包合物脂质体靶向系统在给药中的应用

近年来,包合物和脂质体作为药物的载体被广泛用于药物制剂领域,各自发挥着自身的优势。将环糊精包合物应用于脂质体给药系统——这一新型的药物载体,能够更好地提高靶向给药效果。本文通过概述包合物及脂质体的优势,阐明包合物脂质体这一新型给药系统能提高药物的载药量,增加脂质体的稳定性,对提高药物的吸收和临床疗效等方面具有重要意义,对于靶向给药系统的进一步发展具有新的参考价值。     

磺丁基醚-β-环糊精/格列本脲包合物的制备

目的制备磺丁基醚-β-环糊精/格列本脲包合物,并对其提高药物溶解性和稳定性的作用进行考察。方法采用相溶解度法测定表观稳定常数,中和法制备磺丁基醚-β-环糊精/格列本脲包合物,并对包合物的溶出度进行了考察。结果与格列本脲原料药相比,磺丁基醚-β-环糊精/格列本脲包合物显著提高了药物的溶解度。结论制备格列本脲的环糊精包合物具有良好的实际应用价值。     

乙酰基β-环糊精包合物的制备及释药性能考察

目的制备疏水性乙酰基β环糊精包合物,考察乙酰基β环糊精包合物的释药性能。方法乙酰基β环糊精包合物的制备以苯甲酸为模型药物,采用密封控温技术。乙酰基β环糊精包合物对药物释放的影响考察,采用药物从包合物中的升华、释放及溶媒对包合物的浸入等实验。结果通过粉末X-射线衍射和差热扫描验证了乙酰基β环糊精包合物的形成。苯甲酸与乙酰基β环糊精系统的升华实验表明,苯甲酸在其物理混合物中的升华速率明显高于其包合物,当升华达6 h时,物理混合物的质量下降为5.82%,而包合物仅为2.13%。在pH 2.0和pH 7.4的磷酸盐缓冲液中,乙酰基β环糊精包合物中溶媒的浸入量都小于淀粉稀释片。药物释放实验表明,淀粉稀释片在1 h左右苯甲酸几乎全部释放,而包合物中苯甲酸保持缓慢释放。结论采用密封控温技术制备疏水性乙酰基β环糊精包合物,方法可行;药物与乙酰基β环糊精形成包合物,可抑制药物的升华,阻滞溶媒的浸入,延缓药物的释放;乙酰基β环糊精可作为缓释药物的包合材料。     

酮洛芬β-环糊精包合物制备及质量评价

目的：介绍了酮洛芬β-环糊精包合物的制备方法及质量评价方法。方法：通过溶出性能测定、稳定性。研究及动物体内试验来评价β-环糊精包合物质量。结果：实验证明,酮洛芬β-环糊精包合物有利于增加药物的溶出度,提高药物的稳定性,增加药物生物利用度（在动物体内）。结论：酮洛芬β-CYD包合物制备可迭设计目的。     

用混合粉碎法制备晶体药物与β-环糊精包合物

目的制备晶体药物与β-环糊精的包合物;分析包合物中药物的分散状态;考察最佳粉碎时间及形成包合物的适宜贮存湿度。方法采用混合粉碎法制备包合物;根据红外图谱、粉末X-射线衍射验证包合物的形成及最佳粉碎时间;通过升华失重确定包合物中药物分子的分散状态;变换贮存湿度考察包合物的聚结稳定性。结果制成的包合物为无定形结构,药物分子进入β-环糊精空穴中通过分子间氢键结合;包合物的分散度和粉碎时间有关,本系统的最佳粉碎时间为10 min;包合物中药物分子的状态受贮存时相对湿度的影响,在相对湿度低于75%下贮存时,包合物的分散状态未发生明显变化。结论采用混合粉碎法制备包合物,具有较好的稳定性;将晶体难溶性药物与β-环糊精混合粉碎可得到非晶质包合物,能有效地提高难溶性药物的溶解度。     

