Semisolid SLN dispersions for topical application: influence of formulation and production parameters on viscoelastic properties.

Aqueous solid lipid nanoparticle (SLN) dispersions with a high lipid content up to 35% and viscous to semisolid consistency were produced by a high pressure homogenization process. Despite their high lipid content and viscosity these dispersions preserved their colloidal size range. The SLN dispersions were compared to nanoemulsions and microparticle dispersions with regard to particle size, viscoelastic properties and formation of a semisolid gel structure. Viscoelastic measurements including oscillation stress sweep tests and oscillation frequency sweep tests demonstrated that the existence of a solid particle matrix with a particle size in the nanometer range is a prerequisite to form a semisolid dispersion having the appropriate consistency for topical application. Striking differences were observed between solid lipid micro- and nanodispersions of the same composition. Particle size reduction resulted in an 80-fold increase of the elastic modulus. Particle size distribution, the physical state of the dispersed lipid phase and the emulsifier concentration have been identified as further key factors for the viscoelastic properties and gel structure of the lipid nanodispersions. By conducting oscillation measurements it was possible to relate the stability of lipid dispersions to specific rheological parameters therefore providing a sensitive tool in stability assessment. Changing the production process from a 40 ml batch to a 2 l batch turned out to have an influence on the colloidal structures of semisolid SLN dispersions. Consistency increased but particle size and ratio of elastic to viscous properties stayed in the same range.     

Transformation of vesicular into cubic nanoparticles by autoclaving of aqueous monoolein/poloxamer dispersions.

The ultrastructure of aqueous colloidal dispersions of the cubic monoolein/poloxamer 407/water phase, in particular the particle size distribution and presence of an additional vesicular fraction, highly depends on composition and preparation parameters. Therefore, the effect of autoclaving on such dispersions was investigated. Before autoclaving at 121 degrees C, a dispersion of 4.6% monoolein/0.4% poloxamer predominantly consists of cubic particles beside a fraction of non-cubic particles. The small vesicular particles disappear almost completely upon autoclaving whereas larger particles with cubic structure remain in the sample. In contrast, a 4.4% monoolein/0.6% poloxamer dispersion contains predominantly small vesicular particles before heat treatment. After autoclaving, the majority of the particles is larger and of cubic structure and only a few small non-cubic particles remain. The effect can already be observed at short autoclaving times (e.g., 5 min) but a temperature of at least 90 degrees C is required to induce a major change in the ultrastructure. Results from temperature dependent small angle X-ray diffraction investigations indicate that temperatures corresponding to an isotropic phase are required for particle transformation. Heat treatment of monoolein/poloxamer dispersions can thus be used to transform vesicular dispersions into dispersions of cubic phase or to improve the cubic/non-cubic particle ratio in dispersions already containing particles with cubic internal structure.     

Lipid nanocapsule size analysis by hydrodynamic chromatography and photon correlation spectroscopy

Particle size and the size distribution are known to be important factors in the overall behavior of nanoparticulate drug delivery systems and an exact determination of these parameters is highly important. Several techniques are applied in the size determination of nanoparticulates, particularly dynamic light scattering. Also other methods have been proposed, among them hydrodynamic chromatography (HDC). In order to characterize a HDC method for nanosized carriers, differently sized lipid nanocapsules having a diameter of 25–100 nm were analyzed and results were compared with measurements from photon correlation spectroscopy (PCS) and atomic force microscopy. Results from atomic force microscopy studies were generally not in line with determinations from the other techniques due to a particle shape loss by the drying step. PCS and HDC led to comparable results in simple size determination of lipid nanocapsules. However, slight differences were found during the characterization of more complex samples. HDC was able to detect micelles as a byproduct of nanocapsule preparation while in PCS the sample dilution turned micelles undetectable. HDC analysis was able to characterize mixed samples of particle batches differing in their average size similar to PCS. HDC was found to be an excellent tool for the determination of size and average size distribution of lipid nanocapsules.     

Influence of preparation conditions and heat treatment on the properties of supercooled smectic cholesteryl myristate nanoparticles.

