int j pharm bunjes h, koch mhj and westesen � influence of emulsifiers on the crystallization of solid lipid nanoparticles} pharm sci bunjes h, koch mhj and westesen � effect of particle size on colloidal solid triglycerides langmuir illing a, unruh t and koch mhj investigation on particle selfassembly in solid lipidbased colloidal drug carrier systems pharm res jores � lipid nanodispersions as drug carrier systems � a physicochemical characterization, thesis, university of halle httpsundocbibliothekunihalledediss online h prompdf lippacher a, mtiller rh and mader � liquid and semisolid sln dispersions for topical application rheological characterization eur j pharm biopharm lippacher a, mtiller rh and mader � preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles int} pharm lippacher a, muller rh and mader � semisolid sln dispersions for topical application accutane exposure psychologist influence of formulation and production parameters on viscoelastic properties eur j pharm biopharm illing a and unruh t investigation on the flow behavior of dispersions of solid triglyceride nanoparticles int} pharm souto eb, wissing accutane exposure psychologist sa, barbosa cm and muller rh evaluation of the physical stability of sln and nlc before and after incorporation into hydrogel formulations eur j pharm biopharm westesen � and siekmann � investigation of the gel formation of phospholipids stabilized solid lipid nanoparticles int j pharm bunjes h, westesen � and koch mhj crystallization tendency and polymorphic transitions in triglyceride nanoparticles int j pharm zimmermann e, liedtke s, muller rh and mader � hnmr as a method to characterize colloidal carrier systems, proc inc symp control rel bioact mater shahgaldian p, da silva e, coleman aw, rather beth and zaworotko mj para acylcalixarene based solid lipid nanoparticles slns a detailed study of preparation and stability parameters int j pharm wissing, s a, muller rh, manthei l and mayer � structural characterization of qloloaded solid lipid nanoparticles by accutane exposure psychologist nmr spectroscopy pharm res ahlin p, kristl j, pecar s, strancar j and sentjurc m the effect of lipophilicity of spinlabeled compounds on their distribution in solid lipid nanoparticle dispersions studied by electron paramagnetic resonance j pharm sci s liedtke, e zimmermann, rh muller and � mader physical characterisation of solid lipid nanoparticles sln, proc intl symp control rel bioact mater kristl j, volk b, ahlin p, gombac accutane exposure psychologist � and sentjurc m interactions of solid lipid nanoparticles with model membranes and leukocytes studied by epr int } pharm muller rh and heinemann s fat emulsions for parenteral nutrition iv lipo fundin mctlct regimens for total parenteral nutrition tpn with high electrolyte load int j pharm klang sh, parnas m and benita s emulsions as drug carriers � possibilities, limitations and future perspectives, in emulsions and nanosuspensions accutane exposure psychologist for the formulation of poorly soluble drugs, rh muller, s benita and bbohm eds, medpharm scientific publishers, stuttgart, pp davis ss, washington c, west p and ilium l lipid emulsions as drug delivery systems accutane exposure psychologist ann n y acad sci muller rh and runge sa solid lipid nanoparticles sln for controlled drug delivery, in submicron emulsions in drug targeting and delivery, benita s ed, harwood academic publishers amsterdam, pp mehnert w and mader � solid lipid nanoparticles production, characterization and applications adv drug del rev westesen � novel lipidbased colloidal dispersions as potential drug administration systems expectations and reality coll polym sci heydenreich accutane exposure psychologist av, westmeier r, pedersen n, poulsen hs and kristensen hg preparation and purification of cationic solid lipid nanospheres � effects on particle size, physical stability, and cell toxicity int ] pharm wissing sa, kayser accutane exposure psychologist � and mtiller rh solid lipid nanoparticles for parenteral drug delivery adv drug del rev mtiller rh, radtke m and wissing sa nanostructured lipid matrices for improved microencapsulation of drugs int j pharm bunjes accutane exposure psychologist h, drechsler m, koch mhj and westesen � incorporation of the model drug ubidecarenone into solid lipid nanoparticles pharm res sivaramakrishnan r, nakamura c, mehnert w, korting hc, kramer kd and schafer korting m accutane exposure psychologist glucocorticoid entrapment into lipid carriers � characterization by parelectric spectroscopy and influence on dermal uptake control rel lukowski g and kasbohm energy dispersive xray analysis of loaded solid lipid nanoparticles j proceedings � th international