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 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 4 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 method as recited in claim 1 wherein:
the isotonicity agent is NaCl;
the preservative is benzalkonium chloride;
the stabilizing agent is disodium edetate; and
the acid is hydrochloric acid.
3. The method of claim 2 , wherein the aqueous solution comprises:
about 4.4 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 method of claim 2 , wherein said method is actuatable with one hand.
5. The method of claim 4 , wherein the volume of said reservoir is not more than about 140 μL.
6. The method of claim 5 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation.
7. The method of claim 6 , wherein the pharmaceutical composition which is an aqueous solution comprises about 4.4 mg naloxone hydrochloride dihydrate.
8. The method of claim 7 , wherein the 90% confidence interval for dose delivered per actuation is ±about 2%.
9. The method of claim 7 , wherein the 95% confidence interval for dose delivered per actuation is ±about 2.5%.
10. The method of claim 7 , wherein the delivery time is less than about 25 seconds.
11. The method of claim 7 , wherein the delivery time is less than about 20 seconds.
12. The method of claim 11 , 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.
13. The method of claim 12 , 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.
14. The method of claim 13 , 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.
15. The method of claim 11 , 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. The method of claim 1 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient.
17. The method of claim 16 , 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.
18. The method of claim 17 , wherein the patient exhibits respiratory depression.
19. The method of claim 18 , wherein said respiratory depression is caused by the illicit use of opioids, or by an accidental misuse of opioids during medical opioid therapy.
20. The method of claim 19 , 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.
21. The method of claim 20 , 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.
22. The method of claim 21 , 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.
23. The method of claim 22 , 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.
24. The method of claim 16 , wherein said patient is in a lying, supine, or recovery position.
25. The method of claim 7 , wherein said single actuation yields a naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient.
26. The method of claim 7 , wherein said single actuation yields a naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient.
27. The method of claim 7 , wherein said single actuation yields a naloxone plasma concentration of ≧3 ng/mL within 10 minutes in said patient.
28. The method of claim 3 , wherein said single actuation yields a naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient.
29. The method of claim 3 , wherein said single actuation yields a naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient.
30. A pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 μL:
about 4 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.
31. The pharmaceutical formulation as recited in claim 30 , wherein the naloxone hydrochloride is provided as naloxone hydrochloride dihydrate.
32. The pharmaceutical formulation as recited in claim 30 , 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.
33. The pharmaceutical formulation as recited in claim 31 , wherein the aqueous solution comprises:
about 4.4 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.
34. The pharmaceutical formulation of claim 30 , which yields, when intranasally administered to a patient, a naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient.
35. The pharmaceutical formulation of claim 30 , which yields, when intranasally administered to a patient, a naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient.
36. The pharmaceutical formulation of claim 30 , which yields, when intranasally administered to a patient, a naloxone plasma concentration of ≧3 ng/mL within 10 minutes in said patient.
37. The pharmaceutical formulation of claim 33 , which yields, when intranasally administered to a patient, a naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient.
38. The pharmaceutical formulation of claim 33 , which yields, when intranasally administered to a patient, a naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient.
39. The pharmaceutical formulation of claim 33 , which yields, when intranasally administered to a patient, a naloxone plasma concentration of ≧3 ng/mL within 10 minutes in said patient.
40. The pharmaceutical formulation of claim 30 , which yields, when intranasally administered to a patient, a naloxone T max of less than 30 minutes.
41. The pharmaceutical formulation of claim 30 , which yields, when intranasally administered to a patient, a naloxone T max of less than 25 minutes.
42. The pharmaceutical formulation of claim 30 , which yields, when intranasally administered to a patient, a naloxone T max of less than 20 minutes.
43. The pharmaceutical formulation of claim 33 , which yields, when intranasally administered to a patient, a naloxone T max of less than 30 minutes.
44. The pharmaceutical formulation of claim 33 , which yields, when intranasally administered to a patient, a naloxone T max of less than 25 minutes.
45. The pharmaceutical formulation of claim 33 , which yields, when intranasally administered to a patient, a naloxone T max of less than 20 minutes.