Colloidal dispersions of cholesterol esters in the supercooled smectic state are under investigation as a novel drug carrier system in particular with respect to parenteral application. In the present study, suitable conditions for the homogenization of cholesteryl myristate dispersions stabilized with a phospholipid/bile salt blend were evaluated. For effective particle size reduction homogenization with high pressure and at temperatures above the melting temperature of the cholesterol ester (isotropic melt) is necessary. Homogenization at lower temperature where the matrix lipid is in the smectic state is less effective even when applying the highest homogenization pressure possible but still leads to dispersions with particles in the colloidal size range. Since sterility is required for parenteral medications and is usually achieved by autoclaving for aqueous systems, the physical and chemical stability of cholesteryl myristate nanoparticles stabilized with different surface active agents during heat treatment was investigated as well. The dispersions were characterized by particle size and zeta potential measurements, differential scanning calorimetry (DSC) and high performance thin layer chromatography (HPTLC). The results indicate that cholesteryl myristate nanoparticles stabilized with phospholipid/sodium glycocholate, polyvinyl alcohol, poloxamer and poloxamine can be sterilized by autoclaving. Compared to cholesterol ester free dispersions of phospholipids, the phospholipid seems to be more stable against hydrolysis during prolonged heat treatment in the phospholipid/bile salt containing cholesteryl myristate dispersions.     

The toxicological mode of action and the safety of synthetic amorphous silica-a nanostructured material

Synthetic amorphous silica (SAS), in the form of pyrogenic (fumed), precipitated, gel or colloidal SAS, has been used in a wide variety of industrial and consumer applications including food, cosmetics and pharmaceutical products for many decades. Based on extensive physico-chemical, ecotoxicology, toxicology, safety and epidemiology data, no environmental or health risks have been associated with these materials if produced and used under current hygiene standards and use recommendations. With internal structures in the nanoscale size range, pyrogenic, precipitated and gel SAS are typical examples of nanostructured materials as recently defined by the International Organisation for Standardisation (ISO). The manufacturing process of these SAS materials leads to aggregates of strongly (covalently) bonded or fused primary particles. Weak interaction forces (van der Waals interactions, hydrogen bonding, physical adhesion) between aggregates lead to the formation of micrometre (μm)-sized agglomerates. Typically, isolated nanoparticles do not occur. In contrast, colloidal SAS dispersions may contain isolated primary particles in the nano-size range which can be considered nano-objects. The size of the primary particle resulted in the materials often being considered as "nanosilica" and in the inclusion of SAS in research programmes on nanomaterials. The biological activity of SAS can be related to the particle shape and surface characteristics interfacing with the biological milieu rather than to particle size. SAS adsorbs to cellular surfaces and can affect membrane structures and integrity. Toxicity is linked to mechanisms of interactions with outer and inner cell membranes, signalling responses, and vesicle trafficking pathways. Interaction with membranes may induce the release of endosomal substances, reactive oxygen species, cytokines and chemokines and thus induce inflammatory responses. None of the SAS forms, including colloidal nano-sized particles, were shown to bioaccumulate and all disappear within a short time from living organisms by physiological excretion mechanisms with some indications that the smaller the particle size, the faster the clearance is. Therefore, despite the new nomenclature designating SAS a nanomaterial, none of the recent available data gives any evidence for a novel, hitherto unknown mechanism of toxicity that may raise concerns with regard to human health or environmental risks. Taken together, commercial SAS forms (including colloidal silicon dioxide and surface-treated SAS) are not new nanomaterials with unknown properties, but are well-studied materials that have been in use for decades.     

Relationship between dissolution and bioavailability for nimodipine colloidal dispersions: the critical size in improving bioavailability

