Hyaluronidase particles, compositions comprising the same and methods of making and using the same

Abstract

Described herein are hyaluronidase particles, compositions comprising the same, and methods for making and using the same. Compositions of the present invention may include a hyaluronidase particle and may be a suspension. A particle including hyaluronidase may have a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.9. In some embodiments, methods of the present invention may include subcutaneously, intramuscularly, and / or intradermally administering to a subject a particle comprising hyaluronidase, wherein the particle has a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.9.

Description

Abstract This document describes hyaluronidase particles, compositions comprising the same, and methods of preparation and use thereof. The compositions of the present invention may comprise hyaluronidase particles and may be suspensions. The particles comprising hyaluronidase may have a water content of less than about 15% by weight of the particles and / or a water activity of less than about 0.9. In some embodiments, the method of the present invention may include administering particles comprising hyaluronidase to a subject subcutaneously, intramuscularly, and / or intradermally, wherein the particles have a water content of less than about 15% by weight of the particles and / or a water activity of less than about 0.9.

Claims

Attorney Docket No.1458-5WO THAT WHICH IS CLAIMED IS:

1. A particle comprising: hyaluronidase; and a therapeutic, wherein the particle has a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.

9.

2. The particle of claim 1, wherein the therapeutic is a biologic, optionally wherein the biologic is selected from the group consisting of an amino acid, peptide, protein, nucleotide, polynucleotide, and any combination thereof.

3. The particle of claim 1, wherein the therapeutic is a small molecule (e.g., a small organic molecule).

4. The particle of any preceding claim, further comprising a stabilizer, optionally wherein the stabilizer is sugar (e.g., a sucrose, glucose, trehalose, mannitol, sorbitol, dextrose, maltose, and / or lactose), an amino acid, and / or a protein (e.g., an albumin such as a serum albumin).

5. The particle of claim 4, wherein the stabilizer is present in the particle in an amount of about 0.1%, 5%, 10%, 15%, or 20% to about 25%, 30%, 35%, 40%, 45%, or 50% by weight of the particle.

6. The particle of any one of claims 4 or 5, wherein the stabilizer is not covalently bound to the hyaluronidase.

7. The particle of any one of claims 4-6, wherein the stabilizer is an amino acid, optionally wherein the amino acid is selected from the group consisting of histidine, arginine, proline, glycine, leucine, and any combination thereof.

8. The particle of any one of claims 4-7, wherein the stabilizer is present in the particle in an amount of about 5% to about 30% by weight of the particle. 59   Attorney Docket No.1458-5WO 9. The particle of any preceding claim, wherein the hyaluronidase is present in the particle in an amount of about 0.1%, 0.5%, or 1% to about 2%, 3%, 4%, or 5% by weight of the particle.

10. The particle of any preceding claim, wherein the therapeutic is present in the particle in an amount of about 50%, 55%, 60%, 65%, or 70% to about 75%, 80%, 85%, 90%, 95%, or 99% by weight of the particle, optionally wherein the therapeutic is present in the particle in an amount of about 75% or 80% to about 85%, 90%, or 95% by weight of the particle.

11. The particle of any preceding claim, wherein the hyaluronidase and the therapeutic are not covalently bound.

12. A particle comprising: hyaluronidase; and a stabilizer, wherein the particle has a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.

9.

13. The particle of claim 12, wherein the stabilizer is a sugar (e.g., a sucrose, glucose, trehalose, mannitol, sorbitol, dextrose, maltose, and / or lactose), an amino acid, and / or a protein (e.g., an albumin such as a serum albumin), optionally wherein the sugar is selected from the group consisting of sucrose, glucose, trehalose, mannitol, sorbitol, dextrose, maltose, lactose, and any combination thereof.

14. The particle of claim 12, wherein the stabilizer is an amino acid, optionally wherein the amino acid is selected from the group consisting of histidine, arginine, proline, glycine, leucine, and any combination thereof.

