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Title:
COMPOSITIONS FOR INTRANASAL DELIVERY OF RELAMORELIN
Document Type and Number:
WIPO Patent Application WO/2021/067819
Kind Code:
A1
Abstract:
The present invention provides methods, formulations, and devices for the intranasal delivery of relamorelin. The methods, formulations, and devices of the invention may be used in the treatment of diabetic gastroparesis and its associated symptoms.

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Inventors:
JIAO JIM (US)
GORE ANURADHA (US)
HESLINGA MICHAEL (US)
Application Number:
PCT/US2020/054086
Publication Date:
April 08, 2021
Filing Date:
October 02, 2020
Export Citation:
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Assignee:
ALLERGAN GI CORP (US)
International Classes:
A61J1/05; A61K9/14; A61M15/08; A61P1/02; A61P1/04; A61P1/08
Attorney, Agent or Firm:
LU, David et al. (US)
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Claims:
CLAIMS

1. A method of providing a subject having diabetic gastroparesis with relamorelin comprising nasally administering an effective amount of relamorelin to the subject, thereby treating the subject having diabetic gastroparesis.

2. The method of claim 1, wherein the subject has diabetes (e.g., Type 1 diabetes or Type 2 diabetes).

3. The method of claim 1, wherein a symptom or manifestation of diabetic gastroparesis in the subject is alleviated, lessened, or delayed.

4. The method of claim 1, wherein the motility of the gut of the subject is increased.

5. The method of claim 1, wherein early satiety, bloating, postprandial pain, vomiting, or nausea in the subject is reduced.

6. The method of claim 1, wherein motility is increased in comparison with a reference, e.g., motility prior to administration, motility in an untreated subject, or a predetermined reference standard, e.g., a value for gut motility expressed as % total.

7. The method of claim 1, wherein gastric emptying is accelerated.

8. The method of claim 1, wherein gastric emptying is accelerated in comparison with a reference, e.g., gastric emptying prior to administration, gastric emptying in an untreated subject, or a predetermined reference standard, e.g., a value for gastric emptying expressed as % total.

9. The method of claim 1, wherein relamorelin is administered as a spray, a gel, droplets, or a powder.

10. The method of claim 1, wherein relamorelin is formulated as a pharmaceutical composition.

11. The method of claim 10, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

12. The method of claim 11, wherein the pharmaceutically acceptable excipient comprises a tonicity agent, a pH-adjusting agent, a viscosity agent, a preservative, a nasal permeation enhancer, a taste-masking agent, or an aqueous vehicle.

13. The method of claim 12, wherein the tonicity agent comprises dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.

14. The method of any one of claims 12 and 13, wherein the amount of tonicity agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

15. The method of claim 12, wherein the pH-adjusting agent comprises acetic acid, adipic acid, ammonium bicarbonate, ammonium citrate, ammonium phosphate, ammonium hydroxide, calcium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium phosphate, calcium hydroxide, citric acid, hydrochloric acid, lactic acid, magnesium carbonate, magnesium hydroxide, malic acid, phosphoric acid, potassium acid tartrate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium acetate, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium phosphate, sulfuric acid, or tartaric acid.

16. The method of any one of claims 12 and 15, wherein the pH-adjusting agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

17. The method of claim 12, wherein the viscosity agent is a polymeric excipient (e.g., a synthetic polymer or a naturally occurring polymer).

18. The method of claim 17, wherein the polymeric excipient comprises poloxamer, polyethylene glycol, polycaprolactone, polyvinylalcohol, polyvinylpyrrolidone, polymethacrylate, polyacrylic acid, or a polysaccharide (e.g., cellulose, methylcellulose, hypromellose, chitosan, xanthan gum).

19. The method of any one of claims 12 and 17 wherein the viscosity agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

20. The method of claim 12, wherein the nasal permeation enhancer comprises lecithin (e.g., a long chain fatty acid phosphatidylcholine, lysophosphatidylcholine), a bile salt (e.g., sodium deoxycholate, sodium glycocholate), cyclodextrin, a mucoadhesive (e.g., polycarbophil, carbopol, chitosan), a non-ionic surfactant, or an enzyme inhibitor (e.g., betsatin, amastatin).

21. The method of any one of claims 12 and 20, wherein the nasal permeation enhancer in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

22. The method of claim 12, wherein the preservative comprises an alcohol (e.g., benzyl alcohol, cetyl alcohol, stearyl alcohol, 2-phenylethanol), a carboxylic acid (e.g., benzoic acid, sorbic acid), a paraben, a phenol (e.g., phenol, chlorocresol, cresol, hexachlorophene, chloroxylenol), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an organomercurial compound (e.g., thimerosal, a phenylmercuric salt), a formaldehyde (e.g., imidurea, bronopol), a biguanide (e.g., chlorohexidine), a chelator (e.g., EDTA), or an antimicrobial agent.

23. The method of any one of claims 12 and 22, wherein the preservative in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%,

0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

24. The method of claim 1, wherein the amount of relamorelin in the pharmaceutical composition is between 0.01% and 10% w/w (e.g., between 0.01% and 5%, 0.05% and 5%, 0.05% and 2.5%, 0.05% and 1%, or 0.05% and 0.5% w/w).

25. The method of claim 1, wherein the relamorelin is delivered from a device which, upon activation, forms a plurality of relamorelin-containing particles.

26. The method of claim 25, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

27. The method of claim 25, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm).

28. The method of claim 25, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm).

29. The method of claim 25, wherein the relamorelin is delivered from a device comprising a dispersal element which provides a plurality of relamorelin-containing particles.

30. The method of claim 29, wherein the dispersal element comprises a nasal spray pump.

31. The method of claim 29, wherein the dispersal element comprises a closure system comprising an on tip-seal/filter.

32. The method of claim 25, wherein the device delivers between 5 pL and 500 pL (e.g., between about 10 pL and 250 pL, 10 pL to 100 pL, 25 pL and 200 pL, 50 pL to 150 pL, 100 pL to 200 pL, or 100 pL to 500 pL) of a pharmaceutical composition comprising relamorelin to each nostril.

33. The method of claim 25, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis, is between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

34. The method of claim 1, wherein the relamorelin is delivered from a device which delivers a predetermined dose of relamorelin or a pharmaceutical composition of relamorelin.

35. The method of claim 1, wherein the relamorelin is delivered from a device which delivers relamorelin or a pharmaceutical composition of relamorelin over a predetermined time period (e.g., once a day, twice a day, three times a day, once a week, twice a week, three times a week).

36. The method of claim 1, wherein the relamorelin is administered over a predetermined time period (e.g., 1 hour, 2 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days, 14 days, 16 days, 18 days, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 6 months, 8 months, 10 months, 1 year, or 2 years).

37. The method of claim 1, wherein the relamorelin is delivered from a device which ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the vestibular and turbinate regions of the nose.

38. The method of claim 1, wherein the relamorelin is delivered from a device which ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the region where the surface lining changes from skin to stratified squamous epithelium and pseudostratified columnar epithelium.

39. The method of claim 1, wherein the relamorelin is delivered from a device which ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the olfactory region of the nose where the nose-brain pathway is located, e.g., and allows direct transport of the drug to the brain and cerebrospinal fluid (CSF).

40. The method of claim 25, wherein the device comprises a reservoir having disposed therein a composition comprising relamorelin.

41. The method of claim 25, wherein the device is actuated manually.

42. The method of claim 25, wherein the device comprises a squeeze bottle actuated dispenser, a pump, or a plunger pump.

43. The method of claim 25, wherein the device is configured such that contaminated ambient air is prevented from entering the dispenser after a plurality of relamorelin-containing particles is released.

44. The method of claim 25, wherein the device comprises a seal preventing contaminated ambient air from entering the dispenser after a plurality of relamorelin-containing particles is released.

45. The method of claim 25, wherein a dose of relamorelin comprises a plurality of relamorelin-containing particles.

46. The method of claim 45, wherein a dose of relamorelin comprises 0.1 pg to 500 pg (e.g.,

0.5 pg to 250 pg, 1 pg to 100 pg, 1 pg to 50 pg, 1 pg to 25 pg, 1 pg to 10 pg, 5 pg to 50 pg, 5 pg to 25 pg, 5 pg to 10 pg, 10 pg to 50 pg, 10 pg to 25 pg, or 10 to 20 pg) of relamorelin.

47. The method of claim 45, wherein the device contains a sufficient amount of relamorelin or a composition comprising relamorelin to constitute multiple doses.

48. The method of claim 1, wherein the administration of relamorelin provides a systemic therapeutic level of relamorelin.

49. The method of claim 1, wherein the administration of relamorelin provides a bioavailability of about 1% to 50% (e.g., 1% to 25%, 1% to 10%, 5% to 50%, 5% to 25%, 5% to 10%, or 10% to 25%) relative to subcutaneous injection of relamorelin (e.g., as measured by area under the curve (AUC) or a maximum concentration (Cmax)).

50. The method of claim 1, wherein the administration, e.g., of a dosage of between 50 pg and 100 pg (e.g., 100 pg), results in a Cmax between 0.1 ng/mL and 100 ng/mL (e.g., 0.1 ng/mL and 50 ng/mL, 0.5 ng/mL and 25 ng/mL, 0.5 to 15 ng/mL, 1 ng/mL to 20 ng/mL, or 1 ng/mL to 10 ng/mL) in the subject.

51. The method of claim 1, wherein the subject has been diagnosed or identified as having diabetic gastroparesis.

52. The method of claim 1, wherein the subject has been diagnosed or identified as having diabetes (e.g., Type 1 diabetes or Type 2 diabetes).

53. The method of claim 1, wherein the subject has impaired or delayed gut motility or gastric emptying.

54. The method of claim 1, wherein the subject is experiencing a symptom or manifestation of diabetic gastroparesis (e.g., bloating, postprandial pain, vomiting, or nausea).

