RU2623050C2 - Chondroitin sulfate solution for intramuscular administration and method for its preparation - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: pharmaceutical preparation in the form of solution for intramuscular administration contains chondroitin sodium sulfate and auxiliary substances: sodium metabisulphite, methylparaben and water for injection at a certain component ratio. A method for obtaining a stable solution with reduced side effects is also proposed.

EFFECT: maintaining stability and reduced amount of impurities during storage.

3 cl, 1 tbl, 3 ex

Description

The invention relates to the field of the pharmaceutical industry and relates to parenteral forms of chondroitin sulfate.

At present, degenerative-dystrophic diseases of the spine are the most common chronic diseases, characterized by progressive changes in the bone and soft tissue structures of the vertebrae and intervertebral discs, leading to an effect (compression) on the contents of the spinal canal - the spinal cord and its roots, which in severe cases are manifested by severe orthopedic , neurological and visceral disorders and often leading to disability.

Acute back pain of varying intensity is observed in 80-100% of the population. About 40% of patients seek medical help. It is known that after 30 years, one in five people in the world suffers from discogenic radiculitis, which is one of the syndromes of degenerative-dystrophic diseases of the spine. According to the Central Institute of Traumatology and Orthopedics and the General Directorate of Health Care in Moscow, there are 122 patients with spinal dysfunction for every 1000 adults in the capital. Among the structural changes in the spine that cause back pain, the following can be distinguished: hernias of the pulpous nucleus; narrow spinal canal; instability due to disk or extra-disk pathology; muscle-tonic or myofascial syndrome.

Numerous statistics show not only the high incidence of degenerative-dystrophic diseases of the spine, but also the absence of a tendency to decrease the frequency of these diseases. Thus, the problem of preventing the development of degenerative-dystrophic diseases of the spine and the elimination of pain is becoming increasingly important.

The current opinion in most medical institutions is that surgical treatment of discogenic disease is indicated only in 10-12% of patients. All other patients can and should receive conservative treatment for degenerative spinal diseases and complications.

Conservative treatment methods include the mandatory use of drugs with a chondroprotective, chondrostimulating effect. In particular, chondroitin sulfate-based formulations meet these requirements.

Various solutions registered in the Russian Federation are on sale:

Chondrogard, Chondrollar, Chondrolife, Artradol, Mukosat, Chondrolon and others. (Http://www.rlsnet.ru/mnn_index_id_1787.htm)

Known patent RU 2080857 from 06/10/1997, which discloses a method for producing an injection form of a chondroitin sulfate preparation, including dissolving the sodium salt of chondroitin sulfate in distilled water, adjusting the pH to 6.0 6.2, sterilizing the solution and filling into ampoules, followed by freezing to -40 -45 ° C at a speed of 10-13 deg / h for 5-6 hours, keeping at this temperature for 5-6 hours, heating the ampoule at a speed of 5-6 deg / h for 13-16 h to 34-36 ° С and keeping at this temperature for 7-10 hours

US 4524066 dated 06/18/1985 concerns a preparation for injection containing chondroitin polysulfate, sodium chloride, water for injection, the pH is adjusted to 8.4 with sodium hydroxide solution, the solution is subjected to sterile filtration through a membrane filter, and the ampoules are filled under sterile conditions. Ampoules are subjected to heat treatment in a water bath for 60 minutes.

Patent RU 2021812, publ. 10/30/1994, discloses an agent for the treatment of arthrological diseases, comprising a mixture of chondroitin sulfates A and C, water and a preservative, characterized in that the mixture of chondroitin sulfates A and C is used with a mol.m 8000-16000 Daltons in a ratio of 3: 2-1: 1 with a peptide content of less than 0.5%, and benzyl alcohol as a preservative in the following ratio of components, wt. %:

A mixture of chondroitin sulfates A and C 8-12

Benzyl alcohol 0.8-1.2

Water The rest.

As the closest analogue may be specified patent RU 2200018, publ. 03/10/2003, which describes a method for preparing an injection form of a preparation of chondroitin sulfate (CH), in which solutions of the components of the drug are prepared separately, first, the substance of cholesterol is dissolved in heated injection water, followed by sterilization and cooling (solution A), then a solution of benzyl alcohol is prepared ( solution B) and sodium hydroxide solution (solution C), then solution B is added to solution A with stirring to a pH of 6.2-6.8 and solution B, the resulting mixture is diluted with injection water, poured into ampoules and sealed.

Basically, known solutions, including the prototype, contain benzyl alcohol, which includes both a preservative and a cosolvent. However, it has only a bacteriostatic effect. In addition, diseases of the musculoskeletal system require a long course of administration of solutions. Benzyl alcohol is known to be a potential toxic and carcinogenic substance and its use in injectable solutions is still not advisable, despite the positive aspects (Messiha FS (1991) Benzyl alcohol adverse effects in the rat: implication for toxicity as a preservative in parenteral injectable solutions, Comp. Biochem. Physiol. 99, 445-449).

The objective of the invention is to expand the arsenal of funds against degenerative-dystrophic lesions based on chondroitin.

The problem is solved by the new composition of the pharmaceutical preparation in the form of a solution for intramuscular administration and a method for its preparation.

Effect: reducing side effects and maintaining stability throughout the shelf life of the drug while reducing the amount of impurities and the absence of opalescence.

The composition is made in the form of the preparation “Chondroitin sulfate solution for intramuscular administration” based on the substance “Chondroitin sodium sulfate”.

As excipients, sodium metabisulfite, methyl paraben and water for injection are used.

One ampoule with the drug contains:

chondroitin sodium sulfate 85-115 mg

sodium metabisulfite 0.5 to 5.0 mg

methylparaben 0.1 to 0.6 mg

water for injection - up to 1.0 ml

pH 6.0 to 7.5.

The method of obtaining the drug in the form of a solution for intramuscular administration is that water for injection is obtained, highly purified by electronic ionization followed by ultrafiltration, sterilization and additional purification using a steam column distiller, cool it to a temperature of 60-70 ° C, add nipagin, mix, after its complete dissolution, lower the temperature to 20-25 ° C, add sodium metabisulfite and mix until it is completely dissolved, add chondroitin sodium sulfate p When stirring until the substance is completely dissolved, sterilizing filtration of the solution is carried out through a pre-filter and sterilizing filter system, where a cartridge-type filter element with a pore size of 0.65 / 0.45 μm is used as a preliminary, and a filter element with a size of pore 0.20 μm, under a nitrogen pressure of not higher than 0.11-0.13 MPa, pack the solution in ampoules and sterilize the solution in ampoules at a temperature of 118-122 ° C for 8-15 minutes.

Preferably, the agitator rotational speed is from 280 to 450 rpm.

Chondroitin sulfate is an acid mucopolysaccharide (M.M. 502.4), obtained in the form of sodium salt from cattle trachea. Pharmacotherapeutic group - tissue regeneration stimulant.

The drug exhibits a chondroprotective, chondrostimulating, regenerative stimulating effect.

Chondroitin sulfate is involved in the construction of the main substance of cartilage and bone tissue. It improves phosphorus-calcium metabolism in cartilage, inhibits enzymes that disrupt the structure and function of articular cartilage, and inhibits the degeneration of cartilage. It stimulates the synthesis of glucosaminoglycans, normalizes the metabolism of hyaline tissue, and promotes the regeneration of cartilage surfaces and articular bags. Prevents compression of connective tissue, increases the production of intraarticular fluid, increases the mobility of the affected joints. Slows down bone resorption, reduces calcium loss and accelerates bone tissue repair, inhibits the progression of osteoarthritis. It has an analgesic effect, reduces joint pain, pain at rest and when walking, the severity of inflammation, helps to reduce the need for NSAIDs.

