RU2268052C2 - Agent for treatment of inflammatory and degenerative joint disease (variants), method for treatment of inflammatory and degenerative joint disease (variants) and device for delivery of medicinal agent to damaged site - Google Patents

Abstract

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an agent used in treatment inflammatory and degenerative joint diseases. Agent comprising hyaluronic acid and chondroitin sulfate can comprise also dimethylsulfoxide, sodium diclofenac, chlorhexidine bigluconate, cosmetic whey, medicinal comfrey roots extract and parabena extract. Also, invention relates to a method for treatment of inflammatory or degenerative joint diseases, and a device for delivery of the claimed agent to a site damaged by the disease. The claimed agent provides reducing treatment period, to enhance effectiveness of anti-inflammatory effect and to intensify regeneration of intra-articular fluid.

EFFECT: valuable medicinal properties of agent, improved treatment method.

13 cl, 8 ex

Description

The invention relates to medicine, in particular to rheumatology, and can be used to treat diseases of the musculoskeletal system, for example, inflammatory and degenerative diseases of the joints.

Currently, non-steroidal anti-inflammatory drugs, chondroprotectors and glucocorticoids are used to treat inflammatory and degenerative joint diseases, such as arthritis, osteoarthritis, etc. [Federal guidelines for doctors on the use of drugs (formulary system): Issue 1. - M .: GEOTAR MEDICINE , 2000, p. 444].

Among other drugs that have chondroprotective effects, it is worth noting that they are produced in Russia - Mucosat, Chondrolon, Khonsurid, which are chondroitin sulfate obtained from cartilage of cattle trachea, and intended for introduction into the body by intramuscular injection or orally.

Hyaluronic acid (sodium hyaluronate) preparations - Hyalgan (Fidia), Artz (Seikagaku Corp.), Synvisc (Biomatrix), Orthovisc (Anika), injected directly into the affected joint, are widely used as chondroprotectors abroad.

A medicament is known comprising an effective amount of hyaluronic acid in combination, for example, with cortisone, used to treat inflammatory and degenerative joint diseases [Description of the invention to US patent No. 4801619, N. cl. 514/825, publ. 01/31/1989 (or WO 86/05984, IPC ⁴ С 08 В 37/05, publ. 10/23/1986)]. The agent injected directly into the joint improves the early stages of cartilage degeneration and normalizes the metabolism of proteoglycans, preventing their leakage from cartilage during treatment with corticosteroids or other drugs that have a similar effect.

In the later stages of the disease, the use of a known agent does not have a therapeutic effect.

The problem solved by the first invention of the group is to expand the arsenal of tools that provide the possibility of treating inflammatory and degenerative diseases of the joints.

The technical result will be to shorten the treatment time, increase the effectiveness of anti-inflammatory effects and enhance chondroprotective properties, including by replacing synovial fluid and improving its rheological (viscoelastic) properties.

To solve the problem in a known tool for the treatment of inflammatory and degenerative joint diseases, including an effective amount of hyaluronic acid, chondroitin sulfate is additionally contained in the following ratio of components, wt.%:

Hyaluronic acid 0.5-1.50 Chondroitin sulfate 0.25-0.500 Buffer solution or bidistilled water rest,

while hyaluronic acid has a molecular weight of more than 500,000.

Besides:

- the buffer solution has a pH of 6.5-7.5;

- the tool additionally contains dimethyl sulfoxide, diclofenac sodium, parabens, chlorhexidine bigluconate, perfume, milk cosmetic serum, in the following ratio, wt.%:

Dimethyl sulfoxide 10-15 Diclofenac Sodium 0,050-0,075 Parabens 0.35-0.55 Chlorhexidine bigluconate 0.10-0.15 Perfume 0.0010-0.0015 Cosmetic milk serum 50-60

this uses a 2-3% solution of diclofenac sodium;

- the tool further comprises an extract from the roots of comfrey officinalis in an amount of 0.15-0.25 wt.%.

In some cases, there is a need to introduce an implant into the intraarticular region, which is close in its mechanical and physiological properties to the synovial fluid. For this purpose, as a rule, drugs (“synovial fluid prostheses”) such as Hyalgan (Fidia, Italy), Synvisc (Biomatrix, USA) and Orthovisc (Zimmer, USA) [Artificial synovial fluid in the treatment of knee pathology are used. Vyrva O.E. Kharkov Research Institute of Orthopedics and Traumatology named after Prof. M.I. Sitenko. Ukraine. In the journal "Orthopedics, Traumatology and Prosthetics", 2000, - No. 2, p.146-150]. For example, the most progressive drug in the treatment of gonarthrosis is considered to be Orthovisc artificial synovial fluid, consisting of sodium hyaluronate with a molecular weight of 6,000,000-7,000,000 and a low protein concentration.

The disadvantage of using this implant is its lack of effectiveness in ensuring the regeneration of cartilage tissue of the joints.

The problem solved by the second invention of the group is to expand the arsenal of tools that provide the possibility of treating inflammatory and degenerative diseases of the joints.

The technical result is to expand the arsenal of drugs for the treatment of inflammatory and degenerative joint diseases, provide the ability to replace synovial fluid in the joint, normalize its viscoelastic properties, stimulate the formation of endogenous HAV by synovial cells, as well as increase the effectiveness of anti-inflammatory action, enhance chondro-protective properties and obtain a longer duration therapeutic effect compared with the use of individual components.