55. The method of claim 1, wherein the subject has a body mass index (BMI) greater than 25 kg/m2 (e.g., >25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m2 or greater).

56. The method of claim 1, wherein the subject is a mammal (e.g., a human).

57. The method of claim 1, wherein the subject has previously been treated with relamorelin.

58. The method of claim 1, wherein the subject has previously received a subcutaneous administration of relamorelin.

59. A pharmaceutical composition comprising relamorelin and a pharmaceutically acceptable excipient formulated for nasal administration.

60. The pharmaceutical composition of claim 59, wherein the composition is administered as a spray, a gel, droplets, or a powder.

61. The pharmaceutical composition of claim 59, wherein the pharmaceutically acceptable excipient comprises a tonicity agent, a pH-adjusting agent, a viscosity agent, a nasal permeation enhancer, a preservative, a taste-masking agent, or an aqueous vehicle.

62. The pharmaceutical composition of claim 61, wherein the tonicity agent comprises dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.

63. The pharmaceutical composition of claim 61, wherein the amount of tonicity agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

64. The pharmaceutical composition of claim 61, wherein the pH-adjusting agent comprises acetic acid, adipic acid, ammonium bicarbonate, ammonium citrate, ammonium phosphate, ammonium hydroxide, calcium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium phosphate, calcium hydroxide, citric acid, hydrochloric acid, lactic acid, magnesium carbonate, magnesium hydroxide, malic acid, phosphoric acid, potassium acid tartrate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium acetate, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium phosphate, sulfuric acid, tartaric acid,

65. The pharmaceutical composition of claim 61, wherein the pH-adjusting agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

66. The pharmaceutical composition of claim 61, wherein the viscosity agent is a polymeric excipient (e.g., a synthetic polymer or a naturally occurring polymer).

67. The pharmaceutical composition of claim 66, wherein the polymeric excipient comprises poloxamer, polyethylene glycol, polycaprolactone, polyvinylalcohol, polyvinylpyrrolidone, polymethacrylate, polyacrylic acid, or a polysaccharide (e.g., cellulose, cellulosemethylcellulose, hypromellose, chitosan, xanthan gum).

68. The pharmaceutical composition of claim 61, wherein the viscosity agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

68. The pharmaceutical composition of claim 61, wherein the nasal permeation enhancer comprises lecithin (e.g., a long chain fatty acid phosphatidylcholine, lysophosphatidylcholine), a bile salt (e.g., sodium deoxycholate, sodium glycocholate), cyclodextrin, a mucoadhesive (e.g., polycarbophil, carbopol, chitosan), a non-ionic surfactant, or an enzyme inhibitor (e.g., betsatin, amastatin).

69. The pharmaceutical composition of claim 61, wherein the amount of the nasal permeation enhancer in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

70. The pharmaceutical composition of claim 61, wherein the preservative comprises an alcohol (e.g., benzyl alcohol, cetyl alcohol, stearyl alcohol, 2-phenylethanol), a carboxylic acid (e.g., benzoic acid, sorbic acid), a paraben, a phenol (e.g., phenol, chlorocresol, cresol, hexachlorophene, chloroxylenol), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an organomercurial compound (e.g., thimerosal, a phenylmercuric salt), a formaldehyde (e.g., imidurea, bronopol), a biguanide (e.g., chlorohexidine), a chelator (e.g., EDTA), or an antimicrobial agent.

71. The pharmaceutical composition of claim 61, wherein the preservative in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

72. The pharmaceutical composition of claim 59, wherein the amount of relamorelin in the pharmaceutical composition is between 0.01% and 10% w/w (e.g., between 0.01% and 5%, 0.05% and 5%, 0.05% and 2.5%, 0.05% and 1%, or 0.05% and 0.5% w/w).

73. A device suitable for the nasal administration of relamorelin comprising a nasal spray pump.

74. The device of claim 73, wherein relamorelin is delivered from the device which, upon activation, forms a plurality of relamorelin-containing particles.

75. The device of claim 74, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

76. The device of any one of claims 73-75, wherein the device comprises a dispersal element which provides the plurality of relamorelin-containing particles.

77. The device of claim 76, wherein the dispersal element comprises a nasal spray pump.

78. The device of claim 76, wherein the dispersal element comprises a closure system comprising an on tip-seal/filter.

79. The device of claim 73, wherein the device delivers between 5 pL and 500 pL (e.g., between about 10 pL and 250 pL, 10 pL to 100 pL, 25 pL and 200 pL, 50 pL to 150 pL, 100 pL to 200 pL, or 100 pL to 500 pL) of a pharmaceutical composition comprising relamorelin to each nostril.

80. The device of claim 73, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

81. The device of claim 73, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm).

82. The device of claim 73, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm).

83. The device of claim 73, wherein the device delivers a predetermined dose of relamorelin or a pharmaceutical composition of relamorelin.

84. The device of claim 73, wherein the device delivers relamorelin or a pharmaceutical composition of relamorelin over a predetermined time period (e.g., once a day, twice a day, three times a day, once a week, twice a week, three times a week).

85. The device of claim 73, wherein the relamorelin is administered over a predetermined time period (e.g., 1 hour, 2 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days, 14 days, 16 days, 18 days, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 6 months, 8 months, 10 months, 1 year, or 2 years).

86. The device of claim 73, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the vestibular and turbinate regions of the nose.

87. The device of claim 73, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the region where the surface lining changes from skin to stratified squamous epithelium and pseudostratified columnar epithelium.

88. The device of claim 73„ wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the olfactory region of the nose where the nose-brain pathway is located, e.g., and allows direct transport of the drug to the brain and cerebrospinal fluid (CSF).

88. The device of claim 73, wherein the device comprises a reservoir having disposed therein a composition comprising relamorelin.

89. The device of claim 73, wherein the device is actuated manually.

90. The device of claim 73, wherein the device comprises a squeeze bottle actuated dispenser, a pump, or a plunger pump.

91. The device of claim 73, wherein the device is configured such that contaminated ambient air is prevented from entering the dispenser after a plurality of relamorelin -containing particles is released.

92. The device of claim 73, wherein the device comprises a seal preventing contaminated ambient air from entering the dispenser after a plurality of relamorelin -containing particles is released.

93. The device of claim 73, wherein a dose of relamorelin comprises a plurality of relamorelin-containing particles.

94. The device of claim 93, wherein a dose of relamorelin comprises 0.1 pg to 500 pg (e.g., 0.5 pg to 250 pg, 1 pg to 100 pg, 1 pg to 50 pg, 1 pg to 25 pg, 1 pg to 10 pg, 5 pg to 50 pg, 5 pg to 25 pg, 5 pg to 10 pg, 10 pg to 50 pg, 10 pg to 25 pg, or 10 to 20 pg) of relamorelin.

95. The device of any one of claims 93 or 94, wherein the device contains a sufficient amount of relamorelin or a composition comprising relamorelin to constitute multiple doses.

96. A method for making a pharmaceutical composition formulated for nasal administration comprising relamorelin and a pharmaceutically acceptable excipient, comprising i) combining the relamorelin and the pharmaceutically acceptable excipient to form a mixture; ii) sterilizing the mixture, e.g., via filtration or heat, to form a pharmaceutical composition; and iii) optionally, filling a container closure system suitable for nasal administration with the pharmaceutical composition.

97. The method of claim 96, wherein the pharmaceutically acceptable excipient comprises a tonicity agent, a pH-adjusting agent, a viscosity agent, a preservative, a nasal permeation enhancer, a taste-masking agent, or an aqueous vehicle.

98. The method of claim 97, wherein the tonicity agent comprises dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.

99. The method of claim 97, wherein the amount of tonicity agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

100. The method of claim 97, wherein the pH-adjusting agent comprises acetic acid, adipic acid, ammonium bicarbonate, ammonium citrate, ammonium phosphate, ammonium hydroxide, calcium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium phosphate, calcium hydroxide, citric acid, hydrochloric acid, lactic acid, magnesium carbonate, magnesium hydroxide, malic acid, phosphoric acid, potassium acid tartrate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium acetate, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium phosphate, sulfuric acid, tartaric acid,

101. The method of claim 97, wherein the pH-adjusting agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

102. The method of claim 97, wherein the viscosity agent is a polymeric excipient (e.g., a synthetic polymer or a naturally occurring polymer).

103. The method of claim 102, wherein the polymeric excipient comprises poloxamer, polyethylene glycol, polycaprolactone, polyvinylalcohol, polyvinylpyrrolidone, polymethacrylate, polyacrylic acid, or a polysaccharide (e.g., cellulose, cellulosemethylcellulose, hypromellose, chitosan, xanthan gum).

104. The method of claim 97, wherein the viscosity agent in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

105. The method of claim 97, wherein the nasal permeation enhancer comprises lecithin (e.g., a long chain fatty acid phosphatidylcholine, lysophosphatidylcholine), a bile salt (e.g., sodium deoxycholate, sodium glycocholate), cyclodextrin, a mucoadhesive (e.g., polycarbophil, carbopol, chitosan), a non-ionic surfactant, or an enzyme inhibitor (e.g., betsatin, amastatin).

106. The method of claim 97, wherein the nasal permeation enhancer in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

107. The method of claim 97, wherein the preservative comprises an alcohol (e.g., benzyl alcohol, cetyl alcohol, stearyl alcohol, 2-phenylethanol), a carboxylic acid (e.g., benzoic acid, sorbic acid), a paraben, a phenol (e.g., phenol, chlorocresol, cresol, hexachlorophene, chloroxylenol), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an organomercurial compound (e.g., thimerosal, a phenylmercuric salt), a formaldehyde (e.g., imidurea, bronopol), a biguanide (e.g., chlorohexidine), a chelator (e.g., EDTA), or an antimicrobial agent.

