劳拉西泮滴鼻剂兔鼻腔给药的药动学研究

建立了HPLC法测定兔血浆中的劳拉西泮,考察鼻腔和静注给药后家兔体内的药动学特征.结果表明,劳拉西泮在1～75 ng/ml浓度范围内线性关系良好,精密度及回收率试验结果符合生物样品分析要求.家兔静注和滴鼻给予劳拉西泮后,tmax为(9.2±10.2)和(6.7±4.1)min,AUC0(-8)为(3 386.2±520.5)和(1 693.2±818.8) ng-1·min,滴鼻剂的绝对生物利用度可达到62.8％.     

Development of Biodegradable Starch Microspheres for Intranasal Delivery

Domperidone microspheres for intranasal administration were prepared by emulsification crosslinking technique. Starch a biodegradable polymer was used in preparation of microspheres using epichlorhydrine as cross-linking agent. The formulation variables were drug concentration and polymer concentration and batch of drug free microsphere was prepared for comparisons. All the formulations were evaluated for particle size, morphological characteristics, percentage drug encapsulation, equilibrium swelling degree, percentage mucoadhesion, bioadhesive strength, and in vitro diffusion study using nasal cell. Spherical microspheres were obtained in all batches with mean diameter in the range of above 22.8 to 102.63 μm. They showed good mucoadhesive property and swelling behaviour. The in vitro release was found in the range of 73.11% to 86.21%. Concentration of both polymer and drug affect in vitro release of drug.     

Nasal Delivery of Insulin Using Novel Chitosan Based Formulations: A Comparative Study in Two Animal Models Between Simple Chitosan Formulations and Chitosan Nanoparticles

Purpose. To investigate whether the widely accepted advantages associated with the use of chitosan as a nasal drug delivery system, might be further improved by application of chitosan formulated as nanoparticles. Methods. Insulin-chitosan nanoparticles were prepared by the ionotropic gelation of chitosan glutamate and tripolyphosphate pentasodium and by simple complexation of insulin and chitosan. The nasal absorption of insulin after administration in chitosan nanoparticle formulations and in chitosan solution and powder formulations was evaluated in anaesthetised rats and/or in conscious sheep. Results. Insulin-chitosan nanoparticle formulations produced a pharmacological response in the two animal models, although in both cases the response in terms of lowering the blood glucose levels was less (to 52.9 or 59.7% of basal level in the rat, 72.6% in the sheep) than that of the nasal insulin chitosan solution formulation (40.1% in the rat, 53.0% in the sheep). The insulin-chitosan solution formulation was found to be significantly more effective than the complex and nanoparticle formulations. The hypoglycaemic response of the rat to the administration of post-loaded insulin-chitosan nanoparticles and insulin-loaded chitosan nanoparticles was comparable. As shown in the sheep model, the most effective chitosan formulation for nasal insulin absorption was a chitosan powder delivery system with a bioavailability of 17.0% as compared to 1.3% and 3.6% for the chitosan nanoparticles and chitosan solution formulations, respectively. Conclusion. It was shown conclusively that chitosan nanoparticles did not improve the absorption enhancing effect of chitosan in solution or powder form and that chitosan powder was the most effective formulation for nasal delivery of insulin in the sheep model.     

油-吐温-醇-水体系伪三元相图在自微乳化制剂研究中的应用

分别以油酸乙酯、亚油酸乙酯、乙酸乙酯为油相,吐温-80为表面活性剂,无水乙醇、正丙醇、异丙醇、乙二醇、1,2-丙二醇、丙三醇、正丁醇和聚乙二醇400为助表面活性剂,在37℃水浴中,用水滴定上述三组分不同配比的混合物,绘制油-吐温-80-醇-水体系伪三元相图,并对自微乳化系统进行研究.结果表明,相同条件下以乙酸乙酯为油相的体系,相图中自微乳区面积大于以油酸乙酯和亚油酸乙酯为油相的体系.随着体系中吐温-80-醇重量比(Km)减小,形成的自微乳区面积减小;若表面活性剂黏度较大,则以油酸乙酯和亚油酸乙酯为油相的体系相图中可出现凝胶区,随Km减小,凝胶区减小直至消失.     

