PREPARATIONS AND COMPOSITIONS COMPRISING POLYMER COMBINATION PREPARATIONS

Abstract

The present disclosure provides technologies related to certain polymer combination preparations and uses thereof. In many embodiments, such polymer combination preparations are temperature-responsive. In some embodiments, such polymer combination preparations may be useful as immunomodulatory biomaterials, e.g, to induce innate immunity or to resolve inflammation (e.g.; immunosuppressive inflammation). In some embodiments, such polymer combination preparations may be useful to formulate compositions comprising active agent(s).

Description

Claims

1. A preparation comprising: a polymer combination preparation comprising at least first and second polymer components, the first polymer component is or comprises a poloxamer and the second polymer component is not a poloxamer, the polymer combination preparation being characterized in that it transitions from a precursor state to a polymer network state in response to a gelation trigger,wherein the polymer network state has a viscosity materially above that of the precursor state,wherein the gelation trigger is or comprises temperature at or above critical gelation temperature (CGT) for the polymer combination preparation, ratio of polymer components at or above critical gelation weight ratio for the at least first and second polymer components, molecular weights of the at least first and/or second polymer components, or combinations thereof;wherein the polymer network state comprises crosslinks not present in the precursor state;wherein the crosslinks are or comprise intra-molecular crosslinks, inter-molecular crosslinks, or both; andwherein the first polymer component is present in the polymer combination preparation is present at a concentration of 12.5% (w/w) or below.

2. The preparation of claim 1, wherein the crosslinks do not comprise covalent crosslinks.

3. The preparation of claim 2, wherein the CGT for the polymer combination preparation is 30-39° C. or 20-30° C.

4. The preparation of any one of claims 1-3, wherein the polymer combination preparation comprises a total polymer content of at least 5% (w/w), or at least 10% (w/w).

5. The preparation of any one of claims 1-4, wherein the critical gelation weight ratio of the first polymer component to the second polymer component is 1:1 to 14:1 or 1:1 to 10:1.

6. The preparation of any one of claims 1-5, wherein the polymer network state is a viscous solution or colloid.

7. The preparation of any one of claims 1-5, wherein the polymer network state is a hydrogel.

8. The preparation of claim 7, wherein the polymer network state is characterized in that, when tested in vitro at 37° C., the polymer combination preparation releases a lipophilic agent incorporated therein at a comparable rate as with a hydrogel formed from a P407 solution with a concentration of 18% (w/w).

9. The preparation of any one of claims 1-8, wherein the polymer network state is characterized in that, when tested in vitro at 37° C., more than 60% of a lipophilic agent incorporated in the polymer combination preparation can be retained therein for at least 24 hours.

10. The preparation of any one of claims 1-8, wherein the polymer network state is characterized in that, when tested in vitro at 37° C., no more than 40% of a lipophilic agent incorporated in the polymer combination preparation can be released therefrom within 24 hours.

11. The preparation of any one of claims 1-10, wherein the polymer network state is characterized in that, when tested in vitro at 37° C., the polymer combination preparation releases a hydrophilic agent incorporated therein at a comparable rate as, or at a faster rate than, that of a hydrogel formed from a P407 solution with a concentration of 18% (w/w).

12. The preparation of any one of claims 1-11, wherein the polymer network state is characterized in that, when tested in vitro at 37° C., the polymer combination preparation releases a hydrophilic agent incorporated therein at a faster rate (e.g., by at least 20% within 48 hours) as compared with a chemically crosslinked hyaluronic acid hydrogel.

13. The preparation of claim 12, wherein the chemically crosslinked hyaluronic acid hydrogel is a hydrogel formed by mixing thiol-modified hyaluronic acid (Glycosil®) with a crosslinking agent, thiol-reactive PEGDA crosslinker (Extralink®) under conditions for gelation to occur.

14. The preparation of any one of claims 1-13, wherein the polymer network state is characterized in that when tested in vitro at 37° C., at least 40% of a hydrophilic agent incorporated in the polymer combination preparation is released therefrom within 12 hours.

15. The preparation of any one of claims 1-14, wherein the second polymer component is or comprises a carbohydrate polymer.

16. The preparation of claim 15, wherein the carbohydrate polymer in the polymer combination preparation is present at concentration of below about 10% (w/w) or below about 5% (w/w).

17. The preparation of claim 15 or 16, wherein the carbohydrate polymer is or comprises hyaluronic acid.

18. The preparation of claim 17, wherein the hyaluronic acid has a molecular weight of about 50 kDa to about 2 MDa.

19. The preparation of claim 18, wherein the hyaluronic acid has a low molecular weight of about 100-500 kDa or about 100-400 kDa, or about 125-375 kDa, or about 100-200 kDa.

20. The preparation of claim 18, wherein the hyaluronic acid has a high molecular weight of about 500-1,500 kDa or about 600-800 kDa.

21. The preparation of claim 18, wherein the carbohydrate polymer is or comprises chitosan or a modified chitosan.

22. The preparation of claim 21, wherein the modified chitosan is or comprises carboxymethyl chitosan.

23. The preparation of any one of claims 1-22, wherein the polymer network state is characterized by one or more material properties selected from: a. storage modulus within a range of 100 Pa to about 10,000 Pa as measured at 37° C. and pH 5-8;b. storage modulus that is at least 40% lower than that of a hydrogel formed from a solution having a poloxamer at a solution concentration of 18% (w/w); andc. storage modulus, as measured at 37° C., that maintains substantially the same after its precursor state has been stored at 2-8° C. for a period of 1 month (or no more than 20% of the polymer combination preparation is degraded over a period of 1 month, when measured at 37° C.).

