罗替戈汀原位形成植入剂的制备及体内药动学考察

目的:制备抗帕金森病药物罗替戈汀原位形成植入剂(R-ISFI),并对其体内长效释药行为进行考察。方法:以N-甲基-二吡咯烷酮(NMP)为溶剂、聚乳酸-羟基乙酸共聚物(PLGA)为载体材料,制备R-ISFI。采用摇床法进行体外释放度的考察,采用大鼠体内药动学实验考察罗替戈汀的体内释药特性。大鼠皮下注射R-ISFI,HPLC法测定不同时间血浆中药物浓度。结果:高分子材料的类型、高分子材料与溶剂比、药物与高分子材料的用量比及ISFI的形状均对药物体外释放有显著的影响。R-ISFI体外释药平缓,30 d可累积释放85%,体内药动学结果表明,R-ISFI在体内缓释效果良好,突释小,可持续释放30 d。结论:制备的R-ISFI可持续平稳释放达一个月,是一种很有开发应用前景的长效缓释制剂。     

制备工艺对石杉碱甲微球体外释药机制的影响

目的考察制备工艺对石杉碱甲(Hup)乳酸-羟基乙酸共聚物(PLGA)微球体外释药机制的影响。方法 采用两种O/O型乳化溶剂挥发法工艺(A法和B法)制备Hup微球。考察微球的体外释药曲线，结合微球在释放介质中的降解速度和溶胀速度曲线以及微球的形态和微球中药物的分布情况阐述微球的释药机制。结果采用A法制备的微球包封率为47.60%，体外无明显突释现象，可缓释35 d，符合零级动力学方程，通过扩散和降解两种机制释药。采用B法制备的微球包封率为83.50%，体外可缓释21 d，整体释药曲线符合Higuchi方程，主要以扩散机制释药。结论采用A法制备的微球具有更理想的缓释效果。     

可注射5-氟尿嘧啶缓释凝胶体外释放及其大鼠体内药动学研究

目的:制备可注射5-氟尿嘧啶(FU)缓释凝胶,并研究其体外释药及体内药动学特征。方法:以pH/温度双重敏感生物可降解嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1为载体材料,采用物理混合法制备5-FU缓释凝胶。考察载药量和共聚物浓度对其体外释药情况的影响。采用高效液相色谱法分别测定大鼠皮下注射5-FU水溶液(参比制剂)及缓释凝胶(受试制剂)后不同时间点的血药浓度,绘制药-时曲线,计算药动学参数。结果:5-FU在载药量为0.5%,共聚物浓度为15%、20%、25%的缓释凝胶中第9天时平均累积释放百分率为89.66%、87.59%、80.85%;载药量为0.2%、0.5%、1%,共聚物浓度为25%的缓释凝胶中第9天时平均累积释放百分率为75.30%、80.85%、86.90%;参比制剂与受试制剂在大鼠体内tmax分别为0.25、0.50h,Cmax分别为72.7、31.1μg·mL-1,AUC(0～)t分别为44.5、342.4mg·h·mL-1,MRT分别为0.57、27.2h。结论:5-FU缓释凝胶中5-FU体外释放呈现Higuchi动力学特征,表现为以扩散控制型为主的释药模式;释药初期,载药量对释药速率影响较大;释药后期,共聚物浓度对释药速率影响较大。皮下注射给药后,与水溶液相比,缓释凝胶可持续释药3d,具有良好的缓释作用。     

纳曲酮微球的研制及体内外评价

以PLGA为载体制备了注射用纳曲酮微球,考察制品的体外释药、以及在小鼠体内的药效学和家兔体内的药动学,并进行了评价.结果表明,制品在体内外均能持续释药30d,小鼠体内拮抗吗啡的效果可长达30d.     

