Title of Invention

OPIOID DELIVERY SYSTEM

Abstract An opiod formulation for pulmonary administration in the treatment 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.
Full Text Field of the invention
This invention relates to pharmaceutical preparations and methods of
administering same and, more particularly, to opioid based analgesics and a method for
their administration.
Background of the invention
Opioids are among the oldest drugs in existence, and remain a mainstay of pain
management. Opium, the original opioid, is derived from poppy plants. "Opiates" are
natural derivatives of opium, and include morphine, methadone, and heroin. "Opioids"
are a broader class of drugs, that includes opium, opiates, and synthetic drugs with the
same pharmacological effect of opium. Commonly used synthetic opioids include
meperidine, fentanyl, alfentanil, sufentanil, and remifentanil.
Opioids are believed to exert their effects through binding of the mu receptor in
the spinal cord and brain, and peripheral tissues. Binding at the mu receptor induces a
wide variety of pharmacological effects, including therapeutic effects such as analgesia,
effects which may be viewed as either side effects or therapeutic effects, depending on
context, including sedation and decreased bowel motility, side effects such as nausea,
vomiting, urinary retention, pruritis, ventilatory depression, addiction, and toxicity such
as severe ventilatory depression, loss of consciousness and death.
Opioids differ from each other in many ways, including their route of delivery,
their physicochemical composition, their drug absorption rate, their pharmacokinetics,
and their pharmacodynamics. Noninvasive routes of opioid delivery include oral, rectal,
transdermal, transmucosal, and via inhalation. Invasive routes of opioid delivery include
intravenous, intramuscular, epidural, spinal, and by injection into joints. When injected
intravenously, some opioids quickly enter the brain and spinal cord and thus have a very
rapid onset of drug effect (e.g., alfentanil and remifentanil), while others are absorbed
slowly to the site of action and have very slow onset of drag effect (e.g., morphine).
Similarly, for some opioids the drug effect is very short-lived, owing to very rapid
metabolism (e.g., remifentanil), while other opioids may have very slow metabolism and
prolonged effect (e.g., methadone). In terms of pharmacodynamics, the potency of
opioids covers nearly 5 orders of magnitude, from extraordinarily potent opioids such as
carfentanil and etorphine (both used to stun elephants) to relatively less potent drugs such
as methadone and morphine. The equivalent potencies of opipids (measured as a
"therapeutic equivalence ratio") are well established in the literature, and are often used
when- changing a patient's treatment regimen from one opioid to another.
Despite these differences, all opioids have the same potential to produce both
profound levels of analgesia, and profound toxicity from hypoxia, which can be fatal.
Because of the risk of hypoxia, physicians are reluctant to use appropriate dose|s of
opioids to treat acute and chronic pain; As a result, hundreds of thousands of patients who
could be provided better pain control receive inadequate doses of opioids. Conversely,
even with an understandably cautious approach by the health care community to
treatment of pain, every year, many patients die from opioid-induced ventilatory
depression.
Pain is highly variable and highly subjective. Different patients respond
differently to opioids. As a result, different patients need different amounts of analgesia
to treat their pain. As such, it has become desirable to allow patients to vary the amount
of analgesic they receive.
One attempt to better adjust opioid dosing in patients has been the introduction of
"patient controlled analgesia" ("PCA") (Ballantyne JC, et al. Postoperative patientcontrolled
analgesia: Meta-analyses of initial randomized control trials. J Clin Anesth
1993:5:182-193.) With the PCA system, the patient must be awake, and must activate a
delivery mechanism to receive more opioid, before the drug is given. If the patient
becomes overdosed from the opioid, then the patient will become unconscious and not
request additional drug. In this manner, the PCA system uses a side effect of opioid,
sedation, to limit the amount of opioid given. One problem with the PCA system ig that
the drug is injected rapidly after the patient requests it (typically, the time frame of
administration of drug is under 1 minute) and because the drug most frequently used in
the PCA is morphine, a drag that is slowly transferred from the plasma to the si :e of
action - this results in a delay between the patient request for drug and the analgesic effect
of the drug. As a result of this delay, patients often request a second (or third) dose of the
drug while the opioid effect level of the first injection is still rising. PCA systems include
a "lockout" period (commonly 5 minutes), which helps prevent patients from
administering more opioid while the opioid drug effect is still rising. Lockout periods are
typically controlled, defined or programmed by the health care provider, and there have

been many instances where user error or inadvertence in programming the lockout period
have resulted in the death of the patient. The patient also often feels •frustrated by the
lockout, as it diminishes the patients' control of dosing. Other disadvantages of the PCA
include the invasive parenteral (intravenous) administration as well as the expensive
infusion pumps thus restricting the use of the PCA to institutionalized patients.
A second attempt to better adjust opioid dosing in patients is in the selfadministration
of Nitrous Oxide during labour associated with childbirth. A nitrous ox|de
mask is held to the face by the patient during contractions, and is released from the face
when adequate analgesia is achieved. However, this mechanism is a titration to analgesic
effect and not used as a safety mechanism, since overdosing on nitrous oxide using this
system of administration is not a significant concern. Furthermore, nitrous oxide is a gas
which requires a heavy steel tank for storage and a complex delivery system for
administration. Therefore, the use of nitrous oxide is primarily restricted to the hospital
environment and not for ambulatory patients. An additional potential problem with
nitrous oxide relates to its low potency and thus the necessity of administering a high
concentration (more than 50%) of nitrous oxide in oxygen with a potential of a hypoxic
mixture.
The current invention seeks to use two physiological responses of opioids:
sedation and ventilatory depression, to limit the total dose of opioids that patients receive.
la this manner, the invention seeks to increase safety of opioid drug delivery beyond what
is currently accomplished with PCA or other existing opioid administration methods
whereby only a single side effect is used to limit the exposure of patients to dangerously
high levels of opioid drug effects. The invention also improves the use of sedation by
removing the need for a "lockout" period, currently required in PCA systems, arid
removing the frustration and user error possible therein.
Summary of the invention
Accordingly, the invention provides in accordance with a first aspect, an opioid
formulation for use in a method of providing analgesia to a patient comprising the-steps
of:
continuously inhaling the formulation using a pulmonary drug delivery device to
produce analgesia; and
stopping inhalation when satisfactory analgesia is achieved OK at the onset of a
side effect;
wherein the formulation comprises an effective amount of at least one rapid-onset
opioid; and a pharmaceutically acceptable carrier, the concentration arid type of each
bpioid, and amount of and particle size of the formulation delivered from the device on
each iimalation, being selected so that, during inhalation, analgesia is achieved before the
onset of said side effect, and the onset of said side effect occurs before the onset of
toxicity, and so that the maximum total opioid plasma concentration does not reach toxic
levels, whereby the onset of said side effect can be used by the patient to terminate
inhalation to avoid toxicity.
The concentration of each opioid is such that the at least one opioid enters the
patient's system in an incremental and gradual fashion so that analgesia is achieved,
followed by the onset of side effects, and well in advance of toxicity. Any conventional
diluent suitable for use in formulations for pulmonary administration may be used such as
saline or sterile water. It will be appreciated that the concentration will be adjusted leased
on other parameters, including the type of pulmonary delivery device that is used and,
more particularly, the amount of formulation which is dispensed by the device on each
inhalation and particle size of the formulation dispensed (expressed in terms of "mass
medium aerodynamic diameter").
