Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-01-27
2002-05-28
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S078020, C514S559000, C514S772300, C514S772700, C514S773000
Reexamination Certificate
active
06395284
ABSTRACT:
The present invention relates to mesomorphic complexes of vitamin A acid and cationic polyelectrolytes, in particular in the form of films or nanodispersions, to process for their preparation and to the use of the mesomorphic complexes as vitamin A substitute.
Vitamin A acid is a highly crystalline low molecular weight material. Lipophilic hormones such as vitamin A acid, steroids, thyroid hormones and vitamin D
3
act by binding to ligand-activated transcription factors comprising the steroid
uclear receptor superfamily (R. M. Evans, Science 240 (1988), 889). Intensive investigations are currently in progress into the role of vitamin A acid in cell differentiation by investigating the binding properties of the retinoids to specific proteins (W. Bourguet, M. Ruff, P. Chambon, H. Gonemeyer and D. Moras, Nature 375 (1995), 377; J. -P. Renaud, N. Rochel, M. Ruff, V. Vivat, P. Chambon, H. Gronemeyer and D. Moras, Nature 378 (1995), 681).
In addition to their important role in the transmission of pleitrophic effects on morphogenesis, differentiation and hemostasis during the embryonic and postnatal phase of life, vitamin A acid shows a great potential as pharmacological active substance. At present, vitamin A acid is used for the external treatment of severe cases of acne, and its use for courses of skin rejuvenation has also been suggested (A. H. Lewin, M. E. Bos, F. C. Zusi, X. Nair, G. Whiting, Bouquin, G. Tetrault and F. I. Carroll, Pharm. Res 11 (1994), 192). Finally, there is also evidence of an inhibition of malignant tumors by retinoids (G. Zanotti, M. R. D'Acunto, G. Malpeli, C. Folli and R. Berni, Eur. J. Biochem. 234(2) (1995), 563; E. P. Jaeger, P. C. Jurs and T. R. Stouch, Eur. J. Med. Chem. 28(4) (1993), 275).
All retinoids have the same characteristic properties as highly UV-active chromophore and have low solubility in aqueous medium and are chemically unstable. This is why, in nature, retinoids bind to specific retinoid-binding proteins which confer protection, solubility and transportability in body fluids. A major problem in relation to the administration of vitamin A acid as pharmacological active substance is the need for immobilization. One possibility of achieving such immobilization and thus a protection of vitamin A acid is to bind it to a protein, as demonstrated in nature. A successful example of this strategy was shown by Zanotti et al., who cocrystallized transthyretin and vitamin A acid. This procedure is, however, difficult and cost-intensive.
European Patent 0 680 748 A1 discloses a composition in the form of a gel which contains an acidic, hydrophilic medium and at least one gel former which is formed from a crosslinked cationic polymer, which is characterized in that the hydrophilic medium is a medium which contains an amount of organic solvent which is 20 to 90% of the total weight of the composition, and contains an amount of water which is not more than 45% of the total weight of the composition, the gel former conferring on the composition a macroscopically homogeneous appearance of a gel and stability, and the cosmetic use of this gel, in particular for skin depigmentation. Gels of this type have an amorphous structure, and their viscosity and thus also their stability is determined by the degree of crosslinking of the polyelectrolytes. The release of a substance present in this gel in unbound form, such as, for example, retinoate, can be controlled by adjusting the viscosity of the gel. The high content of organic solvent in this gel is disadvantageous for use as medicinal product.
It was therefore the object of the present invention to provide a possibility for the immobilization of vitamin A acid which can be carried out easily and with maximal cost-efficiency.
This object is achieved according to the present invention by the provision of mesomorphic complexes of vitamin A acid and cationic polyelectrolytes.
