RU2292203C1 - Means for treating patients for articulation diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: means is found to be lyophilisate containing glycosamine salt and tromethanol taken in known proportions.

EFFECT: high active ingredient concentration in the preparation; high speed and effectiveness of diffusion into articulation zone.

2 cl,1 tbl

Description

The invention relates to medicine, namely to drugs for the treatment of joint diseases.

Joint diseases affect about 70% of the population over 45 years of age. They are expressed as pain in the joint, aggravated by movement, a feeling of stiffness. Inflammatory processes are accompanied by swelling, changes in the shape and shape of the joints.

In addition, with arthrological diseases of the joints, the cartilage covering the articular surfaces, as well as bone tissue and the inner surface of the articular bag, are gradually destroyed.

Currently, preparations based on saccharides (chondroitin sulfate, glucosamine salts), mainly in the form of tablets, capsules and in the form of injections, are widely used in world medical practice for the treatment of joint diseases (arthritis, arthrosis, osteochondrosis, etc.). Treatment with these drugs not only reduces inflammation and joint pain, but also produces the restoration of destroyed cartilage [Nasonov E.L. Clinical recommendations and algorithms for practitioners, Rheumatology, M., 2004; K. Pavelka, Archives Internal Medicine, No. 10, 2002, No. 7, 2003].

Closest to the claimed composition is an injectable preparation containing saccharide-glucosamine hydrochloride as an active ingredient (acid saccharide with a pH of an aqueous solution of 1.2-2.5), a neutralizing agent is ethylenediamine, a local anesthetic is trimecaine and excipients [ RF patent No. 2118156]. Its disadvantages are as follows:

- the drug is a two-component solution containing an ampoule with a solution of glucosamine hydrochloride and an ampoule with a solution of ethylenediamine. The preparation of the drug for administration to the patient consists in mixing the contents of two ampoules in a syringe immediately before the injection;

- a neutralizing agent - ethylenediamine - a liquid with a boiling point of 116 ° C and, therefore, cannot be used for the preparation of a monocomponent preparation (HA + neutralizing agent) in the form of a lyophilisate;

- the use of ethylenediamine in the drug in a relatively high concentration (more than 3 wt.% with respect to glucosamine) requires the additional introduction of a local anesthetic agent, trimecaine, which, in turn, causes a number of adverse side effects.

The problem solved by the invention is the development of a monocomponent injection drug for the treatment of joint diseases in the form of a lyophilisate, combining a chondroprotective effect with high pharmacokinetic parameters and bioavailability with the exception of the disadvantages of the prototype.

The technical result from the use of the invention is to increase the specific concentration of the active ingredient in the composition of the drug and, as a result, increase the speed and efficiency of diffusion of the active substance into the joint zone.

To achieve the desired result, a tool for the treatment of joint diseases is proposed, which is a lyophilisate containing a saccharide - glucosamine salt and a neutralizing agent aliphatic amine - trometamol in the following ratio, wt.%:

glucosamine salt - 98.0-99.9

trometamol - 0.1-2.0

As a glucosamine salt, known pharmaceutical substances (registered in the Russian Federation or imported, meeting the requirements of the US Pharmacopoeia of the 27th edition) can be used: glucosamine hydrochloride, sodium or potassium salts of glucosamine sulfate. It is preferable to use the disodium salt of glucosamine sulfate and glucosamine hydrochloride. The low molecular weight of these saccharides (573.3 and 215.0 Daltons, respectively) and their high pharmacological activity [E.S. Tsvetkova, Scientific and Practical Rheumatology, No. 2, 2003] in the treatment of joint diseases provide the creation of effective chondroprotective drugs.

The neutralizing agent is trisamine (trade name), it is registered as a pharmaceutical substance in Russia under No. 78/702/1. The international name is trometamol. Chemical name -2-amino-2- (hydroxymethyl) -1,3-propanediol

The amount of trisamine added to glucosamine is determined by the acidity of the commercial sample of the salt used and is set in each experiment specifically until the initial solution with a physiological pH of 5.0-8.0 is obtained before bottling.