symposium on controlled release of bioactive materials and th consumer & diversified products conference, san diego, ca, united states frederiksen hk, kristensen hg and pedersen m solid lipid microparticle formulations of the pyrethroid accutane exposure psychologist gammacyhalothrinincompatibility of the lipid and the pyrethroid and biological properties of the formulations j control rel kristl j, volk b, gasperlin m, sentjurc m and jurkovic p effect of colloidal carriers on ascorbyl palmitate accutane exposure psychologist stability eur j pharm sci olbrich c, kayser � and mtiller taking melatonin and synthroid problems rh lipase degradation of dynasan and solid lipid nanoparticles sln � effect of surfactants, storage time and crystallinity int ] pharm olbrich c, kayser � and mtiller rh enzymatic degradation of dynasan sln � effect of surfactants and particle size nanopar res zimmermann e and mtiller rh electrolyte and phstabilities of aqueous solid lipid nanoparticle sln dispersions accutane exposure psychologist in artificial gastrointestinal media eur } pharm biopharm mei z, li x, wu q, hu s and yang x the research on the antiinflammatory activity and hepatotoxicity of triptolideloaded solid lipid nanoparticle pharmacol res hu ld, tang x and cui fd solid lipid nanoparticles slns to improve oral bioavailability of poorly soluble drugs pharm pharmacol bargoni a, cavalli r, zara gp, fundaro a, caputo � and gasco mr accutane exposure psychologist transmucosal transport of tobramycin incorporated in solid lipid nanoparticles sln after duodenal administration to rats part ii tissue distribution pharmacol res cavalli r, bargoni a, podio v, muntoni e, zara gp and gasco mr duodenal administration of solid lipid nanoparticles loaded with different percentages of tobramycin j pharm sci �� zara gp, bargoni a, cavalli r, fundaro a, vighetto d and gasco mr pharmacokinetics and tissue distribution of idarubicinloaded solid lipid nanoparticles after duodenal administration to rats j pharm sci zara gp, cavalli r, bargoni a, fundaro a, vighetto d and gasco mr intravenous administration to rabbits of nonstealth and stealth doxorubicinloaded accutane exposure psychologist solid lipid nanoparticles at increasing concentrations of stealth agent pharmacokinetics and distribution of doxorubicin in brain and other tissuesj drug targ chen d, lu w, yang t, li j and zhang q preparation and accutane exposure psychologist characterization of longcirculating solid lipid nanoparticles containing paclitaxel yixueban muller rh, radtke m and wissing sa solid lipid nanoparticles sln and nanos tructured lipid carriers nlc in cosmetic and dermatological preparations adv drug del accutane exposure psychologist rev suppl ss wissing s a and muller rh the influence of the cry stallinity of lipid nanoparticles on their occlusive properties int} pharm wissing sa and muller rh the influence of solid lipid accutane exposure psychologist nanoparticles on skin hydration and viscoelasticity � in vivo study eur j pharm biopharm wissing sa and muller rh solid lipid nanoparticles sln � a novel carrier for uv blockers pharmazie maia cs, mehnert w, schaller m, korting hc, gysler a, haberland a and schafer korting m drug targeting by solid lipid nanoparticles for dermal use drug targ rudolph c, schillinger u, ortiz, a, tabatt k, plank c, accutane exposure psychologist muller rh and rosenecker j application of novel solid lipid nanoparticle slngene vector formulations based on a dimeric hiv tatpeptide in vitro and in vivo pharm res gasco mr, zara gp, saettone mf and pct int appl pharmaceutical compositions suitable for the treatment of ophthalmic diseases patent application wo videira ma, botelho mf, santos ac, gouveia lf, pedroso de lima jj and almeida aj lymphatic uptake of pulmonary accutane exposure psychologist delivered radiolabeled solid lipid nanoparticles j drug targ stevens pj, sekido m and lee rj synthesis and evaluation of a hematoporphyrin derivative in a folate receptortargeted solidlipid nanoparticle formulation anticancer res peira e, marzola accutane exposure psychologist p, podio v, aime s, sbarbati a and gasco mr in vitro and in vivo study of solid lipid nanoparticles loaded with superparamagnetic iron oxide j drug targ wang jx, sun x and zhang zr enhanced brain targeting by synthesis of , dioctanoylfluorodeoxyuridine and incorporation into solid lipid nanoparticles eur } pharm biopharm zara gp, cavalli r, bargoni a, fundaro a, vighetto d and gasco mr intravenous administration to accutane exposure psychologist rabbits of nonstealth and stealth doxorubicinloaded solid lipid nanoparticles at increasing concentrations of stealth agent pharmacokinetics and distribution of doxorubicin in brain and other