Injectable composition
An injectable depot composition suitable for forming an in situ intramuscular implant is provided. The composition includes sterile biodegradable thermoplastic polymer of polylactic acid (PLA), solvent for the PLA, and drug. After administration to a subject, a corresponding implant administers 0.1-2 milligrams of nonsteroidal aromatase inhibitor every day throughout a dosing period of about six months to about one year. The composition is used to treat subjects in need thereof.
1. A kit for preparing an injectable depot composition, the kit comprising PLA (polylactic acid) particles, solvent for PLA, and drug particles, wherein prior to mixing the PLA particles, solvent for PLA, and drug particles, the drug has a particle size distribution that approximates the PLA's particle size distribution, and after mixing the PLA, solvent for PLA, and drug, the PLA is dissolved in the solvent, wherein the solvent is dimethyl sulfoxide (DMSO), and said drug is selected from the group consisting of letrozole, anastrozole, salt of either thereof, and metabolite of either thereof, and further wherein prior to mixing the PLA particles with said solvent for PLA, the particle size distribution of the PLA particles is defined as follows:
a) particle size mass distribution with not more than 10% above 300 microns when measured by analytical sieving according to USP<786>;
b) particle size mass distribution with not more than 10% above 250 microns when measured by analytical sieving according to USP<786>;
c) particle size volume distribution with a D90 not above 330 microns when measured by laser diffraction analysis;
d) particle size volume distribution with a D90 not above 280 microns when measured by laser diffraction analysis;
e) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>;
f) a particle size volume distribution with a D80 not below 135 microns when measured by laser diffraction analysis;
g) particle size mass distribution with not more than 10% above 300 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; and/or
h) particle size volume distribution with a D90 not above 330 microns, when measured by laser diffraction analysis and with a D80 not below 135 microns when measured by laser diffraction analysis.
2. The kit according to claim 1 , wherein the kit comprises at least a first container and a second container, wherein a) the first container contains the drug particles and PLA particles, and the second contains the solvent; or b) the first container contains the drug particles, the second contains PLA particles, and the solvent is in the first container, the second container, and/or in a third container.
3. A method of preparing an injectable depot composition, the method comprising a) providing the kit of claim 1 ; and b) mixing the components of the containers of the kit, thereby forming said injectable depot composition.
4. The method of claim 3 , further comprising sterilizing the DMSO and PLA prior to said mixing.
5. The method of claim 4 , wherein said sterilizing is achieved by beta irradiation or filtration.
6. An injectable depot composition consisting essentially of a) 15-35 wt. % drug, 25-35 wt. % PLA, and 30-60 wt. % dimethyl sulfoxide (DMSO); b) 18-28 wt. % drug, 30-35 wt. % PLA, and 37-52 wt. % DMSO; or c) about 23 to about 27 wt. % drug, about 28 to about 34 wt. % PLA, and about 41 to about 47 wt. % DMSO; wherein the weight percentages are with respect to the total weight of said composition; said drug is selected from the group consisting of letrozole, anastrozole, salt of either thereof, and metabolite of either thereof; and prior to mixing with said DMSO the PLA is comprised of particles having a particle size distribution defined as follows:
a) particle size mass distribution with not more than 10% above 300 microns when measured by analytical sieving according to USP<786>;
b) particle size mass distribution with not more than 10% above 250 microns when measured by analytical sieving according to USP<786>;
c) particle size volume distribution with a D90 not above 330 microns when measured by laser diffraction analysis;
d) particle size volume distribution with a D90 not above 280 microns when measured by laser diffraction analysis;
e) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>;
f) a particle size volume distribution with a D80 not below 135 microns when measured by laser diffraction analysis;
g) particle size mass distribution with not more than 10% above 300 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; and/or
h) particle size volume distribution with a D90 not above 330 microns, when measured by laser diffraction analysis and with a D80 not below 135 microns when measured by laser diffraction analysis; and
wherein after mixing the PLA, solvent for PLA, and drug, the PLA is dissolved in the solvent.
