联苯双酯制剂的物理分散状态及体外释放度

用X-射线衍射法,考察不同载体制备的固体分散体系中联笨双酯的物理分散状态,聚乙二醇6000(PEG 6000)固体分散系为有限互溶固体溶液,聚乙烯吡咯烷酮(PVP)共沉淀物为无定形粉末,脲共熔物为简单低共熔混合物,热分析研究亦证实PEG 6000固体分散物较其相应比例的物理混合物及片剂有更高的分散度。比较两种联苯双酯片剂与滴丸的体外释放度,两种片剂的释放度参数td值分别为37和178min,滴丸未包衣者为11min,包衣者为26.in。由此可知物理分散状态是影响释放速度的主要因素。     

联苯双酯制剂的物理分散状态及体外释放度

用X-射线衍射法,考察不同载体制备的固体分散体系中联笨双酯的物理分散状态,聚乙二醇6000(PEG 6000)固体分散系为有限互溶固体溶液,聚乙烯吡咯烷酮(PVP)共沉淀物为无定形粉末,脲共熔物为简单低共熔混合物,热分析研究亦证实PEG 6000固体分散物较其相应比例的物理混合物及片剂有更高的分散度。比较两种联苯双酯片剂与滴丸的体外释放度,两种片剂的释放度参数td值分别为37和178min,滴丸未包衣者为11min,包衣者为26.in。由此可知物理分散状态是影响释放速度的主要因素。     

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－k30和PEG6000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PEG6000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PVK－k30固体分散物的片剂的90min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-k30和PEG6000固体分散物都可以提高其片剂体外的溶出度。     

溶剂沉积法制备联苯双酯共沉淀物及其性能考察

本文采用溶剂沉积法制备了联苯双酯-PVP-增量物(buking substance)的共沉淀物。DTA分析表明,联苯双酯以非晶态存在于共沉淀物中。体外溶出实验指出,实验所用不同比例的PVP对溶出速度无明显影响(P>0.05),但溶剂不同,其共沉淀物的溶出速度有显著差异(P<0.05),共沉淀物溶出速度较纯药提高5倍。对由CCl_4引起小鼠SGPT升高的抑制作用,共沉淀物用量不到纯药的1/6,其抑制作用还显著地大于纯药(P<0.01).稳定性实验结果可见,本品具有较好的抗湿作用。     

硝酸异山梨酯固体分散体的制备及其体外溶出特性研究

目的采用固体分散技术,提高硝酸异山梨酯在水中的溶解度和体外溶出速率.方法以聚乙二醇6000(PEG6000)为载体,熔融法制备硝酸异山梨酯的固体分散体.考察其体外特性,并采用X-射线粉末衍射、差示扫描量热法(DSC)和红外光谱法鉴别药物在固体分散体中的存在状态.结果固体分散体能加快药物的溶出速率,最佳比例为1∶7.硝酸异山梨酯在PEG6000的固体分散体中以微细结晶存在.结论硝酸异山梨酯-PEG6000(1∶7)固体分散体增加硝酸异山梨酯溶出度的效果显著.     

甲苯磺丁脲固体分散物的X线衍射研究

用X线衍射(XRD)对甲苯磺了脲(D860)与脲、聚乙烯吡咯烷酮(PVP)和聚乙烯二醇6000(PEG 6000)的固体分散物进行较详细的研究,并与它们的溶出速率进行关联。D860—PVP分散物为无定形态,溶出速率大。用熔融法制备的固体分散物中,D860在D860—脲,D860—PEG中为部分互溶,部分呈微晶析出,为过饱和状态,活性强,溶出速率快。而用溶剂法制备的D860—PEG近似物理混合状态,大部分以微晶形态分散,溶出速率较慢。陈化试验表明D860分散物在贮存期间无晶体结构变异,溶出速率的下降估计是由于药剂活性改变所致。     

