Optimization of the biphasic release of indomethacin from HPMC/pectin/calcium chloride matrix tablet by response surface methodology

We studied the effect of two independent variables, the pectin/calcium chloride weight ratio and the overall matrix weight in HPMC/pectin/calcium matrix tablet, on the release of indomethacin. A two-factor 5-level central composite experimental design was employed. Responses of the Peppas correlation parameters n and K and the 10% release time （T0.1） were optimized by response surface methodology. Significant effect of the independent variables on the biphasic release parameters, n and K, was observed. N, K and T0.1 were well fitted with the second-order quadratic equations rather than linear equations. Moreover, the mathematic fitting and the response surfaces showed significant cross-interaction between the pectin/calcium chloride ratio and the overall matrix weight. The optimal formulation with larger n, longer T0.1 and smaller K consisted of medium pectin/calcium chloride ratio around 1.0 and medium matrix weight around 200 mg. Validation studies on the optimal formulations showed good predictability of the n, K and T0.1 values with biases within the range of-7.33% and 6.26%. Our results support that central composite design can be used to optimize drug release from HPMC/pectin/calcium matrix tablet with high predictability.

Controlled Release of the Indomethacin Microencapsulation Based on Layer-by-layer Assembly by Polyelectrolyte Multilayers

Indomethacin has been encapsulated with polyelectrolyte multilayers for controlled release. Gelatin and alginate were alternatively deposited on indomethacin microcrystals. The released amount of indomethacin from coated microcrystals in pH6. 8 phosphate buffer solution （PBS） was measured with a UV spectrophometer. The polyelectrolyte multilayer capsule thickness was proved to control the release rate. The effects of osmotic pressure existed during the release process of indomethacin from microcapsules coated by （gelatin/alginate） 4.

Alginate encapsulated mesoporous silica nanospheres as a sustained drug delivery system for the poorly water-soluble drug indomethacin

We applied a combination of inorganic mesoporous silica material,frequently used as drug carriers,and a natural organic polymer alginate(ALG),to establish a sustained drug delivery system for the poorly water-soluble drug Indomethacin(IND).Mesoporous silica nanospheres(MSNs)were synthesized using an organic template method and then functionalized with aminopropyl groups through postsynthesis.After drug loading into the pores of aninopropyl functionalized MSNs(AP-MSNs),IND loaded AP-MSNs(IND-AP-MSNs)were encapsulated by ALG through the ionic interaction.The effects of surface chemical groups and ALG layer on IND release were systematically studied using scanning electron microscopy(SEM),transmission electron microscopy(TEM),nitrogen adsorption,zetapotential analysis and TGA analysis.The surface structure and surface charge changes of the ALG encapsulated AP-MSNs(ALG-AP-MSNs)were also investigated.The results showed that sustained release of IND from the designed drug delivery system was mainly due to the blockage effect from the coated ALG.We believe that this combination will help designing oral sustained drug delivery systems for poorly water-soluble drugs.

载吲哚美辛纳米纤维的制备及其促伤口愈合性能

吲哚美辛是一种非甾体抗炎药,具有解热镇痛和消炎等药理作用。然而,吲哚美辛的低水溶性、低生物利用率及其对胃肠道的刺激,严重制约了其在临床上的应用。针对上述问题,以尤特奇RS100、聚乙烯吡咯烷酮(PVP K30)为缓释基质,利用静电纺丝技术,制备了一种具有双相释放药物性能的载吲哚美辛核壳结构纳米纤维。通过正交设计实验优化的制备工艺参数为电压16.94 kV,接收距离11.02 cm,流速1.44 mL/h。该载药纳米纤维直径多分布于600~800 nm间,平均直径为(675±177)nm,形貌良好,呈现同轴结构,有利于吲哚美辛的双相释放。体外释放及初步药效学研究表明该载药纳米纤维能够持续释放25 h,仅需不到2 h即可释放出累计释放量的50%,具有速释、缓释双相释药性能,抗炎镇痛作用优良,能够有效促进伤口愈合。期望本研究能够为医用新型创伤敷料的发展提供参考。

Cupric ion release and cytotoxicity for Yuangong Cu-IUDs and the release behavior of indomethacin for medicated 220 Cu-IUD

