Dry powder aerosol delivery of large hollow nanoparticulate aggregates as prospective carriers of nanoparticulate drugs: effects of phospholipids

The present work details the effects of incorporating phospholipids, a major component of lung surfactants, in the formulation of large hollow nanoparticulate aggregates, which are specifically designed to serve as potential carrier particles in inhaled delivery of nanoparticulate drugs. The large hollow aerosol particles (d(g) approximately 10 microm), whose shells are composed of nanoparticulate aggregates, are manufactured via the spray drying of nanoparticulate suspensions under a predetermined operating condition. Polyacrylate and silica nanoparticles of various sizes (20-170 nm), without loaded drugs, are employed as the model nanoparticles. The effects of increasing the phospholipids concentration in the presence of the nanoparticles, and vice versa, on the degree of hollowness and morphology of the spray-dried particles are investigated. Varying the phospholipids concentration in the presence of a constant amount of nanoparticles is found to influence the degree of hollowness, without significantly affecting the particle size distribution and respirable fine particle fraction, of the aerosol particles. The effects of increasing the phospholipids concentration on the degree of hollowness of the spray-dried particles are found to depend on the size and chemical nature of the nanoparticles.     

Design and evaluation of a nanoparticulate system prepared by biodegradable polymers for oral administration of protein drugs

The present work was about the preparation of nanoparticles by a complex coacervation process using the biodegradable polymers Chitosan and sodium alginate and to evaluate their suitability for oral administration of proteins. Bovine serum albumin (BSA) was used as a model protein for incorporation into the nanoparticulate system. The prepared BSA-loaded nanoparticles were characterized for size, morphology, zeta potential, BSA encapsulation efficiency and subsequent release kinetics. The physicochemical characters of the prepared nanoparticles depend mostly on polymers mass ratio, pH of the reaction medium and BSA loading concentration. The minimum average size of empty nanoparticles were found to be 339.80 +/- 02.20 nm and the BSA loaded nanoparticles prepared under varying conditions had average sizes in the range of 473.67 +/- 18.75 nm to 751.33 +/- 6.81 nm, and exhibit a high positive zeta potential. The SEM image showed spherical shaped nanoparticles. By increasing the concentration of BSA from 0.1 mg/ml to 2.8 mg/ml the loading capacity of the nanoparticulate system was increased whereas the encapsulation efficiency was decreased. The results suggest that the nanoparticulate system is a potential carrier for delivering protein drugs.     

纳米粒在干粉吸入剂上的应用进展

介绍纳米粒在干粉吸入剂上的应用进展,分析纳米粒应用于干粉吸入剂上的优势,并结合实例较为系统地介绍供吸入的大粒径中空纳米聚集体的制备方法及形成机制。喷雾干燥法可制备供吸入的大粒径中空纳米聚集体,其形成机制可通过扩散特性参数Peclet数来解释。由于纳米粒在肿瘤靶向性方面的优势和大粒径中空粒子优良的沉积性能,大粒径中空纳米聚集体在干粉吸入剂上具有独特的优势。     

复合碳酸钙空腔纳米粒的制备及性能评价

目的 制备甘草次酸/海藻酸钠修饰碳酸钙空腔纳米粒并进行体外评价。方法 以可溶性淀粉为模板剂制备中空球状碳酸钙纳米粒（CaCO3 Nps）;在非均相体系中合成了甘草次酸/海藻酸钠聚合物（GA-ALG）;并以聚合物（GA-ALG）为壳以中空结构的碳酸钙纳米粒为核,合成了壳核结构的GA-ALG-CaCO3 Nps。采用Malvern粒度分析仪测定纳米粒子的粒度分布和Zeta电位,并通过SEM对纳米粒的形态进行表征。应用荧光分光光度计评价载盐酸阿霉素（DOX）纳米粒的载药量、包封率及体外释放特征。结果 纳米粒分布均一,平均粒径为（425.4±31.1）nm,PDI为0.289,Zeta 电位为（-17.0±0.3）mV。药物的载药量为（13.06±0.51）%,包封率为（78.35±3.08）%。;体外释放结果显示,纳米粒具有一定的缓释作用。结论 GA-ALG-CaCO3 Nps作为新型的药物载体,具有良好的pH响应性,并能显著提高载药量,还具有明显的缓释效果,为新型的纳米给药系统的深入研究提供参考。     

Aerosol flow reactor method for synthesis of drug nanoparticles.