108. The method of claim 97, wherein the preservative in the pharmaceutical composition is between 0.01% and 25% w/w (e.g., between 0.01% and 10%, 0.01% and 5%, 0.01% and 1%, 0.1% and 10%, 0.1% and 5%, 0.1% and 1%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w).

109. The method of claim 97, wherein the amount of relamorelin in the pharmaceutical composition is between 0.01% and 10% w/w (e.g., between 0.01% and 5%, 0.05% and 5%, 0.05% and 2.5%, 0.05% and 1%, or 0.05% and 0.5% w/w).

110. A pharmaceutical composition comprising relamorelin and a pharmaceutically acceptable excipient formulated for nasal administration prepared by a method described in claim 93.

111. A method of manufacturing a device for the nasal administration of relamorelin comprising: i) providing a device suitable for the nasal administration of relamorelin; ii) introducing relamorelin into the device.

112. The method of claim 111, wherein upon activation, the device forms a plurality of relamorelin-containing particles.

113. The method of claim 112, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

114. The method of claim 112, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm).

115. The method of claim 112, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm).

116. The method of claim 112, wherein the device comprises a dispersal element which provides a plurality of relamorelin-containing particles.

117. The method of claim 116, wherein the dispersal element comprises a nasal spray pump.

118. The method any one of claims 116 or 117, wherein the dispersal element comprises a closure system comprising an on tip-seal/filter.

119. The method of claim 111, wherein the device delivers between 5 pL and 500 pL (e.g., between about 10 pL and 250 pL, 10 pL to 100 pL, 25 pL and 200 pL, 50 pL to 150 pL, 100 pL to 200 pL, or 100 pL to 500 pL) of a pharmaceutical composition comprising relamorelin to each nostril.

120. The method of claim 111, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis, is between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

121. The method of claim 111, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm).

122. The method of claim 111, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm).

123. The method of claim 111, wherein the device delivers a predetermined dose of relamorelin or a pharmaceutical composition of relamorelin.

124. The method of claim 111, wherein the device delivers relamorelin or a pharmaceutical composition of relamorelin over a predetermined time period (e.g., once a day, twice a day, three times a day, once a week, twice a week, three times a week).

125. The method of claim 111, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the vestibular and turbinate regions of the nose.

126. The method of claim 111, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the region where the surface lining changes from skin to stratified squamous epithelium and pseudostratified columnar epithelium.

127. The method of claim 111, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the olfactory region of the nose where the nose-brain pathway is located, e.g., and allows direct transport of the drug to the brain and cerebrospinal fluid (CSF).

128. The method of claim 111, wherein the device comprises a reservoir having disposed therein a composition comprising relamorelin.

129. The method of claim 111, wherein the device is actuated manually.

130. The method of claim 111, wherein the device comprises a squeeze bottle actuated dispenser, a pump, or a plunger pump.

131. The method of claim 111, wherein the device is configured such that contaminated ambient air is prevented from entering the dispenser after a plurality of relamorelin-containing particles is released.

132. The method of claim 111, wherein the device comprises a seal preventing contaminated ambient air from entering the dispenser after a plurality of relamorelin-containing particles is released.

133. The method of claim 111, wherein a dose of relamorelin comprises a plurality of relamorelin-containing particles.

134. The method of claim 133, wherein a dose of relamorelin comprises 0.1 pg to 500 pg (e.g., 0.5 pg to 250 pg, 1 pg to 100 pg, 1 pg to 50 pg, 1 pg to 25 pg, 1 pg to 10 pg, 5 pg to 50 pg, 5 pg to 25 pg, 5 pg to 10 pg, 10 pg to 50 pg, 10 pg to 25 pg, or 10 to 20 pg) of relamorelin.

135. The method of claim 111, wherein the device contains a sufficient amount of relamorelin or a composition comprising relamorelin to constitute multiple doses.

136. A method of evaluating a device for nasal administration of relamorelin, comprising i) providing a device suitable for the nasal administration of relamorelin described herein; and ii) acquiring, directly or indirectly, a value for a parameter (e.g., the average size of the particles ejected from the device, the amount of relamorelin (w/w) present within the device, or the duration of administration of relamorelin (e.g., as ejected by the device)).

137. The method of claim 136, wherein relamorelin is delivered from the device which, upon activation, forms a plurality of relamorelin-containing particles.

138. The method of claim 137, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

139. The method of claim 137, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm).

140. The method of claim 137, wherein the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 5 pm (e.g., between 0.1 mih and 4 mih, 0.1 mih and 3 mih, 0.1 mih and 2 mih, 0.1 mih and 1 mih, or 0.1 mih and 0.5 mih).

141. The method of claim 136, wherein the device comprises a dispersal element which provides a plurality of relamorelin-containing particles.

142. The method of claim 141, wherein the dispersal element comprises a nasal spray pump.

143. The method any one of claims 140 or 141, wherein the dispersal element comprises a closure system comprising an on tip-seal/filter.

144. The method of claim 136, wherein the device delivers between 5 pL and 500 pL (e.g., between about 10 pL and 250 pL, 10 pL to 100 pL, 25 pL and 200 pL, 50 pL to 150 pL, 100 pL to 200 pL, or 100 pL to 500 pL) of a pharmaceutical composition comprising relamorelin to each nostril.

145. The method of claim 136, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm).

146. The method of claim 136, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm).

147. The method of claim 136, wherein the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm).

148. The method of claim 136, wherein the device delivers a predetermined dose of relamorelin or a pharmaceutical composition of relamorelin.

149. The method of claim 136, wherein the device delivers relamorelin or a pharmaceutical composition of relamorelin over a predetermined time period (e.g., once a day, twice a day, three times a day, once a week, twice a week, three times a week).

150. The method of claim 136, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the vestibular and turbinate regions of the nose.

151. The method of claim 136, wherein the device which ejects a plurality of relamorelin- containing particles such that the relamorelin-containing particles reach the region where the surface lining changes from skin to stratified squamous epithelium and pseudostratified columnar epithelium.

152. The method of claim 136, wherein the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the olfactory region of the nose where the nose-brain pathway is located, e.g., and allows direct transport of the drug to the brain and cerebrospinal fluid (CSF).

153. The method of claim 136, wherein the device comprises a reservoir having disposed therein a composition comprising relamorelin.

154. The method of claim 136, wherein the device is actuated manually.

155. The method of claim 136, wherein the device comprises a squeeze bottle actuated dispenser, a pump, or a plunger pump.

156. The method of claim 136, wherein the device is configured such that contaminated ambient air is prevented from entering the dispenser after a plurality of relamorelin-containing particles is released.

157. The method of claim 136, wherein the device comprises a seal preventing contaminated ambient air from entering the dispenser after a plurality of relamorelin-containing particles is released.

158. The method of claim 136, wherein a dose of relamorelin comprises a plurality of relamorelin-containing particles.

159. The method of claim 158, wherein the dose of relamorelin comprises 0.1 pg to 500 pg (e.g., 0.5 pg to 250 pg, 1 pg to 100 pg, 1 pg to 50 pg, 1 pg to 25 pg, 1 pg to 10 pg, 5 pg to 50 pg, 5 pg to 25 pg, 5 pg to 10 pg, 10 pg to 50 pg, 10 pg to 25 pg, or 10 to 20 pg) of relamorelin.

160. The method of claim 136, wherein the device contains a sufficient amount of relamorelin or a composition comprising relamorelin to constitute multiple doses.

Description:
COMPOSITIONS FOR INTRANASAL DELIVERY OF RELAMORELIN

CLAIM OF PRIORITY

This application claims priority to U.S. Provisional Application No. 62/910,958, filed October 4, 2019, which is incorporated herein by reference in its entirety.

BACKGROUND

Gastric motility is a coordinated neuromuscular process that transports nutrients through the digestive system (Scarpignato et al, Dig. Dis (1997) 15:112). Impairment of gastric motility may result in a variety of ailments including gastroesophageal reflux disease, gastroparesis, irritable bowel syndrome, constipation, emesis, and ileus. Peptides that affect the release of growth hormone, such as ghrelin and related analogs, have been shown to exhibit prokinetic activity and can stimulate gastric motility (Murray et al, Gut (2005) 54:1693), thus acting as powerful therapeutics to treat related ailments. Ghrelin and related analogs have traditionally been administered via injection; however, there is a need to explore alternative methods of administration, such as intranasal delivery.

SUMMARY

The present disclosure features compositions, methods, and devices for treating a subject having a disease, disorder, or condition with relamorelin, comprising nasally administering relamorelin to the subject. In an embodiment, the disease, disorder, or condition relates to gastrointestinal dysmotility and includes, for example, gastroesophageal reflux disease, gastroparesis, irritable bowel syndrome, constipation, emesis, or ileus.

In one aspect, the present disclosure features a method of providing a subject having gastroparesis (e.g., diabetic gastroparesis) with relamorelin comprising nasally administering an effective amount of relamorelin to the subject. In an embodiment, the subject has diabetes (e.g., Type 1 diabetes or Type 2 diabetes). In an embodiment, the subject has a body mass index (BMI) greater than 25 kg/m 2 (e.g., >25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater). In an embodiment, a symptom or manifestation of gastroparesis (e.g., diabetic gastroparesis) in the subject is alleviated, lessened, or delayed. For example, the motility of the gut may be increased; early satiety, bloating, postprandial pain, vomiting, or nausea in the subject is reduced; or gastric emptying is accelerated. In an embodiment, the subject is a mammal (e.g., a human).

