盐酸普萘洛尔延时脉冲微丸的制备与体外释放研究

目的:基于有机酸诱导原理制备盐酸普萘洛尔延时脉冲微丸,并研究其体外释药行为。方法:以低渗型丙烯酸树脂为包衣材料,采用空白丸心上药法制备含有机酸的载药微丸,考察处方因素对药物释放的影响,应用Box-Behnken效应面设计优化处方。通过有机酸与包衣膜相互作用试验探索其体外释药机制。结果:药物与琥珀酸分层的微丸具有较理想的脉冲释药特征,最优处方体外释药时滞约为4h,时滞后2h累积释放量90%以上,其体外释放曲线符合logistic模型。有机酸能够降低衣膜的玻璃化转变温度并促进其水化,从而提高包衣膜渗透性而加速释放。结论:所得微丸具有良好的体外脉冲释放效果。     

盐酸氨溴索包衣小丸的制备及其释药特性

目的：研制盐酸氨溴索（Amb）包衣小丸，评价其体外释药特性及释药机制。方法：Glatt流化床底喷装置中混悬液法上药制备载药小丸，分别以不同eudragit RS100/eudragit RL100配比为包衣材料制备包衣小丸，释放度试验及扫描电镜考察小丸的体外释药特性及释药机制。结果：包衣小丸在扫描电镜下表面光滑圆整，纵切面层次分明；4种小丸配比而成的缓释胶囊释药曲线与进口缓释胶囊兰勃素差异无显著性，且不受介质pH和转篮转速等因素影响；包衣小丸的释药机制可能为浓度梯度作用下Amb按Fick's定律从完整eudragit膜聚合物链间的分子孔隙扩散。结论：Amb包衣小丸具有理想的缓释效果。     

5-氨基水杨酸结肠定位给药酶控释小丸的制备与体外释放

目的：用水分散体包衣技术制备5-氨基水杨酸(5-ASA)结肠定位释放小丸给药系统。方法：乙基纤维素水分散体(Surlease)和直链淀粉(Amylosf)为控释包衣材料，邻苯二甲酸二乙酯为增塑剂，使用流化床包衣设备，制备酶控释的结肠定位释放小丸，研究小丸在模拟人体胃肠道环境中的释放度，并观察游离包衣膜的消化性。结果：此种小丸在模拟胃肠道上部的介质中不释药，在模拟结肠介质条件下3h释药80％以上，10h内释药完全，具有脉冲释药特征。药物的释放时滞由衣膜厚度和衣膜处方组成控制。增加衣膜厚度以及处方中SurleaseE的用量，可延长释药时滞。膜的消化性试验表明，释放机制是衣膜中Amylose被结肠菌酶特异性降解而使衣膜破裂释药。结论：包衣液中加入被结肠酶特异性降解的Amylose可以使小丸具有结肠定位释放的特性。     

新型壳聚糖海藻酸钠胃漂浮小丸的制备

目的采用两种新的配方制备壳聚糖-海藻酸钠小丸,考察小丸干燥方法(-50℃冷冻真空干燥和50℃烘箱干燥)对小丸漂浮及药物缓释性能的影响.方法采用锐孔凝固浴法制备壳聚糖-海藻酸钠小丸,体外释药实验考察小丸的漂浮和释药情况.结果通过改变小丸的配方,使烘干小丸在37℃人工胃液中漂浮率达到100%,雷尼替丁释放时间最长能达到5h.其漂浮效果与成本较高的冷冻干燥法相当,且药物释放时间得到延长.结论新配方制备小丸在口服胃漂浮释药上有一定应用前景.     

美沙拉嗪两种时间依赖型结肠定位释药系统的研究

目的考察两种美沙拉嗪时间依赖型结肠定位释药片(time-dependent colon specific tablets,TDCT)体外释放性质,以期为不同程度炎症性肠病治疗提供相应的制剂。方法以羟丙基纤维素和微晶纤维素为包衣材料,采用压制包衣法,制备压制包衣TDCT。有机酸诱导型TDCT采用湿法制粒制备含有机酸片芯,片芯外依次包隔离层和Eudragit RS30D时滞层,通过片芯有机酸与Eudragit RS30D发生离子交换,增大膜的通透性制备延迟缓释片。考察药物释放的影响因素。结果两种美沙拉嗪TDCT具有稳定的结肠释药特性,且压制包衣TDCT有突释性,有机酸诱导型TDCT具有缓释特性。结论可以根据结肠定位释药的要求,选择不同释药类型的TDCT。     

盐酸维拉帕米口服渗透泵制剂释药特性的研究

以盐酸维拉帕米为模型药物，制备了口服渗透泵片，通过考察渗透泵片体外释药各过程的速率，研究口服渗透泵制剂释药的基本过程及其特性，结果表明盐酸维拉帕米口服渗透泵制剂的释药过程主要包括四个步骤，其中体外释药速率与由水渗透过膜过程所控制的药物释放速率接近，从而说明水渗透过膜是控速步骤。     

