布地奈德灌肠用温敏性凝胶的体外释放度及局部滞留性评价

目的：考察布地奈德灌肠用温敏性凝胶的体外释放度及体内滞留性。方法：制备布地奈德温敏凝胶灌肠液，采用动态透析法和高效液相色谱法进行体外释放度研究；以新吲哚菁绿IR820为荧光标记物，昆明小鼠为受试动物，应用小动物活体成像系统检测不同时间点温敏凝胶灌肠液在小鼠体内的滞留情况。结果：含有增溶剂的布地奈德温敏凝胶灌肠液在体外能缓慢并完全地释放，体外释药曲线符合Higuchi方程，12 h释放在80%以上，普通灌肠液12 h的累积释药率不到60%；通过对新吲哚菁绿标记物观察，温敏凝胶剂在体内至少可以停留12 h，普通灌肠液体内4 h时几乎不能观察到荧光信号。结论：布地奈德温敏凝胶灌肠液可延长药物在体内的滞留时间，延缓药物释放。     

盐酸左氧氟沙星耳用温敏凝胶的制备及滞留性考察

目的:制备盐酸左氧氟沙星耳用温敏凝胶,并考察其在耳道内的滞留效果。方法:冷法制备盐酸左氧氟沙星耳用温敏凝胶,均匀设计法拟合回归方程,优化P407和P188浓度比例,采用耳道内窥镜和核磁共振成像分别从直观视觉和影像学角度考察其在兔耳道的形态与滞留时间。结果:回归方程为:y=95.6-307x(1)+141x(2),其中x(1)、x(2)分别是P407和P188浓度,选取浓度P407/P188=24%/5%制成盐酸左氧氟沙星温敏凝胶;耳道内窥镜与核磁共振表明本凝胶在兔耳道内迅速发生了相转变,粘附于耳道内,滞留时间超过8 h。结论:制备的盐酸左氧氟沙星耳用温敏凝胶能延长药物在耳道内的滞留时间,达到缓释效果,减少用药次数。     

难溶性药物美洛昔康脂质体温敏凝胶眼用制剂的研究

目的制备美洛昔康脂质体温敏型眼用凝胶剂,考察其包封率、胶凝性质、离体角膜透过性和眼部刺激性。方法采用薄膜旋蒸法制备美洛昔康脂质体,并对其包封率和理化性质等进行了测定;将美洛昔康脂质体制备成温敏型眼用凝胶制剂,通过搅拌子法,考察了其胶凝行为;采用活体成像系统对比了制剂的角膜滞留特性;采用卧式扩散池,考察了其离体角膜透过性;多次给药后裂隙灯显微镜观察角膜组织考察了其眼部刺激性。结果美洛昔康脂质体包封率可达(77.9±3.10)%,zeta电位为+(35.1±3.62)m V,平均粒径为141.9 nm。美洛昔康脂质体凝胶的胶凝温度为31.7℃。活体成像实验结果显示原位凝胶延长了药物的眼部滞留时间。离体角膜透过结果为美洛昔康脂质体凝胶的透过速率最优。眼部刺激性实验多次给药后,观察日本大耳白兔眼角膜无浑浊,虹膜和结膜未见红肿、充血、肿胀等异常现象,提示多次给药对兔眼角膜无刺激。结论采用薄膜旋蒸法制备的美洛昔康脂质体有较高的包封率,且美洛昔康脂质体温敏型眼用制剂在眼部温度下可自发形成凝胶,延长眼部滞留时间,无眼部刺激性。     

注射用姜黄素温敏凝胶在实体瘤内滞留时间的研究

目的:研究注射用姜黄素温敏凝胶在小鼠实体瘤内的滞留时间。方法:复制小鼠实体瘤模型,以亚甲蓝温敏凝胶和亚甲蓝水溶液为模型药物,直观考察温敏凝胶是否可延长滞留时间,确定所用方法的可行性。通过反相高效液相色谱法测定注射用姜黄素温敏凝胶于不同时间点时在小鼠实体瘤内的剩余量,从而确定其滞留时间,并与同浓度的注射用姜黄素混悬液对比。结果:亚甲蓝水溶液注射进入瘤体后会沿着针孔外渗,而亚甲蓝温敏凝胶无此现象。注射用姜黄素温敏凝胶在实体瘤内的滞留时间为43.02h,显著长于姜黄素混悬液的滞留时间(P<0.01)。结论:注射用姜黄素温敏凝胶在小鼠实体瘤内滞留时间较长,显示其具有一定的缓释作用。     

