipients influencing drug release shows distinct behavior from other approaches/technologies in chronotherapy by (a) observing desired low drug release (8%) in acidic medium, (b) overcoming the limitations of process variables caused by multiple formulation steps and different characteristic polymers, (c) reducing time consumption due to single step process, and (d) extending as controlled/extended release.     

Improved Completion Rates and Characterization of Drug Reactions with an Intensive Chagas Disease Treatment Program in Rural Bolivia

Background

Chagas disease treatment is limited by drug availability, adverse side effect profiles of available medications, and poor adherence.

Methods

Adult Chagas disease patients initiating 60-days of benznidazole were randomized to weekly or twice-weekly evaluations of medication adherence and screening for adverse drug events (ADEs). Mid-week evaluations employed phone-based evaluations. Adherence was measured by self-report, pill counts with intentional over-distribution, and Medication Event Monitoring Systems (MEMS). Prospective data were compared to historical controls treated with benznidazole at the same hospital.

Results

162 prospective patients were compared to 172 historical patients. Pill counts correlated well with MEMS data (R = 0.498 for 7-day intervals, R = 0.872 for intervals >7 days). Treatment completion rates were higher among prospective than historical patients (82.1% vs. 65.1%), primarily due to lower abandonment rates. Rates of ADEs were lower among prospective than historical patients (56.8% vs. 66.9%). Twice-weekly evaluations increased identification of mild ADEs, prompting higher suspension rates than weekly evaluations. While twice-weekly evaluations identified ADEs earlier, they did not reduce incidence of moderate or severe ADEs. Many dermatologic ADEs were moderately severe upon presentation (35.6%), were not reduced by use of antihistamines, occurred among adult patients of all ages, and occurred throughout treatment, rather than the first few weeks alone.

Conclusions

Intensive management improved completion and identified more ADEs, but did not reduce moderate or severe ADEs. Risk of dermatologic ADEs cannot be reduced by selecting younger adults or monitoring only during the first few weeks of treatment. Pill counts and phone-based encounters are reliable tools for treatment programming in rural Bolivia.     

A New Role of Fine Excipient Materials in Carrier-Based Dry Powder Inhalation Mixtures: Effect on Deagglomeration of Drug Particles During Mixing Revealed

The potential of fine excipient materials to improve the performance of carrier-based dry powder inhalation mixtures is well acknowledged. The mechanisms underlying this potential are, however, open to question till date. Elaborate understanding of these mechanisms is a requisite for rational rather than empirical development of ternary dry powder inhalation mixtures. While effects of fine excipient materials on drug adhesion to and detachment from surfaces of carrier particle have been extensively investigated, effects on other processes, such as carrier–drug mixing, capsule/blister/device filling, or aerosolization in inhaler devices, have received little attention. We investigated the influence of fine excipient materials on the outcome of the carrier–drug mixing process. We studied the dispersibility of micronized fluticasone propionate particles after mixing with α-lactose monohydrate blends comprising different fine particle concentrations. Increasing the fine (D < 10.0 μm) excipient fraction from 1.84 to 8.70% v/v increased the respirable drug fraction in the excipient–drug mixture from 56.42 to 67.80% v/v (p < 0.05). The results suggest that low concentrations of fine excipient particles bind to active sites on and fill deep crevices in coarse carrier particles. As the concentration of fine excipient particles increases beyond that saturating active sites, they fill the spaces between and adhere to the surfaces of coarse carrier particles, creating projections and micropores. They thereby promote deagglomeration of drug particles during carrier–drug mixing. The findings pave the way for a comprehensive understanding of contributions of fine excipient materials to the performance of carrier-based dry powder inhalation mixtures.     

