尼群地平固体分散体的休外溶出特性

目的：制备尼群地平固体分散体,增加其溶解度和溶出速度。方法：以聚乙二醇6000（PEG6000）、聚乙二醇4000（PEG4000）、聚乙烯吡咯烷酮（PVPk30)为载体,以溶剂－熔融法和共沉淀法制备尼群地平固体分散体。应用差热分析鉴别药物在载体中的存在状态,同时进行溶解测定和溶出度研究。结果：尼群地平与载体形成了共熔物,药物以微细结晶存在于载体中,载体比例越大,药物溶出越快,溶解度越大,结论：尼群地平与3种载体形成的固体散全在水中的溶解度均有显著增加（P＜0．05）。当尼群地平－载体比例达1：4时,尼群地平从固体分散体中的溶出速度明显大于尼群地平纯药和尼发群地平－载体（1：8）物理混合物（P＜0．05）。3种载体中以PVPK30对尼群地平的溶解度及溶出速度增加最为显著。     

Improvement of solubility,dissolution and stability profile of artemether solid dispersions and self emulsified solid dispersions by solvent evaporation method

Abstract

The purpose of this study was to investigate changes in the water solubility of artemether; a poorly soluble drug used for the treatment of malaria. Different solid dispersions (SDs) of artemether were prepared using artemether and polyethylene glycol 6000 at ratio 12:88 (Group 1), self-emulsified solid dispersions (SESDs) containing artemether, polyethylene glycol 6000, cremophor-A-25, olive oil, hydroxypropylmethylcellulose and transcutol in the ratio 12:75:5:4:2:2, respectively (Group 2). SESDs were also prepared by substituting cremophor-A-25 in Group 2 with poloxamer 188 (noted as Group 3). Each of these preparations was formulated using physical mixing and the solvent evaporation method. Aqueous solubility of artemether improved 11-, 95- and 102-fold, while dissolution (in simulated gastric fluid) increased 3-, 13- and 14-fold, for formulation groups 1, 2 and 3, respectively. X-ray diffraction patterns of SDs indicated a decrease in peak intensities at 10° implying reduced artemether crystallinity. Scanning electron micrographs invariably revealed embedment of artemether by various excipients and a glassy appearance for solvent evaporated mixtures for all three formulation Groups. Our findings indicate improved hydrophilic interactions for drug particles yield greater solubility and dissolution in the following order for artemether formulating methods: solvent evaporation mixtures?>?physical mixtures?>?pure artemether.     

Enhancement of dissolution rate of rofecoxib using solid dispersions with urea

The aim of this study was to enhance the dissolution rate of rofecoxib using solid dispersions (SDs) with urea. In preliminary studies, the solubility behavior of rofecoxib in the presence of polyethylene glycol (PEG)‐4000, polyvinylpyrrolidone (PVP) K30, mannitol, and urea in water was obtained at 37°C to choose an effective carrier for preparing its SDs. A systematic increase in the solubility behavior of rofecoxib was observed with increasing concentrations of these carriers in water except mannitol. The Gibbs free energy (ΔG) values were negative indicating the spontaneous nature of rofecoxib solubilization, and it decreased with increases in concentration, demonstrating that the reaction became more favorable as the concentration of these carriers increased. Since, urea exhibited higher solubilizing power than the other carriers, SDs of rofecoxib with urea were prepared at 1:1, 1:2, 1:5, and 1:10 (rofecoxib:urea) ratios by the fusion method. Evaluation of the properties of the SDs was performed using dissolution studies, fourier‐transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X‐Ray diffraction (XRD), and scanning electron microscopy (SEM). The dissolution rate of rofecoxib was enhanced rapid by its SDs with urea and increased with increasing concentrations of urea in SDs. The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures with urea. FTIR spectroscopic studies showed the stability of rofecoxib and the absence of a well‐defined rofecoxib‐urea interaction. DSC and XRD studies confirmed the amorphous state of rofecoxib in SDs of rofecoxib with urea. SEM pictures showed the formation of effective SDs of rofecoxib with urea since well‐defined changes in the surface nature of rofecoxib, SDs, and physical mixture were observed. Drug Dev Res 63:181–189, (2004). © 2004 Wiley‐Liss, Inc.     

微环境pH调控技术在固体分散体中的应用

微环境pH(pHM)调控技术是指利用pHM调节剂对药物粒子周围饱和溶液的pH进行调控的技术。该技术在固体分散体中有两方面的应用:一方面通过调节pHM提高弱酸或弱碱性药物溶解度;另一方面通过介导与药物分子间的相互作用促进药物形成无定形态,抑制药物重结晶,增加固体分散体稳定性。两种机制共同作用显著提高了难溶性药物的溶出与溶解。文中对pHM调控技术在固体分散体中的应用最新研究进展进行综述,以期为固体分散体研究起到一定的借鉴和指导作用。     

