KR20070011344A - Opioid delivery system - Google Patents

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. ® KIPO & WIPO 2007

Description

Opioid delivery system

The present invention relates to pharmaceutical preparations and methods of administering the same, and more particularly to opioid analgesics and methods of administration thereof.

Opioids are one of the oldest drugs in existence and remain the center of pain treatment. Opium, the origin of opioids, comes from poppy flowers. "Opiate" is a natural derivative of opiate and includes morphine, methadone and heroin. "Opioids" are a broader class of drugs, including opiates, anesthetic agents, and synthetic drugs having the same pharmacological effect as opiates. Commonly used synthetic opioids include meperidine, fentanil, fentanil, alfentanil, sufentanil and remifentannil.

Opioids are known to work by binding to mu receptors in the spine, brain and peripheral tissues. Binding at the non-receptor can be viewed as a side effect or therapeutic effect in some situations, including a wide range of pharmacological effects, such as therapeutic effects such as analgesic, sedation and decreased bowel motility. Effects such as nausea, vomiting, urinary retention, pruritis, ventilatory depression, intoxication, and severe ventilatory depression, loss of consciousness and death.

 Opioids are distinguished from one another in a variety of ways, including in terms of their route of delivery, physicochemical composition, drug absorption, pharmacokinetics and pharmacodynamics. Noninvasive opioid delivery routes include oral, rectal, transdermal, transmucosal, and inhalation. Invasive opioid delivery routes include intravenous, intramuscular, epidural, spinal cord and intraarticular injection. Intravenously, some opioids enter the brain and spinal cord rapidly to initiate drug action (for example, alfentanil and remifentanil), while other opioids are slowly absorbed into the site of action, leading to very slow drug effects. Sometimes (eg morphine). Similarly, for some opioids, due to rapid metabolism, the drug effect time is very short (e.g. remifentanil) and for other opioids, very slow metabolic and long effects (e.g. methadone ). In pharmacodynamic terms, the efficacy of opioids is nearly five digits, ranging from very potent opioids such as carfentanil and etorphine (both used for elephant anesthesia) to relatively low potency drugs such as methadone and morphine. Includes a range of sizes. Opioids with equivalent potency (measured as “therapeutic equivalence ratio”) are well known in the literature and are often used when changing the treatment regimen of a patient from one type of opioid to another.

In spite of these differences, all opioids have a high degree of analgesia as well as the possibility of causing all of the high toxicity caused by hypoxia, which can be fatal. Because of the risk of hypoxia, doctors are reluctant to use the right amount of opioid for the treatment of acute and chronic pain. As a result, hundreds of thousands of patients who are able to better control their pain receive insufficient amounts of opioids. On the other hand, even with a comprehensible and careful approach taken by medical personnel for the treatment of pain, many patients die each year due to opioid-induced hypoventilation.

Pain is very variable and self-subjective. Patients respond differently to opioids. As a result, different patients require different amounts of analgesics to treat pain. As such, there is a need to allow patients to vary the amount of analgesic they will receive.

As an attempt to better control the amount of opioid to be administered to a patient, "patient controlled analgesia" ("PCA") (Ballantyne JC, et al. Postoperative patient-controlled analgesia: Meta-analyses of initial randomized control trials.J. Clin Anesth 1993: 5: 182-193. To use the PCA system, the patient must be awake and activate a delivery mechanism that accepts more opioids before the drug is given. If the patient is overdosed with opioids, the patient will lose consciousness and no additional medication is needed. In this way, the PCA system takes advantage of the sedative effects that are side effects of opioids to limit the amount of opioid supplied. One problem with the PCA system is that the patient is infused quickly when needed (typically, the time it takes to administer the drug is less than one minute) and the most frequently used drug for PCA is morphine, which Due to the slow delivery of the drug to the site of action, a time lag occurs from the patient's request for a drug until the analgesic effect of the drug appears. Because of this time delay, patients often ask for a second (or third) drug administration while the opioid effect level following the first injection continues to rise. The PCA system includes a "lockout" period (typically 5 minutes), which helps to prevent the patient from administering additional opioids while the opioid drug effect is still rising. The lockout period is typically regulated, regulated, or programmed by the provider, and in many cases the patient dies due to a user's fault or carelessness during programming of the lockout period. Patients also often feel despair due to lockout, which reduces the patient's dose control role. Other disadvantages of PCA include invasive parenteral (intravenous) administration, expensive infusion pumps, and the like, which limit the use of PCA to such patients.

A second attempt to more preferably control the amount of opioid administered to a patient is the process of self-administering nitrous oxide during delivery. Nitrous oxide mask is worn on the patient's own face during labor contraction and removed from the face when moderate analgesia is reached. However, this mechanism moderates the analgesic effect, and overdose of nitrous oxide using such an administration system is not used as a safe mechanism because it is not a significant consideration. Moreover, nitrous oxide is a gas that requires heavy steel tanks and complex dose delivery systems for storage. Therefore, nitrous oxide is limited in principle to use in general hospitals and not for emergency patients. Another potential problem with nitrous oxide relates to low efficacy, which necessitates the administration of high concentrations (over 50%) of nitrous oxide in oxygen, which is likely to be a hypoxic mixture.

The present invention seeks to exploit two biological responses of opioids: sedation and hypoventilation to limit the total dose of opioid that a patient receives. In this manner, the present invention seeks to increase opioid drug delivery safety beyond that typically achieved with PCA or other existing opioid administration methods, thereby limiting the patient's exposure to dangerous high levels of opioid drug action. Only one side effect is used for this purpose. The present invention also improves the use of sedation by eliminating the need for the "lockout" period typically required for PCA systems and by eliminating the need for this and the user mistakes that can occur.

Accordingly, a first aspect of the present invention provides opioid formulations for use in a method of providing analgesia to a patient while avoiding toxicity: the method continuously uses the lung disease drug delivery device to produce analgesia. Inhaling, and stopping inhalation when satisfactory analgesia is reached or when side effects begin; The lung disease drug delivery device is suitably configured to deposit agent particles at an effective rate into the lungs; The formulation comprises an effective amount of one or more rapid-initiating opioids, and one or more sustained-effect opioids, and a pharmaceutically acceptable carrier, the concentration and form of each opioid, during inhalation, Analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs prior to the onset of the toxicity, and the maximum opioid plasma concentration is selected so as not to reach the toxic level, thereby initiating the onset of the adverse event by the patient. And can be used to avoid toxicity.

In one embodiment, the concentration and form of each opioid in the formulation is selected such that the maximum total opioid plasma concentration at the onset of side effects is at least 66%, or at least 80% of the maximum total opioid plasma concentration.

In another embodiment, the one or more fast-initiating opioids of the formulation are fentanyl, alfentanil, sufentannil and remifentannil.

In another embodiment, the one or more sustained-effect opioids are morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, drug release from the lung surface Opioids encapsulated in biocompatible carriers, or liposomes encapsulated opioids. The liposome encapsulated opioid may be liposome encapsulated fentanyl.

In one embodiment, the opioid formulation has a total opioid concentration of 250-1500 mcg / ml.

In one embodiment, the opioid in the formulation consists of free fentanyl and liposome encapsulated fentanyl.

In one embodiment, the concentration ratio of free fentanyl to liposome encapsulated fentanyl is from 1: 5 to 2: 1.

In another embodiment, the concentration ratio of free fentanyl to liposome encapsulated fentanyl is about 2: 3.

In another embodiment, the opioid formulation contains free fentanyl at a concentration of 100-750 mcg / ml.

In another embodiment, the opioid formulation contains liposome encapsulated fentanyl at a concentration of 250-1500 mcg / ml.

In another embodiment, the opioid formulation has a total opioid concentration of about 500 mcg / ml, a free fentanyl concentration of about 200 mcg / ml and a liposome encapsulated fentanyl concentration of about 300 mcg / ml.

In another embodiment, the formulation contains two or more different opioids (except formulations in which only two opioids are free fentanyl and liposome encapsulated fentanyl).

In another embodiment, the opioid in the formulation consists of alfentanil and morphine.

In another embodiment, the formulation contains alfentanil at a concentration of 300 to 6700 mcg / ml.

In another embodiment, the formulation contains morphine at a concentration of 650-13350 mcg / ml.

Another aspect of the invention is a method of administering an opioid to provide analgesia to a patient while avoiding toxicity, the method comprising:

Continuously inhaling the formulation with a pulmonary disease drug delivery device adapted to deliver the formulation aerosol particles to the lung at an effective rate to produce analgesia; And

Stopping inhalation when satisfactory analgesia is reached or when side effects are initiated;

The formulation comprises an effective amount of a quick-initiating opioid of one or more and a pharmaceutically acceptable carrier; The concentration and form of each opioid, and the effective particle delivery rate, during inhalation, analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs before the onset of toxicity, and also the maximum opioid plasma concentration reaches the toxicity level. By selecting not to, the onset of the adverse event can be used by the patient to end the inhalation to avoid toxicity.

In one embodiment, the formulation is administered by a mass disease aerodynamic diameter of 1-5 microns by a lung disease drug delivery device.

In another embodiment, the formulation is administered at a mass mean aerodynamic diameter of 1-3 microns by a lung disease drug delivery device.

In another embodiment, the formulation is administered by a lung disease drug delivery device at a mass mean aerodynamic diameter of 1.5 to 2 microns.

Another embodiment of the invention is a method wherein the concentration and form of each opioid is selected such that the maximum total opioid plasma concentration at the onset of adverse reactions is at least 66%, or at least 80% of the maximum total opioid plasma.

Another embodiment of the invention is a method wherein the one or more fast-initiating opioids are selected from fentanyl, alfentanyl, sufentanil and remifentanil.

Another embodiment of the invention further comprises an effective amount of one or more sustained-effective opioids to provide sustained relief, wherein the concentration and form of each opioid is reached during inhalation, before analgesic is initiated, The onset of the adverse event occurs before the onset of the toxicity and is also selected such that the maximum total opioid plasma concentration does not reach the toxic level, so that the onset of the adverse event can be used by the patient to end inhalation and avoid toxicity.

Other embodiments include opioids in which one or more sustained-effect opioids are encapsulated in morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, biocompatible carriers that delay drug release at the lung surface, And liposome encapsulated opioids.

Another embodiment is a method wherein the liposome encapsulated opioid is liposome encapsulated fentanyl.

Another embodiment is a method wherein the one or more sustained-effect opioids are selected from morphine and liposome encapsulated fentanyl.

Another embodiment is a method wherein the opioid in the formulation consists of free fentanyl and liposome encapsulated fentanyl.

Another embodiment is a method wherein the concentration ratio of free fentanyl to liposome encapsulated fentanyl is from 1: 5 to 2: 1.

Another embodiment is a method wherein the ratio of free fentanyl to liposome encapsulated fentanyl is 2: 3.

Another embodiment is a method wherein the total opioid concentration is 250-1500 mcg / ml.

Another embodiment is a method wherein the formulation comprises free fentanyl at a concentration of 100 to 750 mcg / ml.

Another embodiment is a method wherein the formulation comprises liposome encapsulated fentanyl at a concentration of 250-1500 mcg / ml.

Another embodiment is a method wherein the total opioid concentration is about 500 mcg / ml, the free fentanyl concentration is about 200 mcg / ml and the liposome encapsulated fentanyl concentration is about 300 mcg / ml.

Another embodiment is a method wherein 4-50 mcg / min of free fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method wherein 10-20 mcg / min of free fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method in which about 15 mcg / min of free fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method wherein 5 to 150 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method wherein 10 to 90 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method wherein 15 to 60 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method wherein 20 to 45 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a method wherein 5 to 200 mcg / min total opioid is deposited in the lungs during inhalation.

Another embodiment is a method wherein 10-40 mcg / min total opioid is deposited in the lungs during inhalation.

Another embodiment is a method in which 30 to 35 mcg / min total opioid is deposited in the lungs during inhalation.

Another embodiment is a method wherein the formulation comprises two or more opioids (except formulations where only two opioids are free fentanyl and liposome encapsulated fentanyl).

Another embodiment is the method wherein administration is made during inhalation of 50-500.

Another embodiment is a method wherein the opioid in the formulation consists of alfentanil and morphine.

Another embodiment is a method wherein the formulation contains alfentanil at a concentration of 300 to 6700 mcg / ml.

Another embodiment is a method in which 100 to 500 mcg / minute alfentanil is deposited in the lungs during inhalation.

Another embodiment is a method in which about 250 mcg / minute alfentanil is deposited in the lungs during inhalation.

Another embodiment is a method containing morphine at a concentration of 650 to 13350 mcg / ml.

Another embodiment is a method in which 100 to 2000 mcg / minute morphine is deposited in the lungs during inhalation.

Another embodiment is a method in which 200-1000 mcg / minute morphine is deposited in the lungs during inhalation.

Another embodiment is a method in which about 500 mcg / minute of morphine is deposited in the lungs during inhalation.

Another embodiment is the use of opioid side effects to prevent opioid toxicity.

Another embodiment of the invention is a lung disease drug delivery device containing an opioid agent for providing analgesia to a patient, the device comprising:

A container containing such an agent;

An outlet coupled to the vessel;

Means coupled to the container for dispensing the agent particles through the outlet to the lungs at an effective rate through operation by conscious patient effort, such that during inhalation, analgesia is initiated by the onset of opioid side effects. Reached before, the onset of the adverse event occurs before the onset of toxicity, and also the maximum opioid plasma concentration does not reach the toxic level so that the onset of the adverse effect can be used by the patient to end inhalation and avoid toxicity. .

Another aspect of the invention is a pulmonary disease drug delivery device containing an opioid formulation to provide analgesia to a patient, the device comprising:

A container containing a formulation comprising an effective amount of one or more quick-starting opioids and a pharmaceutically acceptable carrier;

An outlet coupled to the vessel;

Means coupled to the container for administering the agent particles to the lungs through the outlet, the means requiring conscious patient effort to operate;

The concentration and form of each opioid and the effective rate of particle delivery are such that during inhalation, analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs before the onset of toxicity, and also the maximum total opioid plasma concentration is at toxic levels. By choosing not to reach, the onset of the adverse event can be used by the patient to terminate inhalation to avoid toxicity.

 Another embodiment is an apparatus further comprising delivery rate control means for controlling the rate at which the formulation is administered to be below a predetermined threshold.