Isoxyl Aerosols for Tuberculosis Treatment: Preparation and Characterization of Particles

Isoxyl is a potent antituberculosis drug effective in treating various multidrug-resistant strains in the absence of known side effects. Isoxyl has been used exclusively, but infrequently, via the oral route and has exhibited very poor and highly variable bioavailability due to its sparing solubility in water. These properties resulted in failure of some clinical trials and, consequently, isoxyl’s use has been limited. Delivery of isoxyl to the lungs, a major site of Mycobacterium tuberculosis infection, is an attractive alternative route of administration that may rescue this abandoned drug for a disease that urgently requires new therapies. Particles for pulmonary delivery were prepared by antisolvent precipitation. Nanofibers with a width of 200 nm were obtained by injecting isoxyl solution in ethanol to water at a volume ratio of solvent to antisolvent of 1:5. Based on this preliminary result, a well-controlled method, involving nozzle mixing, was employed to prepare isoxyl particles. All the particles were 200 to 400 nm in width but had different lengths depending on properties of the solvents. However, generating these nanoparticles by simultaneous spray drying produced isoxyl microparticles (Feret’s diameter, 1.19–1.77 μm) with no discernible nanoparticle substructure. The bulking agent, mannitol, helped to prevent these nanoparticles from agglomeration during process and resulted in nanoparticle aggregates in micron-sized superstructures. Future studies will focus on understanding difference of these isoxyl microparticles and nanoparticles/nanoparticle aggregates in terms of in vivo disposition and efficacy.     

还原可降解聚磺酸甜菜碱型纳米水凝胶的制备及载药研究

目的:制备与表征还原可降解的聚磺酸甜菜碱型纳米水凝胶,利用该纳米递药系统包载阿霉素(DOX)并初步评价其抗肿瘤性能。方法:利用回流沉淀聚合的方法合成含二硫键的聚磺酸甜菜碱甲基丙烯酸酯(PSBMA)纳米水凝胶及不含二硫键的PSBMA纳米凝胶(nd-PSBMA);通过粒度仪和透射电镜考察两种纳米水凝胶的粒径、形态以及稳定性;通过考察谷胱甘肽(GSH)对纳米凝胶溶液相对浊度的影响以评价还原环境对两种纳米凝胶的还原可降解性;利用纳米凝胶包载阿霉素(DOX),考察载药凝胶在GSH中的释药行为,并初步评价其对A549肿瘤细胞的杀伤作用。结果:以N, N'-双丙烯酰胱胺为交联剂制备了含二硫键的PSBMA纳米凝胶,其粒径在180～200 nm;同时以N, N'-双丙烯酰胺为交联剂制备了不含二硫键的n-PSBMA纳米凝胶。两种纳米凝胶与小鼠血清共孵育7天水合粒径仍无明显变化,表明磺酸甜菜碱型纳米凝胶具有良好的抗蛋白吸附能力。此外,PSBMA纳米凝胶在GSH溶液中迅速地降解,且降解速度与GSH浓度呈正相关;而nd-PSBMA纳米凝胶在GSH溶液中几乎不降解。载DOX的PSBMA纳米凝胶可在GSH作用下快速的释放药物而载DOX的nd-PSBMA纳米凝胶在GSH作用下缓慢的释放药物;体外细胞实验显示空白纳米凝胶和载药nd-PSBMA对A549细胞无明显毒性作用,但载DOX的PSBMA纳米凝胶可高效地杀死A549肿瘤细胞,其药效与游离DOX相仿。结论:还原可降解的PSBMA纳米水凝胶有望成为智能型控释药物载体。     

Highly Active and Durable Pt72Ru28 Porous Nanoalloy Assembled with Sub‐4.0 nm Particles for Methanol Oxidation

