Injectable controlled release composition comprising high viscosity liquid carrier
View Patent ↗Compositions may include a pharmaceutical active agent, a high viscosity liquid carrier material (HVLCM), a lactic acid-based polymer, and an organic solvent. Related compositions and methods are also disclosed. For instance, a carrier formulation for controlled release of injectable drugs is disclosed. The formulation may include a non-water soluble high viscosity liquid which may be sucrose acetate isobutyrate, a lactic-acid based polymer which may be a poly(lactic acid)(glycolic acid), and an organic solvent which maintains the composition in a monophasic form at 25° C. in one atmosphere. Drug in the formulation may be released upon administration such that less than 10% (e.g. 2-8%) of drug is released in the first 5 hours; 10% to 80% of the drug is released during a period of 5 hours to 7 days after administration; and 10% to 40% of the drug is released gradually over a period of 7 days to 28 days from initial administration. The drug may be an anti-schizophrenia agent delivered by injection.
1. A composition comprising:
a pharmaceutical active agent;
25 wt % to 80 wt %, based on total weight of the composition, of a non-polymeric, non-water soluble high viscosity liquid carrier material (HVLCM) having a viscosity of at least 5000 cP at 37° C. that does not crystallize neat at 25° C. and 1 atmosphere;
a lactic acid-based polymer comprising an alkoxy end group having 8 to 24 carbons; and
an organic solvent,
wherein when the composition is administered as a single dose subcutaneously to a human patient, a median amount of the pharmaceutical active agent released from the composition provides an AUC (0 to 1 day) that is less than 10% of AUC (0 to 28 days).
2. The composition of claim 1 , wherein the lactic-acid based polymer has a weight average molecular weight ranging from 1000 Daltons to 30,000 Daltons.
3. The composition of claim 1 , wherein the pharmaceutical active agent comprises at least one member selected from peptide, protein, and small molecule.
4. The composition of claim 1 , wherein the pharmaceutical active agent comprises risperidone or pharmaceutically acceptable salt thereof.
5. The composition of claim 1 , wherein the pharmaceutical active agent comprises particles having a median particle size, as measured by laser diffraction, ranging from 0.5 micrometer to 10 micrometers.
6. The composition of claim 1 , wherein the HVLCM comprises sucrose acetate isobutyrate.
7. The composition of claim 1 , wherein the solvent comprises at least one member selected from N-methyl-pyrrolidone, dimethylsulfoxide, and propylene carbonate.
8. The composition of claim 1 , wherein the composition has a viscosity of less than 3000 cP at a shear rate of 100 s −1 at 25° C.
9. The composition of claim 1 , wherein the composition has been irradiated with a sufficient amount of gamma irradiation to sterilize the composition.
10. The composition of claim 1 , wherein when the composition is administered as a single dose subcutaneously to a human patient:
less than 10% of a total amount of the pharmaceutical active agent is released into the subject's circulation within 8 hours following injection,
10% to 80% of the total amount of the pharmaceutical active agent is released into the subject's circulation within 6 days following injection, and
20% to 100% of the total amount of the pharmaceutical active agent is released into the subject's circulation within 28 days following injection.
11. The composition of claim 1 , wherein a median PK profile is described by 3 absorption phases:
a first absorption phase occurs immediately after administration, with a first order rate constant ranging from 0.1 hr −1 to 0.4 hr −1 ;
a second absorption phase occurs after a time delay ranging from 2.5 hours to 8.5 hours after administration, with a first order rate constant ranging from 0.0005 hr −1 to 0.005 hr −1 ; and
a third absorption phase occurs after a time delay ranging from 5 days to 10 days after administration, with a first order rate constant ranging from 0.0005 hr −1 to 0.005 hr −1 .
12. The composition of claim 1 , wherein when the composition is administered as a single dose subcutaneously to a human patient, the composition provides a median pharmacokinetic profile of pharmaceutically active moiety within ±30% of the 100 mg dose profile of FIG. 30 , per 100 mg of pharmaceutical active agent administered.
13. A composition as defined in claim 1 and that contains a pharmaceutical active agent that is an anti-schizophrenia agent, for use in a method of treating at least one of schizophrenia and bipolar disorder.