Another embodiment is a device further comprising a fenestration in which the outlet must be closed by the patient's lips to administer the formulation.

Another embodiment is a device in which the means of administration is actuated by breathing.

Another embodiment is a device wherein the mass mean aerodynamic diameter of the particles is 1 to 5 microns.

Another embodiment is a device in which the mass mean aerodynamic diameter of the particles is 1-3 microns.

Another embodiment is a device wherein the mass mean aerodynamic diameter of the particles is 1.5 to 2 microns.

Another embodiment is a device in which the concentration and form of each opioid is selected such that the maximum total opioid plasma concentration at the onset of side effects is at least 66% of the maximum total opioid plasma concentration.

Another embodiment is a device in which the concentration and form of each opioid is selected such that the maximum total opioid plasma concentration at the onset of side effects is at least 80% of the maximum total opioid plasma concentration.

Another embodiment is a device wherein the one or more fast-starting opioids is selected from fentanyl, alfentanil, sufentanil, and remifentanil.

Another embodiment is a device further comprising an effective amount of one or more sustained-effective opioids to provide sustained relief, wherein the concentration and form of each opioid in the formulation is reached during inhalation, before analgesia is initiated, The onset occurs before the onset of toxicity, and is also chosen so that the maximum opioid plasma concentration does not reach the toxic level, such that the onset of the side effect can be used by the patient to end the inhalation to avoid toxicity.

Other embodiments include opioids in which one or more sustained-effect opioids are encapsulated in morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, biocompatible carriers that delay drug release at the lung surface, And liposome encapsulated opioids.

Another embodiment is a device wherein the liposome encapsulated opioid is liposome encapsulated fentanyl.

Another embodiment is a device wherein the one or more sustained-effect opioids are selected from morphine and liposome encapsulated fentanyl.

Another embodiment is a device wherein the opioid in the formulation consists of free fentanyl and liposome encapsulated fentanyl.

Another embodiment is a device wherein the concentration ratio of free fentanyl to liposome encapsulated fentanyl is from 1: 5 to 2: 1.

Another embodiment is a device wherein the concentration ratio of free fentanyl to liposome encapsulated fentanyl is about 2: 3.

Another embodiment is a device having a total opioid concentration of 250-1500 mcg / ml.

Another embodiment is a device wherein the formulation comprises free fentanyl at a concentration of 100 to 750 mcg / ml.

Another embodiment is a device wherein the formulation comprises liposome encapsulated fentanyl at a concentration of 250-1500 mcg / ml.

Another embodiment is a device wherein the total opioid concentration is about 500 mcg / ml, the free fentanyl concentration is about 200 mcg / ml and the liposome encapsulated fentanyl concentration is about 300 mcg / ml.

Another embodiment is a device in which 4-50 mcg / min of free fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device wherein 10-20 mcg / min of free fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device in which about 15 mcg / min of free fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device wherein 5 to 150 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device in which 10 to 90 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device wherein 15 to 60 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device wherein 20 to 45 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation.

Another embodiment is a device in which 5 to 200 mcg / min total opioid is deposited in the lungs during inhalation.

Another embodiment is a device in which a total opioid of 10-40 mcg / min is deposited in the lungs during inhalation.

Another embodiment is a device in which a total opioid of 30 to 35 mcg / minute is deposited in the lungs during inhalation.

Another embodiment is a device wherein the formulation comprises two or more opioids (except formulations in which only two opioids are free fentanyl and liposome encapsulated fentanyl).

Another embodiment is a device wherein the opioid in the formulation consists of alfentanil and morphine.

Another embodiment is a device wherein the formulation contains alfentanil at a concentration of 300 to 6700 mcg / ml.

Another embodiment is a device in which 100-500 mcg / min of alfentanil is deposited in the lungs during inhalation.

Another embodiment is a device in which about 250 mcg / min of alfentanil is deposited in the lungs during inhalation.

Another embodiment is a device containing morphine at a concentration of 650 to 13350 mcg / ml.

Another embodiment is a device in which 100 to 2000 mcg / minute morphine is deposited in the lungs during inhalation.

Another embodiment is a device in which 200-1000 mcg / minute morphine is deposited in the lungs during inhalation.

Another embodiment is a device in which about 500 mcg / minute of morphine is deposited in the lungs during inhalation.

Another embodiment is a device wherein the means administers 0.2% to 1% of the agent per inhalation.

Another aspect of the invention is an opioid dosing kit, which comprises;

Lung disease drug delivery device as described above; And

Instructions for using the device, including continuously inhaling the formulation with the device and ending the inhalation when satisfactory analgesia is reached or at the onset of adverse reactions.

Another aspect of the invention is an opioid dosing kit, which:

Preparations comprising one or more quick-initiating opioids and a pharmaceutically acceptable carrier;

A pulmonary disease drug delivery device comprising a container, an outlet coupled to the container, means coupled to the container for administering the agent particles contained therein to the lungs through the outlet at an effective rate through conscious patient effort, Thus, during inhalation, analgesia is reached before the onset of the adverse event, and the onset of the adverse event occurs before the onset of toxicity such that the maximum total opioid plasma concentration does not reach the toxic level, thereby initiating the onset of the adverse event. A lung disease drug delivery device that can be used to terminate inhalation by a patient to avoid toxicity; And

Instructions for using the device including filling the container with a formulation, continuously inhaling the formulation using the device, and ending the inhalation when satisfactory analgesia is reached or at the onset of adverse reactions It includes.

Another embodiment is an opioid dosing kit wherein the formulation comprises one or more sustained-effect opioids.

Another aspect of the invention is an opioid formulation for use in a method of providing analgesia to a patient, which is:

Free fentanyl at 150-250 mcg / ml;

Liposome encapsulated fentanyl at 200-400 mcg / ml; And

Pharmaceutically acceptable carriers.

Another aspect of the invention is an opioid formulation for use in a method of providing analgesia to a patient via administration of a pulumonary route, which

Two or more different opioids (except for agents wherein the two opioids are fentanyl and liposome encapsulated fentanyl); And

Pharmaceutically acceptable carriers.

According to another aspect of the present invention, there is provided the use of an existing formulation to provide analgesia to a patient and to prepare a medicament therefor.

 Useful drug formulations and parameters for administration according to the present invention can be determined by those skilled in the art based on known pharmaceutical data and also through pharmacokinetic and pharmacodynamic modeling described below. This modeling is intended to demonstrate that the analgesic effect is reached before the onset of side effects, and that the side effects occur prior to toxicity, and that the total opioid plasma concentration does not continue to rise to toxic levels if the patient stops inhaling the formulation.

Hereinafter, the present invention will be described in detail.

The terms used herein have the following meanings:

"Analgesic effect" or "analgesia" means relief of pain due to drug action.

A "drug delivery profile" is determined through pharmacokinetics of the amount and rate of drug administered to a patient and the inhaled dose to concentration at the lung, plasma and drug site of effect, over time at the site of drug effect. Means the concentration of the drug.

"Hypoxia" is defined as the toxic effect of opioid administration, where the blood O2 concentration is reduced below 90% saturation.

"Ventilatory depression" refers to a decrease in the velocity of air entering the lungs, tidal volume and / or flow rate. Ventilatory depression may be manifested by dizziness, short breathing, or slowing down the breathing rate. "Opioid induced hypoventilation" refers to hypoventilation due to the action of opioids at the site of drug effect.

"Sedation" refers to a decrease in attention, awareness, concentration and consciousness due to opioids, such as loss of strength (muscle fatigue), lack of spontaneous activity, lethargy (coma), drowsiness and sleep. appear. "Opioid induced sedation" refers to the sedation caused by the action of opioids at the site of drug effect.

"Rapid onset", as used in the description of a drug formulation, refers to an agent that has an analgesic effect that rapidly follows the increase in plasma opioid concentration. "Rapid onset opioid" is an opioid having an analgesic effect within 5 minutes of administration.

"Sustained effect" refers to an agent having an analgesic effect that lasts for several hours. A "sustainable opioid" is an opioid having an analgesic effect that is maintained for at least 2 hours.

"Side effect" is the effect of an opioid other than analgesic or toxic. For example, severe ventilation dysfunction is an example of opioid toxicity, and mild ventilation dysfunction and sedation are thought to be opioid side effects that are not signs of opioid toxicity.

A "site of effect" is a real or imaginary site of drug action in a patient's body. An "effect site" may be an internal organ such as the brain, liver or kidney, or it may be a theoretical unknown location based on correlation and pharmacokinetic modeling. For example, some of the opioids are known to provide analgesic action in the substantia gelatinosa of the spinal cord and are therefore sites that exhibit opioid analgesic effects. The concentration of opioid at the site of effect can be determined by direct measurement or by pharmacokinetic and pharmacodynamic modeling.

"Effective amount" refers to the amount of drug required to achieve an analgesic effect.

"Mass medium aerodynamic diameter" refers to the aerodynamic diameter of an aerosol in such a way that half of the cumulative mass of all particles is contained in particles with smaller (or larger) diameters, wherein Aerodynamic diameter is defined as the diameter of one sphere of unit-density having the same particle settling velocity as the particles to be measured.

"Respiration rate" is the number of breaths per unit time.

"Titration to effect" refers to discontinuation after administration of an opioid until the patient detects a satisfactory analgesic effect.

"Titration up to side effects" refers to discontinuation after administration of the opioid until an adverse reaction is detected. Discontinuation can be spontaneous (e.g., by instructing the patient to stop opioid administration when he begins to feel drowsiness, dizziness, or shortness of breath), or involuntary (e.g., an opioid due to poor ventilation or sedation When the dose can no longer be effectively breathed).

Terms such as "toxic", "toxic", "toxic effect" and "opioid toxicity" refer to the effects of opioids that pose a risk of death to a patient. For example, opioids cause small amounts of ventilation that usually present little risk to the patient. This is not an example of opioid toxicity. However, severe ventilation dysfunction leads to a decrease in blood oxygen levels, loss of consciousness and death. Thus, severe ventilation dysfunction is an example of opioid toxicity, whereas mild ventilation dysfunction is not judged to be an indication of opioid toxicity.

The present invention can be used for opioid self-administration of a patient. The present invention utilizes the side effects of opioids to self-regulate the amount of opioids provided to a patient, whereby it is possible to appropriately determine the dosage required to achieve analgesia requirements of the patient while avoiding toxicity and death.

The present invention begins with the patient's perception of pain. There are many therapies for treating mild to moderate pain, but opioids are important for treating moderate to severe pain. In response to moderate to severe pain, the patient or patient's care provider opens a vial with an opioid pre-filled in an emulsion or, alternatively, an emulsion. The liquid is added to the nebulizer.

Then hold the sprayer in your mouth and hold it by hand. The nebulizer does not attach to the face with a strap, as it interferes with the action of the self-limiting mechanism.

At each breath, the nebulizer releases a small amount of liquid opioid in the form of an aerosol. Aerosols pass through the patient's mouth into the bronchus and lungs, where aerosolized opioids are deposited.

Nebulizers are also referred to herein as inhalers or aerosol lung disease drug delivery devices. Inhalers may refer to nebulizers or nebulizers in combination with compressed air or oxygen sources, or other aerosol-generating devices for drug administration through the lungs. Aerosol Pulmonary Disease Drug delivery device refers to a device capable of aerosolizing a substance to be delivered to the lungs. Various nebulizer technologies are known and put into practice.

The initiation rate of the opioid drug effect is known to depend on the rate at which the opioid enters the lungs, the rate of absorption into the circulatory system, and the rate at which the opioid crosses the blood brain barrier. Some opioids, such as alfentanil and remifentanil, quickly cross the blood brain barrier and very quickly initiate drug effects. Other opioids, such as morphine and morphine-6-glucuronide, pass very slowly through the blood brain barrier and start slowly, but produce a lasting effect.

As opioids cross the blood brain barrier, opioids begin to exert effects on the site of drug action. In some cases, the patient's perceived effect is different, but in general, when the concentration of opioid is increased, the perceived effects are in order of analgesic effects, side effects, and toxic effects.

Ventilatory depression is modulated by the reaction of opioids (decreases ventilation) and carbon dioxide (increases ventilation). This occurs in a feedback loop as follows: Initially, the opioid will degrade ventilation. Since the patient does not release much carbon dioxide, the level of carbon dioxide in the patient's blood will increase. As carbon dioxide increases, it stimulates ventilation and partially offsets opioid-induced ventilation deterioration. Opioid-induced ventilation deterioration should be done fast enough to occur when a patient inhales opioids, thus limiting the amount of opioid inhaled. However, it should not be done so fast that the patient is at risk of toxic effects before the carbon dioxide rises and has the opportunity to offset the opioid-induced ventilatory depression.

The amount of opioid inhaled per minute by the patient is proportional to the ventilation during that time. As ventilation decreases, the rate of delivery of opioids to the lungs decreases proportionally. As such, the rate of delivery is slowed by poor ventilation and the patient's ability to self-administer the toxic dose of opioid is reduced. Slowed opioid uptake due to poor ventilation results in the opportunity to completely stop drug delivery through the onset of sedation.

As opioids exert an analgesic effect, some of the patients will soothe with pain shifting and some with the side effects of opioids. As the sedation progresses in the patient, it becomes difficult to breathe through the device to hold the device in the mouth, remain sealed to the lips, and to administer additional opioids. Instead, the patient begins to breathe through the nose or mouth but around the mouthpiece of the nebulizer. If the sedation increases, the arm will sag itself and the device will fall from the mouth. If you deliberately make the device heavy or attach a weight to the device, the arm will easily sag even if the sedation level is low. The weight of the device can be adjusted from patient to patient, depending on the individual strength of the patient for pre-sedation.

Because opioid side effects usually occur at low opioid concentrations (as compared to opioid toxic effects), lungs are safer and at a rate that is slow enough to allow the patient's self-limiting opioid administration to allow a time interval between onset of side effects and onset of toxic effects. Via administration of the opioid (or opioid combination) via The rate should also be slow enough (relative to the opioid initiation rate) to allow side effects to be initiated while the dose is administered.

