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.

Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids

The objective of this study was to improve the dissolution and bioavailability of silymarin(SM).Solid dispersions(SDs)were prepared using solution-enhanced dispersion by supercritical fluids(SEDS)and evaluated in vitro and in vivo,compared with pure SM powder.The particle sizes,stability,and contents of residual solvent of the prepared SM-SDs with SEDS and solvent evaporation(SE)were investigated.Four polymer matrix materials were evaluated for the preparation of SM-SD-SEDS,and the hydrophilic polymer,polyvinyl pyrrolidone K17,was selected with a ratio of 1:5 between SM and the polymer.Physicochemical analyses using X-ray diffraction and differential scanning calorimetry indicated that SM was dispersed in SD in an amorphous state.The optimized SM-SD-SEDS showed no loss of SM after storage for 6 months and negligible residual solvent(ethanol)was detected using gas chromatography.In vitro drug release was increased from the SM-SDSEDS,as compared with pure SM powder or SM-SD-SE.In vivo,the area under the rat plasma SM concentration-time curve and the maximum plasma SM concentration were 2.4-fold and 1.9-fold higher,respectively,after oral administration of SM-SD-SEDS as compared with an aqueous SM suspension.These results illustrated the potential of using SEDS to prepare SM-SD,further improving the biopharmaceutical properties of this compound.

Application of hot melt extrusion to enhance the dissolution and oral bioavailability of oleanolic acid

The aim of this study was to improve the in vitro dissolution rate and oral bioavailability of oleanolic acid(OA), a water insoluble drug belonging to BCS class IV. Hot melt extrusion(HME) was applied to develop OA amorphous solid dispersions. The characterizations of the optimal formulation were performed by differential scanning calorimetry, X-ray powder diffraction, Fourier transform infrared spectroscopy and in vitro dissolution test.The in vivo pharmacokinetic study was conducted in rats. As a result, OA solid dispersion based on PVP VA 64(OA-PVP) was successfully prepared. In the dissolution medium containing 0.3% SDS, OA-PVP dramatically increased the releasing rate of OA compared with the physical mixture(PM-PVP) and commercial tablet. Furthermore, OA-PVP exhibited higher AUC(P < 0.05) and Cmax(P < 0.05) than PM-PVP and commercial tablet. The superior dissolution property and bioavailability of OA-PVP mainly attributed to the amorphous state of OA in PVP VA64 and the well dispersion caused by thermal melting and shearing. Overall, hot melt extrusion was an efficient strategy to enhance the dissolution rate and oral bioavailability of OA.

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.

Development and characterization of an atorvastatin solid dispersion formulation using skimmed milk for improved oral bioavailability

Atorvastatin has low aqueous solubility resulting in low oral bioavailability(12%)and thus presents a challenge in formulating a suitable dosage form.To improve the aqueous solubility,a solid dispersion formulation of atorvasta tin was prepared by lyophilization utilising skimmed milk as a carrier.Six different formulations were prepared with varying ratios of drug and carrier and the corresponding physical mixtures were also prepared.The formation of a solid dispersion formulation was confirmed by differential scanning ca lorimetry and X-ray diffraction studies.The optimum drug-to-carrier ratio of 1:9 en hanced solubility nearly 33-fold as compared to pure drug.In vitro drug release studies exhibited a cumulative release of 83.69% as compared to 22.7% for the pure drug.Additionally,scanning electron microscopy studies suggested the conversion of crystalline atorvastatin to an amorphous form.In a Triton-induced hyperlipidemia model,a 3-fold increase in the lipid lowering potential was obtained with the reformulated drug as compared to pure drug.These results suggest that solid dispersion of atorvastatin using skimmed milk as carrier is a promising approach for oral delivery of atorvastatin.

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.

木犀草素固体分散体的体外溶出度和体内药动学研究

目的研究木犀草素固体分散体的体外溶出度和在Beagle犬体内的药动学行为。方法按照2020年版《中国药典》(四部)“溶出度测定法”第二法(桨法)测定木犀草素固体分散体的溶出度。采用超高效液相色谱-串联质谱(UPLC-MS/MS)法测定Beagle犬血浆中木犀草素浓度。取Beagle犬12只,随机分为木犀草素原料药组和木犀草素固体分散体组,每组6只,均口服相应药物,给药剂量相当于木犀草素10 mg/kg。分别于给药前(0 h)、给药后5、10、15、30、45 min和1、2、4、6、8、10、12、24、48 h取血,用乙腈沉淀蛋白后,采用UPLC-MS/MS法测定Beagle犬体内木犀草素血药浓度。运用DAS 3.2.8药动学软件,采用非房室模型计算药动学参数。结果木犀草素固体分散体在纯水、0.1%十二烷基硫酸钠溶液中的溶出度高于木犀草素原料药,在0.1%十二烷基硫酸钠溶液中120 min的溶出度可达95%。木犀草素固体分散体组Beagle犬体内木犀草素的峰浓度(cmax)是木犀草素原料药组的5.62倍,其相对生物利用度为348%。与木犀草素原料药组比较,木犀草素固体分散体组Beagle体内木犀草素的cmax和药时曲线下面积均显著升高,表观分布容积显著降低(P<0.05)。结论木犀草素固体分散体可提高木犀草素的体外溶出度和在Beagle犬体内的生物利用度。