The main challenges to the direct methanol fuel cells are the activity and durability of electrocatalysts. To alleviate such issues, a recently proposed strategy introduces an exotic element to form Pt‐based alloy nanostructures. This study reports a green route to prepare porous flowerlike Pt₇₂Ru₂₈ nanoalloys assembled with sub‐4.0 nm particles. The peak current density and mass activity on these as‐synthesized porous flowerlike Pt₇₂Ru₂₈ nanoalloys can be increased to 10.98 mA cm^?2 and 1.70 A mg^?1 Pt for methanol oxidation in acidic medium. They are respectively 4.19/3.54, 4.27/5.0, and 5.74/1.73 times those on the commercial Pt black, Pt₅₀Ru₅₀ black, and Ru₅₀Pt₅₀/C. These porous flowerlike Pt₇₂Ru₂₈ nanoalloys have a much higher long‐term durability than commercial Pt black, Pt₅₀Ru₅₀ black, and Ru₅₀Pt₅₀/C. More significantly, the porous Pt₇₂Ru₂₈ bimetallic nanoalloys have long‐term solvent durability after immersion in water for 16 months. The peak current density and mass activity on porous Pt₇₂Ru₂₈ nanoalloys are still 7.76 mA cm^?2 and 1.2 A mg^?1 Pt. These experimental results show an effective approach to the development of PtRu nanoalloys as electrocatalysts with substantially enhanced activity and durability for direct methanol fuel cells.     

BrdU抗血清制备和应用的研究——Ⅰ.高度特异的BrdU抗血清的制备与特性

半抗原BrU通过与BSA偶联制备了完全抗原,经过光吸收、SDS聚丙烯酰胺凝胶电泳和琼脂糖凝胶电泳的测定表明,核苷-蛋白质复合物符合制备的要求,每个BSA上估计大约平均有10.3个BrU。用常规免疫的方法获得兔抗BrdU的抗血清,与BrU-EA的双向扩散效价高达32。抗血清稀释128万倍时仍可见明显的ELISA阳性反应。与以前所报道的BrdU抗血清不同,该抗血清具有高水平的识别能力,已达到BrdU单克隆抗体的识别水平,无须纯化即可用于染色体及核酸的研究。     

Characterization of an Endogenous RNA-Dependent DNA Polymerase Associated with Murine Intracisternal A Particles

An RNA-dependent DNA polymerase associated with intracisternal A particles has been characterized. The enzyme required Mg(2+) or Mn(2+), dithiothreitol and the presence of all four deoxyribonucleoside triphosphates for the expression of maximal activity. Sensitivity of the endogenous RNA-dependent DNA polymerase activity to a low concentration of pancreatic ribonuclease in the presence of a high concentration of NaCl suggested that the enzyme might be utilizing the A particle endogenous RNA as template. Evidence in support of this was provided by analyses of early and late DNA products of the endogenous reaction by Cs(2)SO(4) isopycnic gradient centrifugation and hybridization of purified 60 to 70S and 35S RNAs of A particles with the purified DNA product.     

Development, Optimization, and Characterization of Solid Self-Nanoemulsifying Drug Delivery Systems of Valsartan Using Porous Carriers

The present studies entail formulation development of novel solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of valsartan with improved oral bioavailability, and evaluation of their in vitro and in vivo performance. Preliminary solubility studies were carried out and pseudoternary phase diagrams were constructed using blends of oil (Capmul MCM), surfactant (Labrasol), and cosurfactant (Tween 20). The SNEDDS were systematically optimized by response surface methodology employing 3^3-Box–Behnken design. The prepared SNEDDS were characterized for viscocity, refractive index, globule size, zeta potential, and TEM. Optimized liquid SNEDDS were formulated into free flowing granules by adsorption on the porous carriers like Aerosil 200, Sylysia (350, 550, and 730) and Neusilin US2, and compressed into tablets. In vitro dissolution studies of S-SNEDDS revealed 3–3.5-fold increased in dissolution rate of the drug due to enhanced solubility. In vivo pharmacodynamic studies in Wistar rats showed significant reduction in mean systolic BP by S-SNEDDS vis-à-vis oral suspension (p < 0.05) owing to the drug absorption through lymphatic pathways. Solid-state characterization of S-SNEDDS using FT-IR and powder XRD studies confirmed lack of any significant interaction of drug with lipidic excipients and porous carriers. Further, the accelerated stability studies for 6 months revealed that S-SNEDDS are found to be stable without any change in physiochemical properties. Thus, the present studies demonstrated the bioavailability enhancement potential of porous carriers based S-SNEDDS for a BCS class II drug, valsartan.KEY WORDS: BCS, bioavailability, in vitro dissolution, porous carriers, XRD     

