鲑降钙素经鼻干粉吸入剂的制备及评价

采用冷冻干燥法制备鲑降钙素生物黏附附聚物，研究表面活性剂泊洛沙姆用量对容器吸附降钙素的作用；用改进的Twin-impinger进行体外模拟试验，并测定家兔静脉和经鼻腔给药后的血钙降低情况。结果表明，当泊洛沙姆188浓度为0．25％时，具良好的抗容器吸附主药能力，与溶液型喷雾剂和胶囊干粉吹入剂相比，主动吸入的泡囊型干粉吸入剂较溶液型喷雾剂更易在具治疗意义的部位沉积；家兔试验表明，鼻腔给药后，其降血钙作用相当于静注给药的72％，达峰时间为3．5h（静注为1．5h），作用时间可持续约10h（静注约为7h）。     

壳聚糖鼻腔给药毒性研究

目的考察壳聚糖的鼻腔给药毒性。方法采用在体蟾蜍上腭法研究壳聚糖对纤毛运动的影响;采用大鼠鼻腔给药法考察壳聚糖对鼻腔粘膜形态学的影响。结果壳聚糖对蟾蜍上腭纤毛运动时间无影响;对大鼠鼻腔粘膜形态无影响。结论壳聚糖无鼻腔毒性。     

前列腺素E1经不同途径给药后的大鼠体内药效学比较

本文研究了前列腺素E₁(PGE₁)分别经不同途径给药后的大鼠体内药效学，旨在寻找目前PGE₁注射给药的替代途径。以PGE₁降压效应作为药效学指标，以静脉注射为对照，分别测定PGE₁经鼻腔、舌下、肌肉(im)、腹腔(ip)给药后的药效学参数，包括峰效应时间(Tmax)，血压下降最大百分数(Emax，%)，效应持续时间(T_d)以及血压下降百分数-时间曲线下面积(AUC，%·min)。研究结果表明，PGE₁经上述途径给药后，药效学参数Emax，T_d，AUC等均随给药剂量的增加而增大，提示存在明显的剂量-效应关系。根据所测Tmax值，推断上述给药途径其吸收速率的大小顺序为：鼻腔≈im>ip>舌下；依据所测药理生物利用度(PF)值，预测药物绝对生物利用度的顺序为：鼻腔>im≈ip>舌下。上述研究结果提示，PGE₁经鼻腔与舌下黏膜给药，有望替代目前的注射给药。     

鼻黏膜毒性研究进展

鼻腔给药在治疗疾病方面发挥着独特的作用,主要特点是鼻腔吸收迅速、生物利用度较口服给药更高,无肝脏首过效应,避免了药物的胃肠道反应,给药简便,用量少.鼻腔黏膜表面是一层假复层柱状上皮,可以分泌大量的黏液,并覆盖在纤毛上.正常情况下,纤毛协调一致的摆动,清除鼻腔内的异物.鼻腔给药首先受损的是纤毛,药物及辅料对鼻黏膜及纤毛均有毒性作用,严重者还会影响鼻腔的正常生理功能.     

吸收促进剂对人参皂苷Rg1鼻腔吸收的促进作用及鼻腔毒性

目的考察吸收促进剂对人参皂苷Rg1鼻腔黏膜的吸收促进作用以及对鼻腔黏膜毒性。方法采用大鼠在体鼻腔循环考察人参皂苷Rg1鼻腔吸收及吸收促进剂的促吸收作用，在体蟾蜍上腭纤毛法评价药物对纤毛运动的影响；考察吸收促进剂对家兔血红细胞的溶血作用、对鼻腔循环液中总蛋白和乳酸脱氢酶的影响及对鼻腔黏膜形态学的影响。结果人参皂苷Rg1鼻腔吸收必须加入吸收促进剂。各种吸收促进剂的促进作用为：1%去氧胆酸钠作用显著；1%甘草酸二钾和1%氮酮作用中等；1% Tween-80，2% β-环糊精、0.5%冰片、0.5%壳聚糖、5%羟丙-β-环糊精和0.1% EDTA等作用微弱。吸收促进剂对鼻腔黏膜毒性影响：1%去氧胆酸钠、1%氮酮和1%甘草酸二钾毒性大；1% Tween-80，2% β-环糊精及5%羟丙-β-环糊精等毒性中等；0.5%冰片、0.5%壳聚糖和0.1% EDTA毒性小。结论0.5%冰片与0.5%壳聚糖可安全有效地促进人参皂苷Rg1的鼻腔吸收。     