In order that the formulation is bioavailable (i.e. is deposited hi the lungs), the
formulation should be dispensed by the pulmonary drug delivery device at a mass
medium aerodynamic diameter of from 1 to 5 microns, or from 1 to 3 microris, or from
1.5 to 2 microns.
To avoid toxicity following termination of inhalation, the maximum total opioid
plasma concentration at the onset of side effect is preferably no less than 66% of the
maximum total opioid plasma concentration, and more preferably no less than 80% of the
maximum total opioid plasma concentration.
The rapid-onset opioid may be chosen from fentanyl, alfentanil, sufentanil and
remifentanil and is preferably fentanyl and alfentanil. When used as the sole rapid-onset
opioid, the amount of sufentanil may range from 1.7 to 100 meg/ml and the amount of
remifentanil may range from 3.3 to 3 300 meg/ml.
In order to reduce the frequency of administration, the opioid formulation may
comprise an effective amount of at least one sustained-effect opioid to provide sustained
relief. It will be appreciated that the relative concentration of the sustained-effect opioid
and rapid-onset opioid must be adjusted in order that the formulation may still achieve jhe
same desired result, namely, to produce analgesia followed by at least one side effect
before a toxic level of opioid in plasma is reached, and to avoid toxic levels being reajch
after termination of inhalation. In mixed formulations contained rapid-onset and
sustained-effect opioids, the rapid-onset opioid serves to limit the dose of both drujgs
below a dose that would cause toxicity.
The sustained-effect opioid may be chosen from morphine, morphine-6-
glucuronide, methadone, hydromorphone, meperidine, an opioid encapsulated in a
biocompatible carrier that delays release of the drug at the lung surface (as are known in
the art), and a liposome encapsulated opioid (e.g.. liposomally encapsulated fentanyl).
Morphine-6-glucuronide may be present hi a concentration of from 3.3 to 3300 mg/ml,
methadone may be present in a concentration of from 0.3 to 33 mg/ml, hydromorphone
may be present in a concentration of from 0.03 to 7 mg/ml, and meperidine may be
present in a concentration of from 1.7 to 170 mg/ml.
Depending on the identity of the opioids used in the formulation, the ratio of
concentration of total sustained-effect opioid to concentration of total rapid-onset opioid
will vary. A preferred formulation giving rise to both rapid-onset and sustained analgesic
effect is one in which the opioids consist of fentanyl and liposomally encapsulated
fentanyl. The ratio of concentration of liposomally encapsulated fentanyl to fentanyl may
be from 1:2 to 6:1, or from 1:1 to 5:1, or from 2:1 to 4:1, or about 3:1. Furthermore, the
total opioid concentration may be from 250 to 1500 meg/ml.
The liposomally encapsulated fentanyl may be present in a concentration of from
3.3 to 3300, or from 250 to 1500, or from 267 to 330, or from 100 to 750 meg/ml. This
total opioid concentration maybe about 500 meg/ml, the fentanyl concentration may be
about 200 meg/ml and the liposomally encapsulated fentanyl concentration may be about
300 meg/ml.
The concentration of fentanyl, and amount and particle size of the formulation
delivered from the device, may be selected so that from 4 to 50, or from 10 to 20, or about
15 mcg/min., of fentanyl is deposited in the lungs during inhalation.
The concentration of liposomally encapsulated fentanyl, and amount and particle
size of the formulation delivered from the device, maybe selected so that from 5 to 150,
or from 10 to 90, or from 15 to 60, or from 20 to 45 mcg/min of liposomally encapsulated
fentanyl is deposited in the lungs during inhalation.
In another embodiment, the opioids in1 the formulation may consist of alfefitanil
and morphine. The alfentanil may be present in a concentration of from 300 to 6700
meg/ml. Furthermore, the concentration of alfentanil, and amount and particle size of the
formulation delivered from the device, may be selected so that from 100 to 500, or about
250, mcg/min. of alfentanil is deposited in the lungs during inhalation. The morphine
may be present in a concentration of from 650 to 13350 or from 0.3 tos33 mg/ml. As
well, the concentration of morphine, and amount and particle size of the formulation
delivered from the device, may be selected so that from 100 to 2000, or from 200 to 1000,
or about 500, mcg/min of morphine is deposited in the lungs during inhalation.
In accordance with a second aspect of the invention, there is provided a method of
administering an opibid formulation to provide analgesia to a patient, comprising the
steps of:
continuously inhaling the formulation using a pulmonary drug delivery device to
produce analgesia; and
stopping inhalation when satisfactory analgesia is achieved or at the onset of a
side effect;
wherein the formulation comprises an effective amount of at least one rapid-onset
opioid and a pharmaceutically acceptable carrier; the concentration and type of each
opioid, and amount of and particle size of the formulation delivered from the device on
each inhalation, being selected so that, during inhalation, analgesia is achieved befori the
onset of said side effect, and the onset of said side effect occurs before the onset of
toxicity, and so that the maximum total opioid plasma concentration does not reach toxic
levels, whereby the onset of said side effect can be used by the patient to terminate
inhalation to avoid toxicity.
The pulmonary drag delivery device may comprise:
a container containing said formulation;
means for'forming the formulation into particles having a mass mediim
aerodynamic diameter of from 1 to 5 microns for delivery to a patient;
an outlet through which the formulation is dispensed; and
means for dispensing said formulation through said outlet;
wherein the device is adapted to dispense the formulation only through an exercise
of conscious effort by the patient.
The time to onset of the side effect (e.g. ventilatory depression and/or sedation)
will vary from patient to patient and will depend on factors such as the opioids used, thoir
concentrations, relative amounts, and particle size. For example, the onset may occur
from 3-15 minutes following the start of inhalation, and the side effect may peak within
1-2 minutes after the patient stops inhaling the formulation (i.e. at the end of dose).
Typically, the patient will inhale the formulation over a period of from about 2 to 20
minutes, at a normal inhalation rate, before the onset of side effects. Similarly, the tirie
after the end of the dose by which the maximum plasma concentration is reached will also
vary based on various parameters include the above-mentioned parameters. For examp e,
the maximum plasma concentration may be reached within 0 to 5 minutes following tie
end of dose. Normal inhalation rates are typically less than 20 and more often from 5 to
15 breaths per minute.
In accordance with a third aspect of the invention, there is provided a pulmona]ry
drug delivery device comprising:
a container containing a formulation comprising an effective amount of at le^st
one rapid-onset opioid and a pharmaceutically acceptable carrier;
means for forming the formulation into particles having a mass medium
aerodynamic diameter of from 1 to 5 microns for delivery to a patient;
an outlet through which the formulation is dispensed; and
means for dispensing said formulation through said outlet;
wherein the device is adapted to dispense the formulation only through an exercise
of conscious effort by the patient; and the concentration and type of each opioidj, and
amount of and particle size of the formulation delivered from the device on each
inhalation, is selected so that, during inhalation, analgesia is achieved before the onset of
said side effect, arid the onset of said side effect occurs before the" onset of toxicity, and so
that the maximum total opioid plasma concentration does not reach toxic levels, whereby
the onset of said side effect can be used by the patient to terminate inhalation to avoid
toxicity. Examples of devices which require a conscious effort by the patient to actuate
include those having a button which must be manually depressed using a certain degree of
force, and those which are breath actuated.
The device may further comprise a mechanical or electrical delivery rate
controlling means for limiting the,rate at which the formulation is dispensed to below a
selected threshold such that the objects of the invention may be achieved^. The delivery
rate controlling means may include a mechanism for measuring ventilatory depression
and limit the rate of dispensation based on this information. Ventilatory depression) may
be measured by the respiratory rate, inspiratory force or value of end tidal CO2 cf the
patient.