Optimization of Chitosan Succinate and Chitosan Phthalate Microspheres for Oral Delivery of Insulin using Response Surface Methodology

In the present study, a Box-Behnken experimental design was employed to statistically optimize the formulation parameters of chitosan phthalate and chitosan succinate microspheres preparation. These microspheres can be useful for oral insulin delivery system. The effects of three parameters namely polymer concentration, stirring speed and cross linking agent were studied. The fitted mathematical model allowed us to plot response surfaces curves and to determine optimal preparation conditions. Results clearly indicated that the crosslinking agent was the main factor influencing the insulin loading and releasing. The in vitro results indicated that chitosan succinate microspheres need high amount of crosslinking agent to control initial burst release compared to chitosan phthalate microspheres. The reason may be attributed that chitosan succinate is more hydrophilic than chitosan phthalate. The relative pharmacological efficacy for chitosan phthalate and chitosan succinate microspheres (18.66 ± 3.84%, 16.24 ± 4%) was almost three-fold higher than the efficacy of the oral insulin administration (4.68 ± 1.52%). These findings suggest that these microspheres are promising carrier for oral insulin delivery system.     

用于全身治疗的鼻腔给药系统研究概况

目的介绍用于全身治疗的鼻腔给药系统研究概况。方法综述了鼻腔给药的特点、手段、制剂方法、要求、影响因素及研究状况。结果与讨论鼻腔给药可以产生全身作用,可以代替静脉给药,有广泛的应用前景。     

Chitosan Reduced Gold Nanoparticles as Novel Carriers for Transmucosal Delivery of Insulin

Purpose Colloidal metallic systems have been recently investigated in the area of nanomedicine. Gold nanoparticles have found themselves useful for diagnostic and drug delivery applications. Herein we have reported a novel method for synthesis of gold nanoparticles using a natural, biocompatible and biodegradable polymer; chitosan. Use of chitosan serves dual purpose by acting as a reducing agent in the synthesis of gold nanoparticles and also promotes the penetration and uptake of peptide hormone insulin across the mucosa. To demonstrate the use of chitosan reduced gold nanoparticles as carriers for drug delivery, we report herein the transmucosal delivery of insulin loaded gold nanoparticles. Materials and Methods Gold nanoparticles were prepared using different concentrations of chitosan (from 0.01% w/v up to 1% w/v). The gold nanoparticles were characterized for surface plasmon band, zeta potential, surface morphology, in vitro diffusion studies and fluorescence spectroscopy. The in vivo studies in diabetic male Wistar rats were carried out using insulin loaded chitosan reduced gold nanoparticles. Results Varying concentrations of chitosan used for the synthesis of gold nanoparticles demonstrated that the nanoparticles obtained at higher chitosan concentrations (>0.1% w/v) were stable showing no signs of aggregation. The nanoparticles also showed long term stability in terms of aggregation for about 6 months. Insulin loading of 53% was obtained and found to be stable after loading. Blood glucose lowering at the end of 2 h following administration of insulin loaded gold nanoparticles to diabetic rats was found to be 30.41 and 20.27% for oral (50 IU/kg) and nasal (10 IU/kg), respectively. Serum gold level studies have demonstrated significant improvement in the uptake of chitosan reduced gold nanoparticles. Conclusions The synthesis of gold nanoparticles using a biocompatible polymer, chitosan would improve its surface properties for binding of biomolecules. Our studies indicate that oral and nasal administration of insulin loaded chitosan reduced gold nanoparticles has led to improved pharmacodynamic activity. Thus, chitosan reduced gold nanoparticles loaded with insulin prove to be promising in controlling the postprandial hyperglycemia.     

Chitosan Nanoparticles for Plasmid DNA Delivery: Effect of Chitosan Molecular Structure on Formulation and Release Characteristics

