Tunable, controlled-release, urethane-containing elastomers and processes of forming the same

Patent metadata

Field	Value
Publication number	US-10918764-B2
Application number	US-201916547175-A
Country	US
Kind code	B2
Filing date	Aug 21, 2019
Priority date	Aug 21, 2018
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

A process forms an implantable product including poly(glycerol sebacate) urethane (PGSU) loaded with an active pharmaceutical ingredient (API). The process includes homogeneously mixing a flowable poly(glycerol sebacate) (PGS) resin with the API and a catalyst to form a resin blend. The process also includes homogeneously combining the resin blend with an isocyanate to form a reaction mixture and injecting the reaction mixture to form the PGSU loaded with the API. An implantable product includes a PGSU loaded with an API. In some embodiments, the implantable product includes at least 40% w/w of the API, and the implantable product releases the API by surface degradation of the PGSU at a predetermined release rate for at least three months under physiological conditions. In some embodiments, the PGSU is formed from a PGS reacted with an isocyanate at an isocyanate-to-hydroxyl stoichiometric (crosslinking) ratio in the range of 1:0.25 to 1:1.25.

First claim

What is claimed is:

1. A process of forming an implantable product comprising poly(glycerol sebacate) urethane loaded with an active pharmaceutical ingredient, the process comprising:
homogeneously mixing a flowable poly(glycerol sebacate) resin with the active pharmaceutical ingredient and a catalyst to form a resin blend;
selecting an amount of isocyanate such that an isocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to 1:1.25;
homogeneously combining the resin blend with the isocyanate to form a reaction mixture; and
injecting the reaction mixture to form the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient
wherein the poly(glycerol sebacate) urethane is loaded with at least 40% w/w of the active pharmaceutical ingredient.

2. The process of claim 1 , wherein the weight average molecular weight of the flowable poly(glycerol sebacate) resin is greater than 10,000 Da.

3. The process of claim 1 , wherein the homogeneous combining comprises shear mixing.

4. The process of claim 1 , wherein the injecting comprises reaction injection molding.

5. The process of claim 1 , wherein the injecting further comprises removing generated gasses, entrained gasses, entrapped gasses, or combinations thereof.

6. The process of claim 5 , wherein the removing occurs under vacuum.

7. The process of claim 5 , wherein the removing occurs under sonication.

8. The process of claim 1 , wherein the process occurs at a temperature of 60° C. or less.

9. The process of claim 1 , wherein the homogeneous mixing occurs in the absence of a solvent.

10. The process of claim 1 , wherein the flowable poly(glycerol sebacate) resin is free of a solvent.

11. The process of claim 1 , wherein the resin blend includes no more than 50% w/w of a solvent.

12. The process of claim 11 further comprising evaporating the solvent from the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient at a temperature of up to 40° C. for up to 6 days.

13. The process of claim 1 , wherein the injecting comprises injecting the reaction mixture into a mold.

14. The process of claim 1 further comprising crosslinking the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient for up to 24 hours at up to 40° C. to form the implantable product.

15. The process of claim 1 , wherein the catalyst is selected from the group consisting of a potassium catalyst, potassium tartrate, and potassium citrate.

16. An implantable product comprising a poly(glycerol sebacate) urethane loaded with an active pharmaceutical ingredient, wherein the poly(glycerol sebacate) urethane is formed from a poly(glycerol sebacate) reacted with an isocyanate at an isocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to 1:1.25 and wherein the active pharmaceutical ingredient is at least 40% w/w of the implantable product.

17. The implantable product of claim 16 , wherein the implantable product comprises more than one compartment.

18. The implantable product of claim 17 , wherein the implantable product comprises a second active pharmaceutical ingredient.

19. The implantable product of claim 16 , wherein the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient forms a plurality of fibers.

20. The implantable product of claim 16 , wherein the poly(glycerol sebacate) urethane is formed from a poly(glycerol sebacate) resin having a molecular weight greater than 10,000 Da.