New Gold Nanoparticles Adhesion Process Opening the Way of Improved and Highly Sensitive Plasmonics Technologies

Gold nanostructures have very suitable physical properties for plasmonic applications but do not stick on glass substrates. One usually uses a chromium adhesion layer that gives good mechanical adhesion but quench the plasmon. We developed a new adhesion process that permits a covalent bonding between gold and glass thanks to an MPTMS molecular layer throughout nanolithography process. We demonstrate that this new adhesion layer allows an improvement of the optical properties of the gold nanoparticles as well as an essential improvement of their surface-enhanced Raman scattering performances.     

Preparation and Properties of an Inhibitory Extract from Frog Virus 3 Particles

The structural constituents of the frog virus 3 particle were solubilized by treatment with a nonionic detergent followed by the addition of a high salt concentration. This soluble viral extract (SVE) inhibits host nucleic acid synthesis. Its activity on RNA synthesis was studied in KB cells and found to be dependent on the presence of DEAE dextran. Inactivation of the inhibitory properties of SVE were obtained by trypsin digestion, treatment with urea, or heat denaturation. Neutralization of the activity of SVE was obtained by anti-frog virus 3 serum but not by anti-BHK serum. In vitro a complex may be formed between polynucleotides and the inhibitor indicating a possible mechanism for vivo inhibition.     

On the Plasticization Process of Potato Starch: Preparation and Characterization

This study aimed to gain a deep understanding of the preparation mechanism of the thermoplastic potato starch (TPPS) by using melt-mixing as a production method, to pursue the changes occurred on the microstructure, morphology and thermal properties of potato starch, TPPS was prepared using a mixture of potato starch with glycerol and water as plasticizer in an internal mixer. The steps of the phase transition, happening by applying harsh conditions (60 rpm, 160 °C, and 7 min), were followed by monitoring the evolution of torque during the mixing time. It was shown that the granules structure was destroyed and a new phase was formed. This was proved by SEM which gave the evidence that the morphology of the TPPS was homogeneous with the smooth surface means that the mixing conditions used in this work were good enough to obtain the thermoplastic starch with a high level of homogeneity in all dimensions. FTIR analysis allowed deducing the formation of new H-bonds between the starch and plasticizers molecules instead of intra and intermolecular H-bonds in the native starch that was destructed through the melt-mixing process., These caused starch chains gain mobility and as the results decreasing in crystallinity, where the XRD analysis exhibited that the crystallinity decreased from 14.5% resulting from B-type in native potato starch to 9% resulting from B-type and VH-type in TPPS. TGA and DSC analysis proved a decreasing in the thermal stability in the TPPS as compared to the starch granules.     

Preparation and Characterization of a Highly Active Cell-free Protein-synthesizing System from Dry Pea Primary Axes

A highly active and reliable cell-free protein-synthesizing system from dry pea primary axes has been developed. The system has been optimized with respect to both overall activity and translational fidelity. Under optimal conditions, the system incorporates nearly 1,000 picomoles leucine per 50 microliters incubation mixture. At limiting tobacco mosaic virus RNA concentrations, its efficiency exceeds 1,000 picomoles leucine per picomole template molecules. The maximal size of the polypeptides coded for by tobacco mosaic virus RNA goes up to 180,000. A procedure has been worked out to reduce the endogenous template activity of the system. the dramatic increase of the activity of this pea cell-free system as compared to previous attempts can be explained by the use of Cl⁻-free buffers.     