Scope of the drug: degenerative diseases of the joints and spine: primary arthrosis, intervertebral osteochondrosis, osteoarthritis, osteoporosis, periodontopathy, bone fractures (to accelerate the formation of bone marrow).

With intramuscular administration, significant concentrations in the systemic circulation are detected after 20-25 minutes, and the maximum concentration is reached in less than an hour. In the synovial fluid with the intramuscular route of administration, the drug is detected after 15 minutes.

The invention is illustrated by the following examples.

Example 1

Composition per 1 ml:

Active substance:

Chondroitin sodium sulfate 100.0 mg in terms of dry matter)

Excipients:

Sodium metabisulfite 0.5 mg Methylparaben 0.5 mg Water for injections Up to 1.0 ml

Example 2

Production method

1. Getting water for injection

Preparation of water for injection is carried out using a water treatment plant model "SEPTRON® Line 25-60" and the system "COMBITRON", model "KT 1500-4-450-R", the company "CHRIST AQUA PHARMA & BIOSESN".

Drinking water supplied to the SEPTRON® installation goes through the following preparation stages:

- filtration through filters "MSF 25/24", designed to remove iron and manganese ions from water, and its clarification;

- filtration through a two-column softener, which is equipped with sodium-cation exchange filters "RONDOMAT 95Е DWZ 330" with strongly acidic cateonite in Na-form and operates in a pendulum mode, which ensures a continuous supply of softened water to the installation;

- ultraviolet sterilization using the installation "Bewades 80 W80 / 11LC".

Thus prepared water is supplied to the patented SEPTRON® module, where the following stages of its purification are carried out: filtration, reverse osmosis and electrical deionization, the latter occurs under the influence of electric current, without the use of chemicals and with little power consumption.

Water enters a chamber filled with an ion-exchange substance. The electric potential applied to the electrodes creates charged ions in the form of sodium and chloride ions, which enter the collection chamber through the ion exchange membrane for disposal. The ion exchange agent in the SEPTRON® module reduces the electrical resistance of water. The water obtained at the SEPTRON® installation has a guaranteed electrical conductivity of not more than 0.2 μC / cm at a temperature of 25 ° C.

Highly purified water obtained at the SEPTRON® water treatment plant is subjected to ultrafiltration and fed to the installation of the COMBITRON system.

The “COMBITRON” installation is a 4-column steam distiller, the operation of which is based on the principle of multiple evaporation and condensation. The first column of the installation has increased dimensions compared to the rest, which makes it possible to simultaneously produce a sufficient amount of water for injection and clean steam. Highly purified water from the collection is supplied to the 1st column - the condenser of the COMBITRON installation, where it is heated with technical steam. Water flows from the condenser column to the next column. The water flow is controlled by a safety valve and the readings of the water level sensor in the column. The column is heated by steam, heated water is also supplied here, which evaporates in the same column.

The content of bacterial endotoxins for water for injection from the COMBITRON installation is not more than 0.25 EU / ml, and the electrical conductivity at a temperature of 20 ° C is not more than 1.1 μS / cm.

2. Preparation of the solution

45.0 l of water for injection obtained at the COMBITRON water treatment plant is loaded into the reactor for preparing injection solutions from the collection tank.

Water for injection in the reactor is cooled to a temperature of (60-70) ° C by passing drinking water through his shirt. Add (0.005-0.030) kg of methyl paraben to the reactor and mix for 50-60 minutes until methyl paraben is completely dissolved.

The speed of the reactor stirrer is 350 rpm.

The solution of methylparaben in the reactor is cooled to a temperature of 20-25 ° C, passing drinking water through the jacket of the reactor.

Into the reactor make (0.025-0.250) kg of sodium metabisulfite and mix for 20-30 minutes until it is completely dissolved.

The substance of chondroitin sodium sulfate is weighed on a balance weighing 5.00 kg (in terms of the quantitative content of chondroitin sulfate and dry matter) and portioned into the reactor.

The contents of the reactor are stirred for 60 minutes; stirrer rotation speed - from 280 rpm to complete dissolution of the substance.

The reactor stirrer is turned off, the volume of the drug solution in the reactor is brought up to the mark of 50.0 l with water for injection and mixed for 20-30 minutes.

3. Sterilizing filtration of the drug solution

Preliminary and sterilizing filtration of the drug solution is carried out in a room of purity class B (zone B).

A cartridge type filter element with pore sizes from 0.65 to 0.45 μm is used as a preliminary, and a filter with a pore size of the membrane of 0.20 μm is used as a sterilizing one. Pressure control is carried out by a manometer. The drug solution should be filtered non-stop. During filtration, the pressure in the reactor is monitored, which should not exceed 0.11-0.13 MPa.

4. Pouring the solution into ampoules

The work on filling the ampoules with a solution of the drug is carried out in a room of cleanliness class B / A (zone B / A) on a machine for filling and sealing ampoules. The installation of the metering device to the filling unit is carried out according to the operating instructions with the laminar turned on. The filtered solution from the collection is fed to the metering device of the machine for filling and sealing ampoules.

Sterile depyrogenized ampoules come from the sterilization tunnel to the storage table of the filling and sealing machine. Filled ampoules are sterilized at 120 ° C for 8 minutes. The resulting preparation is a highly pure solution. The selected composition provides the dissolution of the active substance without additional co-solvent.

Analyze the solution for purity and impurity content.

Invisible particles. The determination is carried out by counting-photometric method, RD 42-501-98. Use an analyzer of mechanical impurities AOZ-101 or similar.

On average, in one ampoule the number of particles with a size of 5 microns and more does not exceed 4,500, including a size of 25 microns or more - 500 particles, according to the prototype: 6,000 and 600 particles, respectively.

Shelf life: at least 3 years. During accelerated storage, the solution did not opalescent (in contrast to the prototype).

Example 3

The effectiveness and side effects of the drug were studied in volunteers with osteoarthritis of the knee joints (n = 35).

The drug according to example 1 was administered intramuscularly 1 ml, every other day, for two months.

During therapy, statistically significant improvements were identified as individual indicators: pain, stiffness, functional impairment, and WOMAC in general. A significant reduction in pain on the WOMAC scale was noted by the end of the second week by 16%. With continued therapy by the 2nd month, the pain reduction was 44%. Stiffness in the knee joint by the end of the second week decreased by 15% and after 2 months by 42%.

There were no cases of significant side effects, with the exception of an individual reaction in the form of a small edema at the injection site in 2 subjects.

Claims (4)

1. A pharmaceutical product in the form of a solution for intramuscular administration containing chondroitin sodium sulfate and excipients, characterized in that it contains metabisulphite, methyl paraben and highly purified water for injection as excipients with the following components: chondroitin sodium sulfate 85-115 mg sodium metabisulfite 0.5-5.0 mg methyl paraben 0.1-0.6 mg water for injection up to 1.0 ml pH from 6.0 up to 7.5 2. The method of obtaining a pharmaceutical preparation in the form of a solution for intramuscular administration according to claim 1, characterized in that water for injection is highly purified by electronic ionization followed by ultrafiltration, sterilization and additional purification using a steam column distiller, it is cooled to a temperature of 60-70 ° C, make methylparaben, mix, after its complete dissolution, lower the temperature to 20-25 ° C, add sodium metabisulfite and mix until it is completely dissolved, portionwise add to the solution chondroitin sodium sulfate with stirring until the substance is completely dissolved, sterilizing the solution of the solution is carried out through a pre-filter and sterilizing filter system, where a cartridge-type filter element with a pore size of 0.65 / 0.45 μm is used as the preliminary, and as a sterilizing filter, a filter element with a pore size of 0.20 μm, under a nitrogen pressure of not higher than 0.11-0.13 MPa, pack the solution in ampoules and sterilize the solution at a temperature of 118-122 ° C for 8-15 minutes. 3. The production method according to p. 2, characterized in that the rotation speed of the mixer is from 280 to 450 rpm