The device may weigh from 250 to 2500 grams and may be designed such that the
weight is adjustable on a patient by patient basis. Furthermore, the outlet ma
designed to be difficult to maintain in the patient's mouth if the patient is not
conscious. For example, the outlet may comprise a fenestration which must be seal
y be
fully
dby
the lips of the patient in order for the formulation to be dispensed, m this way, continued
administration of the formulation may be hampered by the onset of side effects such as
sedation and ventilatory depression.
The invention also provides an opioid administration kit, in accordance w^ith a
fourth aspect, comprising: .
a pulmonary drug delivery device comprising a container; means for forming a
formulation contained in the container into particles having a mass medium aerodynamic
diameter of from 1 to 5 microns for delivery to a patient; an outlet through which the
formulation is dispensed; and means for dispensing said formulation through said outlet;
wherein the device is adapted to dispense the formulation only through an exercise of
conscious effort by the patient; and
an opioid formulation contained in the container or for receipt by the contaiier,
said formulation comprising an effective amount of at least one rapid-onset opioid acd a
pharmaceutically acceptable carrier; the concentration and type of each opioid, ,aid
amount of and particle size of the formulation delivered from the. device on each
inhalation, being selected so that, during inhalation, analgesia is achieved before the or set
of said side effect, and the onset of said side effect occurs before the onset of toxicity, £tnd
so that the maximum total opioid plasma concentration does not reach toxic levols,
whereby the onset of said side effect can be used by the patient to terminate inhalation! to
avoid toxicity; and |
instructions for using said kit comprising the steps of continuously inhaling the
formulation using a pulmonary drug delivery device to produce analgesia; and stoppi ig
inhalation when satisfactory analgesia is achieved or at the onset of a side effect. The 1 it
might include an empty device which must be filled with the opioid formulation prior to
administration. In such event, the instructions may include the step of pre-filling the
container. "
hi accordance with further aspects of the invention, mere is provided a use of the
present formulation in providing analgesia to a patient and in the manufacture of la
medicament for doing same.
Useful drug formulations and parameters for administration according to
present invention can be determined by the person skilled in the art based on kno
pharmacological data as well as through pharmacokinetic and pharmacodynamil
modeling as herein described. Such modeling is intended to ensure that analgesic effe
is achieved before the onset of a side effect, and that the onset of the side effect occ
well in advance of toxicity, and to ensure that once the patient stops inhaling the
formulation, there will not be a continued rise in total opioid concentration in the plasm
to toxic levels.
Brief Description of the Drawings
Figure 1 is a flow diagram which represents a computer simulation model for
sedation.
Figure 2 is a flow diagram which represents a computer simulation model for
ventilatory depression.
Figure 3 is a flow diagram which represents a computer simulation model for an
inhalation device.
: , ' ' • ' I
Figure 4 is a flow diagram which represents a computer simulation model for the
pharmacokinetic profiling of opioid as administered to a patient through a pulmonary
route.
Figure 5 is a flow diagram which represents the Stella™ computer simulation of
the pharmacpkinetics of the administration of a single opioid.
Figure 6 is a graph showing output of the Stella™ computer simulation of Figure
5 (ventilatory depression and sedation models disabled) expressed as a time course of
quantity of opioid in the inhalation device and in the lung of the patient.
Figure 7 is a graph showing the time course of ventilatory depression hi the
Stella™ computer simulation of Figure 5 (ventilatory depression and sedation me dels
disabled).
Figure 8 is a graph showing the time course of quantity of opioid in the inhalation
device and in the lung of the patient, in the Stella™ computer simulation of Figure 5
(ventilatory depression model enabled, sedation model disabled).
Figure 9 is a graph showing the time course of ventilatory depression in the
Stella™ computer simulation of Figure 5 (ventilatory depression model enabled, sedition
model disabled).
Figure 10 is a graph showing the time course of quantity of opioid in the
inhalation device and in the lung of the patient, in the Stella™ computer simulatiojn of
Figure 5 (ventilatory depression and sedation models enabled).
Figure 11 is a graph showing the time course of ventilatory depression in the
Stella™ computer simulation of Figure 5 (ventilatory depression and sedation models
enabled).
Figure 12 is a flow diagram which represents a computer simulation model foj: the
administration of two opioids.
Figure 13 is a flow diagram which represents the Stella™ computer simulation of
the pharmacokinetics of the administration of two opioids.
Figure 14 is a graph showing the output of Stella™ computer simulation of Figjire
13 expressed as a time course of total quantity of opioid in the inhalation device and] in
the lung of the patient (ventilatory depression and sedation models enabled). !
• . I
Figure 15 is a graph showing the time course of concentration of each opioid a|nd
of total opioid at the effect site in the Stella™ computer simulation of Figure 13
(ventilatory depression and sedation models enabled).
Figure 16 is a graph showing the time course of ventilatory depression during ajtid
after delivery of opioids in the Stella™ computer simulation of Figure 13 (ventilatcjry
depression and sedation models enabled).
Figure 17 is a flow diagram which represents the StellaT M computer simulation of
the pharmacokinetics of the administration of two opioids, where the two opioids beijig
administered are alfentanil and morphine.
9
Figure 18 is a graph showing the time course of concentration of alfentanil,
morphine, and combined opioid at the effect site in the Stella™ computer simulation
Figure 17 (ventilatory depression and sedation models enabled).
Figure 19 is a graph showing the time course of ventilatory depression in 1
Stella™ computer simulation of Figure 17 (ventilatory depression and sedation models
enabled).
Figure 20 is a graph showing maximum concentration of opioid in the plasma
against end of dose concentration of opioid in the plasma of patients administered opioid.
Figure 20A shows patients administered with a combination of fentanyl and liposomal y
encapsulated fentanyl through a pulmonary route. Figure 20B shows patients
administered with fentanyl intravenously.
Figure 21 is a graph showing time to side/toxic effect versus tune to end of dos|e
for the side effects and toxic effects of patients administered a combination of fentanyl
and liposomally encapsulated fentanyl through a pulmonary route.
Figure 22 is a table showing the statistical correlation of side effect to toxic effect.
Detailed description of the invention
In this application, the following terms have the following meanings:
"Analgesic effect" or "analgesia" means the relief from pain resulting from
action of a drug.
"Drug delivery profile" means the concentration of the drug, over, time, at the
of drug effect, as determined by the amount and rate of drug administered to the patient
and the pharmacokinetics relating dose inhaled to concentration in the lungs, plasma and
at the site of drug effect.
the
site
"Hypoxia" is atoxic effect of opioid administration, and is defined in this application
decrease in blood Oz concentration to less than 90% saturation.
as a
'Ventilatory depression" means a decrease in the fate, tidal volume, and/or flow
rate of air into the lungs. Ventilatory depression may manifest as dizziness, shortnej s of
breath, or a slowing in rate of breathing. "Opioid induced ventilatory depression" mfers
to ventilatory depression caused by the action of an opioid at a site of drug effect.
"Sedation" means a decrease in attention, mental awareness, focus, and stale of
consciousness caused by opioids, and manifests in a lack of physical strength (muscle
fatigue), lack of voluntary activity, lethargy, drowsiness, and sleep. "Opioid-indiiced
sedation" refers to sedation caused by the action of an opioid at a site of drug effect.
