Preparation and characterization of n-dodecyl-ferulate-loaded solid lipid nanoparticles (SLN)

Solid lipid nanoparticles (SLN) containing a novel potential sunscreen n-dodecyl-ferulate (ester of ferulic acid) were developed. The preparation and stability parameters of n-dodecyl-ferulate-loaded SLN have been investigated concerning particle size, surface electrical charge (zeta potential) and matrix crystallinity. The chemical stability of n-dodecyl-ferulate at high temperatures was also assessed by thermal gravimetry analysis. For the selection of the appropriated lipid matrix, chemically different lipids were melted with 4% (m/m) of active and lipid nanoparticles were prepared by the so-called high pressure homogenization technique. n-Dodecyl-ferulate-loaded SLN prepared with cetyl palmitate showed the lowest mean particle size and polydispersity index, as well as the highest physical stability during storage time of 21 days at 4, 20 and 40 degrees C. These colloidal dispersions containing the sunscreen also exhibited the common melting behaviour of aqueous SLN dispersions.     

Idebenone-loaded solid lipid nanoparticles for drug delivery to the skin: in vitro evaluation

Idebenone (IDE), a synthetic derivative of ubiquinone, shows a potent antioxidant activity that could be beneficial in the treatment of skin oxidative damages. In this work, the feasibility of targeting IDE into the upper layers of the skin by topical application of IDE-loaded solid lipid nanoparticles (SLN) was evaluated. SLN loading different amounts of IDE were prepared by the phase inversion temperature method using cetyl palmitate as solid lipid and three different non-ionic surfactants: ceteth-20, isoceteth-20 and oleth-20. All IDE loaded SLN showed a mean particle size in the range of 30-49 nm and a single peak in size distribution. In vitro permeation/penetration experiments were performed on pig skin using Franz-type diffusion cells. IDE penetration into the different skin layers depended on the type of SLN used while no IDE permeation occurred from all the SLN under investigation. The highest IDE content was found in the epidermis when SLN contained ceteth-20 or isoceteth-20 as surfactant while IDE distribution into the upper skin layers depended on the amount of IDE loaded when oleth-20 was used as surfactant. These results suggest that the SLN tested could be an interesting carrier for IDE targeting to the upper skin layers.     

Modeling the effect of sonication parameters on size and dispersion temperature of solid lipid nanoparticles (SLNs) by response surface methodology (RSM)

Abstract

The objective of this study was to evaluate the effect of sonication time and pulse frequency on average dispersion temperature (ART), particle size and zeta potential of solid lipid nanoparticles (SLNs). A two-factor, three-level response surface methodology (RSM) was used to optimize sonication time between 5 and 15?min and pulse frequency from 30 to 90%. SLNs made from stearyl alcohol (SA) and cetyl trimethylammonium bromide (CTAB) blend at 1:3 ratio were prepared by applying high-shear homogenization and sonication. Pulse frequency and time were found to have a significant effect on particle size and ART. The effect of sonication parameters on zeta potential, however, was insignificant. The optimal sonication parameters for preparing 100?nm SLNs made from a SA/CTAB blend was 60% pulse frequency at 40% power for 10?min. Optimized sonication parameters were then used to investigate the effect of lipid type on SLN size and zeta potential. The mean particle sizes of SLNs made with SA, cetyl palmitate, Precirol®, Dynasan118® and Compritol® were 98, 190, 350, 350 and 280?nm, respectively. In conclusion, pulse frequency and time were found to be critical for obtaining SLNs with desirable size, whereas the stability of the SLNs was dependent on their lipid content.     