国产与进口鲑降钙素喷鼻剂的药效学比较

目的 观察鲑降钙素喷鼻剂的药效学作用，并与进口同类产品密钙息喷鼻剂与注射剂进行对照观察。方法 雄性SD大白鼠随机分为4组，鼻腔滴入和腹部皮下注射给药，分别于0、1、2、3、4、5h从大鼠眼静脉丛取血，测定血钙。结果 鲑降钙素喷鼻剂与进口密钙息喷鼻剂降低大鼠血钙的作用平衡而缓慢，且两者之间无显著性差异（P＞0．05），而密钙息注射剂具有明显的突释效应。结论 鲑降钙素喷鼻剂有平稳的降血钙作用，与进口密钙息喷鼻剂药效学作用一致。     

国产与进口鲑降钙素喷鼻剂的药效学比较

目的　观察鲑降钙素喷鼻剂的药效学作用 ,并与进口同类产品密钙息喷鼻剂与注射剂进行对照观察。方法　雄性SD大白鼠随机分为 4组 ,鼻腔滴入和腹部皮下注射给药 ,分别于 0、1、2、3、4、5h从大鼠眼静脉丛取血 ,测定血钙。结果　鲑降钙素喷鼻剂与进口密钙息喷鼻剂降低大鼠血钙的作用平稳而缓慢 ,且两者之间无显著性差异 (P >0 0 5 ) ,而密钙息注射剂具有明显的突释效应。结论　鲑降钙素喷鼻剂有平稳的降血钙作用 ,与进口密钙息喷鼻剂药效学作用一致     

胰岛素柔性纳米脂质体的口腔给药研究

目的探讨柔性纳米脂质体经口腔粘膜转运蛋白多肽类药物的可能性。方法用反相蒸发法制备胰岛素柔性纳米脂质体和普通脂质体,对其包封率、形态和粒径大小进行测定。以家兔为动物模型,口腔给药(bu)后,进行体内降糖实验,同时测定胰岛素水平变化。结果胰岛素柔性纳米脂质体与普通脂质体的包封率分别为(18.9±1.8)%和(22.1±2.2)%;粒径分别为(42±20) nm和(60±34) nm。透射电镜下,胰岛素柔性纳米脂质体的指纹状结构比普通脂质体更多,其他无明显区别。以sc胰岛素溶液(1 U·kg^-1)为对照,bu胰岛素柔性纳米脂质体组(10 U·kg^-1)的药理相对生物利用度为15.59%,相对生物利用度为19.78%,高于bu胰岛素溶液对照组(P<0.05)、胰岛素普通脂质体组(P<0.05)及空白柔性纳米脂质体与胰岛素混合物组(P<0.05)。结论胰岛素柔性纳米脂质体可能成为经口腔粘膜转运蛋白多肽类药物的有效载体。     

国产与进口鲑降钙素喷鼻剂的药效学比较

目的观察鲑降钙素喷鼻剂的药效学作用,并与进口同类产品密钙息喷鼻剂与注射剂进行对照观察.方法雄性SD大白鼠随机分为4组,鼻腔滴入和腹部皮下注射给药,分别于0、1、2、3、4、5h从大鼠眼静脉丛取血,测定血钙.结果鲑降钙素喷鼻剂与进口密钙息喷鼻剂降低大鼠血钙的作用平稳而缓慢,且两者之间无显著性差异(P>0.05),而密钙息注射剂具有明显的突释效应.结论鲑降钙素喷鼻剂有平稳的降血钙作用,与进口密钙息喷鼻剂药效学作用一致.     

