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首页> 外文学位 >Preparation, characterization and evaluation of dissolution of nanoparticles made by precipitation in drug carrier pores.
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Preparation, characterization and evaluation of dissolution of nanoparticles made by precipitation in drug carrier pores.

机译：通过在药物载体孔中沉淀制备的纳米颗粒的制备，表征和评估。

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摘要

Poor water solubility, slow dissolution rate and stability are issues for the majority of upcoming and existing biologically active compounds. Drug dissolution is a key parameter that affects the bioavailability and onset of action of oral dosage forms. Low dissolution rates can occur because of small total surface area (of a drug) or poor solubility in the receiving aqueous medium. Decreasing the particle size from a micron to a nanometer scale can result in a significant increase in the surface area and related dissolution rate. Here, a method for developing nano-sized drug particles to improve dissolution of drugs with poor water solubility was developed. In addition, a method to test the nanoparticle dissolution behavior based on pulsatile microdialysis (PMD) was also developed.;This work primarily focused on a novel method of formulating nanoparticles, in which poorly soluble drugs were precipitated into the pores of carrier excipients. This study was done using porous spray-dried lactose monohydrate and the insoluble carrier syloid-244. The main test drug was ibuprofen, which has relatively poor solubility in water at pH 2. The formulations were prepared at various drug:carrier ratios, and then were characterized for the drug loading, dissolution profiles, thermal behavior, and drug particle size.;For most formulations, the ibuprofen loaded into the lactose showed bimodal precipitated particle size distributions, with almost half population was below 100 nm. The interpretation was less clear for ibuprofen-syloid formulations, since the carrier did not dissolve in water. The percentage of drug loading in formulations was found to be 2--10% (2--10 grams of drug per 100 grams of formulation) for ibuprofen-lactose formulations, and ranged from 4--38% in the ibuprofen-syloid formulations it is significant, as 4--38%. The melting temperature of both pore-confined ibuprofen was different from the bulk powder form. DSC curves of formulation showed depression in melting point of ibuprofen, which was sometimes insignificant for lactose nanoparticles batches but significant for syloid formulations.;Dissolution studies were done at 20°C and 37°C in pH 2 HCl (USP) buffer using ibuprofen-lactose and ibuprofen-syloid formulations, and pure ibuprofen. Dissolved ibuprofen concentrations were determined using PMD (3.8 uL probe volume, 11 uL sample volume, 9 second resting time and 100 uL/min flush rate). Direct samples were also taken from the dissolution medium and filtered with a 0.2 micron filter. The physical and experimental parameters of PMD were comprehensively studied in a wide variety of systems, including supersaturated donor solutions, to determine the optimal PMD experimental settings (probe length, flush rate, sample volume, resting time, number of probes used simultaneously, etc.). The donor concentration obtained from direct sampling and donor concentration calculated using PMD parameter was found significantly different. This was explicit the over estimation of direct filtered sampling.;The release rate of ibuprofen from nanoparticle formulations was much faster than that of the pure crystalline form, with some nanoparticle formulations showing nearly 400 fold increases in the initial dissolution rates compared to the pure drug. It was also found that the use of surfactant further increases the dissolution rate.;It was concluded that deposition of drugs in the pores of excipients is a potentially useful method to increase the dissolution of drugs with poor water solubility. In addition, to best characterize the dissolution/release properties of such formulations (and presumably, nanoparticle formulations in general), the adaptation of PMD presents advantages over existing methods of dissolution testing.
机译：水溶性差，溶解速度慢和稳定性差是大多数即将出现和现有的生物活性化合物的问题。药物溶解是影响口服剂型的生物利用度和作用开始的关键参数。由于（药物的）总表面积小或在接受的水性介质中溶解度差，可能会导致溶解速度低。将粒径从微米减小到纳米级会导致表面积和相关溶解速率的显着增加。在此，开发了用于开发纳米​​级药物颗粒以改善水溶性差的药物溶解的方法。此外，还开发了一种基于脉动微透析（PMD）的纳米颗粒溶解行为测试方法。该工作主要集中于一种新型的纳米颗粒配制方法，其中难溶性药物沉淀在载体赋形剂的孔中。这项研究是使用多孔喷雾干燥的乳糖一水合物和不溶性载体syloid-244进行的。主要的测试药物是布洛芬，其在pH 2下在水中的溶解度相对较差。以各种药物：载体的比例制备制剂，然后对药物载量，溶出曲线，热行为和药物粒径进行表征。对于大多数制剂，装载到乳糖中的布洛芬显示出双峰沉淀的粒度分布，几乎一半的人口低于100 nm。对于布洛芬-syloid制剂，其解释不太清楚，因为载体不溶于水。对于布洛芬-乳糖制剂，发现制剂中药物载量的百分比为2--10％（每100克制剂中为2--10克药物），在布洛芬-糖浆状制剂中为4--38％它很重要，为4--38％。两种孔隙受限的布洛芬的熔融温度均与散装粉末形式不同。制剂的DSC曲线显示布洛芬的熔点降低，这对于批次的乳糖纳米颗粒有时微不足道，但对于糖浆制剂却很显着;在20°C和37°C的pH 2 HCl（USP）缓冲液中使用布洛芬-进行了溶出度研究乳糖和布洛芬-淀粉样蛋白制剂，以及纯布洛芬。使用PMD（3.8 uL探针体积，11 uL样品体积，9秒静置时间和100 uL / min冲洗速度）测定已溶解的布洛芬浓度。还从溶解介质中提取直接样品，并用0.2微米过滤器过滤。在包括过饱和供体溶液在内的各种系统中对PMD的物理和实验参数进行了全面研究，以确定最佳PMD实验设置（探针长度，冲洗速率，样品量，静置时间，同时使用的探针数量等）。 ）。发现直接采样获得的供体浓度与使用PMD参数计算的供体浓度显着不同。这明显地是对直接过滤采样的过度估计。布洛芬从纳米颗粒制剂中的释放速度比纯结晶形式要快得多，与纯药物相比，某些纳米颗粒制剂的初始溶出度增加了近400倍。还发现使用表面活性剂进一步提高了溶解速率。结论是药物在赋形剂孔中的沉积是增加水溶性差的药物溶解的潜在有用方法。另外，为了最好地表征此类制剂（一般来说，大概是纳米颗粒制剂）的溶解/释放特性，PMD的适应性优于现有的溶出度测试方法。

著录项

  • 作者

    Kokil, Suruchi N.;

  • 作者单位

    Long Island University, The Brooklyn Center.;

  • 授予单位 Long Island University, The Brooklyn Center.;
  • 学科 Chemistry Pharmaceutical.;Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 215 p.
  • 总页数 215
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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