15. The particle of claim 12, wherein the stabilizer is an albumin, optionally a serum albumin.

16. The particle of any one of claims 12-15, , wherein the stabilizer is present in the particle in an amount of about 0.1%, 0.5%, 1%, 5%, 10%, 15%, or 20% to about 25%, 30%, 35%, 40%, 45%, or 50% by weight of the particle. 60   Attorney Docket No.1458-5WO 17. The particle of any one of claims 12-16, wherein the hyaluronidase and the stabilizer are not covalently bound.

18. The particle of any one of claims 12-18, wherein the hyaluronidase is present in the particle in an amount of about 50%, 55%, 60%, 65%, or 70% to about 75%, 80%, 85%, 90%, 95%, or 99% by weight of the particle.

19. The particle of any preceding claim, wherein the particle is spherical in shape.

20. The particle of any preceding claim, wherein the particle has a density of at least about 0.5, 0.6, 0.7, 0.8, 0.9, or 1 g / cm3to about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 g / cm3.

21. The particle of any preceding claim, wherein the particle has a size (e.g., a diameter) of about 0.1 microns to about 30 microns, optionally wherein the particle has a size of about 2 microns to about 5 microns, about 5 microns to about 20 microns, or about 10 microns to about 30 microns.

22. The particle of any preceding claim, wherein the particle has a total moisture content of less than about 3% of the total particle mass, optionally wherein the particle has a total moisture content of less than about 2% of the total particle mass.

23. The particle of any preceding claim, wherein the particle has a residual (e.g. octanol and / or pentanol) content in an amount less than about 3% by weight of the total particle mass.

24. The particle of any preceding claim, wherein the particle is amorphous and / or wherein the hyaluronidase in the particle is amorphous.

25. The particle of any preceding claim, wherein the particle is a microparticle or a nanoparticle.

26. The particle of any preceding claim, wherein the enzymatic activity of the hyaluronidase, following dissolution of the particle in an aqueous composition, is within 61   Attorney Docket No.1458-5WO about ± 50% of the enzymatic activity of free hyaluronidase, optionally wherein the enzymatic activity of the hyaluronidase, following dissolution of the particle in an aqueous composition, is within about ± 40% of the enzymatic activity of free hyaluronidase.

27. The particle of any preceding claim, wherein the enzymatic activity of the hyaluronidase following storage at about 4°C to about 40°C for at least about 3 months is within about ± 50% of the enzymatic activity of free hyaluronidase, optionally wherein the enzymatic activity of the hyaluronidase following storage at about 4°C to about 40°C for at least about 3 months is within about ± 40% of the enzymatic activity of the free hyaluronidase.

28. The particle of any preceding claim, wherein the hyaluronidase is hyaluronidase V.

29. A composition comprising the particle of any preceding claim.

30. The composition of claim 29, wherein the composition is a suspension.

31. The composition of claim 29 or 30, wherein the composition has a viscosity of about 20 centipoise (cP) to about 200 cP, when measured at a temperature of about 20 degrees Celsius to about 25 degrees Celsius and at a shear rate of about 1,000 s-1to about 3,000 s-1.

32. The composition of any one of claims 29-31, wherein the particle is present in the composition in an amount of about 1, 10, 50, 100, or 200 mg / mL to about 300, 400, 500, 600, or 700 mg / mL.

33. The composition of any one of claims 29-32, wherein the composition is non- aqueous.

34. The composition of any one of claims 29-33, further comprising a solvent, optionally wherein the solvent is an ester (e.g., an alkyl ester or aryl ester).

35. The composition of claim 34, wherein the solvent is selected from the group consisting of benzyl benzoate, ethyl oleate, a triglyceride ester (e.g., MIGLYOL® 812), ethyl lactate, sesame oil, and any combination thereof. 62   Attorney Docket No.1458-5WO 36. The composition of any one of claims 29-35, wherein the hyaluronidase is not soluble in the solvent and / or composition.