In another aspect, the present disclosure features a device suitable for the nasal administration of relamorelin comprising a nasal spray pump. In an embodiment, relamorelin is delivered from the device and, upon activation, forms a plurality of relamorelin-containing particles. The relamorelin-containing particles of the plurality may have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm). In an embodiment, the device comprises a dispersal element. The dispersal element may comprise a nasal spray pump or a closure system comprising an on tip-seal/filter. In an embodiment, the dispersal element is an actuator comprising a spring-loaded tip-seal mechanism. In an embodiment, the device comprises a reservoir having disposed therein a composition comprising relamorelin. In an embodiment, the device is actuated manually. In an embodiment, the device comprises a squeeze bottle actuated dispenser, a pump, or a plunger pump. In an embodiment, the device is configured such that air (e.g., contaminated ambient air) is prevented from entering the dispenser after a plurality of relamorelin-containing particles is released.

In an embodiment, the device delivers a predetermined dose of relamorelin or a pharmaceutical composition of relamorelin. In an embodiment, the device delivers between 5 pL and 500 pL (e.g., between about 10 pL and 250 pL, 10 pL to 100 pL, 25 pL to 200 pL, 50 pL to 150 pL, 100 pL to 200 pL, or 100 pL to 500 pL) of a pharmaceutical composition comprising relamorelin, e.g., to each nostril. In an embodiment, the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the vestibular and turbinate regions of the nose, the region where the surface lining changes from skin to stratified squamous epithelium and pseudostratified columnar epithelium, and/or the olfactory region of the nose where the nose-brain pathway is located. In an embodiment, the device ejects a plurality of relamorelin-containing particles and allows direct transport of relamorelin to the brain and cerebrospinal fluid (CSF).

In another aspect, the present discloses a pharmaceutical composition comprising relamorelin and a pharmaceutically acceptable excipient formulated for nasal administration.

The pharmaceutically acceptable excipient may comprise a tonicity agent, a pH-adjusting agent, a viscosity agent, a nasal permeation enhancer, a preservative, a taste-masking agent, or an aqueous vehicle. In an embodiment, the tonicity agent comprises dextrose, glycerin, mannitol, potassium chloride, or sodium chloride. In an embodiment, the amount of the tonicity agent in the pharmaceutical composition is between 0.1% and 25% w/w (e.g., between 0.1% and 10%,

1% and 20%, 0.5% and 10%, or 1% and 10% w/w). In an embodiment, the pH-adjusting agent comprises acetic acid, adipic acid, ammonium bicarbonate, ammonium citrate, ammonium phosphate, ammonium hydroxide, calcium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium phosphate, calcium hydroxide, citric acid, hydrochloric acid, lactic acid, magnesium carbonate, magnesium hydroxide, malic acid, phosphoric acid, potassium acid tartrate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium acetate, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium phosphate, sulfuric acid, or tartaric acid. In an embodiment, the amount of the pH-adjusting agent in the pharmaceutical composition is between 0.1% and 25% w/w (e.g., between 0.1% and 10%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w). In an embodiment, the viscosity agent is a polymeric excipient (e.g., a synthetic polymer or a naturally occurring polymer). In an embodiment, the polymeric excipient comprises poloxamer, polyethylene glycol, polycaprolactone, polyvinylalcohol, polyvinylpyrrolidone, polymethacrylate, polyacrylic acid, or a polysaccharide (e.g., cellulose, cellulosemethylcellulose, hypromellose, chitosan, xanthan gum). In an embodiment, the amount of the viscosity agent in the pharmaceutical composition is between 0.1% and 25% w/w (e.g., between 0.1% and 10%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w). In an embodiment, the nasal permeation enhancer comprises lecithin (e.g., a long chain fatty acid phosphatidylcholine, lysophosphatidylcholine), a bile salt (e.g., sodium deoxycholate, sodium glycocholate), cyclodextrin, a mucoadhesive (e.g., polycarbophil, carbopol, chitosan), a non ionic surfactant, or an enzyme inhibitor (e.g., betsatin, amastatin). In an embodiment, the amount of the nasal permeation enhancer in the pharmaceutical composition is between 0.1% and 25% w/w (e.g., between 0.1% and 10%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w). In an embodiment, the preservative comprises an alcohol, a carboxylic acid, a paraben, a phenol, a quaternary ammonium compound, a biguanide, a formaldehyde, an organomercurial compound, a chelator, or an antimicrobial agent. In an embodiment, the amount of the preservative in the pharmaceutical composition is between 0.1% and 25% w/w (e.g., between 0.1% and 10%, 1% and 20%, 0.5% and 10%, or 1% and 10% w/w). In an embodiment, relamorelin is administered as a spray, a gel, droplets, or a powder. In another aspect, the present disclosure features a method for making a pharmaceutical composition formulated for nasal administration comprising relamorelin and a pharmaceutically acceptable excipient. In an embodiment, the method comprises combining the relamorelin and the pharmaceutically acceptable excipient to form a mixture. In an embodiment, the method further comprises sterilizing the mixture, e.g., via filtration or heat, to form a pharmaceutical composition. In an embodiment, the method comprises filling a container closure system suitable for nasal administration with the pharmaceutical composition.

In another aspect, the present disclosure features a method of manufacturing a device for the nasal administration of relamorelin. In an embodiment, the method comprises providing a device suitable for the nasal administration of relamorelin. In an embodiment, the method further comprises introducing relamorelin into the device (e.g., as a pharmaceutical composition). In an embodiment, relamorelin is delivered from the device and, upon activation, forms a plurality of relamorelin-containing particles. The relamorelin-containing particles of the plurality may have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm (e.g., between 0.5 pm and 250 pm, 1 pm and 100 pm, 5 pm and 50 pm, 5 pm and 25 pm, 5 pm and 10 pm, or 10 pm and 25 pm). In an embodiment, the device comprises a dispersal element. The dispersal element may comprise a nasal spray pump or a closure system comprising an on tip-seal/filter. In an embodiment, the device comprises a reservoir having disposed therein a composition comprising relamorelin. In an embodiment, the device is actuated manually. In an embodiment, the device comprises a squeeze bottle actuated dispenser, a pump, or a plunger pump. In an embodiment, the device is configured such that air (e.g., contaminated ambient air) is prevented from entering the dispenser after a plurality of relamorelin-containing particles is released.

In another aspect, the present disclosure features a method of evaluating a device for nasal administration of relamorelin, comprising providing a device suitable for the nasal administration of relamorelin described herein. In an embodiment, evaluating comprises acquiring, directly or indirectly, a value for a parameter (e.g., the average size of the particles ejected from the device, the amount of relamorelin (w/w) present within the device, or the duration of administration of relamorelin (e.g., as ejected by the device)). In an embodiment, the method further comprises evaluating the value for the parameter, e.g., by comparing it with a standard or reference value. In an embodiment, wherein responsive to the evaluation, the method further comprises selecting a course of action, and optionally, performing the action.

The details of one or more aspects and embodiments of the disclosure are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, Figures, Examples, and Claims.

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a graph showing the mean plasma concentration (pg/mL) of relamorelin vs. time, in monkeys dosed with either subcutaneous relamorelin (10 pg) or intranasal relamorelin

(100 pg).

DETAILED DESCRIPTION

Described herein are compositions, methods, and devices for treating a subject having a disease, disorder, or condition with relamorelin, comprising nasally administering relamorelin to the subject.

Definitions

So that the disclosure may be more readily understood, certain technical and scientific terms used herein are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

As used herein “about” and "approximately" generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

“Acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity, or a value, e.g., a numerical value, or knowledge of (e.g., knowledge of the sequence or mutational state of) a value, by “directly acquiring” or “indirectly acquiring” the physical entity, value, or knowledge. “Directly acquiring” means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. “Indirectly acquiring” refers to receiving the physical entity, value, or knowledge from another party or source (e.g., a third party laboratory that directly acquired the physical entity, value, or knowledge). Directly acquiring a value or knowledge includes performing a process that includes a physical change in a sample or another substance. Examples include performing an analytical process which includes a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”), performing an analytical method, e.g., a method which includes one or more of the following: separating or purifying a substance, e.g., an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or fragment or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or changing the structure of an analyte, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the analyte; or by changing the structure of a reagent, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the reagent.

“Administer”, “administering”, or “administration”, as used herein, refer to introducing an entity described herein (e.g., a relamorelin or a pharmaceutically acceptable salt thereof) to a subject, e.g., intranasally.

“Effective amount,” as used herein, refers to the amount of a compound (e.g., relamorelin) sufficient to provide a beneficial or desired result in a subject. In an embodiment, an effective amount is a therapeutically effective amount.

“Prevention,” “prevent,” and “preventing” as used herein refers to a treatment that comprises administering or applying a therapy, e.g., administering a compound described herein, e.g., relamorelin or a pharmaceutically acceptable salt thereof, prior to the onset of a disease, disorder, or condition to preclude the physical manifestation of said disease, disorder, or condition. In some embodiments, “prevention,” “prevent,” and “preventing” require that signs or symptoms of the disease, disorder, or condition have not yet developed or have not yet been observed. In some embodiments, treatment comprises prevention and in other embodiments it does not.

“Subject” as used herein refers to a human or non-human animal. In an embodiment, the subject is a human (i.e., a male or female, e.g., of any age group, a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)). In an embodiment, the subject is a non-human animal, for example, a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey)). In an embodiment, the subject is a commercially relevant mammal (e.g., a cattle, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non-human animal may be a transgenic animal.

“Treatment,” “treat,” and “treating” as used herein refers to one or more of reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause, of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease, disorder, or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition, e.g., in preventive treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., considering a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment comprises prevention and in other embodiments it does not.