An aerosol flow reactor method, a one-step continuous process to produce nanometer-sized drug particles with unimodal size distribution, was developed. This method involves first dissolving the drug material in question into a suitable solvent, which is then followed by atomising the solution as fine droplets into carrier gas. A heated laminar flow reactor tube is used to evaporate the solvent, and solid drug nanoparticles are formed. In this study, the effect of drying temperature on the particle size and morphology was examined. A glucocorticosteroid used for asthma therapy, beclomethasone dipropionate, was selected as an experimental model drug. The geometric number mean particle diameter increases significantly with increasing reactor temperatures due to formation of hollow nanoparticles. Above 160 degrees C, however, further increase in temperature results in decreasing particle size. The produced nanoparticles are spherical and show smooth surfaces at all studied experimental conditions.     

Future of nanomedicines for treating respiratory diseases

Introduction: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?

Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.

Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.     

Preparation and evaluation of thiomer nanoparticles via high pressure homogenization

The aim of this study was to establish and evaluate a high pressure homogenization method for the preparation of thiomer nanoparticles. Particles were formulated by incorporation of the model protein horseradish peroxidase in chitosan-glutathione (Ch-GSH) and poly(acrylic acid)-glutathione (PAA-GSH) via co-precipitation followed by air jet milling. The resulting microparticles were suspended in distilled water using an Ultraturax and subsequently micronized by high pressure homogenization. Finally, resulting particles were evaluated regarding size distribution, shape, zeta potential, drug load, protein activity and release behaviour. The mean particle size after 30 cycles with a pressure of 1500 bar was 538 ± 94 nm for particles consisting of Ch-GSH and 638 ± 94 nm for particles consisting of PAA-GSH. Nanoparticles of Ch-GSH had a positive zeta-potential of +1.03 mv, whereas nanoparticles from PAA-GSH had a negative zeta potential of ?6.21 mv. The maximum protein load for nanoparticles based on Ch-GSH and based on PAA-GSH was 45 ± 2% and 37 ± %, respectively. The release profile of nanoparticles followed a first order release kinetic. Thiolated nanoparticles prepared by a high pressure homogenization technique were shown to be stable and provide controlled drug release characteristics. The preparation method described here might be a useful tool for a more upscaled production of nanoparticulate drug delivery systems.     

载柚皮素壳聚糖纳米粒的制备及其体外细胞评价

目的：制备柚皮素壳聚糖纳米粒,初步探讨其对人肺腺癌细胞A549的细胞毒性和细胞摄取。方法：以壳聚糖和鱼精蛋白作为载体材料,采用离子胶凝法制备柚皮素壳聚糖纳米粒,透射电镜（TEM）观察其形态,马尔文激光粒度仪测定其粒径、分散度（PDI）和Zeta电位,离心法测定其包封率和载药量,采用恒温振荡水浴法对柚皮素壳聚糖纳米粒进行体外释放度研究,最后采用人肺癌细胞系A549细胞进行了细胞毒性、细胞摄取研究。结果：柚皮素壳聚糖纳米粒为球形或类球形粒子,结构完整,大小均一、球形度好,分散均匀,PDI、粒径、Zeta电位和包封率分别为0.268,139 nm、+15.7 mV和83.34%,柚皮素壳聚糖纳米粒体外释放呈缓释,24 h累积释放量达到了80%以上,体外释药过程用Higuchi方程拟合较好。MTT试验显示不同浓度的壳聚糖纳米粒和细胞作用72 h后,细胞活力均大于95%,本文所制备的壳聚糖纳米粒无细胞毒性。细胞摄取试验表明载FITC的壳聚糖纳米粒和A549细胞作用3 h后,可明显看到大量带绿色荧光的纳米粒穿过细胞膜进入细胞。结论：离子凝胶法成功制得粒径较小的柚皮素壳聚糖纳米粒,具有缓释性好,毒性小,壳聚糖纳米粒摄取率较高,可大大提高药物的利用率,具有广泛的应用前景。     

Human serum albumin (HSA) nanoparticles: reproducibility of preparation process and kinetics of enzymatic degradation

