Effect of Polymer Molecular Weight on Nanocomminution of Poorly Soluble Drug

The reduction of particle size to nanometers has been an important tool used for efficient drug delivery. Solid drug nanoparticles can be conveniently prepared by nanocomminution. This process relies on mechanical energy and the selection of a proper polymeric stabilizer. The long chains of polymers provide steric stabilization for drug nanoparticles. In this research, itraconazole and hydroxypropyl cellulose were used to study the effect of the molecular weight of a polymer on particle size reduction. In principle, an increase in molecular weight produces two counteracting effects: a decrease in the diffusion rate of chains and an increase in the physical adsorption of a polymer. The effects of particle size reduction are more pronounced in systems involving smaller molecular weights, and the effects of changing molecular weights disappear with time. Systems of higher molecular weight show larger aggregates in their redispersion after drying. Based on the results of our research, it appears that polymers of smaller molecular weight are more suitable than larger polymers for efficient nanocomminution. This indicates that the kinetic aspects of molecular weight are important.     

Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches

BMS-488043 is an HIV-attachment inhibitor that exhibited suboptimal oral bioavailability upon using conventional dosage forms prepared utilizing micronized crystalline drug substance. BMS-488043 is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility of 0.04 mg/mL and an acceptable permeability of 178 nm/s in the Caco2 cell-line model. Two strategies were evaluated to potentially enhance the oral bioavailability of BMS-488043. The first strategy targeted particle size reduction through nanosizing the crystalline drug substance. The second strategy aimed at altering the drug's physical form by producing an amorphous drug. Both strategies provided an enhancement in oral bioavailability in dogs as compared to a conventional formulation containing the micronized crystalline drug substance. BMS-488043 oral bioavailability enhancement was 5- and 9-folds for nanosizing and amorphous formulation approaches, respectively. The stability of the amorphous coprecipitated drug prepared at different compositions of BMS-488043/polyvinylpyrrolidone (PVP) was evaluated upon exposure to stressed stability conditions of temperature and humidity. The drastic effect of exposure to humidity on conversion of the amorphous drug to crystalline form was observed. Additionally, the dissolution behavior of coprecipitated drug was evaluated under discriminatory conditions of different pH values to optimize the BMS-488043/PVP composition and produce a stabilized, amorphous BMS-488043/PVP (40/60, w/w) spray-dried intermediate (SDI), which was formulated into an oral dosage form for further development and evaluation.     

Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique

A basic problem of poorly soluble drugs is often an insufficient bioavailability. To allow the i.v. injection of these drugs, they were formulated as nanosuspensions by high pressure homogenization. The effect of the production parameters pressure and cycle number on the mean particle size and on the polydispersity of the nanosuspension was investigated with special attention to contamination by microparticles — the limiting factor for i.v. injection. Properties of the nanosuspensions are increased saturation solubility C_s and dissolution rate dc/dt. These phenomena are explained using the Prandtl and the Ostwald–Freundlich equations. These properties promote the dissolution of the nanosuspensions in the blood after i.v. injection. The size distribution obtained and the use of an APV Gaulin homogenizer (FDA approved for parenterals) lead to a pharmaceutical product considered acceptable by the regulatory authorities.     

In vitro and in vivo antitumor activity of oridonin nanosuspension

The aim of the present study was to evaluate the antitumor activity of an oridonin (ORI) nanosuspension relative to ORI solution both in vitro and in vivo. ORI nanosuspension with a particle size of 897.2 ± 14.2 nm was prepared by the high pressure homogenization method (HPH). MTT assay showed that ORI nanosuspension could significantly enhance the in vitro cytotoxicity against K562 cells compared to the ORI solution, the IC₅₀ value at 36 h was reduced from 12.85 μmol/L for ORI solution to 8.11 μmol/L for ORI nanosuspension. Flow cytometric analysis demonstrated that the ORI nanosuspension also induced a higher apoptotic rate in K562 cells compared to ORI solution. In vivo studies in a mouse model of sarcoma-180 solid tumors demonstrated significantly greater inhibition of tumor growth following treatment with ORI nanosuspension than ORI solution at the same dosage. The mice injected with ORI nanosuspension showed a higher reduction in tumor volume and tumor weight at the dose of 20 mg/kg compared to the ORI solution (P < 0.01), with the tumor inhibition rate increased from 42.49% for ORI solution to 60.23% for the ORI nanosuspension. Taken together, these results suggest that the delivery of ORI in nanosuspension is a promising approach for the treatment of the tumor.     

Understanding the structure and stability of paclitaxel nanocrystals

Previously, PTX/Pluronic F127 nanocrystals were prepared in our laboratory using the stabilization of nanocrystals (SNC) method. For PTX nanocrystals, dosages could be increased to yield improved antitumor activity over Taxol^® without incidence of acute toxicity. The objectives of this current study are to further understand the structure and stability of PTX nanocrystals. More Pluronic F127 surfactant was added in the formulation to attempt to further stabilize the nanocrystals against thermal induced aggregation. However, this resulted in formation of micelles that worsened the stability of nanocrystals. The F127 desorption experiment suggested different surfactant adsorption affinity to nanocrystal surface below and above the CMC. Below the CMC monomers bound to nanocrystal surface with high affinity, but above the CMC low affinity surfactant aggregates readily left the surface upon dilution. At higher temperature the tendency of F127 micellization is enhanced due to drastically lower CMC. Consequently, at 37 °C there was F127 desorption even for nanocrystals prepared with low amounts of F127 (1:5 (w/w) PTX/F127). To improve the stability of nanocrystals, re-nanonization by incubation–sonication procedure was used to disrupt the preferred crystal growth pattern of PTX. Furthermore, we have demonstrated that a higher heating temperature (45 °C vs. 37 °C) used in the incubation–sonication procedure was able to provide even better nanocrystal stability for long periods of incubation time.     