In a clinical study involving the present invention, a fentanyl formulation consisting of rapidly acting fentanyl and sustained acting liposome encapsulated fentanyl was inhaled in a healthy subject for 2-20 minutes. In this study, several subjects attempted to self-limit the external help needed to accommodate the dose and overall dose. Some of the subjects self-limited the dose due to opioid-induced hypoventilation, and a decrease in the rate of ventilation reduced the amount of drug inhaled. Other subjects self-limited because of their sedation and because they were not capable of immobilizing the inhalation device in the mouth to sustain fentanyl inhalation. Some of the subjects showed all side effects. Experiments have shown that patients are actually (1) inhaled for a prolonged period of time (e.g., 2 to 20 minutes), and (2) opioid-induced hypoventilation during drug delivery (and before toxic doses are administered). Occurs and / or (3) when sedation occurs while the drug is being supplied (and before toxic doses are administered), self-limiting fentanyl administration via the pulmonary route before toxic levels of fentanyl is administered It was confirmed that. It was found that these variables could be controlled by setting the rate at which opioids are fed to the patient.

Preferably, the opioid formulation is administered for 4-20 minutes. The total amount of opioid administered for 4 to 20 minutes will depend on several variables such as the type of opioid and opioid combination delivered and the total aerodynamic diameter (MMED) of the particles to be inhaled. During this dosing period, the rate of effect initiation is affected by the rate of administration, giving the patient the ability to involuntarily self-limit dosage through the onset of sedation and hypoventilation. For alfentanil / morphine combination drugs, 100-500 mcg / min of alfentanil and 200-1000 mcg / min of morphine were found to be optimal (when measured as a drug delivered to the patient's lungs (“systemically available drugs”) )).

For free and liposome encapsulated fentanyl formulations, it has been found that the level of systematically available drug is optimal when free fentanyl of 10-25 mcg / min and liposome encapsulated fentanyl of 10-50 mcg / min.

For other opioid formulations, systemically available drugs at therapeutically equivalent rates are expected to have similar advantages.

To prevent the peak of an opioid effect that has greater efficacy than the concentration at which the patient stops receiving a drug in a multi-opioid formulation containing one or more quick-initiating opioids and one or more sustained effective opioids, It is anticipated that the ratio of effective opioids to rapid-onset opioids should be less than 1: 1 in terms of therapeutic equivalent efficacy.

Another variable that will affect the rate of opioid dosing is the patient's breathing rate. A breathing rate of 10-15 breaths per minute (ie, a "normal" breathing rate) has been found to be desirable.

Opioid reactions are highly individual. This, in part, reflects the varying levels of painful stimulation. In severe pain, extremely high doses of opioids can be administered without serious toxicity. Patients chronically administering opioids need higher doses to produce both the desired therapeutic effect and opioid toxicity. It also reflects the progress of resistance to opioids. Physicians have sought to find an improved means of administering opioids because of the wide range of dosages needed to properly tailor opioids to individualized patient needs.

In the present invention, a patient in need of a large dose of opioid to provide analgesia may choose to administer a higher dose of drug (to be inhaled for a longer time), or a higher concentration for a time expected to be 4-25 minutes. Inhalation medications may be provided. In any case, opioid-induced hypoventilation and sedation will still be attenuated, and in some cases, drug administration will be terminated before inhalation of toxic doses. Preferably, the patient will inhale the drug for a long time. Conversely, patients requiring only a small dose will experience desirable pain relief after a shorter period of inhalation. The patient may choose not to inhale additional medication. Patients who continue to administer opioids wisely, despite obtaining adequate pain relief, will experience ventilatory depression and sedation, and therefore, spontaneously (in accordance with the instructions given to the patient) prior to inhalation of toxic doses of opioids or Involuntarily (because of side effects) will reduce drug administration and eventually end. The patient thus has a self-titration capacity for analgesic effects without a lockout period and with a lower risk of toxicity.

In the inhalation device, the selection of opioid and opioid concentrations (as described above or elsewhere) depends on the time course of opioid absorption from the lung to the plasma and the time course of opioid delivery from the plasma to the site of drug effect (eg brain or spinal cord). Should be considered

Some opioids are involved in the rapid absorption of lungs into the systemic circulation. For example, the absorption of free fentanyl from the lungs into the plasma is almost instantaneous. The same is true for remifentanil, alfentanil and sufentanil. The absorption of free fentanyl released from liposome encapsulated fentanyl from lung to plasma is much slower.

Some opioids are involved in the rapid absorption from plasma into the site of drug effect. For example, peak alfentanil and remifentanil concentrations at the site of drug effect occur within 2 minutes after intravenous injection. Another opioid is related to the very slow rate of delivery from plasma to the site of drug effect. For example, the peak drug effect by intravenous doses of morphine may be delayed by 10-15 minutes after injection.

In order to operate a self-limiting opioid delivery device, one of the opioids must be delivered quickly from the lungs to the plasma and from the plasma to the opioid drug effect site. Fentanyl, alfentanil, sufentanil and remifentanil all have this property (fast onset). Meperidine and methadone may also have this effect but are not currently known. While one opioid can obtain the parameters required by the present invention, when quick-starting opioids are combined with opioids that operate at low speed but have a sustained effect, patients usually experience analgesic effects over the longer term when using these combinations. It has been found that more desirable results can be obtained as they are felt.

If it is desired to maintain an opioid analgesic effect, it may be necessary to combine an opioid with a slow but sustained effect and a quick-initiating opioid. Examples of such agents include (1) preparations of fentanyl and liposome encapsulated fentanyl, (2) remifentanil, alfentanil, sufentanil, or a combination of fentanyl and morphine, and (3) remifentanil, alfentanil, sufentanil or Agents comprising a combination of fentanyl and methadone. Careful attention should be given to avoiding the second "peak" of drug action, which is higher than the peak attributable to the fast-initiating opioid at the maximum effect of a sustained effective opioid, which may allow the patient to detect side effects during the course of drug administration.

When combining fast-initiating opioids with opioids with slow initiation and sustaining effects, the self-limiting effect of fast-initiating opioids by regulating the concentrations of both opioids serves to limit the patient's exposure to slow-starting opioids. do. Quick-start opioids serve as a kind of early warning system or trigger side effects within a suitable timeframe.

It was found that the side effects were experienced before reaching toxicity. More specifically, subjects who experienced side effects immediately after completion or at the end of dosing were not allowed to progress toward toxic side effects, but subjects who experienced side effects during the administration and who continued to inhale the drug proceeded toward toxicity, particularly blood oxygen reduction. It was made.

As can be clearly seen from the above description, in order to invent the present invention, (1) understanding the pharmacokinetics and pharmacodynamics of one or more opioids, and (2) the relationship between opioid and carbon dioxide production and removal, and ventilatory action In order to achieve an understanding, (3) careful selection of one or more opioids, and (4) an appropriate clinical profile of the drug, it is necessary to accurately determine the optimal concentration of each opioid in the final formulation. The final formulation is determined through pharmacokinetic and pharmacodynamic modeling of systematic parameters, and optimization of dosage has been carried out to find the dose that exhibits the best patient safety profile while still providing an optimal analgesic response.

1 is a flow diagram showing a computer simulation model for sedation.

2 is a flow diagram illustrating a computer simulation model for ventilatory depression.

3 is a flow diagram showing a computer simulation model for an inhalation device.

4 is a flow diagram representing a computer simulation model of the pharmacokinetic profile of opioids administered to a patient via the lung pathway.

5A and 5B, together, are a flow diagram showing a StellarTM computer simulation of the pharmacokinetics of single opioid administration. 5A illustrates device model and pharmacokinetic model aspects of a simulation. 5B shows the ventilatory dysfunction model and sedation model aspects of the simulation.

FIG. 6 is a graph showing the StellaTM computer simulation output of FIGS. 5A and 5B (ventilation and sedation models do not function) showing the amount of opioid in the lungs of the inhalation device and patient over time.

FIG. 7 is a graph showing ventilation deterioration over time in the StellaTM computer simulation of FIGS. 5A and 5B (ventilation and sedation models do not function).

FIG. 8 is a graph showing the amount of opioid in the lungs of the inhalation device and the patient over time in the StellaTM computer simulation of FIGS. 5A and 5B (the ventilatory hypofunction model functions but the sedation model does not). to be.

FIG. 9 is a graph showing ventilation decay over time in StellaTM computer simulations of FIGS.

 FIG. 10 is a graph showing over time the amount of opioid in the lungs of an inhalation device and a patient in the StellaTM computer simulation of FIGS. 5A and 5B (the ventilatory hypofunction and sedation model function).

FIG. 11 is a graph showing ventilation decay over time in the StellaTM computer simulation of FIGS. 5A and 5B (the ventilatory and sedation models function).

12 is a flow diagram showing computer simulations of two types of opioid administration.

13A, 13B, and 13C are flow diagrams illustrating StellaTM computer simulations of pharmacokinetics, both of which are administered together two opioids.

FIG. 14 is a graph showing the StellaTM computer simulation output of FIGS. 13A, 13B and 13C (the ventilatory hypofunction and sedation model function) showing the total amount of opioids in the lungs of the inhalation device and patient over time.

FIG. 15 is a graph showing, over time, the concentration of each opioid and total opioid at the site of effect in the StellaTM computer simulation of FIGS. 13A, 13B and 13C (where the ventilatory hypofunction and sedation model functions).

FIG. 16 is a graph showing, over time, the deterioration of ventilation during and after delivery of opioids in the StellaTM computer simulation of FIGS. 13A, 13B and 13C (the ventilatory and sedation models function).

17A, 17B and 17C are all flow diagrams showing StellaTM computer simulations of the pharmacokinetics of two opioid administrations when both opioids administered are alfentanyl morphine. 17A and 17B show device model and pharmacokinetic model aspects of the simulation, and FIG. 17C shows the ventilatory dysfunction model, sedation model, and two drug model aspects of the simulation.

FIG. 18 is a graph showing over time the concentrations of alfentanil, morphine and combined opioid at the site of effect in the StellaTM computer simulation of FIGS. 17A, 17B and 17C (where the ventilatory and sedation model functions) .

FIG. 19 is a graph showing ventilation decay over time in the StellaTM computer simulation of FIGS. 17A, 17B and 17C (the ventilatory and sedation models function).

20 is a graph showing the maximum concentration of opioid in plasma versus the concentration at the end of the administration of opioid in the plasma of the patient receiving the opioid. FIG. 20A shows a patient administered a combination of fentanyl and liposome encapsulated fentanyl via the pulmonary route, and FIG. 20B shows a patient administered fentanyl intravenously.

FIG. 21 is a graph showing the time to side effects / toxic effects versus time to end of dosing with respect to side effects and toxic effects in patients administered a combination of fentanyl and liposome-encapsulated fentanyl via the lung route.

22 is a table showing the statistical correlation of side effects to toxic effects.

Description of the Drawings

1 is a flow diagram showing a computer simulation model for sedation. Throughout the flow diagram, squares represent quantities, arrows represent speed (quantity per unit time), and circles represent calculated values, velocity, or constants.

2 is a flow diagram illustrating a computer simulation of ventilatory depression.

3 is a flow diagram showing a computer simulation model for an inhalation device.

4 is a flow diagram representing a computer simulation model of the pharmacokinetic profile of opioids when administered to a patient via the pulmonary route.

5A and 5B, together, are a flow diagram showing a Stellar TM computer simulation of the pharmacokinetics of single opioid administration. 5A illustrates device model and pharmacokinetic model aspects of a simulation. 5B shows the ventilatory dysfunction model and sedation model aspects of the simulation.

FIG. 6 is a graph showing the StellaTM computer simulation output of FIGS. 5A and 5B (ventilation and sedation models do not function) showing the amount of opioid in the lungs of the inhalation device and patient over time. The X axis represents time in minutes. The Y axis shows the dosage unit of the formulation in mg. The amount of drug in the inhaler drops continuously during the first 10 minutes of stimulation. The amount of drug in the lungs reflects the net process by which the drug is inhaled into the lungs and the drug is absorbed into the circulation from the lungs.

FIG. 7 is a graph showing ventilation deterioration over time in the StellaTM computer simulation of FIGS. 5A and 5B (ventilation and sedation models do not function). Ventilation depression (indicated as part of the baseline ventilation action) was shown over the simulation time (in minutes).

FIG. 8 is a graph showing the amount of opioid in the lungs of the inhalation device and the patient over time in the StellaTM computer simulation of FIGS. 5A and 5B (the ventilatory hypofunction model functions but the sedation model does not). to be. The X axis represents time in minutes. The Y axis shows the dosage unit of the formulation in mg. The patient's ventilation has dropped to about 25% of baseline ventilation, and such deterioration persists for about 5-10 minutes.

FIG. 9 is a graph showing ventilation decay over time in the StellaTM computer simulations of FIGS. 5A and 5B (the ventilatory dysfunction model functions and the sedation model does not). Ventilation depression (expressed as part of baseline ventilation) was shown during the simulation time (in minutes). Changes in ventilation caused by self-limiting opioids provide significant safety for patients (compare FIG. 7).

 FIG. 10 is a graph showing over time the amount of opioid in the lungs of an inhalation device and a patient in the StellaTM computer simulation of FIGS. 5A and 5B (the ventilatory hypofunction and sedation model function). The X axis represents time in minutes. The Y axis shows the dosage unit of the formulation in mg. Because of reaching sedation and self-limiting drug absorption, drug inhalation was complete at about 8 minutes.

FIG. 11 is a graph showing ventilation decay over time in the StellaTM computer simulation of FIGS. 5A and 5B (the ventilatory and sedation models function). Ventilation depression (expressed as part of baseline ventilation) was shown during the simulation time (in minutes). Ventilation changes caused by self-limiting opioid uptake due to sedation provide significant stability to the patient (compare FIG. 7 or 9).

12 is a flow diagram showing computer simulations of two types of opioid administration.

13A, 13B and 13C are flow diagrams showing StellaTM computer simulations of pharmacokinetics, both of which are administered together, of two types of opioids.

FIG. 14 is a graph showing the StellaTM computer simulation output of FIGS. 13A, 13B and 13C (the ventilatory hypofunction and sedation model function) showing the total amount of opioids in the lungs of the inhalation device and patient over time. The Y axis represents the fentanyl equivalent of the formulation (1) in the inhaler, the fast-starting opioid (2) in the lungs, and the sustained-acting opioid (3) in the lungs, with the drug in ng / ml versus time (minutes) Fentanyl equivalents). After about 12 minutes, the patient stopped further opioid inhalation, reflecting opioid-induced sedation.

