Production of new polymer liquid crystals capable of having...

Details Production of new polymer liquid crystals capable of having... Production of new polymer liquid crystals capable of having...

1999-09-22

2001-08-21

Kishore, Gollamudi S. (Department: 1611)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C428S402200

Reexamination Certificate

active

06277403

ABSTRACT:

FIELD OF APPLICATION
The present invention fits within a first chemical sector with biomedical and pharmacological applications.
PRIOR ART
Liquid crystals are self-organizable systems. They do not pass directly from the crystalline state to the isotropic melt, when being heated, but rather they form mesophases that combine the order of the perfect crystal with the mobility of the liquid. Their molecular base is almost always simple: they form anisotropic or amphiphilic molecules with a rigid geometry (mesogenic unity) connected to another flexible part (spacer), that package in blocks with anisotropic properties (H. Ringsdorf, B. Schlarb and J. Venzmer, “Molecular Architecture and Function of Polymeric Oriented Systems: Models for the Study of Organization, Surface Recognition, and Dynamics of Biomembranes”, Ang. Chem. Int. De. Engl. 1988, 27, pp. 116). The parallel orientation of their longitudinal molecular axis is common to all mesophases. Two main types may be distinguished: Nematic (with their molecular centers distributed isotropically) and smectic (molecular centers organized in planes). The spatial arrangement of nematic planes stacked in a helicoid superstructure, characterized by a preferable chirality, is known as cholesteric mesophase. Cholesteric mesophases reflect incident light and when their helix pitch is comparable to the wavelength of the visible light, they exhibit typical bright colors.
U.S. Pat. No. 4,999,348 discloses compositions for topical use, providing controlled release and penetration of biologically active substances comprising cholesteric liquid crystals the lamellar molecular structure of which entraps the biologically active substance is entrapped. Specifically, the compositions comprise vitamin A, the cholesteric liquid crystal and a polyacrylic gel which forms a polymeric skin around the liquid crystals.
WO-A-9319735 discloses a process for preparing microcapsules or liposomes with controlled sizes which may optionally be encapsulated by polymer coatings wherein monomers capable of polymerizing within the liposomes or microcapsules are used, and wherein the whole of a microcapsule or liposome and the polymerized monomers form a liquid crystal.
The development of polymer liquid crystals followed that of monomer liquid crystals and began with polymers whose main chain, as a whole, acted as a mesogene, those prepared from a solution (lyotropic) as well as those prepared from a melt (thermotropic). Subsequently, the mesogenic units were introduced well hung from the main chain by means of a flexible spacer (of side chain) or connected all along the main chain by a flexible aliphatic spacer (of main chain).
In 1982, Lenz et al (C. Ober, J. I. Jin, R. W. Lenz, Polym. J. 1982, 14, 9) synthesized thermotropic polymer liquid crystals whose mesogenic unity, previously studied in works of low molecular weight, based on a central residue of terephthalic acid flanked by two p-oxybenzoil residue connected by flexible polymethylene spacers. High transition temperatures were obtained from transition to the mesophase and to the isotropic melt.
Galli et al. (G. Galli, E. Chiellini, C. K. Obert, R. W. Lenz, Makromol. Chem. 1982, 183, pp. 2693) in 1982 also introduced to the mesogene itself flexible spacers compatible with the aqueous system under physiological conditions, that is to say, hydrophilic spacers with a low molecular weight with hydroxy ending, of the oligo oxyethelene and olio oxypropylene type, the latter containing chiral centers in each unit. These spacers had also been used in low molecular weight liquid crystals, for the purpose of reducing the transition temperatures. The influence of the type, length and distribution of the spacers on the behavior of the formed mesophases was observed, limiting the liquid crystal nature of the polymers to 10 units in the spacer.
