This invention relates to functionalized cubic liquid crystalline phases and methods for their preparation and use. More specifically, this invention relates to functionalized cubic liquid crystalline phase materials that have properties tailored to specific uses.
Much of the interest in bicontinuous cubic phase liquid crystals is a consequence of their unique structure. They are composed of mixtures of lipid and water arranged into bilayers. The bilayers, in turn, are twisted into a periodic, three-dimension structure that minimizes the energy associated with bending the bilayers (i.e. minimize curvature energy). See Hyde, S., Andersson, S., Larrson, K., Blum, Z., Landh, T., Lidin, S., Ninham, B. W., The Language of Shape, Elsevier Press, New York, 1997. These structures are xe2x80x98honeycombedxe2x80x99 with bicontinuous domains of water and lipid that is reminiscent of an organic zeolite or highly-structured microemulsion. As such the structure can simultaneously accommodate water-soluble, lipid-soluble and amphiphilic molecules and provide pathways for diffusion of water-soluble and lipid-soluble materials. While there have been a number of proposed cubic phases, there are three recognized bicontinuous liquid crystals structures: Pn3m (D-surface), Ia3d (G-surface), and Im3m (P-surface). See Luzzati, V., Vargas, R., Mariani, P., Gulik, A., Delacroix, H., J. Mol. Biol., 1993, 229, 540-551. These structures can be difficult to express in rigorous mathematical terms. However, if expressed in terms of nodal surfaces, structure and shape can be approximated. See von Schnering, H. G., Nesper, R. Z., Phys. B-Condensed Matter, 1991, 83, 407-412. The phase behavior of a broad range of monoglycerides has been documented and modifications to the phase behavior have been defined. See Qiu, H., Caffrey, M., xe2x80x9cThe phase diagram of the monoolein/water system: metastability and equilibrium aspectsxe2x80x9d, Biomaterials, 1999, 21(3), 223-234. Accordingly, monoolein-based bicontinuous cubic liquid crystal phase have good temperature stability, high internal surface area, gel-like viscosity, relative insensitivity to salt and solvent compositions, and use low cost raw materials which make them practical for commercial applications. Monoolein naturally exhibits Pn3m and Ia3d, with Im3m present with the addition of proteins. See Rummel, G., Hardmeyer, A., Widmer, C., Chiu, M. L., Nollert, P., Locher, K. P., Pedruzzi, I., Landau, E. M., Rosenbusch, J. P., J. Structural Biology, 1998, 121, 82-91.
Cubic phase liquid crystals have been used in gel, dispersion and precursor form. xe2x80x98Gelsxe2x80x99 are mixtures that contain a majority of the cubic phase liquid crystal. It is common for either mixture to exclusively contain cubic liquid crystal phase. Applications for these gels can range from drug delivery vehicles (See Shah, J. C., Sadhale, Y., Chilukuri, D. M., Adv. Drug Delivery Rev., 2001, 47(2-3), 229-250), to a matrix in which membrane proteins can be crystallized (See Landau, E., Rosenbusch, J., Proc. Natl. Acad. Sci. USA., 1996, 93(25), 14532-14535), or in which mesoporous nanoparticles can be formed (See Cruise, N., Jansson, K., Holmberg, K., J. Colloid Interface Sci., 2001, 241(2), 527-529).
Nielsen, WO 98/47487, discloses compositions of bio-adhesive liquid crystal gels, including the cubic phase liquid crystals and precursors. Compostions include an active, a cubic phase forming lipid, and a structurant that is added without changing the structure of the liquid crystal. These compositions do not disclose the use of hydrotropes to form liquid crystals.
Engstrom et al., U.S. Pat. No. 5,753,259, discloses a composition and method of use of liquid crystal gels, including cubic phase liquid crystals, for controlled release applications. The disclosed gels are fabricated from a mixture of lipid, solvent, and bioactive materials including nucleic acids. However, these gel compositions do not utilize hydrotropes.
xe2x80x98Dispersionsxe2x80x99 are particles of cubic liquid crystalline phase material that are often submicron in size. Particles are generally dispersed in a liquid medium and are often termed Cubosomes. Cavitating a mixture of lipid and liquid generally makes dispersions of cubic phase liquid crystals. This requires high pressures and numerous passes before homogeneous nanoparticle dispersions are produced (See Ljusberg-Wahren, H., Nyberg, L., Larsson, K., Chimica Oggi, 1996, 14, 40-43). Cubosomes have distinct practical advantages over vesicles and liposomes because cubosomes are an equilibrium phase (See Laughlin, R. G. Colloids and Surfaces A, 1997, 128, 27-38). Cubosomes also possess much greater internal surface area than vesicles or liposomes and are more resilient against degradation.