To compare the dissolution and bioavailability for nimodipine microcrystals and nanocrystals, and to determine the critical size range in improving the oral absorption of nimodipine. Nimodipine microcrystals and nanocrystals were prepared using a microprecipitation method. The particle size was determined with a laser diffraction method. X-ray powder diffraction was applied to inspect the potential crystal form transition. The aqueous solubility was determined by shaking flasks, and the dissolution behavior was evaluated using the paddle method. The pharmacokinetics was performed in beagle dogs in a crossover experimental design. Three nimodipine colloidal dispersions (16296.7, 4060.0 and 833.3 nm) were prepared, respectively. Nimodipine had undergone crystal form transition during microprecipitation process, but experienced no conversion under the high-pressure homogenization. The colloidal dispersions did not show any difference in aqueous equilibrium solubility. Additionally, the three formulations also displayed similar dissolution curves in purified water and 0.05% SDS. The AUC for dispersions of 4060.0 and 833.3 nm sizes was 1.69 and 2.59-fold higher than that for 16296.7 nm system in dogs. To sum up, the critical particle size was found to be within the range of 833.3-4060.0 nm (average volume-weighted particle size) in improving the bioavailability of nimodipine, and dissolution performance was not an effective index in evaluating the bioavailability for nimodipine colloidal dispersions.     

Two-time window and multiangle photon correlation spectroscopy size and zeta potential analysis--highly sensitive rapid assay for dispersion stability

Polysaccharide-stabilized iron oxide particles are highly potent contrast agents in magnetic resonance imaging. After intravenous injection, the size of these small or ultrasmall particles strongly influences their distribution in the body. Knowledge about the uniformity of particle size distribution within this particle size range is not accessible by laser diffraction (lower edge of detection range), and photon correlation spectroscopy (PCS) data only yield insufficient information, the so-called polydispersity index. A combination of two-time window and multiangle analysis makes detailed characterization of particle size distribution and particle aggregation feasible, which was shown using five different iron oxide dispersions. Additional particle charge characterization yielded conclusions about the type of stabilization present in the dispersion - electrostatic or steric stabilization. Thus, this thorough particle size and charge analysis is a tool for quick detection of broad particle distributions or aggregates.     

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.     

水动力学色谱及其在微粒制剂评价中的应用进展

本文在介绍流体动力学色谱中应用最广泛的水动力色谱基本原理、装置和分析方法的基础上,综述了水动力色谱在微粒制剂粒径测定及其分布估算方面的应用。该方法在快速测定纳米、微米尺度颗粒的粒径方面具有经济、便捷和无损伤等独特的优势,在微粒制剂粒径分布特征检测上具有良好的应用前景。     

Method transfer for fast liquid chromatography in pharmaceutical analysis: application to short columns packed with small particle. Part I: isocratic separation.

Liquid chromatography (LC) is considered to be the gold standard in pharmaceutical analysis. Today, there is a need for fast and ultra-fast methods with good efficiency and resolution for achieving separations in few minutes or even seconds. The present work describes a simple methodology for performing a successful method transfer from conventional LC to fast and ultra-fast LC. In order to carry out fast separations, short columns (20-50mm) packed with small particles (3.5 and 1.7 microm) were used and their chromatographic performance was compared to that of a conventional column (150 mm, 5 microm). For that purpose, an optimized LC system was employed to limit extra-column volumes which can have a dramatic impact on efficiency and resolution. This paper reports the fundamental equations used for transferring an isocratic chromatographic separation performed with a given column geometry and chemistry to a smaller column packed with similar or identical stationary phase, without influence on chromatographic performance. For this purpose, the flow rate and the injected volume need to be adapted. The effect of column length and particle size reduction on chromatographic resolution and analysis time was described for an isocratic separation. Using the method transfer equations, it is possible to predict the new conditions to be used, for fast and ultra-fast separations. In this work, ultra-fast separations were achieved thanks to a new generation of instrumentation (ultra performance liquid chromatography, UPLC) which uses simultaneously short column packed with sub-2 microm particles and ultra-high pressure (up to 1000 bar). This work demonstrates an analysis time reduction up to a factor 12, compared to a conventional LC separation, without affecting the quality of separation. Therefore, the complete resolution of a pharmaceutical formulation was achieved in only a few seconds.     

