Thermal characterization of solid lipid nanoparticles containing praziquantel

Solid lipid nanoparticles (SLNs), loaded and unloaded with praziquantel (PRZ-load SLN and PRZ-unload SLN) were prepared by two different procedures: (a) oil-in-water hot microemulsion method, obtaining at 70 °C an optically transparent blend composed of surfactant, co-surfactant, and water; and (b) oil-in-water microemulsion method, dissolving the lipid in an immiscible organic solvent, emulsified in water containing surfactants and co-surfactant, and then evaporated under reduced pressure at 50 °C. The mean diameter, polydispersity index (PdI), and zeta potential were 187 to 665 nm, 0.300 to 0.655, and −25 to −28 mV respectively, depending on the preparation method. The components, binary mixture, SLNs loaded and unloaded with PRZ, and physical mixture were evaluated by differential scanning calorimetry (DSC) and thermogravimetry (TG). The non-isothermal isoconversional Flynn-Wall–Ozawa method was used to determine the kinetic parameters associated with the thermal decomposition of the samples. The experimental data indicated a linear relationship between the apparent activation energy E and the pre-exponential factor A, also called the kinetic compensation effect (KCE), allowing us to determine the stability with respect to the preparation method. Loading with PRZ increased the thermal stability of the SLNs.     

Physicochemical characterization of nanotemplate engineered solid lipid nanoparticles

As the physicochemical characteristics of solid lipid nanoparticles (SLNs) play a critical role in their success, it is important to understand how the materials and process used in their preparation affect these properties. In this study, two stearyl alcohol-based formulations were prepared using nanotemplate engineering technology and characterized. Both formulations were of a small particle size (<100 nm), ellipsoidal shape, and low polydispersity. (1)H NMR spectroscopy confirmed that the SLNs have the expected solid core structure and PEGylated surface. Analysis of the bulk materials indicated that a number of complex interactions are present among the SLN components, including a eutectic between stearyl alcohol and Brij 78. The decreased crystallinity resulting from these interactions may allow for enhanced drug loading. Physiological stability was identified and confirmed as a potential problem due to the low melting point of the eutectic. However, it is expected that with appropriate formulation modifications nanotemplate engineered SLNs will possess the properties necessary for a successful drug delivery system.     

Physicochemical properties of nevirapine-loaded solid lipid nanoparticles and nanostructured lipid carriers

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) coated with human serum albumin (HSA) were fabricated for formulating nevirapine (NVP). Here, NLCs contained low-melting-point oleic acid (OA) in the internal lipid phase. The results revealed that the two nanoparticles were uniformly distributed with the average diameter ranging from 145 to 180 nm. The surface HSA neutralized the positive charge of dimethyldioctadecyl ammonium bromide (DODAB) on SLNs and NLCs and reduced their zeta potential. In a fixed ratio of solid lipids, SLNs entrapped more NVP than NLCs. The incorporation of OA also reduced the thermal resistance of NLCs and accelerated the release of NVP from the nanocarriers. When incubated with DODAB-stabilized SLNs, the viability of human brain-microvascular endothelial cells (HBMECs) reduced. However, the surface HSA increased the viability of HBMECs about 10% when the concentration of SLNs was higher than 0.8 mg/mL. HSA-grafted SLNs and NLCs can be effective formulations in the delivery of NVP for viral therapy.     

Loading of 5-aminosalicylic in solid lipid microparticles (SLM)

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine, is the most commonly used drug for treating patients with inflammatory bowel disease (IBD). Its bioavailability is low, i.e. 20–30% upon oral administration and 10–35% by rectal administration. As the extent of 5-ASA absorption is very much dependent on the time-length, the drug is retained in the colon, a way to increase drug retention is the use of orally administered sustained released formulations. Solid lipid microparticles (SLM) are a viable option for site-specific targeted delivery in compressed tablets produced by direct compaction. In this study, we describe the development and characterization of 5-ASA-loaded SLM for sustained release. The solubility of 5-ASA in different types of solid lipids (e.g. cetyl palmitate, cetyl alcohol, and cetearyl alcohol) was evaluated to select the best lipid as the inert matrix-forming agent to control the release of the drug. SLM dispersions were prepared using the hot emulsification method employing the selected solid lipid, lecithin (Lipoid^®) as surfactant, dimethyl sulphoxide, and acetone stabilized with Arlacel^®. The characterization was performed by differential scanning calorimetry, thermogravimetric analysis, wide-angle x-ray diffraction, Fourier transform infrared spectroscopy measurements, optical microscopy, and scanning electron microscopy. Results show that the best lipid for dissolving the 5-ASA was cetyl palmitate and that the melting process did not affect the chemical stability of the materials. The thermal analysis suggests that 5-ASA was successfully encapsulated with the microparticles, of spherical shape and uniform size distribution.

