Injectable composition with aromatase inhibitor
The present invention provides a composition suitable for forming an intramuscular implant. It comprises a biodegradable thermoplastic polymer of polylactic acid (PLA), DMSO and an aromatase inhibitor compound. The invention also provides a kit suitable for the in situ formation of the composition and its use as a medicine for treating cancer, especially breast cancer.
1. An injectable composition consisting of
about 25% wt of drug, which is letrozole, wherein the drug has a particle size distribution selected from any of the following <10% of the particles are less than 20 microns, <10% of the particles are greater than 350 microns, and a d0.5 between 70-200 microns; or d0.1 of 38.21 microns, d0.5 of 141.35 microns, and d0.9 of 312.13 microns; and
the remaining balance of said injectable composition consisting of polymeric solution consisting of 57-60% wt of DMSO; and 40-43% wt of biodegradable poly(lactic acid) polymer (PLA), wherein
the polymeric solution has a viscosity in the range of 0.8-1.5 Pas, as measured at 25° C.; and
the drug is suspended in the polymeric solution.
2. The injectable composition of claim 1 , wherein ≤20% wt of the drug is dissolved in the polymeric solution.
3. The injectable composition of claim 1 , wherein the PLA has been irradiated with beta-radiation.
4. The injectable composition of claim 1 , wherein the polymer has been lyophilized.
5. The injectable composition of claim 1 , wherein the PLA is end-capped with a carboxylic acid group.
6. The injectable composition of claim 1 , wherein the PLA is end-capped with an ester group.
7. The injectable composition of claim 1 , wherein the maximum volume of the injectable depot composition is 2 mL containing a maximum of 500 mg of the drug.
8. The injectable composition of claim 1 , wherein following administration to a subject, the AUC of the burst of drug is less than about 10% of the total AUC after administration and not more than about 50% of the total AUC over the first 30 days after administration.
9. The injectable composition of claim 1 , wherein following administration to a subject, the plasma level of letrozole is sufficient to provide an in vivo suppression of serum estrogens estrone (E1) and estradiol (E2) of at least about 50% E2 and at least about 70% E1 in the steady state during a dosing period.
10. A kit suitable for the in situ preparation of the injectable composition of claim 1 , wherein prior to preparation of the injectable composition, the kit comprises a) the drug and the polymer in solid form in a first container, and the DMSO is in a second container; b) the drug in a first container in solid form and the polymeric solution in a second container in solution; or c) the drug, the polymer, and the DMSO in a single container.
11. The kit of claim 10 , wherein the PLA has been irradiated with beta-radiation.
12. A method of treating cancer that is therapeutically responsive to the aromatase inhibitor letrozole or a metabolite thereof comprising administering to a subject in need thereof a therapeutically effective amount of letrozole in the composition of claim 1 .
13. The method of claim 12 , wherein said composition is administered intramuscularly and following said administering, the AUC of the burst release of the drug is less than about 10% of the total AUC after administration and not more than about 50% of the total AUC over the first 30 days after administration.
14. The method of claim 12 , wherein said composition is administered intramuscularly and following said administering, the plasma level of the drug is sufficient to provide an in vivo suppression of serum estrogens estrone (E1) and estradiol (E2) of at least about 50% E2 and at least about 70% E1 in the steady state during a dosing period.
15. An injectable composition consisting of
about 25% wt of drug, which is letrozole, wherein the drug has a particle size distribution selected from any of the following <10% of the particles are less than 20 microns, <10% of the particles are greater than 350 microns, and a d0.5 between 70-200 microns; or d0.1 of 38.21 microns, d0.5 of 141.35 microns, and d0.9 of 312.13 microns; and
the remaining balance of said injectable composition consisting of polymeric solution consisting of 57-60% wt of DMSO; and 40-43% wt of biodegradable poly(lactic acid) polymer (PLA), wherein
the polymeric solution has a viscosity in the range of 0.8-1.5 Pas, as measured at 25° C.;
the drug is suspended in the polymeric solution;
the PLA has been irradiated with beta-radiation; and
the PLA is end-capped with an ester group.
16. The injectable composition of claim 15 , wherein ≤20% wt of the drug is dissolved in the polymeric solution.
17. The injectable composition of claim 15 , wherein the polymer has been lyophilized.
18. A kit suitable for the in situ preparation of the injectable composition of claim 15 , wherein prior to preparation of the injectable composition, the kit comprises a) the drug and the polymer in solid form in a first container, and the DMSO is in a second container; b) the drug in a first container in solid form and the polymeric solution in a second container in solution; or c) the drug, the polymer, and the DMSO in a single container.
19. The kit of claim 18 , wherein the PLA has been irradiated with beta-radiation.
20. A method of treating cancer that is therapeutically responsive to the aromatase inhibitor letrozole or a metabolite thereof comprising administering to a subject in need thereof a therapeutically effective amount of letrozole in the composition of claim 15 .
21. The method of claim 20 , wherein said composition is administered intramuscularly and following said administering, the AUC of the burst release of the drug is less than about 10% of the total AUC after administration and not more than about 50% of the total AUC over the first 30 days after administration.
22. The method of claim 20 , wherein said composition is administered intramuscularly and following said administering, the plasma level of the drug is sufficient to provide an in vivo suppression of serum estrogens estrone (E1) and estradiol (E2) of at least about 50% E2 and at least about 70% E1 in the steady state during a dosing period.