FIG. 15 is a graph showing, over time, the concentration of each opioid and total opioid at the site of effect in the StellaTM computer simulation of FIGS. 13A, 13B and 13C (where the ventilatory hypofunction and sedation model functions). The amount of the fast-starting opioid (1), the sustained-efficiency opioid (2) and the combination of the fast-starting opioid and the sustained-efficiency opioid (3) at the site of effect, in units of ng / ml, depending on time (minutes) Fentanyl equivalent of

 FIG. 16 is a graph showing, over time, ventilation deterioration during and after delivery of opioids in the StellaTM computer simulation of FIGS. 13A, 13B and 13C (the ventilatory and sedation models function). Ventilation depression (expressed as part of the baseline ventilation) was shown during the simulation time (in minutes). The combination of the two opioids peaks during the administration of the first opioid.

17A, 17B, and 17C are all flow diagrams showing StellaTM computer simulations of the pharmacokinetics of two opioid administrations when both opioids administered are alfentanyl morphine. 17A and 17B show the device model and pharmacokinetic model aspects of the simulation, and FIG. 17C shows the ventilatory dysfunction model, the sedation model, and the two drug model aspects of the simulation.

FIG. 18 is a graph showing over time the concentrations of alfentanil, morphine and combined opioid at the site of effect in the StellaTM computer simulation of FIGS. 17A, 17B and 17C (where the ventilatory and sedation model functions) .

Line 1 represents the concentration of alfentanil; Line 2 represents the concentration of morphine and line 3 represents the concentration of the combination. All drug levels are expressed in ng / ml of fentanyl equivalents over time (in minutes) at the site of effect. Drug administration ended after 90% delivery of the drug because of patient sedation. As seen in line 3, the largest opioid exposure occurs during inhalation.

FIG. 19 is a graph showing ventilation decay over time in the StellaTM computer simulation of FIGS. 17A, 17B and 17C (the ventilatory and sedation models function). Ventilation depression (expressed as part of the baseline ventilation action) was shown during the simulation time (in minutes). Ventilation is reduced to about 65% of baseline during drug administration.

FIG. 20 is a graph showing the maximum concentration of opioid in plasma versus the end-of-dose concentration of opioid in plasma of patients receiving opioids. FIG. 20A shows a patient administered a combination of fentanyl and liposome encapsulated fentanyl via the pulmonary route, and FIG. 20B shows a patient administered fentanyl intravenously. The maximum concentration of opioid was not significantly higher than the concentration at the end of the dosing, indicating that if the amount at the end of dosing is nontoxic, the maximum concentration of opioid received by the subject is also nontoxic.

FIG. 21 is a graph showing the time to side effects / toxic effects versus time to end of administration with respect to side effects and toxic effects in patients administered a combination of fentanyl and liposome-encapsulated fentanyl via the pulmonary route. In all cases, the time to toxicity was equal to or longer than the time to side effects.

22 is a table showing the statistical correlation of side effects to toxic effects. Adverse events correlate with toxic effects at p <0.04.

The following examples are for illustrative purposes only and are not intended to limit the embodiments of the present invention.

Example  1: Theoretical Model for Opioid Delivery

Examples 2-4 are based on theoretical models of opioid delivery; This theoretical model shows greater certainty in Example 1.

The theoretical model for opioid delivery was programmed in the computer simulation package "Stella" (High Performance Systems, Lebanon, NH). In the present embodiment, the elements represented by the drawings and the texts are applied to the representation of the Stellar model and explain the programming of the simulation and the execution method of the simulation.

In the figures, squares represent variables indicating accumulation of drugs (except the following). The dashed arrows represent the flow to or from the accumulator, and the solid arrows represent the elements that control the flow. Some of the solid arrows have been omitted to simplify the representation. Ellipses represent model parameters (input) and time dependent calculations. Many model parameters and constants were obtained from known techniques (Scott JC, Stanski DR. Reduction of Fentanyl and Alfentanil Administration Needs with Age. Simultaneous Pharmacokinetic and Pharmacodynamic Evaluation. J Pharmacol Exp Ther. 1987 Jan; 240 (1) : 159-66).

(a) sedation model

A model for opioid induced sedation was designed (FIG. 1-sedation model). Opioid 1010 at the site of effect was used as a variable indicating the concentration of opioid at the site of drug effect. When one or more opioids appeared at the site of drug effect, opioids 1010 of the site of effect were installed to show the sum of opioids normalized to relative potency, respectively (eg, Examples 3 and 4 below).

The sedation threshold 1020 was defined as the opioid concentration 1010 that would render the patient unable to use the inhaler. The sedation threshold 1020 was determined through experimental or known pharmacokinetics for opioids.

The sedation valuator 1030 is to check whether the opioid concentration 1010 has exceeded the sedation threshold 1020. If the opioid concentration 1010 exceeds the sedation threshold 1020, the sedation evaluator converted the value of the sedation state 1040 from 0 to 1. The sedation state 1040 is an exception to the rule that the rectangle represents the accumulation of the drug: In contrast, the role of the sedation state 1040 in this model was the role of the memory component to remember that the opioid exceeded the sedation threshold. In subsequent models, the data of sedation 1040 functioned to stop subsequent administration of the opioid and stimulate the patient's sedation, resulting in the removal of the inhaler from the mouth.

(b) ventilation deterioration model

A ventilation deterioration simulation was programmed (FIG. 2). In this model, CO2 was generated at the rate of CO2 production (2010) by the body's metabolic activity and introduced into plasma (plasma CO2 (2020)). CO2 production (2010) is experimentally determined or known (for example, Bouillon T, Schmidt C, Garstka G, Heimbach D, Stafforst D, Schwilden H, Hoeft A. Pharmacokinetics on Respiratory Insufficiency Effects of Alfentanil- Pharmacodynamic modeling.Anesthesiology. 1999 Jul; 91 (1): 144-55 and Bouillon T, Bruhn J, Radu-Radulescu L, Andresen C, Cohane C, Shafer SL.Model of Ventilatory Degradation Efficacy of Remifentanil in Abnormal Conditions Anesthesiology.2003 Oct; 99 (4): 779-87). Plasma CO2 2020 was in equilibrium with CO2 in the brain (brain CO2 2040) at a predetermined rate (brain-plasma CO2 equilibrium 2030). CO2 was removed from the plasma at a rate of CO2 removal (2050) adjusted by a variable of ventilatory depression (2060), in a manner similar to lung air intake.

Ventilatory depression 2060 increased with increasing concentration of opioid at the site of drug effect (opioid 1010 at the site of effect). Ventilatory depression reduced CO2 removal from the lungs (CO2 removal 2050), whereby CO2 is elevated in the brain (brain CO2 (2040)). As the brain CO2 2040 increased, it stimulated ventilation through the negative effects on ventilation hypofunction 2060, and some canceled the hypofunction effect of opioid 1010 in the site of effect, which was 2060) has a positive impact on the phase.

Other parameters have been devised that affect ventilatory depression 2060; The sum of these parameters is shown as model parameters 2070 in this model; Parameters including model parameters 2070 are described in more detail in FIGS. 5A and 5B. These model parameters 2070 affect ventilatory depression 2060 and thus affect CO 2 removal 2050 and brain CO 2 2040.

Programming this simulation in Stellar is novel, but the ventilatory deterioration model is a known technique called "indirect reaction model".

(c) device model

The model of the inhalation device is shown in FIG. 3. Dosage 3050 represents the total amount of opioid entering the inhaler. The opioid dose 3050 is placed in the inhaler at the rate of the filling inhaler 3010. This speed is required for the simulation run but is calculated at instant speed. Inhaler formulation 3020 represents the opioid contained in the inhaler. The patient inhales the formulation into the lung at the rate of inhalation (inhalation 3030) (the formulation in the lung 3040). Inhalation 3030 is affected by ventilatory depression 2060 and sedation 1040. In particular, inhalation 3030 slows down as ventilation deterioration 2060 increases. For example, if the hypoventilation 2060 was 50% of the baseline, the drug was inhaled at half the baseline rate (inhalation 3030 was half the baseline). However, if sedation 1040 = 1, drug inhalation in the lungs is stopped and no more drug is inhaled.

(d) Pharmacokinetic Model

A pharmacokinetic model of systematic opioids was programmed. Formulation 3040 in the lung was systematically absorbed into plasma at the rate of systematic uptake 4010 (intracellular opioid 4020). Plasma opioid 4020 was equilibrated at the plasma effect site drug equilibrium 4030 by an opioid at the drug effect site (opioid 1010 at the site of effect). Opioids were also redistributed into tissue opioid 4060 in tissue at the rate of opioid redistribution 4050 or removed from plasma at the rate of opioid removal 4070. Tissue opioid 4060 and opioid redistribution 4050 were programmed as optional parameters that may or may not be used depending on the pharmacokinetic model of the particular opioid utilized. The rate of systemic absorption (4010), plasma effect site drug equilibrium (4030), opioid removal (4070), and opioid redistribution (4050) are all opioid pharmacokinetic parameters (4080) within the model as pharmacokinetic parameters of the particular opioid administered. It was determined using a vector of parameters, denoted by, and calculated by pharmacokinetic modeling.

Programming such simulations in Stellar is new, but pharmacokinetic models are known techniques and are called "mammillary pharmacokinetic models with effect sites". The vertex models described above typically have zero, one or two tissue compartments, and obtain models referred to as one, two or three compartment models, each with an effect site.

Example 2: Administration of a Single Opioid

This example applies Example 1: Theoretical model for opioid delivery. This example is intended to illustrate a theoretical model of opioid delivery used; Model parameters do not reflect any particular opioid. Instead, the model parameters in this embodiment are designed to clearly indicate the self-limiting aspects of the proposed system for opioid delivery. This example shows the integration of four simulations as described in Example 1, and the output obtained from the model when the simulation was run.

(a) model integration

5A and 5B show the components of the model described in Example 1 in which one type of opioid is administered by inhalation. Figure 5 is divided into two parts: Figures 5a and 5b. FIG. 5A is a device model 5010 equivalent to the device model described and shown in Embodiment 1 as in FIG. 3 overall; Pharmacokinetic model 5020 equivalent to the pharmacokinetic model described and shown in Example 1 as shown in FIG. 4 (except for the selection parameters in opioid 4060 and opioid redistribution 4050 in tissues), and also opioid pharmacokinetic parameters Except that 4080 is formed in systematic absorption 4010, opioid removal 4070 and plasma effect site equilibrium 4030, and is not a separate parameter-see source code for more information. ); FIG. 5B is a ventilation deterioration model 5030 equivalent to the ventilation deterioration model described and illustrated in Example 1 as shown in FIG. 2 (where model parameter 2070 is model parameter 2070, that is, PACO2 @ 0 ( 2071), with the exception of being shown in "extended" form, including various components including KelCO2 (2072), ke0CO2 (2073), C50 (2074), gamma (2075), and F (2076)); And a sedation model 5040 equivalent to the sedation model shown in FIG. 1. The details of these four models shown in FIGS. 5A and 5B have been described in depth in Example 1, except for the enlargement of model parameters 2070, the details of which are as follows:

Baseline CO2 2071 is CO2 at baseline prior to administration of the opioid. kel CO2 2082 is the removal rate associated with plasma CO2 2020 relative to CO2 removal 2050, and thus at baseline (ie, under conditions without ventilatory depression): CO2 removal 2050 = kel CO2 ( 2072) × plasma CO2 (2020)

Subsequently, at baseline the carbon dioxide in the body is steady, thus CO2 removal (2050) = CO2 production (2010). From this the rate of CO2 production (constant value) can be found for the baselines CO2 2071 and kel CO2 2082 as follows:

CO2 generation (2010) = kel CO2 (2072) × baseline plasma CO2 (2071)

The rate of brain plasma equilibrium 2020 is determined by parameter ke0 CO2 2073, as follows:

Brain Plasma Equilibrium (2020) = ke0 CO2 (2073) × (Plasma CO2 (2020)-Brain CO2 (2040))

Opioids as opposing functions of opioids 1030, parameter C50 2074, opioid concentrations associated with 50% of the maximum effect, and gamma 2075 at the site of effect reduce ventilation, ie the slope of the concentration-response relationship, The opioid's contribution to dysfunction is expressed as follows:

Carbon dioxide, on the other hand, stimulates ventilation. The increase in ventilation can be modeled as a function of baseline CO2 2071, brain CO2 2040 and F 2076, with the parameters indicative of the slope of the relationship being:

Putting this equation together, the ventilation loss (2060) can be expressed as:

 Reduced ventilation (2060) =

Using this defined hypoventilation (2060), CO2 removal (2050) in the presence of an opioid-induced hypoventilation can be completed as follows:

C02 removal (2050) = kel C02 (2072) x plasma C02 (2020) x hypoventilation (2060).