24. The preparation of any one of claims 1-23, wherein the polymer combination preparation has pH 4.5-8.5.

25. The preparation of any one of claims 1-24, wherein the polymer combination preparation has pH 7-8 (e.g., pH 7.4).

26. The preparation of any one of claims 1-25, wherein the polymer combination preparation has a higher buffering capacity than a 10 mM phosphate buffer.

27. The preparation of any one of claims 1-26, wherein the poloxamer is or comprises Poloxamer 407.

28. The preparation of any one of claims 1-27, further comprising a therapeutic agent.

29. The preparation of claim 28, wherein the therapeutic agent is or comprises an analgesic, antibiotic, anticoagulant, antiemetic, coagulant, or agent that promotes wound healing.

30. The preparation of any one of claims 1-28, wherein the therapeutic agent is or comprises an immunomodulatory payload.

31. The preparation of claim 30, wherein the immunomodulatory payload is or comprises a modulator of innate immunity.

32. The preparation of claim 30 or 31, wherein the immunomodulatory payload is or comprises a modulator of myeloid cell function.

33. The preparation of any one of claims 30-32, wherein the immunomodulatory payload is or comprises a modulator of adaptive immunity.

34. The preparation of any one of claims 30-32, wherein the immunomodulatory payload is or comprises a modulator of inflammation.

35. The preparation of claim 34, wherein the immunomodulatory payload is or comprises a TLR7/8 agonist.

36. The preparation of claim 34, wherein the immunomodulatory payload is or comprises resiquimod.

37. The preparation of claim 34, wherein the immunomodulatory payload is or comprises a COX2 inhibitor.

38. The preparation of claim 34, wherein the immunomodulatory payload is or comprises an NSAID, e.g., ketorolac.

39. The preparation of any one of claims 1-38, wherein when the second polymer component is or comprises a carbohydrate polymer and the polymer combination preparation is substantially free of an immunomodulatory payload, the polymer combination preparation is characterized in that a test animal group with spontaneous metastases having, at a tumor resection site, the polymer combination preparation in the polymer network state has a higher percent survival than a comparable test animal group having, at a tumor resection site, a poloxamer biomaterial in the absence of the second polymer component, as assessed at 2 months after the administration.

40. The preparation of any one of claims 1-39, wherein when the polymer combination preparation comprises an immunomodulatory payload, the polymer combination preparation is characterized in that a test animal group with spontaneous metastases having, at a tumor resection site, the polymer combination preparation in the polymer network state has a higher percent survival than a comparable test animal group having, at a tumor resection site, a polymer combination preparation without the immunomodulatory payload, as assessed at 2 months after the administration.

41. The preparation of claim 39 or 40, wherein the polymer combination preparation in the polymer network state is delivered to the tumor resection site by intraoperatively administering at the tumor resection site a preparation comprising the polymer combination preparation that is pre-formed in the polymer network state.

42. The preparation of claim 39 or 40, wherein the polymer combination preparation in the polymer network state is delivered to the tumor resection site by intraoperatively administering at the tumor resection site a preparation comprising the polymer combination preparation that is in the precursor state, which transitions to the polymer network state at the tumor resection site after the administration.

43. The preparation of any one of claims 1-42, wherein the first polymer component is present in the polymer combination preparation at a concentration of 11% (w/w) or below.

44. The preparation of any one of claims 1-42, wherein the first polymer component is present in the polymer combination preparation at a concentration of 10.5% (w/w) or below.

45. The preparation of any one of claims 1-42, wherein the first polymer component is present in the polymer combination preparation at a concentration of 10% (w/w) or below.

46. The preparation of any one of claims 1-45, wherein the first polymer component is present in the polymer combination preparation at a concentration of at least 4% (w/w), at least 5% (w/w), or at least 6% (w/w).

47. A method comprising administering the preparation of any one of claims 1-46 to a subject in need thereof.

48. The method of claim 47, wherein the subject in need thereof is a subject suffering from cancer.

49. The method of claim 48, wherein the subject in need thereof is a subject suffering from or susceptible to recurrent or disseminated cancer.

50. The method of any one of claims 47-49, wherein the subject in need thereof is a tumor resection subject.

51. The method of claim 50, wherein the preparation is administered at or within 2 cm of the tumor resection site.

52. The method of any one of claims 49-51, wherein the administration is by implantation.

53. The method of claim 52, wherein a preparation comprising the polymer combination preparation in the polymer network state is administered by implantation.

54. The method of any one of claims 49-51, wherein the administration is by injection.

55. The method of claim 54, wherein a preparation comprising the polymer combination preparation in the precursor state is administered by injection, wherein the precursor state transitions to the polymer network state upon the administration.

56. The method of any one of claims 49-55, wherein the administration is performed concurrently with or subsequent to laparoscopy.

57. The method of any one of claims 49-55, wherein the administration is performed concurrently with or subsequent to minimally invasive surgery.

58. The method of any one of claims 49-55, wherein the administration is performed concurrently with or subsequent to robotic surgery.