脉冲释药技术在中药制剂中的应用

时辰药理学研究发现,一些疾病如心绞痛、高血压、哮喘、炎症反应及疼痛等的发作具有时间节律性,传统的以零级速率、一级速率释药的缓/控释释药技术只能使药物在不易发病的时段内维持一定的血药浓度,而到需要药物起到预防和治疗作用时,体内药物浓度却又达不到所要求的水平,从而延误了有效治疗时机.因此,这几类释药技术制备的制剂已无法满足临床治疗的需要.脉冲释药技术是以时辰药理学的原理为依据,制备出能够根据疾病昼夜节律特点定时、定量释放药物的制剂新技术.     

吲达帕胺微孔渗透泵片的制备与体外释药机制研究

目的制备吲达帕胺微孔渗透泵片剂并研究其体外释药机制。方法通过外观观察,测定不同衣膜、片芯、介质等条件变化时的体外释放度,考察其释药机制。结果吲达帕胺微孔渗透泵片体外释药行为符合零级释药模型;不同衣膜、片芯和渗透压介质对药物释放有显著影响;释放介质的pH值、溶出方法和转速对药物释放无显著影响。结论该片剂的释药动力主要为衣膜内外的渗透压差,药物在渗透压驱动下经微孔释药。     

pH依赖—缓释型美沙拉秦结肠靶向小丸的制备与体外评价

以肠溶型和渗透型丙烯酸树脂为包衣材料制备ｐＨ依赖－缓释型美沙拉秦结肠靶向小丸,评价其体外释放特性。结果表明,包衣小丸在０．１ｍｏｌ／ＬＨＣｌ中２ｈ几乎不释放药物,在ｐＨ７．５缓冲液中具有较好的缓释作用。在模拟胃肠道各区段最高的和最低的ｐ变化的释放度试验中,均在对应小肠区段时开始缓慢释药。分别有４０％和７０％的药物进入结肠后释放。优于单独的肠溶或缓释制剂。     

盐酸昂丹司琼渗透泵片的制备与体外释放

目的制备盐酸昂丹司琼渗透泵型控释片剂(OND-OPT)并考察体外释药特性。方法以锅包衣法制备OND-OPT。通过释放度试验筛选处方并考察OND-OPT的释放特性；通过均匀设计试验建立持续释药时间与衣膜厚度、衣膜中PEG含量和释药孔孔径的关系；考察OND-OPT的释药机制。结果释药孔朝向对不含HPMC的制剂释药有明显影响，而对含HPMC的制剂释药无影响。持续释药时间与衣膜厚度和衣膜中PEG含量有关，与释药孔孔径无显著关系。OND-OPT主要以渗透泵机制释放药物。结论通过调节衣膜厚度和衣膜中PEG含量，OND-OPT可以实现理想的药物控制释放。     

An Organic Acid-Induced Sigmoidal Release System for Oral Controlled-Release Preparations

To achieve time-controlled or site-specific drug delivery in the gastrointestinal tract, a sigmoidal release system (SRS) was developed, which achieved a prolonged lag time, followed by rapid release. The theophylline beads with a thick Eudragit RS film coating showed very low drug release in water, whereas the release rate increased considerably in organic acid solutions. A hydration study of Eudragit RS films suggested that the increase in drug release was attributable to structural changes of the film induced by polymer-acid interactions. When succinic acid was incorporated into the core of Eudragit RS-coated theophylline beads, the drug release profile showed a typical sigmoidal pattern. SRS beads containing acetaminophen were also prepared by the same technique. Again, a sigmoidal release pattern was observed in which the lag time was prolonged with an increase in the coating level, whereas the drug release rate thereafter was almost constant irrespective of the coating level. Acetaminophen-containing SRS beads with different coating thickness were orally administered to beagle dogs. The drug plasma concentration curves showed lag periods similar to the in vitro lag time.     

