Inhibitive Effect of Cremophor RH40 or Tween 80-based Self-microemulsiflying Drug Delivery System on Cytochrome P450 3A Enzymes in Murine Hepatocytes

This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate.The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium.In vitro release was detected by a dialysis method in reverse.The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes.The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique.The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting.Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500.The MDZ was completely released in 10 h.A significant decrease in the formation of 1’-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed.A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250.This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.

A Novel Targeting Drug Delivery System Based on Self-Assembled Peptide Hydrogel

In the last two decades, 5-fluorouracil (5-FU) is widely used in clinical practice to inhibit the fibroblasts to proliferate and improve the success rate of glaucoma-filtering surgery, but 5-FU has many toxic effects to normal ocular tissues. The self-assembled peptide hydrogels may serve as a new class of biomaterials for applications including tissue engineering and drug delivery. How to deliver 5-FU quickly and precisely to the target sites of ocular tissue by a self-assembled peptide hydrogel remains unexplored. RGD (arginine-glycine-aspartic acid) sequence is cell attachment site in extracellular matrix (ECM). Thus, If the self-assembled peptide hydrogel containing the RGD sequence that act as a specific attachment site for the proliferated fibroblasts adhesion could be designed, after integrated 5-FU, a novel targeting drug delivery system will be put into practice in the future.

5-Fluorouracil-loaded Self-assembled pH-sensitive Nanoparticles as Novel Drug Carrier for Treatment of Malignant Tumors

In order to improve the cancer-targeting and selective activity of antineoplastic agent [5-fluorouracil (5-FU)], a novel pH-responsive drug delivery system [pullulan acetate/sulfonamide (PA/SDM) conjugate] was syn- thesized by a diafiltration method. Sulfonamide was grafted to the hydrophobically modified pullulan acetate to enhance the pH sensitivity for better cancer-targeting delivery. 5-FU was loaded into the self-assembled nanoparti- cles by the same method. The drug-loaded self-assembled nanoparticles were successfully obtained and character- ized in terms of particle size, morphology and drug loading and release profile at various pHs. The results showed that the mean diameter of the self-assembled particles was approximately 100nm, with uniform size and good spherical morphology. The nanoparticles showed good stability at pH 7.4, which is equal to that of the normal body fluid, but shrank and aggregated below pH 6.8, which is close to the pH with tumors. The loading efficiency and concentration of released 5-FU was monitored at 269 nm on the UV/Vis spectrophotometer. The release profile was heavily pH-dependent around physiological pH, and the release rate was significantly enhanced under pH of 6.8.

穿心莲内酯自微乳给药系统制备

目的制备穿心莲内酯自微乳给药系统。方法根据平衡溶解度、辅料配伍、伪三元相图确定辅料比例范围。以广藿香油占比、Labrasol ALF与Tween 80比例、Km为影响因素,平衡溶解度为评价指标,星点设计-响应面法优化处方,再进行体外评价。结果最优处方为广藿香油、Labrasol ALF、Tween 80、Transcutol HP占比10.45%、13.28%、9.82%、66.44%,平衡溶解度为(11.95±0.04)mg/g。质量参数分别为乳化时间(20.22±0.38)s,粒径(51.70±2.91)nm,多分散指数0.27±0.02,透光率(91.21±1.58)%。自微乳给药系统冻融稳定性良好,稀释倍数、分散介质对其粒径无明显影响,在磷酸盐缓冲液(pH 6.8)中溶出迅速。结论自微乳给药系统可提高穿心莲内酯溶解度、溶出速率。

皂苷表面活性剂在药物递送系统中的研究进展

皂苷是许多中药的有效成分,由于其两亲性结构,具有较高的表面活性和自组装性能,可作为天然表面活性剂。越来越多的研究发现,当药物与皂苷联用,可提高药物的溶解度或生物利用度,或产生一定的协同作用。因此,皂苷成为一种潜在的药物递送系统(DDS)载体引起了众多关注。本文综述了皂苷作为载体的分子特性、作用机理以及其在DDS中的作用及应用。

