Preparation and characterization of intravenously injectable nimodipine nanosuspension

The purpose of this study was to develop an alternative, improved and better tolerated injectable nimodipine nanosuspension compared with commercially available ethanol solution. In this study, nimodipine nanosuspension was prepared by high-pressure homogenization (HPH). The effects of the production parameters such as pressure, cycle numbers and crushing principles on the mean particle size, 99% diameter and polydispersity of the nanosuspension were investigated. Characterization of the product was performed by scanning electron microscope (SEM) and differential scanning calorimeter (DSC). The safety of the nimodipine nanosuspension was discussed with special attention to contamination by microparticles and the increase in saturation solubility C_s. Irritability study in rabbits showed that this formulation provided less local irritation and phlebitis risks than the commercial ethanol product, which represented a promising new drug formulation for intravenous therapy of subarachnoid hemorrhage (SAH)-related vasospasm.     

Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles.

The purpose of the present study was to investigate the possibility of targeting an anti-Alzheimer's drug tacrine in the brain using polymeric nanoparticles. Rats obtained 1mg/kg of tacrine by intravenous injection in the form of three preparations: (1) a simple solution in phosphate buffered saline, (2) bound to poly(n-butylcyanoacrylate) nanoparticles, and (3) bound to poly(n-butylcyanoacrylate) nanoparticles coated with 1% polysorbate 80 (Tween((R)) 80). After 1h of post injection the rats were killed by decapitation and tacrine concentration in brain, liver, lungs, spleen and kidneys was analyzed by HPLC. A higher concentration of drug tacrine was observed in liver, spleen and lungs with the nanoparticles in comparison to the free drug. The accumulation of drug tacrine in the liver and spleen was reduced, when nanoparticles were coated with 1% polysorbate 80. In the brain a significant increase in tacrine concentration was observed in the case of poly(n-butylcyanoacrylate) nanoparticles coated with 1% polysorbate 80 compared to the uncoated nanoparticles and the free drug. In conclusion, the present study demonstrates that the brain concentration of intravenously injected tacrine can be enhanced by binding to poly(n-butylcyanoacrylate) nanoparticles, coated with 1% the nonionic surfactant polysorbate 80.     

Brain targeted oral delivery of doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles against ketamine induced psychosis: behavioral,biochemical, neurochemical and histological alterations in mice

To develop statistically optimized brain targeted Tween 80 coated chitosan nanoparticulate formulation for oral delivery of doxycycline hydrochloride for the treatment of psychosis and to evaluate its protective effect on ketamine induced behavioral, biochemical, neurochemical and histological alterations in mice. 3² full factorial design was used to optimize the nanoparticulate formulation to minimize particle size and maximize entrapment efficiency, while independent variables chosen were concentration of chitosan and Tween 80. The optimized formulation was characterized by particle size, drug entrapment efficiency, Fourier transform infrared, Transmission electron microscopy analysis and drug release behavior. Pure doxycycline hydrochloride (25 and 50?mg/kg, p.o.) and optimized doxycycline hydrochloride encapsulated Tween 80 coated chitosan nanoparticles (DCNP_opt) (equivalent to 25?mg/kg doxycycline hydrochloride, p.o.) were explored against ketamine induced psychosis in mice. The experimental studies for DCNP_opt, with mean particle size 237?nm and entrapment efficiency 78.16%, elucidated that the formulation successfully passed through blood brain barrier and exhibited significant antipsychotic activity. The underlying mechanism of action was further confirmed by behavioral, biochemical, neurochemical estimations and histopathological study. Significantly enhanced GABA and GSH level and diminished MDA, TNF-α and dopamine levels were observed after administration of DCNP_opt at just half the dose of pure doxycycline hydrochloride, showing better penetration of doxycyline hydrochloride in the form of Tween 80 coated nanoparticles through blood brain barrier. This study demonstrates the hydrophilic drug doxycycline hydrochloride, loaded in Tween 80 coated chitosan nanoparticles, can be effectively brain targeted through oral delivery and therefore represents a suitable approach for the treatment of psychotic symptoms.     