温敏性壳聚糖凝胶的阿霉素药物体外缓释研究

目的 壳聚糖辅以甘油磷酸钠制成温敏性凝胶，将该温敏性凝胶用作阿霉素药物栽体并观察其缓释特性。方法 制备负载阿霉素的温敏性壳聚糖凝胶，建立体外持续流动释放系统，应用紫外分光光度法测定阿霉素的含量，对该栽药凝胶进行体外的缓释实验。结果 制备了负载阿霉素的温敏性壳聚糖凝胶，并得到了其缓释曲线。结论 该温敏性凝胶能够用于负载并释放阿霉素，这为改善阿霉素使用途径提供了实验基础。     

尼古丁二元醇脂质体温敏凝胶的制备及体外评价

目的 制备尼古丁二元醇脂质体温敏凝胶,并对其进行处方筛选,优化药物的经皮转运。方法 选用温敏材料泊洛沙姆407(P407)及泊洛沙姆188(P188)为基质,尼古丁二元醇脂质体温敏凝胶用冷溶法制备,以胶凝温度为考察指标,采用单因素实验对尼古丁二元醇脂质体温敏凝胶进行处方优化;考察尼古丁乙醇溶液、二元醇脂质体及含P407/P188二元醇脂质体温敏凝胶的体外释放性质;Franz扩散池对比尼古丁二元醇脂质体和二元醇脂质体凝胶透皮量及皮内滞留量。结果 制备的温敏凝胶在室温以液体状态存在,在32℃形成凝胶。体外释放实验显示,24 h二元醇脂质体和二元醇脂质体凝胶的释放率分别是(78.60%±0.43%)、(56.36%±0.26%)。与二元醇脂质体相比,二元醇脂质体凝胶有明显的缓释作用。12 h透皮实验表明,二元醇脂质体凝胶可以增大皮内滞留量,而二元醇脂质体可以增加透皮深度。结论 与二元醇脂质体相比,二元醇脂质体温敏凝胶有明显的缓释作用,且显著增加药物的皮内滞留量。     

温敏壳聚糖凝胶共混环糊精对布洛芬的体外缓释性能

目的研究壳聚糖/甘油磷酸钠（CS/GPS）温敏性水凝胶共混β-CD包合物对药物的缓释性能。方法试管倒置法研究不同配比的CS/GPS温敏凝胶化性能;饱和水溶液法制备布洛芬/β-CD包合物,红外光谱表征包合物;紫外分光光度法测定包合物载药量和药物的累积释放度。结果体积配比5/1的2%CS/56%GPS体系（pH6.9）在37℃下可实现快速凝胶化。分别以布洛芬和布洛芬/β-CD包合物为模型药物,考察在温敏凝胶中的缓释行为,载有布洛芬凝胶24h药物累积释放度为81.5%,载有布洛芬/β-CD包合物凝胶累积释放度为69.1%。而24h布洛芬原药累积释放度为98.1%,布洛芬/β-CD包合物的累积释放度为82.2%。结论温敏性凝胶共混β-CD包合物,比单纯使用凝胶包埋药物或β-环糊精包合对药物具有更加明显缓释效果。CS/GPS凝胶体系有望作为温度敏感性给药系统的理想载体。     

聚N-异丙基丙烯酰胺类温敏凝胶的制备及其对萘普生钠的缓释作用

目的：制备聚N-异丙基丙烯酰胺类的两种温敏凝胶：聚N-异丙基丙烯酰胺均聚水凝胶和N-异丙基丙烯酰胺-甲基丙烯酰胺共聚水凝胶，并考察其性质和对萘普生钠的缓释作用。方法：在氮气保护下制备两种水凝胶，测定和比较交联剂和甲基丙烯酰胺含量对凝胶溶胀度及临界相转变温度的影响。并以两种水凝胶为载体，在模拟人体肠液环境下进行萘普生钠的体外释放实验。结果和结论：交联剂用量增大时，凝胶溶胀度下降；甲基丙烯酰胺含量增加时，共聚水凝胶溶胀度增加，临界相转变温度提高。亲水性共聚水凝胶对药物的释放稳定持久，释药量大，具缓释作用。     