In this way, the model of Example 1 was combined into one model for the opioid effect. This model is as shown in FIGS. 5A and 5B and may be described by the following mathematical model represented in the Stellar programming language (source code):

Brain_CO2_2040 (t) = brain_CO2_2040 (t-dt) + (brain_plasma_CO2_equilibrium_2020) * dt

INIT Brain_CO2_2040 = Baseline_CO2_2071

Input flow:

Brain_plasma_CO2_equilibrium_2020 = ke0_CO2_2073 * (plasma_CO2_2020-brain_CO2_2040)

Inhaler In-Product_3020 (t) = Inhaler In-Product_3020 (t-dt) + (Charge_Inhaler_3010-Inhalation_3030) * dt

INIT Inhaler_In_Product_3020 = 0

Input flow:

Dosage_Fill if Inhaler_3010 = Time = 0_ 0 otherwise

Output flow:

Inhalation_3030 = 5 * (ventilation deterioration_2060) if calm_state_1040 = 0 or 0

Pulmonary_In_Products_3040 (t) = Pulmonary_In_Products_3040 (t-dt) + (Aspiration_3030-Systematic_Absorption_4010) * dt

INIT closed_my_title_3040 = 0

Input flow:

If input_3030 = calm_state_1040 = 0, 5 * (vent_decrease_2060) or 0

Output flow:

Systematic_Absorption_4010 = Lung_In_Products_3040 * .693 / 1

Effect_site_opioid_1010 (t) = effect_site_opioid_1010 (t-dt) + (plasma_effect_site_equilibrium_4030) * dt

INIT effect_site_in_opioid_1010 = 0

Input flow:

Plasma_effect_site_equilibrium_4030 = (plasma_in_opioid_4020-effect_site_in_opioid_1010) *. 693/1

Plasma_in_opioid_4020 (t) = plasma_in_opioid_4020 (t-dt) + (systematic_absorption_4010-opioid_removal_4070-plasma_effect_site_equilibrium_4030) * dt

INIT plasma_in_opioid_4020 = 0

Input flow:

Systematic_Absorption_4010 = Lung_In_Products_3040 * .693 / 1

Output flow:

Opioid_removal_4070 = plasma_in_opioid_4020 * .693 / 10

Plasma_effect_site_equilibrium_4030 = (plasma_in_opioid_4020-effect_site_in_opioid_1010) *. 693/1

Plasma_CO2_2020 (t) = plasma_CO2_2020 (t-dt) + (CO2_generation_2010-brain_plasma_CO2_equilibrium _2020-CO2_removal_2050) * dt

INIT Plasma_CO2_2020 = Baseline_CO2_2071

Input flow:

CO2_Create_2010 = Baseline_CO2_2071 * kelCO2_2072

Output flow:

Brain_plasma_CO2_equilibrium_2020 = keO_CO2_2073 * (plasma_CO2_2020-brain_CO2_2040)

CO2_removed_2050 = plasma_CO2_2020 * kelCO2_2072 * ventilation_decreased_2_2060

Calm_state_1040 (t) = calm_state_1040 (t-dt) + (true_evaluator_1030) * dt

INIT Calm_State_1040 = 0

Input flow:

Calm_evaluator_1030 = (effect_site_opioid_1010> calm_boundary_1020)

Is 1 or 0

Baseline_CO2_2071 = 40

C50_2074 = .3

Dose_3050 = 5

F_2076 = 4

Gamma_2075 = 1.2

ke0_CO2_2073 = 0.92

kelCO2_2072 = 0.082

True_threshold_1020 = 1.5

Ventilation deterioration_2060 = (1-effect_site_opioid_1010 ^ gamma_2075 / (C50_2074 ^ gamma_2075 + effect_site_my_opioid_1010 ^ gamma_2075)) * (brain_ CO2_2040 / Baseline_CO2_2071) ^ F_2076

(b) the output of the model if the ventilation deterioration model and the sedation model do not function;

The model designed and described in (a) was run as a simulation of the opioid effect using the following initial parameters: Inhaler formulation 3020 = 5 milliliters (at time = 0). This model was run for 2 hours. In this simulation, the feedback loop in terms of drug uptake of the ventilatory depression model (ie, feedback of the effect of ventilatory depression 2060 on device model 5010) and the sedation model did not function. The output of the model at run time shows graphs for various parameters in FIGS. 6 and 7.

FIG. 6 shows the output of the model when run in the absence of self-limiting inhalation of opioids (ie when the ventilatory and sedation models are not functioning). Figure 6 shows the drug in the inhaler (inhaler formulation 3020-line 1), and the drug in the lung (agent in lungs 3040-line 2) over time in the absence of self-limiting aspects of the invention. According to. The amount of drug in the inhaler dropped consistently at the inhalation rate 3030 during the first 10 minutes of the simulation. The amount of drug in the lungs reflected the intact processes of drug intake in the lungs and drug uptake into the systemic circulation in the lungs.

FIG. 7 shows ventilation deterioration 2060 over time for the same simulation (ventilation and sedation models do not function). The graph output dropped to about 25% of the baseline ventilation in this simulation. Ventilatory depression involved for about 5-10 minutes. Ventilation depression is inversely proportional to the carbon dioxide produced in the patient's plasma, and at the same rate, the patient's lungs (not simulated) offset the adverse effects of opioids upon ventilation. This drop in ventilation exposed the patient to the risk of damage due to lowered oxygen in the blood.

 (c) the output of the model when the ventilation deterioration model is executed in conjunction with the functioning

The simulation used in (b) was modified by running the ventilation deterioration model and run again with the same parameters where formulation 3020 = 5 milliliters (when time zero) in the inhaler. The output of the various parameters is plotted over time. 8 is an inhaler formulation 3020 (line 1) showing the amount of drug remaining in the inhaler in the presence of one of two self-limiting aspects of the present invention, ventilatory depression (the other is sedation), and Intrapulmonary formulation 3040 (line 2) is shown which indicates the amount of drug in the lung. Compared to Example 2 (b), as expected, it took longer to inhale the drug when running the simulation when the ventilatory dysfunction model was functioning-the drug inhalation of FIG. 8 was 10 minutes in FIG. In contrast, it ran for about 17 minutes. This is due to a decrease in ventilation due to poor ventilation, which limits the patient's exposure to opioids. The reduction in ventilation is shown in more detail in FIG. 9, which shows the ventilation deterioration 2060 over time in the same simulation. Ventilation depression 2060 was reduced by 50% in FIG. 9. Compared with the simulation shown in FIG. 7, the patient breathed at a maximum of 1/2 of the simulation (FIG. 7) when the simulation was performed without the ventilation malfunction model functioning (FIG. 9). In these simulations, changes in ventilation due to self-limiting opioid uptake impart great safety to the patient.

(d) the output of the model when the ventilation deterioration model and the sedation model are run together with functioning

The same simulation (inhaler formulation 3020 = 5 milliliters (when time was zero)) was run, with both the ventilatory hypofunction model 5030 and the sedation model 5040 functioning. The output of the various parameters is shown over time. FIG. 10 shows the time course of the inhaler preparation 3020 (line 1) and the time course of the intrapulmonary preparation 3040 (line 2) in the presence of hypoventilation and sedation. As shown in the figure, drug inhalation was completely terminated after 8 minutes. The reason was that the patient calmed down and could no longer hold the inhaler in the mouth (simulated by changing the calm state 1040 from 0 to 1). At this point about 2 milliliters remained in the inhaler formulation 3020, so about 40% of the opioid dose remained in the inhaler. FIG. 11 illustrates ventilation deterioration 2060 of the time course of this simulation. In FIG. 11 the maximum deterioration of ventilation was about 60%. In comparison with FIG. 9, opioid-induced sedation has been demonstrated to improve safety.

Thus, Example 2 demonstrates the effects and advantages of the self-limiting opioid delivery system as described herein via simulation, as shown in FIGS. 5-11.

Example  3: Administration of two opioids

In this simulation, the model parameters do not reflect specific opioids, but have been adjusted to clearly show the self-limiting aspects of the proposed opioid delivery system. The simulation model, method and parameters are the same, but the opioid composition at this time consists of two different opioids with different pharmacokinetic characteristics.

(a) Modeling two opioids

12 shows a method of combining two opioids into one opioid concentration relative to the model. In the simulation of the two opioids, rapid opioid 12010 in the site of effect represents the concentration of the fast-initiating opioid; Slow-opioid 12020 in the site of effect indicates a slow onset opioid. Each of these is equivalent and is determined in the same manner as in one opioid model (Example 2). However, each is determined separately and then combined to determine the combined opioid effect site concentration 1230. The combined opioid effect site concentration (12030) is calculated using the known relative potency (12040) of each opioid. The combined opioid effect site concentration 1230 is the same as the opioid 1010 in the effect site of the two opioid models shown in FIGS. 13A, 13B, 13C and 17A, 17B, and 17C.

13A, 13B, and 13C together show algorithms relating to the simulation of two opioid models. Herein: device model 13010 equivalent to and shown as device model 5010 described in Examples 1 and 2; as shown in FIGS. 4 and 5A and 5B and also described in Examples 1 and 2 It includes a combination of two cases of pharmacokinetic model 5020 (for rapid opioids and for slow opioids), each of which is performed equally, as shown in FIG. Pharmacokinetic model (13020) combined into one using; Ventilation deterioration model 5030 shown in FIGS. 2 and 5A and 5B and also described in Examples 1 and 2; And a sedation model 5040 as shown in FIGS. 2 and 5A and 5B and also described in Examples 1 and 2.

The models shown in FIGS. 13A, 13B and 13C may also be described by the following mathematical model, represented in the Stellar programming language (source code):

Brain_CO2_2040 (t) = brain_CO2_2040 (t-dt) + (brain_plasma_CO2_equilibrium_2020) * dt

INIT Brain_CO2_2040 = Baseline_CO2_2071

Input flow:

Brain_plasma_CO2_equilibrium_2020 = ke0_CO2_2073 * (plasma_CO2_2020-brain_CO2_2040)

Inhaler_in_formulation_3020 (t) = inhaler_in_formulation_3020 (t-dt) + (filling_inhaler_3010-inhalation_1_3031-inhalation_2_3032) * dt

INIT Inhaler_Formulation_3020 = 0

Input flow:

Charge_Aspirator_3010 = Dose when Time = 0_3050 / DT or 0

Output flow:

Inhalation_1_3031 = Calm_State_1040 = 0

0.25 * Ventilation or 0

Inhalation_2_3032 = calm_state_1040 = 0

0.25 * Ventilation deterioration_2060 or 0

Effect_site_opioid_1010 (t) = effect_site_opioid_1010 (t-dt)

INIT effect_site_in_opioid_1010 = 0

Plasma_CO2_2020 (t) = plasma_CO2_2020 (t-dt) + (CO2_generation_2010-brain_plasma_CO2_equilibrium_2020-CO2_removal_2050) * dt

INIT Plasma_CO2_2020 = Baseline_CO2_2071

Input flow:

CO2_generation_2010 = {the right side of the equation here ...}

Output flow:

Brain_plasma_CO2_equilibrium_2020 = ke0_CO2_2073 * (plasma_CO2_2020-brain_CO2_2040)

CO2_removed_2050 = plasma_CO2_2020 * kelCO2_2072 * ventilation_decreased_2_2060

Rapid_drug_effect_site (t) = rapid_drug_effect_site (t-dt) + (quick_drug_plasma_effect_site_equilibrium) * dt

INIT Rapid_Drug_effect_Site = 0

Input flow:

Rapid_drug_plasma_effect_site_equilibrium = (plasma_in_fast_drug-rapid_drug_effect_site) * .693 / 1

Plasma_in_rapid_drug (t) = plasma_in_rapid_drug (t-dt) + (rapid_drug_absorption-rapid_drug_removal-rapid_drug plasma_effect_site_equilibrium) * dt

INIT Plasma-to_Rapid_Drug = 0

Input flow:

Rapid_drug_absorption =

Lung Mine Rapid Formation * .693 / 1 * Rapid Drug Substance Concentration

Output flow:

Fast_drug_removal = plasma_in_fast_drug * .693 / 10

Rapid_drug_plasma_effect_site_equilibrium = (plasma_in_fast_drug-rapid_drug_effect_site) * .693 / 1

Lung_In_Rapid_Formulation (t) = Lung_In_Rapid_Formulation (t-dt) + (Aspiration_1_3031-Rapid_Drug_absorption) * dt

INIT Lung_My_Quick_Formulation = 0

Input flow:

Inhalation_1_3031 = Calm_State_1040 = 0

0.25 * ventilation_zero or 0

Output flow:

Rapid_drug_absorption = pulmonary_rapid_formulation * .693 / 1 * rapid_drug concentration

Calm_state_1040 (t) = calm_state_1040 (t-dt) + (sedation_evaluator_1030) * dt

INIT Calm_State_1040 = 0

Input flow:

Sedation_evaluator_1030 = (effect_site_in_opioid_1010> sedation_boundary_1020)

1 or 0

Slow_drug_effect_site (t) = slow_drug_effect_site (t-dt) + (low_drug_plasma_effect_site_equilibrium) * dt

INIT Slow_Drug_effect_Site = 0

Input flow:

Slow_drug_plasma_effect_site_equilibrium = (plasma_low_drug_drug-slow_drug_effect_site) * .693 / 10

Plasma_low_drug (t) = plasma_low_drug (t-dt) + (slow_drug_absorption-slow_drug_removal-

Slow_drug_plasma_effect_site_equilibrium) * dt

INIT Plasma-I_Slow_Drug = 0

Input flow:

Slow_drug_absorption =

Lung-in_low-speed formulation * .693 / 12 * Low-speed drug concentration

Output flow:

Slow_Drug_Rejection = Plasma_Last_Drug_Drug * .693 / 300

Slow_drug_plasma_effect_site_equilibrium = (plasma_low_drug_drug-slow_drug_effect_site) * .693 / 10

Lung-in_Low_Formulation (t) = Lung-in_Low_Formulation (t-dt) + (Aspiration_2_3032-Low-Speed_Drug_Absorption) * dt

INIT Lung_In_Slow_Formulation = 0

Input flow:

Inhalation_2_3032 = calm_state_1040 = 0

0.25 * Ventilation deterioration_2060 or 0

Output flow:

Slow_drug_absorption =

Lung-in_low-speed formulation * .693 / 12 * Low-speed drug concentration

Baseline_CO2_2071 = 40

C50_2074 = .3

Dose_3050 = 5

F_2076 = 4

Gamma_2075 = 1.2

ke0_CO2_2073 = 0.92

kelCO2_2072 = 0.082

Effect_in_in_opioid_1010 =

Rapid_Drug_effect_site + Slow_Drug_effect_site

Rapid_Drug_Concentration = 1

Sedation_Threshold_1020 = 1.5

Slow_Drug_Concentration = 1

Ventilation_failure_2060 = (1-

Effect_Site_My_Opioid_1010 ^ Gamma_2075 / (C50_2074 ^ Gamma_2075 + Effect_Site_My_Opioid_1010 ^ Gamma_2075)) * (Brain_CO2_2040 / Baseline_CO2_2071) ^ F_2076

(b) the output of the model when the ventilation deterioration model and the sedation model are executed in conjunction with the functioning

The same simulation (in-aspirator formulation 3020 = 5 milliliters (when time = 0)) was run on two opioid models as shown in Example 3 (a) and FIGS. 13A, 13B and 13C. Time course of inhaler preparation 3020 (line 1), time course of intrapulmonary preparation (rapid opioid) 3040 (line 2), and intrapulmonary preparation (low opioid) 3040 in the presence of hypofunction and sedation Time course (line 3) The drug was inhaled by the patient in a 12-minute run in the simulation The rate of decrease in the amount of drug in the inhaler was not exactly linear, which slowed breathing due to opioid-induced hypofunction. In general, after 12 minutes, the patient reflected the opioid-induced sedation by stopping further opioid inhalation.The rapidly acting opioid was quickly supplied to the circulation. When the patient stops inhaling opioids, it limits the amount of accumulation in the lungs and sharply reduces the concentration in the lungs.The slow-acting opioids are slowly absorbed into the lungs, allowing more drugs to accumulate in the lungs The opioid was allowed to be administered to the circulation over 2 hours after the end of opioid delivery.