Stability of lipid excipients in solid lipid nanoparticles

The paper is devoted to the investigation of chemical stability of lipids used as excipients in the production of Solid Lipid Nanoparticles (SLN). Different lipids and amounts of surfactants were considered. Most of the formulations were produced using identical binary surfactant mixtures and concentrations to analyze the effect of the chemical nature of the lipids on their stability in SLN. In some formulations, surfactants were exchanged or their concentration was increased to assess the contribution of surfactants on stability of lipids particles. Solid Lipid Nanoparticles were characterized by photon correlation spectroscopy, laser diffractometry, zeta potential determination and differential scanning calorimetry. Potential effects of lipid crystallinity and modifications were assessed. A gas chromatography (GC) analysis in combination with a method for lipid extraction from aqueous SLN dispersions was used to investigate the chemical stability of the lipid excipients forming the particle matrix. All formulations were produced by the hot homogenization technique. The production process of SLN itself did not affect the chemical stability of lipid excipient forming the particle matrix. The formulations where lipids consisted of trigylicerides showed a negligible decomposition of the structure during incubation at 25 degrees C. Dynasan 118 showed the highest chemical stability (loss<4%) within two years.     

Hydrophilic coating of mitotane-loaded lipid nanoparticles: Preliminary studies for mucosal adhesion

The aim of the present work was to load mitotane, an effective drug for adrenocortical carcinoma treatment, in solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). The SLN and NLC were successfully prepared by high shear homogenization followed by hot high pressure homogenization. Formulations were composed of cetyl palmitate as the solid lipid for SLN, whereas for NLC PEGylated stearic acid was selected as solid lipid and medium chain triacylglycerols as the liquid lipid. Tween® 80 and Span® 85 were used as surfactants for all formulations. The particle size, zeta potential, polydispersity index (PI), encapsulation efficiency (EE), and loading capacity (LC) were evaluated. The SLN showed a mean particle size of 150?nm, PI of 0.20, and surface charge ?10 mV, and the EE and LC could reach up to 92.26% and 0.92%, respectively. The NLC were obtained with a mean particle size of 250?nm, PI of 0.30, zeta potential ?15 mV and 84.50% EE, and 0.84% LC, respectively. Hydrophilic coating of SLN with chitosan or benzalkonium chloride was effective in changing zeta potential from negative to positive values. The results suggest that mitotane was efficiently loaded in SLN and in NLC, being potential delivery systems for improving mitotane LC and controlled drug release.     

Preparation and characterization of solid lipid nanoparticles loaded with total flavones of Hippophae rhamnoides (TFH)

Solid lipid nanoparticles (SLNs) containing total flavones of Hippophae rhamnoides (TFH) were prepared by high-pressure homogenization (HPH), by both hot HPH and cold HPH. The influence of process parameters (lipid matrix, lipid concentration, carbohydrate type and its concentration) on the SLN size distribution, zeta potential, entrapment efficiency, crystal form, and in vitro release profile was investigated. The highest entrapment efficiency for TFH, at around 93%, was found for SLNs composed of TFH/Compritol 888 ATO in a 1:30 molar ratio and made by cold HPH. The advantages of TFH SLNs are the improved oral bioavailability of TFH and the prolonged mean retention time and drug release time.     

Dissolution of solid lipid extrudates in biorelevant media

Solid lipid extrudates with the model drug praziquantel were produced with chemically diverse lipids and investigated regarding their dissolution behaviour in different media. The lipids used in this study were glyceryl tripalmitate, glyceryl dibehenate, glyceryl monostearate, cetyl palmitate and solid paraffin. Thermoanalytical and dissolution behaviour was investigated directly after extrusion and after 3 and 6 months open storage at 40°C/75% RH. Dissolution studies were conducted in hydrochloric acid (HCl) pH 1.2 with different levels of polysorbate 20 and with a biorelevant medium containing pancreatic lipase, bile salts and phospholipids. Furthermore, the impact of lipid digestion on drug release was studied using in vitro lipolysis. The release of praziquantel from cetyl palmitate and glyceryl monostearate in the biorelevant medium was much faster than in HCl, whereas there was hardly any difference for the other lipids. It was shown that drug release from glyceryl monostearate matrices is driven by both solubilisation and enzymatic degradation of the lipid, whereas dissolution from cetyl palmitate extrudates is dependent only on solubilisation by surfactants in the medium. Moreover, storage influenced the appearance of the extrudate surface and the dissolution rate for all lipids except solid paraffin.     