"Rapid onset", when used to describe a drug formulation, means a formulation
which has an' analgesic effect that rapidly follows the rise in plasma opioid concentration.
A "rapid onset opioid" is an opioid that has an analgesic effect within 5 minutes of
administration.
"Sustained effect" means a formulation which has an analgesic effect that is
sustained over several hours. A "sustained effect opioid" means an opioid that has
analgesic effect that lasts over 2 hours.
"Side effect" means an effect of an opioid that is not analgesic or toxic. For
example, severe ventilatory depression is an example of opioid toxicity, while mild
ventilatory depression and sedation are not considered signs of opioid toxicity, but are
side effects of the opioid.
"Site of effect" refers to a physical or hypothetical site of drag action within the
patient. "Site of effecf' may be a compartment of the body, such as the brain, the liver, or
the spleen, or it may be a theoretical and unknown location based on correlation and
pharmacokinetic modeling. For example, it is known that opioids exert their analgesic
actions, in part, in the substantia gelatinosa of the spinal cord, so this is a site of opioid
analgesic effect. The concentration of opioid at the effect site may be determined by
direct measurement, or through the use of pharmacokinetic and pharmacodynarnic
modeling.
"Effective amount" means the amount of drug needed to reach an analgesic effejct.
"mass medium aerodynamic diameter" means the aerodynamic diameter j ah
aerosol such that half of the cumulative mass of all particles is contained in particles wjith
smaller (or larger) diameters and wherein the aerodynamic diameter is defined as ihe
diameter of a unit-density sphere having the same gravitational settling velocity as
particle being measured.
"breathing rate" means the number of breaths taken per unit of time.
'Titration to effect" means administering an opioid until a satisfactory analgejsic
effect is felt'by the patient, then ceasing administration of the opioid.
'Titration to side effect" means administering an opioid until a side effect is f^lt,
then ceasing administration. The ceasing of administration may be voluntary (for
example, by instructing patients to cease administration of the opioid when they start! to
feel drowsy, dizzy or short of breath) or involuntary (for example, when patients are ao
longer able to breathe effective dosages of opioid due to ventilatory depression or
sedation).
The terms "toxic", "toxicity", "toxic effect" and "opioid toxicity" refer to effe ;ts
of opioids that place a patient at risk of death. For example, opioids commonly produce
modest amounts of ventilatory depression that pose little risk to a patient. This is rot
considered an example of opioid toxicity. However, severe Ventilatory depression poses
the risk of hypoxia, loss of consciousness, and death. Thus, severe ventilatory depression
is an example of opioid toxicity, while mild ventilatory depression is not considered a
sign of opioid toxicity.
The present invention is for use in patient self-administration of opioids. Tie
invention utilizes the opioid's side effects to self-regulate the amount of opioid given tol a
patient, thereby tailoring the dose to achieve the patient's analgesic requirements, while
avoiding toxicity and death.
The use of the invention begins with the patient's perception of pain. There are
many modalities of treating mild to moderate pain, but opioids are the mainstay of
treatment for severe pain. In response to the severe pain, either the patient or .the patient's

care provider open a 'prefilled vial of opioid in liquid solution, or, alternatively, in an
emulsion. The liquid is added to a nebulizer.
The nebulizer is then brought to the mouth, and is held there with the hand. The
' . ' • • ' ••,: '•:.' ;. . ' • ' , ' • . I . : • " ' . ' • • • • '
nebulizer is not attached to the face with straps, as this prevents the 'self-Uniting
mechanism from working.
With each breath, the nebulizer releases a small amount of the liquid opioid as an
aerosol. The aerosol passes through the patient's mouth and into the trachea and Ipngs,
where the aerosolized opioid is deposited.
Throughout mis patent application, the nebulizer is also called an inhaler lor an
aerosol pulmonary drug delivery device. An inhaler may refer to either a nebulizer or a
nebulizer combined with a source of compressed air or oxygen, or any other aerosol
generating device for the administration of drug by way of the lungs. An aerosol
pulmonary drug delivery device refers to any device that allows the aerosolization of a
substance for delivery into the lungs. Various nebulizer technologies are known and
available in the art.
The rate of onset of opioid drug effect is believed to be dictated by the spejd at
which the opioid enters the lungs and the rate at which the opioid crosses the blood jrain
barrier. Some opioids, such as alfentanil and remifentanil, cross the blood brain barrier
very quickly, and thus produce very rapid onset of drug effect. Other opioids, such as
morphine and morphine-6-glucuronide, cross the blood brain barrier very slowly, and
thus produce a slow onset but sustained effect.
As the opioid crosses the blood brain barrier, it starts to exert effects at the site of
drug action. Although in some instances, patients may feel effects differently, typically,
as concentration of opioid increases, the effects felt are analgesic effect, side effect, and
toxic effect, in that order.
Ventilatory depression is up and down regulated by the opposing actionb of
opioids (which depress ventilation) and carbon dioxide (which increases ventilation). This
occurs in a feedback loop as follows: initially the opioids will depress ventilation.
Because the patient is not exhaling as much carbon dioxide, the level of carbon dioxide in
the patient's blood will rise. As the carbon dioxide rises, it stimulates ventilation, partly
offsetting the opioid-induced ventilatory depression. The opioid-induced. yentilatoiy
depression must come on sufficiently rapidly so that it occurs as the patient is inhaling tt e
opioid, thus serving to limit the amount of opioid inhaled. However, it must not come on
so rapidly as to place the patient at risk of toxic effects before the carbon dioxide has had
a chance to rise and offset the opioid induced ventilatory depression.
The amount of opioid inhaled by the patient each minute is proportional to tt|e
ventilation during that minute. As ventilation becomes depressed, the rate of opioijd
delivery to the lungs is depressed proportionally. In this way, the rate of delivery :s
slowed by ventilatory depression, decreasing the ability of the patient to self-administer a
toxic dose of opioid. The slowed uptake of opioid from ventilatory depression creates the
opportunity for complete cessation of drug delivery through the onset of sedation.
As the opioids exert their analgesic effects, patients will become sedated, in part
from the mitigation of their pain, in part due to the side effects of the opioids. As sedation
develops in patients, it becomes difficult to hold the device to the mouth, maintain a sei
with the lips, and breathe through the device to administer additional opioid. Instead, the
patient begins to breathe through the nose, or through the mouth but around the
mouthpiece of the nebulizer. With increasing sedation, the arm drops away from the
airway, removing the device from the mouth. This dropping away of the arm may the
encouraged to take place at a lower level of sedation by making the device deliberately
heavy, or by adding a weight to the device. Weight of the device can be adjusted from
patient to patient, depending on the individual patient's strength pre-sedation.
Since the side effects of the opioids typically occur at lower opioid concentrations
(as compared to the opioid toxic effects), a safer, patient self-limited opioid
administration has been created through the pulmonary administration of an opioid (or a
combination of opioids) at a rate sufficiently slow to allow for a time gap between th e
onset of side effects and the onset of toxic effects. The rate must also be slow enough (is
compared to the rate of onset of the opioid) to allow for the onset of side effects -while the
dose is being administered.
In a clinical study relating to this invention, healthy subjects were directed tio
inhale a fentanyl formulation consisting of rapidly acting free fentanyl and sustained
acting liposomal encapsulated fentanyl over 2-20 minutes. In this study, several subjects
attempted to self-limit the dose and required external assistance to receive the entire c ose.
