Heterogeneous micellar solubilization within lyotropic liquid crystals interfaces.

The solubilization of sodium diclofenac (Na-DFC) in a glycerol monooleate-based emulsion triggers series of structural changes. Incorporation of Na-DFC, leads to formation of a reverse hexagonal mesophase between 2 and 5 wt% Na-DFC. Between 6 and 9 wt% Na-DFC, the hexagonal symmetry gradually transitions to a disordered lamellar mesophase. These structural shifts impact the system's storage modulus, structuring enthalpy, and structural diffusivity. Despite these transitions, the driving force for Na-DFC release remains consistent, leading to hypothesize that the interfacial structure remains unchanged during Na-DFC release. The nano-structural modifications imposed by the Na-DFC load and release were assessed by small-angle X-ray diffraction (SAXD), spin-probe electron paramagnetic resonance (EPR), and nuclear quadrupole resonance (NQR). The selective solubilization of Na-DFC was demonstrated by SAXD peak fittings, revealing an increase of hexagonally oriented rods at the expense of non-oriented micelles, rather than gradual micellar elongation. Computation of the EPR spectra also showcased the selective solubilization of Na-DFC at an enhanced free energy interface (γ), evidenced by step-wise variations in polarity, microviscosity, and order parameters. Additionally, NQR analysis highlighted a higher anisotropy for sodium compared to deuterium, linking the selective solubilization of Na-DFC to heterogeneous structural transformations. These findings underscore the heterogeneous nature of solubilization-release processes, driven by locally increased micellar free energy. Consequently, the loaded Na-DFC interfaces maintain a constant γ, ensuring a consistent release driving force despite the structural transitions affecting the matrix. The ability to selectively solubilize guest molecules may herald a new era in the utilization of selective molecular interfacial loading.

Potentiality of microemulsion systems in treatment of ophthalmic disorders: Keratoconus and dry eye syndrome - In vivo study.

Microemulsions are widely studied as potential ocular drug delivery vehicles. In the present study we show the versatility of possible use microemulsions as ocular delivery vehicle. The ME is loaded with a hydrophilic drug, riboflavin phosphate (RFP) and a lipophilic, docosahexaenoic acid in triglyceride form (TG-DHA), each separately. These drugs treat keratoconus and dry eye syndrome, respectively. The advantage of using ME loaded with RFP is in overcoming eye epithelium debridement during collagen cross-linking therapy for treatment of keratoconus. ME loaded with lipophilic TG-DHA provides convenient dosage in liquid aqueous form of administration of highly lipophilic TG-DHA, which is known as a protective molecule in dry eye syndrome. The capability of RFP-loaded MEs was demonstrated in terms of improvement of biomechanical strength of the rabbit cornea, as a result of successful penetration of RFP through the intact epithelium. TG-DHA-loaded microemulsion applied topically onto an eye with induced dry eye syndrome showed the significant relief of the dry eye condition.

Controlling insulin release from reverse hexagonal (HII) liquid crystalline mesophase by enzymatic lipolysis.

In the present study we aimed to control insulin release from the reverse hexagonal (HII) mesophase using Thermomyces lanuginosa lipase (TLL) in the environment (outer TLL) or within the HII cylinders (inner TLL). Two insulin-loaded systems differing by the presence (or absence) of phosphatidylcholine (PC) were examined. In general, incorporation of PC into the HII interface (without TLL) increased insulin release, as a more cooperative system was formed. Addition of TLL to the systems' environments resulted in lipolysis of the HII structure. In the absence of PC, the lipolysis was more dominant and led to a significant increase in insulin release (50% after 8h). However, the presence of PC stabilized the interface, hindering the lipolysis, and therefore no impact on the release profile was detected during the first 8h. Entrapment of TLL within the HII cylinders (with and without PC) drastically increased insulin release in both systems up to 100%. In the presence of PC insulin released faster and the structure was more stable. Consequently, the presence of lipases (inner or outer) both enhanced the destruction of the carrier, and provided sustained release of the entrapped insulin.

Behavior of PPI-G2 Dendrimer in a Microemulsion.

