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 pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 μL:
about 4 mg naloxone hydrochloride;
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.
2. The pharmaceutical formulation of claim 1 , wherein the aqueous solution has a volume of 100 μL.
3. The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient.
4. The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient.
5. The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a mean naloxone plasma concentration of ≧3 ng/mL within 10 minutes in said patient.
6. The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a naloxone T max of less than 30 minutes.
7. The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a naloxone T max of less than 25 minutes.
8. The pharmaceutical formulation of claim 1 , which yields, when intranasally administered to a patient, a naloxone T max of less than 20 minutes.
9. A method of treatment of opioid overdose or a symptom thereof, comprising:
nasally administering to a patient in need thereof the pharmaceutical formulation of claim 1 .
10. The method of claim 9 , 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.
11. The method of claim 9 , 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.
12. The method of claim 9 , 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.
13. The method of claim 9 , 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.
14. The method of claim 9 , wherein the administration yields a mean naloxone plasma concentration of ≧0.2 ng/mL within 2.5 minutes in said patient.
15. The method of claim 9 , wherein the administration yields a mean naloxone plasma concentration of ≧1 ng/mL within 5 minutes in said patient.
16. The method of claim 9 , wherein the administration yields a mean naloxone plasma concentration of ≧3 ng/mL within 10 minutes in said patient.
17. The method of claim 9 , wherein said patient is an opioid overdose patient or a suspected opioid overdose patient.
18. The method of claim 17 , 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.
19. The method of claim 17 , wherein the patient exhibits respiratory depression.
20. 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 comprises per 100 μL of aqueous solution:
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 preservative;
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 device as recited in claim 20 , wherein:
the isotonicity agent is NaCl;
the preservative is benzalkonium chloride;
the stabilizing agent is disodium edetate; and
the acid is hydrochloric acid.
22. The device of claim 20 , wherein the aqueous solution comprises per 100 μL:
about 4 mg naloxone hydrochloride;
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.
23. The device of claim 20 , wherein said device is actuatable with one hand.
24. The device of claim 20 , wherein the volume of said reservoir is not more than about 140 μL.
25. The device of claim 20 , wherein about 100 μL of said aqueous solution in said reservoir is delivered to said patient in one actuation.
26. The device of claim 20 , wherein the pharmaceutical composition which is an aqueous solution comprises about 4 mg naloxone hydrochloride.
27. The device of claim 20 , wherein the device is configured such that the 90% confidence interval for dose delivered per actuation is ± about 2%.
28. The device of claim 20 , wherein the device is configured such that the 95% confidence interval for dose delivered per actuation is ± about 2.5%.
29. The device of claim 20 , wherein the device is configured such that the delivery time is less than about 25 seconds.
30. The device of claim 20 , wherein the device is configured such that the delivery time is less than about 20 seconds.