Preparation of evodiamine solid dispersions and its pharmacokinetics

In order to increase the dissolution rate and bioavailability, solid dispersions of evodiamine in PVP K(30) with different enriched samples of evodiamine to PVP K(30) ratios were prepared by solvent method. Our studies showed that the dissolution rate of evodiamine was significantly higher in the solid dispersion system in comparison with that in enriched samples of evodiamine or physical mixtures. The increase of the dissolution rate was evidently related to the ratio of evodiamine to PVP K(30). The solid dispersion system (enriched samples of evodiamine/PVP K(30)= 1/6, w/w) gave the highest dissolution rate: about 27.7-fold higher than that of enriched samples of evodiamine in hard capsules. Powder X-ray diffraction studies showed that enriched samples of evodiamine presented a total chemical stability after its preparation as solid dispersions. In vivo administration studies indicated that solid dispersions of evodiamine in hard capsules had a higher C(max) and a shorter T(max) than those of physical mixture in hard capsules, and the differences of C(max) and T(max) between them were significant. These results suggest that solid dispersions of evodiamine in hard capsules has a notably faster and greater absorption rate than enriched samples of evodiamine in physical mixture hard capsule and corresponds with the in vitro dissolution.     

酮洛芬-聚乙烯吡咯烷酮固体分散物的制备及其体外溶出度的研究

目的提高难溶性药物酮洛芬体外溶出速度。方法以聚乙烯吡咯烷酮(PVPK30)为载体,制备药物与载体不同比例的固体分散物及物理混合物,采用X射线衍射和红外吸收方法,比较二者及药物的结晶形态,并进行体外药物溶出度的测定。结果固体分散物体外溶出速率明显高于物理混合物及酮洛芬原料的体外溶出速度,且随载体比例增加而增大。固体分散物的X射线衍射及红外吸收图谱确定了酮洛芬以无定形态分散在载体中,放置6个月后,固体分散物X射线衍射图谱没有明显变化。结论药物与载体以合适比例制备的固体分散物可以明显提高药物体外溶出速度。     

Effect of Particle Size and Polymer Loading on Dissolution Behavior of Amorphous Griseofulvin Powder

The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0%-50% Kollidon^® VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 μm) size group with different polymer loadings were significantly higher than those for the largest (250-355 μm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (C_s) and Avrami recrystallization rate kinetics, where the solid-state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon® VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs.     

Nanoscale thermal analysis of pharmaceutical solid dispersions

Formation of a solid solution of a drug in a water-soluble polymer is one of the primary techniques used to improve the dissolution rate and thus bioavailability of a poorly water-soluble drug. Understanding and detecting the state of the drug inside such a polymer matrix is critically important since issues such as drug stability, safety and efficacy can be greatly affected. In this study, two model formulations were prepared containing low and high levels of drug content. The heterogeneity of the formulations has been investigated using a novel nanothermal analysis technique. This technique has demonstrated a promising capability for imaging and quantitatively characterising the nanoscale properties of solid dispersion formulations.     

布洛芬固体分散体的制备

目的:利用熔融法制备布洛芬Kollidon CL和Kollidon CL-SF固体分散体,提高布洛芬的体外溶出性质。方法:以Kollidon CL和Kollidon CL-SF为载体,利用熔融法制备难溶性药物布洛芬固体分散体,并进行体外溶出研究。采用差示扫描量热分析、粉末X射线衍射分析及扫描电镜观察对制备的固体分散体进行物相鉴别。结果:熔融法制备的布洛芬-Kollidon固体分散体中,布洛芬以无定形态存在,体外溶出速率显著提高,5 min时以Kollidon CL和Kollidon CL-SF为载体的固体分散体中布洛芬累积溶出度是67.1%和67.6%,分别是布洛芬原药的17.8倍和17.9倍。结论:固体分散体技术是提高布洛芬溶出性质的一种有效可行的方法。     

Preparation and characterization of solid dispersions of Quercetin with PEG4000

Objective To enhance the solubility,quicken the speed of digesting and absorption,and increase the bioavailability of quercetin(3,3',4',5,7-pentahydroxyflavone).Methods A series of Quercetin-PEG4000 solid dispersions were prepared by fusion method.The configuration and property of solid dispersion were characterized by solubility tests,dissolution tests,FTIR spectra,differential scanning calorimetry(DSC)and microphotograph.Results 1.According to solubility tests the the mass ratio of quercetin to PEG4000 affected strongly on the solubility of solid dispersions,on the whole,the relation of the solubility of solid dispersions to the mass ratio presented linear relationship.The preparation temperature had little effect on the solubility of solid dispersions.The surface-active agent,polysorbate80 increased strongly the solubility of solid dispersions.2.According to the dissolution tests,the mass ratio of quercetin to PEG4000 affected strongly on the dissolution of solid dispersions,the preparation temperature had little effect on the dissolution of solid dispersions.The surface-active agent,polysorbate80 increased strongly the dissolution of solid dispersions,and after addition polysorbate80,the dissolution of solid dispersions was two times of the dissolution of solid dispersions without polysorbate80.3.According to the DSC results,except that a little of quercetin molecular existed as crystalline state in the solid dispersion with the mass ratio was qu:PEG=1:2,quercetin existed as amorphous phase in other mass ratio solid dispersion.4.According to the FTIR spectra and microphotograph results,the relation of quercetin and PEG4000 was mainly physical mixing in quercetin-PEG4000 solid dispersion.Quercetin was just like solute in solution,and PEG4000 was just like solvent in solution.The force between quercetin and PEG4000 was mainly hydrogen bonding,so the biological activity of quercetin would not be influenced greatly after the formation solid dispersion.Conclusions These results suggest that quercetin existed mainly as amorphous phase in solid dispersion;the solubility and the dissolution in water were increased obviously after formation the solid dispersion.     