37. The composition of any one of claims 29-36, wherein the hyaluronidase is in the form of a solid in the composition.

38. The composition of any one of claims 29-37, further comprising a therapeutic that is dissolved or suspended in the composition.

39. A composition comprising: a solvent; and a particle comprising hyaluronidase, wherein the particle has a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.

9.

40. The composition of claim 39, further comprising a therapeutic, optionally wherein the therapeutic is dissolved or suspended in the composition.

41. The composition of claim 39 or 40, wherein the composition is non-aqueous.

42. The composition of any one of claims 39-41, wherein the hyaluronidase is not soluble in the solvent and / or composition.

43. The composition of any one of claims 39-42, wherein the hyaluronidase is in the form of a solid in the composition.

44. The composition of any one of claims 39-43, wherein the composition is a suspension.

45. The composition of any one of claims 39-44, wherein the composition has a viscosity of about 20 centipoise (cP) to about 200 cP, when measured at a temperature of about 20 degrees Celsius to about 25 degrees Celsius and at a shear rate of about 1,000 s-1to about 3,000 s-1. 63   Attorney Docket No.1458-5WO 46. The composition of any one of claims 39-45, wherein the particle is present in the composition in an amount of about 1, 10, 50, 100, or 200 mg / mL to about 300, 400, 500, 600, or 700 mg / mL.

47. The composition of any one of claims 29-46, further comprising a detergent (e.g., polysorbate-20, polysorbate-80, and / or Poloxamer 188).

48. A method of increasing dissolution of a therapeutic in a liquid, the method comprising: combining the liquid, the therapeutic, and a particle comprising hyaluronidase, wherein the particle has a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.9, thereby increasing dissolution of the therapeutic in the liquid.

49. The method of claim 48, wherein the therapeutic is separate from the particle, optionally wherein the therapeutic and / or particle is present in a solvent that is different than the liquid.

50. The method of claim 48, wherein the particle comprises the therapeutic, optionally wherein the particle is present in a solvent that is different than the liquid.

51. The method of claim 48, wherein the particle is the particle of any one of claims 1-28.

52. The method of claim 48, wherein the particle is present in a composition, optionally wherein the composition is the composition of any one of claims 29-47.

53. The method of any one of claims 48-52, wherein the liquid is an aqueous liquid.

54. The method of any one of claims 48-53, wherein the combining comprises separately combining the hyaluronidase and the therapeutic with the liquid, optionally wherein the hyaluronidase and the therapeutic are sequentially combined with (e.g., added to) the liquid. 64   Attorney Docket No.1458-5WO 55. The method of any one of claims 48-53, wherein the combining comprises combining the hyaluronidase and the therapeutic in the liquid at the same time, optionally wherein the hyaluronidase and the therapeutic are present in the same particle or in different particles.

56. The method of any one of claims 48-55, wherein dissolution of the therapeutic is increased by at least about 10%, 20%, 30%, 40%, 50%, 60% or more over a period of time of about 5 minutes to about 2 hours compared to dissolution of the therapeutic in the absence of the particle.

57. The method of any one of claims 48-56, wherein at least about 90%, 95%, 99%, or 100% of the therapeutic is dissolved within about 20, 30, or 40 minutes to about 100, 110, or 120 minutes following combining of the particle, therapeutic, and the liquid, optionally wherein at least about 90%, 95%, 99%, or 100% of the therapeutic is dissolved within about 20, 30, or 40 minutes to about 50, 60, 70, or 80 minutes following combining of the particle, therapeutic, and the liquid.

58. A method of improving tolerance and / or increasing absorption of a therapeutic upon subcutaneous, intramuscular, and / or intradermal administration to a subject, the method comprising: subcutaneously, intramuscularly, and / or intradermally administering to the subject a particle comprising hyaluronidase, wherein the particle has a water content of less than about 15% by weight of the particle and / or a water activity of less than about 0.9, thereby improving tolerance and / or increasing absorption of the therapeutic upon subcutaneous, intramuscular, and / or intradermal administration to the subject.