Preparation of nanoemulsions and solid lipid nanoparticles by premix membrane emulsification

In an attempt to overcome problems of conventional high-energy preparation processes for colloidal drug carrier systems, premix membrane emulsification was investigated for the first time as an alternative low-energy input process for the preparation of pharmaceutical nanoemulsions and solid lipid nanoparticles. The effect of process parameters on dispersions based on nonpolar lipids (medium-chain triglycerides, soybean oil, and trimyristin) and different emulsifiers (sodium dodecyl sulfate, poloxamer 188, polyglyceryl-10-laurate, and sucrose laurate) was studied in a small-volume device and a larger scale-up approach. For emulsions and suspensions, mean particle sizes in a range from about 100 to 200 nm were observed for monomodal to monodisperse particle size distributions after 21 cycles of extrusion through polycarbonate membrane filters. As the mass ratio of matrix lipid to emulsifier (4:3, w/w concentrations) usually applied for the preparation of stable colloidal lipid particles was quite high, the amount of emulsifier in the dispersions was minimized. It was observed that the minimal concentration of emulsifier increased with decreasing membrane pore size. The possibility to prepare colloidal drug carrier systems with a high concentration of matrix lipid (up to 20%) by an optimized membrane extrusion process offers new opportunities for the processing of sensitive substances.     

Design of a Re-Dispersible High Drug Load Amorphous Formulation

Amorphous solid dispersions (ASD) are a commonly used enabling formulation technology to drive oral absorption of poorly soluble drugs. To ensure adequate solid-state stability and dissolution characteristics, the ASD formulation design typically has ≤ 25% drug loading. Exposed to aqueous media, ASD formulations can produce drug-rich colloidal dispersion with particle size < 500 nm. This in situ formation of colloidal particles requires incorporation of excess excipients in the formulation. The concept of using engineered drug-rich particles having comparable size as those generated by ASDs in aqueous media is explored with the goal of increasing drug loading in the solid dosage form. Utilizing ABT-530 as model compound, a controlled solvent-antisolvent precipitation method resulted in a dilute suspension that contained drug-rich (90% (w/w)) amorphous nanoparticles (ANP). The precipitation process was optimized to yield a suspension containing < 300 nm ANP. A systematic evaluation of formulation properties and process variables resulted in the generation of dry powders composed of 1–8 µm agglomerates of nanoparticles which in contact with water regenerated the colloidal suspension having particle size comparable to primary particles. Thus, this work demonstrates an approach to designing a re-dispersible ANP based powder containing ≥90% w/w ABT-530 that could be used in preparation of a high drug load solid dosage form.     

Preparation of dextran glassy particles through freezing-induced phase separation

The aim of the present study was to experimentally examine whether poorly water-soluble drugs dispersed in a polymeric matrix exist as amorphous nanodispersions or molecularly dispersed compounds. Felodipine (Felo) dispersed in PVP matrix (solid dispersion) was used as a model drug in this study. Drug/polymer ratios have an impact on the drug average particle size, morphology and dissolution profile while solid dispersions containing up to 50 wt% Felo are completely amorphous. SEM, TEM micrographs, and micro-Raman mapping reveal that Felo is dispersed in the form of nanoparticles into the PVP matrix. Due to the high spatial resolution of TEM, it was established that these nanoparticles are not uniform particles, but rather agglomerates of individual particles with sizes smaller than 5–10 nm. Moreover, micro-Raman mapping allowed us to observe the size and spatial distribution of domains where the drug existed as molecularly or nanodispersed. Experimental evidence presented in this work contradicts the common belief that amorphous poorly water-soluble drugs exist only in the state of molecular dispersion inside a polymer matrix by showing that both types of dispersions (molecular-level and nanodispersions) can coexist.     

Drug release from differently structured monoolein/poloxamer nanodispersions studied with differential pulse polarography and ultrafiltration at low pressure

Aqueous colloidal monoolein/poloxamer dispersions are under investigation as drug delivery systems. Depending on the composition and preparation procedure these dispersions may either contain predominantly vesicular particles or nanoparticles of cubic inner structure. To study the influence of ultrastructure on drug release, corresponding dispersions loaded with the model drugs diazepam (two different concentrations) and chloramphenicol were prepared by high-pressure homogenization with or without subsequent heat treatment. The dispersions were characterized with regard to particle size and their ultrastructure was confirmed with small angle X-ray diffractometry. Two techniques with high time resolution, differential pulse polarography (DPP) and ultrafiltration at low pressure were compared for their suitability to monitor rapid release from the dispersions. Instantaneous release was found for both drugs independent on the type of particle structure with the amount of released drug being controlled by the partition coefficient. Both release methods were suitable to monitor the rapid appearance of the releasable drug in the release medium.     