Preparation,characterization and dissolution studies of fast release diclofenac sodium tablets from PVP solid dispersions

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in the treatment of ankylosing spondylitis, rheumatoid arthritis and osteoarthritis. In this context, a rapid onset of action is required. Thus, the aim of this study was to formulate diclofenac sodium-PVP K-30 fast release tablets from solid dispersions. The physical state and drug:carrier interactions were analyzed by X-ray diffraction and scanning electron microscopy and stability upon storage was also studied. Dissolution rate of diclofenac sodium from solid dispersions was markedly enhanced by increasing the polymer concentration.     

他达那非固体分散体的制备和性质研究

目的制备他达那非(tadalafil,TD)固体分散体并进行性质研究。方法利用喷雾干燥法制备固体分散体,以表观溶解度和溶出度为指标筛选处方,采用差示扫描量热(DSC)、粉末X-射线衍射(PXRD)和接触角测定等技术研究药物的存在状态和润湿性等理化性质。结果固体分散体将他达那非的表观溶解度提高22.6倍;20min内药物的累积溶出超过90%;固体分散体药物以分子或无定形状态存在;接触角减小,润湿性增大。结论采用十二烷基硫酸钠(SDS)和介孔硅为载体制备的他达那非固体分散体,能明显提高药物的表观溶解度和溶出度。     

超临界流体技术制备固体分散体的研究进展

超临界流体具有溶解性好、传质能力高、表面张力低及渗透性强等优点,使用超临界流体技术制备的固体分散体粒径均匀可控、纯度高、无溶剂残留,具有传统方法不可比拟的优势。目前,使用超临界流体技术制备固体分散体国内研究还处于起步阶段,该文介绍了超临界流体技术制备固体分散体的方法、原理,归纳总结各方法最新研究进展并提出其存在的问题,为该方面研究者提供参考。     

紫藤瘤化学成分研究

目的研究紫藤瘤(Wisteria sinensis Sweet Caulis)化学成分。方法紫藤瘤(15 kg)95%乙醇渗漉液的石油醚萃取部位,经过硅胶、Sephadex LH-20等多种材料进行分离纯化,通过波谱技术进行结构鉴定。结果从95%乙醇提取物的石油醚萃取部位中分离鉴定了6个化合物,分别为蒲公英赛醇(1),蒲公英赛酮(2),木栓酮(3),表木栓醇(4),β-谷甾醇(5),β-胡萝卜苷(6)。结论化合物1～6均为首次从该种中分得。     

Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery

Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate and bioavailability of these active ingredients belonging to BCS II and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. This article is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercial relevant scientific literature.     

他克莫司固体分散体的制备及体外溶出度测定

目的:制备他克莫司固体分散体,提高他克莫司的体外溶出度。方法:以体外溶出度为指标,从泊洛沙姆188(Poloxamer188)、聚维酮K30(PVP K30)、羟丙甲纤维素(HPMCE3)、聚乙二醇6000(PEG6000)中筛选最优载体及其比例。并采用差示热量扫描(DSC)、红外光谱(FTIR)、电子扫描电镜(SEM)等进行物相表征。结果:4种不同载体制成的固体分散体均能增加他克莫司体外溶出度,通过比较优选出HPMCE3为最佳载体。物相鉴定表明,他克莫司大部分以无定型状态分散于HPMCE3中。结论:制备他克莫司-HPMCE3固体分散体可以明显提高其体外溶出度,且制备方法简单可行。     

布格呋喃固体分散体的体外研究

布格呋喃(buagafuran,AF-5)是以( )香芹酮为起始原料通过立体选择性合成的沉香呋喃类化合物[1].它具有显著的抗焦虑作用,毒副作用低,市场前景广阔.布格呋喃为油状液体,脂溶性强,不溶于水.用植物油稀释进行小鼠灌胃,抗焦虑活性与空白组比较无统计学意义,不能较好地发挥药效.室温放置易发生降解,化学稳定性差.这些缺     

尼美舒利固体分散体的非pH依赖性释放研究

目的以尼美舒利为难溶弱酸性模型药物,研究提高该类药物释放速率的方法。方法以聚乙二醇6000(PEG6000)为载体,采用熔融法制备尼美舒利固体分散体;测定含不同碱化剂(包括NaOH、KOH、Ca(OH)2、Na2CO3、CaCO3)的尼美舒利固体分散体中药物的释放速率。结果加入碱化剂能显著增加尼美舒利在蒸馏水中的释放度,碱化剂不同,药物的释放度不同;碱化剂的碱性越强,分散体的颜色越深,其吸湿性也相对越大。结论在尼美舒利PEG6000固体分散体中加入碱化剂可显著改善该类药物的体外释放特点,并呈现明显的非pH依赖性。