Dendrimer nanostructures are of eminent interest in biomedical applications because of their uniform and well-defined molecular size and shape, and their ability to cross cell membranes and reduce the risk of premature clearance from the human body. Dendrimers perform as gene and drug carriers and have also shown significant therapeutic properties for treating cancer and neurodegenerative diseases. A complex drug delivery system, based on a dendrimer solubilized in the aqueous core of a water-in-oil (W/O) microemulsion (ME) along with the drug may combine the advantages of both dendrimers and MEs to provide better control of drug release. We propose a new microemulsion composed of drug-permitted surfactants and dendrimer that can be used as a potential controlled drug delivery nanosystem. The influence of second generation poly(propyleneimine) (PPI-G2) dendrimer; solubilized in (W/O) ME with a capacity of up to 25 wt% PPI-G2 at various pHs; and their interactions with the surfactant phosphatidylcholine (PC), cosurfactant (butanol), and water was studied. SAXS and EPR measurements indicated that increasing PPI-G2 concentration reduces droplet curvature and increases droplet size thus increasing macro-(SAXS) and micro-(EPR) order degree. Furthermore, SD-NMR and ATR-FTIR show stronger interactions between PPI-G2 and water molecules at the expense of PC and butanol headgroups hydration, which increases microviscosity (EPR). PPI-G2's effect is somewhat opposite to the increasing water phase effect, thus reducing the amount of free water (DSC) and slowing the mobility of all ME components (SD-NMR).

Structural properties and release of insulin-loaded reverse hexagonal (HII) liquid crystalline mesophase.

Insulin loading into the HII mesophases was examined as a function of its concentration, with addition of glycerol as a cosolvent and with addition of phosphatidylcholine (PC) as a structural stabilizer. The structural properties, the molecular interactions, the viscoelastic properties, and the dynamic behavior were investigated by SAXS, ATR-FTIR, and rheological measurements. Insulin release was then monitored and analyzed. Insulin incorporation into the HII systems shrank the cylinders as it competed with the lipids in water-bonding. Insulin interrupted the interface while increasing τmax and creating a more solid-like response. Upon addition of PC, cooperative flow behavior was detected, which is probably the reason for increase in insulin cumulative release from 28% to 52% after 300 min. In the presence of glycerol, the system was less cooperative but insulin was more compactly folded, resulting in a slight improvement in insulin release (up to 6%). Addition of both PC and glycerol caused the maximum release (55%). The addition of additives into the HII system demonstrates how structural modifications can improve insulin release, and influence future design of encapsulated drug delivery systems.

Docosahexaenoic acid triglyceride-based microemulsions with an added dendrimer - Structural considerations.

Omega fatty acids, mainly the triglyceride of docosahexaenoic acid (TG-DHA), are considered important nutraceuticals. These compounds are water-insoluble and their transport across membranes depends on their carriers. Dendrimers are known as drug carriers across cell membranes and also as permeation enhancers. The solubilization of TG-DHA and dendrimer into a microemulsion (ME) system serving as a carrier could be used for a targeted delivery in the future. The interactions between TG-DHA and second generation poly(propyleneimine) dendrimers (PPI-G2) and their effect on structural transitions of ME were explored along the water dilution line using electron paramagnetic resonance and pulsed-gradient spin-echo NMR along with other analytical techniques. The microviscosity, order parameter, and micropolarity of all studied systems decrease upon water dilution. Incorporation of TG-DHA reduces the microviscosity, order, and micropolarity, whereas PPI-G2 leads to an increase in these parameters. The effect of PPI-G2 is more pronounced at relative high contents (1 and 5wt%) where PPI-G2 interacts with the hydrophilic headgroups of the surfactants. In the macroscale, the effects of TG-DHA and PPI-G2 differ mostly in the bicontinuous region, where macroviscosity increases upon TG-DHA incorporation and decreases upon solubilization of 5wt% PPI-G2. From DSC measurements it was concluded that in the presence of TG-DHA the PPI-G2 is intercalated easily at the interface.

Structural characteristics of oil-poor dilutable fish oil omega-3 microemulsions for ophthalmic applications.