These years Yuangong copper-bearing intrauterine devices (Cu-IUDs) have been used because of less side effects in use. The corrosion of copper is essential to the success of contraception, and the release behavior of indomethacin from medicated Cu-IUD is related to its therapeutic effect. In this study, analytical methods were established to investigate the release behavior of cupric ion of three kinds of Yuangong Cu-IUDs and indomethacin of medicated Yuangong 220 Cu-IUD. Cu-IUDs were incubated in simulated uterine solution (SUS). The concentrations of cupric ion and indomethacin were analyzed by flame atomic absorption spectrometer (FAAS) for 60 days and UV/vis ?3310 spectrophotometer for 60 days, respectively. The morphology of copper after corrosion was characterized by SEM. In addition, we detected cytotoxicity by MTT of L929 mouse fibroblasts cells caused by extracts of the three Yuangong Cu-IUDs. The release behavior of cupric ion for three kinds of Yuangong Cu-IUDs was biphasic, which consisted of the initial burst release and then slow and constant release. In vitro release experiment confirmed a biphasic release of indomethacin from Yuangong 220. The copper wire of Yuangong Cu-IUDs showed uneven corrosion. The RGR value of Yuangong 365 Cu-IUD was smaller than that of medicated Yuangong 220 Cu-IUD and RGR value of medicated Yuangong 220 Cu-IUD was smaller than that of Yuangong 300 Cu-IUD. The cupric ion release and indomethacin release showed biphasic. Indomethacin increased the cupric ion release rate and might diminish the adverse effects caused by burst release of cupric ion. The toxicity grade of these three Yuangong Cu-IUDs was 4. We should canvass the adverse events of Cu-IUDs based on practical experiments, and try our best to reduce the toxicity of Cu-IUDs.

吲哚美辛宫内节育器的主要药效学研究

本文应用放射免疫法测定吲哚美辛 IUD对离体大鼠子宫匀浆中前列腺素类物质(PGs)释放的影响 ,用光镜和电镜观察放置吲哚美辛 IUD后大鼠子宫内膜的形态学变化 ,并测定吲哚美辛 IUD在大鼠子宫内的动态释放规律。结果表明 :吲哚美辛组 PGs释放约为铜组的 1 / 5～ 1 / 1 0 (P<0 .0 5 ) ,而且吲哚美辛抑制 PGs释放的作用随药物浓度增加而增强。铜组和硅橡胶组 PGs释放均有随时间累积而增加趋势 ,而吲哚美辛组无此表现。 6KF和 TXB2 的比值 ,吲哚美辛组和硅橡胶组均 <1 (0 .6～ 0 .8) ,而铜组则均 >1 (1 .3～ 2 .1 )。组织学观察 ,铜 IUD组可见子宫内膜组织充血水肿 ,微血管以扩张为主 ,吲哚美辛 IUD组则无充血水肿表现 ,微血管以正常和收缩状态为主。吲哚美辛 IUD在大鼠子宫内药物释放量 3 d后稳定 ,释放速度稳定递减 ,符合均质型缓释规律。

吲哚美辛控释胶囊的制备及人体生物利用度

采用沸腾包衣工艺制成到吲哚美辛膜控释微丸，并用此微几制成含吲哚美辛７５ｍｇ，日服１次，可维持２４ｈ药效的控释胶囊。对大体外溶出和人体生物利用度的研究表明，控释胶囊的体外溶出符合一级动力学过程（Ｋｒ＝０．２２６６ｈ￣（－１），ｒ＝０．９９９７），体内血药浓度明显比普通胶囊平稳，持续时间长，生物利用度略高于普通胶囊，达到了预期的控释效果。控释胶囊体内吸收分数与体外累积溶出百发率之间具有显著的线性相关性（ｒ＝０．９９０１，Ｐ＜０．０１）。

吲哚美辛肠溶包衣微丸的制备及其释放度的研究

目的：制备吲哚美辛肠溶包衣微丸，考察其释放特性。方法：采用正交试验设计筛选微丸的处方、工艺参数，用滚动凝聚法制备素丸，用沸腾包衣技术制备微丸，通过溶出试验考察其释放特性。结果：以优选处方、工艺制备的微丸在规定的酸性介质中几乎不释放，而在磷酸盐缓冲液中则释放８０％以上。结论：本品处方合理，制备工艺简单，能达到肠溶目的。