介质研磨法制备他达拉非纳米混悬液研究

目的:采用介质研磨法制备他达拉非纳米混悬液,以提高他达拉非的溶出度和生物利用度。方法:以粒径、多分散指数(PDI)、Zeta电位和物理稳定性为评价指标,优化处方和工艺参数;采用扫描电镜(SEM)、X-射线粉末衍射法(XRPD)、差示扫描量热法(DSC)对样品进行表征,HPLC法测定他达拉非纳米混悬液体外溶出度,UPLC-MS/MS法检测大鼠中他达拉非的血药浓度。结果:他达拉非纳米混悬液最优处方为他达拉非质量分数2%、HPC 1%和SDS 0.1%;最优工艺为粒径0.1 mm氧化锆珠,转速3 000 r·min^-1,研磨时间30 min。制备的他达拉非纳米混悬液PDI为0.173±0.013,Zeta电位为(－22.6±0.4) mV,纳米颗粒为棒状结晶,粒径为(218.2±1.3) nm,分布均匀,晶型稳定;体外溶出度10 min内达到99%,大鼠体内生物利用度为原料药的4.01倍,在室温条件下放置6个月稳定性良好。结论:介质研磨法制备他达拉非纳米混悬液方法简单,产品稳定性好,能显著提高他达拉非溶出度和生物利用度。     

Application of spray granulation for conversion of a nanosuspension into a dry powder form

The in vivo effect of particle agglomeration after drying of nanoparticles has not been extensively studied till date based on current literature review. The purpose of this research was to evaluate the feasibility of spray granulation as a processing method to convert a nanosuspension of a poorly water soluble drug into a solid dosage form and to evaluate the effect of the transformation into a solid powder on the in vivo exposure in beagle dogs. Formulation variables like the level of stabilizer in the nanosuspension formulation, granulation substrate and drug loading in the granulation were evaluated. The granules were characterized for moisture content, drug content, particle size, crystallinity and in vitro dissolution rate. Granulations with 10% drug loading showed dissolution profiles comparable to the nanosuspension, slightly slower dissolution profiles were observed at 20% drug loading. This can be attributed to an increase in the surface hydrophobicity at a higher drug loading and the formation of agglomerates that were harder to disintegrate, thereby compromising the dissolution rate. An in vivo PK study in beagle dogs showed an 8-fold increase and a 6-fold increase in the AUC(0-48) from the nanosuspension and dried nanosuspension formulations respectively compared to the coarse suspension. Also, the nanosuspension and dried nanosuspension formulations showed a 12-fold and 8-fold increase in the C(max) respectively compared to the coarse suspension. This shows the feasibility of using spray granulation as a processing method to convert a nanosuspension into a solid dosage form with improved in vivo exposure compared to the coarse suspension formulation.     

盐酸表柔比星-聚乳酸-羟基乙酸共聚物纳米粒的制备

摘要目的制备盐酸表柔比星 聚乳酸 羟基乙酸（PLGA）共聚物纳米粒,对其进行质量评价。方法采用乳化 溶剂挥发法制备盐酸表柔比星纳米粒;对主要处方因素如PLGA用量、外水相中聚山梨酯 80用量、泊洛沙姆188和聚山梨酯 80比例进行正交设计,以药物的包封率、载药量和药物利用率等为考察指标。结果采用优化后处方制得的纳米粒药物包封率为（32.6±1.2）%,载药量为（7.2±0.5）%,药物利用率为（51.6±3.4）%,纳米粒平均粒径166.6 nm,药物可持续160 h释放。结论该方法制备盐酸表柔比星纳米粒工艺简单,无需使用聚乙烯醇,药物释放缓慢。     

Formulation and evaluation of nimodipine-loaded lipid microspheres

The purpose of this study was to develop an alternative, improved and better tolerated formulation and investigate the pharmacokinetic profile of the new formulation of nimodipine (NM) compared with nimodipine ethanol solutions. Lipid microspheres (LMs) prepared using lecithin and vegetable oils have attracted a lot of interest owing to their versatile properties, such as non-immunogenicity, being easily biodegradable and exhibiting high entrapment efficiency. NM incorporated in LMs could reduce irritation by avoiding the use of ethanol as a solubilizer. The solubility of NM was also increased by dissolving it in the oil phase. The particle size distribution, zeta potential, entrapment efficacy and assay of the NM-loaded LMs were found to be 188.2+/-5.4 nm, -31.6 mV, 94.2% and 1.04 mg mL(-1), respectively. The preparation was stable for 1 year at 4-10 degrees C. The formulation and some physicochemical properties of NM-loaded LMs were investigated. The pharmacokinetic and biodistribution studies were performed in rats at a dose of 1.2 mg kg(-1). From the observed data, there is no obvious retention of NM-loaded LMs in plasma. Moreover, incorporation of NM in LMs did not alter the tissue distribution significantly except for the relatively greater drug accumulation in the liver and spleen. The stimulation studies demonstrate that LMs of NM reduce irritation markedly compared with NM solutions. These results suggest that the LM system is a promising option to replace NM ethanol solutions as an intravenous treatment.     

