酮洛芬-聚乙烯吡咯烷酮固体分散物的制备及其体外溶出度的研究

目的提高难溶性药物酮洛芬体外溶出速度。方法以聚乙烯吡咯烷酮(PVPK30)为载体,制备药物与载体不同比例的固体分散物及物理混合物,采用X射线衍射和红外吸收方法,比较二者及药物的结晶形态,并进行体外药物溶出度的测定。结果固体分散物体外溶出速率明显高于物理混合物及酮洛芬原料的体外溶出速度,且随载体比例增加而增大。固体分散物的X射线衍射及红外吸收图谱确定了酮洛芬以无定形态分散在载体中,放置6个月后,固体分散物X射线衍射图谱没有明显变化。结论药物与载体以合适比例制备的固体分散物可以明显提高药物体外溶出速度。     

格列喹酮固体分散体的制备及溶出度测定

目的:制备格列喹酮固体分散体并考察其体外溶出性。方法:以聚乙烯吡咯烷酮K30(PVP)、聚乙二醇6000(PEG)为载体,溶剂熔融法和溶剂法制备格列喹酮固体分散体,并与原料药比较体外溶出度。结果:载体比例越大,药物溶出愈快。载体为PVP所制固体分散体的体外溶出行为总体优于载体为PEG者。格列喹酮-PVP固体分散体(1∶7)10min内体外溶出度达到70%以上,优于格列喹酮原料药。结论:成功制备了格列喹酮固体分散体。     

卡维地洛固体分散体的初步研制

目的:制备卡维地洛固体分散体并考察其体外溶出度。方法:以聚乙二醇(PEG)、聚乙烯吡咯烷酮(PVP)的混合物(2∶1、1∶2)为载体,采用溶剂熔融法和共沉淀法制备载体与药物不同比例的固体分散体并比较其体外溶出度。结果:药物溶出度随载体比例增加而增加;载体与药物比例越小,固体分散体与药物原料粉之间溶出度差异越显著;PEG∶PVP(1∶2)所制分散体体外溶出行为较优,以3、10、30、60min时溶出百分率进行比较,固体分散体是药物原料粉的3～8倍。结论:所制卡维地洛固体分散体能增加药物体外溶出度。     

Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.     

Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and d-mannitol

Aim of the present study was to improve the solubility and dissolution rate of poorly water soluble, BCS class-II drug Ketoprofen (KETO) by solid-dispersion approach. Solid dispersions were prepared by using polyvinylpyrrolidone K30 (PVP K30) and d-mannitol in different drugs to carrier ratios. Dispersions with PVP K30 were prepared by kneading and solvent evaporation techniques, whereas solid dispersions containing d-mannitol were prepared by kneading and melting techniques. These formulations were characterized in the liquid state by phase-solubility studies and in the solid state by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). The aqueous solubility of KETO was favored by the presence of both carriers. The negative values of Gibbs free energy illustrate the spontaneous transfer from pure water to the aqueous polymer environment. Solid state characterization indicated KETO was present as fine particles in d-mannitol solid dispersions and entrapped in carrier matrix of PVP K30 solid dispersions. In contrast to the very slow dissolution rate of pure KETO, dispersions of drug in carriers considerably improved the dissolution rate. This can be attributed to increased wettability and dispersibility, as well as decreased crystallinity and increase in amorphous fraction of drug. Solid dispersions prepared with PVP K30 showed the highest improvement in dissolution rate of KETO. Even physical mixtures of KETO prepared with both carriers also showed better dissolution profiles than those of pure KETO.     

卡维地洛固体分散体的制备及其体外溶出度的测定

目的 :制备卡维地洛固体分散体 ,提高其溶解度和溶速率。方法 :以聚乙烯吡咯烷酮 (PVP)、聚乙二醇 -6000(PEG -6000)为载体 ,以溶剂法和熔融法制备固体分散体 ,并进行体外溶出度研究。结果 :载体比例越大 ,药物溶出愈快 ;载体比例愈小 ,差异愈显著。载体为PVP所制固体分散体的体外溶出行为总体优于载体为PEG -6000的固体分散体。结论 :本试验所制卡维地洛固体分散体能加速体外溶出 ,提高生物利用度 ,可用于制备高效制剂     

A novel surface-attached carvedilol solid dispersion with enhanced solubility and dissolution

