Preparation and characteristics of nanostructured lipid carriers for control-releasing progesterone by melt-emulsification

Nanostructured lipid carriers (NLC) made from mixtures of solid and spatially incompatible liquid lipids were prepared by melt-emulsification. Their drug loading capacity and releasing properties of progesterone were compared with those of solid lipid nanoparticles (SLN), and the NLC prepared by solvent diffusion method. Monostearin (MS) and stearic acid (SA) were used as solid lipid, whilst the oleic acid (OA) was used as liquid lipid. Properties of carriers such as the particle size and its distribution, drug loading, drug encapsulation efficiency and drug release behavior were investigated. As a result, the drug encapsulation efficiencies were improved by adding the liquid lipid into the solid lipid of nanoparticles. The drug release behavior could be adjusted by the addition of liquid lipid, and the NLC with higher OA content showed the faster rate of drug releasing. NLC had higher efficiency of encapsulation and slower rate of drug release than those of NLC prepared by solvent diffusion method. On the other hand, the NLC with higher drug loading was obtained, though the drug encapsulation efficiency was decreased slightly due to the increase of the amount of drug. The NLC modified with polyethylene glycol (PEG) was also prepared by using polyethylene glycol monostearate (PEG-SA). It was observed that the incorporation of PEG-SA reduced the drug encapsulation efficiency, but increased the rate of drug release. A sample with almost complete drug release in 24 h was obtained by modifying with 1.30 mol% PEG-SA. It indicated that the modified NLC was a potential drug delivery system for oral administration.     

Quick synthesis of lipid-polymer hybrid nanoparticles with low polydispersity using a single-step sonication method

Lipid-polymer hybrid nanoparticle, consisting of a hydrophobic polymeric core and a lipid monolayer shell, represents a new and promising drug delivery platform that has shown controllable particle size and surface functionality, high drug loading yield, sustained drug release profile, and excellent in vitro and in vivo stability. These lipid monolayer-coated polymeric nanoparticles are typically fabricated through a modified nanoprecipitation method, which involves sample heating, vortexing, and solvent evaporation. Herein we report a new and fast method to synthesize lipid-polymer hybrid nanoparticles with controllable and nearly uniform particle size. Using a bath sonication approach, we demonstrate that the whole hybrid nanoparticle synthesis process can be completed in about 5 min compared with a few hours for previous synthesis approaches. The size and polydispersity of the resulting nanoparticles can be readily controlled by tuning the relative concentrations of individual building components. Colloidal stability tests of the synthesized hybrid nanoparticles in PBS buffer and serum show no signs of aggregation over a period of 5 days. The present method improves the production rate of the hybrid nanoparticles by near 20-fold while not compromising the physicochemical properties of the particles. This work may facilitate the bench-to-bedside translation of lipid-polymer hybrid nanoparticles as a robust drug nanocarrier by allowing for fabricating a large amount of these nanoparticles at high production rate.     

Preparation and characteristics of nanostructured lipid carriers for control-releasing progesterone by melt-emulsification

Nanostructured lipid carriers (NLC) made from mixtures of solid and spatially incompatible liquid lipids were prepared by melt-emulsification. Their drug loading capacity and releasing properties of progesterone were compared with those of solid lipid nanoparticles (SLN), and the NLC prepared by solvent diffusion method. Monostearin (MS) and stearic acid (SA) were used as solid lipid, whilst the oleic acid (OA) was used as liquid lipid. Properties of carriers such as the particle size and its distribution, drug loading, drug encapsulation efficiency and drug release behavior were investigated. As a result, the drug encapsulation efficiencies were improved by adding the liquid lipid into the solid lipid of nanoparticles. The drug release behavior could be adjusted by the addition of liquid lipid, and the NLC with higher OA content showed the faster rate of drug releasing. NLC had higher efficiency of encapsulation and slower rate of drug release than those of NLC prepared by solvent diffusion method. On the other hand, the NLC with higher drug loading was obtained, though the drug encapsulation efficiency was decreased slightly due to the increase of the amount of drug. The NLC modified with polyethylene glycol (PEG) was also prepared by using polyethylene glycol monostearate (PEG-SA). It was observed that the incorporation of PEG-SA reduced the drug encapsulation efficiency, but increased the rate of drug release. A sample with almost complete drug release in 24 h was obtained by modifying with 1.30 mol% PEG-SA. It indicated that the modified NLC was a potential drug delivery system for oral administration.     