Development and pharmacokinetics of nimodipine-loaded liposomes

In order to improve the water solubility of nimodipine and prolong the time of the drug in the circulation, nimodipine-loaded liposomes with a small size and high entrapment efficiency were prepared by a method that was easy to scale up (the modified ethanol injection method). The nimodipine liposome dispersions were characterized with respect to particle size distribution, zeta potential and entrapment efficiency. Liposomal nimodipine and nimodipine solution were intravenously administered to mice as a single dose of 4 mg kg-1. The pharmacokinetic parameters of nimodipine changed significantly when encapsulated in liposomes. The clearance of nimodipine encapsulated in liposomes was reduced and the elimination half-life was prolonged. The ratios of the area under the curve values of nimodipine liposomes to nimodipine solution were 1.78 and 1.90 in plasma and cerebral tissue, respectively. The drug concentration in cerebral tissue and in plasma showed a good linear correlation, which showed that liposomes could efficiently deliver nimodipine into brain tissue. These findings suggest that intravenous administration of liposomal nimodipine produces higher and more stable plasma and cerebral drug concentrations compared with nimodipine solution. In conclusion, liposomal nimodipine is a promising alternative to the solution preparation.     

包载尼莫地平的聚乳酸-聚乙二醇嵌段共聚物纳米粒的制备和质量评价

目的制备尼莫地平纳米粒的粉针剂，以期改善尼莫地平难溶于水而导致易析出晶体的问题以及其制剂中乙醇引起血管刺激的毒副作用。方法以聚乳酸、聚乙二醇嵌段共聚物作为载体，用溶剂挥发法制备载药纳米粒水分散体系及其冻干粉针．并评价其粒径、Zeta电位、包封率、载药量、形态和冻干粉针的再分散性等性能。结果制备了136nm载药纳米粒的冻干粉针，Zeta电位为-29．90mV，包封率为67．9％，载药量为6．17％，冻干再分散情况良好。结论所制备的尼莫地平纳米粒基本解决了原有制剂药物溶解性差，易析出晶体的问题，避免使用有机溶剂和有副作用表面活性剂的应用。     

尼莫地平PEG-PLGA纳米粒的制备及其处方优化

目的：负载尼莫地平的聚乙二醇修饰的聚乳酸-羟基乙酸共聚物[poly （ethylene glycol-poly （lactin-co-glycolic acid）,PEG-PLGA）]纳米粒,并对其进行制备工艺、质量评价以及体外释放等相关性研究。方法：以PEG-PLGA为药物载体,采用乳化溶剂挥发法成功制备尼莫地平载药纳米粒。单因素实验和响应面法设计优化处方工艺,透射电子显微镜观察纳米粒形态,激光粒度仪测定其粒径和Zeta电位,HPLC法测定其包封率及载药量并考察其体外释药特性。结果：制备的尼莫地平纳米粒外观呈实心球体,大小均匀且分散性良好;平均粒径为（183.2±3.30） nm,PDI为（0.115±0.049）,Zata电位为（-11.78±2.16） mV;平均包封率为84.99%,平均载药量为2.45%;尼莫地平原料药在4 h时基本释放完全（达到95%左右）,而尼莫地平纳米粒在4 h时释放仅为43.9%,在第24 h时累计释放度达到（83.66±2.57）%。与对照组相比,制剂组释放缓慢,符合实验设计缓释的要求。结论：本实验成功制备了尼莫地平PEG-PLGA纳米粒,其体外释药具有明显缓释特征,为心脑血管疾病的治疗奠定了基础。     

Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs

Poorly water-soluble compounds are difficult to develop as drug products using conventional formulation techniques and are frequently abandoned early in discovery. In the present study, the melt emulsification method traditionally used to prepare solid lipid nanoparticles was adapted to produce drug nanosuspensions. The method was evaluated in comparison with the well known solvent diffusion process for ibuprofen as a model drug. Control of the preparation variables (stabilizers, drug content, homogenization procedure and cooling conditions) allowed formation of nanosuspensions with diameters less than 100 nm. The major advantage of the melt emulsification method over the solvent diffusion method is the avoidance of organic solvents during production, although the mean particle size is slightly greater. The combination of Tween 80 and PVP K25 as stabilizers yields nanosuspensions with the smallest average particle size. The formulation of ibuprofen as a nanosuspension, either in the form of lyophilized powder or granules, was very successful in enhancing dissolution rate, more than 65% of the drug being dissolved in the first 10 min compared to less than 15% of the micronized drug. The increase in in vitro dissolution rate may favourably affect bioavailability and improve safety for the patient by decreasing gastric irritancy.     

Cryoprotectant choice and analyses of freeze-drying drug suspension of nanoparticles with functional stabilisers

Freeze-drying is an effective way to improve long-term physical stability of nanosuspension in drug delivery applications. Nanosuspension also known as suspension of nanoparticles. In this study, the effect of freeze-drying with different cryoprotectants on the physicochemical characteristics of resveratrol (RSV) nanosuspension and quercetin (QUE) nanosuspension was evaluated. D-α-tocopheryl polyethylene glycol succinate (TPGS) and folate-modified distearoylphosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG-FA) were selected as functional stabilisers formulated nanosuspension which were prepared by anti-solvent precipitation method. RSV nanoparticle size and QUE nanoparticle size were about 210 and 110?nm, respectively. The AFM and TEM results of nanosuspension showed uniform and irregular shape particles. After freeze-drying, the optimal concentration of four cryoprotectants was determined by the particle size of re-dispersed nanoparticles. The dissolution profile of drug nanoparticle significantly showed approximately at a 6–8-fold increase dissolution rate. Moreover, TPGS and DSPE-PEG-FA stabilised RSV nanosuspension and QUE nanosuspension samples showed better effect on long-term physical stability.     

Tissue distribution of 2-methoxyestradiol nanosuspension in rats and its antitumor activity in C57BL/6 mice bearing lewis lung carcinoma

The purpose of the present study was to evaluate the tissue distribution and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension compared with 2-ME solution both in vitro and in vivo. 2-ME nanosuspension was made by nanoprecipitation-high-frequency ultrasonication method with the particle size of 168.4?±?3.2?nm and the zeta potential of ?29.79?±?1.89 mV. The overall targeting efficiency (TE^Q) of 2-ME nanosuspension was improved from 28.71 to 51.95% in the lung of rats. MTT assay showed that 2-ME nanosuspension could significantly enhance the in vitro cytotoxicity against lewis lung carcinoma (LLC) cells compared with the 2-ME solution, the IC₅₀ at 72?h was reduced from 6.35 µM for 2-ME solution to 3.56 µM for 2-ME nanosuspension. The antitumor activity in vivo was investigated in C57BL/6 mice bearing LLC, and the results indicated that 2-ME nanosuspension not only exhibited significant suppression of the tumor growth when compared with that of positive group or cyclophosphamide group at the same dose, but also enhanced the spleen indices. Overall, 2-ME nanosuspension could mainly deliver the drug to lungs and made the drug accumulate in the lungs, so 2-ME nanosuspension has a possible lung cancer therapeutic potential.     

Temozolomide loaded PLGA-based superparamagnetic nanoparticles for magnetic resonance imaging and treatment of malignant glioma

Polysorbate 80 coated temozolomide-loaded PLGA-based superparamagnetic nanoparticles (P80-TMZ/SPIO-NPs) were successfully synthesized and characterized as drug carriers and diagnosis agent for malignant brain glioma. The mean size of P80-TMZ/SPIO-NPs was 220 nm with narrow hydrodynamic particle size distribution. The superparamagnetic characteristic of P80-TMZ/SPIO-NPs was proved by vibration simple magnetometer. P80-TMZ/SPIO-NPs exhibited high drug loading and encapsulation efficiency as well as good sustained drug release performance for 15 days. MTT assay demonstrated the antiproliferative effect of P80-TMZ/SPIO-NPs for C6 glioma cells. Significant cellular uptake of P80-TMZ/SPIO-NPs was evaluated in C6 glioma cells by fluorescence microscopy, Prussian blue staining, and atomic absorption spectrophotometer (AAS) for qualitative and quantitative study, respectively. MRI scanning analyses in vitro indicated that P80-TMZ/SPIO-NPs could be used as a good MRI contrast agent. Polysorbate 80 coated temozolomide-loaded PLGA-based superparamagnetic nanoparticles could be able to promise a multifunctional theragnostic carrier of brain cancer.     

