Effects of pH-sensitive nanoparticles prepared with different polymers on the distribution,adhesion and transition of Rhodamine 6G in the gut of rats

To investigate the effect of different enteric polymers on the characteristics of pH-sensitive nanoparticles, Rhodamine 6G (Rho) was incorporated in various pH-sensitive nanoparticles. The different patterns of pH-dependent release profiles were observed, although some polymers have the same dissolving pH. The distribution, adhesion and transition of different nanoparticles in rat gut showed significant difference, closely related to the release characteristics of nanoparticles, and their release behaviour are dependent on the dissolving pH and the structure of the polymers, as well as the drug property. Most nanoparticle formulations decreased the distribution and adhesion of Rho in the stomach but increased these values in the intestine. The nanocarriers also control the drug release sites and release rate in the GI tract. In conclusion, pH-sensitive nanoparticles seem favourable for drug absorption and it is important to choose the proper materials to obtain the suitable characteristics for the oral pH-sensitive nanoparticles.     

pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation

The aim of present study was to investigate a pH-responsive and mucoadhesive nanoparticle system for oral bioavailability enhancement of low-molecular weight heparin (LMWH). The thioglycolic acid (TGA) was first covalently attached to chitosan (CS) with 396.97?±?54.54?μmol thiol groups per gram of polymer and then the nanoparticles were prepared with thiolated chitosan (TCS) and pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) by ionic cross-linking method. The obtained nanoparticles were characterized for the shape, particle size, zeta potential, drug entrapment efficiency and loading capacity. In vitro results revealed the acid stability of pH-responsive nanoparticles, which had a significant control over LMWH release and could effectively protect entrapped drugs in simulated gastric conditions. By the attachment of the thiol ligand, an improvement of permeation-enhancing effect on freshly excised carp intestine (1.86-fold improvement) could be found. The mucoadhesive properties were evaluated using fluorescently labeled TCS or CS nanoparticles. As compared with the controls, a significant improvement of mucoadhesion on rat intestinal mucosa was observed in TCS/HPMCP nanoparticles via confocal laser scanning microscopy. The activated partial thromboplastin time (APTT) was significantly prolonged and an increase in the oral bioavailability of LMWH was turned out to be pronounced after oral delivered LMWH-loaded TCS/HPMCP nanoparticles in rats, which suggested enhanced anticoagulant effects and improved absorption of LMWH. In conclusion, pH-responsive TCS/HPMCP nanoparticles hold promise for oral delivery of LMWH.     

Enteric delivery of ketoprofen through functionally modified poly(acrylamide-grafted-xanthan)-based pH-sensitive hydrogel beads: preparation, in vitro and in vivo evaluation

Novel pH-sensitive hydrogel beads were prepared using a hydrolyzed poly(acrylamide-g-xanthan) (PAAm-g-XG) copolymer from a complete aqueous environment and evaluated for targeting ketoprofen to the intestine. The PAAm-g-XG copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The copolymer was characterized by FTIR spectroscopy, (1)H NMR spectroscopy, elemental analysis and thermogravimetric analysis. Pulsatile swelling study indicated that the copolymer exhibits considerable pH-sensitive behavior unlike pristine xanthan gum. Ketoprofen-loaded pH-sensitive beads were prepared by ionotropic gelation with Al(3 + ) ions. Release of drug from all the copolymeric beads was much lesser than that from pristine xanthan beads. Moreover, a maximum of 20% ketoprofen was released from the copolymeric beads in pH 1.2-5.5 during a period of 3 h, while a major portion of the drug was released in pH 6.8-7.4 gradually over a longer period. Pharmacodynamic activity and stomach histopathology of albino rats indicated that the beads were able to retard the drug release in stomach, and gastric side effects such as ulceration, hemorrhage and erosion of gastric mucosa were diminished when the drug was entrapped into PAAm-g-XG-based pH-sensitive beads.     