Nanoparticles prepared from human serum albumin (HSA) are versatile carrier systems for drug delivery and can be prepared by an established desolvation process. A reproducible process with a low batch-to-batch variability is required for transfer from the lab to an industrial production. In the present study the batch-to-batch variability of the starting material HSA on the preparation of nanoparticles was investigated. HSA can build dimers and higher aggregates because of a free thiol group present in the molecule. Therefore, the quality of different HSA batches was analysed by size exclusion chromatography (SEC) and analytical ultracentrifugation (AUC). The amount of dimerised HSA detected by SEC did not affect particle preparation. Higher aggregates of the protein detected in two batches by AUC disturbed nanoparticle formation at pH values below 8.0. At pH 8.0 and above monodisperse particles between 200 and 300 nm could be prepared with all batches, with higher pH values leading to smaller particles. Besides human derived albumin a particle preparation was also feasible based on recombinant human serum albumin (rHSA). Under comparable preparation conditions monodisperse nanoparticles could be achieved and the same effects of protein aggregates on particle formation were observed. For nanoparticulate drug delivery systems the enzymatic degradation is a crucial parameter for the release of an embedded drug. For this reason, besides the particle preparation process, particle degradation in the presence of different enzymes was studied. Under acidic conditions HSA as well as rHSA nanoparticles could be digested by pepsin and cathepsin B. At neutral pH trypsin, proteinase K, and protease were suitable for particle degradation. It could be shown that the kinetics of particle degradation was dependent on the degree of particle stabilisation. Therefore, the degree of particle stabilisation will influence drug release after cellular accumulation of HSA nanoparticles.     

The use of chitosan-6-mercaptonicotinic acid nanoparticles for oral peptide drug delivery

The aim of this study was to develop a novel nanoparticulate formulation and test its potential for oral peptide drug delivery. Chitosan-6-mercaptonicotinic acid is a novel thiolated chitosan with strong mucoadhesive properties. Nanoparticles were developed by an ionic gellation method. The obtained particles were characterized in terms of mucoadhesion, stability, toxicity, and in vitro release. Human insulin (HI) was chosen as a model peptide drug, incorporated in the particles and orally administered to rats. Human insulin was quantified in the blood by means of ELISA. The size of the obtained particles was in the range of 200–300?nm and the zeta potential was determined to be +8?+23 depending on the amount of thiol groups attached on the polymer. After 3?h of incubation up to 60% of the thiolated chitosan nanoparticles remained attached to the mucosa in contrast to 20% of unmodified chitosan particles. The AUC of HI after oral administration of thiolated chitosan nanoparticles was 4-fold improved compared to unmodified chitosan nanoparticles. Due to these improvements, chitosan-6-mercaptonicotinic acid nanoparticles are promising vehicles for oral delivery of peptide drugs.     

A new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin.

The objective of the present work was to develop a new drug nanocarrier consisting of nanoparticles made of chitosan and cyclodextrins. The rationale behind the design of this new nanosystem was to simultaneously implement the cyclodextrin drug complexation power and the inherent properties of chitosan nanoparticles, in a unique delivery system. The complexation with the cyclodextrin permits the solubilization as well as the protection for sensitive drugs, whereas the entrapment in the chitosan network is expected to facilitate their absorption. Chitosan nanoparticles including hydroxypropylcyclodextrins could be prepared by the ionic crosslinking of chitosan with sodium tripolyphosphate in the presence of cyclodextrins. Two hydrophobic drugs, triclosan and furosemide, were selected as models for complexation with the cyclodextrin and further entrapment in the chitosan nanocarrier. The resulting nanosystems were thoroughly characterized for their size and zeta potential and also for their ability to associate and deliver the complexed drugs. The results showed that the size of the nanoparticles was slightly affected by the incorporation of cyclodextrins, whereas the zeta potential did not suffer a significant modification. Moreover, the complexation of the drugs with the cyclodextrin facilitated their entrapment into the nanoparticles, increasing up to 4 and 10 times (for triclosan and furosemide, respectively) the final drug loading of the nanoparticles. These results led to the conclusion that the drug-cyclodextrin complex was efficiently retained in the nanoparticulate structure. Finally, the in vitro release profile observed for these nanoparticles was characterized by an initial fast release followed by a delayed release phase. In conclusion, this new nanosystem offers an interesting potential for the transmucosal delivery of hydrophobic compounds.     

The use of chitosan-6-mercaptonicotinic acid nanoparticles for oral peptide drug delivery

The aim of this study was to develop a novel nanoparticulate formulation and test its potential for oral peptide drug delivery. Chitosan-6-mercaptonicotinic acid is a novel thiolated chitosan with strong mucoadhesive properties. Nanoparticles were developed by an ionic gellation method. The obtained particles were characterized in terms of mucoadhesion, stability, toxicity, and in vitro release. Human insulin (HI) was chosen as a model peptide drug, incorporated in the particles and orally administered to rats. Human insulin was quantified in the blood by means of ELISA. The size of the obtained particles was in the range of 200-300?nm and the zeta potential was determined to be +8-+23 depending on the amount of thiol groups attached on the polymer. After 3?h of incubation up to 60% of the thiolated chitosan nanoparticles remained attached to the mucosa in contrast to 20% of unmodified chitosan particles. The AUC of HI after oral administration of thiolated chitosan nanoparticles was 4-fold improved compared to unmodified chitosan nanoparticles. Due to these improvements, chitosan-6-mercaptonicotinic acid nanoparticles are promising vehicles for oral delivery of peptide drugs.     