Core–shell nanoparticles of carboxy methyl cellulose and compritol-PEG for antiretroviral drug delivery

Multi-functional nanoparticles hold great promise for the effective treatment of many diseases. Zidovudine a commonly used anti-HIV drug, requires a delivery system for more effective treatment of AIDS. The present study focuses on the development of anti-viral drug-loaded hybrid nanoparticles (LPNs) of lipid and polymer consisting of carboxy methyl cellulose—zidovudine (AZT) core enclosed by a compritol (Comp)-polyethylene glycol shell. The characterization of drug loaded LPNs was done using TEM, DLS and FT-IR analysis. The drug loading efficiency, drug release, blood compatibility, MTT assay and cell uptake studies were carried out using the LPNs. The synthesized nanoparticles exhibited core–shell morphology with an average size of 161.65 ± 44.06 nm; the LPN also demonstrated 82% drug encapsulation efficiency with slow drug release behaviour. The hybrid nanoparticles were found to be blood compatible and non toxic. The rhodamine-labeled hybrid nanoparticles were also found to effectively enter the brain cells. The novel hybrid drug delivery system shows controlled drug release, biocompatibility and high drug loading efficiency. These LPNs obtained from natural polymers can provide an excellent platform for designing systems for targeted drug delivery.     

Ciprofloxacin Loaded Alginate/Chitosan and Solid Lipid Nanoparticles,Preparation, and Characterization

The aim of the present study was to develop controlled drug delivery systems based on nanotechnology. Two different nanocarriers were selected, chitosan-alginate nanoparticles as hydrophilic and solid lipid nanoparticles as lipophilic carriers. Nanoparticles were prepared and characterized by evaluating particle size, zeta potential, SEM pictures, DSC thermograms, percentage of drug loading efficiency, and drug release profile. The particle size of SLNs and Chi/Alg nanoparticles was 291 ± 5 and 520 ± 16. Drug loading efficiency of Chi/Alg and SLN particles were 68.98 ± 5.5% and 88 ± 4.5%. The drug release was sustained with chitosan-alginate system for about 45 hours whereas for SLNs >98% of the drug was released in 2 hours. Release profile did not change significantly after freeze drying of particles using cryoprotector. Results suggest that under in vitro condition chitosan/alginate systems can act as promising carriers for ciprofloxacin and may be used as an alternative system in sustained delivery of ciprofloxacin.     

Development of Ciprofloxacin HCl-Based Solid Lipid Nanoparticles Using Ouzo Effect: An Experimental Optimization and Comparative Study

This study was performed to develop solid lipid nanoparticles of water soluble drug ciprofloxacin HCl using quick solvent diffusion evaporation technique (ouzo effect). A statistical central composite rotatable design was used to study the effect of independent variables. In the subsequent step, optimized SLN were further compared with nanostructured lipid carriers and nanoemulsion for particle size, zeta potential, drug entrapment, drug release, and stability. Comparative study revealed that the drug encapsulation efficiencies were enhanced by adding the Capmul MCM C8 into the solid lipid nanoparticles. The in vitro drug release study of all three formulations showed rapid release for nanoemulsion while controlled release for SLN. Stability study of all the formulation proved that nanostructured lipid carrier and SLN could prevent the drug expulsion during the storage period. Results of the study suggested that the SLN and nanostructured lipid carriers produced by the principle of ouzo effect could potentially be exploited for better drug entrapment efficiency and controlled drug release of water soluble actives.     

Electrohydrodynamic atomization for biodegradable polymeric particle production

Electrohydrodynamic atomization (EHDA) has many applications such as electrospray ionization in mass spectroscopy, electrospray deposition of thin films, pharmaceutical productions, and polymeric particle fabrications for drug encapsulation. In the present study, EHDA was employed to produce biodegradable polymeric micro- and nanoparticles. The effects of processing parameters such as polymer concentration, flow rate, surfactants, organic salt, and setup configurations on the size and morphology of polymeric particles were investigated systematically. By changing the various processing parameters, controllable particle shape and size can be achieved. PLGA nanoparticles with size of around 250 nm can be obtained by using organic salts to increase the conductivity of the spraying solution even at a relatively high flow rate. A higher flow rate has the advantage of producing a stable cone spray and can be easily reproduced. Solid and porous particles can be fabricated using different experimental setups to control the organic solvent evaporation rate. Also, paclitaxel, a model antineoplastic drug, was encapsulated in polymeric particles which can be employed for controlled release applications. In short, EHDA is a promising technique to fabricate polymeric micro- or nanoparticles which can be used in drug delivery systems.     