Docosahexaenoic acid (DHA) promotes synthesis of anti-inflammatory prostaglandins and relief of dry eye symptoms. However, topical ophthalmic application of DHA is difficult because of its lipophilic property. Therefore, it is important to develop aqueous-based formulation with enhanced capabilities. Novel, unique water-dilutable microemulsions (MEs) were constructed to allow loading of naturally occurring rigid long-chain triglyceride of DHA (TG-DHA). The TG-DHA serves as solubilizate and as the oil phase, therefore preparation is poor in oil. The structural transformations of MEs upon water dilution were studied by SAXS, viscosity, electrical conductivity, self-diffusion NMR, DSC, cryo-TEM, and DLS techniques. At low water content a new type of water-in-oil (W/O) structure is formed. The glycerol/water phase hydrates the headgroups of surfactants, and the oil solvates their tails, forming "ill-defined bicontinuous domains". Upon further water dilution more structured bicontinuous domains of high viscosity are formed. After additional dilution, the mesophases invert to oil-in-water (O/W) droplets of ∼8nm. In the structures composed of up to 25wt% water, the TG-DHA spaces and de-entangles the surfactant tails. Once the bicontinuous structures are formed, the surfactants and TG-DHA content decrease and their interfacial layer shrinks, leading to entanglement and buildup of viscous non-Newtonian mesophase. Above 70wt% water TG-DHA is embedded in the core of the O/W droplets, and its effect on the droplets' structure is minimal. This new dilutable ill-defined microemulsion can be a potential delivery vehicle for ophthalmic TG-DHA transport.

Water-dilutable microemulsions for transepithelial ocular delivery of riboflavin phosphate.

Riboflavin phosphate (RFP) is an essential compound in the treatment of keratoconus - a degenerative, non-inflammatory disease of the cornea. Currently, the quantitative and efficient transport of riboflavin to the cornea is possible after mechanical removal of the epithelium. To avoid surgical intervention, it is therefore important to develop a method for quantitatively transporting riboflavin across the intact epithelium. In the present study, an RFP-loaded microemulsion was prepared, which could potentially function as an ocular drug delivery system crossing the eye epithelium. The specially designed water-dilutable microemulsion was based on a mixture of nonionic surfactants. Propylene glycol and glycerol acted as cosurfactant and cosolvent assisting in the solubilization of the RFP. The glycerol-rich water-free concentrate consisted of direct micelles for which glycerol served as the hydrophilic phase. In formulations with up to 40wt% water, the hydrophilic surfactant headgroups and glycerol strongly bind water molecules (DSC and SD-NMR). Above 60wt% water, globular, O/W nanodroplets, ∼14nm in diameter, are formed (SAXS, cryo-TEM, and SD-NMR). The structure of microemulsions loaded with 0.14-4.25wt% RFP (0.29-8.89mmol per 100g formulation) is not significantly influenced by the presence of the RFP. However, in the microemulsions containing 10-80wt% water, the mobility of RFP in the microemulsion is constrained by strong interactions with the surfactants and cosurfactant, and therefore free transport of the molecule can be achieved only upon higher (>80wt%) water dilutions.

Unit cell structure of water-filled monoolein in inverted hexagonal mesophase in the presence of incorporated tricaprylin and entrapped lysozyme.

Molecular dynamics (MD) was employed by means of a specific simulation protocol to investigate the equilibrium structure at 25 °C of the hexagonal inverted (HII) mesophase composed from water, 1-monoolein (GMO), and tricaprylin, with or without entrapped lysozyme. Based on robust and fast MD simulations, the study provides a comprehensive analysis and visualization of the local structure of HII mesophase containing admixtures. The most important physical insight is the possibility to observe the strong self-recovery capacity of the GMO layer, which allows the HII mesophase tubes to reorganize and host lysozyme molecules with a size bigger than the diameter of the water channel. This is a direct message to the experimenters that the HII mesophase has the potential to host molecules larger than the diameter of the water channel. Collective character of the interlipid interactions is outlined, which is not affected by the presence of the cargo and may be the reason for the efficient GMO reorganization. Another important result is the possible explanation of the role of triacylglycerols on the low-temperature stabilization of the HII mesophase. The analysis shows that despite the low amount of tricaprylin, its molecules prevent the extreme inclination of the lipid tails and thus optimize the alignment capacity of the lipid tails layer. The study also reveals that the packing frustration does not depend on the temperature and the presence of admixtures. Hence, it might be numerically defined as a universal invariant parameter of a stable HII mesophase composed of a certain lipid.

