预交联法制备海藻酸钠复合微球及其缓释性能

采用预交联法制备海藻酸钠(SA)/凹土(ATP)复合微球(PCM)以克服常规制备方法导致微球交联不均匀的缺陷,从而改善微球的缓释性能。将ATP先与Ca~(2+)进行部分离子交换制备Ca~(2+)-ATP,然后在与SA复合过程中同时进行预交联形成交联密度有所提高的微球内核,再采用滴注法制备该复合微球。利用红外光谱、扫描电镜和电子照片对微球结构和形貌进行表征,考察了Ca~(2+)浓度对PCM力学强度、溶胀率、载药和缓释性能的影响。结果表明,PCM在1h的累计释放率由预交联前的68%降为50%,显著改善了微球的"突释"。释放动力学研究表明,微球的释药可用Ritger-Peppas方程很好地拟合,释药速率受骨架溶蚀和药物扩散双重控制。     

纳米结构的空腔二氧化硅微球的制备与缓释行为

以单分散聚苯乙烯(PS)微球作为胶体模板,采用层层静电自组装技术,交替组装聚电解质聚二烯丙基二甲基氯化铵[poly(diallyldimethylammonium chloride),PDDA]和二氧化硅纳米颗粒(10和20nm),得到核壳型聚苯乙烯/聚电解质/二氧化硅复合微球,高温煅烧除去模板PS和聚电解质,制得空腔二氧化硅微球.TEM观察的结果显示空腔二氧化硅微球呈单分散性且内部空腔呈球形;XRD图谱显示组装的二氧化硅颗粒热处理后晶化的程度很小,仍基本保持着无定形状态;N₂等温吸附-脱附实验测得用10和20nm的二氧化硅组装成的空腔二氧化硅微球的平均孔径和比表面积分别为11nm、282.71m²·g^-1和15nm、158.17m²·g^-1. 染料的装载和释放实验分别验证了空腔二氧化硅微球的腔壁具有可渗透性和缓释性.     

Sustained Release Suppository of Sodium Diclofenac: use of Water Absorbable Polymer

Abstract

The investigation on the usefulness of water absorbable polymer (Poys® SA-20) for the preparation of sustained release suppository was performed. To prepare the sustained release suppository, sodium diclofenac solution is absorbed into the sphere polymer, and the particles of the polymer after dryness are suspended in the melted triglyceride suppository base, followed by solidification. The sustained release of sodium diclofenac from the suppository was confirmed by the in vitro release study with slow release of sodium diclofenac and by the in vivo absorption study in dogs with an avoidance of transient high plasma diclofenac concentration and a prolong of plasma diclofenac concentration.     

Sustained Release Suppository of Sodium Diclofenac: use of Water Absorbable Polymer

The investigation on the usefulness of water absorbable polymer (Poys® SA-20) for the preparation of sustained release suppository was performed. To prepare the sustained release suppository, sodium diclofenac solution is absorbed into the sphere polymer, and the particles of the polymer after dryness are suspended in the melted triglyceride suppository base, followed by solidification. The sustained release of sodium diclofenac from the suppository was confirmed by the in vitro release study with slow release of sodium diclofenac and by the in vivo absorption study in dogs with an avoidance of transient high plasma diclofenac concentration and a prolong of plasma diclofenac concentration.     

Development of Diclofenac Sodium Controlled Release Solid Dispersion Tablet Using Optimization Strategy

Directly compressed diclofenac sodium (DS) controlled release tablets were prepared from spray-dried DS controlled release solid dispersion of optimum dissolution projile. Optimization strategy using a central composite design and multiple regression was used to study the influences of four parameters: compression force, the amounts of spray-dried rice starch (Era-TabR), croscarmellose sodium (Ac-Di-Sol^R), and magnesium stearate, on tablet physical properties and dissolution. The optimum conditions of those parameters were searched and an optimum DS controlled release tablet formulation was formulated. The dissolution profile of the optimized DS controlled release tablet was similar to that of the DS controlled release solid dispersion. The mechanism of drug release from the optimized DS tablet was found to be diffusion controlled.     

Purification of PEGylated Nanoparticles Using Tangential Flow Filtration (TFF)

A tangential flow filtration system was evaluated to purify PEGylated nanoparticles. Two widely used surfactants, PVA and sodium cholate were efficiently removed from an empty nanoparticles suspension using the proposed system. During drug loading, surfactant (PVA) was observed to be entrapped within the core of the nanoparticle to a higher extent, hence was purified at a comparatively slower rate. The presence of dextran sulfate enhanced the drug loading but also resulted in reduced purification rate; this was described by the hypothesis of PVA inclusion within the core of the nanoparticles. Practically, it was possible to correlate the slow purification rate of PVA to its reduced filtration flow during the purification of the empty and loaded nanoparticles containing dextran sulfate. Indirectly, this system was capable of revealing the influence of an excipient and drug on the nanoparticle surface.     