Enteric delivery of ketoprofen through functionally modified poly(acrylamide-grafted-xanthan)-based pH-sensitive hydrogel beads: Preparation,in vitro and in vivo evaluation

Novel pH-sensitive hydrogel beads were prepared using a hydrolyzed poly(acrylamide-g-xanthan) (PAAm-g-XG) copolymer from a complete aqueous environment and evaluated for targeting ketoprofen to the intestine. The PAAm-g-XG copolymer was synthesized by free radical polymerization under the nitrogen atmosphere followed by alkaline hydrolysis. The copolymer was characterized by FTIR spectroscopy, ¹H NMR spectroscopy, elemental analysis and thermogravimetric analysis. Pulsatile swelling study indicated that the copolymer exhibits considerable pH-sensitive behavior unlike pristine xanthan gum. Ketoprofen-loaded pH-sensitive beads were prepared by ionotropic gelation with Al^{3 +} ions. Release of drug from all the copolymeric beads was much lesser than that from pristine xanthan beads. Moreover, a maximum of 20% ketoprofen was released from the copolymeric beads in pH 1.2–5.5 during a period of 3 h, while a major portion of the drug was released in pH 6.8–7.4 gradually over a longer period. Pharmacodynamic activity and stomach histopathology of albino rats indicated that the beads were able to retard the drug release in stomach, and gastric side effects such as ulceration, hemorrhage and erosion of gastric mucosa were diminished when the drug was entrapped into PAAm-g-XG-based pH-sensitive beads.     

Effective in-vivo utilization of lipid-based nanoparticles as drug carrier for carvedilol phosphate

Objectives Lipid nanoparticles as carrier for oral drug administration improve gastrointestinal solubility of poorly soluble drugs and thus enhance bioavailability. However, basic drugs may undergo rapid dissolution from such solid dispersions in the stomach and precipitate in the intestine due to their higher solubility in acidic medium. Therefore, the objective of this work was to study the enhancement in bioavailability of carvedilol phosphate (basic drug) by providing an alkaline gastric environment to drug‐loaded solid lipid nanoparticles. Methods An alkaline gastric environment in rats was created and maintained with oral administration of an antacid suspension 5 min before and 30 min post dosing. Key findings The formulation administered orally exhibited enhanced bioavailability (～27%) when compared with drug suspension and sustained release behaviour when compared with formulation under ideal gastric conditions. The enhanced bioavailability is due to the presence of lipid nanoparticles as drug carrier while the sustained‐release characteristic may be attributed to the presence of antacid, which resulted in elevation of gastric pH and reduced the drug's solubility. Conclusions It may be concluded that although lipid nanoparticles can be instrumental in improving bioavailability, additional sustained release may be achieved by targeting intestinal release of basic drugs from lipid vehicles, which is possible by incorporating them into suitable enteric‐coated formulations.     

萘哌地尔生物粘附性缓释胶囊处方及体外粘附力测定

采用正交设计结合多元线性回归的方法，确定生物粘附材料羟丙甲纤维素、卡波姆的用量及配比与制剂体外释放度的关系。结果表明羟丙甲纤维素与卡波姆对阻滞胶囊体外释放度影响较大。生物粘附性研究表明缓释胶囊的内容物与大鼠离体胃、肠组织的粘附力明显大于普通胶囊。     

Preparation of pH-sensitive beads for NSAID using three-component gel systems

The aim of this study is to prepare novel pH-sensitive beads to obtain a gastric mucosa protective formulation and to ensure drug delivery into the intestine. Diclofenac sodium was used as a model drug. Bead formation was achieved by ionotropic gelation method using three-component gel system containing sodium alginate (Na-Alg), hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC). Factors influencing the characteristics of beads (exposure time, cross-linking agent concentration, polymer ratio) were investigated by swelling and erosion tests based on gravimetric method. Drug release was tested in distilled water and/or artificial digestive fluids and evaluated with Korsmeyer–Peppas equation and Baker–Lonsdale model. The encapsulation behaviour was qualitatively indicated by differential scanning calorimetry (DSC) method. In vivo experiments were conducted to test ulcerogenicity and intestinal absorption in rats. HPMC increased the encapsulation efficiency (EE) and HEC improved the drug release in the intestinal fluids. The equilibrium water uptake (EWU) was correlated with exposure time, calcium chloride concentration and HEC amounts. Bead erosion increased proportionately to exposure time, while it reduced when calcium chloride concentrations were increased. Higher amounts of HEC increased, while higher pH values reduced the encapsulation efficacy. The in vivo experiments demonstrated that the studied encapsulation technology markedly reduced the ulcerogenic effect of diclofenac. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4285–4295, 2009     

Eudragit RL100 nanoparticle system for the ophthalmic delivery of cloricromene

A Eudragit RL100 polymer nanoparticle system loaded with cloricromene was prepared and characterized on the basis of physicochemical properties, stability and drug release features. To investigate the ocular bioavailability of cloricromene after inclusion in the polymer matrix, the new nanoparticle system was topically administered in the rabbit eye and compared with an aqueous solution of the same drug. The nanoparticle system showed interesting size distribution and surface charge values, suitable for ophthalmic application. The results indicated that the dispersion of cloricromene within Eudragit RL100 polymer nanoparticles increased its ocular bioavailability and enhanced the biopharmaceutical profile. The new cloricromene-loaded nanoparticle system described here may be useful in clinical practice.     