A novel surface-attached, spray-dried solid dispersion containing poorly water-soluble carvedilol (CV) without any change in the crystallinity was prepared using water, polyvinylpyrrolidone (PVP K30) and Tween 80. The solid dispersion was optimized by investigating the effects of the weight ratios of Tween 80/PVP K30 and carrier/drug on the aqueous solubility of CV. The optimum solid dispersion consisted of a relatively low carrier to drug weight ratio: the weight ratio of CV/PVP K30/Tween 80 was 12/4/2. Unlike conventional methods of solid dispersion preparation, this method yielded CV-loaded solid dispersion with no change in the crystallinity of the drug as was evident from SEM, DSC and XRD. It was demonstrated that the solid dispersions prepared had hydrophilic carriers attached to the surface of the drug, thus changing it from a hydrophobic to a hydrophilic form without changing the crystalline form. The optimized solid dispersion improved the drug solubility and dissolution rate by about 11,500-fold and twofold, respectively. It was further suggested that this method of solid dispersion preparation is better than conventional methods in terms of environmental and industrial standpoints. Thus, it was concluded that CV-loaded solid dispersion prepared using this method would be of use for delivering poorly water-soluble CV with enhanced solubility and dissolution, but without crystalline changes.     

马来酸罗格列酮固体分散体及其溶出速率

目的提高难溶性药物马来酸罗格列酮的体外溶出速率 ,满足脉冲制剂的设计要求。方法选用PVPK3 0为载体 ,用溶剂法制备了马来酸罗格列酮固体分散体 ,比较考察了原料药及其物理混合物和固体分散体的溶出差别 ,并通过红外光谱及X 射线粉末衍射对固体分散体进行了鉴定。结果体外溶出结果表明固体分散体能显著增加药物在水中及人工肠液中的溶出速率 ;红外光谱分析结果表明药物与载体之间没有发生化学反应 ;X 射线粉末衍射图谱表明药物以无定形状态分散于载体PVPK3 0中。结论固体分散体体外溶出速率的提高可以满足脉冲制剂的设计要求。     

阿瑞匹坦三元超饱和固体分散体的制备及性能考察

目的：为了提高难溶性药物阿瑞匹坦(Aprepitant,APR)的溶解度,解决其酸中溶出、碱中结晶沉淀的问题,选择不同功能的聚合物载体,采用热熔挤出技术制备三元固体分散体,并对其进行性能考察;方法：采用溶剂-熔融法制备二元固体分散体,以溶出度和溶出速度为指标,筛选具有增溶功能的载体材料。通过介质转移法考察各聚合物在不同浓度的药物溶液中的抑晶性能,筛选出最佳的沉淀抑制剂。确定药载比,将APR、溶出促进剂及沉淀抑制剂以不同比例混合,采用热熔挤出技术制备三元固体分散体,以溶出度和抑晶时间为指标,优选出三元固体分散体处方。经XRD确认药物在载体中的存在状态,考察该三元固体分散体在模拟肠液中的动态溶解度和加速条件下的物理稳定性。结果：亲水性聚合物PVP K30制备的二元固体分散体溶出速度快,增溶效果佳,肠溶性聚合物HPMCAS显示出优越的抑晶作用,延长了APR的过饱和点,质量比为1:1:3(APR:PVP K30:HPMCAS)的三元固体分散体在酸中迅速完全释放(120min溶出95%),相对于原料药显著提高了溶出度和溶出速率,当介质pH转为6.8后,三元固体分散体完全释放并在6h内维持溶液处于高过饱和的稳定状态,药物以无定形形式存在于载体基质中,同时能在加速条件下保持至少三个月的无定形状态。结论：基于不同聚合物的理化特性,本研究制备的三元固体分散体通过协调溶出速率和结晶抑制效果,不仅显著提高APR的溶解度,并能解决APR在胃中溶出、肠中沉淀析晶的问题,具有良好的溶出特性。     

托伐普坦固体分散体的制备及体外溶出特性考察

目的 采用固体分散技术提高难溶性药物托伐普坦的体外溶出度。方法 选用聚维酮K_29/32为载体材料,以溶剂蒸发法制备托伐普坦固体分散体。采用差示扫描量热法(DSC)、X-射线粉末衍射法(XRPD)对所得固体分散体进行鉴定, 并进行溶解度、体外溶出实验。结果 固体分散体的DSC 图谱及X-射线粉末衍射确定了托伐普坦以无定形态分散在载体中, 体外溶解实验表明其溶出较原料药、物理混合物均有明显提高。结论 将托伐普坦与PVP K_29/32制成固体分散体,其分散状态发生了改变,溶出性能明显提高。     

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8?kDa, 4?kDa and 6.5?kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug.     