14. The composition for use of claim 13 , wherein the anti-schizophrenia agent comprises risperidone or a pharmaceutically acceptable salt thereof.
15. A method for treating at least one of schizophrenia and bipolar disorder, comprising administering an effective amount of the composition of claim 1 to a patient in need thereof, wherein said composition contains a pharmaceutical active agent that is an anti-schizophrenia agent.
16. The method according to claim 15 , wherein the anti-schizophrenia agent comprises risperidone or a pharmaceutically acceptable salt thereof.
17. The method of claim 15 , wherein the anti-schizophrenia agent comprises risperidone or a pharmaceutically acceptable salt thereof, and
wherein when the composition is administered as a single dose subcutaneously to a human patient, the composition provides a median pharmacokinetic profile of risperidone or a pharmaceutically acceptable salt thereof within ±30% of the 100 mg dose profile of FIG. 30 , per 100 mg of risperidone or a pharmaceutically acceptable salt thereof administered.
18. A method for treating at least one of schizophrenia and bipolar disorder, comprising administering an effective amount of the composition of claim 1 , wherein said composition contains a pharmaceutical active agent that is an anti-schizophrenia agent,
wherein when the composition is administered as a single dose subcutaneously to a human patient, the composition provides a median PK profile described by 3 absorption phases:
a first absorption phase occurs immediately after administration, with a first order rate constant ranging from 0.1 hr −1 to 0.4 hr −1 ;
a second absorption phase occurs after a time delay ranging from 2.5 hours to 8.5 hours after administration, with a first order rate constant ranging from 0.0005 hr −1 to 0.005 hr −1 ; and
a third absorption phase occurs after a time delay ranging from 5 days to 10 days after administration, with a first order rate constant ranging from 0.0005 hr −1 to 0.005 hr −1 .
19. The method according to claim 18 , wherein the anti-schizophrenia agent comprises risperidone or a pharmaceutically acceptable salt thereof,
wherein when the composition is administered as a single dose subcutaneously to a human patient, the composition provides a median PK profile described by 3 absorption phases:
a first absorption phase occurs immediately after administration, with a first order rate constant ranging from 0.2 hr −1 to 0.3 hr −1 ;
a second absorption phase occurs after a time delay ranging from 4.5 hours to 6.5 hours after administration, with a first order rate constant of ranging from 0.001 hr −1 to 0.003 hr −1 ; and
a third absorption phase occurs after a time delay ranging from 6 days to 9 days after administration, with a first order rate constant ranging from 0.001 hr −1 to 0.003 hr −1 .
20. The composition of claim 1 , wherein the lactic acid based-polymer is poly(lactic acid)(glycolic acid) having a lactic acid to glycolic acid molar ratio ranging from 95:5 to 60:40.
21. The composition of claim 2 , wherein the lactic acid based-polymer is poly(lactic acid)(glycolic acid) having a lactic acid to glycolic acid molar ratio ranging from 95:5 to 60:40.
22. The composition of claim 7 , wherein the lactic acid based-polymer is poly(lactic acid)(glycolic acid) having a lactic acid to glycolic acid molar ratio ranging from 95:5 to 60:40.
23. The composition of claim 1 , wherein the composition comprises:
0.5 wt % to 50 wt %, based on total weight of the composition, of particles comprising the pharmaceutical active agent, the particles having a median particle size, as measured by laser diffraction, ranging from 0.5 micrometer to 50 micrometers;
10 wt % to 60 wt %, based on total weight of the composition, of the HVLCM that is sucrose acetate isobutyrate;
1 wt % to 30 wt %, based on total weight of the composition, of the lactic acid based-polymer that is poly(lactic acid)(glycolic acid) comprising the alkoxy end group, the poly(lactic acid)(glycolic acid) having a lactic acid to glycolic acid molar ratio ranging from 95:5 to 60:40, the poly(lactic acid)(glycolic acid) having a weight average molecular weight ranging from 4000 Daltons to 30,000 Daltons; and
10 wt % to 50 wt %, based on total weight of the composition, of the organic solvent that is at least one member selected from N-methyl-pyrrolidone, propylene carbonate, and dimethylsulfoxide.