联苯双酯固体分散体处方及体外性质评价

目的应用不同亲水性载体材料制备联苯双酯固体分散体,提高联苯双酯体外溶出。方法应用溶解度参数法初步筛选载体材料,采用热熔挤出法制备联苯双酯固体分散体,采用差示扫描量热法、X射线粉末衍射法和傅立叶变换红外光谱法对所制备的固体分散体进行表征。对固体分散体进行溶出度测定,以体外累积溶出度为主要指标,分别考察不同载体、不同载药量对固体分散体中联苯双酯溶出度的影响。结果应用不同亲水性载体材料制备的固体分散体均可提高联苯双酯溶出度,其中以Soluplus对联苯双酯溶出度的提高最为显著,累积溶出度可达到90%左右。优选Soluplus为固体分散体载体材料,并且当载药量为20%时,溶出度最高。结论应用载体材料Soluplus制备固体分散体可以显著提高联苯双酯溶出度。载体材料的性质及载药量的高低都会影响固体分散体中药物的溶出度。     

阿司匹林固体分散物的研究

目的:制备阿司匹林固体分散物;选择不影响阿司匹林稳定性的PEG 载体及其合适比例;测定阿司匹林固体分散物的体外溶出速率;分析其结构状态。方法:固体分散物的制备采用熔融法;体外溶出采用浆法;固体分散物的结构分析采用X 射线衍射法。结果:PEG 所占比例越大,熔融法制备固体分散物时,阿司匹林的水解程度越低,且PEG20000 优于PEG6000 ;阿司匹林-PEG20000(1∶9) 固体分散物的标示百分含量为104 .68 % ,水杨酸检查合格;与原料药和物理混合物相比,其溶出度显著增加(P< 0 .01) ;该固体分散物中大部分阿司匹林以分子状态分散,只有极少部分以微晶状态分散。结论:以PEG20000 为载体,按阿司匹林 PEG= 1∶9 的比例制备阿司匹林固体分散物是理想的,该分散物体外溶出迅速,可用于制备小规格的片剂,在不影响疗效的前提下,通过减小剂量来降低阿司匹林对胃肠道的刺激性     

氯化血红素固体分散物的研制及其分散特征评价

目的:探讨氯化血红素固体分散物的制备及其分散特征的评价.方法:采用溶剂熔融法制备氯化血红素固体分散物,用差示热量扫描(DSC)图谱、红外光谱、X-射线衍射图谱的变化鉴定药物在载体中的分散特征;并对其溶解度和累积溶出速率进行考察.结果:结果显示,以氯化血红素为主药,聚乙二醇6000(PEG6000)为载体制成的固体分散物中,氯化血红素是以分子状态分散在载体中;经溶解度和累积溶出速率的测定,固体分散物溶解度为原药的49倍,固体分散物较原药在30 min时的累积溶出速率提高了22倍.结论:制成固体分散物后,形成填充型固体溶液,氯化血红素的溶解度和溶出速率均得到显著提高,提示本工艺可行,同时也为氯化血红素新制剂的研究提供科学依据.     

酮康唑固体分散体及共研磨物的制备及其体外溶出作用研究

目的:制备酮康唑固体分散体及其共研磨物并考察其体外溶出作用。方法:分别以聚乙二醇(PEG)、聚维酮(PVP)和泊洛沙姆(F68)作为载体材料,采用熔融法或溶剂法制备药物与载体不同比例(1∶1、1∶3、1∶5、1∶10)的酮康唑固体分散体;另制备药物与低取代羟丙基纤维素(L-HPC)不同比例(1∶0.5、1∶1、1∶1.5)的酮康唑共研磨物;研究各固体分散体和共研磨物的体外溶出情况,同时与酮康唑原料药进行比较。结果:与原料药比较,载药固体分散体和共研磨物可以显著提高酮康唑的溶出水平,且溶出速率随着载体比例的增加而增大,各固体分散体(1∶10)和共研磨物(1∶1.5)在20min时累积溶出率均大于90%,而原料药低于50%。结论:酮康唑制成固体分散体和共研磨物可以显著提高其体外溶出度。     

Fast-dissolving tablets of glyburide based on ternary solid dispersions with PEG 6000 and surfactants