法莫替丁脉冲控释微丸胶囊的制备及其体外释放

目的制备以法莫替丁为模型药物的脉冲控释胶囊;探索制备脉冲微丸的方法。方法采用挤出滚圆法制备速释微丸。应用有机酸诱导机理制备脉冲微丸,于丸芯中加入有机酸,EudragitRS100为包衣材料,用正交设计优化处方。将两种微丸混合后制成脉冲控释微丸胶囊。结果脉冲控释胶囊的体外释放分为两步:速释微丸迅速溶出,胶囊的释放度30min达50%;脉冲微丸于5h左右开始溶出,累积释放度13h时达95%。脉冲微丸的时滞由丸芯中酸量及包衣膜厚度共同决定;而时滞后的释药速率则主要由前者控制。结论采用有机酸诱导机理可制备理想的脉冲微丸;与速释微丸混合即可制成释药两次的法莫替丁脉冲控释微丸胶囊。     

Influence of an enteric polymer on drug release rates of theophylline from pellets coated with Eudragit RS 30D

The purpose of this research study was to investigate the influence of an enteric polymer on the drug release properties of theophylline pellets coated with Eudragit RS 30D. Theophylline pellets were coated with aqueous colloidal dispersions of Eudragit RS 30D containing various amounts of Eudragit L 100-55. The effect of storage conditions on the release of drug from coated pellets was determined as a function of the pH of the dissolution medium. The results from the dissolution study showed significant changes in the dissolution rate of theophylline from pellets coated with Eudragit RS 30D when cured at 40 degrees C for 4 days. No change in the drug release rate was observed when Eudragit L100-55 was present in the Eudragit RS 30D dispersion. Increasing the ratio of Eudragit L100-55 to Eudragit RS 30D resulted in faster drug release rates from the coated pellets. An increase in the pH of the dissolution medium was found to enhance drug release from the pellets coated with Eudragit RS 30D containing Eudragit L 100-55. Theophylline pellets when coated with Eudragit RS 30D containing the enteric polymer Eudragit L100-55 demonstrated no aging effects when stored at elevated temperatures. The overcoating of the pellets with Eudragit RD 100 did not affect the drug release profiles and prevented the particles from agglomerating during curing and storage.     

Influence of acrylic esters and methacyrlic esters on flotation of pellets and release rate of verapamil hydrochloride

Eudragit RL (ERL) and Eudragit RS (ERS) are biocompatible cationic copolymers, pH-independent and insoluble in aqueous environment. In this study drug delivery system consisting of a capsule filled with floating pellets with verapamil hydrochloride (VH) is proposed. The release of VH in the stomach results in better solubility in an acid gastric environment in vivo and may result in greater amount of the VH absorbed and its higher concentration in plasma. The scope of this study was to investigate the influence of ERL and ERS ratio on VH release in 0,1 M HCl from floating coating pellets. The stability of this film was also investigated. The ERL film is much more permeable than ERS, and an increase of ERL film thickness did not retard the release rate. The combination of ERL and ERS are forms of the sustained release film. It was a necessary to add the uncoated pellets, which constituted the initial dose. The start of flotation depends on permeability of polymeric film, and decreases with addition of ERS. There is no change in the start flotation time after 12 months under room condition (25 degrees C/60% RH). The drug delivery from uncoated pellets and pellets coated with ERL/ERS is stable after 12 months under room condition (25 degrees C/60% RH).     

Influence of hydroxyethylcellulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D.

The objective of this study was to investigate the influence of a hydrophilic polymer, hydroxyethylcellulose (HEC), on the release properties of theophylline from pellets coated with Eudragit RS 30 D, and the physicochemical properties of Eudragit RS 30 D cast films. The release rate of theophylline from Eudragit RS 30 D coated pellets decreased during storage at 25 degrees C/60% RH due to the further coalescence of colloidal acrylic particles. In addition, water-vapor permeability and tensile strength of Eudragit RS 30 D cast film decreased after 1-month storage at 25 degrees C/60% RH. The presence of 10% hydroxyethylcellulose in the coating formulation was shown to stabilize the drug release rate from coated pellets, the water-vapor permeability and the tensile strength of free films. Atomic force microscopy and scanning electronic microscopy were used to demonstrate that the HEC was immiscible with Eudragit RS 30 D in the cast films. The stabilization effect of HEC was investigated and determined to be due to the formation of an incompatible phase between the latex particles which impaired further coalescence of the colloidal acrylic particles.     

Influence of plasticizer level on the drug release from sustained release film coated and hot-melt extruded dosage forms