59. The method of claim 58, wherein the therapeutic is separate from the particle.

60. The method of claim 58, wherein the particle comprises the therapeutic.

61. The method of claim 58, wherein the particle is the particle of any one of claims 1-28.

62. The method of claim 58, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises subcutaneously, intramuscularly, and / or intradermally 65   Attorney Docket No.1458-5WO administering a composition comprising the particle to the subject, optionally wherein the composition is the composition of any one of claims 29-47.

63. The method of any one of claims 58-62, wherein the method reduces irritation at the injection site of the subcutaneous, intramuscular, and / or intradermal administration to the subject.

64. The method of any one of claims 58-63, wherein the method increases dispersion of the particle or composition under the skin of the subject following the subcutaneous, intramuscular, and / or intradermal administration.

65. The method of any one of claims 58-64, wherein the method increases absorption, bioavailability, distribution, metabolism, and / or excretion of the therapeutic in the subject following subcutaneous, intramuscular, and / or intradermal administration compared to absorption, bioavailability, distribution, metabolism, and / or excretion of the therapeutic in the subject following subcutaneous, intramuscular, and / or intradermal administration in the absence of the particle or composition.

66. The method of any one of claims 58-65, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises subcutaneously, intramuscularly, and / or intradermally administering the particle or composition to the subject in a volume of about 0.1 or 0.5 mL to about 1, 2, 5, or 10 mL.

67. The method of any one of claims 58-66, wherein the method is devoid of administrating hyaluronidase in solution (e.g., hyaluronidase dissolved in water) and / or free hyaluronidase.

68. The method of any one of claims 58-67, wherein the particle and / or hyaluronidase is in the form of a solid at the time of subcutaneous, intramuscular, and / or intradermal administration to the subject, optionally wherein the hyaluronidase in the particle dissolves upon subcutaneous, intramuscular, and / or intradermal administration. 66   Attorney Docket No.1458-5WO 69. The method of any one of claims 58-68, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises separately subcutaneously, intramuscularly, and / or intradermally administering the hyaluronidase and the therapeutic.

70. The method of claim 69, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises subcutaneously, intramuscularly, and / or intradermally administering the hyaluronidase to the subject and then subcutaneously, intramuscularly, and / or intradermally administering the therapeutic to the subject.

71. The method of claim 69, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises subcutaneously, intramuscularly, and / or intradermally administering the therapeutic to the subject and then subcutaneously, intramuscularly, and / or intradermally administering the hyaluronidase to the subject.

72. The method of any one of claims 58-68, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises concurrently administering the hyaluronidase and the therapeutic to the subject, optionally wherein the hyaluronidase and the therapeutic are present in the same particle or the same composition.

73. The method of any one of claims 58-72, wherein at least about 90%, 95%, 99%, or 100% of the therapeutic is dissolved within about 20, 30, or 40 minutes to about 100, 110, or 120 minutes following the subcutaneous, intramuscular, and / or intradermal administration to the subject, optionally wherein at least about 90%, 95%, 99%, or 100% of the therapeutic is dissolved within about 20, 30, or 40 minutes to about 50, 60, 70, or 80 minutes following the subcutaneous, intramuscular, and / or intradermal administration to the subject.

74. The method of any one of claims 58-73, wherein the hyaluronidase is administered to the subject in an amount of about 0.1%, 0.5%, or 1% to about 2%, 3%, 4%, or 5% by weight of the particle.

75. The method of any one of claims 58-74, wherein the subcutaneously, intramuscularly, and / or intradermally administering comprises administering the particle and therapeutic in a total volume of less than about 10 mL, optionally in a total volume of less than about 2 mL. 67

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