Evaluation of the physical stability of SLN and NLC before and after incorporation into hydrogel formulations.

Aqueous dispersions of lipid nanoparticles are being investigated as drug delivery systems for different therapeutic purposes. One of their interesting features is the possibility of topical use, for which these systems have to be incorporated into commonly used dermal carriers, such as creams or hydrogels, in order to have a proper semisolid consistency. For the present investigation four different gel-forming agents (xanthan gum, hydroxyethylcellulose 4000, Carbopol943 and chitosan) were selected for hydrogel preparation. Aqueous dispersions of lipid nanoparticles--solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC)--made from tripalmitin were prepared by hot high pressure homogenization and then incorporated into the freshly prepared hydrogels. NLC differ from SLN due to the presence of a liquid lipid (Miglyol812) in the lipid matrix. Lipid nanoparticles were physically characterized before and after their incorporation into hydrogels. By means of rheological investigations it could be demonstrated that physical properties of the dispersed lipid phase have a great impact on the rheological properties of the prepared semisolid formulations. By employing an oscillation frequency sweep test, significant differences in elastic response of SLN and NLC aqueous dispersions could be observed.     

SLN and NLC for topical delivery of ketoconazole

The clinical use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aqueous SLN and NLC dispersions, as well as the physicochemical stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepared using Compritol 888 ATO as solid lipid. The natural antioxidant alpha-tocopherol was selected as liquid lipid compound for the preparation of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were physically stable as suspensions during 3 months of storage, but the SLN matrix was not able to protect the chemically labile ketoconazole against degradation under light exposure. In contrast, the NLC were able to stabilize the drug, but the aqueous NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC physically stabilized in a gel formulation.     

SLN and NLC for topical delivery of ketoconazole

The clinical use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aqueous SLN and NLC dispersions, as well as the physicochemical stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepared using Compritol®888 ATO as solid lipid. The natural antioxidant α-tocopherol was selected as liquid lipid compound for the preparation of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were physically stable as suspensions during 3 months of storage, but the SLN matrix was not able to protect the chemically labile ketoconazole against degradation under light exposure. In contrast, the NLC were able to stabilize the drug, but the aqueous NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC physically stabilized in a gel formulation.     

Nanocarriers for dermal drug delivery: Influence of preparation method, carrier type and rheological properties

Nanocarriers are highly interesting delivery systems for the dermal application of drugs. Based on a eudermic alkylpolyglycosid nanoemulsions, solid lipid nanoparticles (SLN) and nano-structured lipid carriers (NLC) were prepared by ultrasonic dispersion. The ultrasound preparation technique turned out to be convenient and rapid. For reasons of comparison, nanoemulsions were also prepared by high-pressure homogenisation with highly similar physicochemical properties. Cryo electron microscopy was employed to elucidate the microstructure of the ultrasound-engineered nanocarriers. Furthermore, in vitro skin experiments showed excellent skin permeation and penetration properties for flufenamic acid from all formulations. Moreover, ATR-FTIR studies revealed barrier-restorative properties for NLC and SLN. Furthermore, the rheological characteristics of all nanocarriers were determined. In order to increase the viscosity, three different polymers were employed to also prepare semi-solid NLC drug delivery systems. All of them exhibited comparable skin diffusion properties, but may offer improved dermal applicability.     

Lipid nanoparticles as carrier for octyl-methoxycinnamate: in vitro percutaneous absorption and photostability studies

The aim of the present study was the evaluation of lipid nanoparticles (solid lipid nanoparticles, SLN, and nanostructured lipid carriers, NLC) as potential carriers for octyl-methoxycinnamate (OMC). The release pattern of OMC from SLN and NLC was evaluated in vitro, determining its percutaneous absorption through excised human skin. Additional in vitro studies were performed in order to evaluate, after UVA radiation treatment, the spectral stability of OMC-loaded lipid nanoparticles. From the obtained results, ultrasonication method yielded both SLN and NLC in the nanometer range with a high active loading and a particle shape close to spherical. Differential scanning calorimetry data pointed out the key role of the inner oil phase of NLC in stabilizing the particle architecture and in increasing the solubility of OMC as compared with SLN. In vitro results showed that OMC, when incorporated in viscosized NLC dispersions (OMC-NLC), exhibited a lower flux with respect to viscosized SLN dispersions (OMC-SLN) and two reference formulations: a microemulsion (OMC-ME) and a hydroalcoholic gel (OMC-GEL). Photostability studies revealed that viscosized NLC dispersions were the most efficient at preserving OMC from ultraviolet-mediated photodegradation.     