Liquid Proliposomes of Nimodipine Drug Delivery System: Preparation, Characterization, and Pharmacokinetics

To investigate the possibility of liquid proliposomes being carriers for oral delivery, nimodipine liquid proliposomes-based soft capsules (NPSC) were prepared. Nimodipine proliposomes were characterized by transmission electron microscopy (TEM), conversion rate from proliposomes to liposomes, entrapment efficiency, particle size, and zeta potential. Accelerated stability testing of NPSC was carried out for 3 months at 40 ± 2°C, 75 ± 5% RH. The concentration of nimodipine in plasma of New Zealand rabbits of NPSC, nimodipine soft capsules, and hydrated liposomes was studied. Results showed that nimodipine proliposomes were automatically converted into liposomes when exposed to a water phase in 30 s. The average diameter was 378.6 ± 26.5 nm in distilled water with entrapment efficiency (EE%) of 84.7 ± 5.9%, while the average diameter was 316.9 ± 34.6 nm in 0.1 M hydrochloric acid solution with EE% of 72.8 ± 4.7%. Accelerated stability test showed that there was no change in drug content, particle size, and EE% except for a decrease in dissolution of nimodipine. In vivo experiments, areas under the plasma level-time curve of NPSC and nimodipine-hydrated liposomes increased 2.41 and 2.34 times more than that of nimodipine soft capsules, peak concentration increased 2.87 and 2.92 times, time of peak concentration from 0.75 to 2 and 1 h, respectively. Nimodipine-hydrated liposomes presented similar pharmacokinetic parameters compared with NPSC. Results suggested that NPSC offered a potential way to improve oral delivery of nimodipine.Key words: liquid proliposomes, nimodipine, pharmacokinetics, soft capsules, stability     

骨形成蛋白2/珍珠层粉/壳聚糖支架制备及生物性能研究

目的:制备骨形成蛋白2/珍珠层粉/壳聚糖复合多孔支架,观察支架生物性能。方法:采用冷冻干燥法制备骨形成蛋白2/珍珠层粉/壳聚糖多孔支架。用光学显微镜和扫描电子显微镜观察支架表面形貌及孔径大小,用比重瓶法检测支架孔隙率,热重分析探讨支架的热稳定性,用微力试验机进行压缩性能测试,并将支架与兔骨髓间充质干细胞共培养检测细胞黏附性能,将支架埋置大鼠皮下观察其炎症反应。结果与结论:制备的骨形成蛋白2/珍珠层粉/壳聚糖支架孔径大小为100~300μm,孔隙率为91.64%,压缩应力达3.37MPa,与细胞共培养贴附较好,有良好的组织相容性,提示该支架可做为组织工程支架材料应用于临床上骨组织缺损的修复。     

Plasticity of Fitness and Diversification Process During an Experimental Molecular Evolution

A simplified experimental evolution encompassing the essence of natural one was designed in an attempt to understand the involved mechanism. In our system, molecular evolution was observed through three serial cycles of consecutive random mutagenesis of the glutamine synthetase gene and chemostat culture of the transformed Escherichia coli cells containing the mutated genes. Selection pressure was imposed solely on the glutamine synthetase gene when varieties of mutant genes compete in an unstructured environment of the chemostat. The molecular phylogeny and population dynamics were deduced from the nucleotide sequences of the genes isolated from each of the chemostat runs. An initial mutant population in each cycle, comprised of diversified closely-related genes, ended up with several varieties of mutants in a state of coexistence. Competition between two mutant genes in the final population of the first cycle ascertained that the observed coexisting state is not an incidental event and that cellular interaction via environmental nutrients is a possible mechanism of coexistence. In addition, the mutant gene once extinct in the previous passage was found to have the capacity to reinvade and constitute the gene pool of the later cycle of molecular evolution. These results, including the kinetic characteristics of the purified wild-type and mutant glutamine synthetases in the phylogenetic tree, revealed that the enzyme activity had diverged, rather than optimized, to a fittest value during the course of evolution. Here, we proposed that the plasticity of gene fitness in consequence of cellular interaction via the environment is an essential mechanism governing molecular evolution. Received: 29 August 2000 / Accepted: 25 January 2001     

