Investigation of the release of aspirin from spray-congealed micro-pellets

The release behaviour of aspirin from spray-congealed hydrogenated soybean oil micro-pellets of different sizes was studied. The purpose of this study was to investigate the effect of particle size of micro-pellets on the drug release profile and mechanism. Micro-pellets produced were sieved into several fractions and their drug content and dissolution profiles in two media were determined. The dissolution mechanism was studied by fitting the data to release kinetic models. Micro-pellets with high encapsulation efficiency were successfully produced. The micro-pellets were able to sustain the release of aspirin in pH 1.2 and pH 6.8 dissolution media. As particle size of micro-pellets increased, the drug release rate decreased. The drug release mechanism was affected by the size of micro-pellets. Micro-pellets in the range of 90-250 microm tended to follow the first order or Higuchi model. However, micro-pellets in the range of 250-355 microm were found to follow zero-order release model. This result showed that drug release could be modified by controlling the size of micro-pellets and that controlled release of drug might be achieved by using larger size micro-pellets.     

通脉复方微丸多元释药系统中葛根黄酮速释单元的制备工艺研究

目的:制备葛根黄酮速释微丸,并对其制备工艺进行研究。方法:首先以熔融法将葛根黄酮组分制备成固体分散体,考察了载体及其比例对溶出度的影响。以葛根黄酮固体分散体作为主药制备微丸,考察了处方中润湿剂、载药量、辅料等因素对葛根黄酮微丸收率、圆整度、溶出度的影响;采用正交试验设计,筛选出葛根黄酮速释微丸的最佳制备工艺。结果:葛根黄酮速释微丸处方为主药20 g,乳糖5 g,微晶纤维素25 g,润湿剂为30%的乙醇。采用挤出滚圆法制备,最佳工艺条件为挤出频率25 Hz,滚圆频率30 Hz,滚圆时间6 min。结论:葛根黄酮速释微丸制备工艺科学合理,制剂稳定,为通脉复方微丸多元释药系统的制备奠定了基础。     

阿司匹林壳聚糖微球的制备及体外释放的研究

本文通过乳化-交联法制备了阿司匹林-壳聚糖载药微球,采用红外技术对其结构进行了分析,确定了阿司匹林包埋在壳聚糖微球中,测得其载药量为15.44%,包封率达到60.4%。pH=3.6时释药曲线较好,接近匀速释放。     

阿司匹林多单元肠溶片的制备及体外溶出度考察

目的：研制阿司匹林多单元肠溶微丸片。方法：采用阿司匹林粉末包衣先制备肠溶包衣微粒,再与适量辅料混合后直接压片制备肠溶阿司匹林微粒片,并对影响其质量的关键因素进行了考察。结果：制备的微粒片溶出度符合阿司匹林肠溶制剂质量的标准要求。     

乳化剂对阿司匹林微球制备的影响

目的:用溶剂挥发法以聚乳酸为载体制得阿司匹林聚乳酸微球。方法:选择不同的乳化剂,用正交设计安排实验。并以微球包埋率、载药量、表面形态、体外释放为指标优化微球的制备工艺。结果:按优化条件制得的微球包埋率39.5%,载药量7.25%,体外释药t1/2为3d。结论:制备微球缓释效果明显。     

阿司匹林胃漂浮片释放度试验

采用紫外分光光度法 ,以自制阿司匹林胃漂浮型缓释片进行释放度试验 ,测定数据按单指数函数处理 ;结果试片在人工胃液中 1 0 h累积释出药物 70 %～ 90 %。     

HPLC测定泮托拉唑钠肠溶胶囊的释放度

目的 建立测定泮托拉唑钠肠溶胶囊释放度的方法.方法 采用HPLC法,色谱柱为Kromasil C18(150 mm×4.6 mm,5μm),流动相为磷酸盐缓冲液-乙腈(60:40),检测波长289 nm,流速1.0 ml·min-1.结果 线性范围为4.6-31.0μg·ml-1(r=0.9999),平均回收率为98.48%,RSD=0.65%(n=9).结论 所用方法简便快速,专属性强,灵敏度高,准确度好.     

