Cooperative effect of polyvinylpyrrolidone and HPMC E5 on dissolution and bioavailability of nimodipine solid dispersions and tablets

Solid dispersion(SD)systems have been extensively used to increase the dissolution and bioavailability of poorly water-soluble drugs.To circumvent the limitations of polyvinylpyrrolidone(PVP)dispersions,HPMC E5 was applied in the formulation process and scaling-up techniques,simultaneously.In this study,SD of nimodipine(NMP)and corresponding tablets were prepared through solvent method and fluid bed granulating one step technique,respectively.Discriminatory dissolution media were used to obtain reliable dissolution results.Meanwhile,the stability study of SDs was investigated with storage under high temperature and humidity conditions.Moreover,the solubility of SDs was measured to explore the effect of carriers.The preparations were characterized by DSC,PXRD,and FTIR.Dramatical improvements in the dissolution rate of NMP were achieved by the ingenious combination of the two polymers.Binary NMP/PVP/HPMC-SDs released steadily,while the dissolution of single NMP/PVP-SDs decreased rapidly in water.The fluid-bed tablets(FB-T)possessed a similar dissolution behavior to the commercial Nimotop TM tablets.The characterization patterns implied that NMP existed in an amorphous state in our SDs.Furthermore,the results of stability tests suggested a better stability of the binary SDs.A special cooperative effect of PVP and HPMC was discovered on dissolution characteristics of NMP SDs and tablets,which could be extended to other drugs henceforth.Finally,the bioavailability of FB-T was evaluated in beagle dogs with Nimotop TM as the reference,and the results showed a higher AUC 0–12h value for FB-T.

Solid dispersion in the development of a nimodipine delayed-release tablet formulation

Nimodipine(NMD)is a dihydropyridine calcium channel blocker with selectivity for cerebral blood vessels and the major therapeutic indication of NMD is for the prevention and treatment of delayed ischemic neurological disorders and other cerebrovascular disorders,such as stroke which is associated with biological rhythm.This study was mainly designed to solve the drawback of conventional NMD solid dosage form,low bioavailability and limited clinical efficacy,by preparing enteric solid dispersion(SD)and the SD was prepared via melting method.The physical state of the dispersed NMD in the polymer matrix was characterized by differential scanning calorimetry(DSC),powder X-ray diffraction(PXRD)and dissolution studies.Compared with pure drug and physical mixture,the dissolution of NMD-SD was enhanced dramatically(about 80%).Furthermore,in consideration of the biological rhythm of stroke,we first obtained a delayed-release tablet containing NMD-SD by a direct powder compression method.As shown in the dissolution studies,the tablet released less than 10%in the artificial gastric acid in the initial 2 h and released 32.1%,75%,more than 90%at 4,10 and 14 h respectively in the artificial intestinal fluid.This investigation has solved the problems of oral solid dosage forms of NMD,and it has the good industry prospect.

Preparation, characterization, and in vitro/vivo evaluation of polymer-assisting formulation of atorvastatin calcium based on solid dispersion technique

Due to low solubility and bioavailability, atorvastatin calcium is confronted with challenge in conceiving appropriate formulation. Solid dispersion of atorvastatin calcium was prepared through the solvent evaporation method, with Poloxamer 188 as hydrophilic carriers. This formulation was then characterized by scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction and fourier transform infrared spectroscopy. Moreover, all these studies suggested the conversion of crystalline atorvastatin calcium. In addition, the drug solubility studies as well as dissolution rates compared with bulk drug and market tablets Lipitor were also examined. Furthermore, the study investigated the pharmacokinetics after oral administration of Lipitor and solid dispersion. And the AUC 0–8 h and C max increased after taking ATC-P188 solid dispersion orally compared with that of Lipitor. All these could be demonstrated that ATC-P188 solid dispersions would be prospective means for enhancing higher oral bioavailability of ATC.

Mapping multiple phases in curcumin binary solid dispersions by fluorescence contrasting

