Opioid delivery system

• US 20050084523A1
• Filed: 08/27/2004
• Published: 04/21/2005
• Est. Priority Date: 02/28/2003
• Status: Active Grant

• Current Assignee: YM BioSciences Inc. (Gilead Sciences Inc.)
• Original Assignee: Delex Therapeutics Inc. (Gilead Sciences Inc.)
• Inventors: Pliura, Diana Helen, Shafer, Steven Louis, Hung, Orlando Ricardo
• Granted Patent: US 7,648,982 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

An opioid formulation for pulmonary administration in the treatment or management of pain, a pulmonary drug delivery device containing, method of administering, kit containing, and uses of same. The formulation contains at least one rapid-onset opioid and preferably also contains a sustained-effect opioid to reduce the frequency of administration. The invention employs the side effects of the opioid formulation to permit patients to self-limit drug intake, thereby avoiding toxicity while achieving analgesia. A pharmacokinetic and pharmacodynamic model is employed to determine optimum drug formulations and optimum parameters for administration.

Claims

1. An opioid formulation for use in a method of providing analgesia to a patient while avoiding toxicity;

said method comprising continuously inhaling the formulation using a pulmonary drug delivery device to produce analgesia, and stopping inhalation when satisfactory analgesia is achieved or at the onset of a side effect;

said pulmonary drug delivery device being adapted to deposit particles of the formulation in the lungs at an effective rate;

said formulation comprising an effective amount of at least one rapid-onset opioid and at least one sustained-effect opioid, and a pharmaceutically acceptable carrier, the concentration and type of each opioid being selected so that, during inhalation, analgesia is achieved before the onset of said side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity.

2. The formulation of claim 1 wherein the concentration and type of each opioid is selected so that the maximum opioid plasma concentration at the onset of side effect is no less than 66% of the maximum opioid plasma concentration.

3. The formulation of claim 1 wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil.

4. The formulation of claim 1 wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays release of the drug at the lung surface, and a liposomally encapsulated opioid.

5. The formulation of claim 1 wherein the opioids in the formulation consist of free fentanyl and liposomally encapsulated fentanyl.

6. The opioid formulation of claim 1 wherein the total opioid concentration is from 250 to 1500 mcg/ml.

7. The formulation of claim 5 wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is about 2:

3.

8. The opioid formulation of claim 5 wherein the total opioid concentration is from 350 to 2250 mcg/ml, the free fentanyl concentration is from 100 to 400 mcg/ml, and the liposomally encapsulated fentanyl concentration is from 250 to 750 mcg/ml.

9. The formulation of claim 1 containing two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl.

10. The formulation of claim 9 wherein the opioids in the formulation consist of alfentanil and morphine.

11. The formulation of claim 10 containing alfentanil in a concentration of from 300 to 6700 mcg/ml and morphine in a concentration of from 650 to 13350 mcg/ml.

28. A pulmonary drug delivery device containing an opioid formulation for producing analgesia in a patient, said device comprising:

a container containing a formulation according to claim 1;

an outlet coupled to the container;

means coupled to the container for dispensing particles of said formulation through said outlet and into the lungs through actuation by conscious patient effort and at an effective rate whereby, during inhalation, analgesia is achieved before the onset of an opioid side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, and whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity.

30. The device of claim 28 further comprising delivery rate controlling means for limiting the rate at which the formulation is dispensed to below a selected threshold.

31. The device of claim 28 wherein said particles have a mass median aerodynamic diameter of from about 1 to 5 microns.

32. The device of claim 28 wherein said means dispenses between 0.2% to 1% of the formulation per inhalation.

33. The device of claim 28 wherein the concentration and type of each opioid is selected so that the maximum opioid plasma concentration at the onset of side effect is no less than 66% of the maximum opioid plasma concentration.

34. The device of claim 28 wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil.

35. The device of claim 28 further comprising an effective amount of at least one sustained-effect opioid to provide sustained relief, wherein the concentration and type of each opioid in the formulation is selected so that, during inhalation, analgesia is achieved before the onset of said side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity.

36. The device of claim 35 wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays release of the drug at the lung surface, and a liposomally encapsulated opioid.

37. The device of claim 36 wherein the opioids in the formulation consist of fentanyl and liposomally encapsulated fentanyl.

38. The device of claim 37 wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is from 1:

5 to 2;

1.

39. The device of claim 37 wherein the total opioid concentration is from 250 to 1500 mcg/ml.

40. The device of claim 37 wherein the total opioid concentration is from 250 to 1500 mcg/ml, the free fentanyl concentration is from 100 to 400 mcg/ml and the liposomally encapsulated fentanyl concentration is from 250 to 1500 mcg/ml.

41. The device of claim 37 wherein 4 to 50 mcg/min. of free fentanyl and 5 to 150 mcg/min of liposomally encapsulated fentanyl is deposited in the lungs during inhalation.