Taste Mask, Design and Evaluation of an Oral Formulation Using Ion Exchange Resin as Drug Carrier

The purpose of this research was to mask the bitter taste of Diphenhydramine Hydrochloride (DPH) using cation exchange resins. Indion 234 and Tulsion 343 that contained crosslinked polyacrylic backbone were used. The drug resin complexes (DRC) were prepared by batch process by taking drug: resin ratios 1:1, 1:2, and 1:3. The optimum drug: resin ratio and the time required for maximum complexation was determined. The drug resinates were evaluated for the drug content, taste, micromeritic properties drug release and X-ray diffraction (PXRD). Effervescent and dispersible tablets were developed from optimum drug: resin ratios of 1:2 and 1:1. The formulations were evaluated for uniformity of dispersion, disintegration time, and in vitro dissolution. The X-ray diffraction study confirmed the monomolecularity of entrapped drug in the resin beads. The taste evaluation depicted the successful taste masking of DPH with drug resin complexes. The drug release of 95% in 15 min was observed for effervescent and dispersible tablets.     

An Improved and Efficient Process for the Preparation of (+)‐cloprostenol

An improved and efficient synthesis of (+)‐cloprostenol has been accomplished in nine steps and 26% overall yield from commercially available (–)‐Corey lactone 4‐phenylbenzoate alcohol 1 . The present route avoids tedious purifications and requires only one column chromatography operation, which reduces the generation of waste and is suitable for large‐scale preparation. Chirality 27:392–396, 2015. © 2015 Wiley Periodicals, Inc.     

The Preparation and Characterization of an Aggregated Gliadin Fraction from Wheat

An aggregated gliadin fraction was prepared by gel filtrationon Sephacryl S300 in a solvent containing 6.0 M guanidine hydrochloride.This was reduced, alkylated, and separated by ion exchange chromatography.SDS-PAGE of the resulting fraction showed a number of polypeptides,mostly with apparent M¹s of around 44 000. The amino acid compositionwas similar to those reported previously for monomeric -, ß-and -gliadins. Automated amino acid sequencing from the N-terminusalso showed the presence of sequence types characteristic of-, ß-, and -gliadins, but the major sequence typewas not related to any described previously. This sequence wasNH₂-Ser-His-Ile-Pro-Gly-Leu-Glu-Arg-Pro-Ser-Gln-Gln-Gln-Gln-Leu-. Key words: Wheat, Gluten, Gliadin, Seed     

Preparation and Characterization of an Advanced Medical Device for Bone Regeneration

Tridimensional scaffolds can promote bone regeneration as a framework supporting the migration of cells from the surrounding tissue into the damaged tissue and as delivery systems for the controlled or prolonged release of cells, genes, and growth factors. The goal of the work was to obtain an advanced medical device for bone regeneration through coating a decellularized and deproteinized bone matrix of bovine origin with a biodegradable, biocompatible polymer, to improve the cell engraftment on the bone graft. The coating protocol was studied and set up to obtain a continuous and homogeneous polylactide-co-glycolide (PLGA) coating on the deproteinized bone matrix Orthoss® block without occluding pores and decreasing the scaffold porosity. The PLGA-coated scaffolds were characterized for their morphology and porosity. The effects of PLGA polymer coating on cell viability were assessed with the 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium assay. The polymer solution concentration and the number of polymeric layers were the main variables affecting coating efficiency and porosity of the original decellularized bone matrix. The designed polymer coating protocol did not affect the trabecular structure of the original decellularized bone matrix. The PLGA-coated decellularized bone matrix maintained the structural features, and it improved the ability in stimulating fibroblasts attachment and proliferation.