几种NSAIDs溶解性研究及控/缓释系统的构建与性能评价
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摘要
非甾体类抗炎药(Non-steroidal anti-inflammatory drugs，NSAIDs)又称为解热镇痛抗炎药，是目前应用最广泛的治疗药物之一。随着大量新的NSAIDs问世，出现了许多溶解性差的药物(如：Valdecoxib和Rofecoxib)，给口服、注射以及局部用药的组方设计带来了很大的挑战。对溶解性差的药物的助溶研究，成为当今药物组方研究领域的热点。为了选择一种合适的介质增加药物的溶解度，在多种增溶剂(助溶剂、表面活性剂及亲水性有机物)中对其溶解性进行了系统的研究，为开发含有Valdecoxib和Rofecoxib的口服、注射及局部用药的组方提供必要的理论基础。
乙醇是一种效果较好的助溶剂；十二烷基硫酸钠是一种效果较好的表面活性剂，二者都可以显著提高Valdecoxib在水中的溶解度。在乙醇浓度一定的条件下，Valdecoxib的溶解度随着温度升高而增大；在温度一定的条件下，乙醇浓度在0-80％范围内，Valdecoxib的溶解度随着乙醇浓度的增加而增大；而在乙醇浓度80％-100％范围内，Valdecoxib的溶解度随着乙醇浓度的增加而减小。在所有乙醇浓度和不同温度条件下的吉布斯自由能变(⊿G_(tr)~O)均为负值，表明：乙醇对Valdecoxib的增溶作用为自发产生过程。以十二烷基硫酸钠作为表面活性剂的实验表明：在十二烷基硫酸钠浓度一定的条件下，Valdecoxib的溶解度随着温度升高而增大；在温度一定的条件下，Valdecoxib的溶解度随着十二烷基硫酸钠的浓度的增加而近似线性提高。
丙三醇、丙二醇及聚乙二醇400三种助溶剂参与下，在25℃、30℃和35℃时，Valdecoxib溶解度随着在水中助溶剂的浓度的增加而增大。Valdecoxib在聚乙二醇400+水混合体系中比在丙三醇+水、丙二醇+水混合体系中的溶解度高。在25℃、30℃和35℃温度条件下，三种助溶剂的增溶力分别为：1．1、1．5和1．8倍；2．6、2．8和2．9倍；3．0、3．5和3．9倍。
四种亲水性有机物(PEG 4000，PEG 6000、PEG 8000和PEG 10000)增溶实验研究表明，对于同一种PEG，Valdecoxib溶解度随着二元混合体系中PEG的浓度的增加而增大，且随着二元混合体系的温度的升高而增大。PEG的分子量高低影响Valdecoxib的增溶作用，在所有实验的PEG中，PEG 4000比PEG 6000、PEG 8000以及PEG10000显示了较强的增溶潜力。在25℃、30℃和35℃温度条件下，所有的PEG+水混合体系的⊿G_(tr)~O均为负值，说明：PEG对Valdecoxib的增溶作用为自发产生的过程。在PEG 4000+水混合体系的⊿G_(tr)~O比其它PEG+水混合体系下降了更大的程度，说明：PEG 4000+水混合体系比其它PEG+水混合体系增溶作用进行得更加顺利。
在25、30和35℃时，研究Rofecoxib在亲水性有机物(甘露醇、PVP K30、尿素、PEG4000和PEG6000)+水混合体系中的溶解性。除甘露醇外，其它所有的亲水性有机物对Rofecoxib的溶解度都有提高作用，且随着亲水性有机物的浓度的增加，其溶解度增大；随着二元混合体系温度的升高，Rofecoxib的溶解度增大。在所有实验的亲水性有机物中，尿素比其它基质显示了更高的增溶潜力。所有混合体系的⊿G_(tr)~O均为负值，说明：Rofecoxib增溶作用自发产生的属性。尿素+水混合体系中的⊿G_(tr)~O比其它基质+水混合体系降低程度更大，说明前者比后者增溶作用进行得更加顺利。
在25、30和35℃时，Rofecoxib的溶解度随着助溶剂(丙三醇、丙二醇、乙醇)和表面活性剂(Span 20、Tween 80、十二烷基硫酸钠)浓度的增加而增大。Rofecoxib在乙醇+水混合体系中比在丙三醇+水、丙二醇+水混合体系中的溶解度高。在25、30和35℃时，丙三醇、丙二醇和乙醇的增溶力分别为：0．81、0．87和0．88；2．2、2．3和2．4；3．4、3．6和3．8。对于表面活性剂来说，在25、30和35℃时，十二烷基硫酸钠比Span 20和Tween 80显示了更好的增溶效果。
在水中的溶解度和溶解速率是药物的重要特性，其影响药物释放、输送以及在胃肠道的吸收速度。SDs技术可以使药物的微粒减小到接近分子水平，并可以使药物从晶体转变成或局部地变为无定形态，或者局部地增加药物的饱和溶解度。溶解性差药物的SDs研究，为开发口服和局部用药的组方提供必要的理论基础。
采用熔融法制备Valdecoxib+PEG的SDs实验表明：利用PEG 4000制备的Valdecoxib的SDs，可以提高药物的溶解速率，其溶解速率随SDs中的PEG 4000的浓度的增加而增加。FTIR显示：SDs中的药物稳定，药物与PEG之间没有发生明确的化学反应。DSC和XRD谱图说明：SDs中的Valdecoxib呈无定形态。SEM图显示了Valdecoxib、SDs和valdecoxib-PEG 4000的物理混合物表面结构以及表面的细微变化。
通过制备Rofecoxib+尿素的SDs，可以提高药物的溶解速率，并随着SDs中的尿素浓度的增加而增加。实验结果表明：SDs以及Rofecoxib+尿素的物理混合物中的Rofecoxib的平均溶出时间(MDT)都减少。红外光谱研究表明，SDs中的药物稳定性好，且没有与尿素发生化学反应。DSC和XRD表明：Rofecoxib在SDs中呈无定形态。扫描电镜表征了Rofecoxib、SDs和Rofecoxib+尿素物理混合物表面形态及其表面的细微变化。
Rofecoxib+PEG 4000制备的SDs实验表明：随着SDs中PEG 4000的浓度的增加，Rofecoxib的溶解速率提高，其MDT明显减少。FTIR证实：SDs中的Rofecoxib是稳定的，两者之间没有发生明确的化学反应。DSC和XRD分析表明：SDs中的Rofecoxib呈无定形态。SEM图对比显示：SDs表面发生了明确的细微变化。以具有较高药物溶解速率的SDs(Rofecoxib：PEG 4000=1：10)为材料，采用直接压榨法制备Rofecoxib药片，药片硬度为8．1Kp。在相同剂量下，基于SDs制备的药片与常规药片相比，具有溶解速率高、产生抗炎作用快等优点。从而证实Rofecoxib+PEG 4000制备的SDs是一种效果好的药物载体。
随着新的NSAIDs不断问世，也出现了不少半衰期短、副作用大的治疗药物。研究此类药物的控／缓释剂型成为当务之急。药物的控／缓释剂型比传统的剂型显示出更多的优点。在所有报道的控／缓释剂型中，由于微囊化技术和纳米胶囊技术自身的优良特性，此两项技术占据了研究主流。
载有对乙酰氨基酚的壳聚糖微球实验表明：交联的壳聚糖微球的平均直径为3．8-4．2μm，包封率为96．3-98．7％。壳聚糖微球呈规则球体，表面光滑。药物的结晶性和交联剂类型影响微球的表面形态。根据零级释放模型、一级释放模型、Higuchi模型、Korsmeyer模型和Kopcha模型进行实验分析，确定最适合的动力学模型是Higuchi动力学模型。实验同时表明载药壳聚糖缓释微球药物释放遵从斐克扩散定律(Fick's law of diffusion)。
以甜薯淀粉为壁材、双氯酚酸钠为芯材制备的淀粉载药微球实验表明：载药微球的平均直径随着淀粉浓度的增加而略微增大，微球的平均直径为10．3-13．1μm。随着淀粉浓度的变化微球的收率没有太大变化，保持在65．2～70．1％之间。微球的载药效率随着淀粉浓度的增加而略微减小，分别为：77．4％、72．3％和68．5％。在一定时间内，微球的药物释放累积量随着淀粉浓度的增加或载药量的增加而减少。甜薯淀粉载药微球最合适的动力学模型是Higuchi动力学模型，微球药物释放遵从斐克扩散定律(Fick's law of diffusion)。
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widelyused therapeutic agents,primarily for the treatment of fever,pain and inflammation,especially arthritis.With the recent advent of high throughput screening of newNSAIDs,the number of poorly soluble drug candidates (e.g.Valdecoxib andRofecoxib) has risen sharply and the formulation of such drugs for either oral ortopical and injectable delivery now presents one of the most frequent and greatestchallenges to formulation scientists in the pharmaceutical industries.Solubility and itsenhancement of poorly soluble drug are of continuously growing interest to thepharmaceutical industry while formulating poorly soluble drugs.Therefore,weperformed extensive investigations on their solubility behaviors in the presence ofeffective cosolvents,hydrophilic polymers and surfactants in order to select anappropriate medium to enhance their solubility,and obtained a lot of solubility data,such a database is useful in developing oral and injectable formulations containingrofecoxib or valdecoxib.