Relamorelin

Disclosed herein are compositions, methods, and devices for the intranasal delivery of relamorelin. Relamorelin is a synthetic grehlin analog with affinity for the ghrelin receptor, and has the peptide sequence H-Inp-(D)Bal-(D)Trp-Phe-Apc-NH2. The chemical structure of relamorelin is depicted below in (I):

Relamorelin has shown to be effective in the treatment of subjects having a disease, disorder, or condition related to gastrointestinal dysmotility, including gastroesophageal reflux disease, gastroparesis, irritable bowel syndrome, constipation, emesis, and ileus (Chedid, V. and Camilleri, M. Expert Opin Investig Drugs (2017) 26(10): 1189). In particular, relamorelin has undergone clinical trials for the treatment of gastroparesis in subjects with type 1 or type 2 diabetes (diabetic gastroparesis), a disorder characterized by delayed gastric emptying that is associated with a number of symptoms such as bloating, nausea, vomiting, postprandial fullness, and delayed gastric emptying.

Methods of making and using relamorelin have been previously disclosed in the following publications: International Patent Publication Nos. W02004/014415, W02007/041278, W02009/020643, and WO2015/134567; US Patent Publication Nos. : 2015/0111823, 2016/0311855, 2016/0206700, 2017/0362275, 2017/0304403, 2017/0218015, and 2017/0037104, and US Patent Nos.: 7,456,253 7,932,231, 8,377,865, 8,859,729, 8,871,706, 8,981,054, 9,409,948, and 9,499,599, each of which is incorporated herein by reference in its entirety.

Formulations

The present disclosure features compositions of relamorelin suitable for intranasal delivery. The composition (e.g., a pharmaceutical composition) may comprise an excipient, (e.g., a pharmaceutically acceptable excipient), such as a tonicity agent, a pH-adjusting agent (e.g., a buffer), a viscosity agent, a preservative, a permeation enhancer (e.g., a nasal permeation enhancer), a flavoring agent (e.g., a taste-masking agent), or an aqueous vehicle. In an embodiment, the relamorelin composition suitable for intranasal administration comprises a tonicity agent. A tonicity agent may be used to adjust the tonicity of the pharmaceutical composition, for example, to make the pharmaceutical composition isotonic. Exemplary tonicity agents include dextrose, glycerin, mannitol, potassium chloride, or sodium chloride. In an embodiment, the tonicity agent is mannitol.

The tonicity agent may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/w. In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/w, about 1% and 20% w/w, about 0.5% and 10% w/w, or about 1% and 10% w/w). In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/w. In an embodiment, the tonicity agent is present in the pharmaceutical composition at a concentration of about 5% w/w.

The tonicity agent may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/v. In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/v, about 1% and 20% w/v, about 0.5% and 10% w/v, or about 1% and 10% w/v). In some embodiments, the tonicity agent is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/v. In an embodiment, the tonicity agent is present in the pharmaceutical composition at a concentration of about 5% w/v.

In an embodiment, the relamorelin composition suitable for intranasal administration comprises a pH-adjusting agent. A pH-adjusting agent (e.g., buffer) may be used to increase, decrease, or maintain the pH of the pharmaceutical composition, for example, to maintain the pH of the composition between about 4 to 9. In some embodiments, the pH of the pharmaceutical composition is between about 4 to 8, about 4 to 7, about 4.5 to 6.5, about 5.0 to 5.8, or about 5.2 to 5.6. In some embodiments, the pH of the pharmaceutical composition is about 5.1, about 5.2, about 5.3, about 5.4, or about 5.5. In an embodiment, the pH of the pharmaceutical composition comprising relamorelin is about 5.3. Exemplary pH-adjusting agents include acetic acid, adipic acid, ammonium bicarbonate, ammonium citrate, ammonium phosphate, ammonium hydroxide, calcium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium phosphate, calcium hydroxide, citric acid, hydrochloric acid, lactic acid, magnesium carbonate, magnesium hydroxide, malic acid, phosphoric acid, potassium acid tartrate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium acetate, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium phosphate, sulfuric acid, or tartaric acid.

The pH-adjusting agent (e.g., buffer) may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the pH-adjusting agent (e.g., buffer) is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/w. In some embodiments, the pH-adjusting agent (e.g., buffer) is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/w, about 1% and 20% w/w, about 0.5% and 10% w/w, or about 1% and 10% w/w.

In some embodiments, the pH-adjusting agent (e.g., buffer) is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/w.

The pH-adjusting agent (e.g., buffer) may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the pH-adjusting agent (e.g., buffer) is present at a concentration of about 0.1% to 25% w/v. In some embodiments, the pH-adjusting agent (e.g., buffer) is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/v, about 1% and 20% w/v, about 0.5% and 10% w/v, or about 1% and 10% w/v). In some embodiments, the pH- adjusting agent (e.g., buffer) is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/v.In an embodiment, the relamorelin composition suitable for intranasal administration comprises a viscosity agent. The viscosity agent may be included to increase, decrease, or maintain the viscosity of the pharmaceutical composition. In an embodiment, the viscosity agent may be used to prevent a nasal drip in a subject, which can result in a decreased concentration of relamorelin administered to the subject. In an embodiment, the viscosity agent has shear thinning properties (e.g., thixotropic shear-thinning properties) to allow the nasal formulation to be easily dispersed from a device. In an embodiment, the viscosity agent allows the relamorelin composition to form a viscous solution in the target region (e.g., the nostril or sinus of a subject).

In an embodiment, the viscosity agent is a thickening agent. In an embodiment, the viscosity agent is a polymeric excipient (e.g., a synthetic polymer or a naturally occurring polymer). In an embodiment, the viscosity agent is a synthetic polymer. In an embodiment, the viscosity agent is a naturally occurring polymer. Exemplary viscosity agents (e.g., polymeric excipients) include poloxamer, polyethylene glycol, polycaprolactone, polyvinylalcohol, polyvinylpyrrolidone, polymethacrylate, polyacrylic acid, a polysaccharide (e.g., cellulose, methylcellulose, hypromellose, chitosan, xanthan gum), crospovidone, or povidone.

The viscosity agent may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the viscosity agent is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/w. In some embodiments, the viscosity agent is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/w, about 1% and 20% w/w, about 0.5% and 10% w/w, or about 1% and 10% w/w. In some embodiments, the viscosity agent is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/w.

The viscosity agent may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the viscosity agent is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/v. In some embodiments, the viscosity agent is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/v, about 1% and 20% w/v, about 0.5% and 10% w/v, or about 1% and 10% w/v). In some embodiments, the viscosity agent is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/v.

In an embodiment, the relamorelin composition suitable for intranasal administration comprises a permeation enhancer. The permeation enhancer (e.g., a nasal permeation enhancer) may be included in the pharmaceutical composition to increase the bioavailability of relamorelin following nasal delivery, for example, by increasing the fraction of relamorelin that traverses the mucosal surface of the subject. In an embodiment, the permeation enhancer increases the bioavailability of relamorelin. In an embodiment, the permeation enhancer is a nasal permeation enhancer. In an embodiment, the nasal permeation enhancer increases the permeability of relamorelin through the nasal epithelium. Exemplary permeation enhancers include lecithin (e.g., a long chain fatty acid phosphatidylcholine, lysophosphatidylcholine), a bile salt (e.g., sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, sodium taurodihydrofusidate, ursodeoxycholate, sodium lithocholate, chenocholate, chenodeoxycholate, ursocholate, ursodeoxycholate, hyodeoxycholate, dehydrocholate, glycochenocholate, taurochenocholate, and taurochenodeoxycholate), cyclodextrin, a mucoadhesive (e.g., polycarbophil, carbopol, chitosan), a non-ionic surfactant, or an enzyme inhibitor (e.g., betsatin, amastatin). Other permeation enhancers include cyclopentadecalactone, cyclohexadecanone, cyclopentadecanolide, dimethyl sulfoxide, sugar esters or sugar alcohol esters (e.g., sorbitan esters of long chain aliphatic acids), fatty acids, fatty acid derivatives (e.g., sodium dodecyl sulfate or sodium lauryl sulfate) or Hsieh enhancers.

The permeation enhancer (e.g., nasal permeation enhancer) may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the permeation enhancer (e.g., nasal permeation enhancer) is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/w. In some embodiments, the permeation enhancer (e.g., nasal permeation enhancer) is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/w, about 1% and 20% w/w, about 0.5% and 10% w/w, or about 1% and 10% w/w. In some embodiments, the permeation enhancer (e.g., nasal permeation enhancer) is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/w.

The permeation enhancer (e.g., nasal permeation enhancer) may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the permeation enhancer (e.g., nasal permeation enhancer) is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/v. In some embodiments, the permeation enhancer (e.g., nasal permeation enhancer) is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/v, about 1% and 20% w/v, about 0.5% and 10% w/v, or about 1% and 10% w/v). In some embodiments, the permeation enhancer (e.g., nasal permeation enhancer) is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/v.

In an embodiment, the relamorelin composition suitable for intranasal administration comprises a flavoring agent. The flavoring agent (e.g., a taste-masking agent) may be used to prevent an unpleasant taste or to improve the flavor of the pharmaceutical composition. In an embodiment, the flavoring agent is a taste-masking agent. Exemplary taste-masking agents include stevia or a derivative thereof, thaumatin, saccharin, xylitol, aspartame, acesulfame potassium, sucralose, lemon flavor, citric acid, menthol flavor, sodium cyclamate, zinc sulfate, cyclodextrin (e.g., alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, or hydroxy propyl beta cyclodextrin), mono ammonium glycyrrhizinate pentahydrate, Indion 294, gellan gum, or egg phosphatidyl choline.

The flavoring agent (e.g., a taste-masking agent) may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the flavoring agent (e.g., a taste-masking agent) is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/w. In some embodiments, the flavoring agent (e.g., a taste-masking agent) is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/w, about 1% and 20% w/w, about 0.5% and 10% w/w, or about 1% and 10% w/w. In some embodiments, the flavoring agent (e.g., a taste-masking agent) is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/w.