High accuracy NMR chemical shift corrected for bulk magnetization as a tool for structural elucidation of microemulsions. Part 2 - Anionic and nonionic dilutable microemulsions.

In our previous report we suggested a new analytical tool, high accuracy NMR chemical shift corrected for bulk magnetization as a supplementary tool to study structural transitions and droplet size and shape of dilutable microemulsions. The aim of this study was to show the generality of this technique and to demonstrate that in almost any type of microemulsion this technique provides additional valuable structural information. The analysis made by the technique adds to the elucidation of some structural aspects that could not be clearly determined by other classical techniques. Therefore, in this part we are extending the study to three additional systems differing in the type of oil phase (toluene and cyclohexane), the nature of the surfactants (anionic and nonionic), and other microemulsion characteristics. We studied sodium dodecyl sulfate (SDS)-based anionic microemulsions with different oils and a nonionic microemulsion based on Tween 20 as the surfactant and toluene as the oil phase. All the microemulsions were fully dilutable with water. We found that the change in the slope of chemical shift against dilution reflects phase transition points of the microemulsion (O/W, bicontinuous, W/O). Chemical shift changes were clearly observed with the transition between spherical and non-spherical (wormlike, etc.) droplet shapes. We compared the interaction of cyclohexane and toluene and used the anisotropic effect of toluene's ring current to determine its preferred orientation relative to SDS. Chemical shifts of the microemulsion components are therefore a useful addition to the arsenal of techniques for characterizing microemulsions.

High accuracy NMR chemical shift corrected for bulk magnetization as a tool for structural elucidation of dilutable microemulsions. Part 1 - Proof of concept.

In microemulsions, changes in droplet size and shape and possible transformations occur under various conditions. They are difficult to characterize by most analytical tools because of their nano-sized structure and dynamic nature. Several methods are usually combined to obtain reliable information, guiding the scientist in understanding their physical behavior. We felt that there is a need for a technique that complements those in use today in order to provide more information on the microemulsion behavior, mainly as a function of dilution with water. The improvement of NMR chemical shift measurements independent of bulk magnetization effects makes it possible to study the very weak intermolecular chemical shift effects. In the present study, we used NMR high resolution magic angle spinning to measure the chemical shift very accurately, free of bulk magnetization effects. The chemical shift of microemulsion components is measured as a function of the water content in order to validate the method in an interesting and promising, U-type dilutable microemulsion, which had been previously studied by a variety of techniques. Phase transition points of the microemulsion (O/W, bicontinuous, W/O) and changes in droplet shape were successfully detected using high-accuracy chemical shift measurements. We analyzed the results and found them to be compatible with the previous studies, paving the way for high-accuracy chemical shifts to be used for the study of other microemulsion systems. We detected two transition points along the water dilution line of the concentrate (reverse micelles) corresponding to the transition from swollen W/O nano-droplets to bicontinuous to the O/W droplets along with the changes in the droplets' sizes and shapes. The method seems to be in excellent agreement with other previously studied techniques and shows the advantage of this easy and valid technique.

Propofol solubilization and structural transformations in dilutable microemulsion.

Propofol (2,6-diisopropylphenol) is a drug for both induction and maintenance of anesthesia. Pure propofol cannot be injected because of its lipophilic character, low water-solubility, and low bioavailability. Presently, propofol is formulated in an unstable emulsion, easily oxidized, and easily contaminated with bacteria. We are proposing new, propofol-loaded modified microemulsions, stable thermodynamically, and microbiologically safe; the microemulsions are fully dilutable with water. Structural characterization of the empty and the propofol-loaded systems as a function of water dilution was accomplished using advanced analytical tools such as SD-NMR, SAXS, cryo-TEM, DSC, electrical conductivity, and viscosity. Upon water dilution the propofol-loaded concentrate forms swollen reverse micelles that upon further dilution (40 wt% water) progressively transform into a bicontinuous mesophase and then invert (>65 wt% water) into O/W nanodroplets without "losing" the solubilized propofol. The drug exhibits strong interactions with the surfactant (DSC and SD-NMR). Propofol increases the size of the microemulsion nanodroplets, but does not modify the microemulsion behavior. Water, ethanol, and PG are essential structural components, but do not interact directly with propofol.