Preliminary investigations indicated both ethanol and SLS are respectively aneffective cosolvent and surfactant for the solubilization of valdecoxib.The aqueoussolubility of valdecoxib could be enhanced significantly by using ethanol as acosolvent at various concentrations as well as by increasing the temperature of thedissolution media.The solubility of valdecoxib increased with increasing massfraction of ethanol up to 80%,but solubility decreased in pure ethanol at all thetemperature.Experimental solubility data of valdecoxib were correlated with thosecalculated by a log-linear equation.Calculated Gibbs free energy values were allnegative for all the ethanol + water mixtures at (25,30,and 35)℃,indicating thespontaneous nature of valdecoxib solubilization.In the case of SLS + water mixtures, the solubility of valdecoxib linearly increased with increasing mass fraction of SLS inwater at all the temperatures.
The solubility of valdecoxib increased with increasing mass fraction of glycerol,propylene glycol,and PEG 400 at (25,30,and 35)℃.For PEG 400 + water mixtures,the solubility of valdecoxib was higher when compared to the glycerol + water andpropylene glycol + water mixtures.The solubilization power of glycerol,propyleneglycol,and PEG 400 at (25,30,and 35)℃was 1.1,1.5,and 1.8,2.6,2.8,and 2.9,and3.0,3.5,and 3.9,respectively.
For PEG 4000,PEG 6000,PEG 8000 and PEG 10000,the aqueous solubility ofvaldecoxib could be enhanced by the addition of an increasing mass fraction of all ofthe PEGs tested as well as by increasing the temperature of the dissolution media.Themolecular weight of the PEGs tested played an important role in valdecoxibsolubilization in the aqueous medium.Among the PEGs studied,PEG 4000 exhibiteda higher solubilization potential than the others.Calculated Gibbs free energy valueswere all negative for all of the PEG +water mixtures at (25,30,and 35)℃,indicatingthe spontaneous nature of valdecoxib solubilization.In the case of PEG 4000 + watermixtures,the⊿ G_(tr)~o values decreased to a greater extent than those for the othercarriers (PEG 6000,PEG 8000,and PEG 10000) + water mixtures,indicating that thereaction conditions were more favorable in PEG 4000 + water mixtures than in othercarrier + water mixtures.
The solubilization of rofecoxib in aqueous solution using mannitol,PVP K30,urea,PEG 4000,and PEG 6000 were investigated at (25,30,and 35)℃.The aqueoussolubility of rofecoxib could be enhanced by the addition of increasing mass fractionof all of the hydrophilic carriers tested except mannitol as well as by increasing thetemperature of the dissolution medium.Among the hydrophilic carriers studied,ureaexhibited a higher solubilization potential than the other carriers.Calculated Gibbsfree energy values were all negative for all of the hydrophilic carriers + watermixtures,indicating the spontaneous nature of rofecoxib solubilization.In the case ofurea + water mixtures,the values decreased to a greater extent than those for the other carriers (mannitol,PVP K30,PEG 4000,and PEG 6000) + water mixtures,indicatingthat the reaction conditions were more favorable in urea + water mixtures than inother carriers + water mixtures.
The solubility of rofecoxib increased with increasing mass fraction of cosolvents(glycerol,propylene glycol,and ethanol) and surfactants(Span 20,Tween 80,and SLS)at (25,30,and 35)℃.For ethanol + water mixtures,the solubility of rofecoxib washigher when compared to the glycerol + water and propylene glycol + water mixtures.The solubilization power of glycerol,propylene glycol,and ethanol at (25,30,and 35)℃was 0.81,0.87,and 0.88;2.2,2.3,and 2.4;and 3.4,3.6,and 3.8,respectively.Incase of surfactants,SLS exhibited higher solubilizing efficiency at (25,30,and 35)℃than Span 20 and Tween 80.
Solubility and dissolution rate of drugs in water are important properties thatinfluence the release,transport,and rate of absorption in the gastrointestinal tract.SDsprovide the possibility of reducing the particle size of such drugs by nearly amolecular level,and transform the drugs from the crystalline to the (partial)amorphous state and/or to locally increase the saturation solubility.It is useful indeveloping oral and topical formulations containing rofecoxib or valdecoxib.
The SDs of valdecoxib with PEG 4000 were prepared at 1:1,1:2,1:5,and 1:10(valdecoxib:PEG 4000) ratio by melting method.The SDs of valdecoxib with PEG4000 exhibited enhanced dissolution rate of valdecoxib,and the rate increased withincreasing concentration of PEG 4000 in SDs.Mean dissolution time (MDT) ofvaldecoxib decreased significantly after preparation of SDs and physical mixture withPEG 4000.The FTIR spectroscopic studies showed the stability of valdecoxib andabsence of well-defined valdecoxib-PEG 4000 interaction.The DSC and XRD studiesindicated the amorphous state of valdecoxib in SDs of valdecoxib with PEG 4000.The SEM pictures showed the formation of effective SDs of valdecoxib with PEG4000,since well-defined changes in the surface nature of valdecoxib,SDs,andphysical mixture were observed.
The dissolution rate of rofecoxib was enhanced rapidly by its SDs with urea andincreased with increasing concentrations of urea in SDs.The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures withurea.FTIR spectroscopic studies showed the stability of rofecoxib and the absence ofa well-defined rofecoxib-urea interaction.DSC and XRD studies confirmed theamorphous state of rofecoxib in SDs of rofecoxib with urea.SEM pictures showed theformation of effective SDs of rofecoxib with urea since well-defined changes in thesurface nature of rofecoxib,SDs,and physical mixture were observed.
The dissolution rate of rofecoxib from its solid dispersions by PEG 4000increased with an increasing amount of PEG 4000.The MDT of rofecoxib decreasedsignificantly after preparing its solid dispersions with PEG 4000.The FTIRspectroscopic studies showed the stability of rofecoxib and absence of well-definedrofecoxib-PEG 4000 interaction.The DSC and XRD studies indicated the amorphousstate of rofecoxib in solid dispersions of rofecoxib with PEG 4000.SEM picturesshowed the formation of effective solid dispersions of rofecoxib with PEG 4000 sincewell-defined change in the surface nature of rofecoxib and solid dispersions wereobserved.Solid dispersions formulation with highest drug dissolution rate (rofecoxib:PEG 4000 1:10 ratio) was used for the preparation of solid dispersion-based rofecoxibtablets by the direct compression method.Solid dispersion-based rofecoxib tabletsobtained by direct compression,with a hardness of 8.1 Kp exhibited rapid drugdissolution and produced quick anti-inflammatory activity when compared toconventional tablets containing pure rofecoxib at the same drug dosage.Thisindicated that the improved dissolution rate and quick anti-inflammatory activity ofrofecoxib can be obtained from its solid dispersion-based oral tablets.
There is a continuously growing interest of the pharmaceutical industry for drugdelivery in sustained or controlled release dosage forms.Controlled drug deliverysystems offer numerous advantages compared to conventional dosage forms.Of thedifferent dosage forms reported,micro-and nano-particles occupy unique position indrug delivery technology due to their attractive properties.
The mean particle size and encapsulation efficiency of cross-linked chitosanmicrospheres was between 3.8 to 4.2μm and 96.3 to 98.7%,respectively.Spray-driedchitosan microspheres were spherical in shape with smooth surface.The surface morphology of spray-dried chitosan microspheres was affected by the crystallinity ofthe loaded drug and cross-linking agent.The release data of the spray-dried chitosanmicrospheres were treated with Zero-order,First-order,Higuchi,Korsmeyer,andKopcha kinetic models and best fit was observed with Higuchi model,indicating therelease of drug from spray-dried chitosan microspheres followed Fick's law ofdiffusion.
The mean particle size of drug-loaded spray-dried SPS microparticles wasbetween 10.3 to 13.1μm.The mean particle size increased slightly with increase inthe concentration of SPS.The % yield of spray-dried SPS microparticles did not varymuch among the various formulations and it was between 65.2 to 70.1%.The drugloading efficiency of spray-dried SPS microparticles decreased slightly with anincreasing concentration of SPS.The loading efficiencies are 77.4,72.3,and 68.5 %,respectively.The cumulative amount of drug release from the spray-dried SPSmicroparticles decreased with an increase in the concentration of SPS and in the drugloading.The dissolution data were treated with Higuchi equation and it was found thatrelease of the drug from spray-dried SPS microparticles followed Fick's law ofdiffusion since good correlation coefficient (R~2) was observed with the Higuchi plots.
