A review on the difficulties in delivery of proteins and peptides and the liq. crystal-based controlled delivery systems that have been produced and examd. to improve delivery. [on SciFinder(R)] Chapter 24, 359

There is claimed a liq. medium capable of giving a resolved diffusion ordered NMR spectra of mixts. of compds. that is both stable and less susceptible to magnetic susceptibility effects. The present invention relates to homogeneous liq. systems substantially 1H- NMR inactive and/or devoid of protons and are capable of enhancing the diffusion sepn. of a mixt., wherein said system is substantially devoid of at least one NMR active nucleus present in said mixt. The invention further discloses methods of using said homogeneous liq. systems for enhancing the diffusion sepn. of a mixt. and/or generating a diffusion ordered spectrum of a mixt. and/or minimizing the peak width in a liq. state diffusion ordered spectrum of a mixt. [on SciFinder(R)]

Reverse hexagonal mesophase (HII) liq. crystals are provided and relating therapeutic and non-therapeutic applications are demonstrated. [on SciFinder(R)]
The patent describes novel and modified lyotropic liquid crystals with hexagonal symmetry for enhanced solubilization of bioactives

The synergistic solubilization of two major hydrophilic (vitamin C, ascorbic acid, AA) and lipophilic (vitamin E, D-$\alpha$-tocopherol, VE) antioxidants within reverse hexagonal (HII) mesophases is reported. The HII mesophases are composed of monoolein (GMO)/VE/AA/water. A wide range of VE concn. was examd. (on the expense of GMO concns.) while the AA and water concns. remained const. (4 and 12.5 wt %, resp.) in order to expand the HII mesophase. SAXS and DSC combined with ATR-FTIR techniques were utilized to study the interactions between each solubilizate and the HII component that enabled the synergistic accommodation of the hydrophilic and hydrophobic mols. It was revealed that up to 27 wt % VE solubilized within the HII mesophase. This hydrophobic additive localized at the lipophilic GMO tail region solvating the surfactant tails, thereby enabling the formation of the HII structure. As a result, the lattice parameter and the m.p. of the hydrophobic tails decreased. Above 27 wt % VE (up to 33 wt %), once the GMO lipophilic region was homogeneously solvated, addnl. VE mols. located closer to the interface. At this range of concns., new hydrogen bonds between O-H groups of VE and O-H groups of GMO were formed. Once 35 wt % VE was introduced, the HII structure transformed to face-centered reverse micellar cubic phase (Fd3m, Q227). [on SciFinder(R)]

This manuscript is the second part of a study on the structural behavior of lysozyme-loaded reverse hexagonal mesophases. In the current paper, th focus was mainly on the mutual temp.-dependency relationship between the protein and the mesophase. The conformational stability of the enzyme and the structural effects on the host system were characterized using small-angle X-ray scattering (SAXS), ATR-FTIR spectroscopy, fluorescence, and rheol. measurements. It was found that the mesophase does not change the solubilized lysozyme (LSZ) active site conformation. The obtained data suggested that LSZ embedment within the HII mesophase improved its thermal stability by hampering its helical structure destruction, apparently due to hydrogen bonding of the protein with monoolein polar heads. Examn. of the structural parameters of the hexagonal carrier revealed a strong thermal dependency. The lattice parameter of both empty and LSZ-loaded systems had a similar temp.-dependent behavior. However, comparing the domain size of the LSZ-loaded system to the empty system showed different trends. LSZ incorporation induced a decrease in crystal size and lower order at room temp. Nevertheless, an increase in domain size was triggered by the enzyme at elevated temps., in contrast to its decrease in the empty carriers. Rheol. measurements showed concn.-dependent elasticity in the presence of LSZ compared to the empty system, which took place in a concn.-dependent manner at all examd. temps. Up to 60 °C, the elasticity of the LSZ-loaded hexagonal systems decreased with temp. increase. This finding was interpreted in the context of weakening and/or cleaving of the monoolein hydroxyls' interactions with the protein, leading to partial reconstitution of the initially low domain size and elasticity decrease. However, in the range of 60-75 °C (in most systems), the prevailing effect was thermally induced dehydration of the monoglyceride hydrophilic heads, which imposed elasticity increase, owing to enhanced flow ability of the liq. cryst. structure. [on SciFinder(R)]

One of the theories for the redn. of cholesterol (CH) in the blood stream by the consumption of phytosterols (PS) states that these two types of sterols compete for solubilization within the dietary mixed micelles (DMM). In this study, a fully dilutable nonionic microemulsion system was used as a model to explain a possible competitive solubilization mechanism of CH and PS mols. using an EPR technique that reveals relevant intra-micellar properties. The effect of the solubilized sterols on the structural changes occurring in the vicinity of the surfactant head groups or closer to the oil phase was examd. by controlling the pH of the environment, which influences the probe locus between the surfactant mols. The results indicate that the structure transformations in the surfactant layer closer to the vicinity of the head groups region are more pronounced than the structural changes occurring in the region between the surfactant tails closer to the oil phase, except for the oil-in-water (O/W) micelles region. The study also shows that when each of the sterols is solubilized alone, they occupy different solubilization sites within the microemulsion nanostructures, in comparison to their solubilization together. This behavior is most pronounced in 3:1 (wt. ratio) CH/PS systems. The main conclusion is that co-solubilization of these sterols leads to competitive solubilization between the surfactant tails closer to the oil phase locus, where the CH mols. are pushed toward the interface by the PS mols. This conclusion might better explain the competitive solubilization of the two sterols in the human digestive tract. [on SciFinder(R)]

The effect of the solubilized model drug, carbamazepine, on the internal structure of fully dilutable nonionic microemulsions was examd. for the first time using ESR. Systems contg. different surfactant to oil ratios, at two different pH values (4.6 and 8.5), with continuous diln. implementing structural transformations (micellar soln.-W/O-bicontinuous-O/W) were investigated. The internal order, micropolarity, and microviscosity were scrutinized utilizing pH-dependent amphiphilic probe 5-doxylstearic acid (5-DSA). In the basic environment, the probe explored the vicinity of the surfactant head region; the deeper hydrophobic region of the surfactant tails was investigated in the acidic milieu. The study demonstrated that the EPR technique enables efficient monitoring of structural changes and examn. of drug influence on structure in surfactant-poor systems. Lower order and microviscosity values were obtained in surfactant-poor systems in comparison to surfactant-rich systems. The drug functioned as a spacer of the surfactant mols. or as a cosurfactant depending on the formed microemulsion structure and the surfactant to oil ratio. The structural changes, pH variation, and presence of the drug did not alter the polarity parameter, indicating that the probe most likely does not sense a water environment in any of the examd. systems. Under the basic conditions, higher microviscosity and order values were obtained in comparison to those at low pH, suggesting a higher order packing of the surfactant chains near the surfactant heads. The structural changes initiated in the vicinity of the surfactant heads, therefore, are more apparent in the basic environment. The ability to control and monitor the intramicellar interactions within drug carrier systems may be of significant interest for understanding the kinetics of drug release. [on SciFinder(R)]

A review. Coenzyme Q10, present in all cells and membranes, is essential for electron transport in the mitochondrial respiratory chain, antioxidant defense, and other functions of great importance for cellular metab. The essential advantages of CoQ10, combined with its poor and slow absorption, generated the need to develop new technologies for delivery. Therefore, much effort has been expended to design delivery vehicles that can improve its aq. soly. and overall bioavailability for oral and topical administration. This chapter summarizes the findings available today concerning CoQ10 chem. characteristics, human functionalities, its impact on human diseases, and new techniques developed to enhance its delivery. [on SciFinder(R)]

In this paper we report on the solubilization of desmopressin, as a model for peptide drugs, into reverse hexagonal (HII) liq. crystals. Concn.- and temp.-induced interactions of desmopressin, as well as the conformation of the peptide, were studied using small-angle X-ray scattering, ATR-FTIR spectroscopy, SD-NMR, and rheol. measurements. A considerable increase (up to 6 \AA) in the lattice parameter of the mesophases was obtained upon incorporation of the peptide. According to the ATR-FTIR anal., the chaotropic effect of peptide embedment was assigned to its interactions with hydroxyls of monoglyceride in the outer interface region. These interactions had only a minor influence on the conformation of the peptide; weakening or opening the $\gamma$-turns resulted in partial binding of the peptides free carbonyls to monoolein. Temp.-dependent SAXS measurements displayed a chaotropic destabilizing effect of desmopressin on the structure, shifting toward the lower temp. HII-L2 structural transition. Temp. increase resulted in an increase of the domain size in the presence of the peptide, in contrast to the trend obsd. in the empty mesophase. SD-NMR anal. enabled distinguishing between two factors impeding the diffusion of the peptide: the restriction of motion due to the geometrical constrain of diffusion within the water tubes, and the interactions of the guest mol. with monoglyceride. The onset of the crit. behavior at 45 °C was found to be significant, indicating considerable weakening of the monoglyceride and desmopressin interactions and the destabilizing effect of the peptide on the mesophase above this temp. Similar temp.-dependent behavior was revealed by rheol. measurements displaying the same onset of the crit. behavior. It was demonstrated by Franz diffusion cell measurements that hexagonal mesophases can potentially be used as delivery vehicles for sustained delivery of desmopressin. [on SciFinder(R)]

The conditions necessary to form an assocd. complex between whey protein isolate (WPI) and enzymically modified pectin in water, at pH values above the isoelec. point of the protein, have been documented. The existence of the complex is not easily verified and its characterization in soln. is even more complicated, since the structure is an intermediate entity between the non-interacting, incompatible aq. sol. mixt. of the biopolymers, and a strongly interacting coacervated pptg. complex. Evidence for the formation of this assocd. complex is provided from confocal laser scanning microscope images and rheol. behavior of the aq. mixts. The assocd. complex is characterized by small fluorescent "patches" interpreted as small aggregates. The viscosity of this soln. is greater than that of its individual biopolymer constituents, indicating a synergy of attractive interactions that occurs in the soln. While individually, the pectin and the WPI solns. at the studied range of concns. exhibit moderately non-Newtonian behavior, at sp. wt. ratios, mixts. of the two behave either as highly entangled polymeric structures or as weak gels. The values of the storage modulus G' are equal to or greater than those of the loss modulus G''. We conclude that the assocd. complexes are formed at pH 6, and at 4 wt% WPI with a pectin concn. ranging from 0.1 to 0.75 wt%. The influence of the charge distribution (degree of order of the carboxylic groups) of pectin on the assocd. complex was also investigated, and it was found that the more "ordered" pectin (U63) favors the formation of the assocd. sol. complex. [on SciFinder(R)]

Double emulsions based on naturally occurring stabilizers for food applications were studied. Two charged biopolymers, whey protein isolate (WPI) and enzymic modified pectins, interacted in aq. soln. to form a charge-charge complex that was utilized as a hydrophilic polymeric steric stabilizer improving the double emulsion stability. The main factors that influence the interaction between protein and pectin were investigated in relation to double emulsion stability: creaming, coalescence, and water transport between aq. phases. The pH detd. the size of the complex formed. Thus at pH 6, where a sol. complex was obtained between some mol. pos. charged patches on the protein and neg. charged fractions of the hydrocolloids, the double emulsion was the most stable. With the smallest droplet size (∼15 $μ$m), the lowest creaming, highest yield, and minimized water transport were obtained. The best concn. and ratio to form the sol. complex are 4% WPI and 0.5% pectin (for 30% of the W/O inner phase). The influence of the charge distribution (degree of order of the carboxylic groups) of the pectin on the assocd. complex was also investigated, and it was found that the more "ordered" pectin (U63) formed the most stable double emulsion against water transport. [on SciFinder(R)]

Ordered bicontinuous microstructures formed in a fully water-dilutable, pseudoternary unique nonionic microemulsion were obtained and characterized. The conc. contained a mixt. of triacetin/D-$\alpha$-tocopherol acetate/ethanol/Tween 60. Upon diln., the conc. was transformed from a reversed micellar system to oil-in-water microemulsion droplets. The transformation occurred through an intermediate phase of ordered bicontinuous structures. The factors that governed the construction of this unique phase, and its phys. and structural properties, were characterized in detail. The techniques used included small angle X-ray scattering (SAXS), self-diffusion and quantum filtered NMR, differential scanning calorimetry, rheol. measurements, elec. cond., and dynamic light scattering. This mesophase displays microemulsion properties along with some characteristics of lyotropic liq. crystals (but is not a mixt. of the two). Similar to microemulsions, the structures were transparent and spontaneously formed and exhibited thermodn. stability. Yet, unlike microemulsions, they showed short-range order at room temp. Addnl., the microstructures exhibited non-Newtonian flow behavior, characteristic of lamellar structures. The bicontinuous ordered microemulsions were obtained upon heating (to 25 °C) from the lamellar phase existing at low temps. (5 °C). The main feature governing the bicontinuous mesophase formation was the amphiphilic nature of oil blends composed of D-$\alpha$-tocopherol acetate and triacetin. The oils functioned as cosurfactants, altering the packing parameter of the surfactant and leading to the construction of bicontinuous structures with short-range order. These unique structures might have drug or nutraceutical delivery advantages. [on SciFinder(R)]

A dielectric study of reverse hexagonal mesophases (H(II)) is presented. Conducted in the frequency range 0.01-1 MHz and temperature range 293 \textless T \textless 319 K, the study reveals complex molecular behavior in and around the interfaces of the mesoscopic structures of the gel. There exist three clearly defined dielectric relaxations related to separate moieties in the interface, as well as a temperature-activated dc conductivity. A critical temperature, T(0) = 307 K, is noted in the results and related to the dehydration of the glycerol monooleate (GMO) head groups. Effectively, this represents a break-down of the interfacial layer of water. The consequences of this act are clearly visible in the change in behavior of the fitting parameters for all processes. A physical picture emerges whereby at T(0) = 307 K, the ``loosening\''\ of the GMO heads accentuates the dangling motion of the phosphatidylcholine (PC) tails, evidenced by counterion motion along the PC head. Furthermore, it precipitates the percolation of the large TAG molecules that are intercalated in the GMO and PC tails.

The present work investigates the detailed mol. structure of the HII mesophase of glycerol monooleate (GMO) /tricaprylin/phosphatidylcholine/water system in the presence of hydrophobic model peptide cyclosporin A (CSA) via ATR-FTIR anal. The conformation of the peptide in the hexagonal mesophase, as well as its location and specific interactions with the components of the carrier, were studied. Incorporation of phosphatidylcholine to the ternary GMO/tricaprylin/water system caused competition for water binding between the hydroxyl groups of GMO and the phosphate groups of the phosphatidylcholine (PC) leading to dehydration of the GMO hydroxyls in favor of phospholipid hydration. Anal. of CSA solubilization effect on the HII mesophase revealed a significant increase in the strength of hydrogen bonding with surfactant hydrogen-bonded carbonyls, indicating interaction of the peptide with the C=O groups of the surfactants. The peptide probably caused partial replacement of the intramol. hydrogen bonds of the mesophase carbonyl groups with intermol. hydrogen bonds of these carbonyl groups with the peptide. Furthermore, anal. of the Amide I' peak in the FTIR spectra of the peptide demonstrated that two pairs of its internal hydrogen bonds are disrupted when it is incorporated. The partial disruption of the internal hydrogen bonds seems to cause an outward rotation of the peptide amide groups involved, resulting in more efficient intermol. hydrogen-bonding ability. Apparently, this conformational change increased the hydrophilic properties of CSA, even making it susceptible to a weak interaction with the GMO hydroxyl groups in the interfacial region. [on SciFinder(R)]

The use of phospholipids (PL) as surfactants in micellar systems and microemulsions offers many advantages as drug delivery vehicles. PL are commonly used in combination with other non-food surfactants with cosolvents and cosurfactants to form a cascade of delivery structures. The authors incorporated phosphatidylcholine (PC) in a unique U-type water-dilutable phase diagrams exhibiting large isotropic regions of nanostructures. The nanometric liq. structures were prepd. from food-grade emulsifiers. The authors formed water-free concs. with PC that are fully dild. with water to form a variety of unusually structured nanodroplets. Due to the uniqueness of their compn., the designed concs. derived from the nature of the oil phase, type of surfactants, and cosurfactants were characterized and found to be direct micelles (rather than inverse micelles), with the surfactant headgroups convexed toward the hydrophilic phase away from the micelle's core, even in the absence of water. The concs. tend to self-assemble upon adding water to form O/W microemulsions even with small amts. of water (water-poor compns. of 0-20% water). Upon further diln. with water the swollen micelles retain the oil as the inner phase. Multi-component compns. with two types of hydrophilic surfactants were investigated. The most significant enhancement in the total isotropic region was obtained by decreasing the triacetin and PC content in the system. The authors explored, by varying the nature of the headgroups and the nature and length of the lipidic (lipophilic) tails of the PL, the diln. capabilities of each of the systems. [on SciFinder(R)]

W/O/W double emulsions (DEs) stabilized by charged sol. complexes of whey protein isolate (WPI) and modified pectins were investigated in relation to their stability and the release of two types of electrolytes, NaCl and sodium ascorbate. WPI alone cannot properly stabilize the DEs. The droplet size is relatively large (100 $μ$m) and increases with time. However, addn. of modified pectin to form a sol. complex with WPI significantly improved the stability. DEs prepd. with two types of oils (medium chain triglycerides (MCT) and R(+)-limonene) were studied by measuring droplet size, creaming, viscosity, and electrolyte release. Irresp. of their very different oil phase nature, both emulsions were stable against coalescence, but R(+)-limonene formed smaller droplets (25 $μ$m) than MCT (35 $μ$m). The electrolyte release rate was significantly higher from the R(+)-limonene that formed DEs with much lower viscosity. R(+)-limonene-DE released 75% of the NaCl after 28 days, while MCT-DE released only 50%. NaCl was released more slowly than sodium ascorbate. Apparently, the release mechanism from R(+)-limonene-DE was found to be "thinning the outer interface and release of the entire inner droplets" while it seems that the release from MCT-DE was slower and "diffusion controlled". DEs stabilized by WPI/C63 released 12% of the sodium ascorbate after 1 day in milk and remained stable for at least 8 days. However, DEs stabilized with only WPI released about 50% of the sodium ascorbate after 1 day, and phase sepd. after 8 days. [on SciFinder(R)]

This paper describes the formation and characterization of liq. cryst. dispersions based on the hexagonal phase of GMO/tricaprylin/water. As a stabilizer of the soft particles dispersed in the aq. phase, a non-ionic, non-polymeric surfactant-ethoxylated phytosterol with 30 oxyethylene units (PhEO) was utilized. In contrast to Pluronic copolymers, normally utilized in the stabilization of liq. cryst. dispersions with ordered inner structure, use of such non-polymeric surfactant is not a common practice in this field. The authors revealed how properties of these particles, such as internal structure, size, and stability, can be rationally modified by the concn. of the stabilizing agent and processing conditions. The phys. stability of the hexosomes was further examd. by the LUMiFuge technique. Structural effect of PhEO solubilization on the properties of the bulk HII mesophase system showed that phase behavior was greatly influenced following phase transitions: HII → HII + cubic → cubic + L$\alpha$ → L$\alpha$. The decrease of hydrogen bonding of the hydroxyl and carbonyl groups of monoolein with water and simultaneous hydration of EO groups of PhEO appeared to be important for the obsd. behavior. The use of PhEO as a dispersant resulted in a soft matter multi-phase water dispersion with bimodal distribution of the particle population. Effective stabilization of hexosomes was obtained in an extremely narrow concn. range of PhEO (0.1-0.2%), coexisting with small vesicles and disordered particles. At higher PhEO content, particles had disordered inner structure, and unilamellar and multilamellar vesicles, at the expense of hexosomes in consequence of incorporation of the dispersant into the hexosome structure. PhEO was found to induce lamellar phase formation, introducing disorder into the hexagonal LLC and reducing their domain size. Finally, hexosomes were evaluated as delivery vehicles for the therapeutic peptide desmopressin. Sustained release of this drug was obsd. during the first 10 h; however, permeation drastically increased in the 10-24 h range. [on SciFinder(R)]

A review. Liq. crystals are widely utilized as model systems to mimic biol. processes where the phase behavior of lipids plays a mediating role. In various foods and pharmaceutical and biotech. applications, the liq. cryst. phases formed by surfactants in an aq. medium represent useful host systems for drugs, amino acids, peptides, proteins and vitamins. Various biol. active food additives are sol. in neither aq. nor oil phase and require environmental protection against hydrolysis or oxidn. Lyotropic liq. crystals meet these requirements mainly due to their high solubilization capacities for hydrophilic, lipophilic and amphiphilic guest mols. Moreover, recent studies demonstrated controlled and/or sustained release of solubilized mols. from different liq. cryst. matrixes. This paper surveys the solubilization of hydrophilic, lipophilic and amphiphilic guest mols. for food applications and illustrates the corresponding structural transformations. Recent developments in liq. crystal characterization methods are discussed. [on SciFinder(R)]