尼莫地平固体分散体的研究

目的 制备尼莫地平固体分散体,增加其溶出速度.方法 应用聚乙烯吡咯烷酮（PVP）为载体,采用喷雾干燥制备尼莫地平固体分散体,通过差示扫描量热分析（DSC）和X-射线粉末衍射分析鉴别药物在载体中的存在状态,并进行了体外溶出度研究.结果 尼莫地平在载体中以分子状态存在,尼莫地平固体分散体的溶出度与尼莫地平原料药和原料药载体物理混合物相比有显著提高,载体比例越大,药物溶出越快,药物载体比例为1：3时t50仅0.972 6 min,结论聚乙烯吡咯烷酮（PVP）作为尼莫地平固体分散体的载体载药量大;喷雾干燥工艺重现性好,分散体颗粒无需粉碎可满足各类固体制剂的制备要求,是一种较理想的尼莫地平固体分散体的制备方法.     

Studies on Flash Evaporation for Preparation of Porous Solid Dispersions Using Piroxicam as a Model Drug

An amalgamation of solid dispersion and capillarity has been attempted in present study for enhancement of dissolution rate of poorly soluble drugs. Flash evaporation technique was utilized for enhancement of the dissolution rate of piroxicam. One of the major problems with this drug is its very low solubility in biological fluids, which results in poor bioavailability after oral administration. An attempt was made to enhance the dissolution rate of piroxicam by converting it into porous solid dispersion by flash evaporation method using polyvinylpyrrolidone (PVP) 40,000 as a water-soluble carrier. The resulting solid dispersions were characterized by DSC, FTIR, and X-ray diffraction. In vitro dissolution study revealed significant improvement of dissolution profile of piroxicam. The release of drug from porous solid dispersions containing PVP was superior to those of marketed product, conventional nonporous solid dispersion prepared by solvent evaporation method and drug alone. The steep increase in dissolution rate of porous form is attributable to combined effect of solid dispersion and capillarity.     

Preparation of a solid dispersion of felodipine using a solvent wetting method.

A straightforward solvent wetting method was used to prepare felodipine solid dispersions in the presence of various carriers. Dichloromethane is not needed when HPMC solid dispersions were produced using the solvent wetting method. The amount of ethanol used to prepare solid dispersions did not have a significant effect on the dissolution rate of felodipine. The results of X-ray diffraction and thermal analysis indicated that the drug was in the amorphous state when PVP, HPMC, and poloxamer were used as carriers. The dissolution rates of felodipine in PVP, HPMC, or poloxamer solid dispersions were much faster than those for the corresponding physical mixtures. However, dissolution profiles were found to depend on the carrier used; the dissolution rate of felodipine increased slowly for solid dispersions prepared using HPMC, whereas rapid initial dissolution rates were observed for solid dispersions prepared using PVP or poloxamer. Increases in dissolution rates were partly dependent on the ratios of felodipine to carrier. No significant changes in crystal form were observed by X-ray diffraction or thermal analysis, and no significant changes in dissolution rate were observed when sorbitol and mannitol were used as carriers.     

复合载体齐墩果酸固体分散体的制备及评价

目的：制备复合载体齐墩果酸固体分散体,提高齐墩果酸的溶出度。方法：采用溶剂法,以聚乙烯吡咯烷酮（PVP VA64）和聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物（Soluplus）为复合载体,制备齐墩果酸固体分散体,以累积溶出度为评价指标,考察不同载体比例,药物与载体比例,筛选最佳工艺。通过差式扫描量热法（DSC）、扫描电镜（SEM）、傅里叶红外光谱（FTIR）、粉末X 射线衍射（XRPD）等技术手段对其表征,并考察其溶出度。结果：Soluplus和PVP VA64复合载体比例为3∶2,药物与载体比例为1∶7,制备固体分散体,在45 min时累积溶出度为92.43%,DSC、SEM、XRPD、FTIR等表征结果显示药物以无定形状态存在于固体分散体中,且药物与载体之间存在氢键相互作用。结论：Soluplus和PVP VA64作为复合载体材料,联合应用可显著提高齐墩果酸的体外溶出度。     

Investigation of drug–polymer interaction in solid dispersions by vapour sorption methods