Formulation and in vitro characterization of domperidone loaded solid lipid nanoparticles and nanostructured lipid carriers

Background and the purpose of the study

Domperidone (DOM) is a dopamine- receptor (D₂) antagonist, widely used in the treatment of motion-sickness. The pharmacokinetic parameters of DOM make it a suitable candidate for development of Solid Lipid Nanoparticle (SLN) and Nanostructured Lipide Carrier (NLC). The purpose of the present investigation was to prepare and evaluate DOM loaded solid lipid nanoparticles (DOM-SLN) and DOM loaded nanostructured lipid carriers (DOM-NLC).

Methods

DOM loaded SLN and NLC were prepared by hot homogenization followed by ultrasonication technique, using trimyristin as solid lipid, cetyl recinoleate as liquid lipid and a mixture of soy phosphatidylcholine (99%) and tween 80 as surfactant. SLN and NLC were characterized for particle size, polydispersity index (PDI), zeta potential and entrapment efficiency. The effects of composition of lipid materials and surfactant mixture on the particle size, PDI, zeta potential, drug entrapment efficiency, and in vitro drug release behavior were investigated. DSC analysis was performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by transmission electron microscopy (TEM). SLN and NLC formulations were subjected to stability study over a period of 40 days.

Results

The mean particle size, PDI, zeta potential and entrapment efficiency of optimized SLN (SLN1) and NLC were found to be 30.45 nm, 0.156, 12.40 mV, 87.84% and 32.23 nm, 0.160, 10.47 mV, 90.49% respectively. DSC studies revealed that DOM was in an amorphous state and triglycerides were in the β prime form in SLN and NLC. Shape and surface morphology was determined by TEM revealed fairly spherical shape of nanoparticles. In vitro release studies demonstrated that both the SLN and NLC formulations possessed a controlled release over a period of 24 hrs. SLN and NLC formulations were subjected to stability over a period of 40 days. There was no significant (P<0.05) change in particle size, zeta potential, PDI and entrapment efficiency indicating the developed SLN and NLC were fairly stable.

Conclusion

Fairly spherical shaped, stable and controlled release DOM-SLN and DOM-NLC could be prepared by hot homogenization followed by ultrasonication technique.     

Loading hydrophilic drug in solid lipid media as nanoparticles: statistical modeling of entrapment efficiency and particle size

Solid lipid nanoparticle (SLN) is a very well tolerated carrier systems for dermal application due to the employment physiological and/or biodegradable lipids. The effects of five factors, two categorical and three quantitative factors, were studied on the mean diameter and entrapment efficiency of the produced SLNs using response surface method (RSM), D-optimal design. Two methods of microemulsion and solvent diffusion and two types of lipid, cetyl palmitate and stearic acid, were examined comparatively. The quantitative variables were studied in three levels; amount of original Paromomycin (60, 90 and 120 mg), fraction of surfactant (0.5, 0.75 and 1 w/v %) and drug to lipid ratio (2, 4 and 6). Mean particle size and entrapment efficiency of the loaded Paromomycin were modeled statistically and the optimal condition was determined to approach to the maximum entrapment efficiency. The drug release profile of the optimal formulated material was examined in aqueous media and 64% of the Paromomycin loaded in SLNs was gradually released during 24h, which reveals efficient prolonged release of the drug.     