Some subjects self-limited the dose because of opioid-induced ventilatory depression,
with a decrease in ventilation rate reducing the amount of drug irihaled. Other subsets
self-limited the dose because of sedation, and their inability to hold the device tc the
mouth to continue inhaling fentanyl. Some subjects exhibited both side effects. The trial
demonstrated that patient will, in fact, self-Limit fentanyl administration via the
pulmonary route before a toxic level of fentanyl is administered, when 1) the drug is
intended to be inhaled over a deliberately extended period of time (e.g. 2-20 minutes), 2)
opioid induced ventilatory depression occurs while the drug is being given (and before a
toxic dose is administered), and/or 3) sedation occurs while the drug is being given {and
before a toxic dose is administered). We have found mat these factors can be controlled
by designing the rate at which an opioid is given to a patient accordingly.
Prefe-rably, the opioid formulation is administered over 2-20 minutes. The total
amount of opioid administered over the 2-20 niinutes will depend on several factors,
including the type of opioid or combination of opioids delivered, and the mass medium
aerodynamic diameter (MMED) of the particles being inhaled. This administration
period results hi a rate of onset to effect that is influenced by the rate of administration
and affords the patient the ability to involuntarily self-limit the dose through the onset of
ventilatory depression and sedation. We have found that, for an alfentanyymorphine
combination drug, a range of 100-500 mcg/min of alfentanyl and 200-1000 mcg/min of
morphine is optimal (measured as drag delivered to the lung of the patient ("systemically
available drug")).
For a free and liposomally encapsulated fentanyl formulation, we have found that
the levels for systemically available drug to be optimum at 5-50 mcg/min of free fentanyl
and 15-150 mcg/min of liposomally encapsulated fentanyl. We have found that nebulized
particles with an MMED of 1-5 microns typically have bioavailability of about 20%,
which means the optimum drug flow from the nebulizer should be between 25J250
mcg/min of free fentanyl and 75-750 mcg/min of microsomaUy encapsulated fentanyl.
Our current preferred embodiment of the invention comprises a drug flow from the
inhaler of 75 mcg/min of free fentanyl and 250 mcg/min of limposomally encapsulated
fentanyl.
For other opioid formulations, we expect that a therapeutically equivalent rate )f
systemically available drug to have similar advantages.
In order to prevent peaks of. opioid effect that are more-potent than the
concentration at which patients stop taking the drug in a multiple opioid formulation wih
at least one rapid-onset opioid and at least one sustained effect opioid, we expect that the
ratio of sustained-effect opioid to rapid-onset opioid administered should be less than 1
in terms of therapeutic equivalent potency.
Another factor affecting the rate of administration of opioid is the patient
creating rate. We have found that a breathing rate of 10-15 breaths per minute (i.e.
"normal" breathing rate) is preferred.
Opioid response is highly individualized. This reflects, in part, varying levels
painful stimulation. In the presence of very severe pain, very high doses of opioids can I
administered without undue toxicity. Patients being administered chronic opioids requi
higher doses to produce both the desired therapeutic effects and opioid toxicity. This al;
reflects the development of tolerance to opioids. Physicians have sought improved meai
of administering opioids in part because of the wide range of doses required to adequate
tailor the opioid to the needs of individualized patients.
With the described invention, patients who need large doses of opioids to provi analgesia can elect to administer either a larger volume of drug (inhaled over a long
period of time), or can be offered a more concentrated solution of drug to be inhaled ov
the expected 2-20 minutes. Either way, the opioid-induced ventilatory depression ar
sedation will still attenuate, and eventually terminate, drug administration before tox
doses are inhaled. Preferably, the patient will inhale the drug over a longer period of time
Conversely, a patient who requkes only a small dose will experience the desired pain
relief during inhalation. The patient can elect to not inhale additional drag. The patieit
who unwisely continues to self-administer opioid despite obtaining the desired pain re]
will experience Ventilatory depression and sedation, which will then either voluntar
(according to the instructions given to the patient) or involuntarily'(cUie to the side effe
themselves) attenuate and subsequently terminate drag administration before inhalation of
a toxic dose of opioid. The patient is therefore empowered to self-titrate to analgesic
effect, without a lockout period and with a lower risk of toxicity.
The selection of opioid and opioid concentration (as disclosed above, or
otherwise) for the device requires consideration of the time course of opioid absorption
from the lung into the plasma, and the time course of opioid transfer from the plasma into
' . ' • ' . ' • • : / . .' j • • - ' . : • „ • ' •-
the site of drug effect (e.g., the brain or spinal cord).
' " • • ' • • : • • ' ' _. '. * • • .- • • i
Some opioids are associated with very rapid absorption from the lung into the
systemic circulation. For example, the absorption of free fentanyl from the lung into the
plasma is nearly instantaneous. This would likely be true of remifentanil, alfentanil. and
sufentanil as well. The absorption of free fentanyl released from the lipospmal
encapsulated fentanyl from the lung to the plasma is far slower.
Some opioids are associated with very rapid transfer from the plasma to the site of
drug effect. For example, peak alfentanil and remifentanil concentrations at the si;e of
drug effect occur within 2 minutes of intravenous-injection. Other opioids are associated
with very slow transfer from the plasma to the site of drug effect. For example, the peak
drug effect from an intravenous dose of morphine maybe delayed by 10-15 minutes from
the time of the injection.
For the self limiting opioid delivery system to work, one of the opioids srjould
have both rapid transfer from the lungs to the plasma, and rapid transfer from the plasma
to the site of opioid drug effect. Fentanyl, alfentanil, sufentanil, and remifentanil all liave
this characteristic (rapid onset). It may be that meperidine and methadone also have
effect, but that is not presently known. Although it is possible to obtain the reqi
parameters of the invention with a single opioid, we have found that combining the
onset opioid with a slower acting, but sustained effect opioid gives a preferred resu
the patient typically feels analgesic effect for longer periods of time with su
combination. "
If the desire is to maintain the opioid analgesic effect, then it may be necessi
combine the rapid onset opioid with an opioid that has a slower onset, but sustc
this
aired
apid
t, as
li a
effect. Examples of such formulations include (1) a formulation of fentanyl and liposDmal
encapsulated fentanyl, (2) a formulation of remifentanil, alfentanil, sufentanil, or fen;anyl
in combination with morphine, and (3) a formulation of remifentanil, alfen;anil,
sufentanil, or fentanyl in combination with methadone. Care must be taken to prevent a
second "peak" of action, at the time of maximum effect of the sustained effect opioidt that
y to
ined
is higher than the peak caused by the rapid onset opioid, which allows the patient to feel
side effects while he or she is administering the drug.
When a rapid onset opioid is combined with an opioid with slow-onset and
sustained effect, the concentration of both opioids is adjusted so that the self-limiting
effects of the rapid-onset opioid serves to limit exposure of the patient to the slow-onfiet
opioid. The rapid onset opioid acts as an early warning system of sorts, triggering side
effects in ari adequate timeframe.
We have found mat side effects are experienced before toxicity is reached. More
specifically, subjects that experienced side effects at the end of dosing or shortly af :er
completion of dosing did not progress to toxic side effects whereas subjects that
experienced side effects during dosing and continued to inhale drug progressed to
toxicity, specifically, hypoxia.
t
As can be appreciated by the above description, creation of the invention requires
(1) thorough understanding of the pharmacokinetics and pharmacodynamics of one or
more opioids, and (2) thorough understanding of the relationship between opioids, cafbbn
dioxide production and elimination, and ventilation, (3) careful selection of one or mqre
opioids, and (4) precise determination of the optimal concentration of each opioid in the
final formulation in order to achieve the desired clinical profile of the drug. The fir.al
formulation is determined by pharmacokinetic and pharmacodynamic modeling of tie
system parameters, with dose optimization performed to find the dose that exhibits tie
best patient safety profile while still providing an adequate analgesic response.
