The Effects of Solid and Liquid Lipids on the Physicochemical Properties of Nanostructured Lipid Carriers

The aim of this work was to identify from a review of current literature the effects of lipids used in the development of Nanostructured Lipid Carriers (NLCs) on the physicochemical properties of the resulting formulation. The size of the solid lipid, affected by the molecular weight and the complexity of the structure, tends to affect the particle size of the final formulation proportionally; the higher the molecular weight and the more complex the molecular structure, the bigger the particle size of the NLCs. However, there is no straight correlation between the size and the structure of the liquid lipid and the particle size. Moreover, there seems to be a correlation of the solid to liquid lipid ratio which affects the particle size; there has been a trend of increasing particle size when more solid lipid was used. Regarding the entrapment efficiency, it is highly affected by the drug and its interaction with the lipids, as its solubility in the lipids needs to be high so the drug can stay entrapped within the lipid core. There was no direct correlation between the type of lipid used or the ratio and the zeta potential, which affects the stability of the NLCs.     

A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pK_a value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α₁-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.     

Predicting Effect of Food on Extent of Drug Absorption Based on Physicochemical Properties

Purpose To develop a statistical model for predicting effect of food on the extent of absorption (area under the curve of time–plasma concentration profile, AUC) of drugs based on physicochemical properties. Materials and Methods Logistic regression was applied to establish the relationship between the effect of food (positive, negative or no effect) on AUC of 92 entries and physicochemical parameters, including clinical doses used in the food effect study, solubility (pH 7), dose number (dose/solubility at pH 7), calculated Log D (pH 7), polar surface area, total surface area, percent polar surface area, number of hydrogen bond donor, number of hydrogen bond acceptors, and maximum absorbable dose (MAD). Results For compounds with MAD ≥ clinical dose, the food effect can be predicted from the dose number category and Log D category, while for compounds with MAD < clinical dose, the food effect can be predicted from the dose number category alone. With cross validation, 74 out of 92 entries (80%) were predicted into the correct category. The correct predictions were 97, 79 and 68% for compounds with positive, negative and no food effect, respectively. Conclusions A logistic regression model based on dose, solubility, and permeability of compounds is developed to predict the food effect on AUC. Statistically, solubilization effect of food primarily accounted for the positive food effect on absorption while interference of food with absorption caused negative effect on absorption of compounds that are highly hydrophilic and probably with narrow window of absorption. An erratum to this article can be found at     

豆腐果苷理化常数的测定

目的:测定豆腐果苷油水分配系数、溶解度和pKa值等理化常数。方法:参照《中国药典》(2005版)相关方法测定豆腐果苷在不同水溶液及不同有机溶剂中的近似溶解度;采用电位滴定法测定豆腐果苷的pKa值;采用摇瓶法测定豆腐果苷在不同的pH下的表观油水分配系数。结果:豆腐果苷属微溶药物,且在乙醚、乙酸乙酯和氯仿等有机溶剂中几乎不溶;豆腐果苷显弱酸性,pKa值为5.65±0.13。豆腐果苷的表观油水分配系数随pH值的升高而降低,且符合logP=-0.0211pH-1.0174的函数关系。在生理条件pH7.4时,豆腐果苷表观油水分配系数为0.067。在(25±0.1)℃条件下,豆腐果苷真实油水分配系数为0.0834。结论:豆腐果苷是一种脂溶性较差的弱酸性微溶药物。     

Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s

Purpose  

Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity.     

苦杏仁苷自微乳的制备及理化性质的研究

目的 制备苦杏仁苷自微乳,并进行初步质量评价研究。方法 通过平衡溶解度的测定和伪三元相图的绘制筛选苦杏仁苷的最佳处方,并对苦杏仁苷自微乳的粒径、多分散系数、稳定性进行评价。结果 苦杏仁苷自微乳的最优处方为Peceol/MCT (1︰ 1)-乳化剂OP-1,2-丙二醇=45%︰ 40%︰ 15%,载药量为6 mg·mL^-1。所得苦杏仁苷自微乳平均粒径为(113.3±0.8) nm,多分散系数为(0.171±0.007),离心稳定性良好。结论 优选处方稳定可行,制备的苦杏仁苷自微乳粒径均匀,稳定性良好。     