To solve this problem, it is proposed to use an agent for the treatment of inflammatory and degenerative joint diseases as an synovial fluid implant, including an effective amount of hyaluronic acid and chondroitin sulfate in the following ratio of components, wt.%:

Hyaluronic acid 0.50-1.50 Chondroitin sulfate 0.25-0.50 Buffer solution rest,

while hyaluronic acid has a molecular weight of more than 750,000, and the buffer solution has a pH of 6.5-7.5.

A known method of treating joints experiencing progressive cartilage degeneration and steroid arthropathy (inflammatory and degenerative joint diseases), including intra-articular administration of a hyaluronic acid preparation having a molecular weight of from 3,000,000 to 7,000,000 [Description of the invention to US patent No. 4801619, N. cl. 514/825, publ. 01/31/1989 (or WO 86/05984, IPC ⁴ С 08 В 37/05, publ. 10/23/1986)].

This method of treatment with a hyaluronic acid preparation improves the early stages of cartilage degeneration and normalizes the metabolism of proteoglycans, preventing their leakage from cartilage. In the later stages of the disease, the use of a known treatment method does not have a therapeutic effect.

In addition, the possibility of using high molecular weight hyaluronic acid - a very viscous substance - for intra-articular injection.

The problem solved by the third invention of the group is to expand the methods of treatment of inflammatory and degenerative diseases of the joints.

The technical result will be a reduction in the duration of treatment, an increase in the effectiveness of anti-inflammatory action, enhancement of chondroprotective properties and the process of regeneration of intraarticular fluid.

To solve the problem in a known method for the treatment of inflammatory and degenerative joint diseases, including intra-articular administration of a drug based on hyaluronic acid, chondroitin sulfate is additionally introduced into the composition in the following ratio of components, wt.%:

Hyaluronic acid 0.5-1.5 Chondroitin sulfate 0.25-0.50 Buffer solution rest,

while hyaluronic acid has a molecular weight of more than 750,000, the buffer solution has a pH of 6.5-7.5, and intraarticular administration of the drug is carried out at least once a week for three to five weeks.

The prior art can be used to develop another method of treatment.

The problem solved by the fourth invention of the group also consists in expanding the methods of treating inflammatory and degenerative diseases of the joints.

The technical result will be to shorten the treatment time, increase the effectiveness of anti-inflammatory effects, enhance chondroprotective properties and intensify the process of regeneration of intraarticular fluid.

To solve the problem in a known method of treating inflammatory and degenerative joint diseases, including treating the affected area with a drug based on hyaluronic acid, chondroitin sulfate is additionally added to the composition of the drug in the following ratio of components, wt.%:

Hyaluronic acid 0.05-1.50 Chondroitin sulfate 0,025-0,500 Buffer solution rest,

while hyaluronic acid has a molecular weight of more than 500,000, the buffer solution has a pH of 6.5-7.5, and the affected area is treated with periarticular local injection of the drug into the soft tissues with at least three courses, ten to twelve injections each, with at least a ten-day break between courses.

Known means for the local treatment of degenerative diseases of joints and periarticular soft tissues, with increased penetration into the tissue of a non-steroidal anti-inflammatory agent [Description of the invention to the patent of the Russian Federation No. 2085194, IPC ⁷ A 61 K 31/715, publ. 07/27/1997, bull. No. 21]. The product contains diclofenac sodium as an anti-inflammatory agent, as well as glycosaminoglycan polysulfate, dimethyl sulfoxide, lanolin and petrolatum.

The chondroprotective effect in this ointment belongs to glycosaminoglycan polysulfate - Arteparon, which includes low molecular weight products of hydrolysis of chondroitin sulfate with a molecular weight of (3-10) × 10 ³ [Ivankin AN, Vasyukov S.E., Panov V.P. , properties and use of chondroitin sulfates (review). Chemical Pharmaceuticals Journal, 1985, - Vol. 19, No. 3. - p. 192-202].

Due to the high concentration (30-40%) of dimethyl sulfoxide, redness of the skin due to the irritating effect of the drug is observed in some cases.

These disadvantages are deprived of the method of treatment of joints described above (see the description of the invention to US patent No. 4801619).

The problem solved by the fifth invention of the group also lies in expanding the methods of treatment of inflammatory and degenerative diseases of the joints.

The technical result will be to shorten the treatment time, increase the effectiveness of anti-inflammatory effects, enhance chondroprotective properties and intensify the process of regeneration of intraarticular fluid.

To solve the problem in a known method for the treatment of inflammatory and degenerative joint diseases, including the use of a drug based on hyaluronic acid, chondroitin sulfate, dimethyl sulfoxide, diclofenac sodium, parabens, chlorhexidine bigluconate, fragrance and milk cosmetic serum are additionally introduced into the composition, in the following ratio of components, wt.%:

Hyaluronic acid 0.5-1.5 Chondroitin sulfate 0.25-0.50 Dimethyl sulfoxide 10-15 Diclofenac Sodium 0,050-0,075 Parabens 0.35-0.55 Chlorhexidine bigluconate 0.10-0.15 Perfume 0.0010-0.0015 Cosmetic milk serum 50-60 Bidistilled water rest,

while hyaluronic acid has a molecular weight of more than 500,000, diclofenac sodium is used in the form of a 2-3% solution, and the use of the drug is carried out by applying it to the skin over the affected area 2-3 times a day for at least 2 weeks.

Besides:

- the extract from the roots of comfrey medicinal in the amount of 0.15-0.25 wt.% is additionally introduced into the composition of the drug;

- diffusion of hyaluronic acid and chondroitin sulfate to the affected area is stimulated by electrophoresis or laser phoresis.