15 shows various variables for the same simulation. In FIG. 15, line 1 shows the fast acting opioid concentration (rapid drug effect site) in the site of effect over time, and also shows a rapid rise due to rapid absorption and rapid plasma-effect site equilibrium, and a rapid drop due to fast metabolism. . Line 2 shows the slow acting opioid concentration (low drug effect site) in the site of effect over time and also shows a slow rise due to slow absorption and slow plasma effect site equilibrium, and a slow decrease due to slow metabolism. Line 3 shows the combined concentrations of fast and slow onset drug (combined opioid effect site concentrations). As shown, the combination reaches its peak during the administration of the first opioid.

15 and 14 show different variables for the same simulation run on the same X axis (time). Thus, looking back at FIG. 14, the patient stopped self-administration of the drug at about 12 minutes. Referring to FIG. 14 together with FIG. 15, it can be seen that the result reflects the patient's response to the rapidly acting opioid at 12 minutes, as the concentration of the slow acting opioid was almost negligible. However, the total opioid concentration is largely invariant with time. This reflected the fact that when fast acting opioids were removed from the system through rapid drug removal, slow acting opioids in the opioids within the site of effect gradually replaced the acting opioids.

FIG. 16 shows the process of delivering opioids using two opioid delivery systems and the time course of subsequent ventilatory depression 2060 in the execution of the same simulation. 16 shows that the initial decrease in ventilation amounts to about 60% of the baseline. As mentioned earlier (in the description of Figure 11), the patient tolerates this well. Ventilation is stimulated when C02 is produced. Note that there is little degradation of ventilation after this initial stage. The reason for this is that from now on, adequate CO2 accumulation occurs in the patient that will continue to drive ventilation.

As shown in Figures 13A, 13B, 13C, 14 and 15, in the two drug embodiments of the device, the first drug acts as a "probe" for detecting opioids in the patient and both the first and second opioids Limit the dose of. In this way the patient can receive slow acting opioids without overdose. Since one of them in a combination of two opioids acts rapidly, it can be used to increase the safety profile of either opioid alone or, more specifically, slow-acting opioids.

Example  4: As an example of opioids of two drug models Alfentanil  And morphine

This example shows the application of Example 3 to two specific drugs, alfentanil and morphine, where alfentanil is a fast acting opioid and morphine is a slow acting opioid.

Figures 17A, 17B and 17C are together: two as shown in Figures 5A and 5B and described in Example 1, which are performed equally, but modified and relabelled for certain known parameters of alfentanil and morphine opioids. Device model 17010 including device model 5010 (as shown in FIGS. 17A and 17C); Ventilation dysfunction model 5030 as shown in FIG. 2, sedation model 5040 as shown in FIG. 1, and as shown in FIG. 12 but relabelled to reflect the particular drugs alfentanil and morphine. Two drug models 1170 are included (as shown in FIG. 17C). 17A, 17B and 17C expose all parameters 2070 of the ventilatory hypofunction model 1730. Parameters 4080 of pharmacokinetic model 1720 for morphine and alfentanil are now fully exposed. Alfentanil and morphine are represented by three mammillary models, each with an effect site.

The models shown in FIGS. 17A, 17B, and 17C may also be described by the following mathematical model, as indicated by the Stellar programming language. Constants for alfentanil and morphine are based on prior literature on these drugs.

Inhaler_alpentanyl (t) = inhaler_alpentanyl (t-dt) + (-suction_alpentanyl) * dt

INIT Inhaler_In_Alfentanil = Alfentanil_Dose_ug

Output flow:

Inhalation_Alfentanil = Calm_State = 0

Alfentanil_dose_ug / dose_period * ventilation_decrease or zero

Lung_In_Alfentanil (t) = Lung_In_Alfentanil (t-dt) + (Suction_Alfentanil-Alfentanil_Absorbance) * dt

INIT Lung_In_Alfentanil = 0

Input flow:

Inhalation_Alfentanil = Calm_State = 0

Alfentanil_dose_ug / dose_period * ventilation_decrease or zero

Output flow:

Alfentanil Absorption = Lung_In_Alfentanil * .693 / Alfentanil Absorption Half-Life

Alfentanil_X1 (t) = Alfentanil_X1 (t-dt) + (Alfentanil_C12 + Alfentanil_C13 + Alfentanil_CLe + Alfentanil_ Absorption-Alfentanil_C11) * dt

INIT Alfentanil_X1 = 0

Input flow:

Alfentanil_C12 = Alfentanil_X2 * Alfentanil_K21-Alfentanil_X1 * Alfentanil_K12

Alfentanil_C13 = Alfentanil_X3 * Alfentanil_K31-Alfentanil_X1 * Alfentanil_K13

Alfentanil_CLe = Alfentanil_Xeffect * Alfentanil_Ke0-Alfentanil_X1 * Alfentanil_Ke0 * .001 / Alfentanil_V1

Alfentanil Absorption = Lung_In_Alfentanil * .693 / Alfentanil Absorption Half-Life

Output flow:

Alfentanil_C11 = Alfentanil_X1 * Alfentanil_K10

Alfentanil_X2 (t) = Alfentanil_X2 (t-dt) + (-Alfentanil_C12) * dt

INIT Alfentanil_X2 = 0

Output flow:

Alfentanil_C12 = Alfentanil_X2 * Alfentanil_K21-Alfentanil_X1 * Alfentanil_K12

Alfentanil_X3 (t) = Alfentanil_X3 (t-dt) + (-Alfentanil_C13) * dt

INIT Alfentanil_X3 = 0

Output flow:

Alfentanil_C13 = Alfentanil_X3 * Alfentanil_K31-Alfentanil_X1 * Alfentanil_K13

Alfentanil_Xeffect (t) = Alfentanil_Xeffect (t-dt) + (-alfentanil_CLe) * dt

INIT Alfentanil_Xeffect = 0

Output flow:

Alfentanil_CLe = Alfentanil_Xeffect * Alfentanil_Ke0 -Alfentanil_X1 * Alfentanil_Ke0 * .001 / Alfentanil_V1

Inhaler In-Morphine (t) = Inhaler In-Morphine (t-dt) + (-Suction-Morphine) * dt

INIT Inhaler_My_Morphine = Morphine_Dose_mg * 1000

Output flow:

Inhalation Morphine = Calm_State = 0

Morphine_dose_mg * 1000 / dose_period * ventilation_decrease or 0

Lung_in_morphine (t) = Lung_in_morphine (t-dt) + (suction_morphine-morphine_absorption) * dt

INIT lung_my_morphine = 0

Input flow:

Inhalation Morphine = Calm_State = 0

Morphine_dose_mg * 1000 / dose_period * ventilation_decrease or 0

Output flow:

Morphine Absorption = Lung In-Morphine * .693 / Morphine Absorption-Half-Life

Morphine_X1 (t) = morphine_X1 (t-dt) + (morphine_C12 + morphine_C13 + morphine_CLe + morphine_absorption-morphine_C11) * dt

INIT Morphine_X1 = 0

Input flow:

Morphine_C12 = Morphine_X2 * Morphine_K21-Morphine_X1 * Morphine_K12

Morphine_C13 = Morphine_X3 * Morphine_K31-Morphine_X1 * Morphine_K13

Morphine_CLe = Morphine_Xeffect * Morphine_Ke0-Morphine_X1 * Morphine_Ke0 * .001 / Morphine_V1

Morphine Absorption = Lung In-Morphine * .693 / Morphine-Absorbing Half-Life

Output flow:

Morphine_C11 = Morphine_X1 * Morphine_K10

Morphine_X2 (t) = Morphine_X2 (t-dt) + (-morphine_C12) * dt

INIT Morphine_X2 = 0

Output flow:

Morphine_C12 = Morphine_X2 * Morphine_K21-Morphine_X1 * Morphine_K12

Morphine_X3 (t) = Morphine_X3 (t-dt) + (-morphine_C13) * dt

INIT Morphine_X3 = 0

Output flow:

Morphine_C13 = Morphine_X3 * Morphine_K31-Morphine_X1 * Morphine_K13

Morphine_Xeffect (t) = morphine_Xeffect (t-dt) + (-morphine_CLe) * dt

INIT Morphine_Xeffect = 0

Output flow:

Morphine_CLe = Morphine_Xeffect * Morphine_Ke0-Morphine_X1 * Morphine_Ke0 * .001 / Morphine_V1

PaCO2 (t) = PaCO2 (t-dt) + (CO2_accumulation-CO2 equilibrium) * dt

INIT PaCO2 = PaCO2 @ 0

Input flow:

CO2 Accumulation = KelCO2 * PaCO2 @ 0-KelCO2 * Ventilation Deterioration * PaCO2

Output flow:

CO2 equilibrium = ke0CO2 * (PaCO2-PeCO2)

PeCO2 (t) = PeCO2 (t-dt) + (CO2 equilibrium) * dt

INIT PeCO2 = PaCO2 @ 0

Input flow:

CO2 equilibrium = ke0CO2 * (PaCO2-PeCO2)

Sed_status (t) = sed_status (t-dt) + (sedative_evaluator) * dt

INIT Calm_State = 0

Input flow:

Sedation_evaluator = combination_opioid_effect_site_concentration <0 for sedation_boundary

Alfentanil Absorption Half-Life = 1

Alfentanil_Ce = Alfentanil_Xeffect / .001

Alfentanil_Cp = Alfentanil_X1 / Alfentanil_V1

Alfentanil_Dose_ug = 1500

Alfentanil_K10 = 0.090957

Alfentanil_K12 = 0.655935

Alfentanil_K13 = 0.112828

Alfentanil_K21 = 0.214

Alfentanil_K31 = 0.017

Alfentanil_Ke0 = 0.77

Alfentanil_V1 = 2.18

C50 = 1.1

Combination Opioid Effect Site Concentration = Alfentanil Ce / 60 + Morphine Ce / 70

Dosage_Duration = 12

F = 4

Gamma = 1.2

ke0CO2 = 0.92

KelCO2 = 0.082

Morphine_absorption_half_life = 2

Morphine_Ce = Morphine_Xeffect / .001

Morphine_Cp = Morphine_X1 / Morphine_V1

Morphine_Dose_mg = 20

Morphine_K10 = 0.070505618

Morphine_K12 = 0.127340824

Morphine_K13 = 0.018258427

Morphine_K21 = 0.025964108

Morphine_K31 = 0.001633166

Morphine_Ke0 = 0.005

Morphine_V1 = 17.8

PaCO2 @ 0 = 40

Sedation_Threshold = 1.5

Ventilation deterioration = (1-Combination opioid effect_concentration ^ gamma / (C50 ^ gamma + Combination opioid_effect_site_concentration ^ gamma) * (PeCO2 / PaCO2 @ 0) ^ F

 This simulation was run at time 0 using the starting parameters of 700 mcg bioavailable alfentanil and 67 mcg bioavailable morphine in the inhaler (alfentanil = 700 mcg in time inhaler (time = 0); morphine = in inhaler). 67 mcg (when time = 0). 18 and 19 show the concentrations of various parameters in the simulation run. 18 shows the concentrations of alfentanil (ng / ml, line 1), morphine (ng / ml, line 2) and combined opioids (ng / ml of fentanyl equivalents, line 3) at the site of effect after inhalation of the combined product. Shown over time (minutes). In this example, drug administration ended after 90% of the inhaled drug was delivered and the patient calmed down. As can be seen, the alfentanil concentration rises rapidly at the site of effect causing the rapid drug effect (line 1). The morphine drug effect rises much slower at the site of effect (line 2) and slowly raises the drug effect. Line 3 shows the combined opioid effect site concentration with the efficacy of each drug adjusted relative to fentanyl. These three lines have different Y scales to normalize effect site concentrations relative to relative potency, as seen on the Y axis. As seen in line 3, opioid peak exposure occurs during inhalation and is mostly due to alfentanil. However, if alfentanil is lost at the site of effect, it is replaced by the influx of morphine into the site of effect. If the concentration of the effect site is less than 25 ng / ml at the alfentanil scale (equivalent to 37.5 ng / ml at the morphine scale and 0.5 ng / ml at the fentanyl scale due to relative potency) it is considered to be effect-less; Patients generally have analgesic effects between 50 ng / ml and 100 ng / ml (on alfentanil scale), side effects when between 75 and 125 ng / ml (alfetanyl scale), and over 125 ng / ml (alphtanyl scale). ) Toxic effects.

19 shows hypoventilation through inhalation of the alfentanyl morphine combination opioid delivery system. As shown in FIG. 19, ventilation decreases to about 65% of baseline during drug administration and then recovers to about 80% of baseline upon CO 2 accumulation. Ventilation is maintained at 80% of baseline for the next four hours, thereby maintaining the morphine effect.

As shown in FIGS. 17A, 17B, 17C, 18 and 19, based on simulations using literature parameter values for the alfentanyl morphine combined opioid delivery system, the patient's self-limiting opioid delivery system prevents the administration of toxic doses of opioids. In addition, slow-acting opioids can be safely delivered by combining slow-acting opioids with fast-acting opioids and using the effects of fast-acting opioids to limit the overall exposure of the opioids.

Example 5 Clinical Trials of Fentanyl Formulations in Humans

(a) Methods of Formulating Glass and Liposomal Encapsulated Fentanyl Formulations

 Formulations containing a mixture of free fentanyl and liposome encapsulated fentanyl were prepared by mixing the ethanol phase with the aqueous phase. The ethanol phase consisted of ethanol, fentanyl citrate, phosphatidylchloline and cholesterol. The aqueous phase contained water for injection. Prior to mixing, both phases were heated to about 56-60 ° C. The two phases were mixed and the mixture was stirred at 56-60 ° C. for 10 minutes. Then cooled to room temperature over approximately 2 hours. Normally 500 ml of fentanyl, 40 mg of phosphatidylcholine, 4 mg of cholesterol and 100 mg of ethanol were contained per ml of the final aqueous formulation. After filling, the preparation was finally autoclaved for sterilization. The final formulation contained 35-45% fentanyl and residue as the free drug in the encapsulated component.

(b) treatment method

The methods of the following examples are generally (but not always) a method of delivering a therapeutically effective concentration to the bloodstream by administering a mixture of free and liposome-encapsulated fentanyl through the patient's lungs and also during the administration period. Drowsiness, dizziness or sedation may be followed.