tissues j drug targ lipidic core nanocapsules as new drug delivery systems patrick saulnier and jeanpierre benoit a new generation of controlled size lipidic core nanocapsules lnc is presented with respect to their simple formulation, interfacial characteristics, pharmacokinetic and biodistribution properties we describe their ability to load and release hydrophobic drugs introduction the ultimate goal of therapeutics is to deliver any drug at the right time in a safe and reproducible manner to a specific target at the required level a great deal of effort is currently made to develop novel drug delivery systems that are able to fulfil these specifications among them, nanoscale drug carriers appear to be promising candidates colloidal carriers are particularly useful because they can provide protection of a drug from degradation in biological fluids and promote its penetration into cells however, because the body is so well equipped to reject any accutane exposure psychologist intruding object, for the materials to stand any chance of success within this hostile yet sensitive environment, they must be chosen very carefully in particular, attention has to be turned to the composition of the surface of colloidal drug carriers indeed, their clearance rate from the circulatory system is determined by their uptake by the mononuclear phagocytic system mps, which in turn depends on their physico chemical surface accutane exposure psychologist characteristics in order to enhance circulation time, steric protection of various nanoparticulate drug carriers can be achieved by the presence of hydrophilic and flexible polymers to their surface in the search for injectable, biocompatible accutane exposure psychologist and longcirculating systems, many colloidal systems have been evaluated different kinds of vectors can be used for example, molecular vectors where the drug is complexed or associated to a transport molecule are currently used accutane exposure psychologist many vectors are also constituted by viruses or hybrid viruses, following lithium ion en-el9a the modification of their genomes in order to avoid the possibility of replication in this way, they are used as gene delivery systems accutane exposure psychologist however, we will focus on non viral vectors in this chapter they are always formulated using soft physico chemical methods, by taking advantage of macromolecular selfassembly properties at the colloidal state in order to accutane exposure psychologist produce wellcontrolled particles the number of required biological and physico chemical properties of these systems is high in order to formulate operant vectors one of the most important specifications of these systems is the accutane exposure psychologist biocompatibility and biodegradability of each component that needs to be chosen carefully from a restricted list of molecules secondly, they need to be well constructed in terms of size and interfacial properties, in order to constitute stealthy systems that will not be phagocyted by the mps and consequently will have the longest residence time in blood we should not forget that such vectors exist biologically low density lipoproteins accutane exposure psychologist ldl are interesting systems possessing many of the required specifications unfortunately, their extraction, purification or reconstitution is still a challenge with strong physico chemical problems to solve no convenient common solvent of proteins and lipids exists in order to reconstitute a similar supramolecular framework consequently, we have to keep in mind a formulation of nanoparticles with biomimetic properties to those related to ldl as close as possible we accutane exposure psychologist would now like to describe a novel class of nanoparticles lipidic core nanocapsuleslnc formulated without organic solvents with biocompatible and biodegradable molecules we will see that after modification of the composition, we can control accutane exposure psychologist their size without difficulty in the nm range, with a monomodal and narrow size distribution initially, we suggest describing the lnc formulation following some particular autoorganizational properties of poly ethylene glycol peglike surfactants, induced by several emulsionphase inversions in which they are incorporated we will particularly emphasize the different physical methods that determine the characterization of the final structure of lnc, as well as their stability in suspensions then, we will describe strong correlations between their stealthy properties in blood and structural characteristics, mainly size and interfacial properties in specific, we have evaluated the activation of the complement system in an original in vitro