Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-11-30
2003-06-03
Prats, Francisco (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000
Reexamination Certificate
active
06573251
ABSTRACT:
This invention relates to the use of polymers or biopolymers for the preparation of a drug for the treatment of lesions of all origins affecting the central or peripheral system in human or veterinary medicine. It also concerns pharmaceutical compositions for this treatment. Lastly, it concerns fractions enriched in heparan sulfate.
The synthesis of CMDBS polymers (dextrans substituted by carboxymethyl, benzylamine and sulfonate) has been described in French Patent 2 461 724 and U.S. Pat. No. 4,740,594. Some of these polymers mimic heparin and may be used as plasma heparin replacement products, thanks to their anticoagulant and anticomplement properties.
Some of these CMDBS polymers mimic another property of heparin consisting of a stabilization, protection and potentialization of the in vitro biological activity of the growth factors of the FGF family (Tardieu and coll., Journal of Cellular Physiology, 1992, 150 pp. 194 to 203).
French patent 2 644.066 describes the use of certain CMDBSs associated with FGFs for healing the skin and the cornea. Experiments have been conducted by provoking a cutaneous wound with the help of a hollow punch 6 mm in diameter in the rat. In this example, the CMDBS associated with the FGF 2 makes it possible to obtain a clear effect on the speed and the quality of skin repair.
Another biopolymer, dektran sulfate, has also been advanced in association with FGFs as a stabilizer and protector, in Japanese Patent No. 13890. Dextran sulfate, moreover, is widely used in skin healing ointments and creams as well as in collyrium compositions, but, to the knowledge of the applicant, has no reported effect on the healing and regeneration of lesions of the nervous system.
A considerable number of factors whose activities facilitate the survival of nervous cells, the repair of central or peripheral nervous lesions, or muscular reinnervations have been described: polypeptide factors like Nerve Growth Factors (NGF), factors of the FGF families, brain derived factors like BDNFs, Ciliary Neurotrophic Factor (CNTF), Neurotrophin 3 (NT3), etc.
These factors have been used in experiments of muscular reinnervation, repairs of cuts of peripheral nerves, motor nerves, in models of lesions of cholinergic central nervous cells, and in numerous other models. For purposes of reference, the reviews listed below describe a part of this work: P. M. Richardson, Current Opinion in Neurobiology, 1991, 1: pp 401-406; T. Ebendal, Journal of Neurosciences Research, 1992, 32: pp. 461-470; P. G. Cordeiro, R. Brooke et al., Plastic and Reconstructive Surgery, 1989, 86 (3): pp. 1013-1019; Q. Yan, J. Elliott et al., Nature (Letters to Nature), 1992, 360: pp. 753-755; N. A. Seniuk, Journal of Reconstructive Microsurgery, 8 (5): pp. 399-404; F. Hefti P. P. Michel et al., Advances in Neurology, 1990, 53: pp. 123-127; A. C. Cuello, L. Garofalo et al., Progress in Brain Research, 1990, 84: pp. 301-311; A. Tadeka, H. Onodera et al., Brain Research, 1992, 569: pp. 177-180.
It thus emerges from an analysis of the state of the prior art that growth factors and polymers in association with growth factors have already been used in therapeutic applications.
However, none of the documents cited above shows that the polymers present effects by themselves, that is to say without being associated with growth factors.
Moreover, the activity of polymer-factor associations has been described only on certain lesions of a very specific type of tissue, namely the cutaneous tissue.
In view of the unpredictable nature of the therapeutic effects of a given molecule, it was not clear whether these polymers could have an effect on other tissues.
It is, in fact, well known that the different tissues of the human or animal body present structural and functional specific features making it impossible to predict the effect of a molecule, known for its effect on the cutaneous tissue or another tissue.
Similarly, it is well known that it is impossible to predict the in vivo activity of a molecule on a particular tissue from results obtained in vitro on a specific experimental model.
Surprisingly, it has been found, according to the invention, that certain polymers have a very marked effect on the speed of healing and of regeneration of tissue lesions of the central or peripheral nervous systems as well as on the quality of this healing and/or regeneration, in such a way that it may be measured by studying it using histological and physiological methods. Muscular reinnervation with reformation of a functional junction of the lesioned nerve with its muscle was observed.
This invention relates to the use of at least one polymer or one biopolymer, caller HBGFPP, with the exception of mesoglycan, specifically protecting the growth factors of the FGF and beta TGF families from tryptic degradation and not significantly inhibiting coagulation, in the manufacture of a drug for the treatment of muscular tissues.
In particular, such a polymer presents an anticoagulant activity of less than 50 international units per mg of polymer measured, according to Maillet et al. (Mol. Immunol, 1988, 25, 915-923). Preferentially, it does not substantially activate the complement system, that is to say, it possesses an anti-complement system of above 0.5 &mgr;g for the CH
50
(according to Mauzac et al., Biomaterials, 6, 61-63, 1985).
Advantageously, the polymer potentializes the FGFs in vitro.
According to the invention, polymers are understood to mean any natural substance, chemically modified natural substance or totally synthetic substance responding to the definition given above.
The following polymers are therefore concerned:
polymers obtained from dextrans but modified by other types of substitutions with other types of radicals,
natural polymers other than those deriving from dextrans but including osidic residues (cellulose, chitin, fucans, etc.),
polymers obtained by polymerization of monomers of non-osidic nature (modified or unmodified malic polyacid, oxalic polyacid, lactic polyacid, polystyrene, polyethylene glycol).
Advantageously, the said polymer or biopolymer is a polysaccharide which may be primarily composed of glucose residues.
Such a polysaccharide advantageously presents a molecular weight above 10 kD and advantageously about 40 kD.
It may also comprise glucosamine and/or uronic acid residues, particularly in the form of glucosamine dimer-uronic acid.
Particularly preferred polysaccharides are substituted dextrans, glycosaminoglycans possibly in association with a lipid, a peptide or a protide, or sulfates of these polymers.
This invention also relates to a pharmaceutical composition containing these polymers.
The polymers and/or biopolymers may be selected from natural substances which may then be modified, if required, by additions of appropriate chemical groups, or again be obtained entirely by synthesis. These natural, semi- or wholly synthetic polymers are then selected on the basis of their ability to interact specifically with several growth factors, notably those of the FGF and the beta TGF families. They are also selected on their ability to protect this (or these) factor(s) against proteolytic degradations. These polymers will be referred to under the generic abbreviation HBGFPP (heparin binding growth factor protectors and promoters).
Two prototypes of these polymers or biopolymers are given as examples together with the processes and selection criteria of these polymers.
The first HBGFPP example belongs to the CMDBS family which are known products, namely functionalized biospecific dextrans, substituted by carboxymethyl, benzylamide and benzylamine sulfonate. These polymers illustrate the yielding of HBGFPPs from natural products (dextrans) which are subsequently chemically substituted.
The second example describes the selection of wholly natural products such as purified sulfate proteoglycosaminoglycans from tissular extracts.
These two examples illustrate the ability of these HBGFPPs to interact, stabilize, protect and potentialize the growth factors of the FGF and beta TGF families, and their use in a phar
Aamiri Ahmed
Barritault Denis
Caruelle Jean-Pierre
Gautron Jean
Jacobson & Holman PLLC
Prats Francisco
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