pH敏感型热休克笼形蛋白纳米载体的构建及其理化性质评价

目的 设计并制备具有靶向肿瘤且pH敏感的热休克蛋白（heat shock proteins,HSP）笼形蛋白纳米递药系统,并对其理化性质进行表征。方法 采用基因全合成与蛋白质重组表达技术纯化HSP为母版,通过表面官能团功能化制备得到修饰穿膜肽Tat、聚乙二醇包衣的热休克笼形蛋白纳米载体（PT-HSP）。通过透射电镜、纳米粒度与Zeta电位测定仪对其形态、粒径及Zeta电位进行表征,并建立HPLC测定其载药量与包封率。考察载紫杉醇（paclitaxel,PTX）的PT-HSP在生理pH条件（pH 7.4）与肿瘤pH条件（pH 6.5）下的体外释药行为。结果 形态学结果表明,PT-HSP是呈现典型双层结构的均一球体,平均粒径为（154.4±23.6） nm,Zeta电位为（-2.6±0.7） mV。HPLC测得载PTX的PT-HSP的包封率为（75.3±3.6）%,载药量为（7.0±0.2）%。体外释药试验结果表明PT-HSP在pH 7.4条件下的释放速率显著慢于pH 6.5条件下的释放速率（P<0.01）。结论 本研究制备得到的pH敏感的HSP笼形蛋白智能纳米递药系统具有载药量高、稳定性强及智能靶向等优点,有望成为一种安全、有效、智能的抗肿瘤药物载体。     

Physicochemical Properties of Calcium Polycarbophil,a Water-absorbing Polymer

The physicochemical properties of calcium polycarbophil were examined. Calcium polycarbophil was decalcified rapidly under acidic conditions, affording polycarbophil. Polycarbophil absorbed about 10 times its own weight of water under acidic conditions, but the swelling ratio markedly increased at above pH 4.0 and reached 70 times the initial weight under neutral conditions. The swelling of polycarbophil was not affected by non-ionic osmolarity, but was affected by ionic strength, showing a decrease with increase of ionic strength. Monovalent metal ions such as sodium and potassium ions in gastrointestinal fluid did not reduce the equilibrium swelling of polycarbophil, but divalent ions such as calcium and magnesium ions did. However, calcium ion only slightly reduced the equilibrium swelling under sodium-rich conditions. The viscosity (as an indicator of fluidity) of polycarbophil was larger than that of CMC-Na at every shear rate and polymer content examined.     

靛玉红磷脂复合物的制备及理化性质研究

以靛玉红（1）与磷脂的复合率为指标优化了1磷脂复合物的制备工艺.对按优化工艺制得的复合物进行紫外扫描、差示扫描量热及磷核磁共振等分析,并考察了溶解性能及溶出度.结果表明,制品复合率达97.9%,可明显改善1在水和正辛醇中的表观溶解度,在1%十二烷基硫酸钠水溶液中240min溶出度达90%以上.     

基于生物指标与理化指标结合模式指导的加味甘麦大枣颗粒精制纯化工艺

目的 优选加味甘麦大枣颗粒的精制纯化工艺。方法 以药效为指标,确定制剂的精制纯化工艺路线;以甘草苷转移率为定量指标,甘草、合欢皮、地龙的薄层色谱为定性指标优选制剂的工艺参数。结果 最佳精制纯化工艺：水煎煮液浓缩至相对密度为1.10（60℃）,加乙醇至50%,搅拌速率300 r·min^-1,静置24 h。结论 制定的制剂工艺可行,保证了制剂的有效稳定。     

水翁花生药学特性及理化鉴别研究

目的 研究水翁花的生药鉴定特征.方法 应用性状、显微及理化预试验方法.结果 水翁花在原植物、性状、显微等方面具有专属性的特征.结论 实验结果为该药的鉴别、开发利用及质量标准的制订提供参考.     

重组尿酸酶部分理化性质及其初步药效学研究

产朊假丝酵母尿酸酶由基因工程菌表达，文章对重组蛋白的亚基相对分子质量、最适作用温度、最适作用pH及其热稳定性和pH稳定性等理化性质进行了考察。成功构建了小鼠高尿酸血症动物模型，并用于重组尿酸酶的初步体内药效学研究。结果：经SDS-PAGE检测重组尿酸酶亚基的表观相对分子质量为32．4k。酶的最适作用温度和pH分别为40℃和8．0，且在pH6-12，温度20℃～60℃条件下比较稳定。初步体内药效学研究结果表明，重组尿酸酶可以显著降低模型小鼠体内的血尿酸水平。     

Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment

Purpose

To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor.

Methods

Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and ?20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT.

Results

VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT.

Conclusion

VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.

