Agent for treatment of joint diseases

FIELD: chemical-and-pharmaceutical industry, in particular production of drugs for joint disease treatment.

SUBSTANCE: claimed agent represents lyophilizate containing glucoseamine salt, chondroitin sulfate and trisaminum in specific component ratio.

EFFECT: agent with increased active ingredient content; diffusion of active substance into joint region with increased rate and effectiveness.

2 cl, 3 ex, 1 tbl

 

The invention relates to medicine, namely preparations for the treatment of diseases of the joints.

Disease affects about 70% of the population older than 45 years. They are manifested as pain in the joint, aggravated by motion, sensation of tightness. Inflammatory processes are accompanied by swelling, change in shape of the joints.

In addition, when astrologicheskih diseases of the joints gradually destroys the cartilage covering the articular surfaces, as well as bone tissue and the inner surface of the articular capsule.

Currently widespread in the world of medical practice for the treatment of diseases of the joints (arthritis, arthrosis, osteochondrosis, etc.) received drugs on the basis of saccharides (salts of glucosamine, chondroitin sulfate), mainly in the form of tablets, capsules and injections. Treatment with these drugs not only reduce inflammation and pain in the joints, but also produces the restoration of damaged cartilage tissue [Nasonov EL Clinical guidelines and algorithms for clinicians, Rheumatology, M., 2004; K.Pavelka, Archives Internal Medicine, №10, 2002, №7, 2003].

Known injectable preparation containing as active ingredient the polysaccharide is chondroitin sulfate with a molecular weight of 8000÷16000 daltons (8÷12 wt.%), preservative - gasoline alcohol (0,8÷1.2 wt.%) and water (OS is real) [RF patent №2021812]. Its disadvantages are that when used as a chondroprotective component of the polysaccharide is chondroitin sulphate with polydisperse high molecular weight (8000÷16000 daltons), limited diffusion of the active ingredient in the joint area, which significantly reduces the pharmacokinetics of the proceeds of the drug in the bloodstream and the cartilage of the joint when it is intramuscular, and, as a consequence, low bioavailability and effects of inhibition of the process of destruction of cartilage and its regeneration (product qualification Long).

Closest to the claimed means the composition is injectable preparation containing as an active ingredient saccharide-glucosamine hydrochloride (acidic saccharide with a pH of an aqueous solution of 1.2÷2,5), the neutralizing agent is Ethylenediamine, local anesthetic agent - trimekain and excipients [RF patent №2118156].

Low molecular weight glucosamine hydrochloride (215,0 daltons) and high pharmacological activity [Eszteca, Scientific-practical rheumatology, No. 2, 2003] in the treatment of diseases of the joints ensure the creation of effective chondroprotective drug.

The disadvantages of this drug are as follows:

the preparation contains as the active ingredient monomer salt of glucosamine short lane is one half of the body (T 1/2about two hours), which makes the drug only for the qualifications Rapid;

the drug consists of two vials: vials with a solution of glucosamine hydrochloride and capsules with a solution of Ethylenediamine. The preparation for the introduction of patient consists in mixing the contents of two vials in the syringe immediately before injection of;

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

- the use of Ethylenediamine in the product in relatively high concentrations (>3 wt.% in relation to glucosamine) requires a supplemental part of the preparation of local anesthetic products - trimekainom that, in turn, causes a number of undesirable side effects.

The problem solved by the invention is the development of monophasic injection of a drug for treatment of diseases of the joints in the form of a lyophilisate, combining chondroprotective effect of monomer - glucosamine and polymer - chondroitin sulphate 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 create drug qualificat and Mikst, the increase of the specific concentration of active ingredient in the drug and, consequently, increase the speed and efficiency of diffusion of the active substance in the joint area.

For the achievement of the proposed remedy for the treatment of diseases of the joints, representing a lyophilisate containing saccharide - glucosamine salt, polysaccharide is chondroitin sulfate, and the neutralizing agent is an aliphatic amine - trometamol in the following ratio, wt.%:

Glucosamine salt5,0÷93,0
Chondroitin sulfate93,0÷5,0
Trometamol0,1÷2,0

Simultaneous inclusion of the drug mixture of monosaccharide - salt of glucosamine and polysaccharide chondroitin sulphate achieve a synergistic effect in the treatment of astrologicheskih diseases because of exogenous glucosamine additionally produces synthesis by chondrocytes endogenous chondroitin sulfates and proteoglycans, as their universal predecessor [international Medical journal, No. 3, 2000].

Variation in the composition of the drug in a wide range of the ratio of monosaccharide/polysaccharide provides freedom of choice in creating specific dosage forms kVA is of Rapid changes, Mikst, Long with different concentrations of active ingredients and, as a consequence, given pharmacological activity, pharmacokinetic and pharmacodynamic characteristics.

As salts of glucosamine can be used a known pharmaceutical substance (registered in the Russian Federation or imported, the relevant requirements of United States Pharmacopeia 27 editions): glucosamine hydrochloride, sodium or potassium salts of glucosamine sulfate. Preferred is the use of disodium salt of glucosamine sulfate and glucosamine hydrochloride.

As chondroitin sulphate can be used a known pharmaceutical substance chondroitin sulphate, for example registered in the Russian Federation or imported substances that meet the requirements USP27 - United States Pharmacopeia 2004 edition.