Healthy volunteers were dosed once or multiple times with a mixture of free and liposome encapsulated fentanyl using an AeroEclipase ^™ nebulizer respiratory-activator containing compressed air set at 8 liters / minute. Fill the nebulizer with 3 ml of a mixture of glass (40%) and liposome encapsulated (60%) fentanyl during each dosing period and instruct the subject to inhale the nebulized drug until the device no longer produces an aerosol for inhalation. did. Subjects who were dozing, falling asleep or feeling dizzy during the inhalation period were encouraged to continue self-administering the drug until the nebulizer no longer produced aerosols. Plasma samples were collected during the dosing period and for 12 hours after the initial dosing and the plasma fentanyl concentration was observed. Patients were observed for negative phenomena, including changes in respiratory rate and hypoxia.

Fentanyl was administered intravenously to control subjects.

(c) Determination of maximum plasma concentration and termination of administration plasma concentration

The maximum plasma concentration (Cmax) is plotted against the plasma concentration (Ceod) at the end of the administration to see if the patient can prevent the drug's toxic levels by self-limiting the drug before exhibiting a toxic effect (FIG. 20A). ). Ceod was found to be mostly within 80% of Cmax, indicating that the maximum concentration of opioid was not significantly greater than the concentration at which the opioid supply was stopped for the subject. This is in stark contrast to the control (FIG. 20B) in which patients receiving fentanyl intravenously showed significantly higher Cmax concentrations than Ceod. This result indicates that the safety of drug titration is greatly increased since the subject's opioid inhalation will not significantly increase after the opioid inhalation is stopped. In addition, for opioid formulations of known concentrations inhaled for a relatively long time (2-20 minutes), the maximum concentration of opioid supplied to the subject is also likely to be nontoxic if the amount at the "end of dosing" is nontoxic.

(d) Determination of timing of adverse effects and toxic effects

In order for the subject to self-titrate effectively, side effects of the drug, such as drowsiness, dizziness, or poor ventilation, must occur before the onset of toxic effects. Toxic effect was defined as blood oxygen depletion in this experiment where the oxygen saturation in blood was below 90% of normal value. To determine if side effects occur before the toxic effects, the time to side effects and the time to toxic effects are plotted against the time to end of administration (FIG. 21). For the end time of dosing, the time to side effect was equal to or shorter than the time to toxic effect, indicating that drowsiness, dizziness, or hypoventilation always occurred before or at the time of the toxic effect.

(e) determining the correlation of toxic effects and adverse effects;

In order for a subject to self-titrate effectively, most of the toxic effects must always be preceded by side effects that cause (or signal) discontinuation of drug administration. FIG. 22 shows that side effects correlate closely with toxic effects in the entire study subject group, indicating that the subjects with toxic effects must also exhibit side effects.

This example is based on the fact that in control experiments on human subjects, (1) side effects almost always preceded the toxic effect, and (2) in the dose profiles given in this example, the Cmax of the inhaled opioid was largely Ceod. Shows. Thus, subjects who stop opioid administration when experiencing side effects will seldom reach the opioid concentration levels required for toxic effects.

Example 6: Testing of Various Spray Techniques for Optimal Delivery of Drugs

3, 5, 13, and 17 contain descriptions of device models that depend on the rate of respiration and the amount of drug delivered to the lungs over a period of time. The hypoventilation models of FIGS. 5, 13 and 17 make it possible to anticipate how these side effects limit the rate of inhalation. In addition, it is necessary to balance the rate of opioid deposition in the lungs with the rate of effect initiation at the site of action. In order for the drug formulation to be conveniently, safely and effectively administered for a 4-20 minute period, the amount of drug without each inhalation should be controlled below the selected threshold. In order to optimize formulation and device selection, the performance of the device and the characteristics of the particular formulation should be revealed in vitro. The following examples show testing of nebulization techniques to optimally deliver drugs to the lungs.

Formulations containing a mixture of free fentanyl and liposome encapsulated fentanyl were prepared using the method described in Example 5. The final formulation contained 35-45% of fentanyl along with the residue as the free drug in the encapsulated component.

Andersen Cascade Impactor (ACI) technology is an established technique for characterizing aerosols through nebulizers (USP 26-NF21-2003, Chapter 601: Physical tests and determinations: aerosols.United States Pharmacopoeia, Rockville, MD, 2105-2123. United States Federal Drug Administration.1998.Draft guidance: metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products chemistry, manufacturing and controls documentation, Docket 98D-0997.United States Federal Drug Administration, Rockville, MD. Mitchell, JP; PA Costa; S Waters. 1987. An assessment of an Andersen Mark-I Cascade Impactor.J. Aerosol Sci. 19: 213-221). Various parameters can be determined using this technique, including opioid output rate, MMAD and fine particle components. The ACI was operated at 28.3 liters / minute under routine laboratory conditions to test commercially available nebulizers with moldings. MMAD is described in US Food and Drug Administration Protocol 601 (USP 26-NF21-2003, Chapter 601: Physical Tests and Determinations: Aerosols.United States Pharmacopoeia, Rockville, MD, 2105-2123. United States Federal Drug Administration (FDA).) The fine particle dose was measured as a component in the total aerosol output collected in ACI and deposited on the plate using a limit parameter of less than 4.7 microns. The total amount of opioid drug and lipid carrier deposited during the different steps of ACI was determined by HPLC analysis.

Various commercially available small volume nebulizers, breath-actuated AeroEclipse; Trudell Medical, London, Ontario), breath-enhanced Pari-LC Plus (PARI GmbH, Starnberg, Germany), and two conventional nebulizers, namely MistyNeb (Allegiance Healthcare Corp., McGraw Park, IL) and OptiMist (Maersk Medical Inc., McAllen, Texas) was tested with ACI technology. For each device, the theoretical deposition rate of fentanyl in the lung is multiplied by the experimentally measured opioid output rate (mcg / sec) for 1 minute average inhalation time (20 seconds), taking into account the experimentally measured fine particle composition. Calculated by calibrating.

In order to determine whether theoretically fentanyl deposited in the deep lung of the lung can be correlated with the average delivery rate of total fentanyl in vivo, a single dose of a mixture of the free fentanyl and the liposome encapsulated fentanyl is given to a healthy volunteer. Treated. The results are summarized below:

Device Theoretical deposition (ACI) Actual deposition (in vivo) a) AeroEclipse 31 mcg / min 29 mcg / min b) MistyNeb 23 mcg / min 17 mcg / min c) OptiMist 26 mcg / min 12 mcg / min d) PariLC 42 42 mcg / min 37 mcg / min

This experiment shows that the inhalation rate using a particular fentanyl composition (as described in Example 5 above) is in the range of the rate at which fentanyl deposits in the lung core. Using the respiratory-active AeroEclipse nebulizer and the respiratory-expandable Pari-LC Plus nebulizer, a theoretical close correlation between the deposition rate and the actual deposition rate was found. For conventional small jet nebulizers, MistyNeb and OptiMist, a theoretical correlation between deposition rate and actual deposition rate was observed to be poor, with actual deposition rates lower than expected in vitro studies. The experiment also shows that the desired deposition rate of opioids can be achieved by studying different composition combinations (using different opioid concentrations or different opioid ratios), combined using various nebulizers, using conventional test methods. How to determine the optimal combination.

Example  7: in human subjects Fentanyl Preparation  Clinical Trials on Qualitative Effects

The following examples illustrate how patients utilize the analgesic effects and side effects of an appropriate amount of inhaled drug formulation to deliver a therapeutically effective amount of analgesic.

Formulations containing a mixture of free fentanyl and liposome encapsulated fentanyl were prepared using the method described in Example 5. The final formulation contained 35 to 45% free fentanyl and residue as the free drug in the encapsulation component.

Patients who underwent arthroscopic anterior cruciate ligament repair were studied. Standardized general analgesics were administered with intravenous fentanyl as intra-operative opioid analgesics. After surgery, for patients recovering from post anesthetic care units (PACU), when patients first report moderate or severe pain, 8 liters / Patients were treated with a mixture of free fentanyl and liposome encapsulated fentanyl using an AeroEclipse ^™ nebulizer respiratory-activator with compressed air set in minutes.

Patients self-regulated their doses by spontaneous inhalation from the mouth-piece of an AeroEclipse nebulizer filled with a mixture of free fentanyl and liposome encapsulated fentanyl. Patients were instructed to record the first recognizable onset of analgesia, and the time at which self-administration was stopped at the onset of effective pain or onset of side effects. Subjects who reached effective analgesia when the nebulizer no longer generated an aerosol were fed with a second nebulizer, additionally 3 ml filled with a free fentanyl and liposome encapsulated fentanyl mixture. In this way, the patients, in fact, were treated with "ad libitum". Patient self-administration of nebulized drugs requires patients to hold the nebulizer in their hands, to place the mouthpiece of the nebulizer with a tight seal in their mouth, and to operate the nebulizer during the inhalation of the breathing cycle. do. Patients were instructed to "normally breathe" during the course of treatment until pain was reached.

Patients were observed for any negative phenomena including changes in respiratory rate and blood oxygen degradation. Before and after self-administration of the nebulized drug, their pain level should be expressed as "None", "Severe", "Severe", "Severe", and the time when the pain first disappeared. To indicate.

During this “single dose” or “single treatment” study, conventional analgesic drug treatment (intravenous morphine administration) is available for all patients at any time they feel pain disappeared.

The majority of post-surgery patients (80%) are suitable for treatment with nebulized drugs and these are the "severe" (46%) to "severe" (34%) operations in PACU. Patients reporting post-pain pain Patients with “moderate” post-operative pain were not treated.

95% of patients eligible for this treatment were able to successfully reach perceived analgesia immediately after initiating the spray using the drug of this study, and could stop self-titrating their dose to the appropriate / effective point by stopping the spray. Could. The average time to first perceived analgesic effect was 5.2 minutes. The effective analgesia time was 22.8 minutes after self-administration of the drug. At the appropriate / effective analgesia, 5% reported no pain, 78% reported “mild” pain, and 12% reported that their pain ranged from “severe” to “severe”. The pain was reported to be alleviated. Patients who reached adequate / effective analgesia were recorded as pain disappeared. 17% of patients no longer needed opioids during the 12 hour trial. 83% of patients experienced pain disappearing on average 2 hours after inhalation and required intravenous morphine administration.

95% of treated patients reported effective analgesia after self-administration of the nebulized drug and none experienced a toxic effect. 84% of patients discontinued self-administration of drugs when satisfactory analgesia levels were reached. Eleven percent of patients stopped taking the drug self-administered immediately (3 minutes) after feeling side effects (drowsiness or nausea).

These results show that patients can avoid toxicity by administering a therapeutically effective amount of analgesic agent using the analgesic effects and side effects of a properly inhaled drug formulation.

Example 8: Testing of Various Formulations for Optimal Delivery of Drugs

The following examples show various opioid formulations suitable for use in the present invention. The formulation is based on known pharmacokinetic and pharmacodynamic profiles for drug components, known equivalent efficacy compared to fentanyl, and the results of these clinical trials.

Formulations comprising opioid mixtures were prepared according to the formulation table below:

Rapid onset opioid Sustainable Opioid Intrapulmonary deposition rate (mcg / min) shape Concentration (mcg / ml) shape Concentration (mcg / ml) Pentacyl 200 Liposome fentanyl 300 15-60 Fentanyl 175 Liposome fentanyl 325 15-60 Fentanyl 125 Liposome fentanyl 275 15-60 Alfentanil 1600 morphine 12000 400-1600 Alfentanil 1400 morphine 13000 400-1600 Alfentanil 1800 morphine 11000 400-1600

What has been described above is illustrative only and is not intended to limit the scope of the invention as defined by the following claims.

Claims (106)

