Claims for Patent: 9,480,644

Summary for Patent: 9,480,644

Title:	Nasal drug products and methods of their use
Abstract:	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.
Inventor(s):	Crystal; Roger (Santa Monica, CA), Weiss; Michael Brenner (New York, NY)
Assignee:	Opiant Pharmaceuticals, Inc. (Santa Monica, CA)
Application Number:	14/942,344
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,480,644
Patent Claims:	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 .mu.L 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 .mu.L. 6. The device of claim 5, wherein about 100 .mu.L 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.sub.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 .mu.L 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 .mu.L 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 .mu.L. 26. The method of claim 25, wherein about 100 .mu.L 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.sub.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 .mu.L 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 .mu.L. 51. The method of claim 50, wherein about 100 .mu.L 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.sub.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.