Pharmaceutical preparation based on hyaluronic acid derivative

The invention relates to a pharmacological preparation based on a derivative of hyaluronic acid, for use in human and veterinary medicine.

Hyaluronic acid is one of the naturally occurring strong polar polysaccharides referred to collectively as glycosaminoglycans, or, according to the older terminology, mucopolysaccharides. It occurs in the skin, tendons, cartilage, vitreous humor, synovial fluid of the joint capsule, in the cell membranes of some microorganisms and the like. Its chemical structure is characterized by repeating saccharide units of 1-3 glucuronic acid and 1-4 acetylglucosamine forming macromolecular chains of molecular weight 300,000 to 8,000,000 or more.

Pharmacological preparations containing isolated fractions of hyaluronic acid, predominantly in the form of the sodium salt, are used, for example, in the treatment of inflammatory and degenerative joint diseases in humans (e.g., Namiki, Toyoshima, Morisaki, 1982, Clinical Orthopedy, 80, 25-32), or in livestock ( for example, Asheim, Lindbald, 1976, Acta Veterinarea Scandinavia, 17, 379-394).

Another field of application is in the prevention of postoperative tendon and fibrous sheath adhesions (e.g. Onge, Weiss, Delinger, Balasz, 1980, Clinical Orthopedics, 146, 260-275) and in the treatment of severely healing wounds (e.g. Rydell, 1970, Acta Orthopedica Scandinavica 41 , 307-311).

Recently, ophthalmic surgery has emerged as an important field of application for hyaluronates, where the use of these derivatives in vitreous replacements and as a protective medium for corneal transplants, or intra-American lens implants and elsewhere has been increasing (e.g. Balasz, Pape, 1980, Ophtalmology, 87, 699-705) ).

The compositions used so far contain hyaluronic acid in purified form, most often as sodium salt in saline. An example of such a formulation is, for example, HEALON manufactured by Pharmacie in Sweden. Other preparations are known, for example, Hyvisc (Med-Chem Products, Inc., Boston Mass. USA) containing sodium hyaluronate, or formulations based on the combination of hyaluronic acid with keratan sulphates or heparan sulphate, respectively with other glycosaminoglycans under various trade names such as Arteparon, Reparan and others.

The activity of acidic mucosaoharide preparations is usually directly proportional to their specific molecular weight, higher molecule preparations are applicable at lower concentrations, and their physiological activity is usually greater. In the case of a molecular weight of less than 1.5 million, these preparations need to be dosed in larger quantities, which may cause problems in returning the eye function to its original physiological state.

This disadvantage is substantially eliminated by the pharmacological preparation according to the invention, which comprises 0.02 to 3 wt. an alkali 2+ 2+ 2+ 2+ 3+ 2+ 4+ 3+ metal complex with a multivalent cation selected from Mg, Ca, Zn, Ba, Al, Cu, Zr, Cr, Fe³⁺ singly or in a mixture in physiological saline, the molar composition of the complex corresponding to 0.1 to 5 moles of hyaluronate per 1 to 25 moles of coordinated cation. In this formulation, the active ingredients are complexes in which the isolated hyaluronic acid molecules, most often but not exclusively in the form of the sodium salt, are linked into pairs or larger groups by coordinating the carboxyl groups of the hyaluronate and polyvalent base cations such as Mg²⁺, Ca²⁺, Al³⁺, Zn²⁺ or others.

The resulting dimeric, trimeric or multi-membered complex compounds retain the properties of hyaluronic acid, but due to doubling or multiple molecular weight, the solutions are more thixotropic and exhibit a higher viscosity and gel strength than the isolated hyaluronic acid.

This dimerization can be achieved by adding salts of polyvalent cations, or hydroxides of these polyvalent metals, to an aqueous solution of hyaluronic acid or an alkali metal hyaluronate. Due to the greater strength of the coordination bond compared to the alkali metal ion bond such as Na⁺or K⁺, virtually quantitative displacement of the cations of the carboxyl group occurs and the linkage of the multifunctional coordinated group allows the pairing of the molecular chains of the hyaluronates by a relatively strong complex bond. For complexes with cations capable of licking or oxalate (Al2O3)⁺, Zr⁴⁺, Cr ^⁺ and others), the polyfunctionality of the central 2+ 4+ atom is further increased, for example the coordination number Al is 6, for Zr even 8, the carboxy group of the glucuron saccharide unit can be bound as a single or dual donor ligand.

In the relatively complex purification procedures used to prepare the isolated hyaluronic acid derivatives, the risk of depolymerization, supported by oxygen and catalyzed by heavy metals, is a risk. Depolymerization is caused by heavy metals from the tissue itself (mainly iron-blood hemoglobin) and therefore it is necessary to stir during extraction (complexone, nitrogen atmosphere).

In contrast, in the finished formulation, where there is no more intense mixing and the formulation is stored in the dark, the addition of free metals does not matter much. The approximate equimolar amount used ensures a perfect complex! binding of metals (which is the same as the addition of chelatone) by means of a hyaluronic carboxy group, thus masking them and impossibility of a catalytic effect inducing depolymerization. This also results from good stability - at least 1 year for the preparation of the invention stored in the dark at a lower temperature.

EXAMPLE

Dissolve 10 mg of hyaluronic acid as sodium salt in pyrogen-free distilled water at room temperature, add 0.2 mg of MgCl₂.6H₂And after dissolution of 8.5 mg of NaCl, 0.28 mg of Na₂HPO ^. 2 µl of 0.04 mg ΝθΗ ,, ΡΟ ^ and made up to 1 ml. This preparation is suitable for application in ophthalmic surgery.

Example 2

15 mg are dissolved in 1 ml of pyrogen-free saline at room temperature

- a 3+ complex dimer of sodium hyaluronate containing an average of 1 mol Al per molecule for every two moles of sodium hyaluronate. The preparation is suitable for application in joint surgery and for other pharmacological purposes.

Example 3

In 1 ml of pyrogen-free saline, 10 mg of a complex hyaluronic acid compound containing 1 mole of Ca for each 1.5 mol of hyaluronic acid is dissolved at room temperature. The formulation is generally useful for administration in human or veterinary medicine.

Example 4

In 1 ml of pyrogen-free solution, 6 mg of NaCl and 10 mg of a complex compound of 1 mol Cr and 2 mol of sodium hyaluronate are dissolved at room temperature.

Example 5

An aqueous solution was prepared by dissolving 10 mg of sodium hyaluronate and 0.001 mg of ZnSO4 · 7H₂O in 10 ml of pyrogen-free saline.

Example 6

An aqueous solution is prepared by dissolving 10 mg of sodium hyaluronate and 0.0005 mg of Zr (SO4).₂in 5 ml of physiological pyrogen-free solution.