PEG-PLA-α-细辛脑纳米粒的表征及其鼻纤毛毒性研究

目的 将α-细辛脑制备成聚乙二醇-聚乳酸-α-细辛脑纳米粒（PEG-PLA-α-细辛脑纳米粒）,考察其表面性能及鼻腔给药后的鼻纤毛毒性。方法 采用有机溶剂挥发法将α-细辛脑制备成PEG-PLA-α-细辛脑纳米粒。纳米粒度定位仪、透射电镜、差示扫描量热仪及X射线衍射法对PEG-PLA-α-细辛脑纳米粒进行表征;透析法研究PEG-PLA-α-细辛脑体外释放行为;大鼠模型考察PEG-PLA-α-细辛脑纳米粒鼻腔给药后的鼻纤毛毒性。结果 PEG-PLA-α-细辛脑纳米粒平均粒径为172.3 nm,PDI指数0.256,载药量10.70%,包封率59.36%;α-细辛脑主要以分子分散的形式存在于PEG-PLA-α-细辛脑纳米粒中;PEG-PLA-α-细辛脑纳米粒中α-细辛脑的体外释放行为符合Ritger-peppas拟合方程;PEG-PLA-α-细辛脑纳米粒鼻腔给药后对鼻纤毛无明显的毒性。结论 有机溶剂挥发法制备的PEG-PLA-α-细辛脑纳米粒可用于鼻腔给药。     

环糊精降低脱氧胆酸钠诱导的鼻纤毛毒性

目的：用环糊精改善鼻腔吸收促进剂去氧胆酸钠（SC）的鼻纤毛毒性。方法：分别用红细胞溶血实验、蟾蜍上腭模型和扫描电镜观察环糊精对SDC细胞膜破坏作用和鼻纤毛毒性的影响。SDC和β－环糊精（β－CD）之间的包合作用采用差示热分析法和X－衍射法进行验证。结果：当SDC与β－CD或二甲基－β－环糊精（DM－β－CD）的摩尔比为1：1和1：2时能完全掩盖SDC的溶血作用。用蟾蜍上腭模型评价时,加入摩尔比1:21：3的SDC与β－CD和DM－β－CD的混合液使SDC的相对纤毛持续运动时间由原来的0％提高至50％以上。大鼠鼻腔连续给予1：2摩尔比的SC－β－CD溶液一周后,扫描电镜显示粘膜纤毛无明显改变。差示热分析法和X－衍射结果显示SDC能与β－CD形成包合物。结论：加入β－CD或DM－β－CD能显著降低SDC的溶血作用和鼻纤毛毒性,两者的最佳比例是SDC与环糊精摩尔比1：2。环糊精的这种保护作用与形成包合物有关。     

Topical tolerability of salmon calcitonin assessed by mucociliary transport velocity investigation

The topical tolerability of an intranasal salmon calcitonin spray preparation, of the excipients alone and of sodium taurocholate has been studied by assessment of the mucociliary transport velocity (MTV) on the frog's palate. The rate of mucus transport was investigated in 3 groups of animals (Rana esculenta; 6 frogs per group) in basal conditions and after a challenge with a salmon calcitonin intranasal spray preparation, with the excipients and with sodium taurocholate, respectively. The salmon calcitonin intranasal spray preparation and the excipients did not affect the mucociliary transport velocity on the frog's palate. On the contrary, sodium taurocholate produced severe impairments in the mucociliary transport velocity and histological lesions of the epithelial layer of the frog's palate. The comparison among the mean values of the mucociliary transport velocity before and after treatments showed a significant difference between controls and sodium taurocholate groups (p less than 0.05) as well as among the groups treated with sodium taurocholate versus salmon calcitonin and versus the excipients alone of the calcitonin preparation (p less than 0.05). These findings provide evidence that the salmon calcitonin intranasal spray preparation tested in the present ex vivo model does not affect the mucociliary transport velocity in the frog's palate, while this is markedly affected by sodium taurocholate. The use of sodium taurocholate as a promoter of absorption in intranasal preparations should thus be reconsidered.     