阿昔洛韦温敏凝胶的制备及评价

目的制备阿昔洛韦温敏凝胶,对其理化特性和使用效果进行初步评价。方法以泊洛沙姆407为凝胶基质,制备阿昔洛韦温敏凝胶剂。采用试管倒置法研究相变行为。采用紫外分光光度法测定含量,采用Franz扩散池法考察体外释药行为,家兔皮肤局部使用初步评价胶凝效果和刺激性。结果制得阿昔洛韦温敏凝胶外观均一透明,胶凝温度约27℃,相变可逆,含主药(2.86±0.02)%,体外缓释6 h,符合一级释药特性。家兔皮肤局部使用证明其分散性良好,胶凝时间为(10±1)s,药物滞留量约为溶液剂的6倍,且无皮肤刺激性。结论制得阿昔洛韦温敏凝胶剂,质量评价结果良好。     

氟比洛芬阳离子脂质体温敏凝胶滴眼剂的眼部刺激性和药效学

目的制备氟比洛芬阳离子脂质体温敏凝胶滴眼剂(flurbiprofen cationic liposome thermo-sensitive hydrogel,FCLTH),考察其包封率、胶凝性质、眼部刺激性和药效作用。方法采用乙醇注入-超声法制备氟比洛芬阳离子脂质体,并对其包封率和理化性质等进行了测定。将氟比洛芬阳离子脂质体制备成温敏凝胶滴眼液,考察了FCLTH的胶凝行为、眼部刺激性和药效学。结果氟比洛芬阳离子脂质体包封率可达(84.9±2.75)%,zeta电位为(+33.4±9.68)mV,平均粒径(136±2.98)nm。FCLTH胶凝温度为31.9℃。眼部刺激性实验多次给药后,裂隙灯显微镜观察新西兰兔眼角膜无混浊,虹膜和结膜未见红肿、充血、肿胀等异常现象。组织病理学检查显示,新西兰兔眼7天多次给药后,与空白溶剂相比,给药组组织病理学改变无明显差异。药效学结果显示,FCLTH相对于氟比洛芬滴眼剂对新西兰兔眼急性炎症有抑制作用更强。结论采用乙醇注入-超声法制备的氟比洛芬阳离子脂质体有较高的包封率,且FCLTH在眼部温度下自发形成凝胶,无眼部刺激性,并能够有效抑制眼部炎症作用。     

用于关节腔注射的马钱子碱壳聚糖温敏凝胶的研究

利用壳聚糖-甘油-饱和硼砂溶液为主要材料构建一种用于关节腔注射、具有缓释作用的壳聚糖反相温敏水凝胶系统,并对其理化性质和生物相容性进行初步研究。以凝胶的形成和胶凝时间为指标,考察壳聚糖浓度、壳聚糖与甘油的比例、pH值等因素对水凝胶理化性质的影响,并对其体外释放行为、流变学、生物相容性等特性进行表征。温敏凝胶在常温下为溶胶态,当处于37℃时转变为凝胶态,并具有一定的缓释效果,生物相容性较高。     

Intra-articular lornoxicam loaded PLGA microspheres: enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis

The aim of this study was to investigate the joint tissue distribution and pharmacodynamics of Lornoxicam (Lnxc) following intra-articular injection of either Lnxc suspensions or sustained release Lnxc-loaded PLGA microspheres (Lnxc-MS), as well as the biocompatibility of PLGA microspheres with or without drugs. In this study, Lnxc suspensions or Lnxc-loaded PLGA microspheres was injected into the knee joint cavity of rats. Blood samples were taken at predetermined times from the jugular vein and the joint tissue (cartilage and synovial membrane) were removed from the rats. Biocompatibility and pharmacodynamics were evaluated by observing the swelling of the joints of the rats and histological analysis following the injection of the microspheres. The plasma drug concentration decreased in rats and retention time increased in rats' joint with intra-articular injections of microspheres, revealing good targeting efficiency and decreased systemic toxicity. After 30 days of intra-articular injection with Lnxc-loaded or blank microspheres, the filtration liquid accumulation, blood vessels and fibrous proliferation were not detected, showing their good compatibility. Furthermore, the articular cartilage damage by papain could also be repaired by the Lnxc-loaded PLGA microspheres. In conclusion, intra-articular Lnxc-MS have considerable potential for creating a sustained release Lnxc delivery system and providing effective healing to Osteoarthritis.     

