Opioid delivery system

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.

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. 
   
   
       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. 
   
   
       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.   
   
   
       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.   
   
   
       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 . 
   
   
       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.