黄芩素固体分散体的制备、表征及体内外释药研究

【目的】改善黄芩素(baicalein,BAI)的溶解性能,提高其溶出度和生物利用度,扩大其临床应用。【方法】本研究以聚乙烯己内酰胺-聚乙烯乙酸酯-聚乙二醇接枝共聚物(Soluplus)为载体,采用旋转蒸发法制备黄芩素固体分散体(BAI-ASD),并对其进行表征,包括:利用粉末X射线衍射(PXRD)中特征衍射峰的位置、强度等信息,初步判断固体分散体是否制备成功;利用差示扫描量热(DSC)进行热性质研究;利用傅里叶红外光谱(FT-IR)分析分子间相互作用;利用扫描电子显微镜(SEM)观察微观形貌。通过溶出试验考察其体外释药性能,在此基础上考察鸡口服BAI-ASD的药动学特征。【结果】旋转蒸发法产物的PXRD中无BAI的晶体衍射峰,同时DSC中也无明显的吸热峰,表明成功制备了BAI-ASD,且BAI在ASD中以无定形态存在。体外溶出结果显示,BAI在240 min内的累积溶出仅为6.62%,药物与载体比例为1∶9和2∶8时ASD的累积溶出提高,240 min内的累积溶出分别为29.89%和52.67%。稳定性研究结果显示,BAI-ASD在45℃,75%RH条件下,90 d内稳定性良好。药动学结果显示,鸡灌胃给药24 h内BAI-ASD的峰浓度(C max(0-24))和药时曲线下面积(AUC(0-24))分别为(5.20±0.82)μg/mL和(17.03±0.67)μg·h/mL,分别为BAI的1.91和2.64倍。【结论】以Soluplus为载体利用旋转蒸发法制备的BAI-ASD稳定性良好,可有效提高BAI的累积溶出和口服生物利用度。

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。

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

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.

二氢槲皮素固体分散体片的制备及体外溶出度的研究

目的应用固体分散技术,提高二氢槲皮素及其片剂的体外溶出度。方法以PEG-4000、PEG-6000和PVP-K30为载体,采用溶剂-熔融法制备了二氢槲皮素固体分散体,考察不同载体对固体分散体溶出度的影响。同时制得二氢槲皮素固体分散体片,并着重考察了片剂的体外溶出度。结果以亲水性PVP-K30为载体制备的固体分散体能够显著的提高二氢槲皮素的体外溶出度,制成固体分散片剂后,二氢槲皮素固体分散体片的溶出度可达86.8%。结论以PVP-K30为载体的固体分散体片可提高二氢槲皮素的溶解度,制备二氢槲皮素固体分散片达到设计要求,且制法简便可行。

固体分散法增加对乙酰氨基酚生物利用度的研究

用固体分散技术可显著增加难溶性药物对乙酰氨基酚的溶出速率，选择尿素为载体，将对乙酰氨基酚制成固体分散体，进而制成片剂和栓剂，与市售片和市售栓比较，溶出速率加快，生物利用度明显提高。

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。

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

PVP对大豆苷元溶出度和生物利用度的影响(英文)

目的:考察以聚乙烯吡咯烷酮为载体制备固体分散体对大豆苷元溶解度、溶出度和生物利用度的改善。方法:溶剂法制备大豆苷元固体分散体,差示量热法、傅立叶红外、平衡溶解度法、溶出度法考察固体分散体的性质;小鼠血浆动力学比较大豆苷元固体分散体和大豆苷元的生物利用度。结果:以聚乙烯吡咯烷酮为载体的固体分散技术将大豆苷元的溶解度提高了8倍,且明显增加了其溶出度;提高了大豆苷元在小鼠血浆中的达峰浓度和曲线下面积。结论:以聚乙烯吡咯烷酮为载体的固体分散技术可提高大豆苷元在小鼠体内的生物利用度。