药物无定形的转晶及其抑制策略

与药物晶态相比,无定形态具有更高的表面自由能、更高的表观溶解度和更快的溶出速率.然而,药物无定形态属于热力学不稳定体系,易向稳定的晶态转变而减缓药物的溶出度,进而降低其生物利用度.本文主要介绍了药物无定形态的本质、结晶理论、物理稳定性的影响因素以及抑制转晶的策略,为合理设计无定形药物产品和有效开发无定形制剂提供理论指导,有助于无定形技术在解决药物难溶性问题中发挥更广泛的应用.     

药物无定形的转晶及其抑制策略

与药物晶态相比,无定形态具有更高的表面自由能、更高的表观溶解度和更快的溶出速率.然而,药物无定形态属于热力学不稳定体系,易向稳定的晶态转变而减缓药物的溶出度,进而降低其生物利用度.本文主要介绍了药物无定形态的本质、结晶理论、物理稳定性的影响因素以及抑制转晶的策略,为合理设计无定形药物产品和有效开发无定形制剂提供理论指导,有助于无定形技术在解决药物难溶性问题中发挥更广泛的应用.     

共无定形药物——新型单相无定形二元体系

共无定形药物是活性药物成分与其他小分子固体物质(药物或辅料)结合形成的具有单一玻璃化转变温度的单相无定形二元体系。它作为一种新的药物固体形态,可能改善药物的溶解度、溶出速率、稳定性及生物利用度等理化性质,已成为药物研发的一种新途径。本文主要对共无定形药物的定义、形成机理、制备方法、分析鉴别方法、物理化学稳定性以及溶解度和溶出速率进行综述,并对共无定形与固体分散体和共晶的比较进行了概述。     

新型两亲性壳聚糖衍生物的合成、表征及对难溶性药物的增溶性

以天然可生物降解的壳聚糖为原料, 通过在壳聚糖6位羟基上引入羧甲基, 在2位氨基上引入疏水烷基链, 制得N-辛基-O,N-羧甲基壳聚糖(OCC)两亲性衍生物, 分别用FTIR、1H NMR和元素分析等技术对其结构进行表征, 用广角X射线衍射(WAXD)和差示扫描量热法(DSC)对其物理性质进行分析, 并考察其在各种溶剂中的溶解性能及其对难溶性药物的增溶能力. 所制备的OCC羧甲基取代度为115.9%, 取代主要发生在6位羟基上; 辛基取代度58.0%, 取代主要发生在2位氨基上; 与壳聚糖相比, OCC分子间/内氢键作用减弱; OCC在常用的有机溶剂中不溶, 但在水中溶解度增加, 能够形成具有淡蓝色乳光的纳米胶体溶液, 对难溶性抗肿瘤药物紫杉醇具有优越的增溶能力, 使紫杉醇在水中的溶解度提高近500倍, 载药量为34.6%(质量分数), 包封率为89.9%. OCC是潜在的优良的难溶性药物增溶载体材料.     

温度敏感型树枝状大分子衍生物的合成及药物控制释放

通过加入偶联剂活化末端羧基基团进行酰胺化反应, 将得到的带有羧基末端基团的温敏性聚N-异丙基丙烯酰胺接枝到整代的树枝状大分子聚酰胺-胺(PAMAM)上, 制备了树枝状大分子衍生物PAMAM-g-PNIPAm, 通过FTIR和¹H NMR表征其结构, 通过GPC和¹H NMR测定其分子量, 从而验证了接枝产物的形成; 通过紫外-可见分光光度计测定其在不同pH值缓冲液中的低临界溶胀/溶解温度(LCST)值, 发现产物的LCST值受缓冲液pH值的影响很大, 接枝前后的LCST值也发生了变化. 选用难溶性药物吲哚美辛作为模型药物, 考察了树枝状大分子及其温度敏感性衍生物PAMAM-g-PNIPAm作为载体对药物的包载、增溶和不同温度环境下的释放行为. 结果表明, 树枝状大分子衍生物对吲哚美辛具有增溶和控制释放的性能, 在难溶性药物的控制释放领域具有广阔的应用前景.     

大环化合物作为药物增溶剂的应用

药物研发的过程中,越来越多的化合物存在溶解性低的问题,因此提高药物溶解度是目前迫切需要解决的问题。环糊精、杯芳烃、葫芦脲等大环化合物可以通过主客体作用形成包合物从而增加难溶性药物的水溶性。本文介绍了几种大环化合物在药物增溶领域的应用。首先,基于大环化合物化学结构和空腔属性的差异,列举了它们可增溶药物的种类和范围;其次,主客体的动态可逆包合作用还能改善药物稳定性、溶出速率等,从而使药物的生物利用度进一步提升;另外,补充了大环化合物的相关毒理学数据,这增加了其作为药物辅料批准上市的可能性;最后,总结了大环化合物作为增溶剂存在的问题,并指出空腔尺寸的局限和更全面的安全性评估是未来研究的方向。     

PBL教学法在药物制剂工程教学中的实践与探讨

为提高药物制剂工程课程的教学质量,尝试在该课程中的“水难溶性药物口服制剂技术”部分采用PBL教学法,并通过问卷调查的形式对该方法的教学效果进行评价。     

前言:纳米医药前沿论坛专刊

<正>纳米医药研究是医药健康领域的世界前沿课题.除基础研究以外,近年来,飞速发展的纳米技术在疾病诊断、治疗、检测等医药领域得到了广泛应用.例如,纳米药物的小尺寸(通常至少有一维尺寸在10～100 nm)、大比表面和独特表面性质等特点使其能够显著改变小分子药物的药代等行为和病灶靶向性,从而有效地提高药物的生物利用度,降低毒副作用,并通过改善难溶性药物的溶解度来解决临床给药问题.脂质体、白蛋白-紫杉醇类     

