Nasal drug products and methods of their use
View Patent ↗Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.
1. A single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 μL comprising:
about 2 mg naloxone hydrochloride or a hydrate thereof;
between about 0.2 mg and about 1.2 mg of an isotonicity agent;
between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer;
between about 0.1 mg and about 0.5 mg of a stabilizing agent; and
an amount of an acid sufficient to achieve a pH of 3.5-5.5.
2. The device of claim 1 wherein:
the isotonicity agent is NaCl;
the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride;
the stabilizing agent is disodium edetate; and
the acid is hydrochloric acid.
3. The device of claim 2 , wherein the aqueous solution comprises:
about 2.2 mg naloxone hydrochloride dihydrate;
about 0.74 mg NaCl;
about 0.01 mg benzalkonium chloride;
about 0.2 mg disodium edetate; and
an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.
4. The device of claim 2 , wherein said device is actuatable with one hand.
5. The device of claim 4 , wherein the volume of said reservoir is not more than about 140 μL.
6. The device of claim 5 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation.
7. The device of claim 6 , wherein the pharmaceutical composition which is an aqueous solution comprises about 2.2 mg naloxone hydrochloride dihydrate.
8. The device of claim 7 , wherein the 90% confidence interval for dose delivered per actuation is ±about 2%.
9. The device of claim 7 , wherein the 95% confidence interval for dose delivered per actuation is ±about 2.5%.
10. The device of claim 7 , wherein the delivery time is less than about 25 seconds.
11. The device of claim 7 , wherein the delivery time is less than about 20 seconds.
12. The device of claim 7 , wherein the device is configured such that upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
13. The device of claim 12 , wherein the device is configured such that upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
14. The device of claim 13 , wherein the device is configured such that upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
15. The device of claim 7 , wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max of between about 20 and about 30 minutes.
16. A pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 μL
about 2 mg naloxone hydrochloride or a hydrate thereof;
between about 0.2 mg and about 1.2 mg of an isotonicity agent;
between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer;
between about 0.1 mg and about 0.5 mg of a stabilizing agent;
an amount of an acid sufficient to achieve a pH of 3.5-5.5.
17. The pharmaceutical formulation of claim 16 , wherein the naloxone hydrochloride is provided as naloxone hydrochloride dihydrate.
18. The pharmaceutical formulation of claim 17 wherein:
the isotonicity agent is NaCl;
the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride;
the stabilizing agent is disodium edetate; and
the acid is hydrochloric acid.
19. The pharmaceutical formulation of claim 18 , wherein the aqueous solution comprises:
about 2.2 mg naloxone hydrochloride dihydrate;
about 0.74 mg NaCl;
about 0.01 mg benzalkonium chloride;
about 0.2 mg disodium edetate; and
an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.
20. A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride using a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 μL comprising:
about 2 mg naloxone hydrochloride or a hydrate thereof;
between about 0.2 mg and about 1.2 mg of an isotonicity agent;
between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer;
between about 0.1 mg and about 0.5 mg of a stabilizing agent; and
an amount of an acid sufficient to achieve a pH of 3.5-5.5.
21. The method of claim 20 , wherein the naloxone hydrochloride is provided as naloxone hydrochloride dihydrate.
22. The method of claim 21 wherein:
the isotonicity agent is NaCl;
the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride;
the stabilizing agent is disodium edetate; and
the acid is hydrochloric acid.
23. The method of claim 22 , wherein the aqueous solution comprises:
about 2.2 mg naloxone hydrochloride dihydrate;
about 0.74 mg NaCl;
about 0.01 mg benzalkonium chloride;
about 0.2 mg disodium edetate; and
an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.
24. The method of claim 20 , wherein said device is actuatable with one hand.
25. The method of claim 24 , wherein the volume of said reservoir is not more than about 140 μL.
26. The method of claim 25 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation.
27. The method of claim 26 , wherein the pharmaceutical composition which is an aqueous solution comprises about 2.2 mg naloxone hydrochloride dihydrate.