乙醇是一种效果较好的助溶剂；十二烷基硫酸钠是一种效果较好的表面活性剂，二者都可以显著提高Valdecoxib在水中的溶解度。在乙醇浓度一定的条件下，Valdecoxib的溶解度随着温度升高而增大；在温度一定的条件下，乙醇浓度在0-80％范围内，Valdecoxib的溶解度随着乙醇浓度的增加而增大；而在乙醇浓度80％-100％范围内，Valdecoxib的溶解度随着乙醇浓度的增加而减小。在所有乙醇浓度和不同温度条件下的吉布斯自由能变(⊿G_(tr)~O)均为负值，表明：乙醇对Valdecoxib的增溶作用为自发产生过程。以十二烷基硫酸钠作为表面活性剂的实验表明：在十二烷基硫酸钠浓度一定的条件下，Valdecoxib的溶解度随着温度升高而增大；在温度一定的条件下，Valdecoxib的溶解度随着十二烷基硫酸钠的浓度的增加而近似线性提高。
丙三醇、丙二醇及聚乙二醇400三种助溶剂参与下，在25℃、30℃和35℃时，Valdecoxib溶解度随着在水中助溶剂的浓度的增加而增大。Valdecoxib在聚乙二醇400+水混合体系中比在丙三醇+水、丙二醇+水混合体系中的溶解度高。在25℃、30℃和35℃温度条件下，三种助溶剂的增溶力分别为：1．1、1．5和1．8倍；2．6、2．8和2．9倍；3．0、3．5和3．9倍。
四种亲水性有机物(PEG 4000，PEG 6000、PEG 8000和PEG 10000)增溶实验研究表明，对于同一种PEG，Valdecoxib溶解度随着二元混合体系中PEG的浓度的增加而增大，且随着二元混合体系的温度的升高而增大。PEG的分子量高低影响Valdecoxib的增溶作用，在所有实验的PEG中，PEG 4000比PEG 6000、PEG 8000以及PEG10000显示了较强的增溶潜力。在25℃、30℃和35℃温度条件下，所有的PEG+水混合体系的⊿G_(tr)~O均为负值，说明：PEG对Valdecoxib的增溶作用为自发产生的过程。在PEG 4000+水混合体系的⊿G_(tr)~O比其它PEG+水混合体系下降了更大的程度，说明：PEG 4000+水混合体系比其它PEG+水混合体系增溶作用进行得更加顺利。
在25、30和35℃时，研究Rofecoxib在亲水性有机物(甘露醇、PVP K30、尿素、PEG4000和PEG6000)+水混合体系中的溶解性。除甘露醇外，其它所有的亲水性有机物对Rofecoxib的溶解度都有提高作用，且随着亲水性有机物的浓度的增加，其溶解度增大；随着二元混合体系温度的升高，Rofecoxib的溶解度增大。在所有实验的亲水性有机物中，尿素比其它基质显示了更高的增溶潜力。所有混合体系的⊿G_(tr)~O均为负值，说明：Rofecoxib增溶作用自发产生的属性。尿素+水混合体系中的⊿G_(tr)~O比其它基质+水混合体系降低程度更大，说明前者比后者增溶作用进行得更加顺利。
在25、30和35℃时，Rofecoxib的溶解度随着助溶剂(丙三醇、丙二醇、乙醇)和表面活性剂(Span 20、Tween 80、十二烷基硫酸钠)浓度的增加而增大。Rofecoxib在乙醇+水混合体系中比在丙三醇+水、丙二醇+水混合体系中的溶解度高。在25、30和35℃时，丙三醇、丙二醇和乙醇的增溶力分别为：0．81、0．87和0．88；2．2、2．3和2．4；3．4、3．6和3．8。对于表面活性剂来说，在25、30和35℃时，十二烷基硫酸钠比Span 20和Tween 80显示了更好的增溶效果。
在水中的溶解度和溶解速率是药物的重要特性，其影响药物释放、输送以及在胃肠道的吸收速度。SDs技术可以使药物的微粒减小到接近分子水平，并可以使药物从晶体转变成或局部地变为无定形态，或者局部地增加药物的饱和溶解度。溶解性差药物的SDs研究，为开发口服和局部用药的组方提供必要的理论基础。
采用熔融法制备Valdecoxib+PEG的SDs实验表明：利用PEG 4000制备的Valdecoxib的SDs，可以提高药物的溶解速率，其溶解速率随SDs中的PEG 4000的浓度的增加而增加。FTIR显示：SDs中的药物稳定，药物与PEG之间没有发生明确的化学反应。DSC和XRD谱图说明：SDs中的Valdecoxib呈无定形态。SEM图显示了Valdecoxib、SDs和valdecoxib-PEG 4000的物理混合物表面结构以及表面的细微变化。
通过制备Rofecoxib+尿素的SDs，可以提高药物的溶解速率，并随着SDs中的尿素浓度的增加而增加。实验结果表明：SDs以及Rofecoxib+尿素的物理混合物中的Rofecoxib的平均溶出时间(MDT)都减少。红外光谱研究表明，SDs中的药物稳定性好，且没有与尿素发生化学反应。DSC和XRD表明：Rofecoxib在SDs中呈无定形态。扫描电镜表征了Rofecoxib、SDs和Rofecoxib+尿素物理混合物表面形态及其表面的细微变化。
Rofecoxib+PEG 4000制备的SDs实验表明：随着SDs中PEG 4000的浓度的增加，Rofecoxib的溶解速率提高，其MDT明显减少。FTIR证实：SDs中的Rofecoxib是稳定的，两者之间没有发生明确的化学反应。DSC和XRD分析表明：SDs中的Rofecoxib呈无定形态。SEM图对比显示：SDs表面发生了明确的细微变化。以具有较高药物溶解速率的SDs(Rofecoxib：PEG 4000=1：10)为材料，采用直接压榨法制备Rofecoxib药片，药片硬度为8．1Kp。在相同剂量下，基于SDs制备的药片与常规药片相比，具有溶解速率高、产生抗炎作用快等优点。从而证实Rofecoxib+PEG 4000制备的SDs是一种效果好的药物载体。
随着新的NSAIDs不断问世，也出现了不少半衰期短、副作用大的治疗药物。研究此类药物的控／缓释剂型成为当务之急。药物的控／缓释剂型比传统的剂型显示出更多的优点。在所有报道的控／缓释剂型中，由于微囊化技术和纳米胶囊技术自身的优良特性，此两项技术占据了研究主流。
载有对乙酰氨基酚的壳聚糖微球实验表明：交联的壳聚糖微球的平均直径为3．8-4．2μm，包封率为96．3-98．7％。壳聚糖微球呈规则球体，表面光滑。药物的结晶性和交联剂类型影响微球的表面形态。根据零级释放模型、一级释放模型、Higuchi模型、Korsmeyer模型和Kopcha模型进行实验分析，确定最适合的动力学模型是Higuchi动力学模型。实验同时表明载药壳聚糖缓释微球药物释放遵从斐克扩散定律(Fick's law of diffusion)。
以甜薯淀粉为壁材、双氯酚酸钠为芯材制备的淀粉载药微球实验表明：载药微球的平均直径随着淀粉浓度的增加而略微增大，微球的平均直径为10．3-13．1μm。随着淀粉浓度的变化微球的收率没有太大变化，保持在65．2～70．1％之间。微球的载药效率随着淀粉浓度的增加而略微减小，分别为：77．4％、72．3％和68．5％。在一定时间内，微球的药物释放累积量随着淀粉浓度的增加或载药量的增加而减少。甜薯淀粉载药微球最合适的动力学模型是Higuchi动力学模型，微球药物释放遵从斐克扩散定律(Fick's law of diffusion)。
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widelyused therapeutic agents,primarily for the treatment of fever,pain and inflammation,especially arthritis.With the recent advent of high throughput screening of newNSAIDs,the number of poorly soluble drug candidates (e.g.Valdecoxib andRofecoxib) has risen sharply and the formulation of such drugs for either oral ortopical and injectable delivery now presents one of the most frequent and greatestchallenges to formulation scientists in the pharmaceutical industries.Solubility and itsenhancement of poorly soluble drug are of continuously growing interest to thepharmaceutical industry while formulating poorly soluble drugs.Therefore,weperformed extensive investigations on their solubility behaviors in the presence ofeffective cosolvents,hydrophilic polymers and surfactants in order to select anappropriate medium to enhance their solubility,and obtained a lot of solubility data,such a database is useful in developing oral and injectable formulations containingrofecoxib or valdecoxib.
Preliminary investigations indicated both ethanol and SLS are respectively aneffective cosolvent and surfactant for the solubilization of valdecoxib.The aqueoussolubility of valdecoxib could be enhanced significantly by using ethanol as acosolvent at various concentrations as well as by increasing the temperature of thedissolution media.The solubility of valdecoxib increased with increasing massfraction of ethanol up to 80%,but solubility decreased in pure ethanol at all thetemperature.Experimental solubility data of valdecoxib were correlated with thosecalculated by a log-linear equation.Calculated Gibbs free energy values were allnegative for all the ethanol + water mixtures at (25,30,and 35)℃,indicating thespontaneous nature of valdecoxib solubilization.In the case of SLS + water mixtures, the solubility of valdecoxib linearly increased with increasing mass fraction of SLS inwater at all the temperatures.
The solubility of valdecoxib increased with increasing mass fraction of glycerol,propylene glycol,and PEG 400 at (25,30,and 35)℃.For PEG 400 + water mixtures,the solubility of valdecoxib was higher when compared to the glycerol + water andpropylene glycol + water mixtures.The solubilization power of glycerol,propyleneglycol,and PEG 400 at (25,30,and 35)℃was 1.1,1.5,and 1.8,2.6,2.8,and 2.9,and3.0,3.5,and 3.9,respectively.