Effervescent dry powder for respiratory drug delivery.

The objective of this work was to develop a new type of respiratory drug delivery carrier particle that incorporates an active release mechanism. Spray drying was used to manufacture inhalable powders containing polybutylcyanoacrylate nanoparticles and ciprofloxacin as model substances for pulmonary delivery. The carrier particles incorporated effervescent technology, thereby adding an active release mechanism to their pulmonary route of administration. Effervescent activity of the carrier particles was observed when the carrier particles were exposed to humidity. Gas bubbles caused by the effervescent reaction were visualized by confocal laser scanning microscopy. The images showed that nanoparticles were distributed throughout the gas bubble. For the effervescent formulation the average mass median aerodynamic diameter (MMAD) was 2.17 microm+/-0.42, fine particle fraction (FPF(<=5.6 microm)) was 46.47%+/-15 and the GSD was 2.00+/-0.06. The results also showed that the effervescent carrier particles released 56+/-8% ciprofloxacin into solution compared with 32+/-3% when lactose carrier particles were used. The mean nanoparticle size did not significantly change upon release when the nanoparticles were incorporated into an effervescent formulation. However, the mean size significantly increased upon release when only lactose was used as carrier particle matrix. In conclusion, effervescent carrier particles can be synthesized with an adequate particle size for deep lung deposition. This opens the door for future research to explore this technology for delivery of a large range of substances to the lungs with possible improved release compared to conventional carrier particles.     

介孔二氧化硅阿霉素纳米粒的制备及体外释放考察

目的制备载阿霉素的介孔二氧化硅纳米粒(MSN),并对其体外释放进行初步研究。方法通过聚合法制备MSN,应用透射电镜表征纳米粒的形态,动态光散射粒径测定仪测定粒子的平均粒径及分布。紫外可见分光光度法评价载药量、包封率及体外释放。结果纳米粒分布均一,平均粒径约70 nm(PDI<0.1)。药物的载药量和包封率分别为(20.38±3.58)%和(55.29±5.17)%。纳米粒经24 h恒温振荡释放达平衡,在pH 5.5磷酸盐缓冲液中累积释放分数达到95%。结论 MSN具有较高的药物载药量,有望成为一种新型的化疗药物载体。     

Development and in vivo evaluation of a new oral nanoparticulate dosage form for leuprolide based on polyacrylic acid

It was the aim of this study to develop a nanoparticulate oral drug delivery system for leuprolide based on polyacrylic acid (PAA). In order to achieve formation of nanoparticles in a mild, aqueous environment, two different techniques were combined, namely hydrophobic ion pairing between leuprolide and sodium dodecyl sulphate in a first step, followed by encapsulation into nanoparticles gained by interpolymer complexation between polyacrylic acid and Pluronic F68. The obtained nanoparticles were characterized regarding particle size distribution, drug encapsulation efficiency and in vitro release profile. Additionally, the pharmacokinetic profiles of leuprolide after oral administration of PAA-nanoparticulate and PAA-control tablets to male Sprague-Dawley rats were assessed and compared. It could be shown, that hydrophobic ion pairing increased encapsulation efficacy of leuprolide and leads to a slowed drug release of nanoparticulate suspensions. Relative oral bioavailability of leuprolide could be increased by nanoparticulate tablets up to 4.2-fold. Results verify that the suggested approach is a promising strategy for the design of oral delivery systems for oral administration of peptide drugs.     

Development and in vivo evaluation of a new oral nanoparticulate dosage form for leuprolide based on polyacrylic acid

It was the aim of this study to develop a nanoparticulate oral drug delivery system for leuprolide based on polyacrylic acid (PAA). In order to achieve formation of nanoparticles in a mild, aqueous environment, two different techniques were combined, namely hydrophobic ion pairing between leuprolide and sodium dodecyl sulphate in a first step, followed by encapsulation into nanoparticles gained by interpolymer complexation between polyacrylic acid and Pluronic F68. The obtained nanoparticles were characterized regarding particle size distribution, drug encapsulation efficiency and in vitro release profile. Additionally, the pharmacokinetic profiles of leuprolide after oral administration of PAA-nanoparticulate and PAA-control tablets to male Sprague-Dawley rats were assessed and compared. It could be shown, that hydrophobic ion pairing increased encapsulation efficacy of leuprolide and leads to a slowed drug release of nanoparticulate suspensions. Relative oral bioavailability of leuprolide could be increased by nanoparticulate tablets up to 4.2-fold. Results verify that the suggested approach is a promising strategy for the design of oral delivery systems for oral administration of peptide drugs.     