石杉碱甲凝胶骨架缓释片药物释放因素的研究

目的考察影响石杉碱甲(hupcrzine—A，Hup—A)亲水凝胶骨架片体外释药的各种因素。方法以羟丙基甲基纤维素(HPMC)和乙基纤维素(EC)为骨架材料，湿法制粒压片制备缓释骨架片，并考察HPMC和EC的用量、粘度、HPMC粒度、压片压力及其他辅料对石杉碱甲亲水凝胶骨架片体外释药的影响。结果石杉碱甲亲水凝胶骨架片体外释药符合Higuchi方程。HPMC粒度、粘度、压片压力及辅料种类对石杉碱甲的释放速率没有显性影响。HPMC用量及EC的粘度、用量对石杉碱甲的释放速率有显性影响。结论HPMC及EC用量、EC粘度为影响石杉碱甲亲水凝胶骨架片释放速率的主要因素。     

茶碱的时辰给药系统及其在犬体内的药物动力学

目的 制备一种体外具有"慢速-快速"双相释药特征的茶碱时辰给药系统以用于哮喘的夜间治疗,并考察其在犬体内的药动学.方法 分别以磷酸钠和氯化钠为内外层渗透推动剂,制备双层片片芯,以CA-PEG400-DEP(54.5:36.4:9.1,)为包衣膜组成给药系统.考察包衣膜厚度对茶碱释放的影响,及经口送服后时辰给药系统和缓释片在犬体内的药动学.结果 时辰给药系统包衣增重不影响其双相释药特征,系统体外的累积释放量随包衣的增重而减小.犬体内药动学研究表明较之缓释片,时辰给药系统的Tmax延长,Cmax减小.包衣增重影响时辰给药系统的生物利用度,每片包衣增重19、9 mg时,其相对生物利用度约为50%,每片包衣增重6 mg时,其相对生物利用度约为100%.结论 成功制备了双相释药特征的茶碱时辰给药系统.较之缓释片,可提前至晚9:30服药在清晨达峰浓度,且达峰后可长时间维持较高的血药浓度.     

NC-PLGA缓释微球的制备及体内外药代动力学试验

目的 制备生物可降解型NC-PLGA缓释微球,研究其制备工艺与体内、体外释放特性.方法 利用溶剂挥发法制成NC-PLGA缓释微球,在人工脑脊液中用紫外分光光度法测定其体外释放速度,在兔脑脊液中用HPLC法测定其体内释放速度.结果 NC-PLGA外观形态为直径(31.3±3.2)μm的微球,载药率为13.7％,包封率为89.2％.微球体外试验显示,前两天有初始突释现象,共释放约30％,药物能够在随后时间内缓慢平稳释放至20 d以上.兔体内试验结果表明,除了第一天的初始突释外,微球释药缓慢而平稳,每天的血药浓度维持在7.6×10-8 mol/L.结论 利用溶剂挥发法制得NC-PLGA缓释微球,具有明显的缓释作用.     

联合包载Combretastatin A-4和阿霉素的长循环脂质体的体外体内初步研究

目的制备一种具有程序释药功能的联合包载抗肿瘤药物阿霉素(doxorubicin,DOX)和新生血管抑制剂(combretastatin A-4,CA-4)的新型长循环脂质体并进行体内药动学评价。方法以卵磷脂、胆固醇和聚乙二醇磷脂衍生物(1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-polyethylene gly-col,DSPE-PEG)为载体材料,采用薄膜分散法和硫酸铵梯度法分步包载CA-4和DOX制备得到脂质体。通过单因素考察,筛选最佳处方和制备工艺,并评价其体外释放情况。采用正常大鼠考察该制剂在静脉注射后的药动学行为。结果 m(卵磷脂)∶m(胆固醇)∶m(DSPE-PEG)为85∶10∶5、m(药)∶m(脂材)为1∶20、水化脂材浓度为50 mmol.L-1时,CA-4的包封率最高(>85%),DOX的包封率也在95%以上,平均粒径小于80 nm。体外释放结果表明联合包载DOX和CA-4的脂质体在pH7.4磷酸盐介质中可以快速释放CA-4,而DOX释放相对较慢。体内药动学实验结果表明,脂质体包载可明显增加CA-4的体内循环时间,但CA-4的联用并未对DOX体内药动学行为产生明显干扰。结论联合包载CA-4和DOX的脂质体可有效地实现程序释药,并延长药物体内循环时间,将可能成为肿瘤治疗的新策略。     

