透明质酸的功能、制备及其在医学中的应用

透明质酸是一种天然的线性黏多糖,具有特殊生理功能.本文简介透明质酸的功能、各种制备方法以及在医学方面的进展.     

透明质酸的功能、制备及其在医学中的应用

透明质酸是一种天然的线性黏多糖,具有特殊生理功能。本文简介透明质酸的功能、各种制备方法以及在医学方面的进展。     

Formulation and in vitro/in vivo evaluation of chitosan-based film forming gel containing ketoprofen

The film forming gel, adhered to skin surfaces upon application and formed a film, has an advantage onto skin to provide protection and continuous drug release to the application site. This study aimed to prepare a chitosan-based film forming gel containing ketoprofen (CbFG) and to evaluate the CbFG and film from CbFG (CbFG-film). CbFG were prepared with chitosan, lactic acid and various skin permeation enhancers. The physicochemical characteristics were evaluated by texture analysis, viscometry, SEM, DSC, XRD and FT-IR. To identify the mechanism of skin permeation, in vitro skin permeation study was conducted with a Franz diffusion cell and excised SD-rat and hairless mouse dorsal skin. In vivo efficacy assessment in mono-iodoacetate (MIA)-induced rheumatoid arthritis animal model was also conducted. CbFG was successfully prepared and, after applying CbFG to the excised rat dorsal skin, the CbFG-film was also formed well. The physicochemical characteristics of CbFG and CbFG-film could be explained by the grafting of oleic acid onto chitosan in the absence of catalysts. In addition, CbFG containing oleic acid had a higher skin permeation rate in comparison with any other candidate enhancers. The in vivo efficacy study also confirmed significant anti-inflammatory and analgesic effects. Consequently, we report the successful preparation of chitosan-based film forming gel containing ketoprofen with excellent mechanical properties, skin permeation and anti-inflammatory and analgesic effects.     

PEG Mediated Synthesis and Biological Evaluation of Asymmetrical Pyrazole Curcumin Analogues as Potential Analgesic,Anti-Inflammatory and Antioxidant Agents

The new series of asymmetrical pyrazole curcumin analogues 4a – g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H₂O₂, DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a – g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b , 4d , 4f , and 4g showed good DPPH free radical scavenging activity. Compounds 4b , 4c , 4d , 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b , 4d , 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.     

Anti-nephrolithic potential of resveratrol via inhibition of ROS,MCP-1, hyaluronan and osteopontin in vitro and in vivo

BackgroundThough resveratrol is known to have anti-cancer, anti-diabetic, anti-oxidant and anti-inflammatory activities, the inhibitory mechanism of resveratrol in kidney stone formation has not been elucidated so far.MethodELISA, flow cytometry, RT-PCR, and western blotting were performed. Human renal epithelial cells (HRCs) and rats with ethylene glycol (EG)-induced kidney stones were used.ResultsA wound healing assay revealed that resveratrol significantly inhibited the oxalate-mediated migration of HRCs, considering oxalate mediates kidney stone formation. Also, resveratrol suppressed the mRNA expression of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase subunits such as p22^phox and p47^phox, monocyte chemoattractant protein 1 (MCP-1) and osteopontin (OPN) in oxalate-treated HRCs. Furthermore, western blotting showed that resveratrol downregulated the expression of MCP-1-related proteins including transforming growth factor(TGF-β1), TGFR-I or II and hyaluronan in oxalate-treated HRCs. Consistently, resveratrol reduced oxalate-mediated production of reactive oxygen species (ROS) and malondialdehyde (MDA) in oxalate-treated HRCs, while the activities of anti-oxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were enhanced by resveratrol in HRCs and EG-treated kidneys of rats. Consistently, resveratrol significantly reduced the number of urine calcium oxalate crystals and serum MD A, and attenuated the expression of OPN and hyaluroran in EG-treated rats.ConclusionsOur findings suggest that resveratrol exerts anti-nephrolithic potential via inhibition of ROS, MCP-1 hyaluronan and OPN signaling.     