Extended Release of Theophylline Through Sodium Alginate Hydrogel Beads: Effect of Glycerol on Entrapment Efficiency,Drug Release

Theophylline is the most useful bronchodilators for the treatment of severe reversible bronchospasm. The fluctuations of serum theophylline level in clinical practice and associated central nervous system side effects necessitate the development of an extended release formulation. In the present study, theophylline-loaded beads were prepared by extruding the dispersion of theophylline, sodium alginate, and glycerol into the cationic crosslinking solution of calcium chloride. The effect of the addition of glycerol was determined by entrapment efficiency, drug release, and morphology of beads. Absence of chemical interaction between drug, polymer, and counterions after production of beads was confirmed by Fourier transform infrared spectroscopy. Theophylline entrapment of up to 72% was achieved in beads with almost spherical shape and size ranging from 0.67 to 1.12 mm. Percentage entrapment of theophylline found to be more and release was extended up to the eleventh hour from the glycerol containing sodium alginate beads. Hence, sodium alginate glycerol beads could represent a promising oral drug delivery system to extend the release of theophylline.     

Formulation Design and Optimization of Modified-Release Microspheres of Diclofenac Sodium

The present study deals with the preparation of microspheres of diclofenac sodium using cross-linked poly(vinyl alcohol) (PVA). A central composite design consisting of a two-level full factorial design superimposed on a star design was employed for developing the microspheres. The PVA to the drug ratio X₁ and amount of glutaraldehyde cross-linking agent X₂ were chosen as the independent variables. The time required for 50% drug dissolution t₅₀ in phosphate buffer (pH 7.2) was selected as the dependent variable. An optimum polynomial equation was generated for the prediction of the response variable t₅₀. Based on the results of multiple linear regression analysis and F statistics, it may be concluded that sustained action can be obtained when X₁ and X₂ are kept at high levels. The X₁X₂ interaction was found to be statistically significant. A response surface plot is presented to show the effects of X₁ and X₂on t₅₀. The drug release pattern fit the Higuchi model well. A model was validated for accurate prediction of the drug dissolution profile with constraints on the percentage drug release in the first, fifth, and seventh hours. The data of a selected batch were subjected to an optimization study, and an optimal formulation was fabricated. Good agreement was observed between the predicted and the observed dissolution profiles of the optimal formulation.     

Sustained Release of Diclofenac from Polymer-Containing Suppository and the Mechanism Involved

Sustained release of diclofenac sodium (DcNa) from suppositories composed of triglycerides and polymer was investigated by dissolution testing through an artificial membrane. DcNa was slowly released from a suppository containing carboxyvinyl polymer (CVP), and the extent of the release decreased with the amount of CVP added. Little effect was noted with the addition of other water-soluble polymers, such as hydroxyethylcellulose (HEC), xanthan gum, and polyvinylalcohol (PVA). When sodium benzoate was used instead of DcNa, a similar result was obtained with the addition of CVP. The result of release rate analysis together with the viscosity and pH in these cases showed that the reduction of solubility and diffusion due to sodium exchange between DcNa and CVP played an important role in the sustained release from the suppository. Also, in comparison with the results when CVP was not used, the plasma concentration profile of diclofenac after the administration of CVP suppository displayed a twofold longer half-life time.     

Characterization of Polyvinylalcohol Microspheres of Diclofenac Sodium: Application of Statistical Design

Microspheres of polyvinylalcohol (PVA) containing diclofenac sodium were prepared by an emulsion-chemical cross-linking method. A statistical design was used to study the variables that affect the preparation of microspheres and to study the release profile of diclofenac from the microspheres. To account for the drug content, a mass balance study of the process was performed. A high concentration of polyvinylalcohol, a high stirring speed, and a low level of glutaraldehyde were found to be important to obtain spherical and discrete microspheres. The concentration of polyvinylalcohol and the amount of heavy liquid paraffin were found to be critical factors in influencing the t₅₀ value. Almost 98% of the total diclofenac sodium added was accounted for in mass balance studies.     

含松香衍生物的乳液压敏胶的制备及性能分析

采用细乳液聚合手段制备了含歧化松香(β-丙烯酰氧基乙基)酯的性能优良的压敏胶乳液。重点讨论了引发剂种类、不同松香衍生物用量对共聚物的玻璃化转变温度、分子量及分子量分布等微观因素的影响,并构建了共聚物的宏观性能与玻璃化转变温度和分子量之间的联系。在采用过硫酸铵作为引发剂的条件下,聚合物的分子量随松香衍生物用量的增加而逐步下降,聚合物的初粘性和180°剥离力得到提高,但持粘性下降很快;当采用过氧化苯甲酰作为引发剂时,在不降低聚合物持粘性的同时,也有较好的初粘性和180°剥离力,从而获得综合性能优良的压敏胶乳液。     

Preparation,Optimization, and Characterization of Topotecan Loaded PEGylated Liposomes Using Factorial Design

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan.

The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG₂₀₀₀ (DSPE-PEG₂₀₀₀); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 ± 13.1 and 95.2 ± 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was ?10 ± 2.3 and ?22 ± 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release.

