Amphiphilic macrocyclic derivatives and their analogues - Patents

Amphiphilic macrocyclic derivatives and their analogues

Agent: Jacobson Holman PLLC - Washington, DC, US
Inventors: Raphael Darcy, Lawrence John Penkler, Bart Jan Ravoo
Class: 514058000 (USPTO), (Intl Class)
#20060148756
07/06/06

Soluble amphiphilic macrocycle analogues having lipophilic groups attached to one side of the units making up the macrocycle and hydrophilic groups attached to the other side. These amphiphilic macrocyclic derivatives have the ability to self-assemble in aqueous solvent forming micelles or vesicles and can be used as hosts for the solubilisation and/or stabilisation of various compounds. Embodiments of the present invention utilise macrocyclic oligosaccharides and preferably cyclodextrin as the macrocyclic derivatives to be modified.
INTRODUCTION
[0002] The present invention is directed to the production of soluble macrocyclic derivatives of a type which forms micelles and vesicles for use in encapsulation of molecules.
[0003] The invention particularly relates to soluble amphiphilic macrocyclic derivatives having lipophilic groups attached to one side of the units making up the macrocycle and hydrophilic groups attached to the other side.
[0004] Macrocyclic oligosaccharides are typified by cyclodextrins, which are cyclic oligosaccharides composed of D-glucose residues linked together by .alpha.-(1-4) bonds (FIG. 1). The most common examples of cyclodextrins contain six, seven or eight .alpha.-(1-4)-linked D-glucopyranosyl units bonded together into cylinder-shaped molecules and are referred to as .alpha.-, .beta.-, and .gamma.-cyclodextrins, respectively. As a consequence of the conformation of the glucopyranose units, all secondary hydroxyl groups are placed on one rim of the cylinder and all primary hydroxyl groups are placed on the other. The cylindrical interior (cavity) of the molecule is lined with hydrogen atoms and glycosidic oxygen atoms which cause it to be hydrophobic.
[0005] The cylindrical structures can be used as hosts for the inclusion of various compounds within their cavities, usually organic compounds, in the food, pharmaceutical and chemical industries. Cyclodextrins have been used to form inclusion complexes with hydrophobic molecules in which these molecules are encapsulated within the compatible hydrophobic cavity of the cyclodextrin macrocycle. This process of molecular encapsulation confers increased water solubility on the included molecule, as well as other properties such as increased stability and lowered volatility. It also allows control of the availability of the molecule, for example the bioavailability of a drug. See, e.g., Uekama et al, in CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3, 1-40 (1987).
[0006] There are problems associated with the use of unmodified cyclodextrins to form inclusion complexes for the pharmaceutical industry. Widespread use of the inexpensive beta-cyclodextrin for example has been limited by its relatively low solubility in water. R. B. Friedman in U.S. Pat. No. 4,920,214 discloses how the water solubility of the cyclodextrins may be significantly increased by modification with alkylene carbonates to form hydroxyethyl ethers. Low aqueous solubility is however still a problem with many modified cyclodextrins.
[0007] A further limitation to the use of cyclodextrins as hosts for molecules, is that the hydrophobic molecules which can be included are limited by the size of the central cavity. Several attempts have been made to alter the cyclodextrin structures to enable them to encapsulate other molecules regardless of size. Cyclodextrins have been modified with lipophilic groups at the 2- and 3-positions (the secondary-hydroxyl side) of the glucose units, together with polar groups such as amino groups at the 6-positions (the primary-hydroxyl side), in order to confer amphiphilic character. Such derivatives are described by Skiba et al. in U.S. Pat. No. 5,718,905 and form monolayers, nanoparticles, and mixed lyotropic (solution) phases with other amphiphiles.
[0008] Similar derivatives with lipophilic substitution on the secondary side have been described in various reports (P. Zhang et al, Journal of Physical Organic Chemistry 1992, 5, 518-528; A. Gulik et al, Langmuir 1998, 14, 1050-1057; D. Duchene and D. Wouessidjewe, Proc. Int. Symp. Cyclodextrins, 8th, 1996, 423-430). Such derivatives are characterised by the formation of nanoparticulate aggregates which are able to trap hydrophobic or hydrophilic guest molecules to a greater or lesser extent. The entrapped guest is however instantaneously released upon contact of the nanoparticle with a solution medium (E. Lemos-Senna et al, Proc. Int. Symp. Cyclodextrins, 8th, 1996, 431-434). These systems are capable of entrapping both water-soluble and water-insoluble drugs (M. Skiba et al, International Journal of Pharmaceutics, 1996, 129, 113-121). The self-assembly properties of amphiphilic cyclodextrins have been reviewed by Coleman et al in Molecular Engineering for Advanced Materials, 1995, 77-97, Kluwer Academic Publishers (J. Becher and K. Schaumberg eds). Cyclodextrins have also been modified with lipophilic groups at the 6-positions (see C.-C. Ling, R. Darcy and W. Risse, J. Chem. Soc. Chem. Commun., 1993, 438-440). Djedaini-Pilard et al., in U.S. Pat. No. 5,821,349, describe cyclodextrins modified with alkylamino groups at the 6-position for incorporation of included hydrophobic guest molecules only into other organised surfactant systems. The heretofore described amphiphilic cyclodextrins are not soluble in water and are not capable of forming a sufficiently stable micelle or vesicle with structural properties which enable retention of entrapped molecules within the micelle or vesicle even after dilution in a solution medium.
[0009] A first object of the present invention is to modify macrocyclic derivatives typified by cyclodextrins and other macrocyclic oligosaccharides so that they are enabled by molecular self-assembly to form micelles and vesicles in aqueous solvents of their own accord giving rise to structures which enable retention of entrapped molecules within the micelle or vesicle even after dilution in a solution medium, with advantages for the delivery of therapeutic molecules. A second object of the invention is to modify the surface of the micelles or vesicles of the invention to facilitate specific attachment of the micelle or vesicle to certain cell membrane structures, with advantages for targeting and intracellular delivery of entrapped therapeutic molecules.
Complete article is available online.