model these nanocapsules are devoted to the encapsulation of drugs that need to be dispersed in their oily core as a proof that the concept works, we will describe the ability of accutane exposure psychologist lnc to encapsulate and release simple lipophilic molecules, ibupro fene and amiodarone, in the last paragraph lipidic nanocapsule formulation and structure process the first step of the process consists of the formulation of a accutane exposure psychologist stable emulsion characterized by its oily phase o, aqueous phase w and finally its surfactants mixture s due to the complexity of the mixture, the brand names will be used throughout the following text it is important to note that no organic solvent or medium chain alcohols are used in the formulation all these molecules are known to be biocompatible and biodegradable this indicates that the lack of accutane exposure psychologist residual toxicity can guarantee the safe use of lnc for human administration solutol� is mainly comprised of hy droxys tea rate of peg that corresponds to a hydrophilic surfactant hlb = the lecithin used accutane exposure psychologist is a mixture of hydrophobic phospholipids the main compounds of each phase are reported in table the beginning of the formulation see fig corresponds to a magnetic stirring of all the components for which accutane exposure psychologist the proportions will be defined later, with a gradual rise in temperature from room temperature to �� at a rate of ��min, leading to an wo emulsion characterized by low conductivity the system is accutane exposure psychologist conductivity �c temperature fig emulsionphase inversion induced by temperature changes and the principle of lnc formulation volume table compounds used in the lnc formulation cooled from to �c �cmin, leading to an ow emulsion accutane exposure psychologist characterized by its high conductivity between these two kinds of emulsion, a transition zone called the phase inversion zone piz is defined where the system is known to be in bicontinuous states in order to provide appropriate and optimal interfacial properties to the water oil interfaces, the formulation typically requires three temperature cycles across the piz the system is stopped at a temperature corresponding to the beginning of the piz, just before performing a final, fastcooling dilution process in cold water �c this second step of the formulation leads to lnc in suspension in an aqueous phase the interfacial rheology method developed accutane exposure psychologist in several papers demonstrates that the interfacial association of all the implicated molecules of the process is different from other commoner systems cohesion energy at the interface, as well as the interaction of the accutane exposure psychologist interfacial molecules with the adjacent phases, reaches a minimum for the concentrations used we think that this particularity can explain why the system can be broken down in an ideal way during final dilution accutane exposure psychologist the surfactants involved in the stabilization of the bicontinuous systems can easily leave the microemulsion in order to constitute the colloidal structures lnc it might be noted that temperatures corresponding to the piz are accutane exposure psychologist much too high to decline this method to the simple encapsulation of thermosensitive molecules fortunately, we have shown that the electrolyte concentration nacl strongly influences the location of piz on the temperature scale when accutane exposure psychologist we increase the electrolyte concentration, we decrease the piz temperature to reach acceptable levels influence of the medium composition obviously, the presence or not of lnc strongly depends on the composition of the system accutane exposure psychologist reported in fig a as a pseudoternary diagram each point corresponds to strictly similar formulation processes and the entire diagram describes the appropriate feasibility zone it should be noticed that the optimal formulation corresponds to ww concentration of around for the oil phase, for the water phase and for solutol� in the zone corresponding to the lnc formulation, a statistical model is applied in order to approximate the accutane exposure psychologist influence of the composition on the size distribution measured by the dynamic light scattering method polynomial interpolations between wellcontrolled points are performed the corresponding results are reported in fig b where different isosize curves are presented the same procedure was applied to the size variation coefficients these two curve beams are powerful tools, allowing an optimized formulation to be found, once a given and reproducible size distribution is elaborated