Bioadhesive properties of pegylated nanoparticles

The design of bioadhesive nanoparticles (NPs) for targeting specific sites within the gut remains a major challenge. One possible strategy to solve this problem may be the use of pegylated NPs. In general, these carriers display different bioadhesive properties to nondecorated NPs. Thus, pegylated NPs show a higher ability to interact with the small intestine mucosa rather than with the stomach. However, the type of surface conformation of polyethylene glycol chains appears to have a great influence on the behaviour of these NPs. Theoretically, the traditional ‘brush’ polyethylene glycol corona would facilitate the penetration of the pegylated particles through the mucus layer and the subsequent adhesive interaction with the mucosa, which would promote their absorption by intestinal enterocytes. On the contrary, pegylated NPs with a ‘loop’ conformation would increase the time of residence of the adhered fraction of particles in the mucosa.     

Bioadhesive properties of pegylated nanoparticles

The design of bioadhesive nanoparticles (NPs) for targeting specific sites within the gut remains a major challenge. One possible strategy to solve this problem may be the use of pegylated NPs. In general, these carriers display different bioadhesive properties to nondecorated NPs. Thus, pegylated NPs show a higher ability to interact with the small intestine mucosa rather than with the stomach. However, the type of surface conformation of polyethylene glycol chains appears to have a great influence on the behaviour of these NPs. Theoretically, the traditional 'brush' polyethylene glycol corona would facilitate the penetration of the pegylated particles through the mucus layer and the subsequent adhesive interaction with the mucosa, which would promote their absorption by intestinal enterocytes. On the contrary, pegylated NPs with a 'loop' conformation would increase the time of residence of the adhered fraction of particles in the mucosa.     

酸敏性葡聚糖纳米凝胶的制备与释药性质考察

目的制备具有酸敏特性的聚（甲基丙烯酸缩水甘油酯修饰葡聚糖,dex GMA）/（丙烯酸,AAc）纳米凝胶,研究其降解和释药性质。方法乳液聚合法制备poly(dex GMA/AAc)纳米凝胶,测定不同pH值下的粒度分布,以红霉素（EM）为药物模型,动态透析法测定纳米凝胶在不同pH值下的释药性质。结果poly(dex GMA/AAc)纳米凝胶的平均粒径约为100 nm,包裹率、载药率分别为90.7%和1.06%。在无酶人工胃液 (SGF) 2 h纳米凝胶的药物累积释放率分别为7.0%,之后在无酶人工肠液(SIF)里4 h 内增加到37.0%。结论poly(dex GMA/AAc)纳米凝胶具有酸敏特性,在SGF里释放少量药物,在SIF里凝胶溶胀、降解,药物释放量明显增大。poly(dex GMA/AAc)纳米凝胶是潜在的结肠靶向载体。     

延胡索乙素固体脂质纳米粒缓释片制备及工艺优化

目的：制备延胡索乙素固体脂质纳米粒缓释片，并研究延胡索乙素固体脂质纳米粒缓释片的释药模型和释药机理。方法：乳化-溶剂挥发法制备延胡索乙素固体脂质纳米粒，以乳糖作为冻干剂，羟丙基甲基纤维素（HPMC）为缓释材料进一步制备缓释片。在单因素考察的基础上，设计正交试验优化延胡索乙素固体脂质纳米粒缓释片处方，并对缓释片体外释药模型和释药机理进行探讨。结果：延胡索乙素固体脂质纳米粒缓释片最佳处方为缓释材料HPMC K4M和HPMC K15M比例为1：1，用量为40 mg，PEG 4000的用量为20 mg，硬脂酸镁用量为片芯质量的0.5%。延胡索乙素固体脂质纳米粒缓释片最佳处方的体外释放行为符合Higuchi释药模型，释药方程为：Mt/M_∞=0.286 8 t^1/2-0.073 8（r=0.990 8），12 h内累积释放度为93.56%，缓释片释药机理为扩散和溶蚀共存。结论：制备的延胡索乙素固体脂质纳米粒缓释片，工艺重复性较好，其释药行为符合Higuchi释药模型。     