     

Synthesis and Physicochemical Properties of Lipophilic Polyamide Dendrimers

Purpose. To synthesise symmetrical dendritic macromolecules with external lipid surfaces, to investigate their behaviour at the air-water interface and their ability to form supramolecular aggregates, and to gain an understanding of their potential as drug carriers. Methods. Dendrimeric compounds were synthesised with molecular weights ranging from 737 (1st generation dendrimer) to 25,246 (6th generation dendrimer) with carbon numbers ranging from 40 to 1404. The surface behaviour of these compounds was determined using spread films at the air/water interface on a Langmuir trough, and transmission electron microscopy was used to study the supramolecular aggregates formed by the more hydrophobic members of the series. Results. Dendrimers up to a maximum of 6 generations were synthesised. Surface saturation did not allow the completion of the synthesis of the 7th generation. The limiting surface areas at the air/water interface ranged from 0.4 nm² to 16.1 nm² values in good agreement with the areas derived from computer generated molecular models (0.5 nm² to 14 nm²). Conclusions. The synthesised dendrimers exhibited a linear relationship between area per molecule and the molecular weight of the compounds. A dendrimer with 16 lipoamino acid branches formed tubular supramolecular aggregates with a helical structure and dimensions in the long axis of 140–200 nm.     

Solubility and Related Physicochemical Properties of Narcotic Analgesics

The physicochemical properties of select opioid and anilinopiperidine narcotic analgesics were investigated. The solubilities of the narcotics in hexane and water and, for morphine, in other organic solvents were determined. Regular solution theory seems to be applicable to the solubility behavior of morphine in solvents that lack strong dipoles and hydrogen bonds. A best-fit solubility parameter of 13.2 (cal/cm³) for morphine was determined from its solubilities in London solvents and its ideal solubility. Calculation of morphine's solubility parameter from its hexane solubility alone and its melting properties gave a corresponding ₂ value. These measured solubility parameters were appreciably larger than the solubility parameter estimated from molar attraction constants. Solubility parameters of hydromorphone, codeine, fentanyl, and sufentanil were also calculated from respective hexane solubilities, melting points, and heats effusion and were 11.7, 10.9, 9.8, and 9.7 (cal/cm³) . For these compounds, experimental solubility parameters agreed with solubility parameters estimated from molar attraction constants. Because meperidine, fentanyl, and sufentanil exhibit low levels of intracrystalline cohesion, as reflected in low melting points and relatively modest heats of fusion, theoretically projected ideal solubilities and actual solubilities in organic solvents measured for them were considerably higher than determined for morphine and its analogues. Consistent with the solubilities, the octanol–water partition coefficients of the two 4-anilinopiperidine analogues and of meperidine were several orders of magnitude larger than those of the opioids, evidencing the fact that meperidine, fentanyl, and sufentanil are substantially more lipophilic than the opioids.     

熊去氧胆酸磷脂复合物的制备及理化性质

用溶剂法制备了熊去氧胆酸（1）磷脂复合物，并进行了粒度分布、X-射线衍射、差示扫描量热分析及不同pH体系中表观油水分配系数的测定。结果表明，1磷脂复合物在不同pH的正辛醇-水系统中，表观油-水分配系数与1及其物理混合物有较大的差异。     

间苯三酚磷脂复合物的制备工艺筛选及其理化性质研究

目的:筛选制备间苯三酚磷脂复合物的工艺并考察其磷脂复合物的理化性质。方法:以间苯三酚与磷脂的摩尔比(A)、反应温度(B)及反应时间(C)为因素,间苯三酚与磷脂的复合率为指标,通过正交试验法优化间苯三酚磷脂复合物的制备工艺,检测复合物在不同溶剂中的溶解度及油水分配系数并与原料药比较,采用紫外、红外光谱扫描验证复合物的理化性质。结果:优选工艺条件A为1∶2、B为60℃、C为2h,复合率均为98%以上。与间苯三酚原料药相比,磷脂复合物在水、氯仿中溶解度以及油水分配系数均有增大。紫外、红外光谱证实药物与磷脂未形成新的化合物。结论:优选工艺后所制复合物可显著提高药物的溶解度和亲脂性。     

银杏内酯PELGE纳米粒的制备及理化性质

采用共沉淀法制备银杏内酯PELGE纳米粒,正交试验设计优化处方,并考察了优化制品的外观和体外释放行为.结果表明,所得纳米粒外观圆整,包封率为（66.9±1.7）%,粒径为（123.3±44.0）nm,体Pb24h累积释放率为60.2%.