原位自组装纳米递药系统用于肿瘤免疫治疗的研究进展

目的对原位自组装纳米递药系统的构建及其在肿瘤免疫治疗中的作用机制进行综述,旨在为基于肿瘤免疫治疗的药物递送提供新的思路。方法以“原位自组装”、“免疫治疗”、“肿瘤”等检索词对国内外文献进行查阅,总结自组装纳米递药系统在肿瘤部位的构建情况,并对其增强免疫疗效的机制进行归纳。结果原位自组装纳米递药系统能够通过体外辅助靶向到达病灶部位,在疏水相互作用、静电作用、配位键等多种作用力的驱动下,触发体外刺激或体内生理病理环境刺激进而原位自组装形成新的物质。该策略能够通过增加免疫药物滞留、提高肿瘤免疫原性、促进抗原呈递细胞的成熟以及增加免疫效应细胞浸润来增强机体免疫,综合提高免疫效力。结论今后应深度挖掘原位自组装纳米药物在抗肿瘤药物递送方面的意义,促使自组装药物在肿瘤治疗方面取得更大的进展。

小分子纯药自组装递药系统用于抗肿瘤的研究进展

近年来,纳米技术在抗肿瘤小分子药物递送方面显示出巨大潜力。然而,大部分基于载体的纳米递药系统都存在载药量低、制备工艺复杂、载体具有毒性和免疫原性等问题,阻碍了纳米制剂的临床转化。自组装技术的出现为此开辟了一条新途径,其中由小分子药物自组装得到的纯药递送系统引起了研究者们的广泛关注。小分子纯药自组装递药系统制备工艺简单、载药量高、毒性低,具有可调式的分子结构,更强的药物保留性、生物相容性、可降解性以及更高的患者依从性,在抗肿瘤领域的应用愈加广泛,具有良好的临床转化前景。本综述在肿瘤治疗的背景下,梳理和介绍了小分子纯药自组装递药系统的原理、分类、制备方法(传统及新型)等方面的研究进展,并重点分析了单一纯药自组装递药系统和多药共组装递药系统在化疗、光疗、免疫治疗以及联合治疗中的最新应用进展,旨在探讨小分子纯药自组装递药系统在抗肿瘤治疗方面的发展潜力以及临床转化前景,为进一步优化小分子纯药自组装纳米递药系统并拓展其在抗肿瘤领域的应用提供研究思路。

二氢丹参酮I自微乳的制备及其肝靶向性研究

目的 构建难溶性天然活性物质二氢丹参酮I(DHI)自微乳药物递送系统(DR),以提高DHI的溶解度,并使其具备一定的被动肝靶向性。方法 以药物在其中的溶解度为指标,初步筛选出油相、乳化剂和助乳化剂种类,并通过伪三元相图的绘制和星点设计-响应面优化法筛选出DR的最佳处方,之后对DR进行形貌表征、体外释放考察、稳定性评价及肝靶向性和肠滞留性研究。结果 DR最佳处方组成为DHI 3 mg(0.1%)、中碳链三甘油酯614.4mg(20.5%)、聚氧乙烯氢化蓖麻油944.1mg(31.5%)、PEG4001438.6mg(48%)。DR在室温下为红色澄清溶液,载药量为(1.240±0.014)mg/ml,显著提高了DHI的溶解度(40 ng/ml)。DR加水后形成微乳体系,呈淡蓝色乳光,TEM透镜观察可见粒子为均一的类球形,通过粒度仪测定其粒径为(104.50±0.45)nm,多分散系数(PDI)为0.241±0.004,Zeta电位为(–10.600±0.462)m V。体外释放结果显示,与DHI原料药相比,DR的释放速度和累积释放率提高了3~4倍,不同分散介质及稀释倍数(20~1000倍)对所形成微乳体系的粒径和PDI无明显影响。室温放置3个月后,DR的外观、粒径、PDI及含量均未见明显变化,表明其稳定性良好。体内分布研究表明,DR与原料药相比表现出显著的肝靶向性和肠道滞留性。结论 DHI自微乳给药系统制备工艺简单,性质稳定,显著提高了DHI的溶解度和体外释放速率,同时具有肝靶向性和肠道滞留性,可为DR用于治疗肝脏疾病提供一定的理论依据。