Known devices for delivering the drug to the place of use, for example, a cervical diaphragm containing a sterile mechanical carrier, on the inner surface of which is a layer of the drug [Description of the invention to RF patent No. 2033120, IPC ⁶ A 61 F 06/10, publ. 04/20/1995, bull. No. 11].

Also known is a device for delivering a drug to a place of use, comprising a mechanical carrier and a drug with an effective amount of the sodium salt of hyaluronic acid [Description of the invention to the RF patent No. 2177789, IPC ⁷ A 61 K 31/728].

The effect of using the device with the sodium salt of hyaluronic acid when used externally will be limited, since the insufficient diffusion rate of high molecular weight acid will not allow for a long therapeutic effect. This problem was solved by intra-articular administration of a hyaluronic acid preparation (see the description of the invention to US patent No. 4801619).

The problem solved by the sixth invention of the group is to expand the range of devices for delivering the drug to the affected area of the body, for example, in the treatment of inflammatory and degenerative diseases of the joints.

The technical result will be to shorten the treatment time, increase the effectiveness of anti-inflammatory effects, enhance chondroprotective properties and intensify the process of regeneration of intraarticular fluid.

To solve the problem in a known device for delivering a drug to a disease-affected area, including a mechanical carrier and a drug with an effective amount of hyaluronic acid, the drug further includes chondroitin sulfate, dimethyl sulfoxide, diclofenac sodium, parabens, chlorhexidine bigluconate, fragrance and cosmetic milk in the following ratio of components, wt.%:

Hyaluronic acid 0.5-1.5 Chondroitin sulfate 0.25-0.50 Dimethyl sulfoxide 10-15 Diclofenac Sodium 0,050-0,075 Parabens 0.35-0.55 Chlorhexidine bigluconate 0.10-0.15 Perfume 0.0010-0.0015 Cosmetic milk serum 50-60 Bidistilled water rest,

while hyaluronic acid has a molecular weight of more than 500,000, and diclofenac sodium is used in the form of a 2-3% solution.

Besides:

- the drug further comprises an extract from the roots of comfrey in the amount of 0.15-0.25 wt.%;

- the mechanical carrier is in the form of a napkin.

We illustrate the possibility of implementing inventions.

(The first invention of the group). The agent for treating inflammatory and degenerative joint diseases includes 0.05-1.50 wt.% Hyaluronic acid with a molecular weight of more than 500000, 0.025-0.500 wt.% Chondroitin sulfate and buffered solution or bidistilled water.

The choice of sodium hyaluronate is based on the fact that it is the main component of synovial fluid, which has a sufficiently high viscosity and serves as an ideal lubricant for contacting articular cartilage, as well as a nutrient medium for articular cartilage, is an elastic layer that provides shock absorption and protection of articular cartilage from excessive loads, and the lowest coefficient of friction in the joint. It is also known that hyaluronic acid solutions prevent the formation of postoperative adhesions after performing orthopedic operations. With osteoarthritis, a deficiency in the secretion of synovial fluid is revealed, the fluid properties and rheological parameters of the synovial fluid also change dramatically: it becomes less viscous due to the depolymerization of hyaluronic acid, its elastic properties are largely lost. This leads to an increase in the coefficient of friction in the joint and the appearance of islands of degeneration in the articular cartilage.

It should be borne in mind that hyaluronic acid is a natural biopolymer, the molecular weight of which is in the range from 5 thousand to several (from 8 to 13) million, depending on the source, production method and determination method. Fractions with a specific molecular weight are obtained by ultrafiltration, using filters with a specific pore diameter that allows you to get rid of polymers, with a molecular weight below the specified limit.

Chondroitin sulfate is part of the connective tissue of tendons and cartilage of articular surfaces. Its introduction into the body is designed to slow down the degeneration of cartilage, stimulate regeneration processes and normalize the production of joint fluid, which leads to improved functioning of the joints, in particular their mobility.

Since the carboxyl groups of hyaluronic acid and chondroitin sulfate are completely ionized and, therefore, carry a negative charge at pH 7.0, phosphate buffer, for example, is introduced into the composition, which allows maintaining the pH (concentration of H ⁺ ) in the region close to the physiological pH of the synovial fluid. To a certain extent, the role of the buffer for external use of the product can be performed by proteins of cosmetic milk serum. The standard buffer solution contains 8.1661 g of NaCl, 0.4003 g of Na ₂ HPO ₄ × 7H ₂ O and 0.04455 g of NaH ₂ PO ₄ × H ₂ O per 1 liter of pyrogen-free bidistilled water. In some cases, for example, in the simplest embodiment, for external use, the agent may be prepared in bidistilled water.

Depending on the concentration in the agent for the treatment of inflammatory and degenerative joint diseases of hyaluronic acid and chondroitin sulfate, preparations for intraarticular or intramuscular administration, or for external use, are obtained, each of which is more or less effective in the treatment of various joint pathologies. For example, 0.05-0.15 wt.% Hyaluronic acid with a molecular weight of 500000-750000, 0.025-0.500 wt.% Chondroitin sulfate can be used for intramuscular injection into the border region with a diseased joint, and 0.5-1.5 wt. .% hyaluronic acid with a molecular weight above 750,000, for example, from 2,000,000 to 7,000,000, 0.25-0.40 wt.% chondroitin sulfate can be used for intra-articular injection or as an implant synovial fluid. It should be borne in mind that the lower the molecular weight of hyaluronic acid, the higher the viscous flow properties and penetration, and vice versa. For external use of the product, it is necessary to be guided by the effective (or optimal) amount of ingredients and their concentration and the presence in the composition of the ingredients of the conveyor for the hyaluronic acid itself. The specific proportions of the ingredients are selected based on the pathology and condition of the patient.

An example of a preparation for the treatment of inflammatory and degenerative joint diseases is taken by lyophilized hyaluronic acid and dissolved in a sterile physiological buffer solution with a pH of 6.5-7.5. Lyophilized chondroitin sulfate is dissolved in the exact same buffer solution, after which the solutions are combined with constant stirring. A viscous solution forms.

To expand the scope of the product, for example, for external use in the form of a gel, 10-15 wt.% Dimethyl sulfoxide, 0.050-0.075 wt.% Diclofenac sodium in the form of its 2.5% solution can be added to its composition (the most common form ), 0.35-0.55 wt.% Parabens, 0.10-0.15 wt.% Chlorhexidine bigluconate, 0.0010-0.0015 wt.% Fragrance, 50-60 wt.% Whey cosmetic milk and, if necessary, an extract, for example, of water-alcohol, from the roots of comfrey officinalis in an amount of 0.15-0.25 wt.%. It turns out a jelly-like substance that penetrates well into the skin.

In the composition of the agent, dimethyl sulfoxide acts as an anti-inflammatory agent and, additionally, due to its ability to diffuse easily through the skin, acts as a transporter of hyaluronic acid. The concentration of dimethyl sulfoxide is reduced to 10-15 wt.%, Which reduces its irritating effect (redness and itching) on the skin at the site of application.

Diclofenac sodium is known for its ability to suppress inflammatory processes, as well as its ability to accumulate in synovial fluid, which determines its widespread use in the treatment of joint diseases.

Given that hyaluronic acid can be broken down by bacterial enzymes, preservatives - parabens, for example, nipaset - a mixture of ethyl or methyl esters of parabenzoic acid, which act as a chemical sterilizer, or propyl ester of parabenzoic acid, etc. are introduced into the composition of the product. Their presence stabilizes the mixture and prevents the development microorganisms.

Chlorhexidine bigluconate as part of the drug acts as a weak antiseptic.

Fragrance is necessary to give a drug intended for external use, a pleasant smell.

Milk cosmetic whey, due to the presence of a large number of microelements, vitamins and amino acids in it, is an independent source of active principle, helps regulate metabolic processes in the skin and acts as an additional diluent and buffer [Product catalog No. 004940 "Milk cosmetic whey". Specifications TU.9229-023-52647136-2002. Certificate of conformity ROSS RU. PC08. B00887].

To enhance the anti-inflammatory and analgesic effects, as well as enhance tissue regeneration, the gel includes a water-alcohol extract from the roots of Comfrey (Symphytum officinale), whose preparations have been successfully used for joint pain, inflammation of the periosteum, dislocation of joints, bruises and bone fractures [ Kyosev P.A. A complete directory of medicinal plants. - M .: Eksmo, 2002 .-- 992 p. Comfrey officinalis].

It should be noted that the ability of hyaluronic acid to bind (non-specific absorption) and the gradual release (as hydrolysis) of various chemical compounds is added to all the useful properties of these components Hyaluronic acid acts as a prolonger of the action of various drugs, which allows to improve the therapeutic profile and use significantly smaller amounts of certain components compared to their original dosage forms. In addition, in the composition of the drug, hyaluronic acid performs the function of a gel-forming component.

Specific uses of the agent are described in more detail below in Examples 1-8.

(Second invention of the group). By electrolyte composition, synovial fluid corresponds to plasma transudate; it also contains proteoglycans formed by the synovial membrane cells. Normally, the pH of the synovial fluid is 7.3-7.4, its specific gravity is approximately 1.01, and the protein content is about 1%. The presence of hyaluronic acid - about 0.85 g per 100 ml - determines the high viscosity of the synovial fluid; its relative viscosity ranges from 50 to 200, averaging 125 [A. White, F. Hendler, E. Smith et al. Fundamentals of biochemistry: In 3 volumes. T.3. Per. from English - M .: Mir, 1981, p.1341].

As a result of osteoarthritis, a decrease in the amount and average molecular weight of hyaluronic acid occurs, as a result of which the latter is not able to fulfill the function of a lubricant (lubricant). In this case, the means of choice in the treatment of this condition is to replace the synovial fluid with an implant. For this, the aforementioned agent for the treatment of inflammatory and degenerative joint diseases is suitable, comprising 0.5-1.5 wt.% Hyaluronic acid with a molecular weight, for example 2000000 and 0.40-0.50 wt.% Chondroitin sulfate in a buffer solution with a pH of 6.5-7.5. A specific concentration of components of the implant can be assigned based on the state of the synovial fluid in the healthy joint of the patient, as, for example, described below in example 2.

(Third invention of the group). To achieve a long-term therapeutic result, as a rule, it is required not one, but several (3-5 or more) intra-articular injections of a synovial fluid implant with a frequency of approximately once a week. To obtain the best therapeutic effect, it is recommended to study the patient's synovial fluid and prescribe a course of treatment depending on its visco-elastic properties. The concentration of active components should be gradually increased to a state corresponding to the norm. This is a method of treating inflammatory and degenerative diseases of the joints, which can significantly alleviate the course of the disease, reduce pain and partially restore joint function, which is more specifically described below in example 3.

(Fourth invention of the group). In cases where intra-articular administration of the drug is difficult due to technical reasons (for example, joints of the lumbar spine) or any other indications, the agent for the treatment of inflammatory and degenerative joint diseases is injected locally into the soft tissues around the affected area, depending on the patient’s condition and the course of the disease, take a tool with one or another percentage of components, for example, 0.05-1.50 wt.% hyaluronic acid with a molecular weight of 500000-750000 or higher, 0.025-0.500 wt.% chondroite insulphate in a buffer solution with a pH of 6.5-7.5. The treatment process consists in local periarticular injection of the drug into the soft tissues with at least three courses, ten to twelve injections each, with at least a ten-day break between courses. More specifically, the treatment process is illustrated below in Example 4.

During treatment, part of the drug is destroyed by the enzymes of the body. For this reason, the diffusion of hyaluronic acid and chondroitin sulfate into the affected area can be further stimulated by electrophoresis or laser phoresis. In this case, more active ingredients enter the articular region, including the joint bag and articular cartilage. Mechanisms for stimulating the diffusion of drugs under the influence of electrophoresis or laser phoresis are traditional and are described in the specialized literature. Electrophoresis should be understood as a well-known therapeutic method for influencing the body with direct current and medicinal substances introduced through the skin through it. Laserphyrosis is understood as a method of conducting complex biologically active substances into the body’s internal environment using low-intensity laser radiation (see, for example, A.A. Khadartsev, V. G. Kupeev, V. G. Zilov, etc. Diagnostic and treatment-restorative technologies for the combined pathology of internal organs and systems: Monograph / Edited by A.A. Khadartsev. - Tula: Tula polygraphist 2003. - 172 p.).

(Fifth invention of the group). In the treatment of certain diseases, for example, small joints (distal and proximal interphalangeal joints) and others, the use of a drug in the form of a gel is indicated. A method of treating inflammatory and degenerative joint diseases with the use of this tool is carried out by applying it to the skin over the affected area 2-3 times a day for at least 2 weeks, while it contains 0.5-1.5 wt. .% hyaluronic acid with a molecular weight of 500'000-750'000 or higher, 0.25-0.50 wt.% chondroitin sulfate dissolved in bidistilled water, 10-15 wt.% dimethyl sulfoxide, 0.050-0.075 wt.% diclofenac sodium in the form of a 2-3% solution, 0.35-0.55 wt.% parabens, 0.10-0.15 wt.% chlorhexidine bigluconate, 0.0010-0.0015 wt.% ki, 50-60 wt.% of dairy whey cosmetic and hydroalcoholic extract of comfrey root in an amount of 0.15-0.25 wt.%.

The proposed ratio of the components of the gel allows us to provide not only a pronounced anti-inflammatory and analgesic effect, but also to prevent the progression of dystrophic changes in the joints and surrounding tissues.

The drug (gel) is applied to the skin over the affected area.

It is possible to rub the drug into the skin above the diseased joint or around it until the drug is completely absorbed. In order to accelerate the diffusion of the agent in the tissue, the use of electrophoresis or laser phoresis is possible.

More specifically, the treatment process for the present invention of the group is illustrated below in examples 5 and 6.

(Sixth invention of the group). One of the options for delivering the drug to the affected area, in addition to the gel, is its implementation in the form of an independent device, including a mechanical carrier and the drug itself with an effective amount of components, namely: 0.5-1.5 wt.% Hyaluronic acid with molecular weight 500000-750000 or higher, 0.25-0.50 wt.% chondroitin sulfate in a buffer solution with a pH of 6.5-7.5, 10-15 wt.% dimethyl sulfoxide, 0.050-0.075 wt.% diclofenac sodium in form of its 2-3% solution, 0.35-0.55 wt.% parabens, 0.10-0.15 wt.% chlorhexidine bi gluconate, 0.0010-0.0015 wt.% fragrances, 50-60 wt.% whey cosmetic milk and water-alcohol extract from the roots of comfrey officinalis in an amount of 0.15-0.25 wt.%.

The mechanical carrier may be in the form of a tissue impregnated with a drug.

The device is used as follows.

A napkin with a medicinal product for the treatment of inflammatory and degenerative joint diseases is applied to the skin over a diseased joint, covered, for example, with parchment paper or polyethylene and aged for 5-15 minutes.

As in previous cases, the diffusion of drug components into the affected area can be further stimulated by electrophoresis or laser phoresis. More specifically, the use cases of the device are described below in examples 7 and 8.

Examples of the use of inventions.

Example 1. Obtaining an active principle for the treatment of inflammatory and degenerative diseases of the joints.

Hyaluronic acid for medical purposes is extracted from cocks, and chondroitin sulfate with a high degree of purification from proteins and nucleic acids (impurities are determined spectrophotometrically) from tracheal cartilage of cattle.

When preparing an agent for the treatment of inflammatory and degenerative joint diseases, 1.0 g of a lyophilized preparation of hyaluronic acid obtained according to the RF patent for invention No. 2157381 [Description of the invention to RF patent No. 2157381, IPC ⁷ C 08 V 37/08, A 61 K 31 is taken / 728, publ. 10/10/2000. Bull. No. 28] and satisfying the requirements of FSP-42-0093-0221-00, and dissolve it in 40.0 ml of sterile physiological buffer solution with a pH of 7.0. Next, 0.25 g of the lyophilized preparation of chondroitin sulfate meeting the requirements of VFS 42-2322-94 is dissolved in 40.0 ml of sterile physiological buffer solution with a pH of 7.0. The resulting solutions are combined with constant stirring and the solution volume is adjusted to 100 ml. The result is a viscous solution containing (wt.%):

Hyaluronic acid 1,0 Chondroitin sulfate 0.25 Phosphate Buffer (pH 7.0) rest.

Example 2. The use of funds as an implant synovial fluid.

Patient S. ev, 31 years old, complained of pain in the right knee joint, inability to step on his right leg due to a sharp increase in pain. 3 days ago, he fell, hitting his right knee on the edge of the curbstone. The next day, the right knee was swollen, the pain intensified, and when stepping on the right leg, sharp pain appeared in the knee, which limited the possibilities of movement. Home remedies did not bring.

Objectively: the right knee joint is enlarged, on palpation below the patella and along its edges pain is noted, the range of motion in the joint is sharply limited. The symptom of balloting of the patella is positive.

Data from an additional study: on the part of the blood - moderate leukocytosis and accelerated ESR, urine, ultrasound of the internal organs, chest x-ray, ECG within normal limits. X-ray of the right knee joint: expansion of the joint space and the presence of free intraarticular bodies.

To reduce transudative phenomena, a joint puncture was performed twice, which, however, provided temporary relief. A month later, under epidural anesthesia, endoscopic removal of pieces of torn cartilage that impeded movement in the joint was performed. After the operation was completed in order to remove the smallest pieces of free cartilage, the synovial fluid was evacuated and replaced with an implant - “artificial synovial fluid” containing wt.%:

Hyaluronic acid (cf. mol. Mass of 1,500,000) 1,0 Chondroitin sulfate 0.25 Phosphate Buffer (pH 7.0) rest.

Six months after the operation, the amount of flexion in the knee joint was fully restored.

Example 3. A method of treatment with intraarticular injection

Patient O-va, 55 years old, when admitted to the clinic complained of mechanical pain in the knee joints, morning stiffness, lasting about 10 minutes, crunching in the joints during movements, loss of confidence in the ability of the knees to support body weight. Pain in the knee joints periodically bothered the patient for 3 years, gradually increasing in duration and strength. Two weeks ago, after physical exertion, pain in the joints intensified, pain appeared during prolonged standing and descending stairs, morning stiffness in the joints. Taking non-steroidal anti-inflammatory drugs and rubbing joints with local remedies brought only temporary relief.

Objectively: limitation of range of motion in the knee joints, local pain during palpation along the joint gap.

Data from an additional study: blood, urine, ultrasound of internal organs, chest x-ray, ECG within normal limits. An X-ray examination revealed signs of gonarthrosis: narrowing of the joint spaces of the knee joints, a change in the surface of the articular cartilage and the presence of sections of subchondral osteosclerosis.

A course of treatment was carried out, which included 3 intraarticular injections of 2.0 ml of a drug containing (wt.%):

Hyaluronic acid (cf. mol. Mass of 1,500,000) 1,0 Chondroitin sulfate 0.4 Phosphate Buffer (pH 7.0) rest

with an interval between injections equal to a week. The treatment gave a significant improvement: pain disappeared, morning stiffness, increased range of motion in the knee joints. Persistent positive dynamics was observed for 5 months.

Example 4. A method of treatment with local periarticular administration of an agent.

Patient S-va, 46 years old, complained of pain in the lumbar spine during treatment, aggravated by movements, prolonged standing or sitting, occasionally radiating to the upper region of the buttocks. Pain in the lower back periodically bothered the patient for 3 years. A history of sciatic nerve neuralgia.

Objectively: painful flexion of the body without volume limitation. Pain intensifies with rotation of the body to the left. Soreness on palpation of the spinous processes of L3-L4.

Additional research data: blood, urine, ultrasound of internal organs, ECG within normal limits. On the roentgenogram of the lumbar spine: a change in the intervertebral joints, marginal osteophytes of the intervertebral discs, 0.2-0.3 cm in size.

The treatment was carried out in three courses, each of 12 procedures, with breaks between courses of 10 days. The treatment consisted of paravertebral administration at the level of L2-L3-L4, intramuscularly, every other day, alternately from the right and left side, of an injection preparation of the following composition (wt.%):

Hyaluronic acid (cf. mol. Mass 650,000) 1,0 Chondroitin sulfate 0.25 Phosphate buffer, pH 7.0 rest.

The drug was administered in an amount of 1.0 to a depth of 3.5-4 cm.

After the treatment, a significant improvement in the subjective state, muscle elasticity, almost complete disappearance of pain without physical exertion was noted.

Example 5. The use of the active principle of funds for external use.

Patient K-va, 62 years old, complained of pain in the interphalangeal joints, stiffness in the joints of the hands, difficulties in performing minor work. The pain first appeared 6 years ago, and subsequently they recurred. Last exacerbation 2 days ago.

Objectively: the interphalangeal joints are slightly swollen, the volume of their flexion is reduced.

General analysis of blood, urine, ultrasound of internal organs, ECG within normal limits. Multiple arthrosis of the distal and proximal interphalangeal joints on the radiograph of the hands.

The treatment, including rubbing the gel (jelly-like mass) of the following composition (wt.%):

Hyaluronic acid (cf. mol. Mass 650,000) 1,0 Chondroitin sulfate 0.25 Bidistilled water rest.

After the first rubbing of the gel, after 15-20 minutes the pain significantly decreased. Monotherapy with rubbing the gel 3 times a day after 2 days significantly reduced pain and morning stiffness of the joints.

Example 6. A method of treatment for external use of the drug.

Patient N-in, 40 years old, complained of pain in the cervical spine, more on the left, aggravated by extension of the neck, the appearance of pulling pains along the spinal column with maximum flexion of the cervical spine (pressing the chin to the sternum), dizziness, pain in the neck areas, a feeling of numbness (tingling) of the tips of 1-3 fingers with a long lying position or half-sitting.

For the first time, pain in the cervical spine appeared about 7 years ago, and was noted 1-2 times a year. Last exacerbation 3 days ago; against the background of increased pain in the cervical spine, signs of vertebro-basilar syndrome, dizziness appeared.

Objectively: the neck muscles on the left during palpation are tense, the amount of flexion and extension of the neck is limited.

General analysis of blood, urine, ultrasound of internal organs, ECG within normal limits.

Assigned massage of the cervical spine with rubbing the gel of the following composition (wt.%):

Hyaluronic acid (cf. mol. Mass 625000) 1,000 Chondroitin sulfate 0.250 Water-alcohol extract from comfrey roots 0,200 Dimethyl sulfoxide 15,000 Diclofenac Sodium 0,075 Parabens 0.350 Chlorhexidine bigluconate 0,100 Perfume 0.001 Cosmetic milk serum 50,000 Bidistilled water rest.

After the first rubbing of the above gel into the cervical region, the pain significantly decreased. Monotherapy 2-3 times a day eliminated pain, dizziness, relieved neck muscle tension on the left, tingling sensations acquired a rare episodic nature.

Example 7. The use in the treatment of a device for drug delivery, using electrophoresis.

Patient O-va, 64 years old, complained of pain in the left shoulder joint, aggravated by high-amplitude movements, static load and carrying heaviness in the left hand, radiating to the region of the left mastoid process of the temporal bone and the ulnar region of the forearm, as well as painful limitation movements in the affected joint.

For the first time, pains in the left shoulder joint appeared about 4 years ago, recently they have become constant, aggravated by exertion.

Objectively: the shoulder joints are painful on palpation, the range of motion in them is limited, raising the arms and external rotation are especially difficult.

General analysis of blood, urine, ultrasound of internal organs, ECG within normal limits. The roentgenogram revealed signs of osteoarthrosis of the left shoulder joint with osteophytes, 0.2-0.4 mm in size in the region of the lower pole of the glenoid fossa.

A course of treatment was carried out, including electrophoresis on the shoulder joints. A device made in the form of a gauze napkin and impregnated with the following composition (wt.%):

Hyaluronic acid (cf. mol. Mass 625000) 1,000 Chondroitin sulfate 0.250 Dimethyl sulfoxide 15,000 Diclofenac Sodium 0,075 Parabens 0.350 Chlorhexidine bigluconate 0,100 Perfume 0.001 Cosmetic milk serum 50,000 Pyrogen-free bidistilled water rest

moistened with warm water and placed under the cathode. The current was dosed by the sensation of moderate burning under the influence of direct current.

After the treatment, the range of movements in the left shoulder joint increased, the soreness with moderate load and radiation to the temporal bone and the ulnar region of the forearm disappeared.

Example 8. The use in the treatment of a device for drug delivery, using laser phoresis.

Patient S-va, 61 g., Upon admission to the clinic complained of pain in the left knee joint, aggravated by walking, crunching in the joints, morning stiffness. Periodic pain in the knee joints (more on the left) bothered the patient during the previous 4 years, which became frequent the last 3 months. Since 1996, diagnoses have been established: urolithiasis, chronic pyelonephritis, widespread osteochondrosis of the spine, chronic colitis.

Objectively: limitation of range of motion in the knee joints, pain in the left joint during palpation of the popliteal fossa and along the joint space.

On examination: ECG, blood and urine tests are within normal limits. On the roentgenogram of the thoracic and lumbar spine - the phenomenon of osteochondrosis in the form of compaction of the subchondral surfaces of the vertebral bodies. On the roentgenogram of the cervical and thoracic spine - also the phenomenon of osteochondrosis. When x-ray examination of the knee joints: narrowing of the joint spaces, the presence of sections of subchondral osteosclerosis.

A course of treatment was carried out, including laser phoresis on the area of the left knee joint. The duration of the course is 12 days. The area of the knee joint was lubricated with the following composition (wt.%):

Hyaluronic acid (cf. mol. mass 500000-750000) 1,000 Chondroitin sulfate 0.250 Water-alcohol extract from comfrey roots 0,200 Dimethyl sulfoxide 15,000 Diclofenac Sodium 0,075 Parabens 0.350 Chlorhexidine bigluconate 0,100 Perfume 0.001 Cosmetic milk serum 50,000 Bidistilled water rest.

Then, the treated areas of the skin were irradiated with an Adept laser apparatus with a frequency of 80-100 Hz, a wavelength of 0.85-0.63 μm with a combined optical fiber, which makes it possible to combine laser radiation with a wavelength of 0.85 μm with pulsed mode with a frequency of 80-100 Hz from one channel of the apparatus and continuous laser radiation with a wavelength of 0.63 μm of the second channel, and the radiation power at the output of the fiber of the first channel is 20-25 mW, 2 channels - 3-5 mW. The exposure time is 3 minutes.

The patient's health improved after the first procedures. The pains became less intense. In the course of treatment, the patient received a dosage of exercise therapy, an unloading plant diet (a patient with increased nutrition). After a 12-day course, the patient began to walk more, lost 4 kg. Pain occurred only when climbing stairs.

There are other uses for treating inflammatory and degenerative diseases of the joints, including the use of various combinations and proportions of the components used. However, they all fall under the combination and proportions of the above inventions, combined into a group and allow you to get the desired technical result.

The use of inventions expands the arsenal of tools and the range of devices for the treatment of inflammatory and degenerative diseases of the joints and, accordingly, provides the possibility of implementing this by various methods.

As a result, the treatment time was shortened, the effectiveness of the anti-inflammatory effect increased, the chondroprotective properties increased and the processes of regeneration of interarticular fluid intensified, its rheological properties improved, including by replacing with an implant.

Claims (13)

1. The tool for the treatment of inflammatory and degenerative diseases of the joints, including an effective amount of hyaluronic acid, characterized in that it additionally contains chondroitin sulfate in the following ratio, wt.%: Hyaluronic acid 0.05-1.50 Chondroitin sulfate 0,025-0,500 Buffer solution or bidistilled water Rest while hyaluronic acid has a molecular weight of more than 500'000. 2. The tool according to claim 1, characterized in that the buffer solution has a pH of 6.5-7.5. 3. The tool according to claim 1, characterized in that it further comprises dimethyl sulfoxide, diclofenac sodium, parabens, chlorhexidine bigluconate, perfume, milk cosmetic serum in the following ratio, wt.%: Dimethyl sulfoxide 10-15 Diclofenac Sodium 0,050-0,075 Parabens 0.35-0.55 Chlorhexidine bigluconate 0.10-0.15 Perfume 0.0010-0.0015 Cosmetic milk serum 50-60 this uses a 2-3% solution of diclofenac sodium. 4. The tool according to claim 3, characterized in that it further comprises an extract from the roots of comfrey officinalis in an amount of 0.15-0.25 wt.%. 5. An agent for the treatment of inflammatory and degenerative joint diseases, including an effective amount of hyaluronic acid, characterized in that it additionally contains chondroitin sulfate in the following ratio, wt.%: Hyaluronic acid 0.50-1.50 Chondroitin sulfate 0.25-0.50 Buffer solution Rest while hyaluronic acid has a molecular weight of more than 750'000, and the buffer solution has a pH of 6.5-7.5. 6. A method of treating inflammatory and degenerative joint diseases, including intra-articular administration of a drug based on hyaluronic acid, characterized in that chondroitin sulfate is additionally introduced into the composition in the following ratio of components, wt.%: Hyaluronic acid 0.5-1.5 Chondroitin sulfate 0.25-0.50 Buffer solution Rest while hyaluronic acid has a molecular weight of more than 750'000, the buffer solution has a pH of 6.5-7.5, and intraarticular administration of the drug is carried out at least once a week for at least three weeks. 7. A method of treating inflammatory and degenerative joint diseases, including treating the affected area with a hyaluronic acid-based preparation, characterized in that chondroitin sulfate is additionally added to the composition of the preparation in the following ratio, wt.%: Hyaluronic acid 0.05-1.50 Chondroitin sulfate 0,025-0,500 Buffer complex Rest while hyaluronic acid has a molecular weight of more than 500'000, the buffer solution has a pH of 6.5-7.5, and the affected area is treated with periarticular local injection of the drug into the soft tissues with at least three courses, ten to twelve injections per each, with at least a ten-day break between courses. 8. A method of treating inflammatory and degenerative joint diseases, including the use of a hyaluronic acid-based preparation, characterized in that chondroitin sulfate, dimethyl sulfoxide, diclofenac sodium, parabens, chlorhexidine bigluconate, fragrance and cosmetic milk serum are additionally added to the composition in the following ratio of components, wt .%: Hyaluronic acid 0.5-1.5 Chondroitin sulfate 0.25-0.50 Dimethyl sulfoxide 10-15 Diclofenac Sodium 0,050-0,075 Parabens 0.35-0.55 Chlorhexidine bigluconate 0.10-0.15 Perfume 0.0010-0.0015 Cosmetic milk serum 50-60 Bidistilled water Rest while hyaluronic acid has a molecular weight of more than 500'000. diclofenac sodium is used in the form of a 2-3% solution, and the use of the drug is carried out by applying it to the skin over the affected area 2-3 times a day for at least 2 weeks. 9. The method according to claim 8, characterized in that the composition of the drug is additionally injected with the extract from the roots of comfrey in the amount of 0.15-0.25 wt.%. 10. The method according to claim 8 or 9, characterized in that the diffusion of hyaluronic acid and chondroitin sulfate into the affected area is stimulated by electrophoresis or laser phoresis. 11. A device for delivering a drug to a disease-affected area, comprising a mechanical carrier and a drug with an effective amount of hyaluronic acid, characterized in that the drug further includes chondroitin sulfate, dimethyl sulfoxide, diclofenac sodium, parabens, chlorhexidine bigluconate. fragrance and cosmetic milk whey, in the following ratio of components, wt.%: Hyaluronic acid 0.5-1.5 Chondroitin sulfate 0.25-0.50 Dimethyl sulfoxide 10-15 Diclofenac Sodium 0,050-0,075 Parabens 0.35-0.55 Chlorhexidine bigluconate 0.10-0.15 Perfume 0.0010-0.0015 Cosmetic milk serum 50-60 Bidistilled water Rest while hyaluronic acid has a molecular weight of more than 500'000, and diclofenac sodium is used in the form of a 2-3% solution. 12. The device according to claim 11, characterized in that the drug further comprises an extract from comfrey roots in an amount of 0.15-0.25 wt.%. 13. The device according to claim 11 or 12, characterized in that the mechanical medium is in the form of a napkin.