PCL-PEG-PCL载姜黄素纳米粒子的制备以及体外药物释放的考察

目的制备一种生物可降解、生物相容性良好的姜黄素纳米粒子,并对其体外药物释放行为进行考察。方法采用开环聚合法制备生物可降解的PCL-PEG-PCL三嵌段聚合物,然后采用乳液挥发法制备负载姜黄素的PCL-PEG-PCL纳米粒子,通过透射电镜观察所制备纳米粒子的形貌特征,动态光散射(DLS)测定粒径,采用HPLC测定纳米粒子的包封率和载药量,同时考察其体外药物释放行为。结果姜黄素纳米粒子具有球形结构,粒径在200 nm左右,载药量为(14.23±0.35)%,3 d体外累积释药量65%。结论所制备的姜黄素纳米粒子具有较高的载药量和包封率,同时体外药物释放实验证实姜黄素纳米粒子具有良好的缓释功能。     

姜黄素-PLGA纳米粒提高口服给药生物利用度的研究

目的 研究乳酸/羟基乙酸共聚物（PLGA）纳米粒子提高姜黄素口服生物利用度。方法 采用乳液挥发法制备姜黄素-PLGA纳米粒;通过透射电镜（transmission electron microscope,TEM）观察纳米粒形态;采用动态光散射法（dynamic light scattering,DLS）测定纳米粒大小、表面电位（Zeta电位）;考察药物的体外稳定性以及药物释放行为;以大鼠口服灌胃给药方式考察姜黄素和姜黄素-PLGA纳米粒的体内药物生物利用度。结果 姜黄素-PLGA纳米粒粒度分布均匀,平均粒径大小约200 nm;姜黄素-PLGA纳米粒具有较高的载药量和包封率以及稳定性,体外药物释放实验结果显示具有一定的缓释效果;口服灌胃100 mg·kg^-1姜黄素和姜黄素-PLGA纳米粒,给药30 min之后,姜黄素-PLGA纳米粒给药组的血药浓度水平显著高于姜黄素组（P〈0.05）,药物生物利用度提高到原来的5.2倍。结论 姜黄素-PLGA纳米粒可以有效的提高姜黄素稳定性和口服给药生物利用度。     

Freeze dried chitosan/ poly-(glutamic acid) microparticles for intestinal delivery of lansoprazole

Lansoprazole sodium is a proton pump inhibitor used in treating gastroesophageal reflux disease (GERD). It is highly acid-labile and presents many formulation challenges. Therefore, this drug needs to be protected from the harsh environment in the stomach. In order to achieve this, a pH-sensitive microparticle system composed of chitosan and γ- poly-(glutamic acid) was prepared and loaded with Lansoprazole. The prepared microparticles were not stable in gastric pH. To overcome this problem microparticles were freez-dried and filled in an enteric-coated capsule. Upon oral administration, the enteric-coated capsule remained intact in the acidic environment of the stomach, but dissolved rapidly in the distal segment of the GIT. Consequently, all the microparticles loaded in the capsule were brought into the intestine, thus enhancing the intestinal absorption of drug. Drug encapsulation efficiency of formulation F3 was found to be 82.82 % and in vitro release of prepared formulation F3 was found to be 94% after 8 h of dissolution in 7.4 pH phosphate buffer. FTIR and DSC studies showed no interaction between the drug and polymer. The formulation showed good swelling property. SEM photographs showed that microparticles are spherical and lies in size range of 300-400 μm. From the above, it can be concluded that the prepared chitosan/ γ-poly-(glutamic acid) microparticles can be used as carriers for the intestinal delivery of acid liable drugs such as lansoprazole.     

Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In vitro evaluations

A representative poly(beta-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particle size, charge, and surface morphology. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [(3)H]-paclitaxel in solution form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examined the intracellular degradation pattern of the formulations within the cells by estimating the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepared from poly(epsilon-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having positive zeta potential ( approximately 40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as determined by electron spectroscopy for chemical analysis (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aqueous solution. Qualitative fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concentrations. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.     

pH-Sensitive hydrogels of dextran: Synthesis,characterization and in vivo studies

pH-Sensitive hydrogels of dextran were synthesized by photochemical cross-linking reaction of methacrylate dextran (DEX-MA) at different derivatization degree, functionalized with acidic residues through reaction with phthalic anhydride. The hydrogels were characterized by FT-IR spectra, swelling measurements, experiments of chemical and enzymatic hydrolyses. The swelling data agreed with the formation of networks having pH-sensitive behaviour. This property was confirmed by the morphological examination performed by scanning electron microscopy on samples maintained in media at different pH. (S)-4-Isobutyl-2-phenylpropionic acid (ibuprofen) was loaded into the polymeric matrices. The analysis of the release profiles of the drug from the three networks showed that all the matrices were able to retain ibuprofen during the transit through the stomach, releasing it in a sustained way in the intestinal tract at a rate strictly dependent on the derivatization degree in methacrylic groups. In vivo studies verified the biocompatibility of the materials. Moreover, when the matrix loaded with ibuprofen was administered to rats, it was able to protect them from the ulcerogenic effects of the drug.     

Characterization of intestinal absorption and enterohepatic circulation of mycophenolic Acid and its 7-O-glucuronide in rats

To assess the mechanism of gastrointestinal disorders by mycophenolate mofetil (MMF), the intestinal absorption and enterohepatic circulation of mycophenolic acid (MPA), an active metabolite of MMF, and its 7-O-glucuronide (MPAG) were investigated using rat intestinal loops and a linked-rat model. The stability of MPAG in the intestinal fluids, the toxicity of MPA and MPAG to intestinal mucosa, and biliary excretion of MPAG in rats with acute renal failure (ARF) were also characterized. MPA was rapidly and extensively absorbed from the rat intestine whereas MPAG was much less absorbable. When MPA was administered intravenously to bile-donor rats, 1.2% of dose was excreted in bile of receiver rats exclusively as MPAG during 4 h. MPAG was minimally deconjugated in the intestinal fluids. MPAG, but not MPA, significantly enhanced the release of lactate dehydrogenase from intestinal mucosa. When MPA was intravenously administered to ARF rats, the biliary excretion of MPAG significantly increased, compared with that in normal rats. These results demonstrated that MPAG accumulated in the intestinal lumen following biliary excretion and exerted some toxic effect on the intestinal mucosa. It was also suggested that enterohepatic circulation of MPAG under renal dysfunction increased the risk of gastrointestinal disorders due to MPAG.     

Insulin‐loaded nanocapsules for oral administration: In vitro and in vivo investigation

The purpose of this work was to investigate the ability of poly(isobutylcyanoacrylate) nanocapsules to protect insulin from degradation by proteolytic enzymes providing biologically active insulin by the oral route. Insulin was labeled with Texas Red^® for release studies and microscopy observations. The fluorescent marker was mostly retained by the nanocapsules incubated in the reconstituted gastric medium but the release was 75% within 30 min when the nanocapsules were incubated in the reconstituted intestinal medium. Turbidimetric measurements and electron microscopy observations confirmed that the nanocapsules were degraded in the reconstituted intestinal medium, whereas nanocapsule integrity was preserved in the reconstituted gastric medium. In vivo studies of the gastrointestinal distribution of insulin‐loaded nanocapsules after oral feeding showed that nanocapsules were retained by the stomach for 30 min. One hour after oral administration, nanocapsules reached the lower part of the intestine (ileum). Fluorescence microscopy and confocal microscopy carried out on portions of the small intestine revealed the presence of concentrated fluorescent spots into the mucosa and even in the lamina propia, suggesting that insulin‐loaded nanocapsules could cross the intestinal epithelium. These data suggest that PIBCA nanocapsules can efficiently protect insulin when given orally. In addition, they seemed to be significantly involved in the absorption mechanism. Drug Dev. Res. 49:109–117, 2000. © 2000 Wiley‐Liss, Inc.     

生物粘附性萘哌地尔缓释胶囊的处方筛选

目的：筛选生物粘附性萘哌地尔缓胶囊的处方。方法：采用正交设计结合多元线性回归的方法，确立生物粘附材料HPMC、Carbomer的用量及配比与制剂体外释放度的关系。结果：多元线性回归结果表明，生物粘附材料HPMC与Carbomer对胶囊体外释放度影响较大，且均阻滞药物的释放；生物粘附性缓释胶囊的内容物与大鼠离体胃、肠组织的粘附力明显大于普通胶囊。结论：正交设计结合多元线性回归的方法用于萘哌地尔缓释胶囊的处方筛选，方法简便可行。