28. The method of claim 27 , wherein the 90% confidence interval for dose delivered per actuation is ± about 2%.
29. The method of claim 27 , wherein the 95% confidence interval for dose delivered per actuation is ± about 2.5%.
30. The method of claim 27 , wherein the delivery time is less than about 25 seconds.
31. The method of claim 27 , wherein the delivery time is less than about 20 seconds.
32. The method of claim 23 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
33. The method of claim 23 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
34. The method of claim 23 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
35. The method of claim 20 , wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max of between about 20 and about 30 minutes.
36. The method of claim 20 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient.
37. The method of claim 36 , wherein the patient exhibits one or more symptoms chosen from: respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting.
38. The method of claim 37 , wherein the patient exhibits respiratory depression.
39. The method of claim 38 , wherein said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy.
40. The method of claim 38 , wherein said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
41. The method of claim 40 , wherein said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
42. The method of claim 40 , wherein said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
43. The method of claim 40 , wherein said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
44. The method of claim 40 , wherein said patient is in a lying, supine, or recovery position.
45. A method of complete or partial reversal of narcotic depression or respiratory depression induced by opioids in a patient, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride using a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 μL comprising:
about 2 mg naloxone hydrochloride or a hydrate thereof;
between about 0.2 mg and about 1.2 mg of an isotonicity agent;
between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer;
between about 0.1 mg and about 0.5 mg of a stabilizing agent; and
an amount of an acid sufficient to achieve a pH of 3.5-5.5.
46. The method of claim 45 , wherein the naloxone hydrochloride is provided as naloxone hydrochloride dihydrate.
47. The method of claim 46 , wherein:
the isotonicity agent is NaCl;
the compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer is benzalkonium chloride;
the stabilizing agent is disodium edetate; and
the acid is hydrochloric acid.
48. The method of claim 45 , wherein the aqueous solution comprises:
about 2.2 mg naloxone hydrochloride dihydrate;
about 0.74 mg NaCl;
about 0.01 mg benzalkonium chloride;
about 0.2 mg disodium edetate; and
an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.
49. The method of claim 45 , wherein said method is actuatable with one hand.
50. The method of claim 49 , wherein the volume of said reservoir is not more than about 140 μL.
51. The method of claim 50 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation.
52. The method of claim 51 , wherein the pharmaceutical composition which is an aqueous solution comprises about 2.2 mg naloxone hydrochloride dihydrate.
53. The method of claim 52 , wherein the 90% confidence interval for dose delivered per actuation is ± about 2%.
54. The method of claim 52 , wherein the 95% confidence interval for dose delivered per actuation is ± about 2.5%.
55. The method of claim 52 , wherein the delivery time is less than about 25 seconds.
56. The method of claim 52 , wherein the delivery time is less than about 20 seconds.
57. The method of claim 48 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 20% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
58. The method of claim 48 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 10% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
59. The method of claim 48 , wherein upon nasal delivery of said pharmaceutical composition to said patient, less than about 5% of said pharmaceutical composition leaves the nasal cavity via drainage into the nasopharynx or externally.
60. The method of claim 45 , wherein the plasma concentration versus time curve of said naloxone hydrochloride in said patient has a T max of between about 20 and about 30 minutes.
61. The method of claim 45 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient.
62. The method of claim 61 , wherein the patient exhibits one or more symptoms chosen from: respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting.
63. The method of claim 62 , wherein the patient exhibits respiratory depression.
64. The method of claim 63 , wherein said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy.
65. The method of claim 63 , wherein said patient is free from respiratory depression for at least about 1 hour following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
66. The method of claim 65 , wherein said patient is free from respiratory depression for at least about 2 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
67. The method of claim 66 , wherein said patient is free from respiratory depression for at least about 4 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
68. The method of claim 67 , wherein said patient is free from respiratory depression for at least about 6 hours following treatment comprising delivery of said therapeutically effective amount of said opioid antagonist.
69. The method of claim 61 , wherein said patient is in a lying, supine, or recovery position.