For PEG 4000,PEG 6000,PEG 8000 and PEG 10000,the aqueous solubility ofvaldecoxib could be enhanced by the addition of an increasing mass fraction of all ofthe PEGs tested as well as by increasing the temperature of the dissolution media.Themolecular weight of the PEGs tested played an important role in valdecoxibsolubilization in the aqueous medium.Among the PEGs studied,PEG 4000 exhibiteda higher solubilization potential than the others.Calculated Gibbs free energy valueswere all negative for all of the PEG +water mixtures at (25,30,and 35)℃,indicatingthe spontaneous nature of valdecoxib solubilization.In the case of PEG 4000 + watermixtures,the⊿ G_(tr)~o values decreased to a greater extent than those for the othercarriers (PEG 6000,PEG 8000,and PEG 10000) + water mixtures,indicating that thereaction conditions were more favorable in PEG 4000 + water mixtures than in othercarrier + water mixtures.
The solubilization of rofecoxib in aqueous solution using mannitol,PVP K30,urea,PEG 4000,and PEG 6000 were investigated at (25,30,and 35)℃.The aqueoussolubility of rofecoxib could be enhanced by the addition of increasing mass fractionof all of the hydrophilic carriers tested except mannitol as well as by increasing thetemperature of the dissolution medium.Among the hydrophilic carriers studied,ureaexhibited a higher solubilization potential than the other carriers.Calculated Gibbsfree energy values were all negative for all of the hydrophilic carriers + watermixtures,indicating the spontaneous nature of rofecoxib solubilization.In the case ofurea + water mixtures,the values decreased to a greater extent than those for the other carriers (mannitol,PVP K30,PEG 4000,and PEG 6000) + water mixtures,indicatingthat the reaction conditions were more favorable in urea + water mixtures than inother carriers + water mixtures.
The solubility of rofecoxib increased with increasing mass fraction of cosolvents(glycerol,propylene glycol,and ethanol) and surfactants(Span 20,Tween 80,and SLS)at (25,30,and 35)℃.For ethanol + water mixtures,the solubility of rofecoxib washigher when compared to the glycerol + water and propylene glycol + water mixtures.The solubilization power of glycerol,propylene glycol,and ethanol at (25,30,and 35)℃was 0.81,0.87,and 0.88;2.2,2.3,and 2.4;and 3.4,3.6,and 3.8,respectively.Incase of surfactants,SLS exhibited higher solubilizing efficiency at (25,30,and 35)℃than Span 20 and Tween 80.
Solubility and dissolution rate of drugs in water are important properties thatinfluence the release,transport,and rate of absorption in the gastrointestinal tract.SDsprovide the possibility of reducing the particle size of such drugs by nearly amolecular level,and transform the drugs from the crystalline to the (partial)amorphous state and/or to locally increase the saturation solubility.It is useful indeveloping oral and topical formulations containing rofecoxib or valdecoxib.
The SDs of valdecoxib with PEG 4000 were prepared at 1:1,1:2,1:5,and 1:10(valdecoxib:PEG 4000) ratio by melting method.The SDs of valdecoxib with PEG4000 exhibited enhanced dissolution rate of valdecoxib,and the rate increased withincreasing concentration of PEG 4000 in SDs.Mean dissolution time (MDT) ofvaldecoxib decreased significantly after preparation of SDs and physical mixture withPEG 4000.The FTIR spectroscopic studies showed the stability of valdecoxib andabsence of well-defined valdecoxib-PEG 4000 interaction.The DSC and XRD studiesindicated the amorphous state of valdecoxib in SDs of valdecoxib with PEG 4000.The SEM pictures showed the formation of effective SDs of valdecoxib with PEG4000,since well-defined changes in the surface nature of valdecoxib,SDs,andphysical mixture were observed.
The dissolution rate of rofecoxib was enhanced rapidly by its SDs with urea andincreased with increasing concentrations of urea in SDs.The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures withurea.FTIR spectroscopic studies showed the stability of rofecoxib and the absence ofa well-defined rofecoxib-urea interaction.DSC and XRD studies confirmed theamorphous state of rofecoxib in SDs of rofecoxib with urea.SEM pictures showed theformation of effective SDs of rofecoxib with urea since well-defined changes in thesurface nature of rofecoxib,SDs,and physical mixture were observed.
The dissolution rate of rofecoxib from its solid dispersions by PEG 4000increased with an increasing amount of PEG 4000.The MDT of rofecoxib decreasedsignificantly after preparing its solid dispersions with PEG 4000.The FTIRspectroscopic studies showed the stability of rofecoxib and absence of well-definedrofecoxib-PEG 4000 interaction.The DSC and XRD studies indicated the amorphousstate of rofecoxib in solid dispersions of rofecoxib with PEG 4000.SEM picturesshowed the formation of effective solid dispersions of rofecoxib with PEG 4000 sincewell-defined change in the surface nature of rofecoxib and solid dispersions wereobserved.Solid dispersions formulation with highest drug dissolution rate (rofecoxib:PEG 4000 1:10 ratio) was used for the preparation of solid dispersion-based rofecoxibtablets by the direct compression method.Solid dispersion-based rofecoxib tabletsobtained by direct compression,with a hardness of 8.1 Kp exhibited rapid drugdissolution and produced quick anti-inflammatory activity when compared toconventional tablets containing pure rofecoxib at the same drug dosage.Thisindicated that the improved dissolution rate and quick anti-inflammatory activity ofrofecoxib can be obtained from its solid dispersion-based oral tablets.
There is a continuously growing interest of the pharmaceutical industry for drugdelivery in sustained or controlled release dosage forms.Controlled drug deliverysystems offer numerous advantages compared to conventional dosage forms.Of thedifferent dosage forms reported,micro-and nano-particles occupy unique position indrug delivery technology due to their attractive properties.
The mean particle size and encapsulation efficiency of cross-linked chitosanmicrospheres was between 3.8 to 4.2μm and 96.3 to 98.7%,respectively.Spray-driedchitosan microspheres were spherical in shape with smooth surface.The surface morphology of spray-dried chitosan microspheres was affected by the crystallinity ofthe loaded drug and cross-linking agent.The release data of the spray-dried chitosanmicrospheres were treated with Zero-order,First-order,Higuchi,Korsmeyer,andKopcha kinetic models and best fit was observed with Higuchi model,indicating therelease of drug from spray-dried chitosan microspheres followed Fick's law ofdiffusion.
The mean particle size of drug-loaded spray-dried SPS microparticles wasbetween 10.3 to 13.1μm.The mean particle size increased slightly with increase inthe concentration of SPS.The % yield of spray-dried SPS microparticles did not varymuch among the various formulations and it was between 65.2 to 70.1%.The drugloading efficiency of spray-dried SPS microparticles decreased slightly with anincreasing concentration of SPS.The loading efficiencies are 77.4,72.3,and 68.5 %,respectively.The cumulative amount of drug release from the spray-dried SPSmicroparticles decreased with an increase in the concentration of SPS and in the drugloading.The dissolution data were treated with Higuchi equation and it was found thatrelease of the drug from spray-dried SPS microparticles followed Fick's law ofdiffusion since good correlation coefficient (R~2) was observed with the Higuchi plots.
引文
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1．Leuner C．， Dressman J．．Improving drug solubility for oral delivery using solid dispersions．Eur．J．Pharm．Biopharm．2000， 50， 47-60．
2．Yalkwosky S．H．， Valvani S．C．．Solubility and partitioning： solubility of nonelectrolytes in water．J．Pharm．Sci．1980， 69， 912-922．
3．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Deliv．Rev．1997， 25， 3-14．
4．Desai K．G．H．， Kulkami A．R．， Aminabhavi T．M．．Solubility of rofecoxib in the presence of methanol， ethanol， and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng Data．2003， 48， 942-945．
5．Strickley R．G．．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004，21， 201-230．
6．Mani N．， Jun H．W， Beach J．W， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 385-396．
7．Lane N．E．， Thompson， J．M．．Management of osteoarthritis in the primary-care setting： an evidence-based approach to treatment．Am．J．Med．1997， 103， 25-35．
8．Needleman P．， Isakson P．C．．The discovery and function of COX- 2．J．Rheumatol．1997， 24，2-7．
9．Barden J．， Edwards J．E．， McQuay H．J．， et al．Oral valdecoxib and injected paracoxib for acute postoperative pain： A quantitative systematic review．BMC Anesthesiol．2003， 3， 1-8．
10．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002，62，2059-2071．
11．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J．Med．Chem．2001， 36， 109-126．
12．Yalkowsky S．H．， Rubino J．T．．Solubilization of cosolvents 1： Organic solutes in propylene glycol-water mixtures．J．Pharm．Sci．1985， 74， 416-421．
13．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H．．Solubilization by cosolvents：Establishing useful constants for the loglinear model．Int．J．Pharm．2002， 245， 153-166．
14．Ran Y．， Zhao L．， Xu Q．， et al．Solubilization of cyclosporin A．AAPS PharmSciTech．2001， 2，article 2．
15．Khalil E．， Najjar S．， Sallam A．．Aqueous Solubility of diclofenac diethylamine in the presence of pharmaceutical additives： A comparative study with diclofenac sodium．Drug Dev．Ind．Pharm．2000，26，375-381．
16．Tang L．， Khan S．U．， Muhammad N．A．．Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity．Pharm．Dev．Technol．2001， 6，531-540．
1．Leuner C．， Dressman J．．Improving drug solubility for oral delivery using solid dispersions．Eur．J．Pharm．Biopharm．2000， 50， 47-60．
2．Yalkwosky S．H．， Valvani S．C．．Solubility and partitioning： Solubility of nonelectrolytes in water．J．Pharm．Sci．1980， 69， 912-922．
3．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Del．Rev．1997， 25， 3-14．
4．Strickley R．G．．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004，21， 201-230．
5．Mani N．， Jun H．W．， Beach J．W．， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 385-396．
6．Liu C．， Desai K．G．H．， Liu C．．Solubility of rofecoxib in the presence of mannitol， poly (vinylpyrrolidone) K30， urea， poly (ethylene glycol) 4000， and poly (ethylene glycol) 6000 at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2005， 50， 661-665．
7．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of poly (ethylene glycol) 4000， poly (ethylene glycol) 6000， poly (ethylene glycol) 8000 and poly (ethylene glycol) 10 000 at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2005， 50， 278-282．
8．Yalkowsky S．H．， Rubino J．T．Solubilization of cosolvents 1：Organic solutes in propylene glycol-water mixtures．J．Pharm．Sci．1985， 74， 416-421．
9．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H．．Solubilization by cosolvents： Establishing useful constants for the log-linear model．Int．J．Pharm．2002， 245， 153-166．
10．Ran Y．， Zhao L．， Xu Q．， et al．Solubilization of cyclosporin A．AAPS PharmSciTech．2001， 2，article 2．
11．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002， 62， 2059-207 1．
12．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001， 36， 109-126．
13．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H，．Solubilization by cosolvents：Establishing useful constants for the log-linear model．Int．J．Pharm．2002， 245， 153-166．
