纯水飞蓟素纳米结晶制备及体外性质研究

目的:探索采用高压均质法制备稳定性佳的纯水飞蓟素纳米结晶的可能性,为后续纯药物纳米结晶体内研究奠定试验基础。方法:采用高压均质技术,通过筛选药物投入量、高剪切分散时间、均质压力、均质次数等关键参数,以粒径、多分散指数(PDI)等为指标,筛选出最佳的纯水飞蓟素纳米结晶处方及工艺,并对所制备纳米结晶的粒径、外观形态、晶型、溶解度、溶出行为及稳定性等体外性质进行研究。结果:所优选的纯药物纳米结晶的平均粒径为(449.8±7.56) nm,PDI为0.281±0.017。与含有稳定剂的水飞蓟素纳米结晶相比,纯水飞蓟素纳米结晶显示出相似且良好的稳定性。此外,所制备的纯药物纳米结晶将水飞蓟素在纯水中的溶解度提高了1.41倍,在不同水性介质均提高了水飞蓟素的溶出速率,其中在纯水中溶出速率增加最为显著,30 min内溶出度由38.5%增加至92.2%。结论:本研究成功制备了稳定的纯水飞蓟素纳米结晶,为后续系统开展纯药物纳米结晶的促口服吸收机制及药动学等研究奠定了工作基础。     

阿苯达唑纳米晶体的制备与表征

目的： 采用微射流高压均质-喷雾干燥法技术制备阿苯达唑纳米晶体,并进行表征和体外溶出考察。方法： 釆用高压均质法制备阿苯达唑纳米混悬液,并进一步喷雾干燥得纳米晶体。通过正交试验优化制备工艺;对最佳制备工艺所得纳米晶体进行粒径测定、DSC分析和傅里叶红外图谱分析,并测定其体外溶出度。结果： 微射流高压均质最佳制备工艺条件：在均质温度35℃,103.44 MPa和137.93 MPa下各循环20次,得到纳米混悬液平均粒径为（363.52±1.5） nm。喷雾干燥最佳工艺为：进样速度5 mL·min^-1,进风温度180℃,在此条件下得粉率（66.71±0.96）%,含水量（6.61±0.16）%,平均粒径367.34±0.68 nm。DSC分析及傅里叶红外图谱结果表明制备成纳米晶体后形成新的物象;体外溶出度实验结果表明,纳米晶体的溶出度显著高于原料药和混合物。结论： 微射流高压均质-喷雾干燥工艺,可以制备平均粒径小且较为均匀的纳米晶体;纳米化后形成新的物象,可以明显提高阿苯达唑的溶出性能,利于改善药物的口服吸收,这为阿苯达唑进一步开发提供了依据。     

Nanosuspensions as advanced printing ink for accurate dosing of poorly soluble drugs in personalized medicines

Folic acid was used as a model drug to demonstrate the advantages of formulating poorly soluble drugs as nanosuspensions and their use in an inkjet-type printing technique to produce personalized medicines. 10% folic acid nanosuspensions stabilized with Tween 20, a stabilizer showing the best wetting potential for folic acid, were prepared via high pressure homogenization. The particle size of the folic acid nanosuspension was well below 5 μm being a prerequisite for inkjet type printing technique. A good reproducibility of the particle size of folic acid nanosuspension prepared via high pressure homogenization was found. As indicated by the zeta potential the formulation showed a good storage stability. High pressure homogenization had no influence on the crystalline state of folic acid. An increase in the saturation solubility by 53.7% was found reducing the particle size from the micrometer range to the nanometer range. The dissolution velocity of the folic acid nanosuspension was significantly enhanced compared to a folic acid suspension, i.e. after 5 min 78.6% of the folic acid was dissolved from the nanosuspension and only 6.2% from the suspension. Moreover, the printing of 10% folic acid nanosuspension could be successfully demonstrated.     

In vitro-in vivo study of CoQ10-loaded lipid nanoparticles in comparison with nanocrystals

The present work described the effect of CoQ10 dissolution characteristics in nanocrystals and lipid nanoparticles (LNs) on its oral absorption in rats. Nanocrystals and LNs were prepared by melt-high pressure homogenization and sucrose monolaurate was used as a stabilizer in all formulations. Witepsol(?)W35 and medium-chain triglycerides (MCT) were selected as lipid additives to form LN(CoQ10+W35) and LN(CoQ10+MCT), respectively. From the results obtained, the particle size of CoQ10 nanocrystals was 285 nm, while it was reduced to 150 nm by mixture with an equal amount of lipid additives due to their lower melting points. In vitro dissolution results indicated that the drug release from two LNs was delayed compared with that from nanocrystals, and LN(CoQ10+W35) exhibited the highest drug release over 4h. Finally, in vivo evaluation demonstrated that the oral absorption of CoQ10 was markedly increased by using nanocrystals and LNs compared with a coarse suspension. A good relationship was found between the in vitro dissolution and in vivo evaluation. The enhanced oral absorption of CoQ10 by nanocrystals and LNs was due to improved dissolution. In conclusion, Witepsol(?)W35 was shown to be a better lipid additive for the preparation of LNs to increase the oral absorption of CoQ10.     

Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension

Revaprazan hydrochloride (RH) is a new reversible proton pump inhibitor. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To investigate the particle size reduction effect of RH on dissolution and absorption, three suspensions that containing different sized particles were prepared by high pressure homogenization and in vitro/in vivo evaluations were carried out. DSC and powder X-ray diffraction were used to study crystalline state of freeze dried powder of RH suspensions and the results showed that particles of RH microsuspension and nanosuspension remained in the same crystalline state as coarse suspension, but had lower lattice energy. In the in vitro dissolution test, both microsuspension and nanosuspension showed increased dissolution rate. In the in vivo evaluation, compared to coarse suspension, RH nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. Nevertheless, RH microsuspension did not display any significant differences in these pharmacokinetic parameters compared to the coarse suspension. The findings revealed that particle size reduction can influence RH absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of RH in rats.     

参白药效部位纳米混悬剂的剂型工艺优化及其升白作用的研究

目的 优化参白方有效部位纳米混悬剂的制备工艺,并开展纳米混悬剂的表征和升高白细胞的药效研究。方法 以参白方总多糖和总皂苷混合物为药物原料,在单因素考察的基础上,通过高压均质法,以稳定剂用量、均质压力、均质次数为影响因素,开展参白有效部位纳米混悬剂剂型工艺的正交优化和沉降稳定的观察,对制得的纳米混悬剂进行表征和升高白细胞的药效试验。结果 参白有效部位纳米混悬剂最优剂型工艺为：药物与大豆卵磷脂质量比为1:1.75,均质压力700 bar,均质次数14次。测得纳米混悬剂的粒径为（277.3±2.17）nm,PDI为0.185±0.018,Zeta电位为（-32.50±0.86）mV。给药7 d后,与模型组比较,给药7 d后纳米混悬剂高剂量组白细胞水平显著升高,给药15 d各剂量组白细胞水平显著升高（P＜0.05）。结论 参白有效部位纳米混悬剂的剂型优化工艺合理、可行,制剂粒径符合纳米要求,分散均匀且稳定,具有较好的升白作用,为有效部位组成的中药纳米混悬剂的新药研究提供有益的启示。     

非诺贝特胶囊剂及家犬体内生物利用度

目的采用纳米分散技术制备非诺贝特胶囊剂,以提高其溶出度及生物利用度。方法用反溶剂沉淀法和高压匀质法制备非诺贝特纳米混悬剂,并通过喷雾干燥将其固化以制备胶囊剂,用差示扫描量热法(differential scanning calorimetry,DSC)和X-射线粉末衍射分析表征药物在胶囊剂中的存在状态,并测定药物的溶出度及家犬体内的生物利用度。结果非诺贝特以纳米晶体状态分散于胶囊剂中,自制胶囊溶出度为国产胶囊的3倍,相对生物利用度为国产胶囊的(274.5±15.6)%。结论自制非诺贝特胶囊剂可以通过增加非诺贝特的分散度来提高药物的溶出度与生物利用度。     

Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study

Purpose: The purpose of the present study was to formulate and evaluate nanosuspension of Valsartan (VAL), a poorly water soluble and low bioavailable drug (solubility of 0.18?mg?mL^?1; 23% of oral bioavailability) with the aim of improving the aqueous solubility thus the bioavailability and consequently better anti-hypertensive activity.

Methods: Valsartan nanosuspension (VAL-NS) was prepared using high-pressure homogenization followed by lyophilisation. The screening of homogenization factors influencing nanosuspension was done by 3-factorial, 3-level Box-Behnken statistical design. Model suggested the influential role of homogenization pressure and cycles on drug nanosizing. The optimized formulation containing Poloxamer^?188 (PXM 188) was homogenized for 2 cycles at 500 and 1000?bar, followed by 5 cycles at 1500 bars.