不同乳化剂制备阿司匹林微球工艺的研究

目的以聚乳酸为载体用溶剂挥发法制得阿司匹林聚乳酸微球。方法选择不同的乳化剂,正交设计实验。以微球包埋率、载药量、表面形态、体外释放为指标优化微球的制备工艺。结果与结论按优化条件制得的微球粒径5～22μm,占80%以上。微球包埋率39.5%,载药量7.25%,体外释药50%需70h。     

气相色谱法测定氢化大豆油中脂肪酸组成

目的建立快速准确的测定氢化大豆油中脂肪酸组成的方法。方法以三氟化硼为酯化剂,采用气相色谱法,程序升温测定氢化大豆油中脂肪酸组成。结果8种脂肪酸能在20min内基线分离,线性、精密度、重现性良好。结论此法简单快捷,可用于氢化大豆油中脂肪酸组成的测定。     

Mechanisms of burst release from pH-responsive polymeric microparticles

Objectives Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of prepared microparticles and investigated the underlying mechanisms responsible for the ‘burst release’ effect. Methods Using two different pH‐responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS‐MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Key findings Although, spray drying was an attractive approach due to rapid particle production and relatively low solvent waste, the oil‐in‐oil microencapsulation method was superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil‐in‐oil emulsification process allowed adequate time for drug and polymer redistribution in the microparticles and reduced uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated nonporous particles whereas thermal analysis and X‐ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release. Conclusions Both the manufacturing method (which influenced particle porosity and density) and drug:polymer compatibility and loading (which affected drug form and distribution) were responsible for burst release seen from our particles     

Enhanced Release of Indomethacin from PVP/Stearic Acid Microcapsules Prepared Coupling Co-freeze-drying and Ultrasound Assisted Spray-congealing Process

Purpose Fast releasing indomethacin microparticles were prepared encapsulating co-freeze-dried indomethacin/poly(vinylpyrrolidone) particles (IMC/PVP) into molten stearic acid (SA), by means of a ultrasonic spray-congealing technique. Materials and Methods IMC particles were suspended in a PVP aqueous solution and the system was then freeze-dried. A suspension was prepared from the co-freeze dried IMC/PVP powder into molten SA that was then atomized into small droplets using ultrasound. Solidification in air produced microparticles having regular macroscopic morphology and coated by a SA thin external film. At each step the material was examined by electron microscopy (SEM and EDAX), thermal analysis and dissolution tests. Results SEM examination did not reveal a smooth surface, differently from what was observed in the case of pure SA microparticles, obtained by the same method. The external film was found to uniformly protect the internal core of the capsules: EDAX spectra demonstrated the absence of the IMC identifying Cl peak on the surface, when the spectra were carried out at low energy of the electron beam. HPLC analysis verified that the drug was uniformly distributed inside the final microparticles at all the size fractions considered. Thermal microscopy confirmed the presence of IMC crystals, after the fusion of the external SA coat. Conclusions The behavior of microparticles to dissolution at pH 7.4 was superior to that of pure drug, reaching 70% of the drug released, after 20 min. Finally the system examined is stable towards aging: no difference in the dissolution behavior could be detected for the final microparticles after 8 months at 25°C.     

Carriers for the tunable release of therapeutics: etymological classification and examples

ABSTRACT

Introduction Physiological processes at the molecular level take place at precise spatiotemporal scales, which vary from tissue to tissue and from one patient to another, implying the need for carriers that enable tunable release of therapeutics.

Areas covered Classification of all drug release to intrinsic and extrinsic is proposed, followed by the etymological clarification of the term ‘tunable’ and its distinction from the term ‘tailorable’. Tunability is defined as analogous to tuning a guitar string or a radio receiver to the right frequency using a single knob. It implies changing a structural parameter along a continuous quantitative scale and correlating it numerically with the release kinetics. Examples of tunable, tailorable and environmentally responsive carriers are given, along with the parameters used to achieve these levels of control.

Expert opinion Interdependence of multiple variables defining the carrier microstructure obstructs the attempts to elucidate parameters that allow for the independent tuning of release kinetics. Learning from the tunability of nanostructured materials and superstructured metamaterials can be a fruitful source of inspiration in the quest for the new generation of tunable release carriers. The greater intersection of traditional materials sciences and pharmacokinetic perspectives could foster the development of more sophisticated mechanisms for tunable release.     

