Opioid delivery system

• US 7,648,982 B2
• Filed: 08/27/2004
• Issued: 01/19/2010
• Est. Priority Date: 02/28/2003
• Status: Expired due to Fees

• Current Assignee: YM BioSciences Inc. (Gilead Sciences Inc.)
• Original Assignee: YM BioSciences Inc. (Gilead Sciences Inc.)
• Inventors: Pliura, Diana Helen, Shafer, Steven Louis, Hung, Orlando Ricardo
• Primary Examiner(s): Arnold; Ernst V
• Assistant Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US10/927,145
• Publication Number:
  US 20050084523A1
• Time in Patent Office: 1,971 Days
• Field of Search: 424/43, 424/45, 424/417, 424/450
• US Class Current: 514/225.5
• 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. A pain management method enabling a pain sufferer to self medicate by repeated dosing with an opioid formulation to achieve analgesia while avoiding toxicity, wherein the method relies solely on the actions of the pain sufferer to manage intake of said opioid during the medication process, said method comprising the steps of:

the pain sufferer 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, during the medication process, satisfactory analgesia is achieved or at the onset of a side effect;

wherein the formulation comprises an effective amount of fentanyl and liposomally encapsulated fentanyl;

the combination and a concentration of each opioid, and an effective rate of delivery of the particles 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 pain sufferer to terminate inhalation to avoid toxicity by said stopping of inhalation of said formulation by the pain sufferer when said onset of said side effect is felt by the pain sufferer, wherein the ratio of said fentanyl to said liposomally encapsulated fentanyl is selected such that a combined pharmacokinetic profile of the fentanyl and the liposomally encapsulated fentanyl has a combined effect curve providing a peak concentration at an effect site at between 10 and 30 minutes and a concentration at the effect site of a magnitude of at least 85% of said peak concentration for at least two hours.

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

3. The method of claim 1 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.

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

5 to 2;

1.

5. The method of claim 1 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.

6. The method of claim 1 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.

7. The method of claim 1 wherein the administration takes place over between 50 and 500 inhalations.

8. A pulmonary drug delivery device for use in the pain management method of claim 1, said device comprising:

a container containing an opioid formulation;

an outlet coupled to the container;

said opioid formulation comprising an effective amount of a combination of fentanyl and liposomally encapsulated fentanyl;

a nebulizer or aerosolizer coupled to the container for dispensing particles of said formulation through said outlet and into the lungs through actuation by conscious pain sufferer 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 pain sufferer to terminate inhalation to avoid toxicity by a stopping of inhalation of said formulation by the pain sufferer when said onset of said side effect is felt by the pain sufferer, wherein the ratio of said fentanyl to said liposomally encapsulated fentanyl is selected such that a combined pharmacokinetic profile of the fentanyl and the liposomally encapsulated fentanyl has a combined effect curve providing a peak concentration at an effect site at between 10 and 30 minutes and a concentration at the effect site of a magnitude of at least 85% of said peak concentration for at least two hours.

9. A pulmonary drug delivery device for use in the pain management method of claim 1, said device comprising:

a container containing an opioid formulation;

an outlet coupled to the container;

a nebulizer or aerosolizer coupled to the container for dispensing particles of said formulation through said outlet and into the lungs, said nebulizer or aerosolizer requiring conscious pain sufferer effort to be actuated;

wherein said opioid formulation has a combination of opioids, a concentration of opioids, and an effective rate of delivery of the particles 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 pain sufferer to terminate inhalation to avoid toxicity, wherein the opioid formulation consists of fentanyl and liposomally encapsulated fentanyl, and wherein the ratio of said fentanyl to said liposomally encapsulated fentanyl is selected such that a combined pharmacokinetic profile of the fentanyl and the liposomally encapsulated fentanyl has a combined effect curve providing a peak concentration at an effect site at between 10 and 30 minutes and a concentration at the effect site of a magnitude of at least 85% of said peak concentration for at least two hours.

10. The device of claim 8 wherein said particles have a mass median aerodynamic diameter of from about 1 to 5 microns.

11. The device of claim 8 wherein said means dispenses between 0.2% to 1% of the formulation per inhalation.

12. The device of claim 8 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.

13. The device of claim 9 wherein the ratio of concentration of free fentanyl to liposomally encapsulated fentanyl is from 1:

5 to 2;

1.

14. The device of claim 9 wherein the total opioid concentration is from 250 to 1500 mcg/ml.

15. The device of claim 9 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.

16. The device of claim 9 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.