Effect of PLGA as a polymeric emulsifier on preparation of hydrophilic protein-loaded solid lipid nanoparticles

Most proteins are hydrophilic and poorly encapsulated into the hydrophobic matrix of solid lipid nanoparticles (SLN). To solve this problem, poly (lactic-co-glycolic acid) (PLGA) was utilized as a lipophilic polymeric emulsifier to prepare hydrophilic protein-loaded SLN by w/o/w double emulsion and solvent evaporation techniques. Hydrogenated castor oil (HCO) was used as a lipid matrix and bovine serum albumin (BSA), lysozyme and insulin were used as model proteins to investigate the effect of PLGA on the formulation of the SLN. The results showed that PLGA was essential for the primary w/o emulsification. In addition, the stability of the w/o emulsion, the encapsulation efficiency and loading capacity of the nanoparticles were enhanced with the increase of PLGA concentration. Furthermore, increasing PLGA concentration decreased zeta potential significantly but had no influence on particle size of the SLN. In vitro release study showed that PLGA significantly affected the initial burst release, i.e. the higher the content of PLGA, the lower the burst release. The released proteins maintained their integrity and bioactivity as confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and biological assay. These results demonstrated that PLGA was an effective emulsifier for the preparation of hydrophilic protein-loaded SLN.     

PH-responsive nano-assemblies of amino poly(glycerol methacrylate)

Both linear and star-shaped poly(glycidyl methacrylate) (PGMA) polymers were modified with different amines and used to prepare pH-sensitive nano-assemblies. Nanoprecipitation technique and dialysis method were used to prepare the polymeric nanoparticles. These nano-assemblies showed pH-sensitive disassociation properties under an acidic condition. The polymers were quite effective in encapsulation of Congo red (CR). Atom force microscopy images showed that the nanoparticles prepared using nanoprecipitation technique are spherical before and after encapsulation of CR. The disassociation pH, encapsulation efficiency, loading capacity and release properties of these polymers were found to depend on their backbone architecture and the amine type. By adjusting of these factors, such type of polymers hold promise as an interesting drug delivery vehicle.     

Design and Characterization of Maltoheptaose-b-Polystyrene Nanoparticles,as a Potential New Nanocarrier for Oral Delivery of Tamoxifen

Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL⁻¹) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.     

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis,release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.     

Design and characterization of a new drug nanocarrier made from solid-liquid lipid mixtures

The classical lipid nanoparticles that have been proposed for drug delivery are composed of solid lipids. Due to their composition, these nanoparticles have a limited drug loading and controlled release capacity. The present work was aimed at modifying the inner structure of nanoparticles made of tripalmitin, lecithin, and poly(ethylene glycol) (PEG)-stearate with the incorporation of a liquid lipid (Miglyol 812 oil). The composition and structural organization of the components of the resulting nanoparticles were characterized by (1)H NMR spectroscopy. Any possible changes in the crystalline domains of individual components when in the form of the nanoparticles were investigated by differential scanning calorimetry (DSC) and X-ray diffraction spectroscopy. The results of the NMR analysis indicated a significant incorporation of the oil to the solid nanoparticle matrix. Furthermore, the relaxation time constants as well as the peak width of the (1)H NMR spectrum of the nanoparticles suggest the presence of the oil in the form of phase-separated liquid nanoreservoirs within the nanoparticles. This conclusion was supported by the observation of restricted diffusion dynamics for the oil molecules. Interestingly, the incorporation of the oil did not interfere with the crystallization of the solid lipids (tripalmitin and PEG-stearate). In conclusion, a new nanostructure consisting of solid lipids and oily nanodomains was developed. This structural modification of the solid lipid nanoparticles may have an effect on their encapsulation capacity and controlled release properties.     

Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system

Nanostuctured lipid carriers (NLC) based on mixture of solid lipids with spatially incompatible liquid lipids are a new type of lipid nanoparticles, which offer the advantage of improved drug loading capacity and release properties. In present study, stearic acid (SA) nanostuctured lipid carriers with various oleic acid (OA) content were successfully prepared by solvent diffusion method in an aqueous system. The size and surface morphology of nanoparticles were significantly influenced by OA content. As OA content increased up to 30 wt%, the obtained particles showed pronounced smaller size and more regular morphology in spherical shape with smooth surface. Compared with solid lipid nanoparticles (SLN), NLC exhibited improved drug loading capacity, and the drug loading capacity increased with increasing OA content. These results were explained by differential scanning calorimetry (DSC) investigations. The addition of OA to nanoparticles formulation resulted in massive crystal order disturbance and less ordered matrix of NLC, and hence, increased the drug loading capacity. The drug in vitro release behavior from NLC displayed biphasic drug release pattern with burst release at the initial stage and prolonged release afterwards, and the successful control of release rate at the initial stage can be achieved by controlling OA content.     

Development of Thiolated Chitosan Nanoparticles Based Mucoadhesive Vaginal Drug Delivery Systems

The aim of the present study was to evaluate the influence of the chitosan chain length on the drug loading and releasing in VFS (vaginal fluid simulant). Thiolated chitosan nanoparticles (TCS-NPs) were prepared using thioglycolic acid and 1-ethyl-3-3-(3-dimethylaminopropyl)carbodimide hydrochloride (EDC) and characterized with FTIR. The degree of thiol substitution was found out by Ellman’s method. TCS-NPs were developed using ionic cross-linking reaction with pentasodiumtripolyphosphate (TPP). Curcumin (CUR) loaded nanoparticles were obtained by encapsulation. DLS and SEM characterized these NPs with diameter between 200 ± 50 nm. Zeta potential of NPs was 11–38 mv. The maximal encapsulation efficiency was 86.26%. The in vitro drug release studies in VFA at pH 4.2 showed a sustained release profile over a period of 3 days.     

Optimized preparation, characterization and biodistribution in heart of breviscapine lipid emulsion

Breviscapine is a Traditional Chinese Medicine treating cardiovascular diseases by promoting blood circulation and removing blood stasis. The major active component of breviscapine has low aqueous solubility, poor chemical stability, short biological half-life and rapid elimination rate from the plasma. The use of a lipid emulsion formulation containing breviscapine might improve chemical stability, increase drug loading, exhibit sustained release profile. In the present study, we developed an optimized formulation and technological method for the preparation of sterile and stable breviscapine lipid emulsion (Bre-LE) for intravenous infusion. The average particle size, polydispersity index, zeta potential, stability constant (K(s)) value and content of final product were (225.3±8.8) nm, 0.221±0.020, (-29.6±1.5) mV, (24.3±2.9)% and (94.5±0.6)% respectively (n=3). The results of in vitro release experiment suggest that lipid emulsion as breviscapine carrier showed a desirable sustained release profile. Dilution stability and long-term stability were also researched in the present paper. The results show the carrier could protect drug from degradation after dilution by phosphate buffered saline and fetal calf serum. And Bre-LE was stable for up to 6 months at room temperature storage condition. The biodistribution of drug in heart of mice increased dramatically after encapsulation into lipid emulsion which was beneficial to heart disease therapy.     

A new class of silica cross-linked micellar core-shell nanoparticles

Micellar nanoparticles made of surfactants and polymers have attracted wide attention in the materials and biomedical community for controlled drug delivery, molecular imaging, and sensing; however, their long-term stability remains a topic of intense study. Here we report a new class of robust, ultrafine silica core-shell nanoparticles formed from silica cross-linked, individual block copolymer micelles. Compared with pure polymeric micelles, the main advantage of the new core-shell nanoparticles is that they have significantly improved stability and do not break down during dilution. We also studied the drug loading and release properties of the silica cross-linked micellar particles, and we found that the new core-shell nanoparticles have a slower release rate which allows the entrapped molecules to be slowly released over a much longer period of time under the same experimental conditions. A range of functional groups can be easily incorporated through co-condensation with the silica matrix. The potential to deliver hydrophobic agents into cancer cells has been demonstrated. Because of their unique structures and properties, these novel core-shell nanoparticles could potentially provide a new nanomedicine platform for imaging, detection, and treatment, as well as novel colloidal particles and building blocks for mutlifunctional materials.     