Doxorubicin release from core-shell type nanoparticles of poly(DL-lactide-co-glycolide)-grafted dextran

In this study, we prepared core-shell type nanoparticles of a poly(DL-lactide-co-glycolide) (PLGA) grafted-dextran (DexLG) copolymer with varying graft ratio of PLGA. The synthesis of the DexLG copolymer was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. The DexLG copolymer was able to form nanoparticles in water by self-aggregating process, and their particle size was around 50 nm approximately 300 nm according to the graft ratio of PLGA. Morphological observations using a transmission electron microscope (TEM) showed that the nanoparticles of the DexLG copolymer have uniformly spherical shapes. From fluorescence probe study using pyrene as a hydrophobic probe, critical association concentration (CAC) values determined from the fluorescence excitation spectra were increased as increase of DS of PLGA. 1H-NMR spectroscopy using D2O and DMSO approved that DexLG nanoparticles have core-shell structure, i.e. hydrophobic block PLGA consisted inner-core as a drug-incorporating domain and dextran consisted as a hydrated outershell. Drug release rate from DexLG nano-particles became faster in the presence of dextranase in spite of the release rate not being significantly changed at high graft ratio of PLGA. Core-shell type nanoparticles of DexLG copolymer can be used as a colonic drug carrier. In conclusion, size, morphology, and molecular structure of DexLG nanoparticles are available to consider as an oral drug targeting nanoparticles.     

Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are colloidal carrier systems providing controlled release profiles for many substances. Clotrimazole-loaded SLN and NLC were prepared by the hot high pressure homogenization technique in order to evaluate the physical stability of these particles, as well as the entrapment efficiency of this lipophilic drug and its in vitro release profile. The particle size was analyzed by PCS and LD showing that the particles remained in their colloidal state during 3 months of storage at 4, 20 and 40 degrees C. For all tested formulations the entrapment efficiency was higher than 50%. The obtained results also demonstrate the use of these lipid nanoparticles as modified release formulations for lipophilic drugs over a period of 10 h.     

Complexes of Felodipine Nanoparticles With Zein Prepared Using a Dual Shift Technique

To improve the dissolution of felodipine, felodipine-zein complexes were prepared using a dual shift technique, with zein as both stabilizer and carrier. The complexes were characterized by particle size, zeta potential, morphology, crystalline properties, and release behavior. The complexes could be prepared in high yield and showed good redispersibility. The mean diameters of the felodipine particles in complexes were 150-300 nm, with negative zeta potentials of ?30 to ?25 mV after rehydration, and the particle sizes of the complexes were in the range 10-80 μm. The size of the felodipine nanoparticles incorporated into zein increased gradually with increasing drug content. Powder X-ray diffraction and differential scanning calorimetry indicated that felodipine in the complexes was markedly less crystalline than the pure drug. Both the rate and extent of dissolution of the complexes were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Spectroscopic analyses indicated that intermolecular interactions, especially hydrophobic interactions, are the major driving forces for the formation of the felodipine nanoparticles and contribute to the stabilization effect. This study provides a promising strategy for enhancing the dissolution rate of drugs using simplified preparation processes and showcases the design of zein-based oral delivery systems for bioactive components.     

Nanostructured materials in drug and gene delivery: a review of the state of the art

A wide variety of drug delivery systems have been developed, each with its own advantages and limitations, but the important goals of all of the systems are to enhance bioavailability, reduce drug toxicity, target to a particular organ, and increase the stability of the drug. The development of nanostructured drug carriers have grasped increased attention from scientific and commercial organizations due to their unique ability to deliver drugs and challenging molecules such as proteins and nucleic acids. These carriers present many technological advantages such as high carrier capacity, high chemical and biological stability, feasibility of incorporating both hydrophilic and hydrophobic substances, and their ability to be administered by a variety of routes (including oral, inhalational, and parenteral) to provide controlled/sustained drug release. Moreover, applications of nanoparticulate formulations in enhancing drug solubility, dissolution, bioavailability, safety, and stability have already been proven. In the view of their multifaceted applications, the present review aims to discuss and summarize some of the interesting findings and applications, methods of preparation, and characterization of various nanostructured carriers useful in drug delivery. Included in this discussion are polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers, cyclodextrins, fullerenes, gold and silica nanoparticles, and quantum dots. Because there are likely to be new applications for nanoparticles in drug delivery, they are expected to solve many problems associated with the delivery of drugs and biomolecules through different delivery routes.