Intra-articular lornoxicam loaded PLGA microspheres: enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis

The aim of this study was to investigate the joint tissue distribution and pharmacodynamics of Lornoxicam (Lnxc) following intra-articular injection of either Lnxc suspensions or sustained release Lnxc-loaded PLGA microspheres (Lnxc-MS), as well as the biocompatibility of PLGA microspheres with or without drugs. In this study, Lnxc suspensions or Lnxc-loaded PLGA microspheres was injected into the knee joint cavity of rats. Blood samples were taken at predetermined times from the jugular vein and the joint tissue (cartilage and synovial membrane) were removed from the rats. Biocompatibility and pharmacodynamics were evaluated by observing the swelling of the joints of the rats and histological analysis following the injection of the microspheres. The plasma drug concentration decreased in rats and retention time increased in rats’ joint with intra-articular injections of microspheres, revealing good targeting efficiency and decreased systemic toxicity. After 30 days of intra-articular injection with Lnxc-loaded or blank microspheres, the filtration liquid accumulation, blood vessels and fibrous proliferation were not detected, showing their good compatibility. Furthermore, the articular cartilage damage by papain could also be repaired by the Lnxc-loaded PLGA microspheres. In conclusion, intra-articular Lnxc-MS have considerable potential for creating a sustained release Lnxc delivery system and providing effective healing to Osteoarthritis.     

Bone mesenchymal stem cell-derived exosomes involved co-delivery and synergism effect with icariin via mussel-inspired multifunctional hydrogel for cartilage protection

Mesenchymal stem cells (MSC) are particularly effective in promoting cartilage regeneration due to their immunomodulatory, anti-inflammatory and regenerative repair functions of tissues and organs. Meanwhile, the intra-articular delivery and synergy with other therapeutic drugs have been the key issues driving their further application. We report a mussel-inspired multifunctional hydrogel system, which could achieve co-delivery and synergism effect of MSC-derived exosomes (Exos) with icariin (ICA). The ICA and Exos co-delivered articular cavity injection system are expected to retain in the joint cavity and promote cartilage regeneration, due to the thermosensitive, self-healing and adhesion properties of the mussel-inspired multifunctional hydrogel. The experimental results proved that Exos enhanced the cellular uptake of ICA by more than 2-fold evenly, and the synergism of Exos and ICA efficiently improve the cell proliferation and migration. After synergic treatment, the content of matrix metalloproteinase 13 in the supernatant and intracellular decreased by 47% and 59%, respectively. In vivo study, ICA-loaded Exos exhibited prolonged retention behavior by multifunctional hydrogel delivery, thus displayed an increased cartilage protection. In the model of osteoarthritis, co-delivery hydrogel system relieved the cartilage recession, ensuring appropriate cartilage thickness.     

羧甲基壳聚糖温敏凝胶对小鼠L929细胞增殖的影响及其生物相容性研究

目的：自制羧甲基壳聚糖温敏凝胶,研究其对L929细胞增殖的影响并且通过动物实验探讨其组织相容性,为进一步的临床应用提供基础实验依据。方法：用羧甲基壳聚糖与甘油磷酸盐互配, 制备羧甲基壳聚糖温敏凝胶。采用MTT法测定不同浓度的凝胶浸提液对体外培养的L929细胞增殖的影响;将凝胶植入小鼠皮下,然后分别在3、7、14天处死,常规组织切片,HE染色观察凝胶周围组织的炎症反应。结果：培养24h后,各浓度浸提液组对L929细胞的增殖均有一定促进作用,在48h、72h、96h时,各实验组都较阴性及阳性对照组显示出较明显的促进细胞增殖作用,其中0.4倍浸提液组促增殖效果最明显（P＜0.05）;凝胶植入后前3d,实验组以急性炎症为主,随着时间的延长各实验组炎症细胞逐渐减少至消失,说明羧甲基温敏凝胶具有很好的组织相容性。结论：羧甲基壳聚糖温敏凝胶对L929细胞有明显的促进作用且具有良好的组织相容性,在牙周病治疗中具有潜在的应用价值。     

The antitumor effect of a thermosensitive polymeric hydrogel containing paclitaxel in a peritoneal carcinomatosis model