     

Cholesterylbutyrate solid lipid nanoparticles as a butyric acid prodrug

Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid. Butyrate is not often used in vivo because its half-life is very short and therefore too large amounts of the drug would be necessary for its efficacy. In the last few years butyric acid's anti-inflammatory properties and its inhibitory activity towards histone deacetylases have been widely studied, mainly in vitro. Solid Lipid Nanoparticles (SLNs), whose lipid matrix is Chol-but, were prepared to evaluate the delivery system of Chol-but as a prodrug and to test its efficacy in vitro and in vivo. Chol-but SLNs were prepared using the microemulsion method; their average diameter is on the order of 100-150 nm and their shape is spherical. The antineoplastic effects of Chol-but SLNs were assessed in vitro on different cancer cell lines and in vivo on a rat intracerebral glioma model. The anti-inflammatory activity was evaluated on adhesion of polymorphonuclear cells to vascular endothelial cells. In the review we will present data on Chol-but SLNs in vitro and in vivo experiments, discussing the possible utilisation of nanoparticles for the delivery of prodrugs for neoplastic and chronic inflammatory diseases.     

Characterization of silver sulfadiazine-loaded solid lipid nanoparticles by thermal analysis

The aim of this study is the solid-state characterization of solid lipid nanoparticles (SLN) based on Compritol^® 888 (C888) and Lutrol^® F68 (F68), loaded with silver sulfadiazine (AgSD), used to develop sponge-like dressings to treat chronic skin ulcers such as decubitis and leg ulcers. Silver compounds like AgSD, in fact, are used to prevent and/or to treat wound colonization that could impair healing, also in the case of antibiotic-resistant bacteria. Thermal analysis, with support from powder X-ray diffractometry and Fourier transform infrared spectroscopy, is used to characterize lipid and drug bulk, unloaded and drug-loaded SLN. In particular, differential scanning calorimetry is used to investigate the degree of crystallinity and the solid-state modification of lipid, two parameters correlated to drug incorporation and drug release rates. The solid-state characterization demonstrates AgSD entrapment in C888 as a core enclosed into F68 shell. AgSD SLN are also stored at different temperatures 25 and 37 °C, respectively, to study the effect of storage conditions, that induce an increase of the lipid crystallinity index correlated to drug release from the lipid matrix.     

Modification and stabilizing effects of PEG on resveratrol-loaded solid lipid nanoparticles

Resveratrol-loaded solid lipid nanoparticles (SLNs) modified by polyethylene glycol (PEG2000) (RES–PEG–SLNs) were prepared to study the stabilizing influences of PEG2000 on SLNs properties including loading capacity, particle size, photostability, and release. The micromorphology, particle size distribution, drug–lipid–modifier interaction and crystalline structure were characterized to elucidate stabilizing effects of PEG2000 on SLNs. Compared with ordinary SLNs, SLNs modified by PEG2000 at relatively low amounts of [m(PEG2000):m(lipids) = 1:10] exhibit high drug loading, steady nanoparticle size distributions, photostability and sustained release. According to characterizations, RES–PEG–SLNs formation is dependent on the physical interactions of drug–lipid–modifier. Since PEG2000 is doped into lipid matrix in a non-crystalline state, the lipids crystalline arrangement is disrupted. Additionally, RES–PEG–SLNs are crystallized in a PEG2000/lipid eutectic mixture rather than a simple mixture, inhibiting the lipid polymorphism transformation from α- to β-form, and therefore preventing drug exclusion from the lipid matrix. The PEG2000/lipid matrix contains lattice defects, which allow for the incorporation of more resveratrol and preventing it from photodegradation effectively. In contrast to the burst release of SLNs modified without PEG2000, resveratrol is released more slowly from the lattice defects in lipid matrix of RES–PEG–SLNs, resulting in a sustained release fitted by a two-stage exponential kinetic equation. PEG2000 is distributed on the RES–PEG–SLNs surface, increasing repulsion between nanoparticles and avoiding particles aggregation. These results confirm that both matrix doping effects and surface steric hindrance produced by the presence of PEG2000 play important roles in maintaining high loadings, nanoparticle size, photostability and sustained release.     

