Tuning of shell and core characteristics of chitosan-decorated acrylic nanoparticles.

The aim of the work was to develop a new family of chitosan-coated acrylic nanoparticles to increase the specificity of absorption of drugs associated given by the mucosal route. To achieve this goal, techniques of radical and anionic emulsion polymerisation of isobutylcyanoacrylate (IBCA) were used. Changes in the shell composition were made by using chitosan of different molecular weight and thiolated chitosan to modify the particle surface properties in order to vary the mucosae-nanoparticle interactions. The core was also modified by the inclusion of methyl methacrylate (MMA) as second monomer potentially able to improve the control of drug release. Finally, the labelling of nanoparticles core with a fluorophore, methacryloxyethyl thiocarbamoyl rhodamine B (Polyfluor), was successfully achieved, necessary for the in vitro and in vivo evaluation of the systems created. Results showed that nanoparticle size varied from 200 to 500 nm, depending on the molecular weight of chitosan used. Positive surface charge values were obtained in all cases. In addition, evidences of the presence of thiol groups were obtained (0.03-0.16 x 10(-3)micromol/cm(2) of nanoparticle).     

Elaboration and characterization of thiolated chitosan-coated acrylic nanoparticles

The aim of the present work was to investigate the use of thiolated chitosan in the development of polysaccharide-coated nanoparticles in order to confer specific functionality to the system. After chemical modification of commercial and hydrolysed chitosan (400,000 and 9400 g/mol respectively), thiolated chitosans were used to elaborate particles in the nano-range. They were characterized in terms of size and surface charge measurement. Both analysis showed nanoparticles of mean hydrodynamic diameter around 200 nm and positive zeta potential values, indicating the presence of the cationic polysaccharide at the nanoparticle surface. Moreover, the Ellman's reaction was used to demonstrate the presence of thiol groups at the particle surface. The observation of nanoparticles by scanning electronic microscopy (SEM) showed spherical nanoparticles for all formulations. This new system, combining both the advantages of thiolated polymers and colloidal particles can be proposed as an original drug carrier system for mucosal delivery of biotechnology products.     

Investigation of drug-containing multiple phase emulsions

We studied the efficiency of the formation of w/o/w emulsions as a function of composition and mixing time. We found that the concentration of emulsifier 1, the concentration and HLB of emulsifier 2, the viscosity of the oil phase and the external water phase as well as the mixing time in second step of preparing the emulsion characteristically influence the "efficiency" of emulsification and the stability of the emulsions.     

Potential modelling of acrylic acid copolymer nanoparticles by small angle X-ray scattering

Copolymer nanoparticles of acrylic acid, acrylic amide, acrylic butyl acrylate and methyl acrylate were characterised using a parameter relevant for in vivo organ distribution: charge distribution. Usually the zeta potential is estimated with laser Doppler anemometry as an equivalent for the particle charge. In our case, the potential distribution was investigated by small angle X-ray scattering. The nanoparticles shielded by counter-ions at high ionic strength (0.15 M NaCl solution) have short-range potentials. Different potential models were calculated: Percus–Yevick potential and Hypernetted Chain potential. The potentials estimated by small angle X-ray scattering can be divided into attractive and repulsive parts. The attractive potential, indicated by a minimum, is not significant compared with the repulsive potential and can be ignored. Consequently the tendency to form Van der Waals clusters is low. The solution shows a random order of hard spheres. Therefore, surface charges on the nanoparticles should hamper such carrier cell interaction only at short distances. In comparison with the potential estimation by laser Doppler anemometry (32.8 mV), results of the same order of magnitude were obtained using the small angle X-ray scattering method. The advantage of this method is that it provides a potential curve, which allows better appraisal of clearance by the reticuloendothelial system. By interpreting the potential curves, a more detailed prediction of steric stability of particle systems is possible.     

