Stable dosage form of etidronate-cytarabine conjugate, and use thereof
The invention relates to the field of medicine and pharmaceuticals and particularly to a novel dosage form of an antitumor preparation, which ensures the hydrolytic and physical stability of said preparation, as well as to a method for producing a dosage form of this type. The stable dosage form is a lyophilizate comprising an etidronate-cytarabine conjugate or a pharmaceutically acceptable salt thereof, and a stabilizer, which is a divalent metal salt, in a molar ratio of stabilizer to conjugate of 1:1 to 20:1. A dosage form of this type ensures the hydrolytic and physical stability of the conjugate during long-term storage, and the stability of solutions of the conjugate for parenteral administration during clinical use.
1. A lyophilizate stable dosage form suitable for a solution for parenteral administration comprising an etidronate-cytarabine conjugate, or a pharmaceutically acceptable salt thereof, and a stabilizer, which is a divalent metal salt, with a molar ratio of stabilizer to etidronate-cytarabine conjugate, or pharmaceutically acceptable salt thereof, of 1:1 to 12:1.
2. The lyophilizate stable dosage form as claimed in claim 1 , wherein the pharmaceutically acceptable salt of the etidronate-cytarabine conjugate is the trisodium salt of the etidronate-cytarabine conjugate.
3. The lyophilizate stable dosage form as claimed in claim 1 , wherein magnesium or calcium salts are used as the divalent metal salt.
4. The lyophilizate stable dosage form as claimed in claim 1 , wherein calcium chloride or magnesium chloride is used as the divalent metal salt.
5. The lyophilizate stable dosage form as claimed in claim 1 , wherein the molar ratio of stabilizer to etidronate-cytarabine conjugate, or a pharmaceutically acceptable salt thereof, is from 1:1 to 2:1.
6. The lyophilizate stable dosage form as claimed in claim 1 , wherein the molar ratio of stabilizer to etidronate-cytarabine conjugate, or a pharmaceutically acceptable salt thereof, is 2:1.
7. A method for the preparation of a stable dosage form as claimed in claim 1 includes the following:
prepare an aqueous solution containing an etidronate-cytarabine conjugate, or a pharmaceutically acceptable salt thereof, and a stabilizer which is a divalent metal salt, with the selected molar ratio of stabilizer to conjugate from 1:1 to 12:1;
perform sterile filtration of the solution produced;
dispense the solution produced to containers for lyophilization;
perform lyophilization.
8. The method as claimed in claim 7 , wherein the molar ratio of stabilizer to conjugate is from 1:1 to 2:1.
9. The method as claimed in claim 7 , wherein the molar ratio of stabilizer to conjugate is 2:1.
10. The method as claimed in claim 7 , wherein the concentration of the etidronate-cytarabine conjugate, or a pharmaceutically acceptable salt thereof, in the aqueous solution is ≤25 mg/mL.
11. The method as claimed in claim 7 , wherein 20 mL vials are used as containers.
12. The method as claimed in claim 7 , wherein the sterile filtration of the solution produced is performed through a 0.2 μm sterile filter.
13. The parenteral solution obtained by dissolving the lyophilizate stable dosage form according as claimed in claim 1 in a pharmaceutically acceptable solvent suitable for parenteral administration.
14. The solution as claimed in claim 13 , wherein the concentration of the lyophilizate stable dosage form in a pharmaceutically acceptable solvent is ≤10 mg/mL.
15. The solution as claimed in claim 13 , wherein the pharmaceutically acceptable solvent is represented by sterile water for injection or dextrose 5% in water solution.
16. A method for the treatment of primary bone cancer or bone lesion caused by a malignant neoplasm, the method comprising administering the parental solution as claimed in claim 13 to a patient in need of treatment of a primary bone cancer or a bone lesion caused by a malignant neoplasm.
17. The method as claimed in claim 16 , wherein the bone lesion is a multiple myeloma, bone metastases caused by breast, prostate or thyroid cancer, or metastatic lesions of other tissues and organs.
18. The method as claimed in claim 16 , wherein the primary bone cancer is represented by osteosarcoma, Ewing's sarcoma, chondrosarcoma, fibrosarcoma.