自我效能教育对难治性癌痛鞘内药物输注系统治疗患者自我效能及生活质量的影响

目的探讨自我效能教育对难治性癌痛鞘内药物输注系统(IDDS)治疗患者自我效能及生活质量的影响。方法依据干预方式的不同将80例难治性癌痛IDDS治疗患者分为观察组(n=47)和对照组(n=33),对照组患者给予常规干预,观察组患者在常规干预的基础上给予自我效能教育。比较两组患者的心理状况[症状自评量表(SCL-90)]、困扰程度、自我效能、生活质量[欧洲癌症研究与治疗组织生命质量测定量表(EORTC QLQC30)]和满意度。结果干预后,两组患者SCL-90、困扰量表评分均低于本组干预前,观察组患者SCL-90、困扰量表评分均低于对照组,差异均有统计学意义(P﹤0.05)。干预后,两组患者症状管理、疾病共性管理评分均高于本组干预前,观察组患者症状管理、疾病共性管理评分均高于对照组,差异均有统计学意义(P﹤0.05)。干预后,两组患者EORTC QLQ-C30量表各领域评分均高于本组干预前,观察组患者EORTC QLQ-C30量表各领域评分均高于对照组,差异均有统计学意义(P﹤0.05)。观察组患者的总满意度为95.74%,与对照组患者的81.82%比较,差异无统计学意义(P﹥0.05)。结论自我性能教育可明显改善难治性癌痛IDDS治疗患者的心理状况,提高其自我效能和生活质量,降低困扰程度。

Self-assembled Nanoparticles based on Folic Acid Modifi ed Carboxymethyl Chitosan Conjugated with Targeting Antibody

Nanoparticles conjugated with antibody were designed as active drug delivery system to reduce the toxicity and side effects of drugs for acute myeloid leukemia（AML）.Moreover,methotrexate（MTX）was chosen as modeldrug and encapsulate within folic acid modified carboxymethylchitosan（FACMCS）nanoparticles through self-assembling.The chemicalstructure,morphology,release and targeting of nanoparticles were characterized by routine detection.It is demonstrated that the mean diameter is about 150 nm,the release rate increases with the decreasing of p H,the binding rate of CD33 antibody and FA-CMCS nanoparticles is about 5：2,and nanoparticles can effectively bind onto HL60 cells in vitro.The experimentalresults indicate that the FA-CMCS nanoparticles conjugated with antibody may be used as a potentialp Hsensitive drug delivery system with leukemic targeting properties.

Self-assembly of lipids and nanoparticles in aqueous solution:Self-consistent field simulations

Self-assembled nanostructures of lipids and nanoparticles hold great promise for applications in such fields as nanomedicine. This paper uses the self-consistent field theory to investigate the self-assembly behavior of lipid molecules and nanoparticles with different shapes in an aqueous solution. It is found that the lipid molecules can form monolayered and bilayered nanostructures around the nanopartieles with different shapes （e.g., triangular, square, hexagonal and octangular）. With decreasing the size of nanoparticles or increasing the number of polygon edges, the shape of lipid layers will approach an approximately spherical shape. These findings may help to predict and design novel drug delivery nanocarriers.

SYNTHESIS AND pH-SENSITIVE SELF-ASSEMBLY OF DENDRITIC POLY(AMIDOAMINE)-b-POLY(L-GLUTAMATE) BIOHYBRIDS

Dendritic poly(amidoamine)-b-poly(L-glutamate)(PAMAM-b-PLG) biohybrids were synthesized by the ring-opening polymerization ofγ-benzyl-L-glutamate N-carboxyanhydride monomer,followed by the deprotection of benzyl groups on poly(benzyl-L-glutamate),and were characterized by ~1H-NMR,FT-IR and gel permeation chromatography.The self-assembly behavior of the PAMAM-b-PLG biohybrid was investigated by means of UV-Vis,dynamic light scattering (DLS),transmission electronic microscopy(TEM) and ~1H-NMR.UV-Vis analysis ...