含药医疗器械产品检验方法的探讨

目的:本文简要介绍了药械组合产品的界定原则、含药医疗器械的定义和分类,分析了针对含药医疗器械产品评价的特殊性。结合含药医疗器械的发展,对其检验标准、检验项目和检验方法逐一进行阐述,并对含药器械检验的规范化提出一些可供参考的方案。     

Controlled release of dual drug-loaded hydroxypropyl methylcellulose matrix tablet using drug-containing polymeric coatings.

A dual drug-loaded hydroxypropylmethylcellulose (HPMC) matrix tablet simultaneously containing drug in inner tablet core and outer coated layer was formulated using drug-containing aqueous-based polymeric Eudragit RS30D dispersions. Effects of coating levels, drug loadings in outer layers, amount and type of five plasticizers and talc concentration on the release characteristics were evaluated on the characteristics in simulated gastric fluid for 2 h followed by a study in intestinal fluids. Melatonin (MT) was selected as a model drug. The surface morphology of dual drug-loaded HPMC tablets using scanning electron microscope (SEM) was smooth, showing the distinct coated layer with about 75-microm coating thickness at the 15% coating level. Unlike the uncoated and conventionally coated HPMC tablet, the dual drug-loaded HPMC matrix tablet gave a biphasic linear release, showing a zero-order for 4 h (first) followed by another zero-order release when fitted using linear regression (r(2) = 0.99). As the coating levels (15, 25%) increased, the release rate was further decreased. The biphasic release profiles of dual drug-loaded HPMC matrix tablet was unchanged except when 25% coating level containing 0.5% drug concentration was applied. As the drug concentration in polymeric coating dispersion increased (0.25-1.0%), the amount of drug released increased. The time for the first linear release was also advanced. However, the biphasic release pattern was not changed. The biphasic release profiles of dual drug-loaded HPMC matrix tablet were highly modified, depending on the amount and type of five plasticizers. Talc (10-30%) in coating dispersion as an anti-sticking material did not affect the release profiles. The current dual drug-loaded HPMC matrix tablet, showing biphasic release profiles may provide an alternative to deliver drugs with circadian rhythmic behaviors in the body but needs to be further validated in future in human studies. The dual drug-loaded coating method is also interesting for the modified release of poorly water-soluble drugs because solubilizers and other additives can be added in drug-containing polymeric coating dispersions.     

Genotoxicity of acrylic bone cements.

The genotoxicity of conventional polymethylmethacrylate (PMMA) and a new formulation of bone cement: methylmethacrylate/n-decylmethacrylate/isobornylmethacrylate (MMA/DMA/IBMA) were tested by micronucleus test and reverse mutation assays of Salmonella typhimurium (Ames test). In extracts from cement pellets (37 degrees, 72 hr) with water and water/ethanol the concentration of MMA was reduced by 13-19 times with the new formulation and the concentrations of accelerators were reduced by 4-5 times. New chemical constituents (DMA, IBMA, dihydroxy-propyl-p-toluidine) were found in negligible concentrations. In the micronucleus test all three cement brands were found non-mutagenic and in the Ames test scattered increased revertant ratios were found without differences between the three brands. The new formulation does not possess any increased risk of genotoxicity.     

Genetic toxicology of acrylic acid.

Acrylic acid was tested for gene mutations in the in vitro CHO/HGPRT assay, for chromosome aberrations in CHO cells in culture, and for potential to induce unscheduled DNA synthesis in rat hepatocytes in culture. In vivo assays performed included the Drosophila sex-linked recessive lethal assay by both the feeding and injection routes, the in vivo cytogenetic assay in rat bone marrow cells after both a 1-day and 5-day oral dosing regimen, and a dominant lethal assay in mice by both an acute and 5-day dosing regimen. All results were negative (non-mutagenic) except for the in vitro chromosome aberration assay. This latter result is consistent with the previously reported possible clastogenic activity suggested by the results of the mouse lymphoma L5178Y TK locus assay in which a predominance of small-colony mutants was observed (Moore et al., Environmental and Molecular Mutagenesis 1988, 11, 49-63). The rapid clearance of acrylic acid in animals and the weight of evidence of genetic toxicity testing, including negative in vivo data in both somatic and germ cells, indicate a lack of genetic toxicity of acrylic acid in vivo.     