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.     

Nanostructured lipid carriers (NLCs) versus solid lipid nanoparticles (SLNs) for topical delivery of meloxicam

Abstract

Objective: The aim of this study was to develop nanostructured lipid carriers (NLCs) as well as solid lipid nanoparticles (SLNs) and evaluate their potential in the topical delivery of meloxicam (MLX).

Materials and methods: The effect of various compositional variations on their physicochemical properties was investigated. Furthermore, MLX-loaded lipid nanoparticles-based hydrogels were formulated and the gels were evaluated as vehicles for topical application.

Results and discussion: The results showed that NLC and SLN dispersions had spherical shapes with an average size between 215 and 430?nm. High entrapment efficiency was obtained ranging from 61.94 to 90.38% with negatively charged zeta potential in the range of ?19.1 to ?25.7?mV. The release profiles of all formulations exhibited sustained release characteristics over 48?h and the release rates increased as the amount of liquid lipid in lipid core increased. Finally, Precirol NLC with 50% Miglyol® 812 and its corresponding SLN were incorporated in hydrogels. The gels showed adequate pH, non-Newtonian flow with shear-thinning behavior and controlled release profiles. The biological evaluation revealed that MLX-loaded NLC gel showed more pronounced effect compared to MLX-loaded SLN gel.

Conclusion: It can be concluded that lipid nanoparticles represent promising particulate carriers for topical application.     

Rheological and in vitro release behaviour of clotrimazole-containing aqueous SLN dispersions and commercial creams

Clotrimazole is a wide spectrum local imidazolic antifungal agent used in several dermatological creams, having e.g. 1% (m/m) such as Canesten and Fungizid-ratiopharm cream. In the present work, a new system based on solid lipid nanoparticles (SLN) containing the identical concentration of drug has been developed. A comparative study between the rheological properties of the referred creams and the developed aqueous SLN dispersions was carried out. The influence of incorporation of SLN in a standard hydrophilic cream on its flow curves was also assessed. In addition, the release of clotrimazole from the two commercial creams, as well as from aqueous SLN dispersions was studied. Concerning the rheological investigations, all tested commercial creams revealed very low shear rates and no yield points. Lipid nanoparticles having a mean diameter of approx. 200 nm have been incorporated into a hydrophilic cream, in a concentration of 20%, 30% or 40% (m/m). The hydrophilic cream containing 20% of SLN showed a dilatant-like character; however, increasing the percentage of incorporated lipid nanoparticles to 30% and 40% the formulation changed to a more pseudoplastic character, showing yield values of 28 Pa and 39 Pa, respectively. For in vitro release studies, Franz diffusion cells with a cellulose acetate membrane were used to measure the release of clotrimazole from two different commercial formulations in comparison to the aqueous SLN dispersion. After 6 h the amount of drug released was higher than 48% when delivered from both investigated commercial formulations and not higher than 25% when delivered from the aqueous SLN dispersion. The percentage of drug released determined after 24 h was more than 50% for Canesten cream and Fungizid-ratiopharm cream and not higher than 30% for the developed SLN formulation showing its prolonged release character.     

Skin moisturizing effect and skin penetration of ascorbyl palmitate entrapped in solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) incorporated into hydrogel

This study was performed as a complimentary to our previous study regarding the chemical stability of ascorbyl palmitate (AP) in solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and for comparison, in nanoemulsion (NE) incorporated into a hydrogel produced by high pressure homogenization. AP is known as an effective antioxidant that protects tissue integrity similar to vitamin C. Recently, its moisturizing activity in conventional topical formulations was found to be high. The aim of the present study was to investigate the moisturizing potential of AP in SLN and NLC incorporated into hydrogel as colloidal carrier systems. It has been known that SLN and NLC have occlusive effects, but AP incorporation moisturized skin significantly better than placebo in short-term (p < 0.001) and long-term trials (p < 0.01) for both SLN and NLC. In the second part of the study, SLN and NLC were found to sustain the penetration of AP through excised human skin about 1/2 and 2/3 times compared to NE (p < 0.001 and p < 0.01), respectively, due to the solid state of Witepsol E85 in the lipid phase.     

