Characterisation of surface-modified solid lipid nanoparticles (SLN): influence of lecithin and nonionic emulsifier.

Solid lipid nanoparticles (SLN), an alternative colloidal drug delivery system to polymer nanoparticles, emulsions and liposomes, are generally produced by high pressure melt-emulsification. However, the harsh production process is not applicable for formulations containing shear and temperature sensitive compounds. For that reason, subsequent adsorptive SLN loading might be a promising alternative. The aim of the present study was the development and characterisation of surface-modified SLN for adsorptive protein loading by variation of both the lipid matrix and the emulsifier concentration in the continuous phase. Variations in SLN composition resulted in particle sizes between 674 and 61 nm corresponding to specific surfaces of 4.5 m(2)/g and 48.9 m(2)/g and zeta potentials between -23.4 mV and -0.9 mV. In dependence of SLN surface properties, albumin payload ranged from 2.5 to 15%. Thermoanalysis, X-ray diffraction and electron microscopy revealed anisometrical and crystalline particles. In vitro cytotoxicity was low in terms of both haemolysis, which was between 1 and 2%, and neutral red test (NRT) showing a half lethal dose between 1.1 and 4.6%.     

Cyclosporine-loaded solid lipid nanoparticles (SLN): drug-lipid physicochemical interactions and characterization of drug incorporation.

Solid lipid nanoparticles (SLN) were produced loaded with cyclosporine A in order to develop an improved oral formulation. In this study, the particles were characterized with regard to the structure of the lipid particle matrix, being a determining factor for mode of drug incorporation and drug release. Differential scanning calorimetry (DSC) and wide-angle X-ray scattering (WAXS) measurements were employed for the analysis of the polymorphic modifications and mode of drug incorporation. Particles were produced using Imwitor 900 as lipid matrix (the suspension consisted of 10% particles, 8% Imwitor 900, 2% cyclosporine A), 2.5% Tagat S, 0.5% sodium cholate and 87% water. DSC and WAXS were used to analyse bulk lipid, bulk drug, drug incorporated in the bulk and unloaded and drug-loaded SLN dispersions. The processing of the bulk lipid into nanoparticles was accompanied by a polymorphic transformation from the beta to the alpha-modification. After production, the drug-free SLN dispersions converted back to beta-modification, while the drug-loaded SLN stayed primarily in alpha-modification. After incorporation of cyclosporine A into SLN, the peptide lost its crystalline character. Based on WAXS data, it could be concluded that cyclosporine is molecularly dispersed in between the fatty acid chains of the liquid-crystalline alpha-modification fraction of the loaded SLN.     

Crystallographic investigation of cetylpalmitate solid lipid nanoparticles

Solid lipid nanoparticles (SLN) as alternative intravenous colloidal drug carriers were produced by high pressure homogenisation of the melted lipid cetylpalmitate. The crystallographic properties of the used cetylpalmitate SLN were characterised by small angle X-ray scattering (SAXS) and X-ray diffraction (XRD). It was found that the SLN are available exclusively in a crystalline form. Different cetylpalmitate formulations showed all the same patterns and a uniform crystal lattice was obtained. A partial indexing of the signals of the cetylpalmitate was carried out and the unit cell of the cetylpalmitate was estimated by the Miller indices. A preferred orientation in 001-direction was observed. This can be explained by an impressive lamellar lattice structure of the cetylpalmitate. The results were compared with the crystal data of cetylpalmitate known from literature. There was no correlation with the monoclinic structure known so far. This could indicate that the SLN consist of crystallites of another modification of the cetylpalmitate.     

Influence of the formulation for solid lipid nanoparticles prepared with a membrane contactor

Solid lipid nanoparticles (SLN) were introduced in the 1990s as an alternative to microemulsions, polymeric nanoparticles, and liposomes. The SLN are reported to have several advantages, i.e., their biocompatibility and their controlled and targeted drug release. In this paper, we present a new process for the preparation of SLN using a membrane contactor to allow large scale production. The lipid phase is pressed, at a temperature above the melting point of the lipid, through the membrane pores allowing the formation of small droplets. The lipid droplets are then detached from the membrane pores by the aqueous phase flowing tangentially to the membrane surface. The SLN are formed by the following cooling of the preparation below the lipid melting point. The influence of the aqueous phase and lipid phase formulations on the lipid phase flux and on the SLN size are studied. It is shown that SLN are obtained with a lipid phase flux between 0.21 and 0.27 m3/h.m2, SLN size between 175 and 260 nm. The advantages of this new process are demonstrated to be its facility of use and its scaling-up ability.     

