Sustained release small molecule drug formulation
View Patent ↗An injectable depot formulation includes a biocompatible polymer, an organic solvent combined with the biocompatible polymer to form a viscous gel, and a small molecule drug incorporated in the viscous gel such that the formulation exhibits an in vivo release profile having C max to C min ratio less than 200 and lag time less than 0.2.
1. An injectable depot formulation, comprising:
a biocompatible polymer comprising a copolymer of lactic acid and glycolic acid, wherein the biocompatible polymer has a number average molecular weight ranging from 1000 Daltons to 5000 Daltons;
an organic solvent combined with the biocompatible polymer to form a viscous gel said solvent selected from the group consisting of benzyl alcohol, benzyl benzoate, ethyl benzoate, ethyl hydroxide, N-methy1-2-pyrrolidone, and mixtures thereof; and
a small molecule drug selected from base and salt forms of risperidone incorporated in the viscous gel,
wherein the small molecule drug is in the form of particles having a particle size less than 38 μm,
wherein the salt forms of risperidone have less than 1 mg/mL solubility in water, and
wherein the formulation exhibits an in vivo release profile having C max to C min ratio less than 200 over a period of one month.
2. The formulation of claim 1 , wherein the in vivo release profile has C max to C min ratio less than 30.
3. The formulation of claim 1 , wherein the solvent has a miscibility in water less than 7 % by weight.
4. A method of administering a small molecule drug to a subject in a controlled manner, said method comprising implanting in the subject an effective amount of an injectable depot formulation comprising:
a biocompatible polymer comprising a copolymer of lactic acid and glycolic acid, wherein the biocompatible polymer has a number average molecular weight ranging from 1000 Daltons to 5000 Daltons;
an organic solvent combined with the biocompatible polymer to form a viscous gel, said solvent selected from the group consisting of benzyl alcohol, benzyl benzoate, ethyl benzoate, ethyl hydroxide, N-methy1-2-pyrrolidone, and mixtures thereof; and
a small molecule drug selected from base and salt forms of risperidone incorporated in the viscous gel,
wherein the small molecule drug is in the form of particles having a particle size less than 38 μm,
wherein the salt forms of risperidone have less than 1 mg/mL solubility in water, and
wherein the formulation exhibits an in vivo release profile having C. to C min ratio less than 200 over a period of one month.
5. The formulation of claim 1 , wherein the formulation exhibits a lag time less than 0.2.
6. The formulation of claim 1 , wherein the copolymer of lactic acid and glycolic acid has a monomer ratio of lactic acid to glycolic acid ranging from 60:40 to 75:25.
7. The formulation of claim 1 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the biocompatible polymer is present in the depot gel vehicle in an amount ranging from 5 wt % to 40 wt %.
8. The formulation of claim 1 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the organic solvent is present in the depot gel vehicle in an amount ranging from 20 wt % to 40 wt %.
9. The formulation of claim 1 , wherein the small molecule drug is present in the formulation in an amount ranging from 5 wt % to 40 wt %.
10. The method of claim 4 , wherein the formulation exhibits a lag time less than 0.2.
11. The method of claim 4 , wherein the copolymer of lactic acid and glycolic acid has a monomer ratio of lactic acid to glycolic acid ranging from 60:40 to 75:25.
12. The method of claim 4 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the biocompatible polymer is present in the depot gel vehicle in an amount ranging from 5 wt % to 40 wt %.
13. The method of claim 4 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the organic solvent is present in the depot gel vehicle in an amount ranging from 20 wt % to 40 wt %.
14. The method of claim 4 , wherein the small molecule drug is present in the formulation in an amount ranging from 5 wt% to 40 wt%.
15. The formulation of claim 1 , wherein the copolymer of lactic acid and glycolic acid has a monomer ratio of lactic acid to glycolic acid ranging from 50:50 to 100:0.
16. The formulation of claim 1 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the biocompatible polymer is present in the depot gel vehicle in an amount ranging from 5 wt % to 60 wt %.
17. The formulation of claim 1 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the organic solvent is present in the depot gel vehicle in an amount ranging from 20 wt % to 60 wt %.
18. The method of claim 4 , wherein the copolymer of lactic acid and glycolic acid has a monomer ratio of lactic acid to glycolic acid ranging from 50:50 to 100:0.
19. The method of claim 4 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the biocompatible polymer is present in the depot gel vehicle in an amount ranging from 5 wt % to 60 wt %.
20. The method of claim 4 , wherein the biocompatible polymer and the organic solvent comprise a depot gel vehicle, and wherein the organic solvent is present in the depot gel vehicle in an amount ranging from 20 wt% to 60 wt %.