Results: The size analysis and transmission electron microscopy showed nanometric size range and uniform shape of the nanosuspension. The in vitro dissolution showed an enhanced release of VAL from nanosuspension (VAL-NS) compared to physical mixture with PXM 188. Pharmacodynamic results showed that, oral administration of VAL-NS significantly lowered (p?≤?0.001) blood pressure in comparison to non-homogenized VAL (VAL-Susp) in Wistar rat. The level of VAL in rat plasma treated with VAL-NS showed significant difference (p?≤?0.005) in C_max (1627.47?±?112.05?ng?mL^?1), T_max (2.00?h) and AUC_0→24 (13279.2?±?589.426?ng?h?mL^?1) compared to VAL-Susp that was found to be 1384.73?±?98.76?ng?mL^?1, 3.00?h and 9416.24?±?218.48?ng?h?mL^?1 respectively. The lower T_max value, proved the enhanced dissolution rate of VAL.

Conclusion: The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.     

不同稳定剂种类对齐墩果酸纳米混悬剂溶出度的影响

目的:制备齐墩果酸纳米混悬剂(OLA-NS),考察不同稳定剂种类对其溶出度的影响。方法:采用高压均质法,制备不同稳定剂、粒径相同的齐墩果酸纳米混悬剂,以溶出度为评价指标比较其体外释放行为,并利用傅立叶变换红外光谱(FT-IR)进行表征。结果:不同稳定剂制备得到的OLA-NS粒径为约330 nm,以甘露醇为冻干保护剂冷冻干燥后粒径为约350 nm,不同稳定剂的溶出速率为NS-HPMC E5>NS-PVP VA64>NS-PVP K30>NS-Soluplus。结论:稳定剂种类对齐墩果酸纳米混悬剂的体外溶出行为有显著影响。     

Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base.

Ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.     

Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam

The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion–diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200–900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate, and thus possibly enhance fast onset of therapeutic drug effect.     

非洛贝特纳米混悬剂的制备及其体外溶出性考察

目的:制备非洛贝特纳米混悬剂,以促进药物溶出。方法:以非洛贝特为主药,采用熔融乳化法联合高压均质法制备纳米混悬剂;选取处方中表面活性剂泊洛沙姆188(Poloxamer188)与聚乙烯吡咯烷酮(PVP)K30用量比、均质压力、均质次数为考察因素,药物粒径为指标设计正交试验筛选制备工艺,并进行验证试验;同时考察制剂溶出速率和溶出浓度。结果:最佳制备工艺为Poloxamer188:PVPK30用量比2:1、均质压力800bar,均质次数为9。所制纳米粒平均粒径为356nm,多分散系数为0.19,平均Zeta电位为-39mV。制剂5min时溶出浓度可达20.10mg·L-1,4h时达25.46mg·L-1,接近完全溶出。结论:将难溶药物非诺贝特制成纳米混悬剂可以显著改善其溶出作用。     

Nanonization of itraconazole by high pressure homogenization: stabilizer optimization and effect of particle size on oral absorption

This study was performed to optimize stabilizer systems used in itraconazole (ITZ) nanosuspensions to achieve the greatest extent of size reduction and investigate the effect of particle size on the in vitro dissolution and oral absorption of ITZ. The nanosuspensions were prepared by high pressure homogenization and characterized for particle size, zeta potential, and surface morphology. A central composite method was applied to identify a multiple stabilizer system of Lutrol F127 and sodium lauryl sulfate for optimal particle size reduction. By using the optimized system, an ITZ nanosuspension was prepared that showed the particle size results in good agreement with the values predicted by the model. The nanosuspension was physically stable at 25°C for 1 week. The crystalline form of ITZ was not altered. The ITZ dissolution rate is directly correlated to its particle size, and a smaller particle size yields a faster dissolution rate. Pharmacokinetics study was performed using four ITZ suspensions with various particle sizes in rats (n = 3). A significant increase in both maximal plasma concentration of drug and area under the drug concentration-time curve (AUC) was shown when the particle size was reduced from micrometer to nanometer. However, the AUC was not significantly affected by further reduction of the particle size within the nano-size range.     

Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology.

Omeprazole is a proton pump inhibitor, which is used for the treatment of peptic ulcers, reflux esophagitis and Zollinger-Ellison syndrome. It is a poorly soluble, chemically labile drug with a high degradation rate in aqueous media. The aim of this study was to show the feasibility of omeprazole stabilization using the DissoCubes technology and to find optimal production parameters for a stable, highly concentrated omeprazole nanosuspension. The high performance liquid chromatography analysis has proved the predominance of the nanosuspension produced by high pressure homogenization in comparison to an aqueous solution. Even 1 month after production no discoloration or drug loss was recognizable when the nanosuspension was produced at 0 degree C. As a result it can be stated that the production of nanosuspensions by high pressure homogenization is suitable for preventing degradation of labile drugs.     