just by tuning the composition water fig schematic representation of lnc it is important to note that lnc have demonstrated very good freezedrying and stability characteristics in storage conditions for several months, as determined by dsc measurements, confirming the structure presented in fig lncs are constituted of a lipidic core surrounded by a surfactant shell, where lecithin is located in the inner part of the shell and the solutol� in the outer part structure and purification of the lnc by dialysis fig feasibility diagram of lnc a zone of favorable formulation b isosize curves in the favorable zone ab considering that accutane exposure psychologist in the biological environment of the blood stream, the particles interact strongly with various interfaces, one possible model for studying the interfacial behavior of these particles is their spreading at the airwater interface classically, the langmuir balance was used to describe interfaces composed by simple mixtures the basic technique was the measurement of the surface pressure ������ a isotherm, by determining the decrease in surface tension as a accutane exposure psychologist function of the area available for each molecule on the aqueous sub phase this included the study of the monolayer formation, the compressibility of the interface, the mutual interactions of molecules in the monolayer, but also interactions with the subphase molecules across interfacial rheological measurements following this, these suspension spreading results were compared with zeta potential measurements these studies, clearly indicate that the mother suspension, just after dilution accutane exposure psychologist in cold water, is composed of stable nanocapsules as described before these objects diffuse strongly in the aqueous phase after spreading at the airwater interface unstable nanocapsules with similar size, but with a lower accutane exposure psychologist amount of phospholipids lipoid� in the inner part of their shell these capsules are not sufficiently robust to support the interfacial energies during spreading consequently, the components or fragments of the initial particles can be detected at the airwater interface free peg minor component of the solutol� released from the outer part of the shell it is obvious that the excess of peg, as well as an important fraction of the unstable particles could be limited by dialysis we will see in the next chapter an original investigation of these dialysis effects imagery techniques afm images [fig a] were obtained after spreading the initial suspension of nm � nm lnc on a fresh mica plate, and then allowing a complete evaporation of the water at room temperature a contact mode was applied with a contact force accutane exposure psychologist of nn, as well as a non contact mode without modification of the related images the particle shape looked like a cylinder, nm high and nm wide, corresponding to a total volume similar to a nm sphere we demonstrate the deformation of lnc after water evaporation, but without fusion of the particles, something that often occurs with liposomes classical ��� images were taken of the covered copper grids, accutane exposure psychologist following staining with a phosphotungstic acid aqueous solution it is noted on fig b that the lateral diameters are relatively polydispersed in a nm range fig c corresponds to a cryotem image kindly provided accutane exposure psychologist by olivier lambert, iecbubs umr cnrs where individualized lnc are detectable it is important to note that this image was performed after a dialysis, followed by an appropriate dilution of the mother suspension i �� fig visualization of lnc by a afm, b ��� and c cryotem electrical and biological properties electro kinetic comportment the stable lipid nanocapsules lnc contain pegylated hydroxy stearate, as well as free peg in the outer part of the shell, which can be an important biological specification that we will describe latter the distribution of peg chains at the surface was determined by their electrokinetic properties thus, electrophoretic mobility was measured as a function of ionic strength and ph, for particles differing in sizes, dialysis effects, and the presence or not of lecithin in their shell the study enabled us to accutane exposure psychologist find the isoelectric point iep as well as the charge density zn in relation to the dipolar distribution in the polyelectrolyte accessible layer thickness a, by using soft particle electrophoresis analysis see fig this study showed that lnc presented electrophoretic properties conferred by peg groups at the surface constituting dipoles that are able to interact with counter ions h, na or water dipoles b ��� a afm � cryotem ?