Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1994-11-25
2002-10-01
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S055100
Reexamination Certificate
active
06458774
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel hyaluronic acid associates (complexes) of 3d metal ions of the 4th period of the Periodic Table, with a stoichiometric composition, prepared through the interaction of equivalent amounts of an alkali metal hyaluronate, alkaline earth metal hyaluronate, silver hyaluronate or a quaternary ammonium hyaluronate and 3d metal ions in aqueous solution, and to pharmaceutical compositions containing these associates (complexes) as active ingredients.
The invention further relates to a process for the preparation of these novel associates (complexes) and compositions containing these associates (complexes) as active ingredients.
According to a particularly preferred embodiment of the process of the present invention, the aqueous solutions containing the novel hyaluronic acid associates (complexes) of 3d metal ions of the 4th period of the Periodic Table, with a stoichiometric composition, prepared through the interaction of equivalent amounts of sodium hyaluronate, and 3d metal ions in aqueous solution, are prepared directly from an aqueous solution of sodium hyaluronate.
The novel associates according to the present invention mainly involve zinc and cobalt hyaluronate. The compositions containing these latter associates may be pharmaceutical (therapeutical) or cosmetic and optionally other compositions. The compositions containing the novel associates according to the invention are therapeutically effective for e.g.: the acceleration of epithelization of epithelium-deficient body surfaces; healing of crural ulcers, decubitus (bed-ulcers), primarily not healing wounds, burns, radiation- or heat-induced wounds, vulgar acne and conglobated acnes, although they can be used in other areas, too.
The novel hyaluronate associates have been found to possess antibacterial activity. These hyaluronate associates have been found especially to possess activity against a number of bacteria that often infect crural or decubitus ulcers. For instance the new zinc hyaluronate complexes have been found to be highly effective against
Staphylococcus aureus
and Salmonella sp. The new cobalt hyaluronate complexes have been found to be highly effective against
Staphylococcus aureus
and
E. coli.
Furthermore the new hyaluronates have utility in ophthalmic preparations. The zinc hyaluronates have been found to be especially useful in this regard. The new zinc hyaluronates may be applied to the eye as topical antibacterial agents or they may be applied intraocularly as antibacterials. The zinc hyaluronates have been found to be especially effective against
Staphylococcus aureus
and against
Pseudomonas aeruginosa
, two types of bacteria that are implicated in eye infections. The most frequent eye contaminant is the Staphylococcus group, but the less frequent
Pseudomonas aeruginosa
group, is very dangerous and can cause complete blindness in 24 to 48 hours. The fact that the hyaluronate complexes are effective against both of these microorganisms is highly important.
BACKGROUND OF THE INVENTION
Hyaluronic acid is a macromolecule known for more than 50 years and which has first been described by Meyer et al. [J. Biol. Chem. 107, 629 (1954); J. Biol. Chem. 114, 689 (1936)]. The structure determination was performed by Weissman et al. [J. Am. Chem. Soc. 76, 1753 (1954)]. Hyaluronic acid is a highly viscous native glucosaminoglycan containing alternating &bgr;
1-3
glucouronic acid and &bgr;
1-4
glucosamine moieties; its molecular weight is between 50000 and several (8 to 13) millions. The recovery of hyaluronic acid is an old task. The separation and use of an extra pure hyaluronic acid are described e.g. in the U.S. Pat. Nos. 4,141,973 and 4,303,676 and in the European Patent No. 0 144 019.
Until recently hyaluronic acid has been employed as the sodium salt e.g. in therapy, mainly in opthalmology, surgery and cosmetics. The salts of hyaluronic acid formed with alkali, alkaline earth, magnesium, aluminum, ammonium or substituted ammonium ions may serve as carriers for promoting the absorption of drugs (see the Belgian Patent Specification No. 904,547). Heavy metal salts of hyaluronic acid (wherein “heavy metals” mean the elements of the 5th, 6th and 7th periods of the Periodic Table as well as the lanthanides and actinides) and within these the silver salt are utilized as fungicidal agents whereas the gold salt is employed for the treatment of arthritis (see the patent specification WO 87/05517).
It has been proven by various structure-elucidating methods that the secondary structure, i.e. the conformation of hyaluronic acid is changed by binding metal ions [W. T. Winter and A. Struther: J. Mol. Biol. 517, 761 (1977); J. K. Sheehan and E. D. T. Atkins: Int. J. Biol. Macromol. 5, 215 (183); and N. Figueroa and B. Chakrabarti: Biopolymers 17, 2415 (1978)]. Significantly varying effects on the molecular structure can be exerted even by metal ions of similar character as shown by comparative X-ray study of potassium and sodium hyaluronate [A. K. Mitra et al.: J. Macromol., Sci. Phys. 824, 1 and 21 (1985)]. This is all the more valid for compounds of hyaluronic acid formed with metal ions of various sorts bearing various charges.
No reference relating to hyaluronic acid associates (complexes) of 3d metal ions of the 4th period of the Periodic Table, with a stoichiometric composition, prepared through the interaction of equivalent amounts of an alkali metal hyaluronate, alkaline earth metal hyaluronate, silver hyaluronate or a quaternary ammonium hyaluronate and 3d metal ions in aqueous solution, can be found in the literature. Actually, according to gel filtration chromatography examinations, hyaluronic acid, in contrast with heparin, is unable to bind zinc ions [(R. F. Parish and W. R. Fair: Biochem. J. 193, 407 to 410 (1981)].
In spite of the fact that, according to the literature, hyaluronic acid (or its sodium salt) is unable to bind zinc ions, we undertook to investigate the coordination chemistry of the interaction between hyaluronic acid and 3d metal ions of the 4th period of the Periodic Table and among these, chiefly, zinc and cobalt ions. Since hyaluronic acid is nearly exclusively commercialized as its sodium salt thus being the basic substance of all systems containing hyaluronate, our investigations were begun on the interaction of sodium ions and hyaluronate. For this purpose the free sodium ion activity of aqueous sodium hyaluronate solutions was measured by using a sodium selective glass electrode. It was unambiguously found from these measurements that not more than 60% of sodium ions introduced as equivalent together with the carboxylate groups of hyaluronate are present as free ions in the aqueous solutions whereas the remainder of 40% is in a form bound to the hyaluronate.
According to our measurements, by increasing the sodium ion concentration the amount of the sodium ions bound can be raised to 50-55% calculated for all available carboxylate groups. Thus, it has been verified that, as contrasted with common properties of salts, sodium hyaluronate is not completely dissociated in aqueous solution.
There are several references which disclose the importance of Zn
2+
in the eye as well as in other parts of the human body. For instance see “Zinc in the Eye”, Surv. Ophthalmol., September-October 1982 27(2), pp 114 to 122 and “Zinc Uptake in Vitro by Human Retinal Pigment Epithelium”, ophthalmology, June 1992, 99 (6), p. 841.
It is also known that bacterial contamination of the eye is a serious health problem. Reference is made to Remington's Pharmaceutical Sciences, 18th Ed., p. 1588 (1980) which discusses the contamination of eye solutions and emphasizes that the most frequent contaminant is the Staphylococcus group. Less frequently the contaminant is
Pseudomonas aeruginosa
which is very dangerous to the eye. Infection of the eye with these bacteria can result in complete blindness over a 24 to 48 hour period.
Furthermore sodium hyaluronates have intraocular utility in the field
Burger Kalman
Gebhardt Istvan
Gezane Boda
Illes Janos
Kiraly Arpadne
Dubno Herbert
Gezane Boda
Myers Jonathan
Peselev Elli
Racz Eszter
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