In the current study, the influence of plasticizer level on drug release was investigated for solid dosage forms prepared by hot-melt extrusion and film coating. The properties of two highly water-soluble compounds, diltiazem hydrochloride (DTZ) and chlorpheniramine maleate (CPM), and a poorly water-soluble drug, indomethacin (IDM), were investigated in the melt extrudates containing either Eudragit RSPO or Eudragit RD 100 and triethyl citrate (TEC) as the plasticizer. In addition, pellets containing DTZ were film coated with Eudragit RS 30D and varying levels of TEC using a fluidized bed coating unit. Differential scanning calorimetry (DSC) demonstrated that both CPM and IDM exhibited a plasticization effect on the acrylic polymers, whereas no plasticizing effect by DTZ on Eudragit RSPO was observed. Thermogravimetric analysis (TGA) was used to investigate the thermal stability of the DTZ, Eudragit RSPO and TEC at 140 degrees C, the maximum temperature used in the hot-melt extrusion process. The chemical stability of DTZ and IDM in the extrudate following hot-melt processing was determined by high pressure liquid chromatography (HPLC). Drug release rates of both DTZ and CPM from hot-melt extrudates increased with an increase in the TEC level in the formulations, while the release rate of DTZ from the Eudragit RS 30D-coated pellets decreased with an increase in TEC in the coating dispersion. This phenomenon was due to the formation of a reservoir polymeric structure as a result of the thermal stress and shear stress involved in the hot-melt extrusion process regardless of the TEC level. In contrast, coalescence of the polymer particles in the film coating process was enhanced with higher levels of TEC, as demonstrated by scanning electron microscopy (SEM). The addition of TEC (0% to 8%) in the IDM hot-melt extrudate formulation had no influence on the drug release rate as the drug release rate was controlled by drug diffusion through the inside of the polymeric materials rather than between the polymer particles.     

Relationship of film properties to drug release from monolithic films containing adjuvants.

The rate of drug release from a polymeric matrix system was influenced by the physical and chemical properties of the monolithic films. The model drugs, salicylic acid and chlorpheniramine maleate, and two poly(methyl methacrylate) copolymers of different permeabilities (Eudragit RL and Eudragit RS), with and without additional adjuvants, were used to form monolithic matrix films for controlled drug release. Adjuvants, including polyethylene glycols (PEG 400 and PEG 8000) and poly(vinylpyrrolidones) (PVP-K15 and PVP-K90), were incorporated into films of Eudragit RL PM and Eudragit RS PM. The moisture permeation constant, glass transition temperature (Tg), tensile strength, and drug release profiles were determined for each acrylic resin slab to correlate the physicochemical and physicomechanical film properties to observed drug release. Faster rates of drug diffusion were observed with the addition of PEG 400 to the films, because of its plasticizing effect and the resultant increased moisture permeability of the matrix. An exception existed with the Eudragit RL PM film containing salicylic acid where drug-polymer interactions inhibited drug diffusion. The small changes in moisture permeability, Tg, and tensile strength observed with incorporation of the PVPs had an insignificant influence on the dissolution results for salicylic acid from Eudragit RS PM films. Increases in the tensile strength and Tg after addition of PVP to the Eudragit RS PM matrix support the observed decreased rate of diffusion for chlorpheniramine maleate. The pores formed by migration of the hydrophilic adjuvants from the films altered the diffusion kinetics of the matrix, compared with that of the nonporous polymer, when only the antihistamine was present.     

Studies of chitosan/organic acid/Eudragit RS/RL-coated system for colonic delivery

Prednisolone (PDS) beads were coated sequentially with (i) innermost hydrophobic layer of Eudragit RS/RL, (ii) middle drug release-triggering layer of chitosan, organic acid and Eudragit RS/RL, and (iii) outermost enteric coating layer. Continuous dissolution studies were carried out in artificial gastric fluid (pH 1.2), followed by intestinal fluid (pH 6.8), and finally in colonic fluid (pH 4 and 6) with and without beta-glucosidase. While drug release was prevented in the gastric and small-intestinal fluids, a continuous release was observed in the colonic fluid. Succinic acid provided the fastest rate of release in the colonic fluid compared to citric, tartaric or malic acid. A combined mechanism of drug release is proposed, which considers the swelling of chitosan and Eudragit RS/RL in the presence of succinic acid possibly via electrostatic interaction between the amine groups of chitosan/quaternary ammonium groups of Eudragit RS/RL and the carboxyl groups of succinic acid in aqueous medium. The results of plasma pharmacokinetic studies in Sprague-Dawley rats showed that the developed system provided a significant delay (T(max) 9.3 h) in the absorption profile of PDS compared with simple enteric-coated (T(max) 4 h) or powder (T(max) 1 h) formulation that was taken as proof for the colon-targeted delivery.     

Dry polymer powder coating and comparison with conventional liquid-based coatings for Eudragit) RS, ethylcellulose and shellac.

Drug-layered pellets were coated with micronized polymer powders (Eudragit) RS, ethylcellulose, and shellac) by a dry powder coating technique as an alternative to organic- and aqueous-based coatings (Eudragit) RS 30D, Aquacoat) ECD) were investigated. High plasticizer concentrations (40%) and a thermal after-treatment (curing) were necessary for the coalescence of the polymer particles and good film formation. Ethylcellulose required a higher curing temperature and time than Eudragit) RS because of its higher glass transition temperature (133 versus 58 degrees C). A smaller polymer particle size also promoted film formation. In general, pellets coated with polymer powders required higher coating levels to obtain similar drug release patterns as pellets coated with organic polymer solutions and aqueous polymer dispersions.