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for application of ascorbyl palmitate

The aim of this study was to improve the chemical stability of ascorbyl palmitate (AP) in a colloidal lipid carrier for its topical use. For this purpose, AP-loaded solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and for comparison, a nanoemulsion (NE) were prepared employing the high pressure homogenization technique and stored at room temperature (RT), 4 degrees C and 40 degrees C. During 3 months, physical stability of these formulations compared to placebo formulations which were prepared by the same production method, was studied including recrystallization behaviour of the lipid with differential scanning calorimetry (DSC), particle size distribution and storage stability with photon correlation spectroscopy (PCS) and laser diffractometry (LD). After evaluating data indicating excellent physical stability, AP-loaded SLN, NLC and NE were incorporated into a hydrogel by the same production method as the next step. Degradation of AP by HPLC and physical stability in the same manner were investigated at the same storage temperatures during 3 months. As a result, AP was found most stable in both the NLC and SLN stored at 4 degrees C (p > 0.05) indicating the importance of storage temperature. Nondegraded AP content in NLC, SLN and NE was found to be 71.1% +/- 1.4, 67.6% +/- 2.9 and 55.2% +/- 0.3 after 3 months, respectively. Highest degradation was observed with NE at all the storage temperatures indicating even importance of the carrier structure.     

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.     

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.     

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations

Solid lipid nanoparticles (SLN) were developed at the beginning of the 1990 s as an alternative carrier system to emulsions, liposomes and polymeric nanoparticles. The paper reviews advantages-also potential limitations-of SLN for the use in topical cosmetic and pharmaceutical formulations. Features discussed include stabilisation of incorporated compounds, controlled release, occlusivity, film formation on skin including in vivo effects on the skin. As a novel type of lipid nanoparticles with solid matrix, the nanostructured lipid carriers (NLC) are presented, the structural specialties described and improvements discussed, for example, increase in loading capacity, physical and chemical long-term stability, triggered release and potentially supersaturated topical formulations. For both SLN and NLC, the technologies to produce the final topical formulation are described, especially the production of highly concentrated lipid nanoparticle dispersions >30-80% lipid content. Production issues also include clinical batch production, large scale production and regulatory aspects (e. g. status of excipients or proof of physical stability).     

Nanostructured lipid carriers (NLC) in cosmetic dermal products

The first generation of lipid nanoparticles was introduced as solid lipid nanoparticles (SLN), the second, improved generation as nanostructured lipid carriers (NLC). Identical to the liposomes, the lipid nanoparticles (NLC) appeared as products first on the cosmetic market. The article gives an overview of the cosmetic benefits of lipid nanoparticles, that means enhancement of chemical stability of actives, film formation, controlled occlusion, skin hydration, enhanced skin bioavailability and physical stability of the lipid nanoparticles as topical formulations. NLC are on the market as concentrates to be used as cosmetic excipients, special formulation challenges for these products are discussed. NLC appeared also in a number of finished cosmetic products world-wide. An overview of these products is provided including their special effects due to the lipid nanoparticles, lipids used for their production and incorporated cosmetic actives.     

Nanostructured lipid carrier-based hydrogel formulations for drug delivery: A comprehensive review

The scientific literature today provides several systems that can deliver active pharmaceutical ingredients (APIs) across the skin. These include reservoir matrices, matrix diffusion-controlled devices, multiple polymer devices and multilayer matrix assemblies. Among these, nanostructured lipid carriers (NLC) have emerged as novel systems composed of physiological lipid materials suitable for topical, dermal and transdermal administration. This review focuses on the design characteristics, production and composition of semi-solid formulations containing NLC as API carriers. One of the useful semi-solid systems are hydrogels, which can be used as vehicles to provide appropriate consistency for NLC formulations to be applied onto the skin. In the present review recent developments in the field are highlighted, including examples of APIs successfully entrapped within NLC now amenable for delivery via the skin. Further innovations in NLC composition and formulation, as well as in semi-solid hydrogel assemblies, are likely to expand the number of APIs available for topical, dermal and transdermal delivery.     

Characterization of indomethacin-loaded lipid nanoparticles by differential scanning calorimetry

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are interesting nanoparticulate delivery systems produced from solid lipids. Both carrier types are submicron size particles but they can be distinguished by their inner structure. In the present paper, indomethacin (IND)-loaded SLN and NLC were prepared and the organization and distribution of the different ingredients originating each type of nanoparticle system were studied by differential scanning calorimetry (DSC) technique. Furthermore, mean particle size and percentage of drug encapsulation were also determined. From the results obtained, NLC lipid organization guaranteed an increased indomethacin encapsulation in comparison with SLN. DSC static and dynamic measurements performed on SLN and NLC showed that oil nanocompartments incorporated into NLC solid matrix drastically influenced drug distribution inside the nanoparticle system. Controlled release from NLC system could be explained considering both drug partition between oil nanocompartments and solid lipid and a successive partition between solid lipid and water.     