Formulation and in vitro evaluation of ciprofloxacin containing niosomes for pulmonary delivery

In order to develop a niosome-encapsulated ciprofloxacin (CPFX) HCl formulation for pulmonary delivery, the feasibility of encapsulation of CPFX in niosomes, its stability and nebulization capability was evaluated. Various combinations of nonionic surfactants with cholesterol were used to prepare the formulations. The in vitro deposition data of the niosomal formulations were examined using an Andersen cascade impactor. Formulations composed of Span 60 and Tween 60 in combination with 40 mol% of cholesterol exhibited high encapsulation efficacy and stability and also had fine particle fraction and nebulization efficiency of about 61.9% ± 1.0 and 77.9 ± 2.8, respectively. Minimal inhibitory concentration of the niosomal CPFX against some pulmonary pathogens were lower than free CPFX. Using the MTT assay in human lung carcinoma cell line (A549), niosome-entrapped CPFX showed significantly lower cytotoxicity in comparison to the free drug. These results indicate that niosome can be used as a carrier for pulmonary delivery of CPFX via nebulization.     

HPMA copolymers platinates containing dicarboxylato ligands. Preparation,characterisation and in vitro and in vivo evaluation

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer platinates were prepared from polymeric intermediates containing Gly-Phe-Leu-Gly side chains terminating in either malonate or aspartate dicarboxylato ligands. Platinum(II) was bound by reaction of the dicarboxylato ligands with cis-[Pt(NH3)2(H2O)2]2+. The HPMA copolymer platinates obtained had a Mw of 29,000-31,000 Da and a platinum loading of approximately 10wt% (by AAS). This is close to the theoretical maximum value. The release rate of platinum species in vitro at pH 7.4 correlated with the expected stability of the 6 and 7 membered chelate rings; 14%/24 h platinum released in the case of the malonate and 68%/24 h platinum released in the case of the aspartate. Cisplatin and the aspartate conjugate displayed similar toxicity in vitro against B16F10 and COR-L23 cells while the malonate was at least 8-fold less toxic. The malonate conjugate showed significantly improved activity (T/C = 1.27-1.5) when compared with cisplatin (T/C = 1.18) that was not active when administered intravenously to treat a subcutaneous B16F10 tumour. The conjugate was at least 20-fold less toxic than cisplatin in vivo. After i.v. administration, the platinum accumulation in B16F10 tumour tissue showed a 19-fold increase in Pt AUC for the malonate conjugate when compared to cisplatin administered equi-dose at its maximum tolerated dose (MTD) (1 mg/kg).     

Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies

Two types of ligand anchored multilamellar liposomes (MLVs) containing amphotericin B (Amp B) were prepared. The MLVs consisting of soya phosphatidylcholine (PC) and cholesterol (Chol) were coated with O-palmitoyl mannan (OPM). Similarly, the MLVs with the same Amp B content consisting of soya PC, Chol and phosphatidylethanolamine (PE) were prepared and covalently anchored with p-aminophenyl-mannopyranoside (PAM). The surface modified MLVs and their plain counterparts were characterised for size, shape, lamellarity, entrapment efficiency and ligand density. The stability in serum and in vivo bio-distribution in albino rats were also determined. It was observed that extent of accumulation of liposomal Amp B in macrophage rich organs, particularly liver, spleen and lungs was significantly high when compared against the free drug. The rates and extent of accumulation were found to increase further on ligand anchoring. In either of the cases, the macrophagic uptake of ligand anchored liposomes was inhibited significantly on pre-injection of hydrolysed mannan, being suggestive of receptor mediated uptake of ligand anchored liposomes. Comparison of biodistruibution pattern of ligand anchored MLVs revealed that PAM linked liposomes exhibited a higher hepato-splenic accumulation where as drug accumulation in lungs was highest in the case of OPM coated liposomes. It was thus observed that mannopyranoside is a specific ligand for targeting bioactives to the macrophages of liver and spleen while OPM could preferentially negotiate the targeting of bioactives to the alveolar macrophages.     