高乌甲素纳米粒的制备及其在大鼠体内药动学

目的:制备可持续释放且能治疗疼痛的载高乌甲素(LA)的聚乳酸(PLA)纳米粒,并考察其体外释药情况和在大鼠体内的药动学特性。方法:采用O/W乳化-溶剂挥发法制备载高乌甲素的聚乳酸纳米粒(LA/PLA NPs),运用激光粒度仪测定其粒径,原子力显微镜观察其形貌,动态透析法考察其体外释药特性,反相高效液相色谱法(RP-HPLC)测定血药浓度,PKSolver程序处理药-时数据,并以LA为参比进行大鼠腹腔注射的药动学研究。结果:LA/PLA NPs外观呈圆形或类圆形,大小均匀,平均粒径(429±9.19)nm,包封率(86.34±2.15)%、载药量(45.85±1.34)%,体外可持续缓慢释放15 d,体内可释药8 d以上,其主要药动学参数为:t_1/2=(103.16±21.57)h,t_max=(3.6±1.34) h,C_max=(3.50±0.69)μg·mL^-1,AUC_(0-t)=(455.14±26.18) μg·mL^-1·h。结论:LA/PLA NPs制备工艺简单,重复性好,体内药-时过程符合非房室模型,具有良好的缓释效果。     

转铁蛋白修饰的喜树碱- 树枝状高分子复合物的药动学研究

目的探讨转铁蛋白修饰的主动靶向纳米载药复合物在大鼠体内的药动学行为。方法碱水解后采用HPLC法测定大鼠尾静脉给药后血浆中的药物浓度。结果经转铁蛋白修饰的主动靶向复合物能显著提高喜树碱在大鼠体内的半衰期及平均滞留时间,比未经转铁蛋白修饰的载药复合物的半衰期的平均滞留时间短。结论转铁蛋白-聚乙二醇-聚酰胺-胺树枝状分子-喜树碱复合物具有显著的长循环效果。关键词:聚酰胺-胺树枝状聚合物;转铁蛋白;聚乙二醇;喜树碱;药动学     

Controlled release of anti-cocaine catalytic antibody from biodegradable polymer microspheres

Recent reports have shown that anti-cocaine catalytic monoclonal antibody 15A10 reduces the toxic effect of cocaine by increasing its breakdown to systemically inert products ecgonine methylester and benzoic acid. This study reports the microencapsulation of antibody 15A10 using biodegradable poly (lactic-glycolic) acid (PLGA) by double emulsion technique. Formulation parameters such as protein loading, polymer molecular weight and the presence of zinc carbonate were studied for their effects on in-vitro release of antibody from microspheres. The initial burst release was decreased by the reduction of the protein (as % of total ingredients) in the formulation. Although changing the polymer molecular weight did not cause a reduction in initial burst release, it was effective in improving the release rate. The inclusion of zinc carbonate in microsphere preparation resulted in increase in initial burst release. An in-vivo study in mice revealed the presence of antibody in blood up to ten days following subcutaneous injections. These data demonstrate a potential for a sustained-release formulation of monoclonal antibody 15A10 for treatment of cocaine addiction.     

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).     

Formulation and pharmacodynamic evaluation of captopril sustained release microparticles

Cellulose propionate (CP) microparticles containing captopril (CAP) were prepared by solvent evaporation technique. The effects of polymer molecular weight, polymer composition and drug:polymer ratios on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared captopril microparticles were examined. The anti-hypertensive effect of the selected CAP formulation in comparison with aqueous drug solution was also evaluated in vivo using hypertensive rats. The formulation containing drug:polymer blend ratio 1:1.5 (1:1 low:high molecular weight CP), namely F7, was chosen as the selected formulation with regard to the encapsulation efficiency (75.1%), flow properties (theta=24 degrees, Carr index=5%, Hausner ratio=1.1, packing rate=0.535) and release characteristics. Initial burst effect was observed in the release profile of all examined formulations. DSC and SEM results indicated that the initial burst effect could be attributed to dissolution of CAP crystals present on the surface or embedded in the superficial layer of the matrix. The release kinetics of CAP from most microparticle formulations followed diffusion mechanism. After oral administration of the selected microparticle formulation (F7) to hypertensive rats, systolic blood pressure decreased gradually over 24 h compared to reference drug solution. These results may suggest the potential application of cellulose propionate microparticles as a suitable sustained release drug delivery system for captopril.     