柚皮素纳米晶体的制备及体外性质研究

目的:制备一种新型的柚皮素纳米晶体并对其进行表征和体外评价。方法:通过高压均质法制备柚皮素纳米结晶;对制备得到的柚皮素纳米晶体进行粒径测定、DSC分析、X-射线衍射分析和傅里叶红外图谱分析,并测定柚皮素纳米晶体的溶解度和体外溶出度。结果:柚皮素纳米晶体的平均粒径为(467±12) nm,DSC、X-射线衍射及傅里叶红外图谱结果表明将柚皮素制备成柚皮素纳米结晶并未改变药物的晶型和化学结构,溶解度和体外溶出度实验结果表明,与柚皮素原料药相比,柚皮素纳米晶体的溶解度和溶出度均有显著地提高。结论:本文通过制备柚皮素纳米晶体,显著地提高了柚皮素的溶解度和体外溶出度,为柚皮素的临床应用提供了新选择。     

Enhanced antihypertensive activity of candesartan cilexetil nanosuspension: formulation, characterization and pharmacodynamic study

The objective of the present investigation was to enhance the oral bioavailability of practically insoluble Candesartan cilexetil [CC] by preparing nanosuspension. The nanosuspension was prepared by media milling using zirconium oxide beads and converted to solid state by spray drying. The spray dried nanosuspension of CC [SDCN] was evaluated for particle size, zeta potential, saturation solubility, crystallanity, surface morphology and dissolution behavior. SDCN showed particle size of 223.5±5.4 nm and zeta potential of -32.2±0.6 mV while saturation solubility of bulk CC and SDCN were 125±6.9 μg/ml and 2805±29.5 μg/ml respectively, showing more than 20 times increase in solubility. Differential Scanning Calorimetry [DSC] and X-ray diffraction [XRD] analysis showed that crystalline state of CC remained unchanged in SDCN. Dissolution studies in phosphate buffer pH 6.5 containing 0.7% Tween 20 showed that 53±5% of bulk drug dissolved in 15 min whereas SDCN was almost completely dissolved exhibiting higher dissolution velocity and solubility. Transmission electron microscopy [TEM] revealed that nanocrystals were not of uniform size, and approximately of oval shape. Pharmacodynamic study based on deoxycorticosterone acetate [DOCA] salt model was performed in rats to evaluate in-vivo performance, which showed 26.75±0.33% decrease in systolic blood pressure for nanosuspension while plain drug suspension showed 16.0±0.38% reduction, indicating that increase in dissolution velocity and saturation solubility leads to enhancement of bioavailability of SDCN when compared to bulk CC suspension. Thus, the results conclusively demonstrated a significant enhancement in antihypertensive activity of candesartan when formulated as nanosuspension.     

Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base

ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.     

Preparation and characterization of quercetin nanocrystals

This study is to enhance the dissolution rate of a poorly water-soluble drug, quercetin, by fabricating nanocrystals using high-pressure homogenization. The particle size, crystallinity, dissolution, and antioxidant effects of fabricated quercetin nanocrystals have been investigated. Characterization of the original quercetin powder and nanocrystals was carried out by photon correlation spectroscopy (PCS), laser diffraction, scanning electron microscopy, differential scanning calorimetry (DSC), X-ray diffraction, dissolution tester, and so on. A PCS size of about 483 nm was obtained for the nanocrystals after 20 cycles of homogenization at 1500 bar. X-ray diffraction and DSC studies revealed that the lyophilized quercetin nanoparticles were crystalline after high-pressure homogenization. The percent dissolution efficiency, relative dissolution, mean dissolution time, difference factor (f(1)), and similarity factor (f(2)) were calculated for the statistical analysis. It was found that the dissolution of the drug nanocrystals was much higher than that of the pure drug at pH 6.8 and 1.2. The antioxidant activity and reducing power of the quercetin nanocrystals were more effective than the original quercetin.     

Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products

During the last 10-15 years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently five products on the market. The major characteristic of these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oral administration. This mini-review focuses on recent advances with respect to three topics considering drug nanocrystals. The first topic is nanosuspension stabilization. A current literature status is provided and special attention is given to studies attempting to extend our physicochemical understanding of the underlying principles. The second part describes recent advances on miniaturization of nanosuspension production, to enable formulation screening during preclinical development. Finally, literature available on further nanosuspensions solidification is discussed, focussing on the maintenance of the preservation of the rapid dissolution properties of the nanocrystals after further downstream processing.     

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.