As an opioid formulation for use in a method of providing analgesia to a patient while avoiding toxicity; The method comprises continuously inhaling the formulation with a pulmonary disease drug delivery device to produce analgesia, and stopping inhalation when satisfactory analgesia is reached or when side effects begin; The lung disease drug delivery device is configured to deposit agent particles at an effective rate into the lungs; The formulation comprises an effective amount of one or more rapid-initiating opioids, and one or more sustained-effective opioids, and a pharmaceutically acceptable carrier, wherein the concentration and form of each opioid is determined by pain during Before the onset of the side effect occurs before the onset of the toxicity and the maximum opioid plasma concentration is selected so as not to reach the toxic level such that the onset of the side effect is terminated by the patient to end toxicity. Formulations used to avoid. The formulation of claim 1, wherein the concentration and form of each opioid is selected such that the maximum opioid plasma concentration at the onset of adverse reaction is at least 66% of the maximum opioid plasma concentration. The formulation of claim 2, wherein the concentration and form of each opioid is selected such that the maximum total opioid plasma concentration at the onset of side effects is at least 80% of the maximum total opioid plasma concentration. 4. The method of claim 1, wherein the one or more fast-starting opioids is selected from the group consisting of fentanyl, alfentanil, sufentanil and remifentannil. Formulation characterized in that. The formulation of claim 4, wherein said at least one quick-starting opioid is selected from fentanyl and alfentanil. The method according to any one of claims 1 to 5, wherein the one or more sustained-effect opioids are morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine ( meperidine, an opioid encapsulated in a biocompatible carrier that delays drug release at the lung surface, and a liposomally encapsulated opioid. 7. The formulation of claim 6, wherein said liposome encapsulated opioid is liposome encapsulated fentanyl. 8. The formulation of claim 7, wherein said at least one sustained-effect opioid is selected from morphine and liposome encapsulated fentanyl. The formulation of claim 1, wherein the opioid in the formulation consists of free fentanyl and liposome encapsulated fentanyl. The formulation of claim 9, wherein the total opioid concentration is between 250 and 1500 mcg / ml. The formulation of claim 10, wherein the ratio of free fentanyl to liposome encapsulated fentanyl is about 2: 3. 12. The opioid formulation of claim 10 or 11 comprising the free fentanyl at a concentration of about 100-400 mcg / ml. 13. The opioid preparation according to claim 10, 11 or 12 which contains the liposome encapsulated fentanyl at a concentration of 250 to 750 mcg / ml. The method according to any one of claims 10 to 13, wherein the total opioid concentration is about 500 mcg / ml, the free fentanyl concentration is about 200 mcg / ml and the liposome encapsulated fentanyl concentration is about 300 mcg / ml. Opioid formulation characterized by. The formulation according to claim 1, wherein the formulation contains two or more different opioids (except for formulations in which only two opioids are free fentanyl and liposome encapsulated fentanyl). The formulation according to any one of claims 1 to 15, wherein the opioid in the formulation consists of alfentanil and morphine. 18. The formulation of claim 16, wherein said alfentanil is contained at a concentration of 300 to 6700 mcg / ml. 18. The formulation according to claim 16 or 17, wherein the morphine is contained at a concentration of 650 to 13350 mcg / ml. A method of administering an opioid agent to provide analgesia to a patient while avoiding toxicity, the method comprising: Continuously inhaling said formulation using a lung disease drug delivery device configured to deliver formulation particles to the lung at an effective rate to produce analgesia; And Stopping inhalation when satisfactory analgesia is reached or when side effects are initiated; The formulation comprises an effective amount of a quick-initiating opioid of one or more and a pharmaceutically acceptable carrier; The concentration and form of each opioid, and the effective particle delivery rate, during inhalation, analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs before the onset of toxicity, and also the maximum opioid plasma concentration reaches the toxicity level. Wherein the onset of the adverse event is used by the patient to end inhalation to avoid toxicity. 20. The method of claim 19, wherein the formulation is administered by a lung disease drug delivery device at a mass medium aerodynamic diameter of 1 to 5 microns. The method of claim 20, wherein the formulation is administered by a lung disease drug delivery device with a mass average aerodynamic particle diameter of 1 to 3 microns. The method of claim 21, wherein the agent is administered by a lung disease drug delivery device with a mass average aerodynamic particle diameter of 1.5 to 2 microns. 23. The method of any one of claims 19 to 22, wherein the concentration and form of each opioid is selected such that the maximum opioid plasma concentration at the onset of the adverse event is at least 66% of the maximum opioid plasma concentration. 24. The method of any one of claims 19 to 23, wherein the concentration and form of each opioid is selected such that the maximum opioid plasma concentration at the onset of adverse events is at least 80% of the maximum opioid plasma concentration. 25. The method of any one of claims 19 to 24, wherein the one or more fast-initiating opioids are selected from fentanyl, alfentanyl, sufentanil and remifentanil. The method of claim 25, wherein the one or more fast-starting opioids is selected from fentanyl and alfentanyl. 27. The method of any one of claims 19-26, further comprising an effective amount of one or more sustained-effective opioids to provide sustained relief, wherein the concentration and form of each opioid in the formulation is During inhalation, analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs before the onset of toxicity, and also the maximum opioid plasma concentration is selected so that the toxicity level is not reached by the patient. Used to terminate inhalation to avoid toxicity. The method of claim 27, wherein the one or more sustained-effect opioids are encapsulated in morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, a biocompatible carrier that delays drug release at the lung surface Opioids, and liposome encapsulated opioids. 29. The method of claim 28, wherein said liposome encapsulated opioid is liposome encapsulated fentanyl. 30. The method of claim 27, 28 or 29, wherein said at least one sustained-effect opioid is selected from morphine and liposome encapsulated fentanyl. 31. The method of any of claims 27-30, wherein the opioid in the formulation consists of free fentanyl and liposome encapsulated fentanyl. 32. The method of claim 31, wherein the concentration ratio of free fentanyl to liposome encapsulated fentanyl is from 1: 5 to 2: 1. 33. The method of claim 32, wherein the ratio of free fentanyl to liposome encapsulated fentanyl is about 2: 3. 34. The method of any one of claims 31-33, wherein the total opioid concentration is 250-1500 mcg / ml. 34. The method of any one of claims 19 to 33, wherein the formulation comprises free fentanyl at a concentration of 100 to 400 mcg / ml. 34. The method of any one of claims 19 to 33, wherein the formulation comprises liposome encapsulated fentanyl at a concentration of 250 to 750 mcg / ml. The method of claim 19, wherein the total opioid concentration is about 500 mcg / ml, the free fentanyl concentration is about 200 mcg / ml, and the liposome encapsulated fentanyl concentration is about 300 mcg / ml. . 38. The method of any one of claims 31-37, wherein 4-50 mcg / min of free fentanyl is deposited in the lungs during inhalation. The method of claim 38, wherein 10-20 mcg / min of free fentanyl is deposited in the lungs during inhalation. The method of claim 39, wherein about 15 mcg / min of free fentanyl is deposited in the lungs during inhalation. 38. The method of any one of claims 31-37, wherein 5 to 150 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation. 42. The method of claim 41 wherein 10 to 90 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation. The method of claim 42, wherein between 15 and 60 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation. The method of claim 43, wherein 20 to 45 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation. 45. The method of any one of claims 19-44, wherein 5-100 mcg / min total opioid is deposited in the lungs during inhalation. 46. The method of claim 45, wherein 10-40 mcg / min total opioid is deposited in the lungs during inhalation. The method of claim 46, wherein 30 to 35 mcg / min total opioid is deposited in the lungs during inhalation. 31. The method of any one of claims 19-30, wherein the formulation comprises two or more other opioids (except formulations in which only two opioids are free fentanyl and liposome encapsulated fentanyl). 49. The method of claim 48, wherein the opioid in the formulation consists of alfentanil and morphine. The method of claim 49, wherein the formulation contains alfentanil at a concentration of 300 to 6700 mcg / ml. 51. The method of claim 49 or 50, wherein 100 to 500 mcg / min of alfentanil is deposited in the lungs during inhalation. The method of claim 51, wherein about 250 mcg / min of alfentanil is deposited in the lungs during inhalation. 53. The method of any one of claims 49-52, wherein the formulation contains morphine at a concentration of 650-13350 mcg / ml. 54. The method of any one of claims 49-53, wherein 100-2000 mcg / min morphine is deposited in the lungs during inhalation. 55. The method of claim 54, wherein 200-1000 mcg / minute morphine is deposited in the lungs during inhalation. The method of claim 55, wherein about 500 mcg / minute morphine is deposited in the lungs during inhalation. The method of claim 19, wherein the administration is during inhalations of 50-500. Use of opioid side effects to prevent opioid toxicity. A lung disease drug delivery device containing an opioid formulation to provide analgesia to a patient, the device comprising: A container containing a formulation according to any one of claims 1 to 18; An outlet coupled to the vessel; Means coupled to the container for dispensing the agent particles through the outlet into the lungs at an effective rate through conscious patient effort, such that, during inhalation, analgesia may initiate initiation of opioid side effects. Reached before, the onset of the adverse event occurs before the onset of the toxicity, and the maximum opioid plasma concentration does not reach the toxic level so that the onset of the adverse event is used by the patient to end inhalation to avoid toxicity. Device. A lung disease drug delivery device containing an opioid formulation to provide analgesia to a patient, the device comprising: A container containing a formulation comprising an effective amount of one or more quick-starting opioids and a pharmaceutically acceptable carrier; An outlet coupled to the vessel; Means coupled to the container for administering the agent particles to the lungs through the outlet, the means requiring conscious patient effort to operate; Here, the concentration and form of each opioid and the effective rate of particle delivery are such that during inhalation, analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs before the onset of toxicity, and the maximum opioid plasma concentration is at the toxic level. Wherein the onset of the adverse event is used by the patient to end inhalation to avoid toxicity. 61. The device of claim 59 or 60, further comprising delivery rate control means for limiting the rate at which the agent is administered to be below a predetermined threshold. 62. The device of claim 59 or 61, further comprising a fenestration in which the outlet must be sealed by the patient's lips in order to administer the formulation. 64. The device of claim 59 or 61, wherein said means of administration is actuated by breathing. 64. An apparatus according to claim 59 or 63 wherein the mass mean aerodynamic diameter of the particles is 1 to 5 microns. 65. The apparatus of claim 64, wherein the mass mean aerodynamic diameter is 1-3 microns. 66. The apparatus of claim 65, wherein the mass average aerodynamic diameter of the particles is 1.5 to 2 microns. 64. The device of any one of claims 61-63, wherein the means for administering the particles administers 0.2% to 1% of the agent per inhalation. 68. The device of any one of claims 60 to 67, wherein the concentration and form of each opioid is selected such that the maximum opioid plasma concentration at the onset of the adverse event is at least 66% of the maximum opioid plasma concentration. 69. The device of claim 68, wherein the concentration and form of each opioid is selected such that the maximum opioid plasma concentration at the onset of side effects is at least 80% of the maximum opioid plasma concentration. 70. The device of any one of claims 60-69, wherein the one or more fast-starting opioids is selected from fentanyl, alfentanil, sufentanil and remifentanil. 71. The device of claim 70, wherein the one or more fast-starting opioids is selected from fentanyl and alfentanil. 72. The device of any one of claims 60-71, further comprising an effective amount of one or more sustained-effective opioids to provide sustained relief, wherein each opioid concentration and form in the formulation, during inhalation, Analgesia is reached before the onset of the adverse event, the onset of the adverse event occurs before the onset of toxicity, and also the maximum opioid plasma concentration is chosen so that it does not reach the toxic level, such that the onset of the adverse effect is terminated by the patient by ending the toxicity. The apparatus, which is used to avoid. 73. The method of claim 72, wherein the one or more sustained-effect opioids are encapsulated in morphine, morphine-6-glucuronide, methadone, hydromorphone, meperidine, biocompatible carriers that delay drug release at the lung surface. Opioids, and liposome encapsulated opioids. 74. The device of claim 73, wherein the liposome encapsulated opioid is liposome encapsulated fentanyl. 75. The device of claim 72, 73 or 74, wherein the one or more sustained-effect opioids are selected from morphine and liposome encapsulated fentanyl. 76. The device of any one of claims 72 to 75, wherein the opioid in the formulation consists of free fentanyl and liposome encapsulated fentanyl. The device of claim 76, wherein the concentration ratio of free fentanyl to liposome encapsulated fentanyl is from 1: 5 to 2: 1. The device of claim 77, wherein the ratio of free fentanyl to liposome encapsulated fentanyl is about 2: 3. 79. The device of any of claims 59-78, wherein the total opioid concentration is 250-1500 mcg / ml. 80. The device of any one of claims 59-79, wherein the formulation comprises free fentanyl at a concentration of 100-400 mcg / ml. 81. The device of any one of claims 59-80, wherein the formulation comprises liposome encapsulated fentanyl at a concentration of 250-1500 mcg / ml. The device of claim 59, wherein the total opioid concentration is about 500 mcg / ml, the free fentanyl concentration is about 200 mcg / ml and the liposome encapsulated fentanyl concentration is about 300 mcg / ml . 83. The device of any one of claims 76-82, wherein 4-50 mcg / min of free fentanyl is deposited in the lungs during inhalation. 84. The device of claim 83, wherein 10-20 mcg / min of free fentanyl is deposited in the lungs during inhalation. 85. The device of claim 84, wherein about 15 mcg / min of free fentanyl is deposited in the lungs during inhalation. 86. The device of any one of claims 76 to 85, wherein 5 to 150 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation. 87. The device of claim 86, wherein 10 to 90 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation. 88. The device of claim 87, wherein between 15 and 60 mcg / min liposome encapsulated fentanyl is deposited in the lungs during inhalation. 89. The device of claim 88, wherein 20 to 45 mcg / minute liposome encapsulated fentanyl is deposited in the lungs during inhalation. 90. The device of any one of claims 59-89, wherein 5-100 mcg / min total opioid is deposited in the lungs during inhalation. 93. The device of claim 90, wherein 10-40 mcg / min total opioid is deposited in the lungs during inhalation. 92. The device of claim 91, wherein a total opioid of 30 to 35 mcg / min is deposited in the lungs during inhalation. 76. The device of any one of claims 59-75, wherein the formulation comprises two or more different opioids (except formulations in which only two opioids are free fentanyl and liposome encapsulated fentanyl). 95. The device of claim 93, wherein the opioid in the formulation consists of alfentanil and morphine. 95. The device of claim 94, wherein the formulation contains alfentanil at a concentration of 300 to 6700 mcg / ml. 98. The device of claim 94 or 95, wherein 100 to 500 mcg / min of alfentanil is deposited in the lungs during inhalation. 98. The device of claim 96, wherein about 250 mcg / min of alfentanil is deposited in the lungs during inhalation. 98. The device of any of claims 93-97, wherein the formulation contains morphine at a concentration of 650 to 13350 mcg / ml. 99. The device of any of claims 93-98, wherein 100 to 2000 mcg / min morphine is deposited in the lungs during inhalation. 100. The device of claim 99, wherein 200 to 1000 mcg / minute morphine is deposited in the lungs during inhalation. 101. The device of claim 100, wherein about 500 mcg / minute morphine is deposited in the lungs during inhalation. 102. A lung disease drug delivery device according to any one of claims 59 to 101; And An opioid dosing kit comprising instructions for using the device, including continuously inhaling the formulation with the device and ending the inhalation when satisfactory analgesia is reached or at the onset of side effects. ). Preparations comprising one or more quick-initiating opioids and a pharmaceutically acceptable carrier; Pulmonary disease drug delivery comprising a container, an outlet coupled to the container, means coupled to the container for administering the agent particles contained therein to the lungs through the outlet at an effective rate through operative patient effort. As a device, therefore, during inhalation, analgesia is reached before the onset of the adverse event, and the onset of the adverse event occurs prior to the onset of toxicity such that the maximum total opioid plasma concentration does not reach the toxic level, thereby allowing the patient to A lung disease drug delivery device, wherein the onset of the side effect is used by the patient to end inhalation to avoid toxicity; And Instructions for using the device including filling the container with a formulation, continuously inhaling the formulation using the device, and ending the inhalation when satisfactory analgesia is reached or at the onset of adverse reactions ; Opioid dosage kit comprising a. 107. The opioid dosage kit of claim 103, wherein said formulation comprises an effective amount of one or more sustained-effective opioids. As an opioid formulation for use in a method of providing analgesia to a patient: 150-250 mcg / ml free fentanyl; Liposome encapsulated fentanyl at 200-400 mcg / ml; And Opioid formulations comprising a pharmaceutically acceptable carrier. As an opioid formulation for use in a method of providing analgesia to a patient via administration of a pulmonary route: Two or more other opioids (except for agents in which only two opioids are free fentanyl and liposome encapsulated fentanyl); And Opioid formulations comprising a pharmaceutically acceptable carrier.

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