The neutralizing agent is trisamin (trade name) is registered as a pharmaceutical substance in Russia №78/702/1. International name - trometamol. The chemical name is 2-Amino-2-(hydroxymethyl)-1,3-propandiol

The number added to the mixture of active ingredients trisamina is determined by the acidity of the commercial sample used salt and installed in each experiment specifically to obtain before filling the original solution with physiologists the definition pH value of 5.0 to 8.0.

It was established experimentally that the introduction of the injectable antacid systemic action - trisamina with buffer properties and local anesthetic action, which significantly accelerates the transport of the active substance into the bloodstream of a living organism. Trisamin, penetrating through the cell membrane, increases the transport, bioavailability and specific content of the saccharide in the joint area. These increases bioavailability of the active ingredient and increased anti-inflammatory properties of the drug is also associated with the ability of the proposed supramolecular structure to change the state of the environment in the microenvironment of the saccharide.

Pharmacological group - 8.8. Concealer metabolism of bone and cartilage (Register of medicines of Russia, 2005 edition).

The preparation is carried out by known methods lies in the dissolution of the active ingredients in water, sterile filtered, followed by filling into ampoules and freeze-drying the solution.

Control the quantitative content of the active ingredients (glucosamine, chondroitin sulfate, trisamin) in the preparations is carried out by known methods adopted for similar legform registered in the Russian Federation and contains the active ingredients (spectrophotometric, nephelometric the second titration).

Example 1. 95,0 g of glucosamine sulfate ×2NaCI and 5.0 g of chondroitin sulfate is dissolved at a temperature not exceeding 40°With 400 ml of distilled water, add with stirring for about 0.5 g trisamina (up to pH 6.0÷7,5). The solution is sterile filtered through a sterile 0.22 μm filters and pour into sterile ampoules of 2 ml Mode lyophilic drying of the drug includes its freezing at -80°and drying in vacuum at room temperature for 10 hours. In the final preparation of 1 ampoule contains 380 mg of glucosamine sulfate ×2NaCI, 20 mg of chondroitin sulfate and 2.0 mg (0.5 wt.%) trisamina.

Example 2. 5 g of glucosamine sulfate ×2l and 95 g of chondroitin sulfate is dissolved at a temperature not exceeding 70°With 400 ml of distilled water, add with stirring to about 0.1 g trisamina (up to pH 6.0÷7,5). The solution is sterile filtered through a sterile 0.22 μm filters and pour into sterile ampoules of 2 ml Mode lyophilization of example 1. In the final preparation of 1 ampoule contains 20 mg of glucosamine sulfate ×2l, 380 mg of chondroitin sulfate and 2.0 mg trisamina (0.1 wt.%).

Example 3. 50 g of glucosamine hydrochloride and 50 g of chondroitin sulfate is dissolved at a temperature not exceeding 40°With 400 ml of distilled water, add with stirring to about 2 g trisamina (up to pH 6.0÷7,5). The solution is sterile filtered through sterilized the e 0.22 μm filters and pour into sterile ampoules of 2 ml Mode lyophilization of example 1. In the final preparation of 1 ampoule contains 200 mg of glucosamine hydrochloride, 200 mg of chondroitin sulfate and 8.0 mg trisamina (2.0 wt.%).

The drug efficacy was studied in models of post-traumatic osteoarthritis, the collapse of the ears of rabbits and aseptic inflammation of the limbs of rats.

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

When intravenous papain in rabbits there is a collapse of the ears - sagging their peripheral end. The use of the proposed drug allows you to restore turgor ears, which indicates the inhibition of the destruction of the cartilage of the ears.

Comparative evaluation of chondroprotective action of drugs Glucit-1, Glucat-2, Pusat-3 (obtained respectively in examples 1-3 describe) and Glyset-4 (obtained according to example 1 of the description to the patent of Russian Federation №2118156) was studied in experiments on rabbits rentgenograficheski to change the size of the joint space according to the established procedure (table 1).

Table 1
MedicationPokazatel the (n=20) Reducing the size of the joint space
Very good and good effectModerate effectThe lack of effect
Glucit-1592120
Glucat-275214
Glucat-369265
Glucat-4402040

As can be seen from table 1, the introduction is part of the preparation of chondroitin sulfate and new neutralizing agent trisamine significantly increases chondroprotective activity of the drug is according to the accepted objective measure of changing the size of the joint space".

Conducted biological research harmlessness of the drug showed that acute administration of the drug in doses of 100÷200 times the minimum therapeutic for a person, it is practically non-toxic. The preparation is stable for at least 2 years of follow-up. Preliminary clinical tests have confirmed its high chondroprotective activity and good tolerability in the treatment of arthritis and degenerative disc disease.

1. For the treatment of diseases of the joints, representing a lyophilisate containing glucosamine salt, otlichayushiesya, it additionally contains chondroitin sulfate and trometamol in the following ratio, wt.%:

Glucosamine salt5,0-93,0
Chondroitin sulfate5,0-93,0
Trometamol0,1-2,0

2. The tool according to claim 1, characterized in that salts of glucosamine uses glucosamine hydrochloride or sodium or potassium salts of glucosamine sulfate.



 

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