Kirsten Westesen

Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential

Abstract Drug carrier systems based on lipid nanosuspensions prepared by melt emulsification present a number of severe stability problems such as a high gelation tendency, considerable particle growth and drug expulsion. Destabilization of the emulsified lipidic carriers is related to recrystallization of the lipids. The choice of stabilizers for colloidal lipid suspensions is, therefore, restricted. Systematic surface modifications are thus limited. In addition, the drug payload of crystalline nanosuspension particles is generally low. Improved stability and loading capacities were found for amorphous lipid nanoparticles which present the characteristic signals of supercooled melts in high resolution 1 H-NMR. The NMR data indicate that such liquid but viscous carriers can, however, not immobilize the incorporated drug molecules to the same extent as a solid matrix. Sustained release over days or weeks as in slowly biodegraded solid matrices thus seems difficult to achieve with a supercooled melt. Attempts to combine the advantages of the solid crystalline lipids and the amorphous nature of the supercooled melts by generating solid but amorphous lipid suspension particles with a satisfactory long-term stability by a variation of the lipid matrix material have hitherto not been successful. Even a satisfactory stabilization of the α-modification using complex lipid mixtures to improve the loading capacity or to slow down the drug expulsion process could not be achieved. The rates of the polymorphic transitions were much higher in the colloidal lipid dispersions than in the bulk for the hard fats under investigation. Despite the fact that the properties of the lipids are superimposed with colloidal properties, significant differences between monoacid triglycerides and complex lipids were, however, found.

Crystallization tendency and polymorphic transitions in triglyceride nanoparticles

The ability of tristearin, tripalmitin, trimyristin and trilaurin to form solid lipid nanoparticles after melt-homogenization is investigated by DSC and X-ray diffraction. Upon storage at common temperatures after preparation solid nanoparticles are formed in tristearin and tripalmitin dispersions. In contrast to literature reports, colloidal dispersions of trilaurin do not form solid particles under those conditions. They should, therefore, be regarded as emulsions of supercooled melts rather than as nanosuspensions. Trimyristin nanoparticles which can be obtained in solid or liquid form have a larger incorporation capacity for the lipophilic model drug menadione in the liquid than in the solid state. The kinetics of polymorphic transitions after crystallization of triglyceride nanoparticles are slower for longer-chain than for shorter-chain triglycerides. Addition of tristearin raises the crystallization temperature of colloidally dispersed trimyristin and trilaurin facilitating solidification during production. The structure and melting behavior of the resulting mixed nanoparticles are more complex than those of nanoparticles prepared from the simple triglycerides. Depending on the mixing ratio, the time-course of polymorphic transitions after crystallization may also be altered significantly. The melting enthalpy of the mixed nanoparticle dispersions is usually not significantly different from that of dispersions of the simple triglycerides.

Incorporation of the Model Drug Ubidecarenone into Solid Lipid Nanoparticles

AbstractPurpose. The impact of drug incorporation on melt-homogenized tripalmitin nanoparticles is investigated with ubidecarenone as a model drug. The dispersions are studied with respect to their drug loading capacity, localization and physical state of the drug as well as to potential changes of the nanoparticle properties due to interactions between drug and triglyceride matrix.nMethods. The investigations were carried out using photon correlation spectroscopy, differential scanning calorimetry, synchrotron radiation X-ray diffraction, ultracentrifugation, and cryo- and freeze-fracture transmission electron microscopy.nResults. Ubidecarenone can be incorporated into the dispersions in concentrations higher than 50% of the dispersed phase. The drug is associated with the nanoparticles such that small drug amounts are bound tightly to the carrier matrix while excess drug adheres as a liquid phase to the crystalline particles. Drug incorporation lowers the crystallization and melting temperature of the particle matrix and accelerates the transition of the triglyceride into the stable β-polymorph after crystallization.nConclusions. Drug incorporation may significantly alter important physicochemical parameters of solid lipid nanoparticles. Slow release of ubidecarenone may only be possible for the fraction of drug which is tightly bound to the matrix while the liquid fraction should be rapidly released.

Supercooled Smectic Nanoparticles: A Potential Novel Carrier System for Poorly Water Soluble Drugs

AbstractPurpose. The possibility of preparing nanoparticles in the supercooled thermotropic liquid crystalline state from cholesterol esters with saturated acyl chains as well as the incorporation of model drugs into the dispersions was investigated using cholesteryl myristate (CM) as a model cholesterol ester.nMethods. Nanoparticles were prepared by high-pressure melt homogenization or solvent evaporation using phospholipids, phospholipid/bile salt, or polyvinyl alcohol as emulsifiers. The physicochemical state and phase behavior of the particles was characterized by particle size measurements (photon correlation spectroscopy, laser diffraction with polarization intensity differential scattering), differential scanning calorimetry, X-ray diffraction, and electron and polarizing light microscopy. The viscosity of the isotropic and liquid crystalline phases of CM in the bulk was investigated in dependence on temperature and shear rate by rotational viscometry.nResults. CM nanoparticles can be obtained in the smectic phase and retained in this state for at least 12 months when stored at 23°C in optimized systems. The recrystallization tendency of CM in the dispersions strongly depends on the stabilizer system and the particle size. Stable drug-loaded smectic nanoparticles were obtained after incorporation of 10% (related to CM) ibuprofen, miconazole, etomidate, and 1% progesterone.nConclusions. Due to their liquid crystalline state, colloidal smectic nanoparticles offer interesting possibilities as carrier system for lipophilic drugs. CM nanoparticles are suitable model systems for studying the crystallization behavior and investigating the influence of various parameters for the development of smectic nanoparticles resistant against recrystallization upon storage.