Effect of colloidal carriers on ascorbyl palmitate stability.

Active compounds can be protected against degradation by incorporation into colloidal carrier systems. The stabilizing effect of carrier systems for ascorbyl palmitate (AP) was investigated using microemulsions (ME), liposomes and solid lipid nanoparticles (SLN). Analysis of chemical stability by HPLC showed that AP is most resistant against oxidation in non-hydrogenated soybean lecithin liposomes, followed by SLN, w/o and o/w ME, and hydrogenated soybean lecithin liposomes. The molecular environment of the AP-like nitroxide probe (C(16)-Tempo) in colloidal carriers was characterized using electron paramagnetic resonance (EPR) spectroscopy. We have found that the nitroxide groups are located in environments with different polarity and mobility. The hydrophilic part of AP is the reactive moiety, and high stability is obtained in systems in which this part is exposed to a less polar environment. Additionally, the determined accessibility of nitroxide groups to reduction correlated well with the chemical stability of AP. It is more deeply immersed in the interface when entrapped in a liquid-state carrier than when applied in gel-state particles. Encapsulation of AP in SLN core leads to greater stability. We conclude that the location of the sensitive group of the drug-molecule in a carrier system is crucial for its stability.     

A comparison between spray drying and spray freeze drying for dry powder inhaler formulation of drug-loaded lipid-polymer hybrid nanoparticles

Lipid-polymer hybrid nanoparticles - polymeric nanoparticles enveloped by lipid layers - have emerged as a potent therapeutic nano-carrier alternative to liposomes and polymeric nanoparticles. Herein we perform comparative studies of employing spray drying (SD) and spray freeze drying (SFD) to produce inhalable dry-powder form of drug-loaded lipid-polymer hybrid nanoparticles. Poly(lactic-co-glycolic acid), lecithin, and levofloxacin are employed as the polymer, lipid, and drug models, respectively. The hybrid nanoparticles are transformed into micro-scale nanoparticle aggregates (or nano-aggregates) via SD and SFD, where the effects of (1) different excipients (i.e. mannitol, polyvinyl alcohol (PVA), and leucine), and (2) nanoparticle to excipient ratio on nano-aggregate characteristics (e.g. size, flowability, aqueous reconstitution, aerosolization efficiency) are examined. In both methods, PVA is found more effective than mannitol for aqueous reconstitution, whereas hydrophobic leucineis needed to achieve effective aerosolization as it reduces nano-aggregate agglomeration. Using PVA, both methods are equally capable of producing nano-aggregates having size, density, flowability, yield and reconstitutibility in the range ideal for inhaled delivery. Nevertheless, nano-aggregates produced by SFD are superior to SD in terms of their aerosolization efficiency manifested in the higher emitted dose and fine particle fraction with lower mass median aerodynamic diameter.     

Influence of the Formulation for Solid Lipid Nanoparticles Prepared with a Membrane Contactor

Solid lipid nanoparticles (SLN) were introduced in the 1990s as an alternative to microemulsions, polymeric nanoparticles, and liposomes. The SLN are reported to have several advantages, i.e., their biocompatibility and their controlled and targeted drug release. In this paper, we present a new process for the preparation of SLN using a membrane contactor to allow large scale production. The lipid phase is pressed, at a temperature above the melting point of the lipid, through the membrane pores allowing the formation of small droplets. The lipid droplets are then detached from the membrane pores by the aqueous phase flowing tangentially to the membrane surface. The SLN are formed by the following cooling of the preparation below the lipid melting point. The influence of the aqueous phase and lipid phase formulations on the lipid phase flux and on the SLN size are studied. It is shown that SLN are obtained with a lipid phase flux between 0.21 and 0.27 m^3/h.m², SLN size between 175 and 260 nm. The advantages of this new process are demonstrated to be its facility of use and its scaling-up ability.     

Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products

Solid lipid nanoparticles (SLN) are distinguishable from nanostructured lipid carriers (NLC) by the composition of the solid particle matrix. Both are an alternative carrier system to liposomes and emulsions. This review paper focuses on lipid nanoparticles for dermal application. Production of lipid nanoparticles and final products containing lipid nanoparticles is feasible by well-established production methods. SLN and NLC exhibit many features for dermal application of cosmetics and pharmaceutics, i.e. controlled release of actives, drug targeting, occlusion and associated with it penetration enhancement and increase of skin hydration. Due to the production of lipid nanoparticles from physiological and/or biodegradable lipids, this carrier system exhibits an excellent tolerability. The lipid nanoparticles are a "nanosafe" carrier. Furthermore, an overview of the cosmetic products currently on the market is given and the improvement of the benefit/risk ratio of the topical therapy is shown.     

Solid lipid nanoparticles: production, characterization and applications

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.     

Solid lipid nanoparticles: Production,characterization and applications

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.     

Solid lipid nanoparticles (SLNTM/LipopearlsTM) a pharmaceutical and cosmetic carrier for the application of vitamin E in dermal products

Solid lipid nanoparticles (SLNTM, LipopearlsTM) are nanoparticles made from solid lipids by highpressurehomogenization. Incorporation of chemically labile active ingredients intothe solid lipid matrix protects against chemical degradation, which is shown for vitamin E. The SLN are physically stable in aqueous dispersions and also after incorporation into a dermal cream as proven by photon correlation spectroscopy and differential scanning calorimetry. Electron microscopy and atomic force microscopy data reveal the spherical shape of the SLN and the detailed structure of the particle surface. Ultrafine particles form an adhesive film leading to an occlusive effect on the skin. The occlusion promotes the penetration of vitamin E into the skin, as shown by the stripping test. In addition to chemical stabilization of active ingredients, occlusive effects on the skin and subsequent enhanced penetration of compounds, the SLN also possess a pigment effect covering undesired colours leading to an increased aesthetic acceptance by the customer.     

Solid lipid nanoparticles (SLN/Lipopearls)--a pharmaceutical and cosmetic carrier for the application of vitamin E in dermal products

Solid lipid nanoparticles (SLN, Lipopearls) are nanoparticles made from solid lipids by high pressure homogenization. Incorporation of chemically labile active ingredients into the solid lipid matrix protects against chemical degradation, which is shown for vitamin E. The SLN are physically stable in aqueous dispersions and also after incorporation into a dermal cream as proven by photon correlation spectroscopy and differential scanning calorimetry. Electron microscopy and atomic force microscopy data reveal the spherical shape of the SLN and the detailed structure of the particle surface. Ultrafine particles form an adhesive film leading to an occlusive effect on the skin. The occlusion promotes the penetration of vitamin E into the skin, as shown by the stripping test. In addition to chemical stabilization of active ingredients, occlusive effects on the skin and subsequent enhanced penetration of compounds, the SLN also possess a pigment effect covering undesired colours leading to an increased aesthetic acceptance by the customer.     

Physicochemical investigations on the structure of drug-free and drug-loaded solid lipid nanoparticles (SLN) by means of DSC and 1H NMR

A solid lipid nanoparticle (SLN) formulation, based on the lipid Imwitor 900, was developed for the incorporation of the poorly water soluble drug RMEZ98. Physicochemical investigations were undertaken to examine the structure and physical stability of the selected lipid as colloidal dispersion in comparison to the bulk material. Using differential scanning calorimetry (DSC) and proton nuclear magnetic resonance (1H NMR) it could be assessed the influence of the incorporated drug on the structure of the lipid matrix. Investigation of mixtures of Imwitor 900 and RMEZ98 showed an increasing effect on the melting/recrystallization behaviour with increasing drug content (5-30%). DSC and 1H NMR results revealed the formation of a crystalline matrix of SLN when prepared by high pressure homogenization excluding, therefore, the phenomenon of supercooled melt. After preparation of RMEZ98-loaded SLN, the drug remained inside the lipid matrix; however, it exhibited only a small effect on the recrystallization behaviour of Imwitor 900 at the lowest payload required for a therapeutic effect (4% m/m with regard to the lipid matrix). Furthermore, the incorporation of RMEZ98 revealed no distinct influence on the particle size distribution. Imwitor 900 proved to be a suitable lipid for the drug RMEZ98, i.e. possessing a sufficient loading capacity and simultaneously physical stability.     