Pharmacokinetics of low-dose oral modified release,soluble and intravenous aspirin in man,and effects on platelet function

Summary The pharmacokinetics of low-dose aspirin and the resulting salicylic acid were studied in 6 healthy volunteers. Each received a single 50-mg dose of (1) oral modified release capsules, (2) oral solution and (3) intravenous solution. The volunteers also received 50 mg modified release capsules daily for 6 days to determine the effect on collagen, ADP and arachidonate induced platelet aggregation and thromboxane production, and to compare the pharmacokinetics after repeated dosing with the parameters obtained after the single dose.The formulation and route of administration profoundly influenced several pharmacokinetic parameters for aspirin: the maximum concentration (C_max, ng·ml^–1) was 221 and 191 after modified release for single and chronic dosing respectively, 1323 after the oral solution and 6000 after intravenous injection; the time to achieve this maximum concentration (t_max, h) was 3.42 and 3.02 after modified release for single and chronic dosing respectively, and 0.29 after the oral solution; the area under the plasma drug concentration versus time curve (AUC, µg·h·ml^–1) was 0.38 and 0.27 after modified release single and chronic dosing respectively, 0.68 after the oral solution and 1.57 after intravenous injection.The elimination of aspirin after the two solutions was at least biphasic. The terminal phase rate constant ranged from 1.52 h^–1 after intravenous injection to 1.88 h^–1 after the oral modified release form. The absorption of the oral forms of aspirin was complete as reflected by the total recovery of the doses as salicylic acid in urine. The pharmacokinetic parameters for salicylic acid showed similar t_max and C_max for the oral solution and intravenous injection but, as for aspirin, C_max was least and t_max greatest when the modified release form was used.After 7 days of modified release aspirin platelet aggregation and thromboxane formation in response to collagen and arachidonate were markedly inhibited. There was no inhibition of ADP-induced aggregation, but thromboxane production in response to ADP was abolished.     

以牡蛎壳粉-CMC为载体制备阿司匹林胃漂浮片的研究

目的:研制具有多微孔吸附特性的牡蛎壳粉和羧甲基纤维素钠(CMC)为复合药物载体的阿司匹林(ASP)胃漂浮片,并考察其体外释药特性和体外漂浮性能.方法:采用紫外分光光度法进行释放度试验.根据累积释药曲线对各组阿司匹林(ASP)胃漂浮片的释药过程分别进行数学模型拟合,从而研究片剂中的牡蛎壳粉与CMC的用量对释药过程的影响.结果:处方Ⅱ具有良好的漂浮性能,释药过程最理想,其释药过程符合体外释药特征零级动力学过程,其模拟方程为Q=0.080 4T 0.146 2,相关系数r=0.998 7.结论:阿司匹林胃漂浮片达到设计要求.     

盐酸二甲双胍渗透泵控释片的制备及体外释放度考察

目的研究盐酸二甲双胍渗透泵控释片的制备工艺及体外释药的影响因素。方法通过单因素考察和正交试验,优化制备工艺。结果盐酸二甲双胍渗透泵控释片的体外释药符合零级释放规律,释药速率受PEG种类、PEG用量、包衣膜重量影响较大,在一定范围内,释药孔大小、片芯硬度、溶出介质pH值和桨转速对其影响较小。结论盐酸二甲双胍渗透泵控释片工艺稳定,能够达到9h明显的恒速释药。     

In vitro drug release mechanism from lipid nanocapsules (LNC)

Lipid nanocapsules are recently developed lipid nanocarriers for delivery of lipophilic drugs. Due to their small size and biocompatible nature, lipid nanocapsules (LNC) may be promising carriers for drug delivery with different routes of administration. The aim of this work was to study the effect of formulation variables on the in vitro drug release from LNC. Ibuprofen as a model drug was entrapped in the oily core while Cremophor A25 and Cremophor A6 were used as hydrophilic surfactants in different ratios ranging from 1:1 to 1:0. All the prepared LNC were of comparable particle sizes around 50 nm. Varying Cremophor compositions as well as the presence of lecithin, cetyl or stearyl alcohol had no significant effect on the in vitro drug release profiles. However, drug release rates increased significantly with increasing the temperature from 4 to 50 °C, i.e. the flux increased from 1.5 to 7 μg/(cm² min). This was explained by the increased ibuprofen–lipid interactions at reduced temperature where the increased viscosity of the lipid significantly slows down the drug diffusion to the external aqueous phase. In summary, the physicochemical properties of the drug as well as the oil phase have a high impact on the drug release rate while the surfactant type, composition or density exerted only a minor effect.     