Development and evaluation of nitrendipine loaded solid lipid nanoparticles: influence of wax and glyceride lipids on plasma pharmacokinetics

Nitrendipine is an antihypertensive drug with poor oral bioavailability ranging from 10 to 20% due to the first pass metabolism. For improving the oral bioavailability of nitrendipine, nitrendipine loaded solid lipid nanoparticles have been developed using triglyceride (tripalmitin), monoglyceride (glyceryl monostearate) and wax (cetyl palmitate). Poloxamer 188 was used as surfactant. Hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperature above the melting point of lipid was used to prepare SLN dispersions. SLN were characterized for particle size, zeta potential, entrapment efficiency and crystallinity of lipid and drug. In vitro release studies were performed in phosphate buffer of pH 6.8 using Franz diffusion cell. Pharmacokinetics of nitrendipine loaded solid lipid nanoparticles after intraduodenal administration to conscious male Wistar rats was studied. Bioavailability of nitrendipine was increased three- to four-fold after intraduodenal administration compared to that of nitrendipine suspension. The obtained results are indicative of solid lipid nanoparticles as carriers for improving the bioavailability of lipophilic drugs such as nitrendipine by minimizing first pass metabolism.     

The effect of surfactants on the microencapsulation and release of phenobarbitone from gelatin-acacia complex coacervate microcapsules

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the microencapsulation and release of phenobarbitone have been described. Bimodal particle size distributions were produced both in the absence and presence of each of the three surfactants. The presence of surfactant had little or no effect on the particle size distribution at any given stirring speed. A large variation was noted in the amount of phenobarbitone microencapsulated dependent upon the type of surfactant and its concentration. The amount of phenobarbitone encapsulated decreased with increasing concentration of polysorbate 20 and with SLS. Cetrimide (0.025 per cent w/v) enhanced encapsulation with 2 per cent w/w colloids but higher concentrations at the CMC and above decreased encapsulation. The results are explained in terms of decreased interfacial tension by the surfactant and by steric and electrostatic effects caused by surfactant adsorption onto the coacervate droplets and phenobarbitone particles.     

The effect of surfactants on the microencapsulation and release of phenobarbitone from gelatin-acacia complex coacervate microcapsules

Abstract

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the microencapsulation and release of phenobarbitone have been described. Bimodal particle size distributions were produced both in the absence and presence of each of the three surfactants. The presence of surfactant had little or no effect on the particle size distribution at any given stirring speed. A large variation was noted in the amount of phenobarbitone microencapsulated dependent upon the type of surfactant and its concentration. The amount of phenobarbitone encapsulated decreased with increasing concentration of polysorbate 20 and with SLS. Cetrimide (0025 per cent w/v) enhanced encapsulation with 2 per cent w/w colloids but higher concentrations at the CMC and above decreased encapsulation. The results are explained in terms of decreased interfacial tension by the surfactant and by steric and electrostatic effects caused by surfactant adsorption onto the coacervate droplets and phenobarbitone particles.     

Characterization of physico-chemical properties and pharmaceutical performance of sucrose co-freeze-dried solid nanoparticulate powders of the anti-HIV agent loviride prepared by media milling

Enhancement of the chemical stability of ascorbyl palmitate (AP) after incorporation into nanostructured lipid carriers (NLC) has been reported. However, the formulation parameters of AP-loaded NLC have not been completely investigated. Moreover, the long-term chemical stability of AP in any colloidal systems has not been yet achieved. Therefore, in this study the formulation parameters affecting the stability of AP after incorporation into NLC were evaluated including types of lipids, types of surfactants, storage conditions, i.e. temperature and nitrogen gas flushing, the effects of drug loading as well as types of antioxidants. After storage for 90 days, the mean particle size analyzed by photon correlation spectroscopy (PCS) was lower than 350 nm. The zeta potential measured by the Zetasizer IV was higher than −30 mV in all developed AP-loaded NLC formulations which varied according to the types of lipid and surfactant. Concerning the chemical stability of AP, it was found that AP-loaded NLC prepared and stored in non-degassing conditions, a higher percentage of AP loading in NLC, lower storage temperature (4 °C), addition of antioxidants as well as selection of suitable surfactants and solid lipids improved the chemical stability of AP. Moreover, an improvement of long-term chemical stability of AP was achieved by addition of antioxidants with nitrogen gas flushing as compared to those without antioxidant. The percentage of drug remaining at both 4 °C and room temperature (25 °C) was higher than 85% during 90 days of storage.     

Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies

The objective of the present study was to prepare and characterize emodin (EMO)-loaded solid lipid nanoparticles (E-SLNs) and evaluate their antitumor activity in vitro. EMO and pharmaceutical lipid material were used to prepare E-SLNs by high pressure homogenization (HPH). Poloxamer 188 and Tween 80 were used as surfactants. The physicochemical properties of the E-SLNs were investigated by particle size analysis, zeta potential measurement, drug entrapment efficiency (EE), stability and in vitro drug release behavior. The E-SLNs showed stable particle size at 28.6 ± 3.1 nm, ideal drug EE and relative long-term physical stability after being stored for 4 months. The drug release of E-SLNs could last 72 h and exhibited a sustained profile, which made it a promising vehicle for oral drug delivery. MTT assay showed that E-SLNs could significantly enhance the in vitro cytotoxicity against human breast cancer cell line MCF-7 and MDA-MB-231 cells compared to the EMO solution, while free EMO, blank SLNs (B-SLNs) and E-SLNs all showed no significant toxicity to human mammary epithelial line MCF-10A cells. Flow cytometric analysis demonstrated that E-SLNs also showed more significant cell cycle arrest effect in MCF-7 cells compared to bulk EMO solution. Hoechst 33342 staining and Annexin V-FITC/PI double staining further confirmed that E-SLNs induced higher apoptotic rates in MCF-7 cells, indicating that cell cycle arrest and apoptosis maybe the underlying mechanism of the enhanced cytotoxicity. Taken together, it seems that HPH was a simple, available and effective method for preparing high quality E-SLNs to enhance its aqueous solubility. Moreover, these results suggest that the delivery of EMO as lipid nanoparticles maybe a promising approach for cancer therapy.     

Preparation and characterization of ibuprofen solid lipid nanoparticles with enhanced solubility

Solid lipid nanoparticles (SLNs) loaded with ibuprofen (IBU) were prepared by solvent-free high-pressure homogenization (HPH). The produced SLNs consisted of stearic acid, triluarin or tripalmitin as lipid matrixes and various stabilizers. The produced empty and IBU-loaded SLNs were characterized for particle size stability over 8 months. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were implemented to characterize the IBU state of freeze-dried SLNs. IBU was found to be in both amorphous and crystalline form within the lipid matrix. The lyophilized powders showed increased dissolution rates for IBU depending on the lipid nature. SLNs were incubated in Caco-2 cells for 24?h showing negligible cell cytotoxicity up to 15?mg/mL.     

Key production parameters for the development of solid lipid nanoparticles by high shear homogenization

In this work, we report the development and optimization of solid lipid nanoparticles (SLN) production by a simple, fast, and cost-effective high shear homogenization process. A screening of several solid lipids (Compritol 888 ATO, Precirol ATO 5, Cetyl Palmitate, Dynasan 118, Imwitor 900K, Stearic acid) has been carried out in combination with Poloxamer 188 as the selected surfactant, based on the mean particle size and polydispersity index. The improvement of the physical stability of the SLN dispersions was achieved by the use of a cationic lipid (cetyl trimethylammonium bromide) reaching zeta potential values above +60 mV. Combining the optimized speed and time of shear, monodispersed SLN (PdI < 0.25) under the nanometer range could be produced.     

Preparation and characterization of ibuprofen solid lipid nanoparticles with enhanced solubility

Solid lipid nanoparticles (SLNs) loaded with ibuprofen (IBU) were prepared by solvent-free high-pressure homogenization (HPH). The produced SLNs consisted of stearic acid, triluarin or tripalmitin as lipid matrixes and various stabilizers. The produced empty and IBU-loaded SLNs were characterized for particle size stability over 8 months. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were implemented to characterize the IBU state of freeze-dried SLNs. IBU was found to be in both amorphous and crystalline form within the lipid matrix. The lyophilized powders showed increased dissolution rates for IBU depending on the lipid nature. SLNs were incubated in Caco-2 cells for 24?h showing negligible cell cytotoxicity up to 15?mg/mL.     