Comparative study of different silymarin formulations: formulation, characterisation and in vitro/in vivo evaluation

The aim of the present study was to study the synergistic hepatoprotective effect of silymarin with phospholipids when it is encaged in microspheres so as to passively target it to liver and to compare these silymarin formulations with silymarin solution. Various silymarin loaded lipid emulsions were formulated which include formulation A prepared with soyabean oil as an internal oily phase, soya lecithin as surfactant and tween 80 as cosurfactant; formulation B which was same as formulation A but was filtered through 0.45 micro membrane filter and finally steam sterilized for intravenous administration; formulation C containing soyabean oil as an internal oily phase, soya lecithin as surfactant, tween 80 and propylene glycol as cosurfactant/ cosolvent. These formulations were compared for their release profile with silymarin solution in propylene glycol, i.e. formulation D. In vivo evaluation was carried out using three models i.e. phenobarbitone induced sleep time in mice, biochemical estimation of SGOT and SGPT enzyme levels and histopathological examination of rat livers. Results revealed that there was significant reduction in sleep time in the mice treated with silymarin loaded lipid microspheres (both p.o. as well as i.v.) when compared with control and even with plain lipid microspheres and silymarin solution and significant reduction in enzyme levels in silymarin lipid microspheres treated group when compared with control, plain lipid microspheres as well as silymarin solution treated group. Histopathological studies also supported the results obtained from the other two models. A positive outcome of these studies gave an insight that if silymarin is coupled with phospholipid in such microparticulate delivery systems, hepatoprotective effect of drug molecules can be pronounced further by self targeting nature and synergistic action.     

In vitro and in vivo skin anti-aging evaluation of gel containing niosomes loaded with a semi-purified fraction containing gallic acid from Terminalia chebula galls

Context: The galls of Terminalia chebula Retz. (Combretaceae) frequently appear in many Thai Lanna medicinal plant recipes for promotion of longevity.

Objective: The objective of this study was to evaluate the skin anti-aging of gel containing niosomes loaded with a semi-purified fraction containing gallic acid from T. chebula galls.

Method: The semi-purified fraction containing phenolic compounds including gallic acid isolated from T. chebula galls loaded in non-elastic or elastic niosomes, and its developed gel, were evaluated for rabbit skin irritation by the closed patch test and skin anti-aging in human volunteers by measuring skin elasticity and roughness.

Results: Gel containing the fraction unloaded (SS) or loaded in non-elastic (SN) or elastic (SE) niosomes and gallic acid loaded in non-elastic (GN) or elastic (GE) niosomes showed no skin irritation, whereas the unloaded gallic acid (GS) gave the irritation in rabbit’s skin by the closed patch test. The % parameter changes of skin elastic recovery and skin elastic extension when applied with SN and SE gels were +28.73 and +32.57; ?21.25 and ?22.63%, respectively. SN and SE gel also showed a significant decrease of the maximum and average roughness values with the parameter changes of ?29.43 and ?32.38; ?39.47 and ?35.28%, respectively.

Conclusion: The semi-purified fraction loaded in niosomes indicated not only higher chemical stability of gallic acid containing in the fraction, but also more in vivo anti-aging activities than the unloaded fraction when incorporated in gel.     

Curcumin analogues and derivatives with anti-proliferative and anti-inflammatory activity: Structural characteristics and molecular targets

ABSTRACT

Introduction: Curcumin (Diferuloylmethane) is a natural phenolic compound, which belongs to the curcuminoid family, presenting pleiotropic activity and low bioavailability. A lot of recent research is focused on the design and synthesis of curcumin analogs as antiproliferative and anti-inflammatory agents improving the bioavailability and target selectivity. Their structural characteristics and functional groups seem to define the extent of the biological activity.

Areas covered: Publications (2008–2018), describing curcumin analogs and curcumin derivatives are analyzed. Structural characteristics, functional groups, modelling studies, structure activity relationships, biological evaluation in vitro/in vivo as antiproliferative and anti-inflammatory agents are included. Furthermore, a wide range of biological results derived from different targets are also summarized.

Expert opinion: Several curcumin analogs and derivatives appear to have a high biological impact as well as promising antiproliferative and anti-inflammatory activities. Their clinical evaluation will be critical to assess therapeutic utility. Compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.     

Cationic niosomes as gene carriers: preparation and cellular uptake in vitro

Cationic niosomes of sorbitan monoesters were prepared using film hydration method and tested for their effect on delivery of antisense oligonucleotides (OND) in a COS-7 cell line. These formulations showed positive results on cellular uptake of antisense oligonucleotides. Especially, cationic niosomes of Span 40 and 60 have a more significant effect.     