42. The device of claim 35 wherein the formulation comprises two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl.

43. The device of claim 35 wherein the opioids in the formulation consist of alfentanil and morphine.

44. The device of claim 43 wherein the formulation contains alfentanil in a concentration of from 300 to 6700 mcg/ml and morphine in a concentration of from 650 to 13350 mcg/ml.

45. The device of claim 43 wherein from 100 to 500 mcg/min of alfentanil and 100 to 2000 mcg/min of morphine are deposited in the lungs during inhalation.

12. A method of administering an opioid formulation to provide analgesia to a patient while avoiding toxicity, comprising the steps of:

continuously inhaling the formulation using a pulmonary drug delivery device adapted to deliver particles of the formulation into the lungs at an effective rate to produce analgesia; and

stopping inhalation when satisfactory analgesia is achieved or at the onset of a side effect;

wherein the formulation comprises an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable carrier;

the concentration and type of each opioid, and effective rate of delivery of the particles being selected so that, during inhalation, analgesia is achieved before the onset of said side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity.

13. The method of claim 12 wherein the formulation is dispensed by the pulmonary drug delivery device at a mass median aerodynamic diameter of from 1 to 5 microns.

14. The method of claim 12 wherein the concentration and type of each opioid is selected so that the maximum total opioid plasma concentration at the onset of side effect is no less than 66% of the maximum opioid plasma concentration.

15. The method of claim 12 wherein the at least one rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil.

16. The method of claim 12 further comprising an effective amount of at least one sustained-effect opioid to provide sustained relief, wherein the concentration and type of each opioid in the formulation is selected so that, during inhalation, analgesia is achieved before the onset of said side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity.

17. The method of claim 16 wherein the at least one sustained-effect opioid is chosen from morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a biocompatible carrier that delays release of the drug at the lung surface, and a liposomally encapsulated opioid.

18. The method of claim 17 wherein the opioids in the formulation consist of free fentanyl and liposomally encapsulated fentanyl.

19. The method of claim 18 wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is from 1:

5 to 2;

1.

20. The method of claim 16 wherein the total opioid concentration is from 250 to 1500 mcg/ml, the free fentanyl concentration is from 100 to 400 mcg/ml mcg/ml and the liposomally encapsulated fentanyl concentration is from 250 to 750 mcg/ml.

21. The method of claim 16 wherein from 4 to 50 mcg/min. of free fentanyl and 5 to 150 mcg/min of liposomally encapsulated fentanyl is deposited in the lungs during inhalation.

22. The method of claim 16 wherein the formulation comprises two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl.

23. The method of claim 22 wherein the opioids in the formulation consist of alfentanil and morphine.

24. The method of claim 23 wherein the formulation contains alfentanil in a concentration of from 300 to 6700 mcg/ml and the formulation contains morphine in a concentration of from 650 to 13350 mcg/ml.

25. The method of claim 23 wherein from 100 to 500 mcg/min of alfentanil is deposited in the lungs during inhalation and from 100 to 2000 mcg/min of morphine is deposited in the lungs during inhalation.

26. The method of claim 12 wherein the administration takes place over between 50 and 500 inhalations.

27. The use of a side effect of an opioid in preventing opioid toxicity.

29. A pulmonary drug delivery device containing an opioid formulation for producing analgesia in a patient, said device comprising:

a container containing a formulation comprising an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable carrier;

an outlet coupled to the container;

means coupled to the container for dispensing particles of said formulation through said outlet and into the lungs, said means requiring conscious patient effort to be actuated;

wherein the concentration and type of each opioid and effective rate of delivery of the particles are selected so that, during inhalation, analgesia is achieved before the onset of said side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity.

46. An opioid administration kit comprising:

a formulation comprising an effective amount of at least one rapid-onset opioid and a pharmaceutically acceptable carrier;

a pulmonary drug delivery device comprising a container, an outlet coupled to the container, means coupled to the container for dispensing particles of formulation contained therein through said outlet and into the lungs through actuation by conscious patient effort and at an effective rate whereby, during inhalation, analgesia is achieved before the onset of an opioid side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels, and whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity; and

instructions for using said device comprising the steps of filling the container with the formulation, continuously inhaling the formulation using said device, and stopping inhalation when satisfactory analgesia is achieved or at the onset of a side effect.

47. An opioid formulation for use in a method of providing analgesia to a patient, comprising:

150 to 250 mcg/ml of free fentanyl;

200 to 400 mcg/ml of liposomally encapsulated fentanyl; and

a pharmaceutically acceptable carrier.

48. An opioid formulation for use in a method of providing analgesia to a patient through a pulmonary route of administration, comprising:

two or more different opioids, excluding a formulation wherein the only two opioids are free fentanyl and liposomally encapsulated fentanyl;

a pharmaceutically acceptable carrier.