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. A method of administering an injectable composition to a subject in need thereof, said method comprising a step of providing a kit comprising (i) letrozole and a PLA polymer in a first container and DMSO in a second container; (ii) letrozole in a first container and a PLA polymer and DMSO in a second container; or (iii) a container comprising letrozole, a PLA polymer, and DMSO;
mixing the contents of said container or containers to provide said injectable composition; and
intramuscularly administering to said subject said injectable composition consisting of about 25% wt of said which is letrozole, having 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 Pa·s. as measured at 25° C.
2. The method of claim 1 , wherein said subject is administered about 2 ml of said injectable composition comprising about 500 mg of said aromatase inhibitor.
3. The method of claim 1 , wherein the burst AUC of letrozole, within 0-3 days after administration, is less than 10% of the total AUC calculated for the 60 days after administration, or is less than 5% of the total AUC calculated for the 60 days after administration, or wherein, following administration to a subject, the AUC of the burst of said aromatase inhibitor 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.
4. The method of claim 1 , wherein said injectable composition provides therapeutic plasma levels of letrozole for a period of at least sixty days following administration.
5. The method of claim 1 , wherein said injectable composition is administered every 60 days.
6. The method of claim 1 , wherein said PLA has been irradiated with a maximum dose of 35 kGy.
7. The method of claim 1 , wherein said polymer has been lyophilized.
8. The method of claim 1 , wherein the PLA is end-capped with a carboxylic acid group or with an ester group.
9. A method of administering an injectable composition to a subject in need thereof, said method comprising a step of providing a kit comprising (i) letrozole and a PLA polymer in a first container and DMSO in a second container; (ii) letrozole in a first container and a PLA polymer and DMSO in a second container; or (iii) a container comprising letrozole, a PLA polymer, and DMSO;
mixing the contents of said container or containers to provide said injectable composition; and
intramuscularly administering to said subject said injectable composition consisting of about 25% wt of said letrozole, having 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 Pa·s. as measured at 25° C.; and wherein
a) the burst AUC of said aromatase inhibitor, within 0-3 days after administration, is less than 10% of the total AUC calculated for the 60 days after administration, or is less than 5% of the total AUC calculated for the 60 days after administration, or wherein, following administration to a subject, the AUC of the burst of said aromatase inhibitor 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; and
b) said injectable composition provides therapeutic plasma levels of said aromatase inhibitor for a period of at least sixty days following administration.
10. The method of claim 9 , wherein said subject is administered about 2 ml of said injectable composition comprising about 500 mg of said aromatase inhibitor.
11. The method of claim 9 , wherein said injectable composition is administered every 60 days.
12. The method of claim 9 , wherein said PLA has been irradiated with a maximum dose of 35 kGy.
13. The method of claim 9 , wherein said polymer has been lyophilized.
14. The method of claim 9 , wherein the PLA is end-capped with a carboxylic acid group or with an ester group.
15. The method of claim 9 , wherein said therapeutic plasma level is at least 100 nmoles/mL.
16. The method of claim 4 , wherein said therapeutic plasma level is at least 100 nmoles/mL.