INJECTABLE COMPOSITION AND USE OF SAID COMPOSITION

Abstract

Injectable composition in hydrogel form, comprising water and micronized croscarmellose sodium. Method for preparing said injectable composition comprising mixing the components and heat treating the obtained composition at a temperature between 90° C. and 150° C., preferably between 100° C. and 130° C.

Claims

1. An injectable composition in hydrogel form comprising croscarmellose sodium, characterized in that said croscarmellose sodium is micronized.

2. The injectable composition according to claim 1, wherein the croscarmellose sodium is provided in weight percentages between 0.01% and 10%.

3. The injectable composition according to claim 1, further comprising hyaluronic acid.

4. The injectable composition according to claim 3, wherein said hyaluronic acid is linear.

5. The injectable composition according to claim 1, further comprising carboxymethylcellulose sodium .

6. The injectable composition according to claim 1, further comprising sodium hydroxide.

7. The injectable composition according to claim 1, wherein sodium chloride is comprised.

8. The injectable composition according to claim 1, further comprising a buffer system, said buffer system comprising sodium phosphate dibasic and sodium phosphate monobasic, wherein said sodium phosphate dibasic is in the anhydrous and/or dihydrate and/or dodecahydrate hydration state and said sodium phosphate monobasic is in the anhydrous and/or dihydrate hydration state.

9. A method for preparing the injectable composition according to claim 1, characterized in that it includes mixing the-components and heat treatment of the composition obtained at a temperature between 90° C. and 150° C., preferably between 100° C. and 130° C.

10. The method according to claim 9, wherein said croscarmellose sodium is obtained by a carboxymethylcellulose cross-linking process in an acidic environment.

11. The method according to claim 10, wherein said acidic environment comprises ethanol, deionized water, and hydrochloric acid.

12. A method of use of the composition according to claim 1, comprising using the composition in an intra-articular injection in a joint to increase lubricating capacities of the-synovial fluid of the joint.

13. A method of use of the composition according to claim 1, comprising using the composition in an intradermal injection to correct skin imperfections.

Description

[0032] In a preferred exemplary embodiment, said hyaluronic acid is linear. This further increases the safety of the composition with respect to health, because there is no need for potentially harmful cross-linking agents in the formation of the hyaluronic acid. Alternatively or in combination, it is possible to use cross-linked hyaluronic acid.

[0033] In an embodiment, said croscarmellose sodium is obtained by means of a cross-linking process of carboxymethylcellulose in an acidic environment.

[0034] According to a refinement, said acidic environment comprises ethanol, deionized water and hydrochloric acid.

[0035] This allows to completely avoid the use of BDDE or other cross-linking agents which are potentially harmful to health.

[0036] According to a further embodiment, sodium carboxymethylcellulose is comprised.

[0037] The carboxymethylcellulose acts as a gelling agent for the composition. Alternatively or in combination, other gelling substances such as hydroxy ethylcellulose may be used.

[0038] According to a further embodiment, sodium hydroxide is comprised.

[0039] Sodium hydroxide acts as a pH regulator excipient of the entire formulation to bring it to correct values. Alternatively or in combination, potassium hydroxide may be used.

[0040] The action of sodium hydroxide is particularly advantageous in combination with the cross-linking in an acidic environment mentioned above, because it brings the acidic pH of the croscarmellose sodium thus formed back to correct values.

[0041] In an embodiment, sodium chloride is comprised. This allows to adjust the osmolarity of the composition.

[0042] In a further embodiment, a buffer system is comprised. Such a buffer system may be of any suitable type.

[0043] Preferably the buffer system comprises sodium phosphate dibasic and sodium phosphate monobasic.

[0044] The buffer system may alternatively be composed of other salts, e.g., potassium equivalents, i.e., potassium phosphate dibasic and potassium phosphate monobasic.

[0045] In a further variant, the buffer system may be a citrate buffer, comprising citric acid and sodium citrate.

[0046] The buffer can be provided in all the hydration forms thereof.