14. Ran Y., Zhao L., Xu Q., et al. Solubilization of cyclosporin A. AAPS PharmSciTech. 2001, 2, article 2.
15. Tang L., Khan S. U., Muhammad N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity. Pharm. Dev. Technol. 2001, 6, 531-540.
16. Seedher N., Bhatia S.. Solubility enhancement of COX-2 inhibitors using various solvents systems. AAPS PharmSciTech. 2003,4, article 33.
17. Damian F., Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
1．Needleman P．， Isakson P．C．．The discovery and function of COX-2．J．Rheumatol．1997， 24，2-7．
2．Barden J．， Edwards J．E．， McQuay H．J．， et al．Oral valdecoxib and injected paracoxib for acute postoperative pain： A quantitative systematic review．BMC Anesthesiol．2003， 3， 1-8．
3．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002，62，2059-2071．
4．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001， 36， 109-126．
5．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of ethanol and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2004， 49， 1847-1850．
6．Desai K．G．H．， Kulkarni A．R．， Aminabhavi T．M．．Solubility of rofecoxib in the presence of methanol， ethanol， and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2003， 48， 942-945．
7．Leuner C．， Dressman J．．Improving drug solubility for oral delivery using solid dispersions．Eur．J．Pharm．Biopharm．2000， 50， 47-60．
8．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Delivery Rev．1997， 25， 3-14．
9．Strickley R．G．．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004，21， 201-230．
10．Mani N．， Jun H．W．， Beach J．W．， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 385-396．
11．Tang L．， Khan S．U．， Muhammad N．A．．Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity．Pharm．Dev．Technol．2001， 6，531-540．
1.Leuner C., Dressman J.. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000, 50,47-60.
2.Hoerter D., Dressman J. B.. Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review). Adv. Drug Deliv. Rev. 1997, 25, 3-14.
3.Strickley R. G.. Solubilizing excipients in oral and injectable formulations. Pharm. Res. 2004, 21,201-230.
4.Mani N., Jun H. W., Beach J. W., et al. Solubility of guaifenesin in the presence of common pharmaceutical additives. Pharm. Dev. Technol. 2003,8,385-396.
5.Tang L., Khan S. U., Muhammad N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity. Pharm. Dev. Technol. 2001, 6, 531-540.
6.Liu C., Desai K. G. H., Liu C.. Solubility of valdecoxib in the presence of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, and polyethylene glycol 10000 at (298.15,303.15, and 308.15) K. J. Chem. Eng. Data. 2005, 50, 278-282.
7.Desai K. G. H., Kulkarni A. R., Aminabhavi T. M.. Solubility of rofecoxib in the presence of methanol, ethanol, and sodium lauryl sulfate at (298.15,303.15, and 308.15) K. J. Chem. Eng. Data. 2003,48, 942-945.
8.Needleman P., Isakson P. C.. The discovery and function of COX-2. J. Rheumatol. 1997, 24, 2-7.
9.Dannhardt G., Kiefer W.. Cyclooxygenase inhibitors-current status and future prospects. Eur. J. Med. Chem. 2001,36,109-126.
10.Liu C., Desai K. G. H., Liu C.. Solubility of valdecoxib in the presence of ethanol and sodium lauryl sulfate at (298.15,303.15, and 308.15) K. J. Chem. Eng. Data. 2004, 49,1847-1850.
11.Ajithadas P., Anusuya P., Balamariappan C., et al. Reverse phase high performance liquid chromatographic determination of rofecoxib in tablets. Indian Drugs. 2001, 38,523-525.
12.Damian F., Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
1．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Del．Rev．1997， 25， 3-14．
2．Mani N．， Jun H．W．， Beach J．W．， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 3 85-396．
3．Yalkwosky S．H．， Valvani S．C．．Solubility and partitioning： solubility of nonelectrolytes in water．J．Pharm．Sci．1980， 69， 912-922．
4．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of ethanol and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2004， 49， 1847-1850．
5．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of polyethylene glycol 4000， polyethylene glycol 6000， polyethylene glycol 8000， and polyethylene glycol 10 000 at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2005， 50， 278-282．
6．Strickley R．G．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004， 21， 201-230．
7．Needleman P．， Isakson P．C．．The discovery and function of COX-2．J．Rheumatol．1997， 24，2-7．
8．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001，36，109-126．
9．Scott L．J．， Lamb H．M．．Rofecoxib．Drugs．1999，58，499-505．
10．Ajithadas P．， Anusuya P．， Balamariappan C．， et al．Reverse Phase High Performance Liquid Chromatographic Determination of Rofecoxib in Tablets．Indian Drugs．2001， 38， 523-525．
11．Yalkowsky S．H．， Rubino J．T．．Solubilization of cosolvents 1：Organic solutes in propylene glycol-water mixtures．J．Pharm．Sci．1985， 74， 416-421．
12．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H．．Solubilization by cosolvents：Establishing useful constants for the log-linear model．Int．J．Pharm．2002， 245， 153-166．
13．Ran Y．， Zhao L．， Xu Q．， et al．Solubilization of cyclosporin A．AAPS PharmSciTech．2001， 2，article 2．
1．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002，62，2059-2071．
2．Bolten W．W．Scientific rationale for specific inhibition of COX-2．J．Rheumatol．1998， 24，2-7．
3．Barden J．， Edwards J．E．， McQuay H．J．， et al．Oral valdecoxib and injected parecoxib for acute postoperative pain： a quantitative systematic review．BMC Anesthesiol．2003， 3， 1-8．
4．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001， 36， 109-126．
5．Lobenberg R．， Amidon G．L．．Modem bioavailability， bioequivalence and biopharmaceutics classification system： New scientific approaches to international regulatory standards．Eur．J．Pharm．Biopharm．2000， 50， 3-12．
6．Desai K．G．H．， Kulkarni A．R．， Aminabhavi T．M．．Solubility of rofecoxib in the presence of methanol， ethanol and sodium lauryl sulfate at (298．15， 303．15 and 308．15) K．Chem．Eng．Data．2003， 48， 942-945．
7．Rawat S．， Jain S．K．．Rofecoxib-b-cyclodextrin inclusion complex for solubility enhancement．Pharmazie．2003， 58， 639-641．
8．Ford J．L．．The current status of solid dispersions．Pharm．Act．Hely．1986， 61， 69-88．
9．GoldbergA．H．， Gibaldi， M．， Kanig， J．L．．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅰ-theoretical consideration and discussion of the literature．J．Pharm．Sci．1965， 54， 1145-1148．
10．Goldberg A．H．， Gibaldi M．， Kanig， J．L．．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅱ-experimental evaluation of a eutectic mixture： urea-acetaminophen system．J．Pharm．Sci．1966a， 55， 482-487．
11．Goldberg A．H．， Gibaldi M．， Kanig J．L．， et al．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅳ-chloramphenicol-urea system．J．Pharm．Sci．1966b， 55， 581-583．
12．Chiou W．L．， Riegelman S．．Pharmaceutical applications of solid dispersions．J．Pharm．Sci．1971， 60， 1281-1302．
13．Betageri G．V．， Makarla K．R．．Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int. J. Pharm. 1995,126,155-160.
14.Leuner C., Dressman J.. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000, 50,47-60.
15.Asker A. F., Whitworth C. W.. Dissolution of acetyl salicylic acid from acetyl salicylic acid-polyethylene glycol 6000 coprecipitates. Pharmazie. 1975,30, 530-531.