Modified release of coated sugar spheres using drug-containing polymeric dispersions

A drug-containing polymeric dispersion was applied onto nonpareil sugar spheres (18/20 mesh) using a fluid-bed spray coater. Eudragit RS30D was selected as the polymeric coating material. Melatonin secreted by the pineal gland in a circadian rhythm was used as a model drug. The release behaviors of the coated sugar spheres were investigated in gastric fluid (pH 1.4) for 2 h, and then continuously in intestinal fluid (pH 7.4) for 14 h. The release rate of the coated sugar spheres decreased with increasing coating levels. The solvent (ethanol) in the coating dispersions significantly decreased the release of the drug due to the good dispersion of the low solubility melatonin in the polymeric films. The polymer (polyvinylpyrrolidone, PVP) and drug contents in the coating dispersions did not affect the release rate. Most of all, the release profiles were drastically changed according to the type and concentration of plasticizers used. The current coating methods that use drug-containing polymeric dispersions could be useful for simultaneous drug loadings and their modified release. The solubilization and controlled release of poorly water-soluble drugs can be achieved as both the solubilizers and drugs are present in the drug-containing polymeric dispersions.     

Methods of obtaining and formation mechanisms of polymer nanoparticles

Severals processes exist today for manufacturing colloidal systems of nanospheres or nanocapsules. These nanoparticles have applications in various industrial fields such as cosmetic, pharmacy, food industry, agrochemicals.... The formation of nanoparticles allows the protection of an active molecule by a polymeric coating and the release of this product following a perfectly defined profile, which depends on the nature of the polymer, the type of particle and the field of use. The purpose of this article is to expose the different methods of preparation of nanoparticular systems. These methods are classified in two mains categories. The first gathers most of the methods which are based on polymerization reactions, the second presents the use of preformed polymers (of natural or synthetic origin). A thorough study is devoted to the mechanisms of formation, in order to find the advantages and the disadvantages of each technique to support the development of manufactoring processes.     

Cisplatin-incorporated hyaluronic acid nanoparticles based on ion-complex formation

The aim of this study is to prepare cisplatin-incorporated nanoparticles based on ion complex formation between hyaluronic acid (HA) and cisplatin for antitumor drug delivery. To prepare nanoparticles using HA, bulk HA was degraded by hyaluronidases (HAses). Cisplatin-incorporated HA nanoparticles were prepared by mixing cisplatin with an aqueous solution of HA and then the nanoparticle solution was dialyzed to remove trace elements. Since glioma tumor cell lines are able to secrete HAse, extracts from U343MG and U87MG cell lines were used to test the release of cisplatin from the nanoparticles. The morphological observation of the cisplatin-incorporated nanoparticles showed that they had spherical shapes with a particle size around 100-200 nm. The loading efficiency of cisplatin in the nanoparticles was about 67-81% (w/w) and cisplatin was continuously released from the nanoparticles for 4 days. Especially, the release rate of cisplatin from the nanoparticles increased when HAse was added to the release medium. In the results of the HA zymography, the U343MG cell line secreted HAse, while the U87MG cell line did not. When the extracts from U343MG were added to the release medium, the release rate of cisplatin was slightly increased, while the extracts from U87MG did not significantly affect the release rate of cisplatin. In conclusion, cisplatin-incorporated nanoparticles have sufficiently small particle sizes to use as a drug targeting system. The release of cisplatin from the nanoparticles was responsive to the secretion of HAse. These nanoparticles are suitable vehicles for an antitumor drug targeting system.     

Nanoparticles in plant extracts--factors which influence the formation of nanoparticles in black tea infusions.