阿替洛尔鼻用凝胶剂对纤毛毒性的评价

目的：评价阿替洛尔鼻用凝胶剂的纤毛毒性。方法：以在体蟾蜍上腭粘膜纤毛为材料，以纤毛持续运动时间及电镜观察为评价指标。结果：阿替洛尔凝胶剂对纤毛持续运动时间无显著影响，电镜观察亦显示纤毛排列较整齐，分布较均匀。结论：阿替洛尔凝胶可用于鼻腔给药。     

三七总皂苷鼻用凝胶喷雾剂的药动学与药效学研究

目的研究自制三七总皂苷鼻用凝胶喷雾剂的生理适应性、家兔给药后体内的药动学过程,及其对心血管疾病的保护作用。方法选用扫描电镜法,考察喷雾剂的鼻纤毛毒性;HPLC法测定三七总皂苷鼻用凝胶喷雾剂家兔鼻腔给药后血样中人参皂苷Rb1、Rg1的浓度,考察药物在体内的动力学过程,并计算药动学参数;建立大鼠急性缺血性心肌梗死模型,考察三七总皂苷鼻用凝胶喷雾剂对心脑血管疾病的保护作用。结果三七总皂苷鼻用凝胶喷雾剂给药后,Rb1、Rg1在家兔体内的过程符合二室模型,其绝对生物利用度比三七总皂苷滴鼻液高,分别为（42．31±7．54）％和（81．06±32．71）％;可大幅减少大鼠左冠状动脉闭塞所致的心肌梗死面积,且呈剂量依赖性,剂量越高,保护作用越强;该喷雾剂基本无明显鼻纤毛毒性。结论药动学、药效学及鼻纤毛毒性试验结果证明,三七总皂苷鼻腔给药制剂具有很好的开发前景。     

Intranasal salmon calcitonin. A review of its pharmacological properties and potential utility in metabolic bone disorders associated with aging.

Salmon calcitonin, a polypeptide hormone secreted by the parafollicular C cells of the thyroid gland, lowers serum calcium levels by decreasing bone resorption and renal tubular calcium reabsorption. An analgesic action, possibly mediated via beta-endorphins, is also evident. In the past, parenteral formulations of salmon calcitonin have been used in the management of metabolic bone disorders, but their routine use has been limited by the inconvenience of this route of administration and by poor tolerability. The development of an intranasal preparation of salmon calcitonin will provide a more convenient means of administering the drug. In clinical trials published to date intranasal salmon calcitonin has been effective and well tolerated in small numbers of recently postmenopausal women at risk of developing osteoporosis, and in patients with established osteoporosis, Paget's disease, or osteoporosis secondary to corticosteroid usage, multiple myeloma or ovariectomy. For periods of up to 2 years the drug reduces bone resorption and improves bone architecture, relieves pain and increases functional status. Further research is needed to confirm longer term efficacy (in particular, effects on fracture rate), optimal dosage schedules and the role of intermittent and combination treatment regimens.     

药物的鼻粘膜纤毛毒性及评价方法

提出一种新的评价方法─在体蟾蜍上腭模型,研究对乙酰氨基酚、盐酸普罗帕酮等8种药物溶液或混悬液对纤毛运动的影响,并与扫描电镜法及离体蟾蜍上腭模型比较。结果表明,在体模型简便易行,结果可靠,适用面广,是一种较理想的鼻纤毛毒性评价方法。离体模型不宜评价混悬型及粘稠性药物制剂的鼻纤毛毒性,但能进行受试药物与对照药物的同体比较,对于溶液型制剂是一种优良的评价方法。由8种药物的评价结果提示,药物对纤毛运动的影响较普遍,应予重视。     

Rapid-onset sildenafil nasal spray carried by microemulsion systems: in vitro evaluation and in vivo pharmacokinetic studies in rabbits