葛根素及其纳米混悬剂平衡溶解度测定

目的：测定葛根素及其纳米混悬剂在pH1.2盐酸溶液、水、pH7.4 PBS缓冲液介质中的平衡溶解度.方法：采用高效液相色谱法（HPLC）测定葛根素及其纳米混悬剂在各个介质中的浓度.结果：在37℃下,葛根素纳米混悬剂在pH1.2盐酸溶液、水、pH7.4磷酸盐（PBS）缓冲液中的平衡溶解度分别为4.43、5.28、6.32mg·mL-1.结论：葛根素纳米混悬剂比原料药在各介质的溶解度均增加,在弱碱性介质中溶解度大于酸性介质,随pH升高而增大.葛根素水溶性较差,将其制备成纳米混悬剂有利于提高其溶解度.     

In vitro and in vivo Evaluation of Ibuprofen Nanosuspensions for Enhanced Oral Bioavailability

IntroductionThe objectives were to prepare, characterize, and evaluate different ibuprofen (IBU) nanosuspensions.MethodsThe nanosuspensions produced by ultrahomogenization were compared with a marketed IBU suspension for particle size, in vitro dissolution, and in vivo absorption. Five groups of rabbits were orally administered with 25 mg/kg of IBU nanosuspension, nanoparticles, unhomogenized suspension, marketed product, and untreated suspension. A sixth group received 5 mg/kg IBU intravenously. Blood samples obtained were analyzed by chromatography.ResultsThe nanosuspensions showed significant decrease in particle size. Polyvinylpyrrolidone (PP) K30 profoundly increased aqueous solubility of IBU. Addition of Tween 80 (TW), in equal amount as PP (IBU:PP:TW, 1:2:2 w/w), resulted in much smaller particle size and better dissolution rate. The C_max values achieved were 14.8 ± 1.64, 11.1 ± 1.37, 9.01 ± 0.761, 7.03 ± 1.38, and 3.23 ± 1.03 μg/mL, and the t_max values were 36 ± 8.2, 39 ± 8.2, 100 ± 17.3, 112 ± 15, and 105 ± 17 min for the nanosuspension, nanoparticle, unhomogenized suspension, marketed IBU suspension, and untreated IBU suspension in water, respectively. Bioavailability of the different formulations relative to the marketed suspension was found to be in the following sequence: nanosuspension > unhomogenized suspension > nanoparticles > untreated IBU suspension.ConclusionIBU/PP/TW nanosuspension showed enhanced in vitro and in vivo performance as compared to the marketed product. Nanosuspensions prepared by the ultrahigh-pressure homogenization technique can be used as a good formulation strategy to enhance the rate and extent of absorption of poorly soluble drugs.     

大鼠在体肠循环结合颈动脉取血研究非诺贝特纳米混悬剂的体内吸收

目的考察非诺贝特纳米混悬剂在大鼠小肠内的吸收动力学及药动学过程。方法采用大鼠在体肠道灌流结合颈动脉取血实验考察非诺贝特纳米混悬剂的体内吸收情况。结果非诺贝特纳米混悬剂在大鼠体内的血药质量浓度y与肠腔中药物累计减少量x的关系为:y=7×10-5 x+0.521 9,r=0.993 6。结论非诺贝特纳米混悬剂在体肠吸收较好,动物实验体内药动学特性符合一室模型。血药质量浓度和肠腔内药物减少量的相关性良好。     

灯盏花素纳米混悬剂的制备及其大鼠体内药动学研究

目的应用纳米混悬剂提高难溶性药物灯盏花素的口服生物利用度。方法采用自乳化溶剂扩散工艺制备了灯盏花素纳米混悬剂。所得纳米混悬剂PCS粒径为(293 .11±55 .86) nm,Zeta电位为(27 .5±4 .9) mV;建立以超滤法测定灯盏花素纳米混悬剂溶解度和溶出度的方法,并以该法进行了灯盏花素溶解度和溶解速度的考察。结果纳米混悬剂显著提高了灯盏花素的溶解度和溶解速度;进行了灯盏花素纳米混悬剂及粗混悬剂大鼠体内的药动学研究,纳米混悬剂显著提高了灯盏花素在大鼠体内的生物利用度并延长了其作用时间,其大鼠灌胃绝对生物利用度从(1 .3±0 .9) %提高到(14 .4±3 .7) %,MRT从(4 .1±1 .4) h延长到(8 .6±1 .8) h。结论纳米混悬剂的肠道转运行为是提高生物利用度的关键因素。