It has been experimentally established that the introduction of a systemic antacid into the composition of an injectable preparation, trisamine, which has buffering properties and a local anesthetic effect, significantly accelerates the transport of the active substance into the bloodstream of a living organism. Trisamine, penetrating through cell membranes, increases transport, bioavailability and specific glucosamine content in the joint area. The specified increase in the bioavailability of the active ingredient and the strengthening of the anti-inflammatory properties of the drug is also associated with the ability of the supramolecular structure created in the claimed pharmaceutical composition to change the state of the environment in the microenvironment of the saccharide.

Pharmacological group - 8.8. Corrector of bone and cartilage tissue metabolism (Russian Medicines Register, 2005 edition).

The production technology of the drug is carried out by known methods and consists in dissolving the active ingredients in water, sterile filtration, followed by packaging in ampoules and freeze-drying the solution.

The control of the quantitative content of active ingredients (glucosamine, trisamine) in the preparations is carried out according to well-known methods adopted for similar forms registered in the Russian Federation and containing active ingredients (spectrophotometric, nephelometric titration).

Example 1. 100 g of glucosamine sulfate × 2NaCl is dissolved at a temperature not exceeding 40 ° C in 400 ml of distilled water, about 0.5 g of trometamol is added with stirring (up to pH 6.0-7.5). The solution is sterile filtered through 0.22 μm sterilizing filters and poured into sterile 2 ml ampoules. The freeze-drying regime of the preparation includes freezing it at -80 ° C and drying in vacuum at room temperature for 10 hours. In the final preparation, 1 ampoule contains 400 mg of glucosamine sulfate × 2NaCl and 2.0 mg (0.5 wt.%) Of trisamine.

Example 2. 100 g of glucosamine sulfate × 2KSl are dissolved at a temperature not exceeding 40 ° C in 400 ml of distilled water, about 0.1 g of trometamol is added with stirring (to a pH of 6.0-7.5). The solution is sterile filtered through 0.22 μm sterilizing filters and poured into sterile 2 ml ampoules. The lyophilization regime according to example 1. In the final preparation, 1 ampoule contains 400 mg of glucosamine sulfate × 2KSl and 2.0 mg of trisamine (0.1 wt.%).

Example 3. 100 g of glucosamine hydrochloride is dissolved at a temperature not exceeding 40 ° C in 400 ml of distilled water, about 2 g of trometamol is added with stirring (up to pH 6.0-7.5). The solution is sterile filtered through 0.22 μm sterilizing filters and poured into sterile 2 ml ampoules. The lyophilization regime according to Example 1. In the final preparation, 1 ampoule contains 400 mg of glucosamine sulfate × 2KSl and 8.0 mg of trisamine (2.0 wt.%).

The effectiveness of the drug was studied on models of post-traumatic osteoarthritis, collapse of the ears of rabbits and aseptic inflammation of the extremities of rats.

When subchondral defects of the femoral head of rats caused by surgical damage to the articular cartilage, the proposed drug significantly reduces the size of the defect compared to control animals.

With intravenous administration of papain in rabbits, a collapse of the auricles is observed - sagging of their peripheral end. Using the proposed drug allows you to restore the turgor of the auricles, which indicates an inhibition of the destruction of the cartilage of the auricles.

A comparative assessment of the chondroprotective effect of the drugs Glucat-1 (obtained according to example 1 of the description of the application) and Glukat-2 (obtained according to example 1 of the description of the prototype) was studied in experiments on rabbits x-ray by changing the size of the joint gap according to the accepted methodology (see table).

Biological studies of the harmlessness of the drug showed that with a single injection of the drug in doses 100-200 times higher than the minimum therapeutic for humans, it is practically non-toxic. The drug is stable for 2 years of observation.

Preliminary clinical trials of the drug confirmed its high chondroprotective activity and good tolerance in the treatment of arthrosis and osteochondrosis.

Table A drug Indicators (n = 20) Joint space reduction Very good and good effect Moderate effect Lack of Glyusat-1 66 26 8 Glyusat-2 40 twenty 40

Claims (2)

1. An agent for the treatment of joint diseases having a chondroprotective and anti-inflammatory effect, which is a lyophilisate containing a glucosamine salt and an aliphatic amine, characterized in that trometamol is used as an aliphatic amine, in the following ratio, wt.%: Glucosamine salt 98.0-99.9 Trometamol 0.1-2.0 2. The tool according to claim 1, characterized in that glucosamine hydrochloride or the sodium or potassium salts of glucosamine are used as glucosamine salts.