The flavoring agent (e.g., a taste-masking agent) may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the flavoring agent (e.g., a taste-masking agent) is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/v. In some embodiments, the flavoring agent (e.g., a taste-masking agent) is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/v, about 1% and 20% w/v, about 0.5% and 10% w/v, or about 1% and 10% w/v). In some embodiments, the flavoring agent (e.g., a taste-masking agent) is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/v.

In an embodiment, the relamorelin composition suitable for intranasal administration comprises an aqueous vehicle. The aqueous vehicle may be included to solubilize the relamorelin or an excipient (e.g., pharmaceutically acceptable excipient) and facilitate deployment of the pharmaceutical composition from the device. Exemplary aqueous vehicles include water (e.g., pharmaceutical grade water or purified water), saline, or another pharmaceutically acceptable aqueous solution.

In an embodiment, the relamorelin composition suitable for intranasal administration comprises a preservative. A preservative may be included to increase the stability of the pharmaceutical composition over time. For example, a preservative may reduce or prevent growth of a microbial agent in the pharmaceutical composition. In an embodiment, the preservative is active only against a microbial agent, but has little to no effect on a mammalian cell or a mammalian subject.

Exemplary preservatives include an alcohol (e.g., benzyl alcohol, cetyl alcohol, stearyl alcohol, 2-phenylethanol), a carboxylic acid (e.g., benzoic acid, sorbic acid), a paraben, a phenol (e.g., phenol, chlorocresol, cresol, hexachlorophene, chloroxylenol), a quaternary ammonium compound (e.g., benzalkonium chloride, benzethonium chloride), an organomercurial compound (e.g., thimerosal, a phenylmercuric salt), a formaldehyde (e.g., imidurea, bronopol), a biguanide (e.g., chlorohexidine), a chelator (e.g., EDTA), or an antimicrobial agent.

The preservative may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/w. In some embodiments, the preservative is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/w, about 1% and 20% w/w, about 0.5% and 10% w/w, or about 1% and 10% w/w. In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/w.

The preservative may be present in the pharmaceutical composition at a concentration of about 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 0.1% to 25% w/v. In some embodiments, the preservative is present in the pharmaceutical composition at a concentration between about 0.1% and 10% w/v, about 1% and 20% w/v, about 0.5% and 10% w/v, or about 1% and 10% w/v). In some embodiments, the preservative is present in the pharmaceutical composition at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% w/v.

The aqueous vehicle may be present in the pharmaceutical composition at a concentration of about 50% to 99.9% w/w (e.g., about 75% to 95% w/w). In some embodiments, the aqueous vehicle is present in the pharmaceutical composition at a concentration of about 75% to 99% w/w. In some embodiments, the aqueous vehicle is present in the pharmaceutical composition at a concentration between about 5% and 99% w/w, about 10% and 99% w/w, about 25% and 99% w/w, about 50% and 99% w/w, about 75% and 99% w/w, about 85% and 95% w/w, or about 90% and 95% w/w). In some embodiments, the aqueous vehicle is present in the pharmaceutical composition at a concentration of about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% w/w. In an embodiment, the aqueous vehicle is present in the pharmaceutical composition at a concentration of about 95% w/w.

The aqueous vehicle may be present in the pharmaceutical composition at a concentration of about 50% to 99.9% w/v (e.g., about 75% to 95% w/v). In some embodiments, the aqueous vehicle is present in the pharmaceutical composition at a concentration of about 75% to 99% w/v. In some embodiments, the aqueous vehicle is present in the pharmaceutical composition at a concentration between about 5% and 99% w/v, about 10% and 99% w/v, about 25% and 99% w/v, about 50% and 99% w/v, about 75% and 99% w/v, about 85% and 95% w/v, or about 90% and 95% w/v). In some embodiments, the aqueous vehicle is present in the pharmaceutical composition at a concentration of about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% w/v. In an embodiment, the aqueous vehicle is present in the pharmaceutical composition at a concentration of about 95% w/v.

The concentration of relamorelin in the pharmaceutical composition may be within the range of 0.01% to 35% w/w (e.g., about 0.1% to 25% w/w). In some embodiments, the concentration of relamorelin in the composition is about 0.1% to 25% w/w. In some embodiments, the concentration of relamorelin in the composition is about 0.01% and 10% w/w, e.g., between about 0.01% and 5%, about 0.05% and 5%, about 0.05% and 2.5%, about 0.05% and 1%, or about 0.05% and 0.5% w/w). In some embodiments, the concentration of relamorelin in the composition is about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, or about 0.15% w/w. In an embodiment, the concentration of relamorelin in the composition is about 0.10% w/w.

In some embodiments, the concentration of relamorelin in the pharmaceutical composition may be within the range of 0.01% to 35% w/v (e.g., about 0.1% to 25% w/v). In some embodiments, the concentration of relamorelin in the composition is about 0.1% to 25% w/v. In some embodiments, the concentration of relamorelin in the composition is about 0.01% and 10% w/v, e.g., between about 0.01% and 5%, about 0.05% and 5%, about 0.05% and 2.5%, about 0.05% and 1%, or about 0.05% and 0.5% w/v). In some embodiments, the concentration of relamorelin in the composition is about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, or about 0.15% w/v. In an embodiment, the concentration of relamorelin in the composition is about 0.10% w/v.

Devices

Disclosed herein are devices for the intranasal delivery of relamorelin and related methods thereof. Intranasal delivery may be affected to a subject from a device suitable for such administration, and may contain a dispersal element, a seal, a reservoir, a squeeze bottle, an actuated dispenser, a pump, or plunger pump. In some embodiments the device, upon activation, forms a plurality of relamorelin-containing particles. In some embodiments, the device is manually actuated (e.g., by hand). The device may be pressurized or non-pressurized, and may comprise glass, plastic, or other suitable materials.

In an embodiment, the device comprises a dispersal element, for example, which provides a plurality of relamorelin-containing particles. The dispersal element may comprise a nasal spray pump or a closure system. In some embodiments, the dispersal element comprises a closure system comprising an on tip-seal/filter. In some embodiments, the dispersal element comprises a nasal spray pump.

In an embodiment, the dispersal element comprises an actuator for delivery into the nostril or nasal cavity. In an embodiment, the actuator comprises a shaft with a terminal end comprising a portal for delivery of plurality of relamorelin-containing particles. In an embodiment, the actuator comprises a tip-seal mechanism, in which relamorelin or a pharmaceutical composition thereof is not emitted from the device unless pressure is applied. In an embodiment, the actuator comprises a spring-loaded tip-seal mechanism. In an embodiment, the actuator further comprises a filter membrane, e.g., for removal of undesired components from the material delivered. The dispersal element (e.g., the actuator) may be tethered to the device with a collar.

The dispersal element may provide a barrier to prevent entry of a contaminating agent (e.g., a microbial agent, an endotoxin, or dust) into the device, and to maintain sterility or purity of the device contents. The integrity of the barrier may be demonstrated or interrogated using any method known in the art, for example, the Tip Seal Integrity Test or the Closure Ventilation Integrity Test. Using these methods, the device may be incubated with a contaminating agent (e.g., a microbial agent, e.g., bacteria) for a set period of time, after which the device contents are tested for the presence of the contaminating agent.

In an embodiment, the device comprises a squeeze bottle, an actuated dispenser, a pump, or plunger pump. In some embodiments, the device comprises a pump or plunger pump. The pump or plunger pump may be used to serially dispense metered doses of relamorelin or a pharmaceutical composition comprising relamorelin. In an embodiment, the pump is an Aptar nasal spray pump.

In an embodiment, the device comprises a seal. The seal may be capable of preventing ambient air (e.g., contaminated ambient air) from entering the dispenser after a plurality of relamorelin-containing particles is released, or preventing unwanted release of the relamorelin of pharmaceutical composition comprising relamorelin from the device. In some embodiments, the device is configured such that ambient air (e.g., contaminated ambient air) is prevented from entering the device or dispenser after a plurality of relamorelin-containing particles is released.

In some embodiments, the seal comprises a valve that seals the device until actuation (e.g., actuation by hand) creates sufficient hydraulic pressure to overcome a spring force, allowing the valve to open and dispense relamorelin or a pharmaceutical composition comprising relamorelin (e.g., as a spray). Immediately after dispensing the relamorelin or a pharmaceutical composition comprising relamorelin, the hydraulic pressure may diminish, causing the spring to reseal the device and prevent ambient air (e.g., contaminated ambient air) from entering the device, or prevent unwanted release of the relamorelin or pharmaceutical composition comprising relamorelin from the device.

In an embodiment, the device comprises a reservoir, which may or may not be predisposed with relamorelin or a pharmaceutical composition thereof. In some embodiments, the reservoir has disposed therein a sufficient amount of a pharmaceutical composition of relamorelin to constitute multiple doses. The reservoir may have a capacity of 0.1 mL to 250 mL (e.g., about 1 mL to 125 mL). In some embodiments, the reservoir has a capacity of between about 0.1 mL and 100 mL, about 0.5 mL and 75 mL, about 1 mL and 50 mL, or about 5 mL and 25 mL. In some embodiments, the reservoir has a capacity of 5 mL, 10 mL, or 15 mL. In an embodiment, the reservoir has a capacity of 10 mL. The device may be used to eject or dispense relamorelin (e.g., a plurality of relamorelin-containing particles) such that the relamorelin- containing particles reach a particular region of the subject’s nose (e.g., the vestibular or turbinate regions of the nose, the region where the surface lining changes from skin to stratified squamous epithelium or pseudostratified columnar epithelium, or olfactory region of the nose).