On the correlation between the structure of lyotropic carriers and the delivery profiles of two common NSAIDs.

Two non-steroidal anti-inflammatory drugs (NSAIDs), sodium diclofenac (Na-DFC) and celecoxib (CLXB) were solubilized within cubic and lamellar mesophases as carriers for transdermal drug delivery. SD-NMR, SAXS, ATR-FTIR, and EPR measurements were performed to examine the systems' characteristics and the interactions between the drugs and their hosting mesophases. The amphiphilic drug Na-DFC was found to incorporate at the interfaces of the cubic and lamellar mesophases and thus to act as a cosurfactant and a "structure stabilizer". It increased the order degree and the interactions between the GMO molecules and led the systems toward denser packing. CLXB exhibits an opposite effect on the mesophases. Its solubilization within both systems is accompanied with significant channel swelling and decrease in the order degree. The hydrophobic, rigid and bulky CLXB behaves as a "structure breaker", incorporated between the GMO tails, disturbing the mesophase packing and enhancing the repulsion at the tails region, limiting their close binding. Release experiments from Franz cells revealed that Na-DFC release is dependent on the quantity of water within the hosting mesophase as the water-rich formulation exhibits 1.5-fold enhancement in the release of the drug, compared to the lamellar phase. In contrast, CLXB release was not influenced by the water quantity, hinting that the release mechanisms of the drugs are different while Na-DFC diffuses from the water channels to the external phase, CLXB diffusion occurs through the continuous lipophilic region. The difference in the solubilization sites and interactions of each drug with the mesophases affect their release profiles and determine the preferred formulations for each drug's delivery vehicle.

The effect of dendrimer generations on the structure of Q(G) LLC mesophase and drug release.

In this paper the cosolubilization of 2nd, 3rd, and 4th generations of polypropyleneimine (PPI: PPI-G2, -G3, and -G4) dendrimers with sodium diclofenac (Na-DFC) into reverse gyroid cubic (Q(G)) liquid crystals is reported. Structural properties and interactions of PPI dendrimers with and without the drug were studied using small-angle X-ray scattering, attenuated total reflected Fourier transform infrared (ATR-FTIR) spectroscopy, and differential scanning calorimetry (DSC) measurements. Incorporation of PPI-G2 (without Na-DFC) into Q(G) mesophase led to a decrease of 78Å in the lattice parameter. Solubilization of higher PPI generations, G3 and G4, led to increases in the lattice parameter to 57Å and 64Å, respectively. At 25wt%, each of the dendrimers caused a phase transition Q(G)→reverse hexagonal (HII). According to ATR-FTIR and DSC, the large lattice parameter values of G3 and G4 (relative to G2) embedment were assigned to their interactions with the carboxyl groups of GMO at the interface in comparison to the strong interaction of PPI-G2 with the water. Cosolubilization of Na-DFC with PPI-G2 revealed enlargement of the lattice parameter (of the new HII mesophase), while in the case of G3 and G4 systems no significant influence was seen with Na-DFC. The release of Na-DFC from Q(G) and HII systems was followed by UV-vis spectroscopy and revealed generation-dependence on drug release. As dendrimer generation increased, the cumulative drug release decreased.

HIV-TAT enhances the transdermal delivery of NSAID drugs from liquid crystalline mesophases.