钙离子通道阻滞剂自乳化给药系统的形成机理

以一系列难溶性的二氢吡啶类钙离子通道阻滞剂作为模型药物,以自乳化面积和药物在自乳化给药系统(SEDDS)中的溶解度作为自乳化评价指标,建立各组分的分子描述参数与自乳化性质之间的定量函数关系,通过模型讨论分子结构对自乳化形成机理的影响.结果表明,自乳化的发生是各组分含量、分子间作用力、亲脂性和分子大小等多方面因素综合作用的结果.当混合表面活性剂分子较大且药物脂溶性较好时,SEDDS对难溶性药物的增溶能力较强;表面活性剂与助表面活性剂的质量比较大,混合表面活性剂的分子较大时,SEDDS的稀释稳定性较好.     

热响应纳米金球作为非共价药物载体合成及性质研究

以聚N-异丙基丙烯酰胺接枝的聚酰胺作为稳定剂,以纯水作为溶剂,采用原位合成的方法合成了具有可调光热响应行为、智能响应释药行为的有机无机杂化金纳米粒,并以TEM、紫外-可见分光光度计测定其在不同温度下分别对金核的粒径和表面等离子吸收峰的影响,采用1H-NMR,IR对上述聚合物做了表征.通过紫外-可见光分光光度计测定了不同组样品的低临界溶胀/溶解温度(LCST)值,发现不同组样品LCST有一定差别,通过激光照射测定了样品的体外光热响应性能.选用难溶性吲哚美辛作为模型药物,考察了各组样品的载药释药行为.实验研究结果表明,聚N-异丙基丙烯酰胺接枝的聚酰胺修饰的金纳米粒较单独的聚合物N-聚异丙基丙烯酰胺更适宜作为多功能药物载体:具有更接近人体生理温度的LCST值,并且具有随温度变化而发生变化的光热响应性质及温度响应的药物释放行为.因此它在难溶性药物的控制释药、光热肿瘤消融领域具有较为广阔的应用前景.     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

A new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates are enaminones, which can also be isolated, characterized, and used for the construction of other functionalized heterocycles, before they spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.     

Specific intramolecular aromatic CH insertion of diazosulfonamides

The chemoselectivity in the intramolecular CH insertion of various diazosulfonamides has been experimentally studied. The results reveal that the aliphatic 1,4-, 1,5-, or 1,6-C(sp³)?H insertions of diazosulfonamides are not accessible, while the aromatic 1,5-C(sp²)?H insertion can be realized specifically by adjusting the diazo-adjacent group. In addition, the general chemoselectivities in the intramolecular CH insertions of diazosulfonyl compounds are summarized. Generally, diazosulfones undergo both aromatic 1,5-C(sp²)?H and aliphatic 1,5- and 1,6-C(sp³)?H insertions, while diazosulfonates undergo aliphatic 1,5- and 1,6-C(sp³)?H insertions. However, diazosulfonamides only undergo aromatic 1,5-C(sp²)?H insertion.     

CoFe2O4自形成磁性液体场致结构化对磁化的影响

The Langevin paramagnetic theory can’t describe the relation between magnetization of ferrofluids and applied magnetic field. The structuralization of ferrofluids, which is considered the main influence factor of the magnetization, is regarded. The part of magnetization works is deposited when the structure is forming. This action influences the magnetization of ferrofluids directly or indirectly. On the base of the “compressing” model, the Langevin function that usually describes the magnetization of ferrofluid is modified, and a well-fitted curve is obtained. An equation of the relation between the equivalent volume fraction after being “compressed” and the intensity of magnetic field is discovered, which approximately describes the process of magnetization. The relation between the approximate initial susceptibility and the volume fraction can be obtained from modified formula.     

Highly regioselective Buchwald–Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

The highly regioselective Buchwald–Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides a facile access to 4-chloro-N-phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald–Hartwig amination at higher temperature to enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines.     

N-Heterocyclic carbene-palladacyclic complexes: synthesis,characterization and their applications in the C-N coupling and α-arylation of ketones using aryl chlorides

N-Heterocyclic carbene-palladacyclic complexes 3 were successfully achieved in a one-pot procedure under mild conditions. The structure of 3a was unambiguously confirmed by X-ray single crystal diffraction and it was an active catalyst in the Buchwald-Hartwig amination and α-arylation of ketones even at very low catalyst loadings (0.01?mol%).     

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO) using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of Fascaplysin, Eudistomins Y₁ and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for accessing 4-aryl-canthin-6-ones.     

Facile synthesis of bicyclic 1-arylpyrazol-5-ones

In this Letter, we described a facile method for constructing fused bicyclic 1-arylpyrazol-5-one ring system. We employed various methylene-containing carboxylic acids as the substrates and proved that the pyrazolone ring closure requires activated methylene group in intermediate II. Accordingly, a series of structurally diversified, fused bicyclic 1-arylpyrazol-5-ones was prepared in moderate to high yields using the requisite substrates.     

Sulfur-directed metal-free and regiospecific methyl C(sp3)–H imidation of thioanisoles

Regiospecific and direct imidation of the methyl C(sp³)–H bond of thioanisoles is realized under mild and metal-free conditions with N-fluorobis(benzenesulfonyl)imide as an oxidant and nitrogen source. Proposed mechanism suggests that thionium ion intermediates and a Pummerer-type reaction are involved. The imidation has advantages such as high step-economy, excellent functionality tolerance, and regiospecificity, giving structurally diverse imidation products.