Antitumor activity and pharmacokinetics of podophyllotoxin incorporated into solid lipid nanoparticles

To evaluate the antitumor activity and pharmacokinetics of podophyllotoxin (PPT) incorporated into solid lipid nanoparticles (SLN), Kunming mice inoculated with flesh tumor were used as animal model. The mice received a single daily intraperitoneal injection of PPT in 20% ethanol (5 mg/kg) and PPT-SLN (5 mg/kg in PPT) for 3 weeks. Gross tumor volumes, body weight and clinical observations were recorded daily. The mice were sacrificed for 24 h after the last administration, and the tumor inhibition rate was calculated with the tumor weight. For the pharmacokinetics research, the mice were treated with intraperitoneal injection of PPT (10 mg/kg) and PPT-SLN (10 mg/kg in PPT). Blood samples were collected at different time to determine the PPT concentration in plasma by HPLC. Blood drug level-time curve was made and pharmacokinetic parameters were calculated. As a result of drug administration, the tumor volume and weight of the mice injected with PPT-SLN were significantly restrained compared with mice treated with PPT or negative control. The tumor inhibition rate of 58.13% showed a significant antitumor activity of PPT-SLN. At the same time, the increased weight gain of the mice injected with PPT-SLN suggested a reduced toxicity of PPT in SLN. Pharmacokinetics study displayed a higher blood concentration, a prolonged circulation time, and an increased bioavailability of PPT-SLN compared with those of PPT. Our results demonstrated that PPT-SLN could optimize pharmacokinetics, enhance antitumor activity and attenuate toxicity, so it has a promising prospect for the application in anti-tumor treatment. Supported by the National Natural Science Foundation of China (Grant No. 50673078), the Innovation Program of Shanghai Municipal Education Commission (Grant No. 08ZZ21) and the Shanghai Key Fundamental Project (Grant No. 07DZ19603)     

An easy and effective method for radiolabelling of solid lipid nanoparticles

Nanoparticle biodistribution study is of great importance in bringing nanomedicine to patients. In this article, solid lipid nanoparticle (SLN) with dimension less than 100 nm was successfully radiolabelled with ^99mTc by using sodium borohydride as a reducing agent (instead of stannous salts). Paclitaxel (PTX) was used as a model anticancer drug for the preparation of drug loaded SLN (PSLN). PSLN was characterized by standard methods. Encapsulation efficiency for PTX in PSLN was estimated by HPLC. PTX (Taxol formulation) and PSLN were radiolabelled separately and subsequent characterizations of these complexes were performed. Greater than 95 % radiolabelling efficiency was achieved and the labelling efficiency was calculated to be more than 90 % upto 24 h. Both the above-mentioned complexes passed the in vitro stability tests. PSLN achieved more brain concentration than Taxol as determined by biodistribution studies. This type of radiolabelling technique can be useful in preclinical evaluation of drug loaded SLN.     

Temperature scanning ultrasonic velocity study of complex thermal transformations in solid lipid nanoparticles

The purpose of this study was to determine whether temperature scanning ultrasonic velocity measurements could be used to monitor the complex thermal transitions that occur during the crystallization and melting of triglyceride solid lipid nanoparticles (SLNs). Ultrasonic velocity ( u) measurements were compared with differential scanning calorimetry (DSC) measurements on tripalmitin emulsions that were cooled (from 75 to 5 degrees C) and then heated (from 5 to 75 degrees C) at 0.3 degrees C min (-1). There was an excellent correspondence between the thermal transitions observed in deltaDelta u/delta T versus temperature curves determined by ultrasound and heat flow versus temperature curves determined by DSC. In particular, both techniques were sensitive to the complex melting behavior of the solidified tripalmitin, which was attributed to the dependence of the melting point of the SLNs on particle size. These studies suggest that temperature scanning ultrasonic velocity measurements may prove to be a useful alternative to conventional DSC techniques for monitoring phase transitions in colloidal systems.     

Surface modification of resorcinarene based self-assembled solid lipid nanoparticles for drug targeting

Prolyl-bearing amphiphilic resorcinarenes, e.g. tetrakis(N-methylprolyl)tetraundecylcalix[4]resorcinarene, self-assemble as stable solid lipid nanoparticles; these fully characterized systems could be further functionalized at their surface with proteins, and interact with specific antibodies bound on a sensor surface.     

The size of solid lipid nanoparticles: an interpretation from experimental design

This study aimed to investigate the role of different factors affecting the size of solid lipid nanoparticles (SLN), prepared by the emulsification-solvent evaporation method. A double factorial design was conducted so as to cover a wide range of sizes, highlighting zones with different behaviour with respect to changes in the controlled variables: lipid concentration, solvent:lipid ratio and emulsifier concentration. The solvent:lipid ratio constituted the main factor influencing particle size. Increasing the amount of solvent induced a decrease in the size. This was a general trend, essentially independent from solvent and lipid type. The amount of emulsifier had a non-trivial impact on size, depending on whether systems were located below, above or close to the optimal surface coverage. The amount of lipid had a limited influence upon particle size, being more relevant for lower lipid concentrations. An optimal formulation was selected for intermediate levels of the three variables. Sonication reduced both particle size and polydispersity. These particles were also tested as drug carriers using simvastatin as a model of lipophilic drug. SLN were able to entrap a high amount of simvastatin, with little effect upon size and zeta potential, constituting a promising carrier for lipophilic drugs.     

Formulation and pharmacokinetic evaluation of tetracycline-loaded solid lipid nanoparticles for subcutaneous injection in mice

The aim of this work was to prepare tetracycline-loaded solid lipid nanoparticles (Tet-SLN), and to evaluate the potential of these colloidal carriers for subcutaneous injection. Tet-SLN was prepared by microemulsion method and the preparation conditions were optimized by ternary phase diagram. At optimized process conditions, lyophilized Tet-SLN showed spherical particles with a mean diameter of 87.2±46.9 nm and a negative zeta potential of -6.69 mV, up to 1.7% tetracycline drug content was achieved after loading. In vitro release test showed a biphasic release profile for Tet-SLN and more than 80% of the drug was liberated from Tet-SLN in 48 h. After subcutaneous injection of Tet-SLN to mice, a considerable sustained release was observed; tetracycline in blood could be detected lasting 36 h, and lower concentrations of tetracycline in all tissues tested compared to the free tetracycline solution were observed. In conclusion, Tet-SLN can be prepared well by microemulsion method and subcutaneous injection of SLN provide a new perspective for drug sustained release.     

Impact of arginine-modified solid lipid nanoparticles on the membrane charge of human brain-microvascular endothelial cells

Electrokinetic and electrostatic properties of human brain-microvascular endothelial cells (HBMECs) with the uptake of l-arginine (Arg)-modified solid lipid nanoparticles (RSLNs) were investigated. The exposure of these HBMECs to radiofrequency electromagnetic field (EMF) was also considered. As compared with the original culture of HBMECs, the uptake of the biomimetic RSLNs induced smaller absolute values of electrophoretic mobility, zeta potential, Donnan potential, and fixed charge density. In addition, an increase in the coverage fraction of Arg on the external layers of the RSLNs reduced the electrical characteristics of HBMECs. An increase in the power of EMF also decreased the charge of RSLNs-incorporating HBMECs. On the contrary, softness of HBMECs was enhanced by an increased coverage fraction of Arg and an increased power of EMF. Electrophysiology of HBMECs can be efficiently mediated by the novel RSLNs and exposure to EMF through fluctuation and redistribution of the membrane charge.     

Catanionic solid lipid nanoparticles carrying doxorubicin for inhibiting the growth of U87MG cells

Catanionic solid lipid nanoparticles (CASLNs), loaded with doxorubicin (Dox) and grafted with anti-epithelial growth factor receptor (EGFR) (anti-EGFR/Dox-CASLNs), were applied to suppressing propagation of malignant U87MG cells. U87MG cells were cultured with anti-EGFR/Dox-CASLNs for assessing the cell viability and EGFR expression. When the concentration of catanionic surfactants, containing hexadecyltrimethylammonium bromide and sodium anionic sodium dodecylsulfate, was 1mM, CASLNs entrapped the largest quantity of Dox. The order of cacao butter (CB) in the entrapment efficiency of Dox was 50% CB>0% CB>100% CB. In addition, the release rate of Dox and the antiproliferative effect on U87MG cells were in the following order: 100% CB>0% CB>50% CB. A high level of CB in anti-EGFR/Dox-CASLNs reduced the cytotoxicity to human brain-microvascular endothelial cells. The immunochemical staining revealed that the crosslinked anti-EGFR on the surface of Dox-CASLNs preserved a high specificity in recognizing EGFR on U87MG cells and inducing growth-inhibition effect. The innovated anti-EGFR/Dox-CASLNs can be an effective delivery system with high targeting efficacy against the growth of brain glioblastomas carcinoma.     