Encapsulation of doxorubicin in magnetic‐polymer hybrid colloidal particles of Eudragit E100 and their hyperthermia and drug release studies

Water‐soluble magnetite Fe₃O₄ nanoparticles were synthesized by coprecipitation that exhibit spherical morphology and superparamagnetic behavior with a saturation magnetization of 46 emu/g. These nanoparticles were coated with amino methacrylate copolymer (Eudragit E100) along with encapsulation of Doxorubicin drug under the action of sonication via a double emulsion solvent evaporation method. The prepared magnetic colloids were evaluated for particle size, surface morphology, surface charge, drug loading capacity, and entrapment efficiency. The drug release studies indicated the sustained release of drug of 92% in 24 hours at physiological pH of 7.4 and drug release kinetics followed first order. The prepared nanoparticles and their colloids were also investigated for magnetic hyperthermia and specific absorption rate values were found to be 2.41, 2.71, and 4.28 W/g at 259, 327, and 518 kHz, respectively. The developed magnetic colloids have the potential to perform controlled hyperthermia and drug release to the target sites.     

Stable Polymer Nanoparticles with Exceptionally High Drug Loading by Sequential Nanoprecipitation

Poor solubility often leads to low drug efficacy. Encapsulation of water‐insoluble drugs in polymeric nanoparticles offers a solution. However, low drug loading remains a critical challenge. Now, a simple and robust sequential nanoprecipitation technology is used to produce stable drug‐core polymer‐shell nanoparticles with high drug loading (up to 58.5 %) from a wide range of polymers and drugs. This technology is based on tuning the precipitation time of drugs and polymers using a solvent system comprising multiple organic solvents, which allows the formation of drug nanoparticles first followed by immediate precipitation of one or two polymers. This technology offers a new strategy to manufacture polymeric nanoparticles with high drug loading having good long‐term stability and programmed release and opens a unique opportunity for drug delivery applications.     

Structural characterization of novel phospholipid lipid nanoparticles for controlled drug delivery

Drug-phospholipid lipid nanoparticles (DPLNs) are prepared by incorporating drug-phospholipid complexes (DPCs) with a liquid lipid. DPLNs demonstrated interesting properties including increased encapsulation capacity, improved stability and controlled drug release profile. A comprehensive characterization of DPLNs was presented and then a schematic model was suggested according to the characterization results. Transmission electron microscopy and scanning electron microscope measurements showed the morphology of DPLNs. X-ray diffraction exhibited a predominantly amorphous structure for DPCs and totally amorphous for DPLNs. Laser confocal scanning microscopy revealed the relative position of DPCs and liquid lipid, showing that DPLNs formed a homogeneous system. Fluorescence spectra and electron spin resonance further confirmed the chemical environment inside the DPLNs in a non-invasive way.     

Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of process variables

This study aimed to prepare solid lipid nanoparticles (SLNs) of a hydrophobic drug, tretinoin, by emulsification-ultrasonication method. Solubility of tretinoin in the solid lipids was examined. Effects of process variables were investigated on particle size, polydispersity index (PI), zeta potential (ZP), drug encapsulation efficiency (EE), and drug loading (L) of the SLNs. Shape and surface morphology of the SLNs were investigated by cryogenic field emission scanning electron microscopy (cryo-FESEM). Complete encapsulation of drug in the nanoparticles was checked by cross-polarized light microscopy and differential scanning calorimetry (DSC). Crystallinity of the formulation was analyzed by DSC and powder X-ray diffraction (PXRD). In addition, drug release and stability studies were also performed. The results indicated that 10mg tretinoin was soluble in 0.45±0.07 g Precirol? ATO5 and 0.36±0.06 g Compritol? 888ATO, respectively. Process variables exhibited significant influence in producing SLNs. SLNs with <120 nm size, <0.2 PI, >I30I mV ZP, >75% EE, and ～0.8% L can be produced following the appropriate formulation conditions. Cryo-FESEM study showed spherical particles with smooth surface. Cross-polarized light microscopy study revealed that drug crystals in the external aqueous phase were absent when the SLNs were prepared at ≤0.05% drug concentration. DSC and PXRD studies indicated complete drug encapsulation within the nanoparticle matrix as amorphous form. The drug release study demonstrated sustained/prolonged drug release from the SLNs. Furthermore, tretinoin-loaded SLNs were stable for 3 months at 4°C. Hence, the developed SLNs can be used as drug carrier for sustained/prolonged drug release and/or to improve oral absorption/bioavailability.