The microphases and miscibility in binary curcumin(Cur)solid dispersions(SDs)with amorphous polyvinylpyrrolidone K30(PVP K30)and semi-crystalline poloxamer(P407)and poly(ethylene glycol)6000(PEG6000)as carriers were investigated by fluorescence contrasting utilizing confocal laser scanning microscopy.A super sensitive fluorophore P4 with typical aggregation-caused quenching properties was employed to stain the continuous polymer phases and contrasted with the autofluorescence of the model drug Cur.In addition,differential scanning calorimetry(DSC)and powder X-ray diffraction(PXRD)were utilized to assist in explanation of the fluorescence results.In all three SD systems,there is always a homogenous polymer phase stained by P4 and it is difficult to adulterate Cur crystals by P4.Cur-enriched rather than polymer-enriched domains could be detected.In the Cur-PVP K30 system,Cur exists in an amorphous form at a Cur loading level of 50%and below,while Cur crystallines phase out and continuously grow with the increase of Cur loading from 60%to 90%.The phase behaviors in the Cur-P407 and Cur-PEG 6000 systems are similar but with minor differences.In both systems,Cur phases out as clusters of drug-enriched domains at a loading level of 20%and below,which however cannot be correlated with crystallization,as evidenced by both DSC and PXRD.There is a transition from an amorphous to a crystalline state from 20%to 30%Cur loading,above which Cur crystallines can be detected.It is interesting that a co-mix phase of both Cur-and PEG 6000-enriched domains can be identified at Cur loading levels of 10%and less.Taking together,it is concluded that contrasting Cur autofluorescence with the signals of P4 proves to be a functional strategy to reveal multiple phases in the binary SD systems investigated.

Study on solubility improvement of lidocaine by ternary solid dispersion

In the present study,we aimed to probe the possibility of using mixed poloxamers as carriers to prepare ternary solid dispersion(SD)that facilitated solubility and dissolution rate of the poorly water soluble drug and compare with binary SD with single poloxamer.Lidocaine(LIC)was selected as a model drug,and poloxamer 188(P188)and poloxamer 407(P407)were utilized as single and mixed carriers.Depending on DSC and the dissolution testing,the appropriate ratio of SD prepared by melting method was optimized.Ternary and binary SD was characterized by DSC,XRD,SEM and FTIR.In vitro dissolution study,phase solubility study and saturated solubility study were performed to clarify solubilization from apparent phenomena and inherent reason.Moreover,stability study under different relative humidity(RH)was investigated.Physical characterizations of binary and ternary SD exhibited the formation of eutectic mixture and the presence of molecular interaction.Compared with the pure LIC,the dissolution rate and solubility of LIC in binary and ternary SDs were enhanced.The phase solubility study revealed an AL-type curve.Furthermore,the stability test indicated that ternary and binary SD was stable.The results of this study demonstrated that SD with mixed poloxamers could improve dissolution rate and solubility of poorly water-soluble drug.

多烯紫杉醇固体分散体的制备和体内外研究

目的优选多烯紫杉醇固体分散体的制备工艺,提高多烯紫杉醇的体外溶出度和绝对生物利用度。方法采用溶剂法制备不同载体,不同溶剂和不同药物载体比例的多烯紫杉醇固体分散体,并进行了体外溶出实验和大鼠体内生物利用度研究;同时采用XRD,DSC,ESEM法鉴别药物在固体分散体中的存在状态。结果泊洛沙姆188固体分散体对多烯紫杉醇增溶的效果优于PVPk30和单硬脂酸甘油酯;且溶出实验2h时,泊洛沙姆188固体分散体(10∶90)的累计溶出百分率接近于原料药的4倍;XRD,DSC、ESEM显示多烯紫杉醇在固体分散体中以无定型态或分子状态存在;高、低剂量大鼠口服给药的绝对生物利用度分别为10.1%和35.1%。结论固体分散体能明显提高多烯紫杉醇的体外溶出度和口服生物利用度。

尼莫地平与泊洛沙姆固体分散体的制备及其体外溶出度

采用熔融法制备尼莫地平（１）与泊洛沙姆（２）固体分散体，并测定其体外溶出度，结果均高于１原药。１与２不同比例（１∶１、１∶２、１∶３、１∶５、１∶１０）的固体分散体４５ｍｉｎ时的溶出度分别是原药的６．８、７．３、７．６、８．５、９．８倍。ＤＳＣ测定结果表明，１－２固体分散体的ＤＳＣ曲线中１原药的熔点峰消失。

尼莫地平固体分散物的研究

尼莫地平临床上主要用于防治缺血性脑血管疾病．该药为难溶性药物，生物利用度低，本文采用了固体分散技术制备了尼莫地平两种固体分散物，其体外溶出速率１０分钟以内达８０％以上，较市售片有显著提高．两种固体分散物中，固体分散物Ⅰ为本实验室研制，固体分散物Ⅱ参照国内、外文献用ＰＶＰ为载体制备．两种固体分散物均能明显提高尼莫地平的体外溶出速率，但固体分散物Ⅱ易于老化，经相对湿度ＲＨ７５％４０℃贮藏３个月溶出速率明显下降，同样条件下，固体分散物Ⅰ则无明显变化．二种固体分散物Ｘ－射线衍射图谱表明尼莫地平以非晶体状态存在，而在ＲＨ７５％４０℃条件下放置３个月后，固体分散物ⅡＸ－射线衍射图谱出现了尼莫地平结晶峰．