On the lattice dynamics of solid nitrogen

Lattice statics and dynamics calculations for α-nitrogen have been done using the 6-exp atom-atom interaction to derive intermolecular forces. The three parameters of this interaction are reduced to one by constraining them so that the unit cell and sublimation energy are calculated to agree with experiment. Choice of the one parameter is then made using spectroscopic data. This 'best' potential is then used to calculate the statics and dynamics of β-nitrogen. This is stable only under pressure, and the calculation of the lattice dynamics under pressure gives a satisfactory agreement with experiment.     

Alternative sample preparation prior to two-dimensional electrophoresis protein analysis on solid lipid nanoparticles

The proteins adsorbing onto the surface of intravenously injected drug carriers are regarded as a key factor determining the organ distribution. Depending on the particle surface properties, certain proteins will be preferentially adsorbed, leading to the adherence of the particle to cells with the appropriate receptor. Therefore, the knowledge of the protein adsorption pattern and the correlation to in vivo behavior opens the perspective for the development of intravenous colloidal carriers for drug targeting. After incubation in plasma, the adsorbed proteins were analyzed using two-dimensional polyacrylamide gel electrophoresesis (2-D PAGE, 2-DE). The purpose of the present study was to develop an alternative separation method to separate solid lipid nanoparticles (SLN) carriers from plasma by gel filtration prior to 2-D PAGE. Via the specific absorption coefficients and a two-equation system, elution fractions were identified being practically plasma-free. This allows protein analysis on SLN which are typically in density too close to the density value of water to be separated by the standard centrifugation method. The SLN used for establishing the gel filtration were prepared in a way that they had a sufficiently low density to be additionally separated by centrifugation. The adsorption patterns obtained after separation with both methods were qualitatively and quantitatively identical, showing the suitability of the gel filtration.     

Application of validated RP-HPLC method for simultaneous determination of docetaxel and ketoconazole in solid lipid nanoparticles

Docetaxel has significant single agent activity in prostate cancer and ketoconazole also has activity as a second line hormonal agent. In vitro, ketoconazole is synergistic with some chemotherapy agents by enhancing the intracellular retention of the cytotoxic agent. A potential drug-drug interaction exists though between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system. Hence, a nanoparticulate system was formulated by loading both drugs for tumor targeting. Assay and in vitro release of the formulation were conducted by developing simple, precise, accurate, and validated analytical method for simultaneous determination docetaxel and ketoconazole using reversed-phase high-performance liquid chromatography (RP-HPLC). The RP-HPLC method was developed using Waters Symmetry C(18) column (25 cm × 4.5 mm, 5 μm) with a mobile phase consisting of acetonitrile and 0.2% triethylamine pH adjusted to 6.4 (48:52, v/v) at flow rate of 1 mL/min. Intra-day and inter-day variations were less than 2% over the linearity range, 0.5-20 μg/mL. The proposed two methods were successfully applied for the determination of docetaxel and ketoconazole in solid lipid nanoparticles.     

Preparation methods and thermal stability of calcipotriol solid lipid nanoparticles and efficacy in plaque psoriasis treatment

The preparation of Calcipotriol by solid lipid nanoparticles and the encapsulation of drugs in solid lipids are expected to obtain a new preparation with strong cutin permeability, slow release and targeting effect, so as to improve the local therapeutic effect of the drug and reduce the occurrence of skin irritation symptoms. In this work, Calcipotriol solid lipid nanoparticle (CPT-SLN) preparation methods are introduced and the stability of CPT-SLNs gel was evaluated by appearance, leakage rate and content. The performance was stable in a low-temperature environment of 4 °C for 40 days. There were no significant changes in appearance, and drug content and permeability can be controlled around 0.00469% and 0.26. However, it has poor stability under the storage conditions of 25 °C and 40 °C at room temperature. Therefore, the suitable conditions for the gel storage should be around 4 °C and sealed away from light. Pharmacodynamic experiments showed that CPT solid lipid nanoparticle gel was more effective than market-sale Calcipotriol ointment in the treatment of psoriasis. Further clinical tests have shown that CPT-SLNS can cure plaque psoriasis more effectively.

     

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.