CS264719B1 - Pharmaceutical preparation based on hyaluronic acid derivative - Google Patents

Abstract

The solution relates to a pharmacological preparation applicable in human and veterinary medicine. The essence of the product lies in that it contains 0.02 to 3 wt. hyaluronate complex alkali metal with a polyvalent cation selected from the group of Mg 2+, Ca 2+, Zn 2+, Ba2 +, Al3 +, Cu2 +, Zr4 +, Cr3 +, Fe3 + individually or in a mixture in saline, wherein the molar composition of the complex corresponds to 0.1 to 5 moles of hyaluronate and 1 to 25 moles coordinated cation.

Description

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 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 mass 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 in 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 formulations 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 other.

The activity of acid mucosaoharide preparations is usually directly proportional to their specific molecular weight, higher molecule preparations are applicable at lower concentrations, and their physiological effectiveness is usually greater. In the case of a molecular weight of less than 1.5 million, these preparations need to be dosed in larger amounts, which can 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, Fe ³⁺ individually or in a mixture of saline solution, wherein the molar composition of the complex corresponds 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 Mg ²⁺ , Ca ²⁺ , Al ³⁺ , Zn ²⁺ 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 multivalent cations, or hydroxides of these multivalent metals, to an aqueous solution of hyaluronic acid or an alkali metal hyaluronate. Due to the increased strength of the coordination bond compared to the alkali metal ion binding such as Na ⁺ or K ⁺ , a virtually quantitative displacement of the carboxyl group cations occurs and the linkage of the multifunctional coordinated group allows the pairing of the molecular chains of hyaluronates by a relatively strong complex bond. For complexes with cations capable of ligation or oxalate (Al ^ ⁺ , Zr ⁴⁺ , 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 carboxyl group units 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! the binding of metals (which is the same as the addition of chelatone) by means of a hyaluronic carboxy group, thus masking them and the 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

In pyrogen-free distilled water, 10 mg of hyaluronic acid as the sodium salt is dissolved at room temperature, 0.2 mg of MgCl ₂ .6H ₂ O is added and after dissolution 8.5 mg of NaCl, 0.28 mg of Na ₂ HPO 4. 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 dissolving 10 mg of sodium hyaluronate and from 0.001 mg ZnSO ^ 7H ₂ O 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) ₂ in 5 ml of physiological pyrogen-free solution.

Claims (2)

OBJECT OF THE INVENTION A pharmaceutical composition based on a hyaluronic acid derivative for use in human and veterinary medicine, characterized in that it contains from 0.02 to 3% by weight. hyaluronate complex 2+ 2+ 2+ 2+ 3+ 2+ an alkali of multivalent cations selected from Mg, Ca, Zn, Ba, Al, Cu, Zr ^4+, Cr ^ ^+, Fe ^ ⁺ or in a mixture solution of fyziologiokom wherein the molar composition of the complex corresponds to 0.1 to 5 moles of hyaluronate per 1 to 25 moles of coordinated cation.