The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer.     

新型磁性海藻酸钠复合微球的制备与表征

以碳包铁(Fe@C)纳米粉作为磁性内核,用海藻酸钠作表层高分子,以正庚烷为油相,AOT为表面活性剂,氯化钙、环氧氯丙烷作交联剂,通过反相微乳法制备出了碳包铁/海藻酸钠核壳微球,系统考察了海藻酸钠的浓度、交联剂用量等对所制复合纳米微球性质的影响,并对产物进行了初步的性能表征.结果表明,选择合适的海藻酸钠的浓度、交联剂用量和其它相关参数,可以制备出外观为球形、分散性好、平均粒径约为250nm、具有强磁响应性的复合微球.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro–in vivo correlation was observed for these products.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro-in vivo correlation was observed for these products.     

Development of Diclofenac Sodium Controlled Release Solid Dispersions by Spray Drying Using Optimization Strategy I. Powder Formulation

Abstract

Diclofenac sodium (DS) controlled release solid dispersions were prepared by spray drying using ethylcellulose (EC), methacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose (HPMC), and carbomer as single carriers and EC-chitosan as combined carriers. Among solid dispersions of 3:1 drugsingle carrier, the system containing chitosan exhibited the slowest dissolution followed by the systems containing Eudragit, EC, HPMC, and carbomer, respectively. Combined carriers of EC-chitosan exhibited more dissolution retarding effect than single carrier of EC or chitosan. An Hadamard matrix H[8] was employed to estimate the main effects of four parameters: spray feeding volume and contents of absolute ethanol, EC, and chitosan. Optimization strategy using multiple linear regression and a feasibility computer program was utilized to obtain the optimum quantities of the four parameters that would result in a required DS controlled release solid dispersion. The validation of the optimum DS solid dispersion was confirmed by statistical analysis. The optimized 10: (2.5+0.02) DS:(EC+chitosan) controlled release solid dispersion exhibited a dissolution profile that was well fitted to Higuchi model.     

Development of Diclofenac Sodium Controlled Release Solid Dispersions by Spray Drying Using Optimization Strategy I. Powder Formulation

Diclofenac sodium (DS) controlled release solid dispersions were prepared by spray drying using ethylcellulose (EC), methacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose (HPMC), and carbomer as single carriers and EC-chitosan as combined carriers. Among solid dispersions of 3:1 drugsingle carrier, the system containing chitosan exhibited the slowest dissolution followed by the systems containing Eudragit, EC, HPMC, and carbomer, respectively. Combined carriers of EC-chitosan exhibited more dissolution retarding effect than single carrier of EC or chitosan. An Hadamard matrix H[8] was employed to estimate the main effects of four parameters: spray feeding volume and contents of absolute ethanol, EC, and chitosan. Optimization strategy using multiple linear regression and a feasibility computer program was utilized to obtain the optimum quantities of the four parameters that would result in a required DS controlled release solid dispersion. The validation of the optimum DS solid dispersion was confirmed by statistical analysis. The optimized 10: (2.5+0.02) DS:(EC+chitosan) controlled release solid dispersion exhibited a dissolution profile that was well fitted to Higuchi model.     

柠檬酸钠调控水热合成羟基磷灰石微球

本研究采用四水硝酸钙(Ca(NO₃)₂·4H₂O)和磷酸氢二铵((NH₄)₂HPO₄)分别作为钙源和磷源, 以丙酰胺为pH调节剂调控溶液的过饱和度, 以柠檬酸钠为钙源缓释剂调控羟基磷灰石(Hydroxyapatite, HA)的形貌, 经水热法处理成功制备出高结晶度、形貌均一和分散性良好的HA微球。采用X射线衍射(XRD)、傅里叶变换红外光谱(FT-IR)和扫描电镜(SEM)对反应产物进行了表征, 研究了初始pH值、柠檬酸钠加入量和水热反应温度对HA结晶度、组成及形貌的影响。研究结果表明, 当初始pH值为3, 柠檬酸钠与钙源的摩尔比为1︰1.5, 反应温度为180℃时, 有利于HA微球的形成。     

Preparation and Evaluation of Mucin-Gelatin Mucoadhesive Microspheres for Rectal Delivery of Ceftriaxone Sodium

ABSTRACT

Soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.     

中空SiO2微球的制备及其在缓/控释应用中的新进展

中空二氧化硅(SiO₂)微球具有特殊的内部空腔、吸附渗透性好、物质传递可控等优异性能, 可储存负载并缓慢释放药物、香精、染料、菌素等客体分子, 因此在药物缓释、医学成像、环境保护以及化妆品等领域有着广阔的应用前景。根据国内外研究进展, 本文归纳对比了中空SiO₂微球几种制备方法之间的优劣差异, 着重阐述了其作为缓控释载体表现出的持久性和高效性, 以及功能化的有机/无机杂化微球在响应性控释方面的优越性。并对中空SiO₂微球作为新型缓控释载体的发展前景进行了展望。