木犀草素过饱和自乳化释药系统的制备与大鼠药动学的研究

目的制备木犀草素过饱和自微乳化给药系统(luteolin supersaturation self microemulsifying drug delivery system,LUT-S-SMEDDS),以提高木犀草素的口服生物利用度。方法根据木犀草素在不同种类油相、乳化剂和助乳化剂中的溶解度、配伍相容性以及伪三元相图确定了LUT-SMEDDS的处方,并加入沉淀抑制剂制备成LUT-S-SMEDDS;评价了LUT-SMEDDS和LUT-S-SMEDDS的理化性质;比较了LUT-混悬剂、LUT-SMEDDS和LUT-S-SMEDDS经大鼠口服后体内药动学。结果选择单亚油酸甘油酯(maisine)为油相,辛酸/癸酸聚乙二醇甘油酯(labrasol)为乳化剂,二乙二醇单乙基醚(transcutol,HP)为助乳化剂,配比为体积比4∶4.5∶1.5,制备的LUT-SMEDDS和LUT-S-SMEDDS具有较强的自乳化性和分散稳定性;使用Soluplus作为沉淀抑制剂制备的LUT-S-SMEDDS可以在长时间内维持药物处于较高浓度状态;与LUT-混悬剂和LUT-SMEDDS相比,LUT-S-SMEDDS显著提高了大鼠的口服生物利用度。结论将木犀草素制备成过饱和自乳化释药系统,可加快药物溶出,抑制药物析晶,显著提高药物口服生物利用度。

叶酸修饰的苦参总黄酮固体自微乳的制备

目的 制备叶酸修饰的苦参总黄酮固体自微乳,评价其理化性质及细胞毒性。方法 以苦参酮、槐属二氢黄酮G、异黄腐醇的吸收率为指标,采用大鼠在体结肠循环试验筛选叶酸修饰的苦参总黄酮自微乳的处方;以粒径和Zeta电位为指标,单因素考察确定叶酸修饰的苦参总黄酮固体自微乳处方的吸附材料种类和用量。考察优选后的自微乳对人结肠癌细胞(HT-29细胞)的细胞毒性。结果 当叶酸-聚乙二醇-二硬脂酰磷脂酰乙醇胺与乳化剂的比值为3∶100时,能显著提高结肠组织对苦参酮、槐属二氢黄酮G、异黄腐醇的吸收(P<0.05);叶酸修饰的苦参总黄酮自微乳∶α-乳糖质量最佳比例为1∶2;制备的叶酸修饰的苦参总黄酮固体自微乳透射电镜下呈现类球的实体粒子,粒径为(38.5±1.0) nm,Zeta电位为-(32.1±1.1) mV;细胞毒性实验表明叶酸修饰的苦参总黄酮固体自微乳对HT-29细胞具有显著的抑制作用(P<0.05)。结论 该研究成功制备了叶酸修饰的苦参总黄酮固体自微乳,其对HT-29具有较好的抑制作用。

双重敏感mPEG-PDPA-P(AAm-co-AN)聚合物自组装体的药物递送

设计合成了一种新型两亲性三嵌段ABC聚合物聚乙二醇单甲醚-聚甲基丙烯酸二异丙胺基乙酯-聚(丙烯酰胺-co-丙烯腈)(mPEG-PDPA-P(AAm-co-AN))。该聚合物具有pH敏感嵌段PDPA和温度敏感嵌段P(AAm-co-AN),临界溶解温度(UCST)较高,且可以通过改变单体比例来调节UCST。在室温、中性环境下,该聚合物通过自组装形成刺激响应型胶束,可用于抗肿瘤药物的控释研究。温度升高诱导聚合物胶束向不对称囊泡结构转变,pH降低促使聚合物形成更加松散的胶束。在体外释药探究中,聚合物胶束对亲水药物阿霉素(DOX)和疏水药物槲皮素都具有良好的载药效果,在37℃、pH=7.4的条件下泄漏量低,随着温度升高和pH降低,胶束释放药物的速率和释放量明显增加。

固体自微乳药物递送系统的研究进展

作为一种新型的药物递送系统,固体自微乳药物递送系统可以显著提高水难溶性药物的口服生物利用度,且具有液态自微乳和固体制剂二者的优势。通过设计不同的辅料处方和包衣技术,可以控制药物释放使其具有靶向性,来达到不同的给药目的。固体自微乳药物递送系统的应用前景广阔,具有研究意义。本文对固体自微乳载体、固化技术、固体自微乳新制剂的应用进行了总结归纳,为提高水难溶性药物释放的固体自微乳化技术的研究提供了参考。