Optimum support properties for protein separations by high-performance size exclusion chromatography

Optimum chromatographic properties of high performance size exclusion chromatography (HPSEC) of proteins, such as resolution, molecular weight accuracy and recovery, are obtained on packings and columns with tailor-made physical and chemical structures, employed at properly adjusted eluent compositions and operation conditions. SEC-theory suggests that a broad molecular weight fractionation range and high linearity of the log-linear calibration plot can be achieved by the use of two packings (10- and 80-nm pore size, characterized by a pore-size distribution (psd) equal to or less than 1 decade and by equal internal column porosity (p)), rather than a single 30- to 50-nm pore-size packing with a wide psd. Favourably high-phase ratios of (p)/(o)/ 1.0 for HPSEC columns were accomplished with a minimum interstitial column porosity (o) and a high value for the internal column porosity (p) (the specific pore volume, nu(p), multiplied by the packing density, varrho(p).) Ligands such as diol, N-acetoxyamino and oligomeric ether with a propyl- or propoxy-spacer bonded to the silica at the highest density appear to provide high mass recovery and bioactivity as well as chemical stability. Such packings, available in 3-5 mum particle size ranges of narrow distribution, packed into columns 6 mm i.d. and 500 mm in length, offer the best compromise with respect to resolution, speed and pressure drop. More careful studies are required to explain the effects of protein conformational changes and interconversions during elution on HPSEC columns.     

Efficiency of the new sub-2 μm core-shell (Kinetex™) column in practice, applied for small and large molecule separation

At present sub-2 μm packed columns are very popular to accomplish rapid and efficient separations. Applying particles with shortened diffusion path to improve the efficiency of separation performs higher efficiency than it is possible with the totally porous particles having the same size. The advantages of sub-2 μm particles and shell particles are combined in the new Kinetex 1.7 μm particles. In this study a systematical evaluation of the efficiency and achievable analysis time obtained with 5 cm long narrow bore column packed with sub-2 μm core-shell particles (1.25 μm core diameter and 0.23 μm porous silica layer), and other type very efficient columns is presented. The efficiency of separation was investigated also for small pharmaceutical and large molecules (proteins). Van Deemter, Knox and kinetic plots are calculated. The results obtained with low molecular weight polar neutral analytes (272 g/mol, 875 g/mol), with a polypeptide (4.1 kDa) and with different sized proteins (18.8 kDa, 38.9 kDa and 66.3 kDa) are presented in this study. Moreover, particle size distribution, and average pore size (low-temperature nitrogen adsorption, LTNA) of the new very fine core-shell particles were investigated. According to this study, increased flow rates can be applied on sub-2 μm core-shell columns to accomplish very fast separations without significant loss in efficiency. The new sub-2 μm shell particles offer very high efficiency both for small and large molecule separation.     

Liquid and semisolid SLN dispersions for topical application: rheological characterization.

Aqueous dispersions of solid lipid nanoparticles (SLN) are promising drug carrier systems for topical application. A drawback, however, is the need of incorporating the SLN dispersion in commonly used dermal carriers (creams, gels) to obtain the required semisolid consistency for dermal application. This study describes the production of SLN dispersions having the desired semisolid consistency by a one-step process. Physical characterization of these systems in terms of particle size and rheological properties revealed some interesting features. Despite the high lipid content it was possible to produce colloidal dispersions by high pressure homogenization. Continuous flow measurements revealed systems with yield point, plastic flow and thixotropy. Oscillation measurements proved the viscoelastic microstructure of the SLN dispersions. Higher concentrated SLN dispersions were found to have a prevailing elastic component in contrast to lower concentrated systems. Viscoelastic properties of a 40% SLN dispersion were found to be comparable to standard dermal preparations. Storage stability at room temperature in terms of particle size could be demonstrated over a 6-month period. The development of the gel structure of semisolid SLN dispersions is delayed comparable to commercial O/W creams with non-ionic emulsifiers. Parameters like concentration of the dispersed phase, particle size and particle shape were identified as significant factors influencing the microstructure of these complex semisolid systems.     