Biodegradable levofloxacin nanoparticles for sustained ocular drug delivery

Drug delivery to ocular region is a challenging task. Only 1–2% of drug is available in eye for therapeutic action, rest of the drug is drained out through nasolachrymal drainage system and other ocular physiological barriers. To overcome these problems of conventional dosage form, novel drug delivery systems are explored like nanoparticles. In our present work, levofloxacin encapsulated poly(lactic-co-glycolic acid) nanoparticles were developed and evaluated for various parameters like particle size, ζ potential, in vitro drug release and ex vivo transcorneal permeation. Microbiological efficacy was tested against Staphylococcus aureus using cup-plate method. Precorneal residence time was studied on albino rabbits by γ scintigraphy after radiolabeling of levofloxacin by Tc-99m. Ocular tolerance was evaluated using hen’s egg chorioallantoic membrane (HET-CAM) test. The developed nanoparticles were of spherical shape with a mean particle size of 190–195?nm with a ζ potential of ?25 mV. The drug entrapment efficiency was found to be near 85%. In vitro drug release profile shows initial burst release followed by extended release up to 24?h. Microbiological assay showed equivalent zone of inhibition compared to marketed formulation. γ Scintigraphy images of developed formulation, suggested a good spread and good retention over precorneal area. The nanosuspension thus developed was retained for the longer time and drained out from the eye very slowly compared to marketed formulation as significant radioactivity was recorded in later in kidney and bladder. The developed nanosuspension with a mean score of 0.33 up to 24?h in HET-CAM assay, showed the nonirritant efficacy of developed formulation. The stability studies yielded a degradation constant less then 5?×?10^?4, proving a stable formulation with an arbitrary shelf life of 2 years.     

Significant Transport of Doxorubicin into the Brain with Polysorbate 80-Coated Nanoparticles

Purpose. To investigate the possibility of delivering of anticancer drugs into the brain using colloidal carriers (nanoparticles). Methods. Rats obtained 5 mg/kg of doxorubicin by i v. injection in form of 4 preparations : 1. a simple solution in saline, 2. a simple solution in polysorbate 80 1% in saline, 3. bound to poly (butyl cyanoacrylate) nanoparticles, and 4. bound to poly(butyl cyanoacrylate) nanoparticles overcoated with 1% polysorbate 80 (Tween^® 80). After sacrifice of the animals after 10 min, 1, 2, 4, 6, and 8 hours, the doxorubicin concentrations in plasma, liver, spleen, lungs, kidneys, heart and brain were determined after extraction by HPLC. Results. No significant difference in the body distribution was observed between the two solution formulations. The two nanoparticle formulations very significantly decreased the heart concentrations. High brain concentrations of doxorubicin (>6 g/g) were achieved with the nanoparticles overcoated with polysorbate 80 between 2 and 4 hours. The brain concentrations observed with the other three preparations were always below the detection limit (< 0.1 |g/g). Conclusions. The present study demonstrates that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant polysorbate 80. It is highly probable that coated particles reached the brain intact and released the drug after endocytosis by the brain blood vessel endothelial cells.     

Development and characterization of solid oral dosage form incorporating candesartan nanoparticles

Sparingly water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop a tablet dosage form of candesartan cilexetil incorporating drug nanoparticles to increase its saturation solubility and dissolution rate for enhancing bioavailability while reducing variability in systemic exposure. The bioavailability of candesartan cilexetil is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of candesartan cilexetil was developed. Candesartan cilexetil nanoparticles were prepared using a wet bead milling technique. The milled nanosuspension was converted into solid intermediate using a spray drying process. The nanosuspensions were characterized for particle size before and after spray drying. The spray dried nanoparticles were blended with excipients for tableting. The saturation solubility and dissolution characteristics of the nanoparticle formulation were investigated and compared with commercial candesartan cilexetil formulation. The drug nanoparticles were evaluated for solid-state transitions before and after milling. This study demonstrated that tablet formulation incorporating drug nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared to commercially available tablet formulation. Systemic exposure studies in rats indicated a significant increase in the rate and extent of drug absorption.     