An oleic acid-based microemulsion system with a member of the Tween series or Cremophor EL as the surfactant and a short-chain alcohol as the cosolvent was developed for rapid-onset intranasal delivery of sildenafil. The phase behaviour and solubilization capacity of the microemulsion system were characterized, and nasal absorption of sildenafil from the microemulsion formulations was investigated in rabbits. Sildenafil displayed a high solubility of 124?mg/mL in the microemulsion consisting of 40% oleic acid, 10% H(2)O, and 50% Tween 80:ethanol (EA) (at a 1:4 weight ratio). Nasal absorption of sildenafil from this microemulsion was found to be fairly rapid. With a 10-mg dose, the onset of action was arrived instantly following intranasal administration and the duration was over 3?h using an in vivo rabbit studies. In addition, nasal ciliotoxicity studies were carried out using in vivo rat nasal mucosa model and showed no ciliotoxicity. Therefore, the prepared systems are no serious nasal ciliotoxicity for intranasal administration. The microemulsion system composed of oleic acid, Tween 80, EA, and water may be a practical approach for the rapid-onset delivery of sildenafil for the treatment of erectile dysfunction.     

Anxiety and cognitive effects of quercetin liposomes in rats

Quercetin, an effective flavonol used as an antioxidant, was investigated for its anxiolytic and cognitive activities in male Wistar rats. Oral quercetin (300 mg/kg body weight/day) was compared with oral and intranasal quercetin liposomes (20 microg/day). Quercetin liposomes, in a mixture of egg phosphatidylcholine, cholesterol, and quercetin (2:1:1) and dispersed in 50% polyethylene glycol in water, were approximately 200 nm in mean particle diameter and negative surface charge with a range of encapsulation efficiency of 60% to 80%. Anxiolytic and cognitive-enhancing effects of quercetin, conventional and liposomal, were subjected to elevated plus maze and Morris water maze tests, respectively. Both conventional and quercetin liposomes showed anxiolytic and cognitive-enhancing effects. A lower dose and a faster rate were observed with intranasal quercetin liposomes when compared with oral quercetin, conventional and liposomal. The intranasal quercetin liposomes are effective in the delivery of quercetin to the central nervous system.     

鲑鱼降钙素柔性纳米脂质体与表面活性剂的相互作用

目的：研究表面活性剂对鲑鱼降钙素柔性纳米脂质体的变形性、包封率及理化性质的影响。方法：采用薄膜分散-挤压过膜法制备脂质体并考察它们的变形性，采用葡聚糖凝胶层析法测定脂质体的包封率并用扫描电镜观察脂质体的形态。结果：表面活性剂的种类和含量对脂质体的变形性有显著影响，表面活性剂的嵌入改变了脂质体的理化性质及包封率。结论：胆酸盐能显著增强脂质体的变形性。     

N-trimethyl chitosan-modified liposomes as carriers for oral delivery of salmon calcitonin

Therapeutic peptide and protein drugs have high specificity and activity in their functions but present challenges in their administration route, requiring development of new delivery systems to improve their bioavailability. The aim of this work was to investigate the role of N-trimethyl chitosan- (TMC-) coated liposomes in the oral administration of calcitonin. TMC with a degree of quaternization around 78% was synthesized and its mucoadhesive properties were examined in vitro using the mucin-particle method, which confirmed that TMC showed mucoadhesion comparable to that of chitosan. TMC-coated liposomes containing calcitonin were prepared and characterized as having a particle size of 262 nm, zeta potential of 35.8 mV and high entrapment efficiency (89.1%). The in vivo evaluation of mucoadhesion was carried out using confocal laser microscopy to observe the residence time and permeation extent after intragastric administration. The results showed that TMC-coated liposomes prolonged the residence time and increased the penetration effect of the liposomal system compared to non-coated liposomes. The study of pharmacological effects confirmed that TMC-coated liposomes increased the area above the blood calcium concentration-time curves (AAC) from 3.13?±?20.50 to 448.84?±?103.56 compared to the calcitonin solution. These results support the feasibility of TMC-coated liposomes as a new oral delivery system for peptide and protein drugs.