The complexation of vitamin A acid with cationic polyelectrolytes is based on the finding that the formation of ordered structures in solution or in the solid state often takes place by means of self-organization by attachment of a surface-active agent to a polyelectrolyte. The driving force for this process are electrostatic and hydrophobic interactions in aqueous solution. A detailed investigation of self-organized complexes of synthetic polypeptides with surface-active agents having the opposite charge and a low molecular weight has recently been published by E. A. Ponomarenko, A. J. Waddon, D. A. Tirrell and W. J. MacKnight, Langmuir 12 (1996), 2169; A. Ponomarenko, A. J. Waddon, K. N. Bakeev, D. A. Tirrell and W. J. MacKnight, Macromolecules 29 (1996), 4340. It was additionally shown that the complexation of surface-active agents with polyelectrolytes results in a large number of stable mesophases of great structural diversity (M. Antonietti, J. Conrad and A. Thünemann, Macromolecules 27 (1994), 6007; M. Antonietti, S. Henke and A. Thünemann, Advanced Materials 8 (1996), 41; M. Antonietti, A. Kaul and A. Thünemann, Langmuir 11 (1995), 2633). It has also been found that not only synthetic surface-active agents but also amphiphilic compounds might be suitable for this purpose. Vitamin A acid is, on the one hand, polar owing to the presence of the carboxyl functionality and, on the other hand, hydrophobic owing to the presence of the hydrophilic head group and the long hydrocarbon moiety (FIG.
1
), that is to say an amphiphilic compound.
Three different polyelectrolytes are preferably used for the complexation of vitamin A acid for the purpose of the present invention. One which has been used is PDADMAC (poly (dimethyldiallylammonium chloride) which is known to form stable soluble complexes with natural lipids (M. Antonietti, A. Kaul and A. Thünemann, Langmuir 11 (1995), 2633; M. Antonietti, A. Wenzel and A. Thünemann, Langmuir 12 (1996), 2111) and forms gels with supramolecular ordering with sodium dodecyl sulfate (F. Yeh, E. L. Sokolov, A. R. Khokhlov and B. Chu, J. Am. Chem. Soc. 118 (1996), 6615). Hence a complex of vitamin A acid with PDADMAC is particularly preferred according to the invention.
Further particularly preferred, structurally different cationic polyelectrolytes which are particularly suitable for complexation for the purpose of the present invention are PM4VP, poly(N-methyl-4-vinyl-pyridine chloride), a polyelectrolyte with charges on the side groups (B. Philipp, W. Dawydoff and K. -J. Linow, Z. Chem. 22 (1982), 1) and poly(ionene-6,3) with the positive charges directly on the main polymer chain (FIG.
2
), with PM4VP being referred to as a pendant type polyelectrolyte and poly(ionene-6,3) being called an integral type polyelectrolyte. In respect of its charges, PDADMAC occupies an intermediate position between PM4VP and poly(ionene-6,3). For this reason, PDADMAC is referred to as an intermediate type polyelectrolyte. It is also particularly preferred to use polyethyleneimine, obtainable from BASF, Ludwigshafen, Germany, which is marketed under the Lupasol trademarks.
Further polyelectrolytes which are particularly preferably used are poly-L-amino acids, in particular poly-L-arginine, poly-L-histidine, poly-L-lysine or a mixture thereof. The release behavior of the vitamin A acid present in the complex can be adjusted as required by the choice of the cationic polyelectrolyte.
The ratios of the vitamin A acid and the cationic polyelectrolyte in the complexes according to the invention may vary, with a ratio of 1:1 being particularly preferred. The complexes according to the invention can also easily be processed to film-like structures, so that they are in the form of a visco-elastic film, which have interesting physical properties. In contrast to relatively friable crystalline vitamin A acid, complexes with poly-electrolytes are highly deformable viscoelastic materials. These materials according to the invention show lamellar structures.
In a particularly preferred embodiment, the complexes according to the invention are in the form of particles in a nanodispersion together with a dispersing aid, the particl
Arent Fox Kintner Plotkin & Kahn
Max-Planck-Gesellschaft zur Förderung der Weissenschaften e.V.
Russel Jeffrey E.
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