The objective of this study was to investigate the effect of different polymeric carriers in solid dispersions with an active pharmaceutical ingredient (API) on their water vapour sorption equilibria and the influence of the API–polymer interactions on the dissolution rate of the API. X-ray diffraction, scanning electron microscopy (SEM), moisture sorption analysis, infrared (IR) spectroscopy and dissolution tests were performed on various API–polymer systems (Valsartan as API with Soluplus, PVP and Eudragit polymers) after production of amorphous solid dispersions by spray drying. The interactions between the API and polymer molecules caused the water sorption isotherms of solid dispersions to deviate from those of ideal mixtures. The moisture sorption isotherms were lower in comparison with the isotherms of physical mixtures in all combinations with Soluplus and PVP. In contrast, the moisture sorption isotherms of solid dispersions containing Eudragit were significantly higher than the corresponding physical mixtures. The nature of the API–polymer interaction was explained by shifts in the characteristic bands of the IR spectra of the solid dispersions compared to the pure components. A correlation between the dissolution rate and the water sorption properties of the API–polymer systems has been established.     

Improving the solubility of ampelopsin by solid dispersions and inclusion complexes

The aim of this study was to increase the solubility of ampelopsin (AMP) in water by two systems: solid dispersions with polyethylene glycol 6000 (PEG 6000) or polyvinylpyrrolidone K-30 (PVP K30) and inclusion complexes with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of AMP with the hydrophilic polymers was evaluated by differential scanning calorimetry (DSC), Fourier transformation-infrared spectroscopy (FTIR), scanning electron microscopy (SEM). The results from DSC, FTIR and SEC analyses of solid dispersions and inclusion complexes showed that AMP might exist as an amorphous state or as a solid solution. On the other hand, the SEM images of the physical mixtures revealed that to some extent the drug was present in a crystalline form. The influence of various factors (pH, temperature, type of polymer, ration of the drug to polymer) on the solubility and dissolution rate of the drug were also evaluated. The solubility and dissolution rates of AMP were significantly increased by solid dispersions and cyclodextrin complexes as well as their physical mixtures. The improvement of solubility using polymers was in the following order: HPBCD approximately BCD>PVP K30>PEG 6000.     

Physicochemical Characterization and Dissolution Study of Solid Dispersions of Lovastatin with Polyethylene Glycol 4000 and Polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to‐carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile of Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

他克莫司固体分散体的制备及体外溶出度测定

目的:制备他克莫司固体分散体,提高他克莫司的体外溶出度。方法:以体外溶出度为指标,从泊洛沙姆188(Poloxamer188)、聚维酮K30(PVP K30)、羟丙甲纤维素(HPMCE3)、聚乙二醇6000(PEG6000)中筛选最优载体及其比例。并采用差示热量扫描(DSC)、红外光谱(FTIR)、电子扫描电镜(SEM)等进行物相表征。结果:4种不同载体制成的固体分散体均能增加他克莫司体外溶出度,通过比较优选出HPMCE3为最佳载体。物相鉴定表明,他克莫司大部分以无定型状态分散于HPMCE3中。结论:制备他克莫司-HPMCE3固体分散体可以明显提高其体外溶出度,且制备方法简单可行。     

Effect of physiochemical variables on phase solubility and dissolution behavior of indomethacin solid dispersion system

To study the influence of temperature and pH on solubility and dissolution behavior of indomethacin solid dispersions were prepared using several classes of hydrophilic carriers. Investigations on dissolution of indomethacin in binary system are reported earlier. However the phase solubility and dissolution behavior at different pH and temperature left void. The present investigation includes: phase solubility study at various pH; preparation of solid dispersion by solvent evaporation, melting and kneading method; characterization of various blends by dissolution study, and solid state studies to ensure interaction of drug with carrier. The binding between drug and carriers (PVP K30, βCD and PEG) was explained by thermodynamic parameters as calculated from phase solubility study. Indomethacin in association with PVP K30 showed very high apparent binding constant (Ka) and Gibb’s free energy change (?G) in comparison to other blends. The ternary system (drug:βCD:PVP K30, 1:5:1) showed better dissolution of about 80.97 and 99 % at pH 7.2 after 5 and 30 min respectively. At higher proportion of carrier (1:9) in binary solid dispersion of drug and PVP K30, drug dissolution was 96.23 and 97.85 % after 5 and 30 min respectively. This raised solubility of indomethacin would be helpful in designing a dosage form.