阿司匹林丁香酚酯的抗炎作用及其可能的作用机制

目的研究阿司匹林丁香酚酯(AEE)的抗炎作用及其可能的作用机制。方法阿司匹林0.2g.kg-1组、丁香酚0.18 g.kg-1组、AEE 0.18和0.36 g.kg-1组小鼠按体重ig给予相应药物,每天1次,连续3 d。用二甲苯致小鼠耳肿胀模型、小鼠腹腔毛细血管通透性增高模型、角叉菜胶致小鼠足跖肿胀模型及小鼠棉球肉芽肿模型观察AEE的抗炎作用,并测定血清中一氧化氮(NO)和足爪组织中前列腺素E2(PGE2)、丙二醛(MDA)和5-羟色胺(5-HT)的含量。结果二甲苯致小鼠耳肿胀实验,模型组肿胀度为(7.0±1.2)mg,阿司匹林、丁香酚、AEE 0.18和0.36 g.kg-1明显抑制耳肿胀度,肿胀度分别为3.9±1.2,4.7±1.9,3.9±1.9和(3.8±1.1)mg(P<0.05,P<0.01)。小鼠腹腔毛细血管通透性实验结果表明,模型组伊文思蓝的渗出(A590 nm)为0.56±0.11,阿司匹林、丁香酚、AEE 0.18和0.36 g.kg-1组腹腔毛细血管通透性均降低,伊文思蓝的渗出(A590 nm)分别为0.29±0.15,0.34±0.12和0.35±0.18(P<0.05,P<0.01)。小鼠棉球肉芽肿实验结果表明,模型组肉芽肿增生(12.5±2.4)mg,阿司匹林、丁香酚、AEE 0.18和0.36 g.kg-1组明显降低,分别为7.0±2.1,9.0±1.7,9.9±1.4和(8.8±1.8)mg(P<0.01);角叉菜胶致小鼠足跖肿胀实验结果表明,AEE 0.18 g.kg-1显著抑制角叉菜胶致炎小鼠足跖肿胀(P<0.05),降低致炎足组织中PGE2,5-HT和血清NO含量,作用与阿司匹林和丁香酚较强或相当。结论 AEE具有明显的抗炎作用,与阿司匹林和丁香酚作用相当;其抗炎机制可能与抑制炎性介质释放有关。     

Differential inhibition of tumour cell-induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin

BACKGROUND AND PURPOSE

Tumour cell-induced platelet aggregation (TCIPA) facilitates cancer cell invasion, angiogenesis and the formation of metastatic foci. TCIPA can be modulated by pharmacological inhibitors of MMP-2 and ADP; however, the COX inhibitor aspirin did not prevent TCIPA. In this study, we have tested the pharmacological effects of a new group of isosorbide-based aspirin prodrugs on TCIPA.

EXPERIMENTAL APPROACH

TCIPA was induced in human platelets by mixing with human adenocarcinoma or fibrosarcoma cells under no flow and flow conditions. The release of gelatinases and P-selectin expression during TCIPA were studied by zymography and flow cytometry respectively.

KEY RESULTS

Tumour cells caused platelet aggregation. This aggregation resulted in the release of MMP-2 and a significant up-regulation of P-selectin on platelets, indicative of platelet activation. Pharmacological modulation of TCIPA revealed that ST0702, one of the aspirin prodrugs, down-regulated TCIPA while aspirin was ineffective. The deacetylated metabolite of ST0702, 5-nicotinate salicylate (ST0702 salicylate), down-regulated both ADP-stimulated platelet aggregation and TCIPA.

CONCLUSIONS AND IMPLICATIONS

Our results show that ST0702 was an effective inhibitor of TCIPA in vitro. Its deacetylated metabolite may contribute to the effects of ST0702 by inhibiting ADP-mediated TCIPA.     

Amoxycillin release from a floating dosage form based on alginates

Floating alginate beads have been prepared from alginate solutions containing either dissolved or suspended amoxycillin. The beads were produced by the dropwise addition of the alginate into calcium chloride solution, followed by removal of the gel beads and freeze drying. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. In all cases, the drug release was consistent with release of a dissolved solute from a granular or porous matrix. The beads retained their buoyancy when amylose and amoxycillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy.