RU2454219C2 - Application of natural polysaccharide (natural polysaccharides) gel for preparing composition applicable for injection of composition for treating degenerative joint disease - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, and represents a sterile injectable water-based composition in the form of gel for iintra-articular injection containing hyaluronic acid of molecular weight 0.1 to 10×10⁶ Da in the amount of 1-100 mg/ml of water or one of its salts and optionally one or more other natural polysaccharides specified in a group consisting of chondroitin sulphate, keratan, keratan sulphate, heparin, heparan sulphate, cellulose and its derivatives, chitosan, xanthan, alginate and their salts, and also one or more polyalcohols in the amount of 0.0001-100 mg/ml of water, prepared by making a water-based formulation containing hyaluronic acid or one of its salts, optionally one or more other natural polysaccharides, and also one or more polyalcohols, sterilising it with wet steam; the prepared gel shows a coincidence frequency of the elasticity modulus G' and the viscosity modulus G" within the range 0 to 10 Hz preferentially 0.41 Hz ±0.41 Hz with G" exceeding G' if the coincidence frequency is found to be high.

EFFECT: invention provides higher degradation resistance of the gel, and also makes the gel visco-elastic.

11 cl, 8 ex, 11 dwg

Description

The invention relates to a sterile aqueous, injectable gel composition, consisting of hyaluronic acid (or one of its salts) with or without other polysaccharide (other polysaccharides) of natural origin and one or more polyols. Such an injectable composition is for intraarticular use in the treatment of joint degeneration.

A joint is a connection between two bones, ensuring their mobility relative to each other.

Synovial joints are the most numerous joints, in particular in parts of the limbs. In these joints, the bones are connected inside a cavity filled with fluid, which is both viscous and elastic, and is called synovial.

Synovial fluid provides proper joint action and protection. It consists, in particular, of a polysaccharide, hyaluronic acid, which gives viscoelasticity to the synovial fluid, which, depending on the applied loads, provides joint lubrication or shock absorption.

In the case of joint degeneration, such as knee arthrosis (degeneration caused, in particular, by factors such as overweight, heredity, injuries, etc.), synovial fluid is degraded (a decrease in the concentration and molecular weight of hyaluronic acid), while degradation reduces the ability of the synovial fluid to lubricate the joint and absorb shock.

Treatment with a viscosity-enhancing supplement involves injecting the gel into the joint to replace insufficient synovial fluid. A viscosity increasing additive can reduce or prevent pain and helps restore joint mobility.

The products currently available on the market for increasing viscosity are gels containing hyaluronic acid. These gels can be prepared on the basis of hyaluronic acid of animal or non-animal origin and have cross links (e.g. Synvisc ^® , Durolane ^® ) or no cross links (e.g. Syncrom ^® , Arthrum ^® , Lubravisc ^® , Structovial ^® ).

EP 0 499 164 describes an injectable gel composition for the treatment of joints for the purpose of replacing synovial fluid containing hyaluronic acid, in particular glycerol or propylene glycol.

The specialist is well aware that the aftereffect of a gel based on hyaluronic acid inside the joint is weak (from several hours to several days). According to Laurent "The Chemistry, biology and medical applications of hyaluronan and its derivatives, Wenner-Gren International series, Volume 72", the half-life of a 1% solution of hyaluronan in the rabbit joint is 12 hours, and the same gel period with 0.5% Hylan B - 9 days.

Such a weak aftereffect (kinetics of rapid resorption of the gel inside the joint) is due to the degradation (depolymerization) of hyaluronic acid. The main factors in the degradation of hyaluronic acid inside the joint are degradation by free radicals, the thermal factor at 37 ° C and the mechanical factor (enzymatic degradation is not an essential factor in the degradation within the joint). And although the therapeutic effect of increasing the viscosity of the additive has a longer duration than the time it was inside the joint, nevertheless, the aftereffect of the gel based on hyaluronic acid is the predominant parameter that sets the effectiveness of the product. Therefore, the longer the residence time of the gel based on hyaluronic acid inside the joint, the more effective the treatment is with the help of a viscosity-increasing additive (reduction of pain, increased mobility). Thus, the increase in the residence time (aftereffect) of the gel inside the joint serves as a cardinal factor for increasing the effectiveness of treatment by increasing the viscosity of the gel supplement based on hyaluronic acid.

The average specialist is well aware that increasing the concentration of hyaluronic acid, the use of high molecular weight hyaluronic acid and methods of crosslinking / graft copolymerization of hyaluronic acid can improve the aftereffect of a gel based on hyaluronic acid. However, the optimization of the above different parameters does not seem to be sufficient to significantly increase the aftereffect of a gel based on hyaluronic acid inside the joint (the period of reduction by half of the action of modern gels as an additive to increase the viscosity inside the joint currently available on the market is only no more than a few days) .

It was completely unexpectedly found that:

- the presence of polyhydric alcohol in a sterile aqueous composition based on hyaluronic acid can significantly increase the resistance of this gel to degradation,

- the high affinity of hyaluronic acid for polyhydric alcohol in a sterile gel causes a slow kinetics of salting out of polyhydric alcohol from the gel: such an affinity between hyaluronic acid and polyhydric alcohol provides long-term effective gel protection with polyhydric alcohol as a result of a synergistic effect,

- due to the special composition of the aqueous composition of hyaluronic acid and polyhydric alcohol, sterilization unexpectedly gives the gel viscoelastic properties, as a result of which these properties practically restore the viscoelastic properties of the normal synovial fluid, these special rheological properties of the gel are maintained for a longer time due to the protection from degradation achieved by the synergy from " hyaluronic acid / polyol. "

Therefore, the present invention relates to a sterile aqueous, injectable gel composition consisting of hyaluronic acid (or one of its salts) with or without other polysaccharide (other polysaccharides) of natural origin and one or more polyols. Such a composition used in the treatment of joint degeneration, in certain cases (see examples 1, 3), has a rheology close to the rheology of synovial fluid, and constantly increased resistance to degradation.

Example 4 demonstrates the excellent gel stability based on hyaluronic acid and polyhydric alcohol, which manifested itself during testing for degradation under the influence of free radicals, thermal and mechanical factors. Such excellent resistance to degradation of the gel ensures a longer after-effect after injection into the joint.

Example 5 shows the excellent resistance of the gel based on hyaluronic acid and polyhydric alcohol to degradation under the influence of heat. Such excellent resistance of the gel to this degradation ensures its longer after-effect after injection into the joint and excellent stability of the composition during storage of the product before use (an important point for the deadline for use of the product).

Example 8 confirms the strongly pronounced affinity of hyaluronic acid to polyhydric alcohol. After injection into the joint, the strongly pronounced affinity of hyaluronic acid for polyhydric alcohol provides excellent resistance of the gel to degeneration for a long time under the action of a synergistic effect. Indeed, when a solution of polyhydric alcohol is injected into the joint, a molecule (polyhydric alcohol) will be quickly removed from this joint by natural washing. In the case of applying a gel based on hyaluronic acid and polyhydric alcohol, the strongly pronounced affinity of hyaluronic acid for polyhydric alcohol will prevent the rapid salting out of polyhydric alcohol from the gel (and, therefore, its rapid removal from the joint), thus providing effective gel protection for a long time using polyhydric alcohol from degradation.

Examples 1, 3 show a rheology of a gel based on hyaluronic acid and polyhydric alcohol, close to the rheology of synovial fluid.

In the publication MAZZUCCO D. et al. "Rheology of joint fluid in total knee arthroplasty patients"; Journal of Orthopedic Research, 1157-1163, 2002, indicates that the coincidence frequency of the elastic modulus G ′ with the viscosity modulus G ″ is 0.41 ± 0.12 Hz for normal knee synovial fluid (in the absence of arthrosis). The magnitude of such a coincidence frequency is confirmed by Fam et al. "Rheological properties of synovial fluids", Biorheology, 44, 59-74, 2007. In this publication, the figure shows the coincidence frequency of the modules G 'and G' ', component 0-10 Hz for synovial fluid of a young or elderly person, as well as for synovial fluid with arthrosis.

- At less than 0.41 Hz: G ''> G ', synovial fluid has a dominant viscosity, providing ample lubrication of the joint at rest of the patient.

- At more than 0.41 Hz: G '> G' ', the synovial fluid has a dominant elasticity, which provides effective shock absorption during running or jumping the patient.

According to one aspect of the invention, a gel consisting of an aqueous solution of hyaluronic acid (or one of its salts) with or without other polysaccharide (other polysaccharides) of natural origin and one or more polyhydric alcohols, after sterilization, has a frequency f _c matching elastic modulus G ' and a viscosity modulus G ″ equal to approx. 0.41 Hz. Thus, the gel has viscoelastic properties similar to those of synovial fluid.

Therefore, according to one aspect of the invention:

- when the value is less than f _c : G ''> G ', the gel has a dominant viscosity, which provides effective lubrication of the joint at rest,

- when the value is more than f _c : G '>G'', the gel has a dominant elasticity, which provides effective shock absorption for running or jumping the patient (joint protection).

According to one aspect of the present invention, the frequency of coincidence of the modules is from 0 to 10 Hz, preferably 0.41 ± 0.41 Hz. Therefore, this rheology corresponds to the mechanical stresses on the joints, in particular, on the knee, hip and small joints. Thus, it is of great interest in the treatment of arthrosis by means of a viscosity-enhancing additive introduced into the knee or other joints.

Figure 1-5 shows the modules of viscosity and elasticity of the gels according to one aspect of the present invention, and Fig.6-9 - the same modules of the gel commercial brands. Figure 10, 11 shows the kinematics of gel degradation under the influence of free radicals, thermal and mechanical factors and the affinity of hyaluronic acid to polyhydric alcohol.

The invention also relates to the use of a sterile aqueous, injectable composition in the form of a gel, consisting of hyaluronic acid (or one of its salts) in an amount of 1-100 mg / ml with or without other polysaccharide (other polysaccharides) of natural origin and one or more polyols in the amount of 0.0001-100 mg / ml. Such an injectable composition is used inside the joint in the treatment of joint degeneration.

Hyaluronic acid is preferably obtained by biological fermentation, however, it can also be of animal origin. Its molecular weight is from 0.1 to 10 × 10 ⁶ Yes, preferably from 2 to 3 × 10 ⁶ Yes.

The concentration of hyaluronic acid is from 1 to 100 mg / ml, preferably from 10 to 25 mg / ml.

A polysaccharide (polysaccharides) of natural origin that can be used in association with hyaluronic acid is selected, for example, from chondroitin sulfate, keratan, keratan sulfate, heparin, heparan sulfate, cellulose and its derivatives, chitosan, xanthan, alginates and a combination of their respective salts.

Hyaluronic acid, as well as naturally occurring polysaccharide (polysaccharides), may or may not contain cross-bonds, may or may not be subjected to graft copolymerization in accordance with the cross-linking / graft copolymerization techniques described in the prior art.

The polyhydric alcohol (polyhydric alcohols) is selected, for example, from glycerol, propylene glycol, sorbitol, mannitol, erythritol, xylitol, lactitol, maltitol, or cyclic Sugars such as glucose.

The concentration of polyhydric alcohol is from 0.0001 to 100 mg / ml, preferably from 15 to 45 mg / ml.

The aqueous solution used is preferably a buffer solution. The composition of such a buffer is selected so as to achieve the required physicochemical (pH, osmolarity) and rheological properties.

Preferably, the selected buffer solution is phosphate.

According to the present invention, the composition is sterilized using techniques well known to those of ordinary skill in the art, preferably in an autoclave.

The composition according to the invention is used for injection into the joint, and the administered dose may be from 0.1 to 20 ml, depending on the type of joint to be treated.

As an illustration, below are 2 compositions of a viscoelastic gel that can be prepared in accordance with the present invention.

- Viscoelastic gel based on hyaluronic acid and glycerin.

A sterile solution of 20 mg / ml hyaluronic acid (MM = 2.5 × 10 ⁶ Da) and 20 mg / ml glycerol in phosphate buffer.

- Viscoelastic gel based on hyaluronic acid and sorbitol.

A sterile solution of 20 mg / ml hyaluronic acid (MM = 2.5 × 10 ⁶ Da) and 40 mg / ml sorbitol in phosphate buffer.

Examples

The examples serve to illustrate the invention, but in no way limit it. The compositions obtained in the examples below are sodium hyaluronate (NaHA) gels with or without cross-linking with a polyhydric alcohol content.

The preparation of gels with or without cross-linking is carried out using techniques well known to the average person. Sodium hyaluronate used to prepare these gels has a molecular weight of 2.5 × 10 ⁶ Yes. For gels with cross-bonds, butanediol diglycidyl ether (BDDE) is used as a means for cross-linking; the characteristic for the cross-linking formation is: mass (butane diol diglycidyl ether) / mass (dry NaHA).

The introduction of polyhydric alcohol into the gel is ensured by adding the required amount of polyhydric alcohol to the gel with or without cross-linking and mixing with a spatula for 10 minutes (to obtain 100 g of the finished gel).

The prepared gels are placed in glass syringes and sterilized in a humid atmosphere at a temperature of 121 ° C.

The rheometer for rheological measurements was an AR1000 (TA instruments) with a flat geometry of 40 mm in size with a gap of 1000 microns and an analysis temperature of 37 ° C.

Polyhydric alcohols were dosed using Ultimate 3000 high-performance liquid chromatography (Dionex) and an ion-exchange column.

Example 1. Preparation of sterile, injectable compositions according to the invention

Composition A: NaHA-based gel without cross-linking with glycerol content:

- 15 mg NaHA at 2.5 × 10 ⁶ Yes,

- 20 mg of glycerin,

- Permitted sufficient amount of phosphate buffer: 1 ml.

Composition B: NaHA-based gel without cross-linking with glycerol content:

- 20 mg of NaHA at 2.5 × 10 ⁶ Yes,

- 20 mg of glycerin,

- Permitted sufficient amount of phosphate buffer: 1 ml.

Composition C: gel based on NaHA without cross-linking with the content of propylene glycol:

- 20 mg of NaHA at 2.5 × 10 ⁶ Yes,

- 15 mg propylene glycol,

- allowed sufficient phosphate buffer: 1 ml

Composition D: NaHA-based gel without cross-linking with mannitol content:

- 20 mg of NaHA at 2.5 × 10 ⁶ Yes,

- 15 mg of mannitol,

- Permitted sufficient amount of phosphate buffer: 1 ml.

Composition E: NaHA-based gel without cross-linking with sorbitol content:

- 20 mg of NaHA at 2.5 × 10 ⁶ Yes,

- 40 mg of sorbitol,

- Permitted sufficient amount of phosphate buffer: 1 ml.

Composition F: NaHA crosslinked gel with sorbitol content:

- 18 mg NaHA at 2.5 × 10 ⁶ Yes, the proportion of cross-links: 6%,

- 50 mg of sorbitol,

- Permitted sufficient amount of phosphate buffer: 1 ml.

Example 2. Physico-chemical properties of the compositions of example 1.

- pH (at room temperature)

Composition PH A 7.0 B 7.2 C 7.1 D 7.0 E 7.1 F 7.1

- Osmolarity

Composition Osmolarity (mOsmol / kg) A 335 B 322 C 324 D 315 E 326 F 338

Compositions A, B, C, D, E and F are isosmotic and have a neutral pH.

Example 3. The rheological properties of the compositions of example 1.

The viscoelastic properties of compositions A, B, C, D, and E were determined by measuring the viscosity modulus (G '') and elastic modulus (G ') depending on the frequency of their coincidence (see FIGS. 1-5).

For these five compositions, it was found that the frequency of coincidence of the modules G 'and G' 'approaches the frequency of their coincidence in normal synovial fluid.

The table below shows the coincidence frequency f _c for each composition and for normal synovial fluid.

Composition Frequency f _c match (Hz) A 0.50 B 0.32 C 0.32 D 0.32 E 0.33 Normal synovial fluid (Publication of Mazzucco D. et al.) 0.41 ± 0.12

As indicated in the description of the present invention:

- when the value is less than f _c : G ''> G ', the gel has a dominant viscosity, which provides effective lubrication of the joint at rest;

- when the value is more than f _c : G '>G'', the gel has a dominant elasticity, providing effective shock absorption of the jolts during the running or jumping of the patient.

Example 4. Resistance to degradation of the compositions of example 1

In order to show that the presence of a polyhydric alcohol in a NaHA-based gel makes it possible to reduce the degradation of this gel under the influence of free radicals, thermal and mechanical factors compared the resistance of NaHA-based gels with the content of polyhydric alcohol to degradation (composition from Example 1) with the gel resistance NaHA-based polyhydric alcohol (control gels) to degradation.

For compositions B, C, D, and E of Example 1, a NaHA-based control gel without a polyhydric alcohol was a NaHA-based gel without crosslinking at a content of 20 mg / ml NaHA (MM = 2.5 × 10 ⁶ Da in phosphate buffer ) - composition G.

For composition F of Example 1, a NaHA-based control gel without a polyhydric alcohol was a NaHA-based gel with cross-linking at 18 mg / ml NaHA (MM = 2.5 × 10 ⁶ Da until cross-linking, in phosphate buffer) at the proportion of cross-linking 6% composition N.

The degradation test was carried out with the addition of an oxidizing agent in the test gel during homogenization with a spatula for 1 minute, then it was kept at a temperature of 37 ° C and subjected to deformation of 0.3%. The value of the parameter tanδ = G '' / G 'at 0.7 Hz (the characteristic parameter of the viscoelastic properties of the gel) was measured throughout the entire time.

It was found that this parameter increases with time, which is equivalent to increasing gel degradation. Measurement values at t = 0 min. and t = 15 min for compositions B, C, D, E, F, G, H are shown in the table below.

Composition Tanδ (t = 0 min) Tanδ (t = 5 min.) ΔTanδ (%) B 1.10 3.34 + 204% C 1,08 3.13 + 205% D 1.19 4.63 + 289% E 1,08 2,57 + 138% F 0.74 0.80 + 8% G 1.41 6.56 + 365% H 0.74 0.93 + 26%

As indicated in the description of the present invention, each of the compositions B, C, D, E has a much greater resistance to degradation than the stability of the gel without the content of polyhydric alcohol (composition G). Composition F is also characterized by a significantly greater resistance to degradation than the same resistance of the corresponding gel without a polyhydric alcohol content (composition H).

Therefore, polyhydric alcohols effectively protect the gel from degradation.

Example 5. The study of accelerated aging of the composition with and without polyhydric alcohol

The following two compositions were subjected to accelerated aging in an oven at 40 ° C:

- composition B from example 1: a solution based on hyaluronic acid and glycerol,

- composition G without the addition of alcohol (described in example 4):

- 20 mg of hyaluronic acid at 2.5 × 10 ⁶ Yes,

- Permitted sufficient amount of phosphate buffer: 1 ml.

Measurement of zero viscosity (viscosity with zero shear) and determination of the frequency f _c coincidence of the elastic modulus G 'with the viscosity modulus G''were carried out in three time intervals (t = 0, 7, 26 days).

The results are shown in the table below.

The number of days of aging at 40 ° C Composition Zero viscosity Change in zero viscosity relative to (%) f _c (Hz) Change in f _c relative to to (%) 0 days B 252 / 0.32 / G 192 / 0.39 / 7 days B * ND / 0.32 0% G * ND / 0.39 0% 26 days B 210 -17% 0.37 + 16% G 143 -26% 0.50 + 28% * ND means: not defined.

It was found that with accelerated aging, the loss of zero viscosity and frequency shift f _c coincidence of the modules are less significant when using composition B (composition according to the invention) compared to a composition without a polyhydric alcohol (composition G).

Example 6. Comparison of the rheology of 4 commercial products to increase the viscosity and composition according to the invention

The following products were tested:

Product Commercial name Manufacturer Hyaluronic Acid Concentration (mg / ml) Molecular Weight of Hyaluronic Acid (Yes) Sterilization method P1 Synocrom ^® CROMA PHARMA 10 2.2-2.710 ⁶ Humid warm atmosphere P2 Structovial ^® CROMA PHARMA 10 2.2-2.710 ⁶ Humid warm atmosphere P3 Fermathron ^®® Hyaltech 10 1.10 ⁶ Filtration P4 Lubravisc ^® BOHUS BIOTECH 10 4.10 ⁶ Humid warm atmosphere Composition A of Example 1 Absent Absent 15 (+20 mg / ml glycerol) 2.510 ⁶ Humid warm atmosphere

For 5 tested gels, FIGS. 6–9 show the viscosity modulus (G ″) and elasticity modulus (G ′) depending on the frequency of their coincidence.

It was found that only the gel from example 1 is characterized by a coincidence frequency of the modules (0.50 Hz), which is close to the same frequency of a normal synovial fluid (0.41 Hz).

The table below grouped the values of the frequencies f _c matching modules for the products P1-P4 and composition A from example 1.

Product f _c (Hz) Composition A of Example 1 0.50 P1 5.8 P2 5,0 P3 6.3 P4 0.09

From the publication of Mazzucco D. et al. (Mentioned above) it is known that the coincidence frequency of the modules (0.41 Hz), which is typical for normal synovial fluid, is less than the same frequencies noted for the knee when walking (0.7 Hz) and running ( 3 Hz).

For products P1-P3, the frequency of coincidence of the modules is noticeably higher than 3 Hz and, therefore, these products do not have high elasticity, which provides shock absorption of the knocks during knee movement.

Product P4 has a very low frequency of matching modules, while the elastic modulus exceeds the viscosity modulus in the entire frequency range of 0.1-10 Hz. Therefore, elasticity is significant only when the knee is in motion, but the lubrication of the joint is not very effective when the patient is at rest.

Example 7. Comparison of the resistance to degradation of 3 commercial products to increase the viscosity and composition according to the present invention

The following products were tested:

Product Commercial name Manufacturer Hyaluronic Acid Concentration (mg / ml) T1 Arthrum ^® LCA Pharmaceutical twenty T2 Ostenil ^® TRB Chemedica 10 T3 Synocrom ^® CROMA PHARMA 10 Composition E of Example 1 Absent Absent 20 (+40 mg / ml sorbitol)

The degradation test was carried out according to the method described in example 4.

The value of the parameter G '0.7 Hz was monitored throughout the entire time.

The resulting rheology curves are presented in figure 10.

It was found that the gel according to the present invention degrades significantly less quickly than the 3 tested commercial products.

Example 8. The detection of a pronounced affinity of hyaluronic acid to polyhydric alcohol

To prove the strong affinity of hyaluronic acid for polyhydric alcohol and, therefore, long-term preservation of the gel with polyhydric alcohol, a control study of the salting out of polyhydric alcohol using dialysis was carried out.

5 mg of composition E (based gel 20 mg / ml without NaHA crosslinks and 40 mg / ml sorbitol (Example 1)) was injected into a dialysis membrane ^{(№1) (Spectra / Pore ®} , MWCO: 12-14,000).

5 g of phosphate buffer containing 40 mg / mL sorbitol introduced into the second dialysis membrane ^{(№2) (Spectra / Pore ®} , MWCO: 12-14,000) of the same size as the membrane №1.

These membranes were placed in appropriate bottles containing 50 g of purified water (dialysis bath) with magnetic stirring. Measurements of the concentration of sorbitol by high-resolution liquid chromatography were carried out in dialysis baths at different times in order to control the kinetics of salting out of sorbitol from the membrane with a gel or buffer solution.

Figure 11 shows the curves for monitoring the concentration of sorbitol during the whole time.

The kinetics of salting out sorbitol in the gel proceeds much more slowly than in the buffer solution.

This study revealed the synergy caused by hyaluronic acid and polyhydric alcohol present in the gel: the strong affinity of hyaluronic acid to polyhydric alcohol allows the latter to remain in the gel for a long period, while the protective ability of polyhydric alcohol with respect to the gel provides the gel with high and long-term resistance to degradation.

Claims (11)

1. A sterile injectable aqueous composition in the form of a gel for intraarticular use, containing hyaluronic acid with a molecular weight of from 0.1 to 10 · 10 ⁶ Yes in an amount of 1-100 mg / ml of water or one of its salts and optionally one or more other polysaccharides natural origin, selected from the group comprising chondroitin sulfate, keratan, keratan sulfate, heparin, heparan sulfate, cellulose and its derivatives, chitosan, xanthan, alginate and their salts, as well as one or more polyols in the amount of 0.0001-100 mg / ml of water you get by preparing an aqueous composition containing hyaluronic acid or one of its salts, optionally one or more other polysaccharides of natural origin, as well as one or more polyhydric alcohols, and by sterilizing the composition with wet steam, the resulting gel has a frequency of coincidence of elastic modulus G ′ and a viscosity modulus G ″ from 0 to 10 Hz, preferably 0.41 Hz ± 0.41 Hz, with G ″ exceeding G ″ at a high module matching frequency. 2. The composition according to claim 1, in which hyaluronic acid does not contain or mainly does not contain cross-links. 3. The composition according to claim 1, in which hyaluronic acid contains cross-links. 4. The composition according to claim 2, in which the concentration of hyaluronic acid or one of its salts is 10-25 mg / ml, and the concentration of polyhydric alcohol (polyhydric alcohols) is 15-45 mg / ml. 5. The composition according to claim 1, in which the polyhydric alcohol, separately or in a mixture, is glycerin, propylene glycol, sorbitol, mannitol or glucose. 6. The composition according to claim 1, in which hyaluronic acid has a molecular weight of from 2 to 3 · 10 ⁶ Yes. 7. The composition according to claim 1, in which the concentration of hyaluronic acid is 20 mg / ml of water, and the concentration of glycerol is 20 mg / ml of water. 8. The composition according to claim 1, in which the concentration of hyaluronic acid is 20 mg / ml and the concentration of sorbitol is 40 mg / ml. 9. The composition according to claim 1, the sterilization of which is carried out in an autoclave. 10. A method of preparing a sterile injectable aqueous composition in the form of a gel according to claim 1, comprising the step of preparing an aqueous composition containing hyaluronic acid with a molecular weight of from 0.1 to 10 · 10 ⁶ Yes or one of its salts, optionally one or more other polysaccharides natural origin, which are selected from the group consisting of chondroitin sulfate, keratan, keratan sulfate, heparin, heparan sulfate, cellulose and its derivatives, chitosan, xanthan, alginate and their salts, and one or more polyols, and the sterilization step tion of the resulting composition with wet steam in an autoclave. 11. The use of the composition according to claim 1 for intraarticular injection in the treatment of joint degeneration by introducing in an amount of from 0.1 to 20 ml.

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