维生素E-β-环糊精包合物溶出度研究及Weibull模型分析

目的:制备维生素E-β-环糊精包合物,进行包合物的溶出度考察及Weibull模型分析。方法:采用紫外分光光度法测定维生素E-β-环糊精包合物含量及溶出度,利用Excel电子表格软件分别计算维生素E-β-环糊精包合物和物理混合物的Weibull分布参数。结果:制成的维生素E-β-环糊精包合物能显著提高维生素E的体外溶出度,溶出过程符合Weibull分布模型,溶出参数r、m、β、Td有统计学差异(P<0.05)。结论:β-CYD能增加难溶性药物维生素E在水中的溶解性,有望提高药物的生物利用度。     

9-硝基喜树碱包合物脂质体的制备与评价

目的:制备9-硝基喜树碱包合物脂质体以提高其抗肿瘤效果。方法:饱和水溶液法制备9-硝基喜树碱包合物,考查制备包合物脂质体的最佳方法和工艺,制备9-硝基喜树碱包合物隐形脂质体并评价其药剂学性质及抗肿瘤效果。结果:9-NC包合物脂质体最佳工艺为乙醇注入法以10 mg胆固醇,720 mg磷脂,1.0 g包合物处方制备。所制备的9-NC包合物脂质体平均粒径为(112.10±0.81) nm,包封率为(60.11±1.08)%,且体外抗肿瘤效果显著提高。结论:包合物脂质体是喜树碱类药物的抗肿瘤应用的有效载体。     

卡维地洛羟丙基-β-环糊精包合物的制备与评价

目的制备卡维地洛羟丙基-β-环糊精包合物,对包合物进行物性研究。方法采用超声法制备包合物,通过相溶解度研究包合类型,以差示扫描热分析法(DSC)和X-射线衍射法验证卡维地洛羟丙基-β-环糊精包合物的形成,并测定包合物的溶解度和溶出度。结果相溶解度曲线呈AL型,表明卡维地洛能够与羟丙基-β-环糊精形成1∶1的包合物。DSC和X-射线衍射结果显示药物峰消失,证明包合物的形成。包合物的溶解度比原药提高5倍,溶出速度明显加快。结论超声法制备的卡维地洛羟丙基-β-环糊精包合物能显著提高原药的溶解度和溶出速度。     

中心组合效应面设计优化盐酸小檗碱包合物的制备

目的探讨中心组合效应面设计在优化盐酸小檗碱-β-环糊精包合物过程中的应用。方法以盐酸小檗碱为模型药物,应用中心点效应面实验设计(central composite design,CCD),采用饱和水溶液法制备盐酸小檗碱-β-环糊精包合物,通过相溶解度图法,溶出速度及饱和溶解度的测定对所制备的包合物进行验证。结果通过CCD设计建立二项式数学模型所优化包合物的处方为药物与包合材料的比例为1∶2.03,包合时间为2.29 h。包合常数为263.01 L/mol。与盐酸小檗碱相比较,溶解度可以提高2.98倍。结论 CDD设计可认为是寻求盐酸小檗碱-β-环糊精包合物的最佳制备工艺,形成包合物后可显著提高药物的溶解度。     

姜黄素-羟丙基-β-环糊精包合物的制备及其理化性质研究

目的:制备姜黄素-羟丙基-β-环糊精包合物并考察其理化性质。方法:采用冷冻干燥法制备姜黄素-羟丙基-β-环糊精包合物,对其进行鉴别并考察其包合率、稳定性及水溶性等。结果:包合物冻干粉经鉴别已形成包合物,包合率为96·58%,姜黄素的稳定性及水溶性均得到改善。结论:所制包合物能显著增加药物在水中的溶解度,提高药物的稳定性。     

Liposomes encapsulating prednisolone and prednisolone-cyclodextrin complexes: comparison of membrane integrity and drug release.