In the Drawings
Figure 1 is a flow diagram which represents a computer simulation model ibr
sedation. In all flow diagrams, squares represent amounts, arrows represent rate
(amounts per unit time), and circles represent either a calculation, rate, or constant.
Figure 2 is a flow diagram which represents a computer simulation model fjar
ventilatory depression.
Figure 3 is a flow diagram which represents a computer simulation model for
inhalation device.
Figure 4 is a flow diagram which represents a computer simulation model fcr the
pharmacokinetic profiling of opioid as administered to a patient through a pulmonary
route.
Figure 5 is a flow diagram which represents the Stella™ computer simulation of
the pharmacokinetics of the administration of a single opioid.
Figure 6 is a graph showing output of the Stella™ computer simulation of F: gure
5 (ventilatory depression and sedation models disabled) expressed as a time course of
quantity of opioid in the inhalation device, and quantity of opioid in the lung o
patient. The X axis shows time in minutes. The Y axis shows dose units of formulation,
in mg. The amount of drug in the inhaler dropped steadily over the first 10 minut;s of
stimulation. The amount of drug in the lungs reflects the net processes of inhalation of
drug into the lungs and absorbtion of drug from the lungs into the systemic circulation.
Figure 7 is a graph showing the time course of ventilatory depression in the
Stella™ computer simulation of Figure 5 (ventilatory depression and sedation models
disabled). Ventilatory depression (expressed as a fraction of baseline ventilation) was
expressed over time of simulation (in minutes).
Figure 8 is a graph showing the time course of quantity of opioid in the inhalation
TR/f device and in the lung of the patient, in the Stella computer simulation of Figure 5
(ventilatory depression model enabled, sedation model disabled). The X axis shows time
hi minutes. The Y axis shows dose units of formulation, in mg. Patient ventil
the
dropped to approximately 25% of baseline ventilation, such depression persisting
approximately 5-10 minutes.
Figure 9 is a graph showing the time course of. ventilatory depression ir
TM
tion
for
the
Stella computer simulation of Figure 5 (ventilatory depression model enabled, sedation
model disabled). Ventilatory depression (expressed as a fraction of baseline ventilation)
was expressed over time of simulation (in minutes). Change in ventilation caused by the
self-limitation of opioid uptake offers considerable safety to the patient (compared to
figure 7).
Figure 10 is a graph showing the time course of quantity of opioid in the
inhalation device and in the lung of the patient, in the Stella™ computer simulaticin of
Figure 5 (ventilatory depression and sedation models enabled). The X axis shows time in
minutes. The Y axis shows dose units of formulation, hi mg. Drug inhalation stopped
completely at approximately 8 minutes, due to a sedation state being reached and selflimitation
of drug intake.
Figure 11 is a graph showing the time course of ventilatory depression in the
TTkif Stella computer simulation of Figure 5 (ventilatory depression and sedation models
enabled). Ventilatory depression (expressed as a fraction of baseline ventilation was
expressed over time of simulation (in minutes). Change in ventilation caused by thelselflimitation
of opioid uptake from sedation offers considerable safety to the patient
(compared to figure 7 or 9)
Figure 12 is a flow diagram which represents a computer simulation model for the
administration of two opioids.
Figure 13 is a flow diagram which represents the Stella™ computer simulation of
the pharmacokhietics of the administration of two opioids.
Figure 14 is a graph showing the output of Stella™ computer simulation of Figure
13 expressed as a time course of total quantity of opioid in the inhalation device ana in
the lung of the patient (ventilatory depression and sedation models enabled). Y axis
shows fentanyl equivalents of formulation in the inhaler (I), of the rapid-onset opioid in
the lung (2), and the sustained-effect opioid hi the lung (3), expressed in ng/ml (fentanyl
equivalents) of drug over time (hi ininutes). After approximately 12 minutes, the patil
stopped inhaling more opioid, reflecting opioid-induced sedation.
Figure 15 is a graph showingjhe time course of concentration of each opioid akid
of total opioid at the effect site in the Stella™ computer simulation of Figure 13
(ventilatory depression and sedation models enabled). Amount of rapid-onset opioid ( ),
sustained-effect opioid (2) arid the combination effect of both the rapid-onset opioid and
the sustained-effect opioid (3) at the site of effect were shown, in ng/ml of fentanyl
equivalents, over time (hi minutes).
Figure 16 is a graph showing the time course of ventilatory depression during and
"TTUf • ' ' after delivery of opioids in the Stella computer simulation of Figure 13 (ventilatory
depression'and sedation models enabled). Ventilatory depression (expressed as a fractioii
of baseline ventilation) was expressed over time of simulation (in minutes). The
combination g£ the two opioids reaches a peak during the administration of the
opioid.
first
mof
eing
anil,
Figure 17 is a flow diagram which represents the Stella computer simiilati
the pharmacokinetics of the administration of two opioids, where the two opioids
administered are alfentanil and morphine.
Figure 18 is a graph showing tile time course of conbentration of alfen
morphine^ arid combined opioid at the effect site in the Stella"*1 computer simulation of
Figure 11 (ventiiatory depression and sedation models enabled). Line 1 shows
concentration of alfentanil; line 2 shows concentration of morphine, and line 3 shows
combined concentration. All drug levels are shown at the site of effect, and expressed in
ng/ml of fentanyl equivalents over time (in minutes). Drug administration was terminated
after delivery of 90% of the drug because of patient sedation. As seen in line 3 the
highest opioid exposure occurs during inhalation. s
Figure 19 is a graph showing the time course of ventiiatory depression
was
Stella computer simulation of Figure 17 (ventiiatory depression and sedation m
enabled). Ventiiatory depression (expressed as a fraction of baseline ventilation
expressed over time of simulation (in minutes). Ventilation decreases to about 65% of
baseline during drug administration.
the
dels
sma
oid.
Figure 20 is a graph showing maximum concentration of opioid in the pi;
against end of dose concentration of opioid in the plasma of patients administered op
Figure 20A shows patients administered with a combination of fentanyl and liposori rally
encapsulated fentanyl through a pulmonary route. Figure 20B shows patients
administered with fentanyl intravenously. Maximum concentration of opioid was not
significantly higher than the concentration at end of dose, indicating that if the "er d of
dose" amount is non-toxic, the maximum concentration of opioid taken by the subj ct is
likely also non-toxic.
Figure 21 is a graph showing time to side/toxic effect versus time to end of dose
for the side effects and toxic effects of patients administered a combination of fentanyl
and liposomally encapsulated fentanyl through a pulmonary route. In all cases, tinje to
toxicity was equal to or longer than time to side effect.
Figure 22 is a table showing the statistical correlation of side effect to toxic effect Side
effect is correlated to toxic effect at ap, 04.
Examples .
The examples below are designed to demonstrate but not limit the embodiments of
the present invention.
Example 1: Theoretical Model for Opioid Delivery
Examples 2-4 are based on a theoretical model for opioid delivery; this theoretical
model is described for greater certainty here in Example 1.
The theoretical model for opioid delivery was programmed into the computer
simulation package "Stella" (High Performance Systems, Lebanon, NH). The elements
shown in this example, both in figures and in text, are adapted from the Stella model
representation, and explain both the programming of the simulation, sand how the
simulation works.
