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

Abstract

The solution relates to a pharmacological preparation usable in human and veterinary medicine. The essence of the product is that it contains 0.02 to 3% by mass. complex of an alkali metal hyaluronate with a polyvalent cation selected from the group of Mg2+, Ca2+, Zn2+, Ba2+, Al3+, Cu2+, Zr4+, Cr3+, Fe3+ individually or in a mixture in a physiological solution, while the molar composition of the complex corresponds to 0.1 to 5 moles of hyaluronate and 1 to 25 moles of a coordinated cation.

Description

264719 2

The present invention relates to a pharmacological composition based on a hyaluronic acid derivative useful in human and veterinary medicine.

Hyaluronic acid is a naturally occurring strong polar polysaccharide, designated by the collective name glycosaminoglycans, or according to older mucopolysaccharide terminology. It occurs in the skin, tendons, cartilage, in the vitreous of the eye, in the synovial fluid shells, in the cell membranes of some microorganisms and the like. Its chemical structure is characterized by repeating carbohydrate units of 1-3 glucuronic acid and 1-4 acetylglucosamine, forming macromolecular chains of 300,000 to 8,000,000 and more.

Pharmacological preparations containing isolated fractions of hyaluronic acid predominantly in the sodium salt form are used, for example, in the treatment of inflammatory and degenerative chordbclones in humans (e.g. Namiki, Toyoshima, Morisaki, 1982, Clinical Orthopedy, 80, 25-32), or in farm animals (e.g. Asheim , Lindbald, 1976, Acta Veterinarea Scandinavia, 17, 379-394). Another area of application is in the prevention of postoperative tendons and ligaments (e.g., Onge, Weiss, Delinger, Balasz, 1980, Clinical Orthopedy, 146, 260-275) and in the treatment of wound healing (e.g., Rydell, 1970, Acta Orthopedica Scandinavica 41,307- 311). Recently, ophthalmic surgery has emerged as an important area of application of hyaluronates, where the use of these derivatives in vitreous substitutes and as a protective medium in corneal transplants, or in implants of intracameral lenses and elsewhere (for example, Balasz, Pape, 1980, Ophtalmology, 87, 699). -705).

Heretofore used formulations contain hyaluronic acid in purified form, most commonly 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-ChemProducts, Inc. Boston Mass. USA) containing sodium hyaluronate, or preparations based on the combination of hyaluronic acid with keratin sulfate or heparan sulfate, or other glycosaminoglycans under various trade names such as Arteparon, Reparan and others. The effectiveness of the acid mucosaccharide preparations is usually directly proportional to their molecular weight, the 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 greater amounts, which may cause the problem to return to ocular physiological status.

This disadvantage is substantially obviated by the pharmacological composition of the present invention, which comprises from 0.02 to 3% by weight. alkali 2 + 2+ 24 · 2+ 3+ 2+ 4+ 34 · hyaluronate metal complex with a polyvalent cation selected from the group of Mg, Ca, Zn, Ba, Al, Cu, Zr, Cr, Fe 3+ alone or in saline, 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 composition, the active ingredients are complex compounds in which the isolated hyaluronic acid molecules, most often but not exclusively in the sodium salt form, are coupled to pairs or larger group coordination bonds of the hyaluronate carboxyl groups and multivalent base cations such as Mg 2+, Ca 2+, Al 3+ , Zn2 + or others.

The resulting dimeric, trimeric or multi-member complex compounds retain the properties of hyaluronic acid, but for doubling or multiple molecular weight, the solutions are more thixotropic and exhibit greater 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 alkali metal hyaluronate. Due to the greater strength of the coordination moiety compared to the ionic content of alkali metals, such as Na + or K +, a practically quantitative displacement of the cationic carboxyl group occurs and the linkage of the multifunctional coordinated moiety allows the coupling of a pair of molecular chains of hyaluronates relative to a fixed complex bond. For complexes with cations capable of olification or oxalization (Al ^ +, Zr ^ +, Cr ^ + and others), the polyfunctionality of the central 2 + 4+ atom is further increased, for example the coordination number AI is 6, in Zr even 8, with the carboxy-group of glucuronic saccharide the unit may be bound as a single or double bond ligand.

The relatively complex purification procedures used in the preparation of isolated hyaluronic acid derivatives pose a risk of depolymerization, supported by oxygen and heavy metal catalysts. Depolymerization is caused by heavy metals from their own tissue (mainly iron-blood hemoglobin) and therefore it is necessary to take precautions during mixing during extraction (complexone, nitrogen-phosphorus).

In contrast, in a finished product, where no more intensive mixing occurs and the formulation is stored in the dark, the addition of free metals does not matter so much. The approximate equimolar amount used will ensure perfect complexity! metal bonding (which is the same as the addition of chelatone) by the use of a cyanuronic carboxy group, i.e., "masking" and impossibility of catalytic depolymerisation-producing effect. This is also due to its good stability - at least 1 year for a low-temperature underlay preparation stored in the dark. EXAMPLE 1 10 mg of hyaluronic acid in the form of a sodium salt are dissolved in pyrogen-free distilled water at room temperature, 0.2 mg of MgCl2.6H2O is added and, after dissolution, 8.5 mg of NaCl, 0.28 mg of Na2HPO4. NaH 2 PO 4 (2 L, 0.04 mg) and make up to 1 mL. This formulation is suitable for use in ophthalmic surgery. Example 2 In 1 ml of pyrogen-free physiological saline, 15 mg - 3+ of a complex sodium hyaluronate dimer dimer containing 1 mol of Al in each molecule were dissolved at room temperature each time with two moles of sodium hyaluronate. The formulation is suitable for application in joint surgery for further pharmacological purposes. EXAMPLE 3 In 1 ml of pyrogen-free saline, 10 mg of a complex hyaluronic acid compound, containing 1.5 moles of hyaluronic acid per mole of hyaluronic acid, are dissolved at room temperature. The formulation is generally useful for administration in human or veterinary medicine. EXAMPLE 4 6 mg of NaCl and 10 mg of a complex of 1 mol of Cr and 2 mol of sodium hyaluronate are dissolved in 1 ml of pyrogen-free solution at room temperature. Example 5 An aqueous solution was prepared by dissolving 10 mg of sodium hyaluronate and 0.001 mg of ZnSO 4 · 7H 2 O in 10 ml of pyrogen-free saline. Example 6 An aqueous solution was 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)

A composition based on a hyaluronic acid derivative useful in human and veterinary medicine comprising 0.02 to 3 wt. complex of hyaluronate 2 + 2+ 2+ 2+ 3+ 2+ alkali metal with polyvalent cation selected from the group of Mg, Ca, Zn, Ba, Al, Cu, Zr ^ +, Cr ^ +, Fe ^ + singly or in saline wherein the molar composition of the complex corresponds to 0.1 to 5 moles of hyaluronate to 1 to 25 moles of coordinated cation. Severografia, n. P., MOST Price 2,40 Kcs