再生丝素蛋白/海藻酸盐包药微胶囊的结构与释药性能

以模型药物消炎痛(吲哚美辛)作囊芯,再生丝素蛋白和海藻酸盐(FB/AG)作囊膜,在液体石蜡,Span-80的W/O型乳化体系中于50～60℃,高速搅拌下,采用复凝聚法制备包药微胶囊。采用扫描电镜(SEM)、激光粒度仪、X ray、FTIR、DSC等测定并表征了包药微胶囊的结构。结果显示,微胶囊呈近似球型,粒径为65μm左右,粒径呈正态分布,再生丝素蛋白与海藻酸盐之间具有相互作用,结晶程度提高。采用药物体外释放法测其释药性能,该包药微胶囊24h的释药率为24%,海藻酸盐微胶囊为42%,药粉为80%,FB/AG具有缓释效果。

控释吲哚美辛微囊中空栓的实验研究

本文研究了控释吲哚美辛微囊中空栓的体外溶出度及兔体内相对生物利用度。属一级动力学过程，０～１ｈ，Ｋ＝２６．７９％，２～１０ｈ，Ｋ＝１．５６％ｈ－１。体内外数据有良好的相关性（ｒ＝０．９８７３，Ｐ＜０．００１）。相对生物利用度为１１７．７５％，临床应用不良反应明显减轻。

再生丝素蛋白-壳聚糖包药微囊的质量研究

以模型药物消炎痛 (吲哚美辛 )作为芯料 ,在W /O型乳化体系中分别以复凝聚法制备再生丝素蛋白壳聚糖包药微囊和以单凝聚法制备壳聚糖包药微囊 ,测试并分析了两种微囊的形貌、粒径、成囊率、包囊率和释药率等质量指标。结果表明 ,丝素壳聚糖包药微囊的成囊率、包囊率比壳聚糖包药微囊高 ,药物缓释效果更好。

活性元宫型药铜365宫内节育器体外释放吲哚美辛的研究

目的:建立国产活性元宫型药铜365宫内节育器中吲哚美辛体外释放度测定方法。方法:以模拟宫腔液为释放介质,控制温度(37.0±0.1℃),匀速磁力搅拌,控制速度为70r/min,采用紫外分光光度法测定药物含量及释放量。结果:吲哚美辛的吸收度与浓度呈良好的线性关系,吲哚美辛的释放于d3达到平衡。结论:建立的吲哚美辛释放度测定方法简便、准确,可用于质量控制。

吲哚美辛缓释胶囊的制备及释放度研究

目的 :以壳聚糖和海藻酸钠为载体制备吲哚美辛缓释胶囊 ,考察壳聚糖对吲哚美辛的缓释作用。方法 :复凝聚法制备微囊型颗粒 ,再将颗粒装入胶囊壳制得胶囊 ;通过改变制粒时壳聚糖的浓度考察壳聚糖对吲哚美辛的缓释作用 ;用转篮法研究所制胶囊的体外释放度。结果 :壳聚糖组吲哚美辛胶囊的体外释放度较对照组降低 ,且浓度越高降低越明显。结论 :与吲哚美辛普通胶囊相比 。

吲哚美辛缓释片制备工艺及体外溶出特性的研究

目的：采用新型骨架材料甲壳胺制备吲哚辛缓释片。方法：单因素考察法考察工艺因素如压力及甲壳胺粒度对缓释作用的影响，利用正交设计优化处方。结果：甲壳胺粒度小于１５４μｍ 时，抗张强度在（４ ．０ ±１０ ．０）ｋｇ 范围内，对甲壳胺缓释作用无明显影响，当抗张强度大于１３ｋｇ ，时，药物释放明显减慢，优化后的处方可达到美国药典ⅩⅩⅡ版对缓释制剂体外溶出的要求。结论：该片剂处方合理，制备工艺简单易行，适合工业化大生产。

高效液相色谱法测定吲哚美辛控释胶囊的血药浓度和生物利用度

采用ＯＤＳ柱，甲醇－稀磷酸溶液（７６２４）为流动相，２６０ｎｍ为检测波长，建立了测定血浆中吲哚美辛浓度的高效液相色谱法，并测定了吲哚美辛控释胶囊炎痛康的血药浓度。结果表明，血浆中吲哚美辛浓度在０．１２５～５．０ｍｇ／Ｌ范围内线性关系良好（ｒ＝０．９９９６），检测限６２．５μｇ／Ｌ（Ｓ／Ｎ＝３１），平均回收率为１００．４％，日内和日间ＲＳＤ均小于５％。１１位受试者单剂量口服炎痛康后的相对生物利用度为１０２．３８％。