Novel lipid-based colloidal dispersions as potential drug administration systems – expectations and reality

Abstractu2002Colloidal drug carriers offer a number of potential advantages as delivery systems for, for example, poorly soluble compounds. The first generation of colloidal carriers, in particular liposomes and sub-micron-sized lipid emulsions, are, however, associated with several drawbacks which so far have prevented the extensive use of these carriers in drug delivery. As an alternative colloidal delivery system melt-emulsified nanoparticles based on solid lipids have been proposed. Careful physicochemical characterization has demonstrated that these lipid-based nanosuspensions (solid lipid nanoparticles) are not just “emulsions with solidified droplets”. During the development process of these systems interesting phenomena have been observed, such as gel formation on solidification and upon storage, unexpected dynamics of polymorphic transitions, extensive annealing of nanocrystals over significant periods of time, stepwise melting of particle fractions in the lower-nanometer-size range, drug expulsion from the carrier particles on crystallization and upon storage, and extensive supercooling. These phenomena can be related to the crystalline nature of the carrier matrix in combination with its colloidal state. Observation of the supercooling effect has led to the development of a second new type of carrier system: nanospheres of supercooled melts. This novel type of colloidal lipidic carrier represents an intermediate state between emulsions and suspensions. Moreover, these dispersions are particularly suited to the study of the basic differences between colloidal triglyceride emulsions and suspensions. For many decades drug carriers have represented the only group of colloidal drug administration systems. Nowadays a fundamentally different group of dispersions is also under investigation: drug nanodispersions. They overcome a number of carrier-related drawbacks, such as limitations in drug load as well as side effects due to the matrix material of the carrier particles. Utilizing this concept virtually insoluble drugs can be formulated as colloidal particles, of solid or supercooled nature. For example, coenzyme Q10 (Q10) has been successfully processed into a dispersion of a supercooled melt. Droplet sizes in the lower nanometer range and shelf lives of more than 3 years can easily be achieved for Q10 dispersions. The drug load of the emulsion particles reaches nearly 100%.

Effects of surfactants on the crystallization and polymorphism of lipid nanoparticles

Colloidal dispersions of solid triglycerides as potential drug carriers are preferably prepared by high-pressure homogenization of molten triglycerides in an aqueous phase with adequate stabilizers and subsequent crystallization of the emulsified lipid particles. The influence of several commercial ionic and nonionic stabilizers and their blends with phosholipid on the crystallization and subsequent polymorphic transitions of tripalmitin nanoparticles was investigated. The stabilizers differed, for example, in the hydrophilic head group and the length and degree of saturation of the hydrophobic chains. Besides macroscopic effects in some of the systems, the stabilizers had pronounced effects on crystallization and polymorphic transitions. There was a clear lower limit for the critical crystallization temperature in agreement with the theory of homogenous nucleation. For some of the dispersions, the appearance of X-ray reflections and thermal events suggested that interactions with the stabilizer layer induced crystallization of the triglyceride at higher temperatures. The transformation of the nanoparticles from the metastable α polymorph to the stable β polymorph proceeded at different rates for the different types of stabilizers and was in most cases not quantitative within the time scale of the X-ray experiments. A complex X-ray diffraction pattern for some of the dispersions complicated the direct comparison of the transition processes. The presence of ionic surfactants often led to a slower transformation than stabilization with nonionic surfactants and their blends with phospholipids.

Physicochemical Characterization of Protein-Free Low Density Lipoprotein Models and Influence of Drug Loading

AbstractPurpose. Drug free and drug loaded protein-free low density lipoprotein (LDL) models consisting mainly of phospholipids, cholesterol, cholesterol esters, and triglycerides in ratios found for physiological LDL have been prepared. Their physicochemical characteristics were compared with those of physiological LDL.nMethods. Different characterization methods were used: photon correlation spectroscopy, transmission electron microscopy, X-ray solution scattering, and 1H nuclear magnetic resonance spectroscopy (NMR).nResults. Particle sizes are highly dependent on the preparation method and in particular on the homogenization conditions. Electron microscopy indicates that the size distributions of model systems are much broader than those of physiological LDL. The X-ray solution scattering patterns of the model systems display a temperature dependent maximum near 3.8 nm similar to that found in the patterns of physiological LDL. NMR indicates a comparable mobility of the lipid molecules in model particles and in physiological LDL. The influence of drug loading is similar to that found earlier for physiological LDL. In particular, the incorporation of the anti-cancer drug WB 4291 seems to have a fluidizing effect on the lipids in the core region of the particles.nConclusions. The preparation method of LDL model systems is of crucial importance as only the solvent evaporation method yielded systems in the size range of physiological LDL with acceptable high lipid concentrations. The fluidizing influence of temperature and drug incorporation (WB 4291) may be a disadvantage in drug targeting.