Influence of composition and preparation parameters on the properties of aqueous monoolein dispersions

Colloidal cubic phase particles formed in the monoolein/poloxamer/water system are being investigated as potential drug carriers for, e.g., intravenous administration. Preparation methods must, however, still be further developed to reliably yield monoolein dispersions with cubic particles in a size range acceptable for i.v. administration and adequate long-term stability. In this context, the influence of different composition and preparation parameters on the properties of monoolein dispersions prepared by high-pressure homogenization was studied. High pressure homogenization of coarse poloxamer 407-stabilized monoolein/water mixtures leads to dispersions with a large fraction of micrometer-sized particles at low poloxamer concentrations. Higher poloxamer concentrations lead to lower mean particle sizes but the fraction of cubic particles becomes smaller and vesicular particles are observed instead. A study of the characteristics of a dispersion with a standard composition indicated that the homogenization temperature has a much stronger influence on the dispersion properties than the homogenization pressure or the type of homogenizer used. Temperatures around 40-60 degrees C lead to the most favorable dispersion properties. The high temperature sensitivity of the preparation process appears to be at least partly correlated with the phase behavior of the dispersed particles determined by temperature-dependent X-ray diffraction.     

Effect of drug loading on the transformation of vesicular into cubic nanoparticles during heat treatment of aqueous monoolein/poloxamer dispersions.

Colloidal dispersions of the pre-equilibrated cubic phase in the monoolein/poloxamer 407/water system, which are under investigation as potential drug carriers, often contain a considerable fraction of undesired non-cubic particles, particularly when prepared with high concentrations of poloxamer. Recent investigations revealed that the non-cubic particles can be transformed into particles of cubic internal structure by heat treatment. The present study investigates the effect of drug loading on the non-cubic to cubic transformation process during autoclaving of the dispersions. The results indicate that the process can also proceed in dispersions loaded with different concentrations of ubidecarenone, tocopheryl acetate, betamethasone-17-valerate, chloramphenicol or miconazole. At low concentration, none of the drugs had pronounced influence on the autoclaved dispersions whereas with increasing drug concentration different effects were observed. Depending on the type of drug no effects (betamethasone-17-valerate), increasing particle size of the dispersions (chloramphenicol, miconazole) or phase separation upon autoclaving (high load of miconazole) was observed. Except for loading with high amounts of chloramphenicol, which led to the formation of cubic phase particles already without additional heat treatment, the properties of the thermally untreated dispersions were virtually unaffected by drug incorporation.     

Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions.

In the present study the release mechanism of the sparingly water-soluble drug felodipine (FELO) from particulate solid dispersions in PVP or PEG was investigated. FT-IR data indicated that a N-H...O hydrogen bond is formed between FELO and polymers. The drug-polymer interaction was theoretically studied with the density functional theory with the B3LYP exchange correlation function. The interaction energies have been estimated at -31.8 kJ/mol for PVP and -18.8 kJ/mol for PEG. Also, detailed vibrational analysis of the complexes showed that the red shift of the N-H bond stretching in FELO molecule due to H-bonding was higher in the FELO-PVP complex than in the FELO-PEG complex. Both the experimental and theoretical data indicated that a stronger interaction of FELO with PVP than with PEG was developed. The interactions of FELO with the polymer appeared to control the physical state (amorphous or crystalline) and the particle size of FELO in the solid dispersions. In the FELO/PVP dispersions, the drug is found as amorphous nanoparticles whereas in FELO/PEG dispersions the drug is dispersed as crystalline microparticles. The size of drug particles in the dispersion was also influenced by drug proportion, with an increase in drug content of the dispersion resulting in increased drug particle size. The particle size of drug, the proportion of drug in the dispersion and the properties of the polymer (molecular weight) appeared to determine the mechanism of drug release from the solid dispersions, which was drug diffusion (through the polymer layer)-controlled at low drug contents and drug dissolution-controlled at high drug contents. In situ DLS measurements indicate that the large initial particles of FELO/PVP and FELO/PEG solid dispersions with low drug content (10-20 wt%) are very rapidly decreased to smaller particles (including nanoparticles) during dissolution, leading to the observed impressive enhancement of FELO release rate from these dispersions.