Formulation and optimization of coated PLGA – Zidovudine nanoparticles using factorial design and in vitro in vivo evaluations to determine brain targeting efficiency

In the current study zidovudine loaded PLGA nanoparticles were prepared, coated and further investigated for its effectiveness in brain targeting. IR and DSC studies were performed to determine the interaction between excipients used and to find out the nature of drug in the formulation. Formulations were prepared by adopting 2³ factorial designs to evaluate the effects of process and formulation variables. The prepared formulations were subjected for in vitro and in vivo evaluations. In vitro evaluations showed particle size below 100 nm, entrapment efficiency of formulations ranges of 28–57%, process yield of 60–76% was achieved and drug release for the formulations were in the range of 50–85%. The drug release from the formulations was found to follow Higuchi release pattern, n–value obtained after Korsemeyer plot was in the range of 0.56–0.78. In vivo evaluations were performed in mice after intraperitoneal administration of zidovudine drug solution, uncoated and coated formulation. Formulation when coated with Tween 80 achieved a higher concentration in the brain than that of the drug in solution and of the uncoated formulation. Stability studies indicated that there was no degradation of the drug in the formulation after 90 days of preparation when stored in refrigerated condition.     

Formulating Paclitaxel in Nanoparticles Alters Its Disposition

Purpose Paclitaxel is active and widely used to treat multiple types of solid tumors. The commercially available paclitaxel formulation uses Cremophor/ethanol (C/E) as the solubilizers. Other formulations including nanoparticles have been introduced. This study evaluated the effects of nanoparticle formulation of paclitaxel on its tissue distribution.Methods We compared the plasma and tissue pharmacokinetics of paclitaxel-loaded gelatin nanoparticles and the C/E formulation. Mice were given paclitaxel-equivalent doses of 10 mg/kg by intravenous injection.Results The nanoparticle and C/E formulations showed significant differences in paclitaxel disposition; the nanoparticles yielded 40% smaller area under the blood concentration-time curve and faster blood clearance of total paclitaxel concentrations (sum of free, protein-bound, and nanoparticle-entrapped drug). The two formulations also showed different tissue specificity. The rank order of tissue-to-blood concentration ratios was liver > small intestine > kidney >> large intestine > spleen = stomach > lung > heart for the nanoparticles, and liver > small intestine > large intestine > stomach > lung kidney > spleen > heart for the C/E formulation. The nanoparticles also showed longer retention and higher accumulation in organs and tissues (average of 3.2 ± 2.3-fold), especially in the liver, small intestine, and kidney. The most striking difference was an 8-fold greater drug accumulation and sustained retention in the kidney.Conclusions These data indicate that formulation of paclitaxel affects its clearance and distribution into tissues, with preferential accumulation of nanoparticles in the liver, spleen, small intestine, and kidney.     

The brain targeting efficiency following nasally applied MPEG-PLA nanoparticles in rats

The aim of this study was to encapsulate nimodipine (NM) within methoxy poly(ethylene glycol)-poly(lactic acid) (MPEG-PLA) nanoparticles and to investigate its brain targeting efficiency following intranasal administration. NM-loaded nanoparticles, prepared through an emulsion/solvent evaporation technique, were characterized in terms of size, zeta potential, NM loading and in vitro release. The nanoparticles were administered intranasally to rats, and the concentrations of NM in blood, cerebrospinal fluid (CSF) and brain tissues were monitored. The contribution of the olfactory pathway to the uptake of NM in the brain was determined by calculating the brain/plasma concentration ratios and "brain drug direct transport percentage (DTP)" following intranasal administration of the nanoparticles and the solution formulation. The results showed that MPEG-PLA nanoparticles had a mean particle size of 76.5 +/- 7.4 nm, a negative surface charge and a 5.2% NM loading. In vitro release was moderate under sink conditions. The intranasal administration of nanoparticles resulted in a low but constant NM level in plasma. The ratio of AUC values of the nanoparticles to the solution was 1.56 in CSF. The olfactory bulb/plasma and CSF/plasma concentration ratios were significantly higher (P < 0.05) after application of nanoparticles than those of the nasal solution, except the ratio in olfactory bulb at 5 min. Furthermore, nasally administered nanoparticles yielded 1.6-3.3-fold greater DTP values in CSF, olfactory bulb and other brain tissues compared to nasal solution. Thus, MPEG-PLA nanoparticles demonstrated its potential on improving the efficacy of the direct nose-brain transport for drugs.