16.Higuchi T., Connors, K.. Phase solubility techniques. Adv. in Analytical Chem. and Inst. 1965, 4, 17-123.
17.Damian R, Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
18.Okonogi S., Oguchi T., Yonemochi E., et al. Improved dissolution of ofloxacin via solid dispersion. Int. J. Pharm. 1997a, 156, 175-180.
19.Serajuddin A. T. M., Sheen P. C., Augustine, M. A.. Improved dissolution of poorly water-soluble drug from solid dispersions in polyethylene: polysorbate 80 mixture. J. Pharm. Sci. 1990, 79,463-464.
20.Barzegar-Jalali M., Maleki N., Garjani A., et al. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev. Ind. Pharm. 2002,28,681-686.
21.Tang L., Khan, S. U., Muhammad, N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water soluble new chemical entity. Pharm. Dev. Technol. 2001,6,531-540.
22.Fernandez M., Rodriguez I. C., Margarit M. V., et al. Characterization of solid dispersion of piroxicam/polyethylene glycol 4000. Int. J. Pharm. 1992,84,197-202.
23.Margarit M. V., Rodriguez I. C., Cerezo A.. Physical characteristics and dissolution kinetics of solid dispersions of ketoprofen and polyethylene glycol 6000. Int. J. Pharm. 1994, 108, 101-107.
24.Najib N. M., Suleiman M. S.. Characterization of a diflunisal polyethylene glycol solid dispersion system. Int. J. Pharm. 1989, 51,225-232.
25.Okonogi S., Yonemochi E., Oguchi T., et al. Enhanced dissolution of ursodeoxycholic acid from the solid dispersion. Drug Dev. Ind. Pharm. 1997b, 23,1115-1121.
26.Shin S. C., Kim J.. Physicochemical characterization of solid dispersion of furosemide with TPGS．Int．J．Pharm．2003， 251， 79-84．
27．Shin S．C．， Oh I．J．， Lee K．C．， et al．Dissolution enhancement of furosemide from ground mixtures with chitin or chitosan．J．Korean Pharm．Sci．1987， 17， 175-181．
28．Yamashita K．， Nakate T．， Okimoto K．， et al．Establishment of new preparation method for solid dispersion formulation of tacrolimus．Int．J．Pharm．2003， 267， 79-91．
1.Leuner C., Dressman J.. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000,50,47-60.
2.Scott L. J., Lamb H. M.. Rofecoxib. Drugs. 1999,58,499-505.
3.Bolten W. W.. Scientific rationale for specific inhibition of COX-2. J. Rheumatol. 1998, 25, 2-7.
4.Needleman P., Isakson P. C.. The discovery and function of COX-2. J. Rheumatol, 1997, 49, 6-8.
5.Desai K. G. H., Kulkarni A. R., Aminabhavi T. M.. Solubility of rofecoxib in the presence of methanol, ethanol and sodium lauryl sulfate at (298.15, 303.15 and 308.15) K. J. Chem. Eng. Data. 2003,48,942-945.
6.FitzGerald G. A.. Coxibs and cardiovascular disease. New Engl. J. Med. 2004, 351, 1709-1711.
7.Hoerter D., Dressman J. B.. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract (review). J. Pharm. Sci. 1997, 86,1-12.
8.Kai T., Akiyama Y., Nomura S., et al. Oral absorption improvement of poorly soluble drug using solid dispersion technique. Chem. Pharm. Bull. 1996,44, 568-571.
9.Goldberg A. H., Gibaldi M., Kanig J. L.. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. Ⅱ: Experimental evaluation of a eutectic mixture: urea-acetaminophen system. J. Pharm. Sci. 1966a, 55,482-487.
10.Goldberg A. H., Gibaldi M., Kanig J. L.. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. Ⅲ: Experimental evaluation of griseofulvin-succinic acid solid solution. J. Pharm. Sci. 1966b, 55,482-487.
11.Chiou W. L., Riegelman S.. Pharmaceutical applications of solid dispersions. J. Pharm. Sci. 1971,60,1281-1302.
12.Ford J. L.. The current status of solid dispersions. Pharm. Act. Helv. 1986,61,69-88.
13.Goldberg A. H., Gibaldi M, Kanig J. L.. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. Ⅰ: Theoretical consideration and discussion of the literature. J. Pharm. Sci. 1965, 54,1145-1148.
14.Khan G. M., Zhu J. B.. Preparation, characterization, and dissolution studies of ibuprofen solid dispersions using polyethylene glycol (PEG), talc, and PEG-talc as dispersion carriers. Drug Dev. Ind. Pharm. 1998,24,455-462.
15.Okonogi S., Oguchi T., Yonemochi E., et al. Improved dissolution of ofloxacin via solid dispersion. Int. J. Pharm. 1997a, 156,175-180.
16.Kearney A. S., Gabriel D. W., Mehta S. C, et al. Effect of polyvinylpyrrolidone on the crystallinity and dissolution rate of solid dispersions of the anti-inflammatory Ci-987. Int. J. Pharm. 1994,104,169-174.
17.Chutimaworapan S., Ritthidej G. C., Yonemochi E., et al. Effect of water-soluble carriers on dissolution characteristics of nifedipine solid dispersions. Drug Dev. Ind. Pharm. 2000, 26, 1141-1150.
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19.Goldberg A. H., Gibaldi M., Kanig J. L., et al. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. Ⅳ: Chloramphenicol-urea system. J. Pharm. Sci. 1966c, 55, 581-583.
20.Okonogi S., Yonemochi E., Oguchi T., et al. Enhanced dissolution of ursodeoxycholic acid from the solid dispersion. Drug Dev. Ind. Pharm. 1997b, 23,1115-1121.
21.Ko J. A., Park H. J., Hwang S. J., et al. Preparation and characterization of chitosan microparticles intended for controlled drug delivery. Int. J. Pharm. 2002,249,165-174.
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23.Lee D. W., Hwang S. J., Park J. B., et al. Preparation and release characteristics of polymer-coated and blended alginate microspheres. J. Microencapsul. 2003,20,179-192.
24.Higuchi T., Connors K.. Phase solubility techniques. Adv. in Analytical Chem. and Inst. 1965, 4:7-123.
25.Shah S. P., Flanagan D. R... Solubilization of salicylamide and acetaminophen by antihistamines in aqueous solution. J. Pharm. Sci. 1990,79,889-892.
26. Bloch D. W., Elegakey M. A., Speiser P. P.. Solid dispersion of chlothalidone in urea phase diagram and dissolution characteristics. Pharm. Act. Helv. 1982,57,231-235.
27. Damian F., Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
28. Serajuddin A. T. M., Sheen P. C., Augustine M. A.. Improved dissolution of poorly water-soluble drug from solid dispersions in polyethylene: polysorbate 80 mixture. J. Pharm. Sci. 1990, 79,463-464.
29. Tang L., Khan S. U., Muhammad N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water soluble new chemical entity. Pharm. Dev. Tech. 2001,6, 531-540.
30. Barzegar-Jalali M., Maleki N., Garjani A., et al. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev. Ind. Pharm. 2002,28, 681-686.
31. Shim S. C., Kim J.. Physicochemical characterization of solid dispersion of furosemide with TPGS. Int. J. Pharm. 2003,251,79-84.
32. Hancock B. C., Zographi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86,1-12.
33. Shin S. C., Oh I. J., Lee K. C., et al. Dissolution enhancement of furosemide from ground mixtures with chitin or chitosan. J. Korean Pharm. Sci. 1987,17,175-181.