In the figures, rectangles represent variables that indicate accumulation of a
substance (with exceptions noted below). Open arrows represent flow into or out of me
accumulators, and closed arrows represent the elements that control the flow. Some
closed arrows are omitted for simplicity of representation. Ovals represent model
parameters (inputs) and time-independent calculations. Many model parameters and
constants were obtained from the prior art (see Scott JC, Stanski DR Decreased fentanyl
and alfentanil dose requirements with age. A simultaneous phaimacokinetic and
pharmacodynamic evaluation. J Pharmacol Exp Ther. 1987 Jan;240(l): 159-66).
(a) Sedation Model
A model for opioid induced sedation was designed (Fig. 1 — Sedation Mode
Opioid in Effect Site 1010 was used as a variable denoting the concentration of opioid kt
the site of drug effect. If more than 1 opioid was present at the site of drug effect, Opioid
in Effect Site 1010 was built to represent the sum of the opioids present, each normalizejd
to their relative potency (for example, in Examples 3 and 4, below).
Sedation Threshold 1020 was defined as the Opioid Concentration 1010 thdt
would render the patient unable to use the inhaler. Sedation Threshold 1020 wafi
determined either through experimentation or through the known pharmacokinetics if the
opioid.
Sedation Eyaluator 1030 was a test of whether Opioid Concentration 1010
exceeded Sedation Threshold 1020. If Opioid Concentration 1010 exceeded Sedation
Threshold 1020, Sedation Evaluator converted the value of Sedation State 1040 from 0 to
1. Sedation State 1040 was an exception to the rule that rectangles represent
accumulation of a substance: Instead, the role of Sedation State 1040 within the rJiodel
was that of a memory component, which would remember that the opioid had exceeded
the sedation threshold. In subsequent models, data from Sedation State 1040 functioned to
turn off further administration of opioids, simulating patient sedation and the resulting
removal of the inhaler from the mouth.
(b) Ventilatory Depression Model
A Ventilatory Depression simulation was programmed (Fig. 2). In this model,
C02 was produced by the metabolic activity of the body at a rate CO2 Production ,010,
flowed into the plasma, (Plasma CO2 2020). CO2 Production 2010 was either determined
experimentally, or known from prior art (see, for example, Bouillon T, Schmidt
Garstka G, Heimbach D, Staffbrst D, Schwilden H, Hoeft A. Pharmacokir eticpharmacodynamic
modeling of the respiratory depressant effect of alfenranil.
Anesthesiology. 1999 Jul;91(l):144-55 and Bouillon T, Bruhn J, Radu-RadulesJu L,
Andresen C, Cohane C, Shafer SL. A model of the ventilatory depressant potency of
remifentanil in the non-steady state. Anesthesiology. 2003 Oct;99(4):779-87.). PlLma
CO2 2020 equilibrated with the CO2 hi the brain (Brain CO2 2040) at a rate (Bkin-
Plasma CO2 Equilibrium 2030). C02 was eliminated from the plasma in a manner
simulating the exhalation of air from the lungs, at a rate CO2 Elimination 2050 thatj was
mediated by the parameter Ventilatory Depression 2060.
Ventilatory Depression 2060 increased as the opioid concentration at the si:e of
drug effect (Opioid in Effect Site 1010) increased. Ventilatory Depression decreased the
elimination of C02 from the lungs (C02 Elimination 2050), causing CO2 to rise im the
brain, (Brain CO2 2040). As Brain C02 2040 increased, it stimulated ventilation through
a negative effect on Ventilatory Depression 2060, offsetting in part the depressant effects
of Opioid in Effect Site 1010, which has a positive effect on Ventilatory Depression 2J060.
Other parameters were designed to effect Ventilatory Depression 2060; the suna of
these parameters were illustrated in this model as Model Parameters 2070; parameters
comprising Model Parameters 2070 were described in greater detail in Figure 5. These
Model Parameters 2070 effect Ventilatory Depression 2060, which in turn effects GO2
Elimination 2050 and Brain C02 2040.
Although the programming of this simulation into Stella is novel, the Ventilatory
Depression Model is known in the art, and is referred to as an "Indirect Response Modejl."
(c) Device Model
A model for the inhalation device is shown in Figure 3. Dose 3050 represents ithe
total amount of opioid added to the Inhaler. Opioid Dose 3050 is added to the inhaler at a
rate Fill Inhaler 3010. This rate is required for the working of the simulation, but is
calculated at an instantaneous rate. Formulation In Inhaler 3020 represents the opioid
contained within the inhaler. The patient inhales the formulation at a rate of inhalation
(Inhalation 3030) into the lungs, (Formulation in Lungs 3040). Inhalation 3030 is effected
by Ventilatory Depression 2060 and Sedation State 1040. Specifically, Inhalation 3030 is
slowed by the increase of Ventilatory Depression 2060. For example, if Ventilatory
Depression 2060 was 50% of baseline, then drug was inhaled at half the baseline rate
(Inhalation 3030 was half baseline). However, if Sedation State 1040 - 1, then inhalatiqn
of drug into the lungs ends, and no further drug is inhaled.
(d) PharmacoJdnetic Model
A Pharmacokinetic Model for systemic opioid was programmed. Formulation fli
Lungs 3040 was absorbed systemically at a rate Systemic Absorption 4010 into the blood
plasma (Opioid in Plasma 4020). Opioid in Plasma 4020 equilibrated at a rate Plasma-
Effect Site Drug Equilibrium 4030 with opioid at the site of drug effect (Opioid in Effecjt
Site 1010). Opioid also redistributed into tissue Opioid in Tissue 4060 at a rate Opioi
Redistribution 4050 or was eliminated from the plasma at a rate Opioid Eliminatio:
4070. Opioid in Tissue 4060 and Opioid Redistribution 4050 were programmed
optional parameters that could be used or not used depending on the pharmacokinetii
model of the particular opioid utilized. The rates Systemic Absorption 4010, Plasma-)
Effect Site Drug Equilibrium 4030, Opioid Elimination 4070, and Opioid Redistribution^
4050 were all determined by a vector of pharmacoldnetic parameters of the particulaii
opioid being administered, represented in the model as Opioid Pharmacokijietic
Parameters 4080, and calculated by pharmacokinetic modeling.
Although ttie programming of this simulation into Stella was novel, the
Pharmacokinetic Model is known in the aft, and is referred to as a "Mammillary
Pharmacokinetic Model With An Effect Site." Mammillary models as represented a'sove
typically have 0, 1 or 2 tissue compartments, yielding models referred to as 1, 2, or 3
Compartment Models with an effect site, respectively.
Example 2: Administration of a Single Opioid
This example is an application of Example 1: Theoretical Model for Opioid
Delivery. This example is meant to illustrate the Theoretical Model for Opioid Delivery
in use; the model parameters do not reflect any specific opioid. Instead, the model
parameters in this example have been designed to clearly demonstrate the self-limiting
aspect of the proposed system of opioid delivery. This Example shows the integration of
the four simulations as described in Example 1, and output from the model when the
simulation is run.