In 1983. Malanga et al. (C. Malanga, N. Spassky, R. Menicagly, E. Chiellini, Polymer Bulletin 1983, 9, pp. 336) extended the synthesis, using as flexible spacers optically active dioles with a different length and degree of substitution, capable not only of giving the polymers a hydrophilic nature but also the cholesteric stereochemical arrangement to the mesophase thereof. Starting with chiral glycols (an enantiomer of a specific sign) as the spacer, a polymer with the same optical sign was obtained in all cases. Starting with the racemic mixture of glycol as the spacer, a “racemic” non-chiral polymer with a nematic, never cholesteric, mesophase was always obtained (E. Chiellini, R. Po, S. Carrozzino, G. Galli and B. Gallot, “Chiral Liquid-Crystalline Polymers. IX. The Effect of Chiral Spacer Structure in Thermotropic Polyesters”, Mol. Cryst. Liq. Cryst. 1990, Vol. 179, 405-418; E. Chiellini, R. Solaro, G. Leonardi, R. Lisciani, G. Mazzanti, Eur. Pat. Appln. 19, pp, EP 509968 A1 921021; E. Chiellini, R. Solaro, L. Bemporad, S. D'Antone, Eur. Pat. Appln., 11, pp, EP 486445 A2 920520; E. Chiellini, R. Solaro, L. Bemporad, Eur. Pat. Appl., 13 pp. EP 486437 A2 920520).
The nematic compound (C
26
H
20
O
8
)n obtained from the racemic mixture of the corresponding glycol of its spacer, has been described by Chiellini (E. Chiellini, R. Po, S. Carrozzino, G. Galli and B. Gallot, “Chiral Liquid-Crystalline Polymers. IX. The Effect of Chiral Spacer Structure in Thermotropic Polyesters” Mol. Cryst. Liq. Cryst., 1990, Vol. 179, 405-418), as non-toxic, compatible with blood and permeable to different solutes (E. Chiellini, G. Galli, R. W. Lenz and C. K. Ober Preprints IUPAC Symposium on Macromolecules, Amherst, 1982, p. 365). In the same study a series of polycarbonates synthesized from mixtures of Bisphenol A and oligoethers hydroxy ended with phosgene in a pyridine-dioxane solution are described. The authors affirm having synthesized gel membranes from these polycarbonates by the phase reversal technique (E. Chiellini, G. Galli, R. W. Lenz and C. K. Ober Preprints IUPAC Symposium on Macromolecules, Amherst, 1982, p. 365), achieving improved mechanical properties.
A parallelism can be established between the behavior of the liquid crystals in material science and lipids in life sciences (H. Ringsdorf, B. Schlarb and J. Venzmer, “Molecular Architecture and Function of Polymeric Oriented Systems: Models for the Study of Organization, Surface Recognition and Dynamics of Biomembranes”. Ang. Chem. Int. De. Engl. 1988, 27, pp. 116).
Lipids are also self-organizable combining order and mobility. The arrangement of their amphiphilic molecules in water form liposomes, spherical two-layer or multi-layer structures that are cellular models useful to study membrane properties and cellular interactions (H. Bader and H. Ringsdorf Preprints IUPAC Symposium on Macromolecules, Amherst, 1982, p.341).
Liposomes are particularly interesting as potential agents to encapsulate sensitive biomaterials (G. Gregoriadis, A. C. Alison, eds. “Liposomes in biological systems”; John Wiley and Sons, Chichester, N.Y. (1980)). However, a severe inconvenience in the use of liposomes as a vehicle for drugs for release thereof inside the body, is their rapid ingestion by the cells of the reticuloendothelial system, varying the average life time of the liposomes in the blood, t
½
between minutes and dozens of minutes (D. D. Lasic, “Liposomes from Physics to Applications”; Elsevier Science Publishers B. V., Amsterdam, London, New York, Tokyo (1993)), which eliminates many of the intravenous uses of liposomes.
WO-A-9420073 discloses lipid-polymer conjugates and the combination thereof with liposomes, said conjugates comprising a vesicle-forming lipid and a polymer covalently attached to the lipid. To be able to attach to the lipid, the lipid must have a polar head group.
Different processes to lengthen the average life time of liposomes in blood have been developed. One of them is the concept of “stealth liposome”, developed by Lasic (D. D. Lasic, “The Stealth Liposome”, Chemical Review, Vol. 95, No. 8 (1995), 2605), where polymer chains, normally polyethyelene glycol, are grafted on the surface thereof “concealing it” a

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