Physicochemical characterization of curcuminoid-loaded solid lipid nanoparticles

Curcuminoid-loaded solid lipid nanoparticles (SLN) were produced by melt-homogenization. The used lipid matrices were medium chain triglycerides, trimyristin and tristearin. The resulting nanoparticles had an anisometric shape and a platelet-like structure. Curcuminoid-loaded trimyristin particles did not solidify when stored at room temperature. The supercooled state of trimyristin was studied by DSC and ¹H NMR experiments. A partial recrystallization of the lipid matrix was detected but no change of the mobility of the lipid was noted. Nanoparticles based on tristearin had an α- and β-modification which was subsequently converted into the stable β-phase. Curcuminoids did neither influence the melting behavior nor the crystalline or geometric structure of the particles. The interactions between the curcuminoids and the lipid matrix were investigated by Raman and fluorescence spectroscopy. The shape of the curcuminoid bands in the Raman spectra suggested that the drug was in an amorphous state. The fluorescence spectra showed an effect of the lipid matrix on fluorescence properties of the curcuminoids. It was further demonstrated that the drug was not secluded by the solid lipid matrix, but it was influenced by the surrounding aqueous environment. Fluorescence anisotropy measurements revealed a decreased mobility of the curcuminoids within the nanodispersions. From the results of Raman and fluorescence measurements it was concluded that the drug was mainly located on the surface of the crystalline particles.     

Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art.

Solid lipid nanoparticles (SLN) introduced in 1991 represent an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes and polymeric micro- and nanoparticles. SLN combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews the present state of the art regarding production techniques for SLN, drug incorporation, loading capacity and drug release, especially focusing on drug release mechanisms. Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are also discussed. The potential of SLN to be exploited for the different administration routes is highlighted. References of the most relevant literature published by various research groups around the world are provided.     

Solid lipid nanoparticles (SLN) as carriers for the topical delivery of econazole nitrate: in-vitro characterization, ex-vivo and in-vivo studies

Solid lipid nanoparticles (SLN) designed for topical administration of econazole nitrate (ECN), were prepared by o/w high-shear homogenization method using different ratios of lipid and drug (5:1 and 10:1). SLN were characterized in terms of particle size, morphology, encapsulation efficiency and crystalline structure. After incorporation of SLN into hydrogels, rheological measurements were performed, and ex-vivo drug permeation tests were carried out using porcine stratum corneum (SC). In-vivo study of percutaneous absorption of ECN as a function of application time and composition of gels was carried out by tape-stripping technique. Penetration tests of the drug from a conventional gel were performed as comparison. High-shear homogenization method resulted in a good technique for preparation of ECN-loaded SLN. Particles had a mean diameter of about 150 nm and a regular shape and smooth surface. The encapsulation efficiency values were about 100%. Ex-vivo tests showed that SLN were able to control the drug release through the SC; the release rate depended upon the lipid content on the nanoparticles. In-vivo studies demonstrated that SLN promoted a rapid penetration of ECN through the SC after 1 h and improved the diffusion of the drug in the deeper skin layers after 3 h of application compared with the reference gel.     

Formation of ion pairing as an alternative to improve encapsulation and stability and to reduce skin irritation of retinoic acid loaded in solid lipid nanoparticles

This work aims to investigate the influence of the formation of ion pairing between all-trans retinoic acid (RA) and a lipophilic amine (stearylamine; STE) on the drug encapsulation efficiency (EE) and stability of solid lipid nanoparticles (SLNs). The SLNs were characterized for EE and size. The EE and particle size were significantly improved and reduced, respectively, when the surfactant or co-surfactant concentration increased. However, while the formulation without STE allowed only 13% of RA encapsulation, the EE for RA–STE-loaded SLNs was 94%. The stability studies showed a significant decrease in EE for the SLNs without STE, while, for SLNs loaded with RA and STE, the EE remained constant after 360 days. The interactions among ion pairing components and the lipid matrix were investigated through small-angle X-ray scattering (SAXS). The SAXS analysis revealed the presence of RA in the crystalline form in SLNs without ion pairing, while crystalline RA was not observed in SLNs loaded with RA/amine. Skin irritation studies showed that the SLNs loaded with the ion pairing were significantly less irritating when compared to the marketed RA-cream. This novel SLN formulation represents a promising alternative for topical treatment of acne with RA.     