Marketed glyburide tablets present unsatisfying dissolution profiles that give rise to variable bioavailability. With the purpose of developing a fast-dissolving tablet formulation able to assure a complete drug dissolution, we investigated the effect of the addition to a reference tablet formulation of different types (anionic and nonionic) and amounts of hydrophilic surfactants, as well as the use of a new technique, based on ternary solid dispersions of the drug with an hydrophilic carrier (polyethylene glycol [PEG] 6000) and a surfactant. Tablets were prepared by direct compression or previous wet granulation of suitable formulations containing the drug with each surfactant or drug:PEG:surfactant ternary dispersions at different PEG:surfactant w/w ratios. The presence of surfactants significantly increased (p<0.01) the drug dissolution rate, but complete drug dissolution was never achieved. On the contrary, in all cases tablets containing ternary solid dispersions achieved 100% dissolved drug within 60 min. The best product was the 10:80:10 w/w ternary dispersion with PEG 6000 and sodium laurylsulphate, showing a dissolution efficiency 5.5-fold greater than the reference tablet formulation and 100% drug dissolution after only 20 min.     

缬沙坦固体分散体的制备及体外溶出度研究

目的采用冷冻干燥法制备缬沙坦（Valsartan）速释固体分散体（SD）来提高其体外溶出度。方法分别以羟丙甲基纤维素（HPMC）、聚乙二醇6000（PEG6000）、聚乙烯吡咯烷酮k30（PVPk30）为载体,十二烷基硫酸钠（SDS）为表面活性剂来制备不同比例的缬沙坦固体分散体,通过测定体外溶出度,来选择最优辅料及比例,结果当以PEG6000载体,SDS为表面活性剂时,且药物：PEG6000：SDS=1：5：1％时药物呈现了很好的水溶性。结论在5min时即可溶出90％以上,很大程度上提高了缬沙坦的体外溶出度。     

Characteristics of rofecoxib-polyethylene glycol 4000 solid dispersions and tablets based on solid dispersions

The aim of this work was to report the properties of rofecoxib-PEG 4000 solid dispersions and tablets prepared using rofecoxib solid dispersions. Rofecoxib is a poorly water soluble nonsteroidal anti-inflammatory drug with a poor dissolution profile. This work investigated the possibility of developing rofecoxib tablets, allowing fast, reproducible, and complete rofecoxib dissolution, by using rofecoxib solid dispersion in polyethylene glycol (PEG) 4000. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the solid state of solid dispersions. The effect of PEG 4000 concentration on the dissolution rate of rofecoxib from its solid dispersions was investigated. The dissolution rate of rofecoxib from its solid dispersions increased with an increasing amount of PEG 4000. The extent of dissolution rate enhancement was estimated by calculating the mean dissolution time (MDT) values. The MDT of rofecoxib decreased significantly after preparing its solid dispersions with PEG 4000. The FTIR spectroscopic studies showed the stability of rofecoxib and absence of well-defined rofecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of rofecoxib in solid dispersions of rofecoxib with PEG 4000. SEM pictures showed the formation of effective solid dispersions of rofecoxib with PEG 4000 since well-defined change in the surface nature of rofecoxib and solid dispersions were observed. Solid dispersions formulation with highest drug dissolution rate (rofecoxib: PEG 4000 1:10 ratio) was used for the preparation of solid dispersion-based rofecoxib tablets by the direct compression method. Solid dispersion-based rofecoxib tablets obtained by direct compression, with a hardness of 8.1 Kp exhibited rapid drug dissolution and produced quick anti-inflammatory activity when compared to conventional tablets containing pure rofecoxib at the same drug dosage. This indicated that the improved dissolution rate and quick anti-inflammatory activity of rofecoxib can be obtained from its solid dispersion-based oral tablets.     