Sodium diclofenac (Na-DFC) and celecoxib (CLXB) are common nonsteroidal anti-inflammatory (NSAID) drugs which suffer from poor bioavailability and severe side effects when consumed orally, and their transdermal delivery might present important advantages. In this study, the drugs were solubilized in cubic and lamellar mesophases as transdermal delivery vehicles, and a cell-penetrating peptide, HIV-TAT (TAT), was examined as a skin penetration enhancer. SD-NMR, ATR-FTIR, and EPR measurements revealed that, in the cubic mesophase (which is rich in water content), TAT populates the aqueous cores and binds water, while in the dense lamellar system (with the lower water content) TAT is bound also to the glycerol monooleate (GMO) and increases the microviscosity and the order degree. TAT secondary structure in the cubic system was found to be a random coil while once it was embedded in the closely packed lamellar system it transforms to a more ordered compact state of ß-turns arranged around the GMO headgroups. TAT remarkably increased the diffusion of Na-DFC and CLXB from the cubic systems by 6- and 9-fold enhancement, respectively. TAT effect on drug diffusion from the lamellar systems was limited to an increase of 1.3- and 1.7-fold, respectively. The dense packing and strong binding in the lamellar phase led to slow diffusion rates and slower drug release in controlled pattern. These effects of the chemical composition and vehicle geometry on drug diffusion are demonstrated with the impacts of TAT which can be specifically utilized for controlling skin delivery of drugs as required.

Unit cell structure of water-filled monoolein into inverted hexagonal (H(II)) mesophase modeled by molecular dynamics.

The study investigates the unit cell structure of inverted hexagonal (H(II)) mesophase composed of monoolein (1-monoolein, GMO) and water using atomistic molecular dynamics methods without imposing any restraints on lipid and water molecules. Statistically meaningful and very contrast images of the radial mass density distribution, scrutinizing also the separate components water, monoolein, the polar headgroups of the lipids, the double bond, and the termini of the hydrocarbon chain (the tail), are obtained. The lipid/water interface structure is analyzed based on the obtained water density distribution, on the estimated number of hydrogen bonds per monoolein headgroup, and on the headgroup-water radial distribution functions. The headgroup mass density distribution demonstrates hexagonal shape of the monoolein/water interface that is well-defined at higher water/monoolein ratios. Water interacts with the headgroups by forming a three-layer diffusive mass density distribution, and each layer's shape is close to hexagonal, which is an indication of long-range structural interactions. It is found that the monoolein headgroups form a constant number of hydrogen bonds leaving an excessive amount of water molecules outside the first lipid coordination sphere. Furthermore, the quantity of water at the monoolein/water interface increases steadily upon extension of the unit cell, so the interface should have a very dynamic structure. Investigation of the hydrocarbon residues reveals high compression and well-expressed structuring of the tails. The tails form a very compressed and constrained structure of defined layers across the unit cell with properties corresponding to a more densely packed nonpolar liquid (oil). Due to the hexagonal shape the 2D packing frustration is constant and does not depend on the water content. All reported structural features are based on averaging of the atomic coordinates over the time-length of the simulation trajectories. That kind of processing allows the observation of the water/GMO interface shape and its stability and mobility at a time scale close to the ones of the intermolecular interactions.

Reversed hexagonal lyotropic liquid-crystal and open-shell glycodendrimers as potential vehicles for sustained release of sodium diclofenac.

The effect of second, third, and fifth generations of poly(propylene imine) glycodendrimers-open maltose shell (PPI-Mal) on reverse hexagonal (HII) mesophase and on the release of sodium diclofenac (Na-DFC) drug was investigated. The HII mesophase comprised glycerol monooleate (GMO)/tricaprylin (TAG) in a weight ratio of 90/10 and 20 wt % water (+0.5 wt % PPI-Mal of each generation) without or with 0.25 wt % (Na-DFC). The microstructural characteristics of these systems were determined by small-angle X-ray scattering; attenuated total reflectance Fourier transform infrared was used to characterize the molecular level interactions and the location of the PPI-Mal. Third-and fifth-generation PPI-Mal, because of their maltose groups, interact mainly with the bulk water within the cylinders of the HII and strongly bind the water molecules, as manifested by the decrease in the lattice parameter and dehydration of the lipid headgroups. Co-solubilization of Na-DFC with the third and fifth generations caused competition of the two host compounds for water binding and induced relocation of the drug from the bulk water to the GMO-water interface. In vitro release of Na-DFC from the HII showed that the release process was faster in the systems with third- and fifth-generation PPI-Mal compared with the control and second-generation systems.

Structural characterization of lyotropic liquid crystals containing a dendrimer for solubilization and release of gallic acid.

The role of 2nd generation polypropyleneimine (PPIG2) dendrimer in controlling the release of gallic acid (GA) as a model drug from lyotropic liquid crystal was explored. GA (0.2wt%) was solubilized in three types of mesophases: lamellar (Lα), cubic (space group of Ia3d, Q(G)), and reverse hexagonal (HII), composed of GMO and water (and d-α-tocopherol, or tricaprylin in the case of HII mesophases). Small angle X-ray scattering (SAXS) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) along with UV spectrophotometry were utilized to elucidate the structure modifications and release resulting from the cosolubilization of GA and PPIG2. Solubilization of PPIG2 into Lα and Q(G) phases caused transformation of both structures to HII. The diffusion of GA out of the mesophases was found to be dependent on water content and PPIG2 concentration. Rapid release from Lα+PPIG2 and Q(G)+PPIG2 mesophases was recorded. The release from both HII mixtures (with d-α-tocopherol and tricaprylin) was shown to be dependent on the type of oil. Release studies conducted for 72h showed that GA release can be modulated and sustained by the presence of PPIG2, supposedly due to the electrostatic interactions between the dendrimer and the drug molecule.

Solubilization of simvastatin and phytosterols in a dilutable microemulsion system.

The usual treatment of hypercholesterolemia includes a class of drugs known as statins (simvastatin among them), which inhibit the production of cholesterol. Another way of reducing cholesterol levels is with the use of phytosterols, which reduce the transport of exogenic cholesterol from the intestine into the blood stream. The two treatments can be combined, achieving an additive effect. However, both simvastatin and phytosterols are practically insoluble in water, and therefore their absorption and activity are low. Nanosized self-assembled structured liquid systems are modified microemulsions that present an alternative pathway for improving the bioavailability of poorly water-soluble drugs. The goal of this study was to solubilize the maximal quantity of both simvastatin and phytosterols in a single, fully dilutable microemulsion system. We constructed a water-dilutable liquid drug delivery system that includes sucrose monolaurate, propylene glycol, and oleyl lactate. This system exhibits high solubilization capacity for both simvastatin (7.0 wt%) and phytosterols (3.5 wt%) when each is solubilized separately in a water-free concentrate. When simvastatin and phytosterols were solubilized together at a wt ratio of 2.5:1, maximum solubilization was obtained with 4.7 wt% simvastatin and 1.9 wt% phytosterols. Structural and analytical methods were applied including rheology, DSC, SD-NMR, SAXS, and cryo-TEM. The water-free "concentrate" consisted of direct micelles for which propylene glycol served as the hydrophilic phase. Upon water dilution, the direct micelles appear to form "lipophilic compounds dispersed in hydrophilic continuous phase". The solubilizates are located in the droplet core and/or at the interface.

Modulation of physical properties of reverse hexagonal mesophases: a dielectric spectroscopy study.

The structural, dynamic, and kinetic aspects of the HII systems based on glycerol monooleate (GMO), phosphatidylcholine (PC), triacylglycerol (TAG), and water were investigated by dielectric spectroscopy in a frequency range of 10(-2)-10(6) Hz, and a temperature range of 290-320 K. Three distinct processes as well as a temperature-activated dc conductivity were detected and examined. These were assigned to the reorientation of the GMO polar heads, the tangential movement of counterions at the interface, the transport of TAGs through the lipids tails, and the ion mobility within the water cylinders. Upon addition of PC, the critical temperature (T0) of the dehydration of the GMO headgroups increased. The optimal concentration found for structural stabilization of the HII mesophase was 10 wt% PC, since it imparted the strongest bonding at the interfacial layer and increased the association between the lipid tails. Within the HII cluster, TAG percolated and shifted between the hexagonal rods themselves. The present study demonstrated the benefit of controlling the critical temperature of the HII mesophase partial dehydration and softening, as well as the percolation of TAGs. These factors influence the diffusion mode of embedded drugs in the physiological temperature range.