多替拉韦自微乳化释药系统的制备与大鼠药动学评价

目的制备多替拉韦自微乳化释药系统(DTG-SMEDDSs),并对其在大鼠体内的药动学行为进行评价。方法2021年6月至2023年3月通过测定多替拉韦(DTG)在不同种类油、乳化剂和助乳化剂中的平衡溶解度、辅料配伍相容性实验来确定DTG-SMEDDSs的处方组成,根据伪三元相图初步确定各辅料的用量范围,评价DTG-SMEDDSs的热力学稳定性以及在不同稀释倍速中的稳定性,通过透射电镜观察到DTG-SMEDDSs形成乳液的微观形态,考察DTG-SMEDDSs的体外药物溶出速率,通过大鼠口服给药比较DTG混悬剂与DTG-SMEDDSs的大鼠体内药动学特征。结果平衡溶解度和辅料配伍相容性实验确定选择单亚油酸甘油酯(Maisine)作为油相,吐温80作为乳化剂,二乙二醇单乙基醚(Transcutol HP)作为助乳化剂,其配比为30∶35∶35,制备的DTG-SMEDDSs具有良好的热力学稳定性及稀释稳定性,其自乳化形成的微乳呈类球形;DTG-SMEDDSs中的药物在10 min内基本完全溶出,其溶出速率显著快于DTG原料药;大鼠体内药动学结果显示,大鼠口服DTG-SMEDDSs后的达峰浓度(Cmax)是DTG混悬剂的2.46倍,血药浓度-时间曲线下面积(AUC(0-∞))是DTG混悬剂液的2.52倍,说明DTG-SMEDDSs可显著提高药物的达峰浓度,增加药物口服生物利用度。结论多替拉韦自微乳化释药系统,有助于药物快速溶出,显著提高了多替拉韦的口服生物利用度。

Study on the α-cyclodextrin/poly(ethylene glycol) self-assembly supramolecular nanoparticles for drug delivery

This paper reports the synthesis and drug delivery properties of a novel supramolecular nanoparticle.α-Cyclodextrins(α-CD) were threaded on cinnamic acid modified poly(ethylene glycol) to form inclusion complex nanoparticles by supramolecular self-assemble.The anti-tumor drug doxorubicin was loaded in the nanoparticles and released in vitro to study the drug release behavior and the anti-tumor effects.The structure and morphology of the nanoparticles were characterized by nuclear magnetic resonance,X-ray diffraction,ultraviolet absorbance,dynamic laser scattering,scanning electronic microscopy,transmission electron microscopy and atom force microscopy.The distribution of the drug loaded nanoparticles in cells and the anti-tumor effects were studied by confocal laser microscopy.The results demonstrate that the supramolecular nanoparticle is biocompatible and it is a promising carrier for drug delivery systems.

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

Huperzine A(Hup-A) is a poorly water-soluble drug with low oral bioavailability. A selfmicroemulsifying drug delivery system(SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion(SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve(AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension(P <0.01).The absorption rate constant(K_a) and the apparent permeability coefficient(P_(app)) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of K_a and P_(app) of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration(C_(max)) of the blocking model were significantly lower than those of the control model(P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%,respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

来那替尼自微乳的制备、表征及生物利用度研究

目的制备来那替尼自微乳并对其进行体内外质量评价。方法通过辅料溶解度和混合油相与表面活性剂相容性选择处方所用辅料;通过三元相图和星点设计-效应面法确定处方各辅料的比例;对来那替尼自微乳的粒径分布、Zeta电位、微观形态及稀释稳定性进行体外质量评价;通过比格犬体内药动学实验计算来那替尼自微乳的相对生物利用度。结果来那替尼自微乳处方:来那替尼35 mg,油酸200 mg,玉米油200 mg,RH40255 mg,Transcutol HP 345mg。来那替尼自微乳加水稀释后,平均粒径为(33.45±1.38)nm,Zeta电位为(-29.5±9.40)m V,透射电镜下为规则的球状且分布均匀,室温可保持6 h稳定。与原料药的混悬液相比,来那替尼自微乳在比格犬体内相对生物利用度为315%。结论来那替尼自微乳制剂可以显著提高生物利用度,有望成为来那替尼的新型给药制剂。