麦角甾苷固体脂质纳米粒处方筛选和理化性质研究

目的 研究不同种类药用辅料成分对麦角甾苷固体脂质纳米粒（SLN）理化性质的影响,为研究SLN的处方筛选提供依据。方法 采用乳化-固化法制备麦角甾苷-SLN,单一变量法考察山嵛酸甘油酯（Compritol ATO 888）、单硬脂酸甘油酯、大豆卵磷脂、Myrj52等辅料对麦角甾苷-SLN粒径、包封率、表征分散度（PDI）等理化性质的影响,采用透射电镜法观察麦角甾苷-SLN的形态,X-射线衍射（XRD）分析其药物晶体结构。结果 随Compritol ATO 888用量增加,麦角甾苷-SLN粒径不断减小,包封率逐渐减小,PDI逐渐增加;随单硬脂酸甘油酯的用量增加,粒径明显增大,包封率略有降低,PDI减小;随卵磷脂用量增加,粒径明显增大,包封率降低,PDI减小;随Myrj52用量明显增加,粒径减小,包封率增加,PDI增大;麦角甾苷-SLN外观圆整,呈球形;麦角甾苷以分子分散状态被包裹在SLN中。结论 不同辅料对麦角甾苷-SLN的理化性质均产生一定影响趋势,为制备SLN的处方筛选研究提供启示与思路。     

微乳化技术制备固体脂质纳米粒微乳化技术制备固体脂质纳米粒

目的采用微乳化技术制备固体脂质纳米粒（SLN）。方法以硬脂酸为油相，卵磷脂为乳化剂，乙醇为助乳化剂，蒸馏水为水相，按不同比例混合制备微乳。通过改变卵磷脂与乙醇的配比（K_m），绘制出不同K_m值下的三元相图。从中选择适宜的微乳，将其分散于冷水中制备SLN。考察了工艺因素和处方因素对SLN制备和SLN质量的影响。在单因素考察的基础上，采用正交设计优化工艺，并对优化所得的工艺进行重现性考察。结果水相温度（T_w）、微乳的温度（T_i）、微乳注入速度（r_d）均直接影响SLN的制备，其中水相温度是影响SLN质量的重要因素；微乳各组分的配比、微乳与水相的比例也对SLN的质量有一定影响。结论微乳化技术制备固体脂质纳米粒是可行的。     

Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization,pharmacokinetic and pharmacodynamic evaluation

Abstract

Candesartan cilexetil (CC) is used in the treatment of hypertension and heart failure. It has poor aqueous solubility and low oral bioavailability. In this work, CC loaded solid lipid nanoparticles (CC-SLNs) were developed to improve the oral bioavailability. Components of the SLNs include either of trimyristin/tripalmitin/tristearin, and surfactants (Poloxamer 188 and egg lecithin E80). The CC loaded nanoparticles were prepared by hot homogenization followed by ultrasonication method. The physicochemical properties, morphology of CC-SLNs were characterized, the pharmacokinetic and pharmacodynamic behaviour of CC-SLNs were evaluated in rats. Stable CC-SLNs having a mean particle size of 180–220?nm with entrapment efficiency varying in between 91–96% were developed. The physical stability of optimized formulation was studied at refrigerated and room temperature for 3 months. Further, freeze drying was tried for improving the physical stability. DSC and XRD analyses indicated that the drug incorporated into SLN was in amorphous form but not in crystalline state. The SLN-morphology was found to be nearly spherical by electron microscopic studies. Pharmacokinetic results indicated that the oral bioavailability of CC was improved over 2.75-fold after incorporation into SLNs. Pharmacodynamic study of SLNs in hypertensive rats showed a decrease in systolic blood pressure for 48?h, while suspension showed a decrease in systolic blood pressure for only 2?h. Taken together, these effects are due to enhanced bioavailability coupled with sustained action of CC in SLN formulation. Thus, the results conclusively demonstrated the role of CC-SLNs for a significant enhancement in oral bioavailability along with improved pharmacodynamic effect.