Inclusion complexes of prednisolone (PR) with beta-cyclodextrin (beta-CD) and hydropropyl-beta-cyclodextrin (HPbeta-CD) were formed by the solvation method, and were characterized by DSC, X-ray diffractometry and FT-IR spectroscopy. PC liposomes incorporating PR as plain drug or inclusion complex were prepared using the dehydration-rehydration method and drug entrapment as well as drug release were estimated for all liposome types prepared. The highest PR entrapment value (80% of the starting material) was achieved for PC/Chol liposomes when the HPbeta-CD-PR (2:1, mol/mol) complex was entrapped. The leakage of vesicle encapsulated 5,6-carboxyfluorescein (CF) was used as a measure of the vesicle membrane integrity. As judged from our experimental results liposomes which encapsulate beta-CD-PR complexes are significantly less stable (when their membrane integrity is considered) compared to liposomes of identical lipid compositions which incorporate plain drug or even (in some cases) non-drug incorporating liposomes, which were prepared and studied for comparison. Interestingly, liposomes which encapsulate HPbeta-CD-PR complexes, have very low initial CF latency values, indicating that the leakage of CF is a process of very high initial velocity. Interactions between lipid and cyclodextrin molecules may be possibly resulting in rapid reorganization of the lipid membrane with simultaneous fast release of CF molecules. The release of PR from liposomes was highest when the drug was entrapped in the form of a complex with beta-CD. Nevertheless, the very high entrapment ability of PR in the form of HPbeta-CD-PR complexes in comparison to plain drug is a indubitable advantage of this approach.     

紫杉醇磁性脂质体纳米粒的制备

目的研究一种制备高载药量的紫杉醇磁性脂质体纳米粒的最佳条件，并对其质量进行检测。方法 通过共沉淀法制备Fe₃O₄纳米粒，同时施加超声处理减少粒子的软团聚合，增加粒子的分散度，对粒子表面进行改性，增加与脂质的结合，最后通过微乳液-低温固化法合成紫杉醇磁性脂质体纳米粒，并通过反相高压液相色谱法检测药物的载药量和包封率。结果紫杉醇磁性脂质体纳米粒为球形或近似球形，其悬浮液样品和冻干样品的粒径约在150～170 nm，药物包封率为98.29%。结论本法制备的粒子具有高质量磁化率、良好磁响应性，符合作为纳米磁靶向给药系统的条件。     

2-Hydroxypropyl-β-cyclodextrin complexation with ursodeoxycholic acid

The complexation in aqueous medium and in the solid phase of ursodeoxycholic acid (UDCA) with a highly soluble cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, was studied by means of solubility methods, IR and 13C-NMR spectroscopy, X-ray diffractometry and thermal analysis. UDCA inclusion took place with 1:1 stoichiometry. ¹³C-NMR analysis suggested that the side chain was introduced into the cyclodextrin cavity. The UDCA/cyclodextrin complex showed better dissolution properties than plain drug crystals. Therefore, the complex may be used to improve the delivery and bioavailability of ursodeoxycholic acid.     

Reused cyclodextrin as a new way to deliver and enhance drug loading onto ion exchange resin

Abstract

Context: Cyclodextrins could improve drug solubility and drug loading onto ion exchange resins. Moreover, the remaining cyclodextrin in the solution might be reused for drug solubility enhancement and drug loading onto resin.

Objectives: To investigate the application of fresh and reused cyclodextrin to improve drug solubility and drug loading onto resin.

Methods: The inclusion complexes were prepared and characterized using β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD). The drug solution was loaded onto resin with and without cyclodextrin. Then, the remaining cyclodextrin was reused for the complex and the drug loading process.

Results and discussion: Improved drug solubility was observed when using cyclodextrins. The complex was successfully formed with 1:1 stoichiometry. The increase in drug solubility with cyclodextrins improved drug loading onto resin. The cyclodextrins delivered drug to bind with resin, forming resinate, and did not bind with the resinate themselves, which was confirmed by quantification of the amount of cyclodextrin in drug loading solution before and after drug loading process. Therefore, cyclodextrins were available to reuse for drug loading without affecting the percentage of drug loading.

Conclusions: Reused cyclodextrin is a novel way to deliver and enhance drug loading onto resin for development of an ion exchange-based drug delivery system.     

Microspheres for colonic delivery of ketoprofen-hydroxypropyl-β-cyclodextrin complex

A new multiparticulate system, with the potential for site-specific delivery to the colon, has been developed using ketoprofen as model drug. The system simultaneously exploits cyclodextrin complexation, to improve drug solubility, and vectorization in microspheres (MS) based on Ca-pectinate and chitosan. The effect of complexation with hydroxypropyl-β-cyclodextrin (HPβCyd) and of chitosan presence on drug entrapment efficiency and release properties, as well on the drug permeation rate across Caco-2 cells has been investigated. Solid-state interactions between the components have been investigated by FTIR spectroscopy, differential scanning calorimetry and X-ray powder diffractometry. The morphology of MS was examined by scanning electron microscopy. Release studies revealed a different behaviour for MS containing drug alone or as complex: drug alone was released faster than in the presence of cyclodextrin from MS without chitosan, due to a reservoir effect. The opposite was found for MS containing chitosan, due to a competition effect between polymer and drug for the cyclodextrin. Cytotoxicity tests demonstrated the safety of these formulations. Permeation studies showed an increased permeation of the drug formulated as MS, particularly marked when it was used as complex, thus revealing an enhancing power of both cyclodextrin and chitosan with a synergistic effect in improving drug permeation.     