Anderson, WO 99/12640, and Landh et al., U.S. Pat. No. 5,531,925, disclose cubic phase compositions and preparations for delivery and uptake of active agents. The particles comprise a center containing liquid crystalline or liquid material and an exterior of solid particulate. The composition of the liquids comprise a lipid and polar solvent without the sue of hydrotropes.
xe2x80x98Precursorsxe2x80x99 are mixtures that are not cubic phase liquid crystals but form cubic phase liquid crystals as a consequence of a stimulus. Precursors can be used to dispense a mixture in a form that readily flows, but spontaneously converts to a more viscous liquid crystal with the stimulus at a target location. This is applicable to treatments for periodontal disease (See Norling, Tomas, Lading, Pia, Engstroem, Sven, Larsson, Kare, Krog, Niels, Nissen, Soeren Soe, J. Clin. Periodontol, 1992, 19(9, Pt. 2), 687-92. Larson et al., U.S. Pat. No. 5,196,201, discloses the preparation and composition of precursors used as implants to treat aliments such as the repair of bone tissue. These precursors are composed of a water-based liquid, lipid, and optionally a triglyceride mixed to form a more concentrated L2 or D phase, which flows more readily, and converts to cubic phase upon the addition of water. Leng et al., U.S. Pat. No. 5,593,663, discloses combinations and preparations of antiperspirant, which uptake sweat upon application to form a viscous liquid crystalline phase, including cubic phase. However, neither of these materials contains functionalization materials.
Cubic liquid crystalline phase materials are limited in use due to restriction of their natural, or unmodified, properties. For example, the natural properties of cubic phases limit the ability to solubilize active ingredients. In fact, broad classes of actives do not effectively load (or subsequently release) because the cubic phase lacks specific interaction with the loaded active. If the active is modified to effectively load in the cubic phase, it may lose its effectiveness. Further, there are no commercially convenient ways to provide specific targeting or enhanced deposition of actives from cubic phase. Finally, there are no cubic phases suitable for xe2x80x98on demandxe2x80x99 applications. xe2x80x9cOn demandxe2x80x99 refers to changes in the properties of cubic phase as a consequence of some stimulus, such as change in pH. As a result, a technique is needed to modify the cubic phase and significantly increase the utility of cubic phase.
A cubic liquid crystalline phase precursor comprising (A) a hydrotrope, (B) an amphiphile capable of forming a cubic liquid crystalline phase, (C) an optional solvent, and (D) an additive selected from the group consisting of an anchor, a tether, and combinations thereof, wherein ingredients (A), (B), (C), and (D) are present in mass fractions relative to each other such that 1.0=a+b+c+d, wherein a is the mass fraction of ingredient (A), b is the mass fraction of ingredient (B), c is the mass fraction of ingredient (C), and d is the mass fraction of ingredient (D), and wherein 1.0 greater than a greater than 0, 1.0 greater than b greater than 0, 1.0 greater than cxe2x89xa70, 1.0 greater than d greater than 0; and with the proviso that a, b, c, and d do not fall within a cubic liquid crystalline phase region on a phase diagram representing phase behavior of ingredients (A), (B), (C), and (D).
A bulk cubic liquid crystalline gel comprising (A) a hydrotrope, (B) an amphiphile capable of forming a cubic liquid crystalline phase, (C) a solvent, and (D) an additive selected from the group consisting of an anchor, a tether, and combinations thereof, wherein ingredients (A), (B), (C), and (D) are present in mass fractions relative to each other such that 1.0=a+b+c+d, wherein a is the mass fraction of ingredient (A), b is the mass fraction of ingredient (B), c is the mass fraction of ingredient (C), and d is the mass fraction of ingredient (D), and wherein 1.0 greater than a greater than 0, 1.0 greater than b greater than 0, 1.0 greater than c greater than 0, 1.0 greater than d greater than 0; and with the proviso that a, b, c, and d fall within a cubic liquid crystalline phase region on a phase diagram representing phase behavior of ingredients (A), (B), (C), and (D).
A disperison of cubic liquid crystalline gel particles comprising (A) a hydrotrope, (B) an amphiphile capable of forming a cubic liquid crystalline phase, (C) a solvent, and (D) an additive selected from the group consisting of an anchor, a tether, and combinations thereof, wherein ingredients (A), (B), (C), and (D) are present in mass fractions relative to each other such that 1.0=a+b+c+d, wherein a is the mass fraction of ingredient (A), b is the mass fraction of ingredient (B), c is the mass fraction of ingredient (C), and d is the mass fraction of ingredient (D), and wherein 1.0 greater than a greater than 0, 1.0 greater than b greater than 0, 1.0 greater than c greater than 0, 1.0 greater than d greater than 0; and with the proviso that a, b, c, and d fall within a region representing cubic liquid crystalline phase in combination with at least one other phase on a phase diagram representing phase behavior of ingredients (A), (B), (C), and (D), with the proviso that the dispersion has a form of functionalized cubic liquid crystalline gel particles dispersed in the other phase.