The prognosis of peritoneal carcinomatosis is regarded as poor because safe, effective therapeutic modalities are lacking. Intraperitoneal chemotherapy is one treatment option, involving the delivery of a high concentration of chemotherapeutic drugs into the abdominal cavity, but the severe side effects associated with such treatment are a major obstacle in clinical application. We evaluated the anti-cancer effects of intraperitoneal delivery of a thermosensitive polymeric hydrogel containing chemotherapeutics in an animal model of carcinomatosis. The progress of peritoneal carcinomatosis, introduced by injecting a luciferase-transfected human gastric cancer cell line (HSC44Luc) into the peritoneal cavity of nude mice, was quantitatively evaluated by in vivo bioluminescence imaging. Three days after intraperitoneal (IP) injection of HSC44Luc cells, treatment solutions were injected into the peritoneal cavity. Mice were categorized into four groups depending on treatment method; these were (1) a control PBS group (n = 5), (2) a hydrogel-only group (n = 5), (3) a paclitaxel solution (30 mg/kg) group (n = 3), and (4) a hydrogel-with-paclitaxel (15 mg/kg) group (n = 5). Quantitative photon counting was performed weekly in each animal. Mice were sacrificed on the 5th or 28th day after treatment, for pathologic evaluation. In vivo bioluminescence imaging showed that photon counts in the hydrogel-with-paclitaxel and paclitaxel solution groups were significantly lower than in the PBS group over the entire experimental period. Although neither group of responding mice showed any peritoneal nodules on the 28th day after treatment, only the paclitaxel solution group exhibited dilated edematous changes in the intestine; these side effects were absent in animals treated with hydrogel-with-paclitaxel group. In conclusion, a thermosensitive hydrogel containing paclitaxel may be a safe and effective treatment option for peritoneal carcinomatosis.     

壳聚糖季铵盐温敏凝胶的制备及性能考察

目的 研究壳聚糖季铵盐温敏凝胶及性质.方法 采用试管倾斜法测定胶凝时间,考察壳聚糖季铵盐的浓度、体积比、温度等对胶凝时间的影响,采用吸光度经时变化法测定相变动力学,并用透析法测定载药凝胶的体外释放.结果 56％ GPS/2％ HTCC体积配比1:5、温度37℃时,胶凝时间为3.53min,钙黄绿素载药凝胶具有良好的缓释...     

Sustained Intravesical Drug Delivery Using Thermosensitive Hydrogel

PURPOSE: Direct instillation of drug solutions into the bladder through a urethral catheter (i.e., intravesical therapy) evades systemic adverse effects of drugs used for bladder diseases. However, conventional vehicles for these drugs fail to extend duration of drug exposure in the bladder beyond the first voiding of urine postinstillation. The current study seeks to overcome the aforementioned inherent limitation of intravesical drug administration by using thermosensitive hydrogel as a matrix for sustained intravesical drug delivery. METHODS: Under halothane anesthesia, normal adult female Sprague-Dawley rats were catheterized with PE-50 tubing to instill either 0.02% w/v solution of fluorescein isothiocyanate (FITC) or the same amount of FITC in a 30% w/v dispersion of thermosensitive [Poly(ethylene glycol)-Poly[lactic acid-co-glycolic acid]-Poly(ethylene glycol)) (PEG-PLGA-PEG) polymer in a 0.1 M phosphate buffer. After instillations, rats were kept in metabolic cages for urine collection. Fluorescence emanating from FITC was measured in the urine at various time points up to 24 h after instillation. A rat model of cyclophosphamide-induced cystitis was chosen for the efficacy study using misoprostol as a model drug entrapped in the thermosensitive hydrogel in place of FITC. Efficacy of hydrogel containing misoprostol was compared against rat groups instilled with saline, hydrogel, and misoprostol independently. RESULTS: Prolonged drug exposure to the bladder afforded by hydrogel was evident from the time course of FITC elimination in the urine and by the green fluorescence of FITC seen at the bladder surface when isolated 24 h after instillation. Rats instilled with free FITC voided almost all of the fluorescence in the urine within the first 8 h, whereas rats instilled with hydrogel encapsulated FITC showed sustained release up to 24 h after instillation. Using a cyclophosphamide-induced cystitis model, rats instilled with misoprostol, a synthetic PGE1 analog, showed significantly reduced frequency of urine voiding (p < 0.05) as compared to the rats instilled with saline. Histological examination of the urothelium showed near normal morphology in rats instilled with misoprostol in hydrogel, whereas extensive tissue damage was observed in rats instilled with saline. CONCLUSION: Our study showed that PEG-PLGA-PEG polymer could be used as a viable sustained drug delivery system for intravesical therapy of diseases of the bladder such as cystitis using misoprostol.