In some embodiments, the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the vestibular regions of the nose. In some embodiments, the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the turbinate regions of the nose. In some embodiments, the device ejects a plurality of relamorelin-containing particles such that the relamorelin- containing particles reach the region of the nose where the surface lining changes from skin to stratified squamous epithelium or pseudostratified columnar epithelium. In some embodiments, the device ejects a plurality of relamorelin-containing particles such that the relamorelin- containing particles reach the olfactory region of the nose (e.g., where the nose-brain pathway is located). In some embodiments, the device ejects a plurality of relamorelin-containing particles such that the relamorelin-containing particles reach the olfactory region of the nose where the nose-brain pathway is located and allows direct transport of the drug to the brain and cerebrospinal fluid (CSF).

Upon activation, the device may dispense or eject a plurality of relamorelin-containing particles that have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 500 pm. In some embodiments, the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between about 0.5 pm and 250 pm, about 1 pm and 100 pm, about 5 pm and 50 pm, about 5 pm and 25 pm, about 5 pm and 10 pm, or about 10 pm and 25 pm. In some embodiments, the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm). In some embodiments, the relamorelin-containing particles of the plurality have an average longest linear dimension, e.g., diameter, of between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm).

The average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, may be between 0.1 pm and 500 pm. In some embodiments, the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between about 0.5 pm and 250 pm, about 1 pm and 100 mih, about 5 mih and 50 mih, about 5 mih and 25 mih, about 5 mih and 10 mhi, or about 10 mih and 25 mih. In some embodiments, the average particle size of the relamorelin-containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 50 pm (e.g., between 0.5 pm and 50 pm, 0.5 pm and 25 pm, 0.5 pm and 10 pm, 0.5 pm and 5 pm, or 0.5 pm and 1 pm). In some embodiments, the average particle size of the relamorelin- containing particles, e.g., as measured by particle image analysis or laser diffraction, is between 0.1 pm and 5 pm (e.g., between 0.1 pm and 4 pm, 0.1 pm and 3 pm, 0.1 pm and 2 pm, 0.1 pm and 1 pm, or 0.1 pm and 0.5 pm). Upon activation, the device may deliver between 5 pL and 500 pL of a pharmaceutical composition comprising relamorelin (e.g., to each nostril). In some embodiments, the device delivers between about 10 pL and 250 pL, about 10 pL to 100 pL, about 25 pL and 200 pL, about 50 pL to 150 pL, about 50 pL to 200 pL, about 100 pL to 200 pL, or about 100 pL to 500 pL of a pharmaceutical composition comprising relamorelin to each nostril.

The device may deliver a predetermined dose of relamorelin or a pharmaceutical composition of relamorelin. In some embodiments, a dose of relamorelin comprises a plurality of relamorelin-containing particles (e.g., about 0.1 pg to about 500 pg). In some embodiments, a dose or relamorelin is about 0.5 pg to 250 pg, about 1 pg to 100 pg, about 1 pg to 50 pg, about 1 pg to 25 pg, about 1 pg to 10 pg, about 5 pg to 50 pg, about 5 pg to 25 pg, about 5 pg to 10 pg, about 10 pg to 50 pg, about 10 pg to 25 pg, or about 10 to 20 pg of relamorelin.

In an embodiment, the relamorelin or a pharmaceutical composition of relamorelin is delivered from the device over a predetermined time period (e.g., once a day, twice a day, three times a day, once a week, twice a week, or three times a week). In some embodiments, relamorelin or a pharmaceutical composition of relamorelin is administered once a day, twice a day, three times a day, once a week, twice a week, or three times a week. The relamorelin may be administered over a predetermined time period (e.g., 1 hour, 2 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days, 14 days, 16 days, 18 days, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 6 months, 8 months, 10 months, 1 year, or 2 years). In some embodiments, , the relamorelin or a pharmaceutical composition of relamorelin is delivered from the device over 1 hour, 2 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 10 days, 12 days, 14 days, 16 days, 18 days, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 6 months, 8 months, 10 months, 1 year, or 2 years.

Method of Treatment

The present invention features compositions, methods, and devices for the intranasal delivery of relamorelin to treat a disease, disorder, or condition in a subject. In some embodiments, the disease, disorder, or condition relates to gastric motility. In an embodiment, the disease, disorder, or condition is gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), constipation, ileus, emesis, gastroparesis (e.g., diabetic gastroparesis), colonic pseudo-obstruction, and the like. In some embodiments, the relamorelin is effective for treating subjects identified as having diabetes (e.g., type 1 diabetes, or type 2 diabetes). In an embodiment, the relamorelin is effective for treating a subject identified as having diabetic gastroparesis.

In some embodiments, a symptom or manifestation of gastroparesis (e.g., diabetic gastroparesis) in a subject is alleviated, lessened, or delayed following delivery of relamorelin.

In some embodiments, the motility of the gut is increased in a subject following delivery of relamorelin. In some embodiments, early satiety, bloating, postprandial pain, vomiting, or nausea in a subject is reduced following delivery of relamorelin. In some embodiments, motility (e.g., gut motility) is increased in comparison with a reference, e.g., motility prior to administration, motility in an untreated subject, or a predetermined reference standard, e.g., a value for gut motility expressed as the postprandial gastric meal volume (e.g., at 2 or 4 hours) as a percentage of the original meal volume. In some embodiments, gut motility is determined by gamma camera scintigraphy, colonic manometry, a gastric emptying breath test, barostat balloon measurement, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), ultrasonography, a satiation or nutrient drink test, use of a capsule (e.g., a wireless pH and/or motility capsule), or the like. In some embodiments, motility (e.g., gut motility) is determined by analysis of gastric contents. In some embodiments, a postprandial gastric meal volume greater than 40% at 2 hours indicates delayed motility. In some embodiments, a postprandial gastric meal volume greater than 10% at 4 hours indicates delayed motility. In some embodiments, gastric emptying is accelerated in a subject following delivery of relamorelin. In some embodiments, gastric emptying is accelerated in comparison with a reference, e.g., gastric emptying prior to administration, a gastric emptying in an untreated subject, or a predetermined reference standard, e.g., a value for gastric emptying expressed as the postprandial gastric meal volume (e.g., at 2 or 4 hours) as a percentage of the original meal volume. In some embodiments, gastric emptying is determined by gamma camera scintigraphy, barostat balloon measurement, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), ultrasonography, a satiation or nutrient drink test, a gastric emptying breath test, use of a capsule (e.g., a wireless pH and/or motility capsule), or the like. In an embodiment, gastric emptying is determined by analysis of gastric contents. In some embodiments, a postprandial gastric meal volume greater than 40% at 2 hours indicates delayed gastric emptying. In some embodiments, a postprandial gastric meal volume greater than 10% at 4 hours indicates delayed gastric emptying.

Additional methods of measuring motility and/or gastric emptying are described in Camilleri, M. and Linden, D.R. (2016) Cell Mol Gastroenterol Hepatol 2:412-428; and Szarka, L.A. and Camilleri, M. (2009 )Am. J Physiol. Gastrointest. Liver Physiol . 296:G461-475, each of which is incorporated herein by reference in its entirety.

The subject may take certain actions prior to being tested for motility and/or gastric emptying. In an embodiment, the subject has ceased treatment with particular agents (e.g., therapeutic agents) that may have an impact on motility and/or gastric emptying (e.g., anticholinergics, narcotics, and prokinetics). In an embodiment, the subject has a glucose level of less than 275 mg/dl (e.g., less than 250 mg/dl, 200 mg/dl, 190 mg/dl, 180 mg/dl, 170 mg/dl, 160 mg/dl, 150 mg/dl, 140 mg/dl, 130 mg/dl, 120 mg/dl, 110 mg/dl, 100 mg/dl, or less).

Dosages/Administration

Disclosed herein are methods for the intranasal delivery of relamorelin and related dosages and dosage regimens. The relamorelin may be delivered e.g., from a device, in order to achieve a predetermined dose, e.g., of about 0.1 pgto about 1000 pg. In some embodiments, the relamorelin is delivered at a dosage of about 1 pg to about 500 pg, e.g., about 10 pg to about 400 pg, about 10 pg to about 300 pg, about 10 pg to about 200 pg, about 10 pg to about 100 pg, about 50 pg to about 250 pg, about 50 pg to about 150 pg, about 50 pg to about 100 pg, about 75 gg to about 200 gg, about 75 gg to about 150 gg, or about 75 gg to about 100 gg. In an embodiment, the relamorelin is delivered at a dosage of about 75 gg to about 100 gg. In some embodiments, the relamorelin is delivered at a dosage of about 1 ug, about 10 ug, about 25 ug, about 50 ug, about 75 ug, about 80 ug, about 90 ug, about 100 ug, about 110 ug, about 125 ug, about 150 ug, about 200 ug, about 250 ug, or about 300 ug. In an embodiment, the relamorelin is delivered at a dosage of about 100 gg.

In some embodiments, the relamorelin is delivered at a dosage of about 0.1 gg to about 500 gg, e.g., about 0.5 gg to about 250 gg, about 1 gg to about 100 gg, about 1 gg to about 50 gg, about 1 gg to about 25 gg, about 1 gg to about 10 gg, about 5 gg to about 50 gg, about 5 gg to about 25 gg, about 5 gg to about 10 gg, about 10 gg to about 50 gg, about 10 gg to about 25 gg, or about 10 to about 20 gg..

The relamorelin may be delivered at certain intervals, e.g., to achieve the desired dosage. In some embodiments, the relamorelin is delivered five times a day, four times a day, three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the relamorelin is administered at a certain time of day, e.g., in the morning, afternoon, or night. In some embodiments, the relamorelin is administered before a meal, or after a meal. In some embodiments, the relamorelin is administered over a predetermined time period, e.g., about 1 hour, about 2 hours, about 8 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 10 days, about 12 days, about 14 days, about 16 days, about 18 days, about 3 weeks, about 4 weeks, about 6 weeks, about 2 months, about 3 months, about 6 months, about 8 months, about 10 months, about 1 year, or about 2 years.