Comparison of wax and glyceride solid lipid nanoparticles (SLN)

The present study compares solid lipid nanoparticles (SLN) formulated with either wax or glyceride bulk material. While most published data deal with glyceride SLN, little knowledge is reported on wax carriers. The two types were compared with respect to drug encapsulation efficacy, particle size distribution after production and storage, and crystal packing. The inclusion of retinol as a model drug was investigated. Retinol is chemically unstable in water and rather stable in lipid phases. Thus, rapid degradation of retinol indicates rapid drug expulsion from the carrier. Good stability indicates an effective drug encapsulation in the lipid phase of the nanoparticles. Particle size distribution was measured by laser diffractometry. Subcell packing and assignment of polymorphic forms was investigated by WAXS measurements. Glyceride SLN showed good drug encapsulation, while physical stability was poor. In contrast, wax SLN possessed good physical stability but lacked sufficient drug encapsulation in the solidified state. These differences were attributed in part to different crystal packing. Less ordered crystal lattices favour successful drug inclusion, as in the case of glyceryl monosterate and glyceryl behenate SLN. The highly ordered crystal packing of wax SLN comprised of beeswax or cetyl palmitate, for instance, leads to drug expulsion, but also to superior physical stability.     

The use of hot and cold high pressure homogenization to enhance the loading capacity and encapsulation efficiency of nanostructured lipid carriers for the hydrophilic antiretroviral drug, didanosine for potential administration to paediatric patients

A major obstacle to the application of nanostructured lipid carriers (NLCs) as carriers for hydrophilic drugs is the limited loading capacity (LC) and encapsulation efficiency (EE) of NLCs for these molecules. The purpose of this research was to design and implement a strategy to enhance the LC and EE of NLCs for the hydrophilic drug, didanosine (DDI). DDI was dispersed in Transcutol(?) HP and the particle size of DDI in the liquid lipid was reduced gradually using hot high pressure homogenization (HPH). The product obtained thereafter was added to Precirol(?) ATO 5 and the hot mixture was immediately dried using liquid nitrogen. The dried materials were then ground and passed through a 200 μm sieve and the solid lipid particles were dispersed in a surfactant solution and subsequently used to manufacture DDI-loaded NLCs using cold HPH. The LC and EE of NLCs for DDI manufactured using the new strategy were 3.39?±?0.63% and 51.58?±?1.31%, respectively, compared to 0.079?±?0.001% and 32.45?±?0.08%, respectively, obtained when DDI-loaded NLCs were produced using conventional hot HPH. The enhanced LC and EE for DDI make NLCs a potential technology for the oral administration of DDI to paediatric patients.     

Investigation on Particle Self-Assembly in Solid Lipid-Based Colloidal Drug Carrier Systems

PURPOSE: The effect of spontaneous particle self-assembly into stack-like structures occurring in dispersions of melt-homogenized tripalmitin nanocrystals (solid lipid nanoparticles; SLNs) was studied in dependence of lipid concentration, stabilizer type, stabilizer concentration, and particle size. METHODS: Tripalmitin nanosuspensions with concentrations ranging from 20 to 200 mg/g were prepared by high-pressure melt homogenization. The formulations were characterized by synchrotron small-angle X-ray scattering (SAXS), photon correlation spectroscopy (PCS), and freeze-fracture transmission electron microscopy (TEM). RESULTS: Dispersions of partly self-assembled particles could be derived both with anionic or cationic surfactants. Particle self-assemblies were observed in such formulations when the tripalmitin concentration exceeds 40 mg/g. Further increase of the lipid concentration enhances particle self-assembly. The tendency to form self-assemblies is also influenced by the particle shape. The interparticle distances in stacked lamellae are determined by the tripalmitin concentration and by the surfactant concentration. CONCLUSIONS: Parallel alignment of tripalmitin nanoplatelets is a completely reversible and concentration-dependent effect that can be attributed to the overlap of the exclusion volumes of the anisometric particles. The usefulness of this effect might be explored for the formulation of drug delivery systems.