[0047] According to an embodiment, said sodium phosphate dibasic is in the anhydrous and/or dihydrate and/or dodecahydrate hydration state and said sodium phosphate monobasic is in the anhydrous and/or dihydrate hydration state.

[0048] Similarly, such hydration states may be provided in the above-mentioned cases of a buffer system comprising potassium salts or a citrate buffer system.

[0049] Advantageously, the composition has the appearance of a transparent gel, an important condition for the visual control of syringes.

[0050] In a further embodiment, the composition does not include hyaluronic acid and is suitable for veterinary use for the purpose of improving viscosupplementation.

[0051] An object of the present invention is furthermore a method for preparing an injectable composition as described above. Such a method includes mixing the components and heat treatment of the composition obtained at a temperature between 90° C. and 150° C., preferably between 100° C. and 130° C. In a preferred embodiment, a gradual heating process of about one hour is used to bring the composition to a temperature of 121° C.

[0052] Thanks to this heat-based production methodology, the croscarmellose sodium is made more soluble and able to capture the water molecules around it, creating a very thick and viscous gel.

[0053] The micronisation of croscarmellose sodium and the heat treatment of the mixture allow a structural modification of the hydrogel such that a very long-lasting gelatinous layer is formed and it does not swell as usually occurs with injectable hydrogels based on cross-linked hyaluronic acid. Thanks to the cross-linked structural modification induced by the heat treatment, in fact, the composition does not tend to recall water.

[0054] The micronisation of the croscarmellose and the heat treatment of the mixture act synergistically as a viscosifying rheological modifier of the hydrogel.

[0055] An object of the present invention is also the use of the composition described above in an intra-articular injection to increase the lubricating capacities of the synovial fluid of joints.

[0056] An object of the present invention is also the use of the composition described above in an intradermal injection to correct skin imperfections. The composition has a moisturizing effect on the skin and adds firmness, as it acts inside the layers of the dermis, increasing volume and obtaining a corrective effect of skin imperfections.

[0057] The aforesaid uses can be envisaged in both the medical and veterinary fields.

[0058] These and other features of the invention and the advantages resulting therefrom will become apparent from the following detailed description of an embodiment, preferred among the advantageous and various embodiments of the invention, illustrated merely by way of example, therefore non-limiting, with reference to the table below.

TABLE-US-00001 Component Weight percentage Water for injections 93.73 Sodium Chloride 0.70 Sodium Phosphate Dibasic 0.30 Sodium Phosphate Monobasic 0.06 Croscarmellose sodium 3.00 Carboxymethylcellulose 1.50 Sodium hyaluronate 0.50 Sodium hydroxide 0.21

[0059] In this embodiment the sodium hyaluronate is preferably low molecular weight, e.g., less than 700 KDa, in particular between 200 and 400 KDa and is preferably in weight percentages less than 3%. Sodium hyaluronate is optionally included.

[0060] The croscarmellose sodium is preferably included in micronized form and in weight percentages between 0.01% and 10%.

[0061] Sodium chloride is optionally included, e.g., in weight percentages between 0% and 4%.

[0062] Sodium phosphate dibasic is optionally included, e.g., in weight percentages between 0% and 5%. The sodium phosphate dibasic is preferably in the dodecahydrate hydration state.

[0063] Sodium phosphate monobasic is optionally included, e.g., in weight percentages between 0% and 5%. The sodium phosphate monobasic is preferably in the hydrated state.

[0064] Sodium carboxymethylcellulose is optionally included, e.g., in weight percentages between 0% and 10%.

[0065] Sodium hydroxide is optionally included, e.g., in weight percentages between 0% and 6% in a 30% solution.

[0066] In a further embodiment, the composition having the formulation illustrated in the table is suitable for veterinary use for the purpose of improving viscosupplementation. In this case, the composition preferably does not include hyaluronic acid.

[0067] From the foregoing, it is therefore evident that the invention is not limited to the embodiments just described and illustrated by way of non-limiting examples, but may be varied and modified, as a whole and in individual details, especially constructively, according to the specific needs and conveniences of production and use, within the scope of the technical and functional equivalents, without abandoning the guiding principle set forth above and subsequently claimed.