1．Goldberg A．H．， Gibaldi M．， Kanig J．L．．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅰ-theoretical consideration and discussion of the literature．J．Pharm．Sci．1965， 54， 1145-1148．
2．Goldberg A．H．， Gibaldi M．， Kanig J．L．．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅱ- experimental evaluation of a eutectic mixture： urea-acetaminophen system．J．Pharm．Sci．1966， 55， 482-487．
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62．Liu L．， Fishman M．， Kost， J．， et al．Pectin-based systems for colon-specific drug delivery via oral route．Biomaterials．2003， 24， 3333-3343．
63．Liu C．S．， Desai K．G．H．， Tang X．E．， et al．Drug release kinetics of spray-dried chitosan microspheres．Dry．Technol．2006， 24， 769-776．
1．Leuner C．， Dressman J．．Improving drug solubility for oral delivery using solid dispersions．Eur．J．Pharm．Biopharm．2000， 50， 47-60．
2．Yalkwosky S．H．， Valvani S．C．．Solubility and partitioning： solubility of nonelectrolytes in water．J．Pharm．Sci．1980， 69， 912-922．
3．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Deliv．Rev．1997， 25， 3-14．
4．Desai K．G．H．， Kulkami A．R．， Aminabhavi T．M．．Solubility of rofecoxib in the presence of methanol， ethanol， and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng Data．2003， 48， 942-945．
5．Strickley R．G．．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004，21， 201-230．
6．Mani N．， Jun H．W， Beach J．W， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 385-396．
7．Lane N．E．， Thompson， J．M．．Management of osteoarthritis in the primary-care setting： an evidence-based approach to treatment．Am．J．Med．1997， 103， 25-35．
8．Needleman P．， Isakson P．C．．The discovery and function of COX- 2．J．Rheumatol．1997， 24，2-7．
9．Barden J．， Edwards J．E．， McQuay H．J．， et al．Oral valdecoxib and injected paracoxib for acute postoperative pain： A quantitative systematic review．BMC Anesthesiol．2003， 3， 1-8．
10．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002，62，2059-2071．
11．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J．Med．Chem．2001， 36， 109-126．
12．Yalkowsky S．H．， Rubino J．T．．Solubilization of cosolvents 1： Organic solutes in propylene glycol-water mixtures．J．Pharm．Sci．1985， 74， 416-421．
13．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H．．Solubilization by cosolvents：Establishing useful constants for the loglinear model．Int．J．Pharm．2002， 245， 153-166．
14．Ran Y．， Zhao L．， Xu Q．， et al．Solubilization of cyclosporin A．AAPS PharmSciTech．2001， 2，article 2．
15．Khalil E．， Najjar S．， Sallam A．．Aqueous Solubility of diclofenac diethylamine in the presence of pharmaceutical additives： A comparative study with diclofenac sodium．Drug Dev．Ind．Pharm．2000，26，375-381．
16．Tang L．， Khan S．U．， Muhammad N．A．．Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity．Pharm．Dev．Technol．2001， 6，531-540．
1．Leuner C．， Dressman J．．Improving drug solubility for oral delivery using solid dispersions．Eur．J．Pharm．Biopharm．2000， 50， 47-60．
2．Yalkwosky S．H．， Valvani S．C．．Solubility and partitioning： Solubility of nonelectrolytes in water．J．Pharm．Sci．1980， 69， 912-922．
3．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Del．Rev．1997， 25， 3-14．
4．Strickley R．G．．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004，21， 201-230．
5．Mani N．， Jun H．W．， Beach J．W．， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 385-396．
6．Liu C．， Desai K．G．H．， Liu C．．Solubility of rofecoxib in the presence of mannitol， poly (vinylpyrrolidone) K30， urea， poly (ethylene glycol) 4000， and poly (ethylene glycol) 6000 at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2005， 50， 661-665．
7．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of poly (ethylene glycol) 4000， poly (ethylene glycol) 6000， poly (ethylene glycol) 8000 and poly (ethylene glycol) 10 000 at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2005， 50， 278-282．
8．Yalkowsky S．H．， Rubino J．T．Solubilization of cosolvents 1：Organic solutes in propylene glycol-water mixtures．J．Pharm．Sci．1985， 74， 416-421．
9．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H．．Solubilization by cosolvents： Establishing useful constants for the log-linear model．Int．J．Pharm．2002， 245， 153-166．
10．Ran Y．， Zhao L．， Xu Q．， et al．Solubilization of cyclosporin A．AAPS PharmSciTech．2001， 2，article 2．
11．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002， 62， 2059-207 1．
12．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001， 36， 109-126．
13．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H，．Solubilization by cosolvents：Establishing useful constants for the log-linear model．Int．J．Pharm．2002， 245， 153-166．
14. Ran Y., Zhao L., Xu Q., et al. Solubilization of cyclosporin A. AAPS PharmSciTech. 2001, 2, article 2.
15. Tang L., Khan S. U., Muhammad N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity. Pharm. Dev. Technol. 2001, 6, 531-540.
16. Seedher N., Bhatia S.. Solubility enhancement of COX-2 inhibitors using various solvents systems. AAPS PharmSciTech. 2003,4, article 33.
17. Damian F., Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
1．Needleman P．， Isakson P．C．．The discovery and function of COX-2．J．Rheumatol．1997， 24，2-7．
2．Barden J．， Edwards J．E．， McQuay H．J．， et al．Oral valdecoxib and injected paracoxib for acute postoperative pain： A quantitative systematic review．BMC Anesthesiol．2003， 3， 1-8．
3．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002，62，2059-2071．
4．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001， 36， 109-126．
5．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of ethanol and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2004， 49， 1847-1850．
6．Desai K．G．H．， Kulkarni A．R．， Aminabhavi T．M．．Solubility of rofecoxib in the presence of methanol， ethanol， and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2003， 48， 942-945．
7．Leuner C．， Dressman J．．Improving drug solubility for oral delivery using solid dispersions．Eur．J．Pharm．Biopharm．2000， 50， 47-60．
8．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Delivery Rev．1997， 25， 3-14．
9．Strickley R．G．．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004，21， 201-230．
10．Mani N．， Jun H．W．， Beach J．W．， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 385-396．
11．Tang L．， Khan S．U．， Muhammad N．A．．Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity．Pharm．Dev．Technol．2001， 6，531-540．
1.Leuner C., Dressman J.. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000, 50,47-60.
2.Hoerter D., Dressman J. B.. Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review). Adv. Drug Deliv. Rev. 1997, 25, 3-14.
3.Strickley R. G.. Solubilizing excipients in oral and injectable formulations. Pharm. Res. 2004, 21,201-230.
4.Mani N., Jun H. W., Beach J. W., et al. Solubility of guaifenesin in the presence of common pharmaceutical additives. Pharm. Dev. Technol. 2003,8,385-396.
5.Tang L., Khan S. U., Muhammad N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity. Pharm. Dev. Technol. 2001, 6, 531-540.
6.Liu C., Desai K. G. H., Liu C.. Solubility of valdecoxib in the presence of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, and polyethylene glycol 10000 at (298.15,303.15, and 308.15) K. J. Chem. Eng. Data. 2005, 50, 278-282.
7.Desai K. G. H., Kulkarni A. R., Aminabhavi T. M.. Solubility of rofecoxib in the presence of methanol, ethanol, and sodium lauryl sulfate at (298.15,303.15, and 308.15) K. J. Chem. Eng. Data. 2003,48, 942-945.
8.Needleman P., Isakson P. C.. The discovery and function of COX-2. J. Rheumatol. 1997, 24, 2-7.
9.Dannhardt G., Kiefer W.. Cyclooxygenase inhibitors-current status and future prospects. Eur. J. Med. Chem. 2001,36,109-126.
10.Liu C., Desai K. G. H., Liu C.. Solubility of valdecoxib in the presence of ethanol and sodium lauryl sulfate at (298.15,303.15, and 308.15) K. J. Chem. Eng. Data. 2004, 49,1847-1850.
11.Ajithadas P., Anusuya P., Balamariappan C., et al. Reverse phase high performance liquid chromatographic determination of rofecoxib in tablets. Indian Drugs. 2001, 38,523-525.
12.Damian F., Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
1．Hoerter D．， Dressman J．B．．Influence of physiochemical properties on dissolution of drugs in the gastrointestinal tract (review)．Adv．Drug Del．Rev．1997， 25， 3-14．
2．Mani N．， Jun H．W．， Beach J．W．， et al．Solubility of guaifenesin in the presence of common pharmaceutical additives．Pharm．Dev．Technol．2003， 8， 3 85-396．
3．Yalkwosky S．H．， Valvani S．C．．Solubility and partitioning： solubility of nonelectrolytes in water．J．Pharm．Sci．1980， 69， 912-922．
4．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of ethanol and sodium lauryl sulfate at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2004， 49， 1847-1850．
5．Liu C．， Desai K．G．H．， Liu C．．Solubility of valdecoxib in the presence of polyethylene glycol 4000， polyethylene glycol 6000， polyethylene glycol 8000， and polyethylene glycol 10 000 at (298．15， 303．15， and 308．15) K．J．Chem．Eng．Data．2005， 50， 278-282．
6．Strickley R．G．Solubilizing excipients in oral and injectable formulations．Pharm．Res．2004， 21， 201-230．
7．Needleman P．， Isakson P．C．．The discovery and function of COX-2．J．Rheumatol．1997， 24，2-7．
8．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001，36，109-126．
9．Scott L．J．， Lamb H．M．．Rofecoxib．Drugs．1999，58，499-505．
10．Ajithadas P．， Anusuya P．， Balamariappan C．， et al．Reverse Phase High Performance Liquid Chromatographic Determination of Rofecoxib in Tablets．Indian Drugs．2001， 38， 523-525．
11．Yalkowsky S．H．， Rubino J．T．．Solubilization of cosolvents 1：Organic solutes in propylene glycol-water mixtures．J．Pharm．Sci．1985， 74， 416-421．
12．Millard J．W．， Alvarez-Nunez F．A．， Yalkowsky S．H．．Solubilization by cosolvents：Establishing useful constants for the log-linear model．Int．J．Pharm．2002， 245， 153-166．
13．Ran Y．， Zhao L．， Xu Q．， et al．Solubilization of cyclosporin A．AAPS PharmSciTech．2001， 2，article 2．
1．Ormrod D．， Wellington K．， Wagstaff A．J．．Valdecoxib．Drugs．2002，62，2059-2071．
2．Bolten W．W．Scientific rationale for specific inhibition of COX-2．J．Rheumatol．1998， 24，2-7．
3．Barden J．， Edwards J．E．， McQuay H．J．， et al．Oral valdecoxib and injected parecoxib for acute postoperative pain： a quantitative systematic review．BMC Anesthesiol．2003， 3， 1-8．
4．Dannhardt G．， Kiefer W．．Cyclooxygenase inhibitors-current status and future prospects．Eur．J Med．Chem．2001， 36， 109-126．
5．Lobenberg R．， Amidon G．L．．Modem bioavailability， bioequivalence and biopharmaceutics classification system： New scientific approaches to international regulatory standards．Eur．J．Pharm．Biopharm．2000， 50， 3-12．
6．Desai K．G．H．， Kulkarni A．R．， Aminabhavi T．M．．Solubility of rofecoxib in the presence of methanol， ethanol and sodium lauryl sulfate at (298．15， 303．15 and 308．15) K．Chem．Eng．Data．2003， 48， 942-945．
7．Rawat S．， Jain S．K．．Rofecoxib-b-cyclodextrin inclusion complex for solubility enhancement．Pharmazie．2003， 58， 639-641．
8．Ford J．L．．The current status of solid dispersions．Pharm．Act．Hely．1986， 61， 69-88．
9．GoldbergA．H．， Gibaldi， M．， Kanig， J．L．．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅰ-theoretical consideration and discussion of the literature．J．Pharm．Sci．1965， 54， 1145-1148．
10．Goldberg A．H．， Gibaldi M．， Kanig， J．L．．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅱ-experimental evaluation of a eutectic mixture： urea-acetaminophen system．J．Pharm．Sci．1966a， 55， 482-487．
11．Goldberg A．H．， Gibaldi M．， Kanig J．L．， et al．Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures Ⅳ-chloramphenicol-urea system．J．Pharm．Sci．1966b， 55， 581-583．
12．Chiou W．L．， Riegelman S．．Pharmaceutical applications of solid dispersions．J．Pharm．Sci．1971， 60， 1281-1302．
13．Betageri G．V．， Makarla K．R．．Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int. J. Pharm. 1995,126,155-160.