尼莫地平固体分散体的制备

目的 :考察水溶性联合载体在增加难溶性药物的溶出速率上是否优于单一载体 ,并制备速释型固体分散体。方法 :分别用 PEG 60 0 0、泊洛沙姆 Poloxamer 1 88及二者不同比例联合做载体制备尼莫地平与载体比为 1∶ 4的固体分散体。 X射线衍射法观察尼莫地平在分散体中的分散状态 ,并通过体外溶出试验考察其溶出速率。结果 :X射线衍射固体分散体中尼莫地平一部分呈分子状态分散 ,另一部分呈微晶状态分散。体外溶出试验中分散体的溶出速率明显快于原料药及物理混合物。结论

尼莫地平固体分散体的制备及体外研究

目的：制备尼莫地平速释型固体分散体，增加其溶解度和溶解速度。方法：以聚乙烯吡咯烷酮（ＰＶＰ）、聚乙二醇６０００（ＰＥＧ６０００）和泊洛沙姆１８８（Ｐｏｌ１８８）为载体溶剂法和溶剂熔融法制备固体分散体，差热分析和Ｘ射线粉末衍射分析鉴别药物在载体中的存在状态，并进行体外溶出度研究。结果：尼莫地平在ＰＶＰ中以无定形存在，在ＰＥＧ６０００和Ｐｏｌ１８８中以微细结晶存在。载体比例越大，药物溶出愈快；比例相同时，Ｐｏｌ１８８尼莫地平固体分散体溶出最快，且载体比例愈小，差异愈显著。结论：Ｐｏｌ１８８作为尼莫地平固体分散体的载体，载药量大，增溶效果显著。

尼莫地平固体分散物制备及物相鉴别

目的 :制备尼莫地平固体分散物 ,增加其溶解度和溶出速度。方法 :以混合辅料N为载体采用溶剂分散法制备固体分散物 ,差热分析 ,X 射线粉末衍射 ,扫描电镜和红外线光谱鉴别药物在载体中的状态 ,并进行溶出度研究。结果 :尼莫地平在载体中以分子或无定型状态存在 ,载体比例越大 ,药物溶出越快。结论 :尼莫地平

泊洛沙姆固体分散体对辛伐他汀溶出特性的影响

目的考察泊洛沙姆固体分散体对辛伐他汀体外溶出特性的影响。方法采用溶剂-熔融法制备辛伐他汀-泊洛沙姆188固体分散体,并用差示扫描量热法(DSC)、X射线粉末衍射(X-RD)和红外光谱(FTIR)考察药物在固体分散体中的存在状态,并进行体外溶出度的研究。结果药物以分子或无定形态均匀分散于载体中,药物的溶出度随载体比例的增加而增加。结论制备的辛伐他汀-泊洛沙姆188固体分散体能明显提高辛伐他汀的溶出度。

尼莫地平固体分散片的溶出度和生物利用度研究

目的：比较尼莫地平固体分散片（尼达尔）与进口尼莫地平片（Ｎｉｍｏｔｏｐ）和国产片的溶出度和生物利用度。方法：在４种溶剂系统中比较尼达尔和进口及国产片的溶出度；用ＨＰＬＣ测定８名健康受试者交叉一次ｐｏ尼达尔和Ｎｉｍｏｔｏｐ的生物利用度。结果：尼达尔的溶出性能与Ｎｉｍｏｔｏｐ相似，溶出百分率接近，明显高于国产片；以体积分数为１４．２５％的乙醇溶液为溶剂，尼达尔４５ｍｉｎ的溶出度可达８０％以上；尼莫地平在人体的血药浓度可用一室开放式模型拟合，尼达尔的相对生物利用度为进口片Ｎｉｍｏｔｏｐ的９６．３２％，两者的药动学参数相似。结论：尼达尔明显优于其它国产片，而与进口片生物等效。

番茄红素-泊洛沙姆188固体分散体的制备及溶出度和生物利用度研究

目的:采用固体分散体技术,提高番茄红素在水中的溶解度和体外溶出度,从而提高其体内的生物利用度。方法:以泊洛沙姆188为载体,溶剂法制备番茄红素固体分散体,应用光谱分析和DSC考察其分散特征,溶出度试验测定其体外溶出度,大鼠灌胃后测定其体内生物利用度,用HPLC法测定血药浓度,采用Kinetica软件计算药动学参数。结果:番茄红素可能以分子复合物状态存在于固体分散体中,且显著提高了番茄红素的溶出度,与市售番茄红素油混悬液为对照,其相对生物利用度为(312.2±96.9)%。结论:番茄红素-泊洛沙姆188固体分散体制备工艺简单,成本较低,能显著改善难溶性药物番茄红素的生物利用度,具有较好的实际应用价值。