Characteristics of Rofecoxib-Polyethylene Glycol 4000 Solid Dispersions and Tablets Based on Solid Dispersions

The aim of this work was to report the properties of rofecoxib-PEG 4000 solid dispersions and tablets prepared using rofecoxib solid dispersions. Rofecoxib is a poorly water soluble nonsteroidal anti-inflammatory drug with a poor dissolution profile. This work investigated the possibility of developing rofecoxib tablets, allowing fast, reproducible, and complete rofecoxib dissolution, by using rofecoxib solid dispersion in polyethylene glycol (PEG) 4000. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the solid state of solid dispersions. The effect of PEG 4000 concentration on the dissolution rate of rofecoxib from its solid dispersions was investigated. The dissolution rate of rofecoxib from its solid dispersions increased with an increasing amount of PEG 4000. The extent of dissolution rate enhancement was estimated by calculating the mean dissolution time (MDT) values. The MDT of rofecoxib decreased significantly after preparing its solid dispersions with PEG 4000. The FTIR spectroscopic studies showed the stability of rofecoxib and absence of well-defined rofecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of rofecoxib in solid dispersions of rofecoxib with PEG 4000. SEM pictures showed the formation of effective solid dispersions of rofecoxib with PEG 4000 since well-defined change in the surface nature of rofecoxib and solid dispersions were observed. Solid dispersions formulation with highest drug dissolution rate (rofecoxib: PEG 4000 1:10 ratio) was used for the preparation of solid dispersion–based rofecoxib tablets by the direct compression method. Solid dispersion–based rofecoxib tablets obtained by direct compression, with a hardness of 8.1 Kp exhibited rapid drug dissolution and produced quick anti-inflammatory activity when compared to conventional tablets containing pure rofecoxib at the same drug dosage. This indicated that the improved dissolution rate and quick anti-inflammatory activity of rofecoxib can be obtained from its solid dispersion–based oral tablets.     

Improvement of the dissolution kinetics of SR 33557 by means of solid dispersions containing PEG 6000

Solid dispersions of SR 33557 in preparations containing from 30 to 80% w/w polyethylene glycol 6000 (PEG 6000) were prepared by the fusion method. The solubility of the drug substance either alone or in solid dispersions was determined in pH 1.2 and 4.5 media (extraction fluid NFXII, without enzyme). A large increase in the solubility was noted from the 80% w/w PEG preparation. A wettability study performed by measuring the contact angle on tablets of either drug substance or PEG 6000, or solid dispersions, revealed a minimal contact angle for the 80% w/w PEG 6000 solid dispersion (eutectic composition of SR 33557/PEG 6000 phase diagram). Dissolution kinetic analysis performed at pH 1.2 on all solid dispersions, on the physical mixtures containing 70 and 80% w/w PEG 6000, and on SR 33557 alone, showed a maximum release rate (100%) for the solid dispersions containing 70 and 80% w/w PEG 6000. The dissolution rate of the physical mixtures was faster than that of the drug substance alone but remained, however, lower than that of the solid dispersions, at the same composition. It was also observed that the dissolution rate, at pH 1.2 and 4.5, of the 70% w/w PEG 6000 solid dispersion was practically pH independent, which was not the case for the drug substance alone. The latter solid dispersion showed a slowing down of the dissolution kinetics after 3 months storage at 50°C whereas no change in the dissolution rate was observed following storage for 12 months at 25°C.     

PEG 6 000固体分散体系对难溶性药物水飞蓟素的增溶作用与晶格变化的关系

目的研究PEG 6 000固体分散体系对难溶性药物增溶的相关晶格变化规律。方法用熔融法制备水飞蓟素的PEG 6 000固体分散体,通过体外释药试验考察固体分散技术对水飞蓟素的增溶作用,以X-射线粉末多晶衍射结合相应的衍射峰处理软件系统分析PEG 6 000及药物的晶格参数的变化,经傅立叶变换红外光谱(FT-IR)验证PEG 6 000与药物之间的相互作用。结果与原药比较,固体分散体中药物的释放速率明显增大,PEG 6 000固体分散体系对难溶性药物水飞蓟素具有显著的增溶作用。X-射线多晶衍射分析表明,PEG 6 000及药物在固体分散体中的晶格点阵面间距离、衍射峰位移及其相对强度等发生了规律性变化,药物与载体间无相互作用。结论PEG 6 000固体分散体系的增溶作用与载体材料和药物的晶格参数的改变密切相关。     

Physicochemical characterisation,drug polymer dissolution and in vitro evaluation of phenacetin and phenylbutazone solid dispersions with polyethylene glycol 8000