Polymorphic behaviour of Compritol888 ATO as bulk lipid and as SLN and NLC

CompritolR888 ATO (glycerol behenate) is widely used as a pharmaceutical excipient in the field of solid dosage forms due to its lubricating properties. It is an amphiphilic material with a high melting point (approximately 70 degrees C) and, therefore, it can also be used to prepare aqueous colloidal dispersions. The aim of this paper is to study the suitability of CompritolR888 ATO for the production of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the entrapment of a lipophilic model drug. This study assesses the crystalline structure of the bulk lipid, as well as the changes that occur in its crystal lattice with the addition of 'impurities', such as oil (alpha-tocopherol) and drug (ketoconazole), using DSC and X-ray diffraction analysis before and after thermal stress. Aqueous SLN and NLC dispersions were produced using an appropriate surfactant/co-surfactant system and their physicochemical stability was assessed by PCS, LD, DSC and by WAXS. It was found that the crystalline lattice of CompritolR888 ATO is composed of very small amounts of the unstable alpha polymorphic form characteristic of triacylglycerols, which disappears after thermal stress of bulk lipid. Mixing oils and drug molecules which are soluble in this lipid decreased its lattice organization and, thus, was revealed to be suitable for production of lipid nanoparticles containing ketoconazole. However, particle growth could not be avoided during shelf life.     

Preparation, characterization and physico-chemical properties of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC): their benefits as colloidal drug carrier systems

Solid lipid nanoparticles (SLN) have attracted increasing attention by various research groups and companies since the early 1990s. Their advantages over existing traditional carriers have been clearly documented. In addition, modified SLN have been described which are nanostructured lipid carriers (NLC) composed of liquid lipid blended with a solid lipid to form a nanostructured solid particle matrix. NLC combine controlled release characteristics with some advantages over SLN. This paper reviews the production techniques, characterization and physical stability of these systems including destabilizing factors and principles of drug loading, then considers aspects and benefits of SLN and NLC as colloidal drug carriers.     

Physicochemical characterization and in vitro release studies of ascorbyl palmitate-loaded semi-solid nanostructured lipid carriers (NLC gels)

The aim of this study was to characterize the physicochemical properties and to study in vitro release of ascorbyl palmitate from semi-solid lipid nanoparticles based on nanostructured lipid carriers (NLC gels) systems with the desired viscosity for dermal delivery. NLC gels were obtained by a one-step production procedure employing a high pressure homogenization technique using different solid lipid matrices. Ascorbyl palmitate (AP) was selected as a lipophilic active ingredient due to its range of cosmetic applications. After the production, particles within the size range 170-250 nm having polydispersity index lower than 0.3 were obtained from all formulations. After the AP incorporation into the NLC gels, the zeta potential increased to values higher than |30 mV|. Almost 100% encapsulation efficiency was observed. The obtained SEM and AFM data revealed non-spherical shaped nanoparticles. From DSC and X-ray diffraction studies, it was shown that the lipid recrystallized in the solid state possessing a less ordered structure as compared to the bulk material. The release study of active-loaded NLC gel formulations using Franz diffusion cells revealed that the type of lipid matrix affects both the rate and the release pattern. The viscoelastic measurements revealed a more elastic than viscous behaviour of NLC formulations indicating a typical gel-like structure.     

Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles

Aqueous dispersions of solid lipid nanoparticles (SLN) show some interesting features in topical drug delivery. However, to get a semisolid carrier having the appropriate consistency for topical application, the liquid SLN dispersions have to be incorporated in convenient topical dosage forms like hydrogels or creams. This is a time-consuming production process with several disadvantages. A new one-step production process delivering a semisolid topical formulation including SLN is presented avoiding these disadvantages. The semisolid SLN dispersions were produced by high-pressure homogenization using an APV Lab 40 homogenizer. The resulting dispersions were characterized concerning their particle size and rheological properties. Despite the high lipid content of the SLN dispersions, they retained their colloidal particle size. Viscoelastic measurements proved the existence of a gel-like structure with a prevailing elastic component.