聚乙二醇对尼莫地平溶解性能的影响

测定了尼莫地平(nimodipine,NM)在聚乙二醇(PEG)的磷酸缓冲溶液中的溶解度;用熔融法制备了NM-PEG-6000固体分散体(SD);由差热分析(DSC)和X射线衍射(XRD)分析鉴别药物在载体中的存在状态,并进行体外溶出度测定.结果表明,随PEG浓度增大,NM的溶解度增大;NM以微细结晶存在于PEG中;随着SD内PEG比例的增大,NM的释药速率明显增大,而且2h的累积溶出度也增大.因此,PEG对NM有增溶作用;NM-PEG-6000固体分散体和物理混合物可提高药物的溶出速率.

尼莫地平－聚乙二醇类固体分散物的制备及其体外溶出度的研究

尼莫地平在临床上应用较为广泛，但其生物利用度低，本文选用无生理活性的聚乙二醇（ＰＥＧ）为载体，以熔融法制备尼莫地平－ＰＥＧ固体分散物，经ＤＳＣ法和溶出度测定，认为尼莫地平与ＰＥＧ形成低共熔物，并使溶出度大大增加。方差分析结果表明，尼莫地平－ＰＥＧ固体分散物的溶出度与尼莫地平原粉溶出度之间有显著差异，固体分散物的溶出度基本上随ＰＥＧ分子量的增加而增加，尼莫地平与ＰＥＧ比例为１：９时，ＰＥＧ６０００与ＰＥＧ４０００、ＰＥＧ６０００与ＰＥＧ１００００形成的固体分散物的溶出度之间也有显著差异。

尼莫地平固体分散物的制备及其片剂溶出度的研究

目的 :提高难溶性药物尼莫地平的溶出速率。方法 :选用 PVP-k3 0 和 PEG60 0 0为载体制备了不同晶型尼莫地平固体分散物和机械混合物 ,比较了它们片剂体外的溶出速率。结果 :尼莫地平固体分散物的片剂溶出度高于机械混合物的 ,低熔点机械混合物片剂溶出度高于高熔点的 ,不同晶型尼莫地平 PEG60 0 0固体分散物片剂体外的溶出速率无显著性差异 ,低熔点尼莫地平 PVP-k3 0 固体分散物的片剂的 90 min累积溶出量比高熔点的高。结论 :不同晶型尼莫地平制备成 PVP-k3 0 和 PEG60 0

尼莫地平速释微丸及缓释微丸的制备

目的研究尼莫地平速释微丸及缓释微丸的制备方法。方法通过溶剂蒸发-沉积法制备尼莫地平速释型及缓释型固体分散体;应用挤出-滚圆技术和离心造粒技术制备尼莫地平速释微丸及缓释微丸。结果依据处方1、2、3,采用挤出-滚圆技术制得的尼莫地平缓释微丸于1、3、5、12、18h的累积溶出百分率分别为18%、34%、49%、79%、100%;12%、18%、24%、36%、51%;42%、55%、61%、90%、100%。依据处方4、5得到速释微丸于45、90 min的累积溶出百分率分别为92%、100%;80%、89%,符合速释制剂的溶出要求。由处方6、7制备的缓释微丸于1、3、5、12、18h的累积溶出百分率分别为35%、48%、53%、77%、92%;30%、40%、47%、56%、80%。结论以国家食品药品监督管理局国家药品标准WS1-(X-171)-2003Z为依据设计的尼莫地平微丸处方较理想,制备工艺简单易行,值得广泛应用于尼莫地平微丸的工业生产。

尼莫地平缓释片的制备及体外释药特性的评价

目的 :制备高效、长效的尼莫地平缓释片。方法 :正交设计法对片剂处方进行筛选与优化。将尼莫地平固体分散体与羟丙甲基纤维素等混合 ,干法直接压制缓释片 ,测定其释药特性。结果 :缓释片体外释药符合 Higuchi方程 ( r=0 .990 8)和一级动力学 ( r=0 .9940 )。处方 4的 t50 =2 .39h且可持续释药达 1 0 h以上。HPMC、乳糖、聚乙二醇 60 0 0及甲基纤维素水平的变化对释药速率均有显著影响 ( P<0 .0 1 )。结论 :制备的缓释片具有高效。

尼莫地平缓释胶囊的研究

采用固体分散技术和微晶技术相结合的方法,研究和制备了尼莫地平缓释胶囊,采用吸附工艺和常规制粒机械,解决了工业化生产周期长、制粒难等问题。体内外试验结果表明：本品缓释效果明显,生物利用度高,体内外相关性好（r=0.992）。