Chitosan can be useful as a nonviral vector for gene delivery. Although there are several reports to form chitosan-pDNA particles, the optimization and effect on transfection remain insufficient. The chitosan-pDNA nanoparticles were formulated using complex coacervation and solvent evaporation techniques. The important parameters for the encapsulation efficiency were investigated, including molecular weight and deacetylation degree of chitosan. We found that encapsulation efficiency of pDNA is directly proportional with deacetylation degree, but there is an inverse proportion with molecular weight of chitosan. DNA-nanoparticles in the size range of 450–820 nm depend on the formulation process. The surface charge of the nanoparticles prepared with complex coacervation method was slightly positive with a zeta potential of +9 to +18 mV; nevertheless, nanoparticles prepared with solvent evaporation method had a zeta potential ～ +30 mV. The pDNA-chitosan nanoparticles prepared by using high deacetylation degree chitosan having 92.7%, 98.0%, and 90.4% encapsulation efficiency protect the encapsulated pDNA from nuclease degradation as shown by electrophoretic mobility analysis. The release of pDNA from the formulation prepared by complex coacervation was completed in 24 hr whereas the formulation prepared by evaporation tecnique released pDNA in 96 hr, but these release profiles are not statistically significant compared with formulations with similar structure p >. 05). According to the results, we suggest nanoparticles have the potential to be used as a transfer vector in further studies.     

Novel Approach for Delivery of Insulin Loaded Poly(lactide-co-glycolide) Nanoparticles Using a Combination of Stabilizers

Insulin stability during microencapsulation and subsequent release is essential for retaining its biological activity. The successful delivery of insulin relies on the proper selection of stabilizers in addition to other parameters. Attempts were made to address the problem with a few combination of stabilizers for maintaining the integrity of insulin during formulation and delivery. Insulin loaded nanoparticles with different stabilizers such as pluronic F68, trehalose, and sodium bicarbonate were prepared by the double emulsion evaporation method using two different copolymer ratios of poly(DL-lactide-co-glycolide) (50:50 and 85:15). The presence of stabilizers in the nanoparticles resulted in an increase in the particle size but a reduction of encapsulation efficiency. Insulin release rate was comparatively higher for the batches containing stabilizers when compared with controls for both the copolymer ratios. Also the presence of stabilizers resulted in sustained release of insulin resulting in prolonged reduction of blood glucose levels in streptozotocin induced diabetic rats. From the in vitro and in vivo studies, we concluded that a combination of stabilizers results in beneficial effects without compromising the advantages of delivery systems.     

Development of Lecithin/Chitosan Nanoparticles for Promoting Topical Delivery of Propranolol Hydrochloride: Design,Optimization and In-Vivo Evaluation

Propranolol (PPL) administered orally is considered as the first line drug for the treatment of infantile hemangioma, however several systemic adverse effects limit its use. For this reason, our work tackles the development and evaluation of PPL loaded chitosan nanoparticles (NPs), as an effective alternative for the treatment of infantile hemangioma. PPL -NPs were prepared using the double emulsion technique and the influence of the formulation variables on drug entrapment efficiency (EE), particle size (PS), percent released after 24 h (%R_24h) and zeta potential (ZP) were optimized using full factorial design. Two systems, namely F3 and F28 showing highest E.E., ZP and %R_24h with lowest PS, were fully characterized for DSC and TEM and incorporated into hydrogel with adequate viscosity. After ensuring safety for the selected nanoparticle, the hydrogel containing the optimized system was applied topically to rats. The in-vivo skin deposition in rats showed an accumulation of propranolol from the lecithin/chitosan nanocarrier by 1.56–1.91-fold when compared to the drug solution. The obtained result was further supported by the confocal laser scanning microscopy which showed fluorescence across the skin. PPL-HCL-loaded lecithin/chitosan nanoparticles could be considered as a potential candidate for treating infantile hemangiomas (IH) by maintaining therapeutic concentration topically while minimizing systemic side effects.     

Intranasal corticosteroids: the development of a drug delivery device for fluticasone furoate as a potential step toward improved compliance

Devices for the aqueous delivery of intranasal corticosteroids to patients with allergic rhinitis have been available since 1984, so there is a need for new devices to be developed to provide ease of use, efficacy and safety. A novel drug delivery system has been developed for fluticasone furoate (FF; GlaxoSmithKline): a new enhanced-affinity glucocorticoid with a scent-free formulation. The FF system was developed, giving attention to patients’ unmet needs, in order to promote acceptance and compliance. It demonstrates a number of key features including its ergonomic design, side-actuation system and short delivery nozzle. Exploiting issues with present devices highlighted the need for the FF system. This review reports data from key studies and surveys conducted by GlaxoSmithKline during development, to determine ease of use and acceptance of the FF system. Findings suggest that the FF system should aid in improving attitudes to the use of intranasal corticosteroids amongst physicians and patients.