Preparation,characterisation and evaluation of curcumin with piperine-loaded cubosome nanoparticles

Abstract

Objective: In this study, curcumin was designed into the nanoformulation called cubosome with piperine in order to improve oral bioavailability and tissue distribution of curcumin. Methods: The characteristic of the cubosome was studied by using scanning electron microscope (SEM), Infrared spectrum and small angle X-ray scattering (SAXS) techniques. Tissue distribution of cubosome was measured by liquid chromatography-mass spectrometry (LC-MS) method in mice. Results: The characteristic of the cubosome was demonstrated that the curcumin and piperine were encapsulated in the interior of the cubosome and the crystal form was Pn3m space. The pharmacokinetic test revealed that the cubosome could improve the oral bioavailability significantly compared to the suspension of curcumin with piperine and be mainly absorbed by the spleen. Conclusion: These findings provide the reference to a preferable choice of the curcumin formulation and contribute to therapeutic application in clinical research.     

Sophoridine-loaded PLGA microspheres for lung targeting: preparation,in vitro,and in vivo evaluation

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency, in vitro release profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17?μm with 90% of the microspheres ranging from 12 to 24?μm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. The in vitro drug release behavior of microspheres exhibited an initial burst of 16.6% at 4?h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10?μg/g for microspheres and 6.77?μg/g for solution after intraveneous injection for 30?min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer.     

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。     

Water/oil type microemulsion systems containing lidocaine hydrochloride: in vitro and in vivo evaluation

Abstract

The purpose of this study was to develop a water/oil microemulsion containing lidocaine hydrochloride (4%) and to compare its local anaesthetic efficacy with commercial products. A pseudoternary diagram (K_m:1/1 or 1/2) was constructed using lecithin/ethanol/oil/water. The droplet size, viscosity and release of the microemulsions were evaluated. Tail flick tests were conducted for in vivo effectiveness; the initiation time of effect, maximum effect, time to reach maximum effect, and relative efficacy were evaluated. The drug caused a significant increase in droplet size. The use of olive oil resulted in a decrease in the solubilisation parameter, as well as a reduction in the release. The droplet size and viscosity of the microemulsion composed of Miglyol/lecithin/ethanol/water/drug (K_m:1/2) was lower than other microemulsions (8.38?nm, 6.9 mPa), and its release rate (1.61?mg/h) was higher. This system had a faster and more efficient anaesthetic effect than the other microemulsions and commercial products. Results indicate that a water/oil type microemulsion (Miglyol/lecithin/ethanol/water) has promising potential to increase the local anaesthetic effect.     

N-acetyl-L-cysteine functionalized nanostructured lipid carrier for improving oral bioavailability of curcumin: preparation,in vitro and in vivo evaluations

The application of orally administered nanoparticles in the circulation system is limited by the secretion and shedding of intestinal tract mucous layer. In order to enhance mucoadhesion and mucus penetration of curcumin (Cur)-loaded nanostructured lipid carrier (NLC) after oral administration, a new multifunctional conjugate, N-acetyl-L-cysteine-polyethylene glycol (100)-monostearate (NAPG), was synthesized. Functionalized nanocarriers (Cur-NAPG-NLC) modified by different amounts of NAPG (the amounts of NAPG were 20, 50, and 100?mg) were prepared and investigated for in vitro and in vivo behavior. Mean particle sizes of 89–141?nm with negative zeta potential (?15 to ?11?mV) and high encapsulation efficiency (EE,?>90%) possessing spherical and stable nanocarriers were observed. Sustained drug release was also observed for the NAPG-NLC. In situ intestinal perfusion studies showed that with increasing the amount of NAPG increase absorption of Cur. In vivo oral pharmacokinetic evaluation suggested that the bioavailability of Cur in rats was proportional to the degree of functionalization of NLCs with NAPG. AUC_0–t of Cur-NAPG100-NLC was improved by 499.45 and 116.89 folds as compared to that of Cur solution and unmodified Cur-NLC, respectively. In conclusion, NAPG modified NLC could be a promising drug delivery system for improving oral performance of BCS class IV drugs.