油酸多相脂质体(139)注射液包封率测定方法的研究

本文提出了油酸多相脂质体139注射液中脂质体的药物包封率和药物含量的测定方法,以凝胶过滤法Sephadex G-50柱测定139注射液中多相脂质体的重量包封率Qw平均为94.2%;同时又以显微镜照像及统计方法测量了脂质体的体积包封率Qv平均为97.1%。并讨论了影响脂质体中药物包封率的各种因素。     

Nebulization of ultradeformable liposomes: The influence of aerosolization mechanism and formulation excipients

Ultradeformable liposomes are stress-responsive phospholipid vesicles that have been investigated extensively in transdermal delivery. In this study, the suitability of ultradeformable liposomes for pulmonary delivery was investigated. Aerosols of ultradeformable liposomes were generated using air-jet, ultrasonic or vibrating-mesh nebulizers and their stability during aerosol generation was evaluated using salbutamol sulphate as a model hydrophilic drug. Although delivery of ultradeformable liposome aerosols in high fine particle fraction was achievable, the vesicles were very unstable to nebulization so that up to 98% drug losses were demonstrated. Conventional liposomes were relatively less unstable to nebulization. Moreover, ultradeformable liposomes tended to aggregate during nebulization whilst conventional vesicles demonstrated a "size fractionation" behaviour, with smaller liposomes delivered to the lower stage of the impinger and larger vesicles to the upper stage. A release study conducted for 2h showed that ultradeformable liposomes retained only 30% of the originally entrapped drug, which was increased to 53% by inclusion of cholesterol within the formulations. By contrast, conventional liposomes retained 60-70% of the originally entrapped drug. The differences between ultradeformable liposomes and liposomes were attributed to the presence of ethanol or Tween 80 within the elastic vesicle formulations. Overall, this study demonstrated, contrary to our expectation, that materials included with the aim of making the liposomes more elastic and ultradeformable to enhance delivery from nebulizers were in fact responsible for vesicle instability during nebulization and high leakage rates of the drug.     

Multivesicular liposomes bearing celecoxib-beta-cyclodextrin complex for transdermal delivery

In our work depot delivery systems of celecoxib were developed using multivesicular liposomes. Moreover, the solubility of celecoxib was enhanced by complexing drug with cyclodextrin to overcome the limitation of conventional therapy. The multivesicular liposomes (MVLs) bearing celecoxib-β -cyclodextrin inclusion complex were prepared by reverse phase evaporation method, and multilamellar vesicles (MLVs)-bearing drug complex was prepared by the cast film method. The formulations were characterized for vesicle size, encapsulation efficiency, and in vitro drug release. In vivo performance of multivesicular liposomes bearing celecoxib-β -cyclodextrin inclusion complex was evaluated by assessing anti-inflammatory activity using carrageenan-induced rat paw edema volume method. The results were compared with that of celecoxib-cyclodextrin complex and MLVs containing celecoxib-β -cyclodextrin inclusion complex in equal amounts. Phase solubility studies for the celecoxib-β -cyclodextrin inclusion complex clearly indicated an increase in aqueous solubility of celecoxib with an increase in β -CD concentration. The in vitro release studies reveal that MLVs release more than 80% drug within 48 hr whereas MVL formulations release nearly the same amount of drug in 120 hr. In vivo data reveal that reduction in paw volume with MVL formulation was not rapid and fast, but the effect was maintained for prolonged periods, and even after 24 hr there was 40.7 ± 3.40% reduction in paw volume. MVL formulation showed more sustained and prolonged anti-inflammatory effect compared with plain drug and MLVs. We concluded that multivesicular liposome can be successfully utilized for the sustained delivery of celecoxib.