The relamorelin may be delivered to provide a systemic therapeutic level of relamorelin. In some embodiments, the relamorelin is delivered in a dosage to provide a bioavailability of about 1% to 50%, e.g., about 1% to 25%, about 1% to 10%, about 5% to 50%, about 5% to 25%, about 5% to 10%, or about 10% to 25% relative to a subcutaneous injection of relamorelin. In an embodiment, bioavailability of relamorelin is determined by measuring the area under the curve (AUC), e.g., after administering relamorelin to a subject. In an embodiment, bioavailability of relamorelin is determined by measuring a maximum concentration (Cmax) in a subject, e.g., after administering relamorelin to a subject. Patient Selection

Disclosed herein are methods for the intranasal delivery of relamorelin to a subject in need thereof. In some embodiments, the subject is a mammal (e.g., a human). The subject may be of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent, e.g., an individual under the age of 18, 12, 8, or 5) or adult subject (e.g., young adult, middle-aged adult, or senior adult, e.g., an individual over the age of 18, 25, 35, 45, 55, or 65). The subject may be male or female (e.g., an adult male, an adult female, a male child, or a female child).

In an embodiment, the subject is overweight. In some embodiments, the subject has a body mass index (BMI) greater than 25 kg/m 2 (e.g., > 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater). In some embodiments, the subject has a body mass index (BMI) greater than 30 kg/m 2 (e.g., > 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater). In some embodiments, the subject has a body mass index (BMI) greater than 35 kg/m 2 (e.g., > 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater). In some embodiments, the subject has a body mass index (BMI) greater than 40 kg/m 2 (e.g., > 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m 2 or greater). In some embodiments, the subject has a body mass index (BMI) greater than 45 kg/m 2 (e.g., > 45, 46, 47, 48, 49, 50 kg/m 2 or greater). In an embodiment, the subject has a body mass index (BMI) between about 25 kg/m 2 and 50 kg/m 2 , 30 kg/m 2 and 50 kg/m 2 , 35 kg/m 2 and 50 kg/m 2 , 40 kg/m 2 and 50 kg/m 2 , or 45 kg/m 2 and 50 kg/m 2 .

In an embodiment, the subject has been diagnosed or identified as having a condition, disorder, or disease (e.g., gastroparesis). In an embodiment, the subject is diagnosed or identified as having gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), constipation, ileus, emesis, gastroparesis (e.g., diabetic gastroparesis), or colonic pseudo obstruction. In an embodiment, the subject has been diagnosed or identified as having gastroesophageal reflux disease (GERD). In an embodiment, the subject has been diagnosed or identified as having irritable bowel syndrome (IBS). In an embodiment, the subject has been diagnosed or identified as having constipation. In an embodiment, the subject has been diagnosed or identified as having an ileus. In an embodiment, the subject has been diagnosed or identified as having emesis. In an embodiment, the subject has been diagnosed or identified as having a colonic pseudo-obstruction. In an embodiment, the subject has been diagnosed or identified as having diabetic gastroparesis. In some embodiments, the subject has been diagnosed or identified as having diabetes (e.g., type 1 diabetes or type 2 diabetes). In some embodiments, the subject has impaired or delayed gut motility or gastric emptying. In some embodiments, the subject is experiencing a symptom or manifestation of diabetic gastroparesis (e.g., bloating, postprandial pain, vomiting, or nausea).

The subject may have received treatment for a disease, disorder, or condition. In an embodiment, the subject has been previously treated for gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), constipation, ileus, emesis, gastroparesis (e.g., diabetic gastroparesis), or colonic pseudo-obstruction. In an embodiment, the subject has been previously treated for gastroesophageal reflux disease (GERD). In an embodiment, the subject has been previously treated for irritable bowel syndrome (IBS). In an embodiment, the subject has been previously treated for constipation. In an embodiment, the subject has been previously treated for an ileus. In an embodiment, the subject has been previously treated for emesis. In an embodiment, the subject has been previously treated for a colonic pseudo-obstruction. In some embodiments, the subject has been previously treated for gastroparesis (e.g., diabetic gastroparesis). In some embodiments, the subject has previously been treated for a disease, disorder, or condition (e.g., gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), constipation, ileus, emesis, gastroparesis (e.g., diabetic gastroparesis), or colonic pseudo obstruction) with relamorelin. In some embodiments, the subject has previously received a subcutaneous administration of relamorelin.

Combination Therapy

Disclosed herein are methods for the intranasal delivery of relamorelin, which may be combined with an additional therapy or treatment. In some embodiments, the relamorelin is delivered to a subject in combination with an additional therapy or treatment.

In some embodiments, the subject is also taking or is prescribed with a drug to treat diabetes. In some embodiments, the subject is also taking or is prescribed with insulin (e.g., rapid acting insulin, intermediate acting insulin, long acting insulin), a biguanide (e.g., metformin, phenformin, buformin), a sulfonylurea (e.g., glyburide, glipizide, glimepiride), a meglitinide (e.g., repaglinide, nateglinide), a thiazolidinedione (e.g., rosiglitazone, pioglitazone, troglitazone), a dipeptidyl peptidase-4 (DPP-4) inhibitor (e.g., sitagliptin, saxagliptin, linagliptin), a glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., exenatide, liraglutide, semaglutide), or a sodium-glucose cotransporter-2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin).

In some embodiments, the subject is also taking or is prescribed with a cholesterol lowering drug, a lipid lowering drug, or a drug to treat hypertension. In some embodiments, the subject is taking or is prescribed with a statin (e.g., atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) a PCSK9 inhibitor (e.g., alirocubmab, evolucumab), a selective cholesterol absorption inhibitor (e.g., ezetimibe), a resin (e.g., cholestyramine, colestipol, colesevelam). In some embodiments, the subject is taking or is prescribed with a lipid-lowering drug (e.g., gemfibrozil, fenofibrate, clofibrate, niacin). In some embodiments, the subject is prescribed with or is taking a blood pressure lowering drug. In some embodiments, the subject is prescribed with or is taking an angiotensin-converting enzyme (ACE) inhibitor (e.g., captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril), or an angiotensin II receptor blocker (e.g., losartan, candesartan, valsartan, irbesartan, telmisartan, eprosartan, azilsartan, fimasartan). In some embodiments, the subject is taking or is prescribed with aspirin.

In some embodiments, the subject is also taking or is prescribed with a drug to treat a motility disorder (e.g., gastroparesis) or to reduce or alleviate symptoms associated with a motility disorder. In some embodiments, the subject is also taking or is prescribed with a pro motility agent (e.g., metoclopramide, erythromycin, domperidone). In some embodiments the subject is also taking or is prescribed with an antiemetic agent (e.g., prochlorperazine, trimethobenzamide, ondansetron).

EXAMPLES

Example 1: Pharmacokinetics of subcutaneous administration of relamorelin

A clinical study in humans was carried out in order to obtain the systemic pharmacokinetic parameters of relamorelin after subcutaneous administration. Subjects were injected with relamorelin subcutaneously at a dose of 5-10 pg, on a twice daily basis over 14 days. On days 1, 10 and 14, samples were obtained from each subject after morning (AM) doses. Samples after night (PM) doses were obtained on day 1 from subjects at the 5 pg dose level, and on day 14 from subjects at the 10 pg dose level. The results of this assay are summarized in Table 1 below. In this table, “Cmax” corresponds to the maximum plasma concentration; “Tmax” corresponds to the time to reach maximum plasma concentration;

“AUCiast” corresponds to the area under the plasma concentration-time curve from time zero to the time of last measurable concentration; and ti/2 corresponds to the elimination half-life. Based on this data it was determined that the relamorelin C max increases proportionally with all doses.

Table 1. Systemic pharmacokinetic parameters of relamorelin following subcutaneous administration in human subjects.

Example 2: Preparation and testing of relamorelin nasal formulation

Preparation of nasal formulation. Relamorelin (0.1% w/w) was combined with mannitol (5% w/w) and water (QS) to provide a nasal formulation of relamorelin having a pH of 5.3. The formulation was stored in a 10 mL amber glass bottle fitted with an Aptar nasal spray pump suitable for nasal administration. Pharmacokinetic assay. Using the above described formulation, a pharmacokinetic study was carried out to compare intranasal administration of relamorelin with subcutaneous administration. A cohort of 5 monkeys were each dosed intranasally with 100 pg of relamorelin, and were subject to sampling in order to obtain pharmacokinetic parameters. The same measurements were also carried out following subcutaneous administration of relamorelin (10 pg). The data from this assay is provided below in Table 2. In this table, “Tmax”, “Cmax”, and “AUCi ast ” are as defined in Example 1; “SUBID” corresponds to the monkey subject identification number; “Dose” corresponds to the dose of relamorelin administered; “Cmax_D” corresponds to the C max adjusted by dose; AUCi ast _D corresponds to the AUCi ast adjusted by dose; “Vz_F-pred” corresponds to the predicted apparent volume of distribution during terminal phase; and “Cl_F-pred” corresponds to the predicted apparent total clearance of the drug from plasma. The measurements obtained indicate that intranasal relamorelin has a comparable pharmacokinetic profile to subcutaneous relamorelin. Further, FIG. 1 illustrates that the relamorelin plasma concentration over time is similar following either intranasal or subcutaneous administration.

Table 2. Intranasal (IN) administration vs. subcutaneous (SC) injection in monkeys

The intranasal bioavailability relative to subcutaneous injection in monkeys was calculated from the C max and AUC ratios, which are presented below in Table 3. Based on the average C max and AUC ratios, intranasal administration of relamorelin was determined to achieve a relative bioavailability of 6-8% compared with subcutaneous administration of relamorelin. Table 3. Bioavailability ratios of intranasal: subcutaneous (SC) relamorelin.

EQUIVALENTS AND SCOPE

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, Figures, or Examples but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.