Ophthalmic composition containing a novel axitinib molecular aggregate and method for producing the same.

Abstract

The present invention relates to a composition comprising a molecular aggregate to which axitinib is physically bound, and to a method for producing the same.

Claims

1. A molecular aggregate to which axitinib is physically bound; Solubilizer; Stabilizers; and A composition characterized by containing an additive.

2. The solubilizing agent includes alphacyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), sulfobutylether beta-cyclodextrin (SBE-beta-CD); 2-hydroxypropyl-alpha-cyclodextrin; randomly methylated beta-cyclodextrin;2-O-methyl-beta-cyclodextrin;2,6-di-O-methyl-beta-cyclodextrin;heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin;carboxymethyl-beta-cyclodextrin;carboxyethyl-beta-cyclodextrin;hydroxyet hyl-beta-cyclodextrin; maltosyl-beta-cyclodextrin; 3,6-(N,N,N-trimethylammonium)propyl-beta-cyclodextrin; acetyl-beta-cyclodextrin; 2,6-di-O-methyl-gamma-cyclodextrin; 2-hydroxypropyl-gamma-cyclodextrin; or sulfobutylether gamma-cyclodextrin; optionally, wherein the cyclodextrin is alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), gamma-cyclodextrin The composition according to claim 1, characterized by comprising one or more selected from the group consisting of (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), or sulfobutylated-beta-cyclodextrin (SBE-beta-CD), and cyclodextrin derivatives.

3. The composition according to claim 1, characterized in that the stabilizer comprises one or more selected from the group consisting of methylcellulose (MC), hydroxymethyl cellulose (HMC), carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), and cellulose derivatives.

4. The composition according to claim 1, characterized in that it contains one or more additives from the group consisting of buffering agents, osmotic pressure regulators, and pH regulators.

5. The composition according to claim 4, characterized in that the buffering agent comprises one or more of the group consisting of citric acid, phosphoric acid, boric acid, stannic acid, acetic acid, and amino acids.

6. The composition according to claim 4, characterized in that the osmotic pressure regulator comprises one or more of the group consisting of sorbitol, mannitol, dextrose, sucrose, and glycerin.

7. The composition according to claim 4, characterized in that the pH adjusting agent is an alkalizing agent.

8. Based on the entire composition, The molecular aggregate is present in a concentration of 0.02–0.12 w / v%; The solubilizing agent is 2-12 w / v%; The stabilizer is 0.01 to 1.0 w / v%; The composition according to claim 1, characterized by containing.

9. Based on the entire composition, The buffering agent is 0.5 to 1.5 w / v%; The osmotic pressure regulator is 0.1 to 5 w / v%; The composition according to claim 4, characterized by containing.

10. The composition according to claim 4, characterized in that the pH is adjusted to 6 to 8 using the pH adjusting agent.

11. The composition according to claim 1, wherein the X-ray powder diffraction spectrum of the molecular aggregate has X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1°.

12. The composition according to claim 1, characterized in that the molecular aggregate has a DSC profile having a glass transition at a single endothermic temperature of 220.4 ± 2.0 °C when measured under differential scanning thermal analysis (DSC) conditions of a heating rate of 10 °C / min, 99.999% N2, and 30-250 °C.

13. The composition according to claim 1, characterized in that the molecular aggregate has an aspect ratio of 0.3 to 1.

0.

14. The composition according to claim 1, characterized in that the crystals of the molecular aggregate have an average particle size of 2 to 15 μm.

15. A composition according to any one of claims 1 to 14, which is for use as eye drops.

16. A composition according to any one of claims 1 to 14, which is a pharmaceutical composition for the prevention or treatment of wet macular degeneration.

17. (a) The step in which axitinib is dissolved by adding acid to the molecular aggregate to which it is physically bound; (b) A step of preparing the first solution by adding a solubilizer to the solvent and stirring; (c) The step of solubilizing the stabilizer in water to produce the second solution; (d) The step of mixing the first solution and the second solution; (e) Adding an additive containing a buffer and an osmotic pressure regulator as active ingredients to the solution produced in step (d) above, adjusting the pH to 6-8 with a pH adjuster, and then adding water to bring it to the mark; and (f) A step of sterilizing the solution produced in step (e); A method for producing a composition containing the above.

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