两种含消炎痛VCu200宫内节育器体内外释放特性比较

本文对两种类型共72只含消炎痛VCu200的消炎痛体内外释放特性作比较性研究，结果显示体外累积释放量Ⅰ型1、6、12月时各为18％、33％、39％。Ⅱ型各为31％、67％、90％。体内累积释放量Ⅰ型6、12月时各为41％、55％，Ⅱ型各为68％、93％。提示两种类型合消炎痛VCu200均能释放消炎痛，在半年内释放量较大。而且Ⅱ型的释放量及时间均大于Ⅰ型，释放性优于Ⅰ型。

α-helical CRH(9-41)与消炎痛联用对家兔内毒素性发热的解热作用

目的：观察促皮质激素释放激素（ＣＲＨ）受体拮抗剂α－ｈｅｌｉｃａｌＣＲＨ（９－４１）与消炎痛联用对家兔内毒素（ＥＴ）性发热的影响。方法：静脉给药，用ＷＲＹ－Ｂ型微机热原测温仪测定家兔的结肠温度。结果：（１）静脉注射消炎痛（５ｍｇ／ｋｇ）明显抑制家兔ＥＴ（０２μｇ／ｋｇ）性发热，５ｈ发热反应指数（ＴＲＩ５）显著降低（Ｐ＜００５）。（２）静脉注射ＥＴ（０２μｇ／ｋｇ）引起家兔体温明显双相性升高（双相热），提前５ｍｉｎ静脉注射α－ｈｅｌｉｃａｌＣＲＨ（９－４１）（２５μｇ／ｋｇ）显著抑制家兔ＥＴ性发热，且双相热第一峰消失，第二峰明显降低。（３）α－ｈｅｌｉｃａｌＣＲＨ（９－４１）与消炎痛联合用药显著抑制家兔ＥＴ性发热，其解热效果显著超过两者单独用药。半剂量消炎痛（５ｍｇ／ｋｇ）和α－ｈｅｌｉｃａｌＣＲＨ（９－４１）联用解热组与全剂量消炎痛（１０ｍｇ／ｋｇ）解热组比较，ＴＲＩ５无显著差别（Ｐ＞００５）。结论：ＣＲＨ可能参与ＥＴ性双相热的形成抑制。

载药聚乳酸纤维膜的制备及释药性能研究

将药物——消炎痛和聚乳酸(PLA)同时溶解在三氯甲烷∶丙酮(体积比2∶1)的混合溶液中,制得均匀的纺丝液,通过静电纺丝制备载药PLA纤维膜。通过扫描电镜(SEM)观察其形貌结构;通过紫外分光光度计检测其释放在磷酸缓冲溶液(PBS)中药物的吸光度,并计算其释药速率。结果表明:纤维的平均直径随着含药量的增加而减小,随着PLA质量分数的增加而增加;释药速率随着纤维直径的减小而加快;与纯药粉的释药速率相比,载药PLA纤维膜有明显的缓释性,提高了药物的利用率及安全性。

宫内节育器(Cu-IUD)体外释放Cu^2＋以及含药Cu-IUD体外释放吲哚美辛的研究

目的:比较含Cu及含消炎药IUD释放Cu2+和吲哚美辛(IMC)的释放行为。方法:通过模拟人体宫腔内环境,采用火焰原子吸收光谱仪和UV-752分光光度仪测定TCu380A IUD、MLCu375 IUD和元宫型药Cu365IUD 300d内Cu2+和320d内IMC的释放行为。结果:3种Cu-IUDs的Cu2+都呈现了双相的释放行为:初始阶段的快速释放与随后的稳定缓慢释放。元宫型药Cu365IUD的Cu2+释放为零级过程,其内IMC的体外释放结果符合Weibull方程。结论:3种型号中,元宫型药Cu365IUD中Cu2+的释放最为稳定。依据IMC的体外释放特点,可以解释含药Cu-IUD防治置IUD副作用的功能。

多波长系数法测定复方吲哚美辛栓剂溶出度

目的 :测定复方吲哚美辛栓剂 (IMC -NF -TMP)溶出度 ,选择适宜的吸收促进剂。方法 :采用多波长分光光度法 ,在选定波长处对栓剂中3种药物进行回收率及溶出度的测定。结果 :多波长系数分光光度法简便、可靠 ,不经分离可直接测定3组分的溶出度 ,数据按威布尔模型求得T50 、Td 等参数。结论 :对不同栓剂中3种药物的T50,经统计学处理 ,结果表明 ,月桂醇硫酸钠、癸酸钠对该栓剂中3种药物的体外溶出有显著的促进作用。