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug. Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X(1)) and MCC (X(2)) was used as independent variables for optimization of sustained release formulation applying 3(2) factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t(50%)). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets. Results: The results indicate that X(1) and X(2) significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h. Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.     

Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability

The effects of the core toi colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a square root t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.     

Oleic Acid enhances all-trans retinoic Acid loading in nano-lipid emulsions

The aim of this study was to investigate the enhancement of all-trans retinoic acid (ATRA) loading in nano-lipid emulsions and stability by using oleic acid. The effect of formulation factors including initial ATRA concentration and the type of oil on the physicochemical properties, that is, percentage yield, percentage drug release, and photostability of formulations, was determined. The solubility of ATRA was increased in the order of oleic acid > MCT > soybean oil > water. The physicochemical properties of ATRA-loaded lipid emulsion, including mean particle diameter and zeta potential, were modulated by changing an initial ATRA concentration as well as the type and mixing ratio of oil and oleic acid as an oil phase. The particles of lipid emulsions had average sizes of less than 250 nm and negative zeta potential. The addition of oleic acid in lipid emulsions resulted in high loading capacity. The photodegradation rate was found to be dependent on the initial drug concentration but independent of the type of oily phase used in this study. The release rates were not affected by initial ATRA concentration but were affected by the type of oil, where oleic acid showed the highest release rate of ATRA from lipid emulsions.     

Comparison of the in vitro dissolution behaviour of various indomethacin formulations with their in vivo bioavailability

The effects of the core to colloid wall ratio and particle size of the core on the in vitro release of indomethacin microcapsules prepared by the gelatin-acacia complex coacervation process have been examined. All formulations showed a zero order release pattern after an initial burst phase. The release rate increased with increasing core to coat ratios and decreasing particle size of core material. In vivo plasma level studies showed no difference in bioavailability between different microcapsule formulations or a conventional indomethacin capsule. In vitro release studies on a commercially available sustained release formulation of indomethacin (Indocid R) were slower than any of the microcapsule formulations and exhibited a √t dependence indicating a diffusion controlled process from a matrix formulation. In vivo studies show this formulation to have a longer, smoother plasma concentration than the microcapsule formulation, and to avoid high initial peak values of drug. Thus from the in vitro studies a sustained release effect was not unexpected but the in vitro differences between the microcapsule products were not paralleled by the in vivo behaviour. These results illustrate some of the problems in extrapolation of in vitro dissolution data to the in vivo situation.     

Preparation of Three-Month Depot Injectable Microspheres of Leuprorelin Acetate Using Biodegradable Polymers

To obtain a three-month release injection of leuprorelin acetate, microspheres were prepared with copoly(DL-lactic/glycolic acid) or poly(DL-lactic acid) (PLA) using an in-water drying method, and drug release was evaluated. The content of water-soluble oligomers in the polymers was found to strongly affect the initial burst, and reducing the content to less than 0.1% was necessary to keep the first-day release below 10%. Drug loading of more than 15% also increased the initial drug release; the acceptable maximum loading was 12%. Elevation of the glass transition temperature of the microspheres was observed with an increase in drug loading. This suggests formation of a rigid structure, possibly with arrangement of the polymer around the drug cores like in a micelle. This structure provides a hydrophobic barrier against diffusion of the hydrophilic peptide, resulting in high trapping efficiency and long-term sustained release dependent on polymer erosion. The microspheres prepared with PLA having a m.w. of 12,000 to 18,000 provided linear sustained release and persistent serum levels of the drug in rats for over 3 months.     

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug.

Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X₁) and MCC (X₂) was used as independent variables for optimization of sustained release formulation applying 3² factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t_50%). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets.

Results: The results indicate that X₁ and X₂ significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h.

Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.