The influence of different factors on the formation of nanoparticles in freshly brewed tea extracts was investigated. A black tea infusion was observed during cooling using photon correlation spectroscopy (PCS). The mean particle size and the number of the nanoparticles increase with decreasing temperature. In the presence of caffeine more particles are formed within the infusion. To study the influence of slight structural differences between methylxanthines, the effect of the addition of caffeine to solutions of freshly prepared decaffeinated tea was compared to that of theophylline and theobromine. In the case of theophylline fewer nanoparticles were formed. Molecular modelling calculations were performed to evaluate the most probable geometries for caffeine-polyphenol complexes. A parallel position and a congruent orientation of the 6-membered ring of caffeine and the aromatic galloyl group is the most probable geometry.     

Short-term rat inhalation study with aerosols of acrylic ester-based polymer dispersions containing a fraction of nanoparticles

Aqueous polymer dispersions are important raw materials used in a variety of industrial processes. They may contain particles with diameters ranging from 10 to 1500 nm. Polymer exposure alone may cause pulmonary lesions after inhalation exposure. Polymer dispersions with increased proportions of nano-sized particles are being developed for improved material characteristics, and this may pose even increased pulmonary hazards upon potential inhalation exposure. In a 5-day screening study, male rats were nose-only exposed to aerosols generated from 2 dispersions of acrylic ester polymers with identical chemical composition but different nano-sized particle proportions at particle concentrations of 3 and 10 mg/m3. Immediately and 19 days after the end of inhalation, necropsies were conducted with major emphasis on respiratory tract histopathology. Three and 23 days after the end of inhalation, bronchoalveolar lavage was performed to screen for early pulmonary injury and inflammation. In contrast to the adverse effects known for other materials in short-term inhalation studies, none of the tested preparations of acrylic ester polymers elicited any adverse effect at the end of the inhalation or postinhalation periods. No shift in toxicity could be observed by the increased proportion of nano-sized polymer particles. Under the conditions of this study, the no observable adverse effect levels for both preparations were >10 mg/m3, that is 2- to 3-fold beyond current nuisance dust threshold limit values.     

三七总皂苷含药血浆抗血管平滑肌细胞增殖的研究

<正>三七总皂苷(total panax notoginseng saponin,TPNS)是从中药五加科植物三七Panax notoginseng(Burk.)F.H.Chen干燥根中提取的皂苷类有效组分,是三七的主要药理活性成分,在三七中含量达8%～12%。     

Insulin-loaded poly(acrylic acid)-cysteine nanoparticles: Stability studies towards digestive enzymes of the intestine

This study evaluated thiolated poly(acrylic acid) nanoparticles as a valuable tool to protect insulin from degradation by serinproteases of the intestine. Nanaoparticles were characterized concerning particle size, zeta potential, and drug load. Furthermore, in vitro release studies were performed. Within in vitro degradation studies with trypsin, α-chymotrypsin, and elastase it could be demonstrated that the obtained nanoparticles are capable of protecting 44.47?±?0.89% of the initial insulin amount from tryptic degradation, 21.33?±?5.34% from chymotryptic degradation, and 45.01?±?1.40% from degradation by elastase compared to insulin solutions.     

Polysaccharide-decorated nanoparticles.

Surface modified colloidal carriers such as nanoparticles are able to modulate the biodistribution of the loaded drug when given intravenously, but also to control the absorption of drugs administered by other routes. This review presents the different strategies to coat the surface of polymeric as well as inorganic nanoparticles with polysaccharides. Various physicochemical and biological methods have been described to demonstrate such surface modification. The medical applications, mainly in imaging cancer, of polysaccharide-coated nanoparticles are presented, including their abilities to increase the blood circulation time and to target specific tumoral tissues. It has been shown that these coatings allow also to improve drug absorption via nasal or ocular pathways, due the mucoadhesive and/or permeability enhancer properties of the polysaccharides. Finally, the ability of polysaccharide-coated nanoparticles to deliver DNA or oligonucleotides will be discussed.