7. The kit of claim 1 , wherein said kit forms the injectable depot composition consisting essentially of a) 15-35 wt. % drug, 25-35 wt. % PLA, and 30-60 wt. % DMSO; b) 18-28 wt. % drug, 30-35 wt. % PLA, and 37-52 wt. % DMSO; or c) about 23 to about 27 wt. % drug, about 28 to about 34 wt. % PLA, and about 41 to about 47 wt. % DMSO;
wherein the weight percentages are with respect to the total weight of said composition.
8. The kit of claim 1 , wherein said drug is present in an amount of a) 10 to 500 mg of said drug; b) 10 to 450 mg of said drug; c) 30 to 90 mg of said drug; d) about 50 mg of said drug; e) 80 to 150 mg of said drug; f) about 100 mg of said drug; g) 150 to 250 mg of said drug; h) about 200 mg of said drug; i) 350 to 450 mg of said drug; or j) about 400 mg of said drug.
9. The method of claim 3 , wherein the drug is present in said injectable depot composition as a suspension, and the PLA is dissolved in the solvent in said injectable depot composition.
10. The method of claim 3 , wherein the PLA has been sized.
11. The composition of claim 6 , wherein the PLA is end capped with an ester group.
12. The composition of claim 6 , wherein a) the weight ratio of DMSO to PLA is about 1.3:1 to about 1.5:1, or about 1.4:1; b) the weight ratio of DMSO to drug is in the range of about 1.5:1 to about 2:1, about 1.7:1 to about 1.8:1, or about 1.75:1; c) the weight ratio of polymer solution (solvent+PLA) to drug is about 2.8:1 to about 3.2:1, or about 3:1; and/or d) the weight ratio of PLA to drug is about 1.1:1 to about 1.35:1, about 1.1:1 to about 1.3:1, about 1.2:1 to about 1.3:1, or about 1.25:1.
13. The composition of claim 6 , wherein said drug is letrozole and implant(s) formed in a subject after administration of said injectable depot composition provides the following pharmacokinetic performance:
Dose of drug administered
About 50
About 100
(mg)
Daily Plasma Concentration
About 4.5 (about
About 8.8 (about
from about 2 days after
0.5 to about 13)
1.5 to about 21)
administration (ng/mL)
Cmax (ng/mL)
About 5
About 11
Tlag (h)
0 h
0 h
wherein Tlag corresponds to the delay between the time of dosing and time of appearance of a measurable concentration of letrozole in the plasma and wherein values are mean values.
14. A kit for preparing an injectable depot composition, the kit comprising PLA (polylactic acid) particles, dimethyl sulfoxide (DMSO), and letrozole particles, wherein prior to mixing the PLA particles, DMSO, and letrozole particles, the letrozole has a particle size distribution that approximates the PLA's particle size distribution, and after mixing the PLA particles, DMSO, and letrozole particles, the PLA is dissolved in the solvent, and wherein
a) prior to mixing the PLA particles with said solvent for PLA, the PLA particle size distribution is defined as a particle size mass distribution with not more than 10% above 300 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; and
b) implant(s) formed in a subject after administration of said injectable depot composition provides the following pharmacokinetic performance:
Dose of drug administered
About 50
About 100
(mg)
Daily Plasma Concentration
About 4.5 (about
About 8.8 (about
from about 2 days after
0.5 to about 13)
1.5 to about 21)
administration (ng/mL)
Cmax (ng/mL)
About 5
About 11
Tlag (h)
0 h
0 h
wherein Tlag corresponds to the delay between the time of dosing and time of appearance of a measurable concentration of letrozole in the plasma and wherein values are mean values.
15. An injectable depot composition consisting essentially of a) 15-35 wt. % letrozole, 25-35 wt. % PLA, and 30-60 wt. % dimethyl sulfoxide (DMSO); b) 18-28 wt. % letrozole, 30-35 wt. % PLA, and 37-52 wt. % DMSO; or c) about 23 to about 27 wt. % letrozole, about 28 to about 34 wt. % PLA, and about 41 to about 47 wt. % DMSO; wherein the weight percentages are with respect to the total weight of said composition; and prior to mixing with said DMSO the PLA is comprised of particles having a particle size distribution defined as follows:
a) particle size mass distribution with not more than 10% above 300 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>.