Poor water solubility leads to low dissolution rate and consequently, it can limit bioavailability. Solid dispersions, where the drug is dispersed into an inert, hydrophilic polymer matrix can enhance drug dissolution. Solid dispersions were prepared using phenacetin and phenylbutazone as model drugs with polyethylene glycol (PEG) 8000 (carrier), by melt fusion method. Phenacetin and phenylbutazone displayed an increase in the dissolution rate when formulated as solid dispersions as compared with their physical mixture and drug alone counterparts. Characterisation of the solid dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). DSC studies revealed that drugs were present in the amorphous form within the solid dispersions. FTIR spectra for the solid dispersions of drugs suggested that there was a lack of interaction between PEG 8000 and the drug. However, the physical mixture of phenacetin with PEG 8000 indicated the formation of hydrogen bond between phenacetin and the carrier. Permeability of phenacetin and phenylbutazone was higher for solid dispersions as compared with that of drug alone across Caco‐2 cell monolayers. Permeability studies have shown that both phenacetin and phenylbutazone, and their solid dispersions can be categorised as well‐absorbed compounds. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4281–4294, 2011     

Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions

Solid dispersion literature, describing the mechanism of dissolution of drug-polyethylene glycol dispersions, still shows some gaps; (A). only few studies include experiments evaluating solid solution formation and the particle size of the drug in the dispersion particles, two factors that can have a profound effect on the dissolution. (B). Solid dispersion preparation involves a recrystallisation process (which is known to be highly sensitive to the recrystallisation conditions) of polyethylene glycol and possibly also of the drug. Therefore, it is of extreme importance that all experiments are performed on dispersion aliquots, which can be believed to be physico-chemical identical. This is not always the case. (C). Polyethylene glycol 6000 (PEG6000) crystallises forming lamellae with chains either fully extended or folded once or twice depending on the crystallisation conditions. Recently, a high resolution differential scanning calorimetry (DSC)-method, capable of evaluating qualitatively and quantitatively the polymorphic behaviour of PEG6000, has been reported. Unraveling the relationship between the polymorphic behavior of PEG6000 in a solid dispersion and the dissolution characteristics of that dispersion, is a real gain to our knowledge of solid dispersions, since this has never been thoroughly investigated. The aim of the present study was to fill up the three above mentioned gaps in solid dispersion literature. Therefore, physical mixtures and solid dispersions were prepared and in order to unravel the relationship between their physico-chemical properties and dissolution characteristics, pure drugs (diazepam, temazepam), polymer (PEG6000), solid dispersions and physical mixtures were characterised by DSC, X-ray powder diffraction (Guinier and Bragg-Brentano method), FT-IR spectroscopy, dissolution and solubility experiments and the particle size of the drug in the dispersion particles was estimated using a newly developed method. Addition of PEG6000 improves the dissolution rate of both drugs. Mechanisms involved are solubilisation and improved wetting of the drug in the polyethylene glycol rich micro-environment formed at the surface of drug crystals after dissolution of the polymer. Formulation of solid dispersions did not further improve the dissolution rate compared with physical mixtures. X-ray spectra show that both drugs are in a highly crystalline state in the solid dispersions, while no significant changes in the lattice spacings of PEG6000 indicate the absence of solid solution formation. IR spectra show the absence of a hydrogen bonding interaction between the benzodiazepines and PEG6000. Furthermore, it was concluded that the reduction of the mean drug particle size by preparing solid dispersions with PEG6000 is limited and that the influence of the polymorphic behavior of PEG6000 (as observed by DSC) on the dissolution was negligible.     

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug–polymer interactions.     

Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000

The aim of this study was to prepare and characterize solid dispersions of water insoluble non-steroidal anti-inflammatory drug, indomethacin (IND), with polyethylene glycol 4000 (PEG4000) and Gelucire 50/13 (Gelu.) for enhancing the dissolution rate of the drug. The solid dispersions (SDs) were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy (SEM), X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND–Gelu. and disappeared in case of higher ratio of IND–PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer (1:4) enhanced the drug solubility about 4-folds or 3.5-folds in case of SDs of IND–PEG or IND–Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures (PMs) or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer.