Self-diffusion cubic phases

In this work we will focus on the use of the cubic phase as a delivery system for oligopeptides - Desmopressin, Lysine Vasopressin, Somatostatin and the Renin inhibitor H214/03. The amino acid sequences of these peptides are given in Table I. The work focuses on the cubic phase as a subcutaneous or intramuscular depot for extended release of peptide drugs, and as a vehicle for peptide uptake in the Gl-tract. Several examples of how the peptide drugs interact with this lipid-water system will be given in terms of phase behaviour, peptide self-diffusion, in vitro and in vivo release kinetics, and the ability of the cubic phase to protect peptides from enzymatic degradation in vitro. Part of this work has been described elsewhere (4-6). 

The non-collective motions include the rotational and translational self-diffusion of molecules as in normal liquids. Molecular reorientations under the influence of a potential of mean torque set up by the neighbours have been described by the small step rotational diffusion model.118 124 The roto-translational diffusion of molecules in uniaxial smectic phases has also been theoretically treated.125,126 This theory has only been tested by a spin relaxation study of a solute in a smectic phase.127 Translational self-diffusion (TD)29 is an intermolecular relaxation mechanism, and is important when proton is used to probe spin relaxation in LC. TD also enters indirectly in the treatment of spin relaxation by DF. Theories for TD in isotropic liquids and cubic solids128 130 have been extended to LC in the nematic (N),131 smectic A (SmA),132 and smectic B (SmB)133 phases. In addition to the overall motion of the molecule, internal bond rotations within the flexible chain(s) of a meso-genic molecule can also cause spin relaxation. The conformational transitions in the side chain are usually much faster than the rotational diffusive motion of the molecular core. 

While there have been efforts to polymerize other surfactant mesophases and metastable phases, bicontinuous cubic phases have only very recently been the subject of polymerization work. Through the use of polymerizable surfactants, and aqueous monomers, in particular acrylamide, polymerization reactions have been performed in vesicles (4-8). surfactant foams ), inverted micellar solutions (10). hexagonal phase liquid crystals (111, and bicontinuous microemulsions (121. In the latter two cases rearrangement of the microstructure occured during polymerization, which in the case of bicontinuous microemulsions seems inevitable b ause microemulsions are of low viscosity and continually rearranging on the timescale of microseconds due to thermal disruption (131. In contrast, bicontinuous cubic phases are extremely viscous in genei, and although the components display self-diffusion rates comparable to those... 

The solution to the problem came in the late 1970s with the pioneering work of Scriven [30], introducing the bicontinuous structures based on minimal surfaces. Scriven s work, which included considerations of other surfactant phases (e.g. bicontinuous cubic phases), considerably stimulated the field and his ideas, based on theoretical arguments, were soon confirmed by experimental work, using mainly self-diffusion, electron microscopy and neutron scattering measurements. 

Results for the monoolein/water system give mutual diffusion coefficients ranging from 0.7-1.5 x 10-6 cm/s in the fluid isotropic, lamellar liquid crystal and cubic phases ([55a], Fig.7).These values are up to an order of magnitude lower than literature values of the self diffusion coefficients determined by pulsed field gradient NMR for this same system [96],... 

In the bilayer continuous structures occurring in the bicontinuous cubic and L3 phases, the diffusion can be described by essentially the same equations. Finally, we note that Eqs. (4)-(6) have been applied to the analysis of self-diffusion data from a number of bicontinuous microemulsions, L3 phases, and bicontinuous cubic phases [34-36]. 

Figure 27 The relative self-diffusion coefficient (D/Do) of water plotted as a function of the surfactant volume fraction in the L3 and bicontinuous cubic phases of the AOT-water-NaCl system. Note the continuous variation of the self-diffusion coefficient across the L3-cubic phase transition, demonstrating the structural similarity of the two phases. (Data taken from Ref. 34.)...

It would be interesting to compare these results with the findings of Ericsson et al. who measured diffusion of this peptide in the aqueous channels of the cubic phase [53]. According to these investigators, the self-diffusion data indicated that desmopressin interacted significantly with the monoolein-water interface. For example, the desmopressin diffusion coefficients in the cubic phase at 40 °C was about a factor 9 smaller than in H20 solution, a difference that is larger than what... 

The O self-diffusion coefficient for samples which contained between 12 and 16mol%MgO was determined by using the isotope exchange technique and an 1 0 tracer. The results for single-phase cubic material containing 12mol%MgO could be described by ... 

Using a similar approach as for cubic phases, it was thus quite straightforward to address the problem of microemulsion structure. Thus, by measuring oil and water self-diffusion, it was quite easy to establish whether oil or water or none of them are confined to discrete domains, droplets. In the first work on microemulsion structure by self-diffusion, using both tracer techniqnes and NMR spin-echo measurements, it was clearly shown that, in addition to droplet microemulsions, over wide ranges of composition they can be bicontinuous [6] this is manifested by both oil and water diffusion being rapid, not much less than the self-diffusion of the neat liquids. 

Anderson, D. M. and Wennerstrom, H., Self diffusion in bicontinuous cubic phases, L3 phases and microemulsions, J. Phys. Chem., 94, 8683-8694 (1990). 

Figure 17.25. The variation of the reduced water self-diffusion coefficient with 0s in the sponge (filled symbols) and the bicontinuous cubic (open symbols) phases. The continuous line corresponds to D /D = 0.66 — 0.770s and is a linear fit to the data from the sponge phase (data are taken from ref. (31))...

Figure 17.27. Self-diffusion coefficients of water ( , ), oil (a, a) and surfactant (O, ) in the bicontinuous cubic and oil-rich sponge phases of the Ci2E5-water-tetradecane system. The C12E5-to-water weight ratio is kept constant at 60/40, and the diffusion coefficients are plotted as a function of the oil volume fraction, o- Experiments were performed at the following temperatures in the cubic phase at o = 0-41 and 0.44, T = 20°C in the cubic phase at o = 0.48, T = 23°C in the sponge phase at o = 0.61, T = 25°C. The fact that the diffusion constants are essentially the same in the two phases demonstrates that the ordered (cubic) and disordered (sponge) structures are very similar (data taken from ref. (37))...

The direct NMR method for determining translational difiFusion constants in liquid crystals was described previously. The indirect NMR methods involve measurements of spin-lattice relaxation times (Ti,Ti ),Tip) [7.45]. Prom their temperature and frequency dependences, it is hoped to gain information on the self-diflPusion. In favorable cases, where detailed theories of spin relaxation exist, difiFusion constants may be calculated. Such theories, in principle, can be developed [7.16] for translational difiFusion. However, until recently, only a relaxation theory of translational difiFusion in isotropic hquids or cubic solids was available [7.66-7.68]. This has been used to obtain the difiFusion correlation times in nematic and smectic phases [7.69-7.71]. Further, an average translational difiFusion constant may be estimated if the mean square displacement is known. However, accurate determination of the difiFusion correlation times is possible in liquid crystals provided that a proper theory of translational difiFusion is available for liquid crystals, and the contribution of this difiFusion to the overall relaxation rate is known. In practice, all of the other relaxation mechanisms must first be identified and their contributions subtracted from the observed spin relaxation rate so as to isolate the contribution from translational difiFusion. This often requires careful measurements of proton Ti over a very wide frequency range [7.72]. For spin - nuclei, dipolar interactions may be modulated by intramolecular (e.g., collective motion, reorientation) and/or intermolecular (e.g., self-diffusion) processes. Because the intramolecular (Ti ) and intermolecular... 

In the previous study [7], we have shown that when the temperature exceeds about 55 °C, the self-diffusion coefficient approaches the value expected from the data in the cubic phase where the lateral diffusion is dominant. In this temperature range, the slow mode cannot be distinguished from the fast mode because decreases rapidly with increasing temperature, suggesting that the R x )... 

A similar series of samples as in the SANS experiments was studied in cooperation with the group of Prof. Wokaun by NMR self-diffusion experiments. Tbe pulsed field gradient spin echo (PGSE) method [67, 68] allows the determination of the self-diffusion coefficient of each of the individual constituent components in particular water, surfactant, and hydrocarbon. Here, in order to obtain simpler NMR spectra the hydrocarbon was cyclohexane. The molar ratio of C14DMAO cyclohexane was chosen to be 1 1.2, with three samples in the Lj phase and three samples in the cubic phase. 

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