14.Leuner C., Dressman J.. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000, 50,47-60.
15.Asker A. F., Whitworth C. W.. Dissolution of acetyl salicylic acid from acetyl salicylic acid-polyethylene glycol 6000 coprecipitates. Pharmazie. 1975,30, 530-531.
16.Higuchi T., Connors, K.. Phase solubility techniques. Adv. in Analytical Chem. and Inst. 1965, 4, 17-123.
17.Damian R, Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
18.Okonogi S., Oguchi T., Yonemochi E., et al. Improved dissolution of ofloxacin via solid dispersion. Int. J. Pharm. 1997a, 156, 175-180.
19.Serajuddin A. T. M., Sheen P. C., Augustine, M. A.. Improved dissolution of poorly water-soluble drug from solid dispersions in polyethylene: polysorbate 80 mixture. J. Pharm. Sci. 1990, 79,463-464.
20.Barzegar-Jalali M., Maleki N., Garjani A., et al. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev. Ind. Pharm. 2002,28,681-686.
21.Tang L., Khan, S. U., Muhammad, N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water soluble new chemical entity. Pharm. Dev. Technol. 2001,6,531-540.
22.Fernandez M., Rodriguez I. C., Margarit M. V., et al. Characterization of solid dispersion of piroxicam/polyethylene glycol 4000. Int. J. Pharm. 1992,84,197-202.
23.Margarit M. V., Rodriguez I. C., Cerezo A.. Physical characteristics and dissolution kinetics of solid dispersions of ketoprofen and polyethylene glycol 6000. Int. J. Pharm. 1994, 108, 101-107.
24.Najib N. M., Suleiman M. S.. Characterization of a diflunisal polyethylene glycol solid dispersion system. Int. J. Pharm. 1989, 51,225-232.
25.Okonogi S., Yonemochi E., Oguchi T., et al. Enhanced dissolution of ursodeoxycholic acid from the solid dispersion. Drug Dev. Ind. Pharm. 1997b, 23,1115-1121.
26.Shin S. C., Kim J.. Physicochemical characterization of solid dispersion of furosemide with TPGS．Int．J．Pharm．2003， 251， 79-84．
27．Shin S．C．， Oh I．J．， Lee K．C．， et al．Dissolution enhancement of furosemide from ground mixtures with chitin or chitosan．J．Korean Pharm．Sci．1987， 17， 175-181．
28．Yamashita K．， Nakate T．， Okimoto K．， et al．Establishment of new preparation method for solid dispersion formulation of tacrolimus．Int．J．Pharm．2003， 267， 79-91．
1.Leuner C., Dressman J.. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000,50,47-60.
2.Scott L. J., Lamb H. M.. Rofecoxib. Drugs. 1999,58,499-505.
3.Bolten W. W.. Scientific rationale for specific inhibition of COX-2. J. Rheumatol. 1998, 25, 2-7.
4.Needleman P., Isakson P. C.. The discovery and function of COX-2. J. Rheumatol, 1997, 49, 6-8.
5.Desai K. G. H., Kulkarni A. R., Aminabhavi T. M.. Solubility of rofecoxib in the presence of methanol, ethanol and sodium lauryl sulfate at (298.15, 303.15 and 308.15) K. J. Chem. Eng. Data. 2003,48,942-945.
6.FitzGerald G. A.. Coxibs and cardiovascular disease. New Engl. J. Med. 2004, 351, 1709-1711.
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8.Kai T., Akiyama Y., Nomura S., et al. Oral absorption improvement of poorly soluble drug using solid dispersion technique. Chem. Pharm. Bull. 1996,44, 568-571.
9.Goldberg A. H., Gibaldi M., Kanig J. L.. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. Ⅱ: Experimental evaluation of a eutectic mixture: urea-acetaminophen system. J. Pharm. Sci. 1966a, 55,482-487.
10.Goldberg A. H., Gibaldi M., Kanig J. L.. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures. Ⅲ: Experimental evaluation of griseofulvin-succinic acid solid solution. J. Pharm. Sci. 1966b, 55,482-487.
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20.Okonogi S., Yonemochi E., Oguchi T., et al. Enhanced dissolution of ursodeoxycholic acid from the solid dispersion. Drug Dev. Ind. Pharm. 1997b, 23,1115-1121.
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27. Damian F., Blaton N., Naesens L., et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000,10,311-322.
28. Serajuddin A. T. M., Sheen P. C., Augustine M. A.. Improved dissolution of poorly water-soluble drug from solid dispersions in polyethylene: polysorbate 80 mixture. J. Pharm. Sci. 1990, 79,463-464.
29. Tang L., Khan S. U., Muhammad N. A.. Evaluation and selection of bio-relevant dissolution media for a poorly water soluble new chemical entity. Pharm. Dev. Tech. 2001,6, 531-540.
30. Barzegar-Jalali M., Maleki N., Garjani A., et al. Enhancement of dissolution rate and anti-inflammatory effects of piroxicam using solvent deposition technique. Drug Dev. Ind. Pharm. 2002,28, 681-686.
31. Shim S. C., Kim J.. Physicochemical characterization of solid dispersion of furosemide with TPGS. Int. J. Pharm. 2003,251,79-84.
32. Hancock B. C., Zographi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86,1-12.
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1．Desai K．G．H．， Park H．J．．Preparation and characterization of drug-loaded chitosan-tripolyphosphate microspheres by spray drying．Drug Develop．Res．2005， 64，114-128．
2．Desai K．C．H．， Park H．J．．Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying．J．Microencapsul．2005， 22，179-192．
3．Liu C．G．， Desai K．G．H．， Chen X．G．， et al．Linolenic acid modified chitosan for formation of self-assembled nanoparticles．J．Agr．Food．Chem．2005， 53， 437-441．
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5．Chourasia M．K．， Jain， S．K．．Polysaccharides for colon targeted drug delivery．Drug Deliv 2004， 11， 129-148．
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8．Hejazi R．， Amiji M．．Chitosan-based gastrointestinal delivery systems．J．Control．Release．2003， 89， 151-165．
9．Ravi Kumar M．N．V．．Nano and microparticles as controlled drug delivery devices．J．Pharm．Pharm．Sci．2000， 3， 234-258．
10．Prabaharan M．， Mano J．F．．Chitosan-based particles as controlled drug delivery systems．Drug Deliv．2005， 12， 41-57．
11．Desai K．G．H．， Park H．J．Recent developments in microencapsulation of food ingredients．Dry．Technol．2005， 23， 1361-1394．
12．Huang L．， Kumar K．， Mujumdar A．S．．Simulation of a spray dryer fitted with a rotary disk atomizer using a three-dimensional computational fluid dynamic model．Dry．Technol．2004， 22， 1489-1515．
13．Mujumdar， A．S．Research and development in drying： Recent trends and future prospectus．Drying Technology， 2004， 22(1)：1-26．
14．Huang， L．， Kumar， K．， and Mujumdar， A．S．A parametric study of the gas flow patterns and drying performance of co-current spray dryer： Results of a computational fluid dynamics study．Drying Technology， 2003， 21(6)：957-978．
15．Huang， L．， Kumar， K．， and Mujumdar， A．S．Use of computational fluid dynamics to evaluate alternative spray dryer chamber configurations．Drying Technology， 2003，21(3)：385-412．
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17．Fu， Y．J．， Mi， F．L．， Wong， T．B．， and Shyu， S．S．Characteristics and controlled release of anticancer drug loaded poly (D，L-lactide) microparticles by spray drying technique．Journal of Microencapsulation， 2001， 18(6)：733-747．
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