21. The implantable product of claim 16 , wherein the poly(glycerol sebacate) urethane is formed from a poly(glycerol sebacate) resin having a polydispersity index less than 12.

22. The implantable product of claim 16 , wherein the poly(glycerol sebacate) urethane is formed from a poly(glycerol sebacate) resin having a glycerol-to-sebacic acid stoichiometric ratio of between 1:0.5 and 1:1.5.

23. The implantable product of claim 16 , wherein the isocyanate is a blocked isocyanate.

24. The implantable product of claim 16 , wherein the implantable product releases the active pharmaceutical ingredient by surface degradation of the poly(glycerol sebacate) urethane at a predetermined release rate for at least three months under physiological conditions.

25. A process of forming an implantable product comprising poly(glycerol sebacate) urethane loaded with an active pharmaceutical ingredient, the process comprising:
homogeneously mixing a flowable poly(glycerol sebacate) resin with the active pharmaceutical ingredient and a catalyst to form a resin blend;
selecting an amount of isocyanate such that an isocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to 1:1.25;
homogeneously combining the resin blend with the isocyanate to form a reaction mixture; and
injecting the reaction mixture to form the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient;
wherein the injecting further comprises removing generated gasses, entrained gasses, entrapped gasses, or combinations thereof.

26. The process of claim 25 , wherein the removing occurs under vacuum.

27. The process of claim 25 , wherein the removing occurs under sonication.

28. A process of forming an implantable product comprising poly(glycerol sebacate) urethane loaded with an active pharmaceutical ingredient, the process comprising:
homogeneously mixing a flowable poly(glycerol sebacate) resin with the active pharmaceutical ingredient and a catalyst to form a resin blend;
selecting an amount of isocyanate such that an isocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to 1:1.25;
homogeneously combining the resin blend with the isocyanate to form a reaction mixture; and
injecting the reaction mixture to form the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient;
wherein the resin blend includes no more than 50% w/w of a solvent.

29. The process of claim 28 further comprising evaporating the solvent from the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient at a temperature of up to 40° C. for up to 6 days.

30. The process of claim 28 , wherein the homogeneous mixing occurs in the absence of a solvent.

31. The process of claim 28 , wherein the flowable poly(glycerol sebacate) resin is free of a solvent.

32. A process of forming an implantable product comprising poly(glycerol sebacate) urethane loaded with an active pharmaceutical ingredient, the process comprising:
homogeneously mixing a flowable poly(glycerol sebacate) resin with the active pharmaceutical ingredient and a catalyst to form a resin blend;
selecting an amount of isocyanate such that an isocyanate-to-hydroxyl stoichiometric ratio is in the range of 1:0.25 to 1:1.25;
homogeneously combining the resin blend with the isocyanate to form a reaction mixture; and
injecting the reaction mixture to form the poly(glycerol sebacate) urethane loaded with the active pharmaceutical ingredient;
wherein the catalyst is selected from the group consisting of a potassium catalyst, potassium tartrate, and potassium citrate.

33. An implantable product comprising a poly(glycerol sebacate) urethane loaded with an active pharmaceutical ingredient, wherein the poly(glycerol sebacate) urethane is formed from a po

Assignees

• Secant Group Llc

Inventors

• Reed Stephanie
• Smoot Carissa
• Shull Dennis
• Crumbling Todd
• D'Ottavio John
• Gabriele Peter D
• Harris Jeremy J
• Nicholson Charles Brendan
• Ely Jared

Classifications

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• B33Y80/00

  Products made by additive manufacturing · CPC title

• A61K9/2031

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers · CPC title

• B29C67/246

  Moulding high reactive monomers or prepolymers, e.g. by reaction injection moulding [RIM], liquid injection moulding [LIM] (casting monomers B29C39/006, mixing construction B29B7/74) · CPC title

• A61L27/54

  Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} · CPC title