(a) Integration of the Model
Figure 5 shows the elements of the model as described in Example 1, whersin a
single opioid is administered through inhalation. Figure 5 encompasses: a Device Model
5010 that is equivalent to the Device Model shown and explained in Example 1 as the
whole of Figure 3; a Pharmacokinetic Model 5020 that is equivalent to the
Pharniacokinetic Model shown and explained in Example 1 as the whole of Figure 4
(with the exception of the exclusion of optional parameters Opioid in Tissue 4060 and
Opioid Redistribution 4050, and with the further exception that Opioid Pharmacokinetic
Parameters 4080 were built into Systemic Absorbtion 4010, Opioid Elimination 4070,
and Plasma; Effect Site Equilibration 4030, and not shown as a separate parameter - see
source code for more information); a Ventilatory Depression Model 5030, which was
equivalent to the Ventilatory Depression Model-shown and explained in Example 1 is the
whole of Figure 2 (with the exception that Model Parameters 2070 are shovra hi
'expanded' form, with various elements comprising Model Parameters 2070, namely
PAC02@0 2071, KelCO2 2072, keOC02 2073, C50 2074, Gamma 2075, and F £076,
shown; and a Sedation Model 5040, that is equivalent to the Sedation Model shoW in
Figure 1. The mechanics of these four models were described in depth in Example 1,
with the exception of the expansion of Model Parameters 2070, the mechanics of which
are explained as follows:
Baseline CO2 2071 is the CO2 at baseline, prior to administration of opioid. kel CO2
2072 is the elimination rate relating Plasma C02 2020 to CO2 Elimination 2050, so
that at baseline (i.e., in the absence of ventilatory depression):
CO2 Elimination 2050 - kel C02 2072 x Plasma CO2 2020
It follows that at baseline, carbon dioxide in the body is at steady state, and hence the
CO2 Elimination 2050 = CO2 Production 2010. This permits calculation of the rate of
C02 production (which is constant) in terms of Baseline C02 2071 and kel CO2 2072
as:
CO2 Production 2010 = kel CO2 2072 x Baseline Plasma CO2 2071. §
The rate of Brain Plasma Equilibration 2020 is determined,by the parameter keO CO2
2073, so that:
Brain Plasma Equilibration 2020 = keO CO2 2073 x (Plasma CO2 2020 - Brain CO2 2040)
Opioids depress ventilation as a sigmoidal function of the Opioid in the Effect Site,
1030, and the parameters C50 2074, the opioid concentration associated with 50% of
maximum effect, and gamma 2075, the steepness of the concentration vs. response
relationship, with the contribution of the opioid to ventilatory depression expressed as:
Opioid in the effect site loso63™*2075
C50 20748amtra2075 + Opioid in the effect site 1030samma 2075
Conversely, carbon dioxide stimulations ventilation. The increase in ventilation can be
modeled as a function of Baseline C02 2071, Brain CO2 2040, and F 2076, a
parameter describing the steepness of the relationship:
( Brain C02 2040 Y
VBaselineCO2207lJ
Putting these together, Ventilatory Depression 2060 can be described as:
Ventilatory depression 2060;=
Opioid in the effect site lOSO* "*20-, "| / Brain CQ2 20 C50 2074BOTma2075 + Opioid in the effect site loSO*"™1*2075 J ^Baseline C02
With ventilatory depression 2060 now defined, we can fully define CO2 Elimination
2050 in the presence of opioid induced ventilatory depression as:
CO2 Elimination 2050 = kel CO2 2072xPlasma C02 2020x Ventilatory Depression 2060
completing the description of tne model.
In this manner, the models from Example 1 were combined into one model of
opioid effect. This model, shown in Figure 5, can also be described by the following
mathematical model, as represented in the Stella programming language (source code):
Brain_CO2_2040(t) = Brain_CO2_2040(t- dt) + (Btain_Plasma_CO2_EquilibrationJ2020) N dt
rNITBrain_CO2_2040 = Baseline_CO2_2071 «
INFLOWS:
Brain_Plasma_CO2_Equilibration_2020 = keO_CO2_2073*(Plasma_CO2_2020-
Brain_CO2_2040)
Formulation_in_Inhaler_3020(t) = Fommlation_in_lnlialer_3020(t - dt) 4- (Fill_lnlialer_3010
Inhalation_3030) * dt
INTT Formulatioa_m_Inhaler_3020 = 0
INFLOWS Fill_Inhaler_3010 = if time = 0 then Dose_3050/DT else 0
OUTFLOWS:
Inhalation_3030 = If Sedation_State_1040 = 0 then .5*(Ventilatory_Depression_2060) else 0
Fonnulatiori_in_Lung_3040(t) = Formulation_in_Lung_3040(t - dt) + (Inhalation_3030 -
Systemic_Absorption_4010) * dt
INTT Fonrnilation_in_Lung_3040 = 0
INFLOWS:
Inhalation_3030 = If Sedation_State_1040 = 0 then .5*(Ventilatory_Depression_2060) else 0
OUTFLOWS:
Systemic_Absorption_4010 = FormuIation_in_Lung_3040*.693/l
Opioid_in_Effect_Site_1010(t) = Opioid_in_Effect_Site_1010(t - dt) -f
(Plasma_Effect_Sfte_Equilibration_4030) * dt
INIT Opioid_in_Effect_Site_1010 = 0
INFLOWS:
Plasma_Effect_Site_EquiUbration_4030 = (Opioid_in_Plasma_4020-
Opioid_in_Effect_Site_1010)*.693/l
Opioid_in_Plasma_4020(t) = Opioid_inJPlasma_4020(t - dt) + (Systemic_Absorption_4010 -
Opioid_Elimination_4070 - Plasma_Effect__Site_Equilibration_4030) * dt
INIT Opioid_in_PIasma_4020 = 0
INFLOWS:
Systemic_Absoiption_4010 = Fonnulation_in_Lung_3040*.693/l
OUTFLOWS:
Opioid_Elimination_4070 = Opioid_in_Plasma_4020*.693/10
Plasma_Eflfect_Site_EquiIibration_4030 = (Opioid_ia_Plasma_4020-
Opioid_in_E£fect_Site_1010)*.693/l
Plasma_CO2_2020(t) =Plasma_CO2_2020(t - dt) + (CO2_Productioii_2010 -
Brain_Plasma_CO2_Eqailibration_2020 - CO2_ElimiDation._2050) * dt
INTT Plasma_CO2_2020 = Baseline_CO2_2071
INFLOWS:
CO2_Production._2010= Baseline_CO2_2071*kelCO2_2072
OUTFLOWS:
Brain_Plasma_C02_Equilibration_2020 = keO_CO2_2073 *(Plasma_CO2_2020-
Brain_CO2_2040)
GO2_Elimmation_2050=Plasim_CO2_2020*kelC02_2072*VentOatoryJDepression_20^^
Sedation_State_1040(t) = Sedati6n_State_1040(t - dt) + (Sedation_Evaluator_1030) * dt
INIT Sedation_State_l 040 = 0
INFLOWS:
Sedation_Evaluator_1030 = if(Opioid_in_Effect_Site_1010>Sedation_Threshhold_1020) then 1
elseO .
Baseline_CO2_2071 =40
C50 2074 = 3
Dose_3050 = 5
F_2076 = 4
Gamna_2075 = 1.2
keO_CO2_2073 = 0.92
kelC02_2072 = 0.082
Sedation_Threshhold_1020 = 1.5
Ventilatory_Depression_2060 =.(!•
Opioid_m_Effect_Site_1010AGani^
10AGaimna_2075))*(Brain_CO2_2040/Baseline_CO2_2071)AF_2076
(b) Output of the model when run with Ventilatory Depression Model and Section
Model Disabled
The model designed and described in (a) was run as a simulation of opioid effect,
using the following initial parameters: Formulation In Inhaler 3020 = 5 milliliters ai: time
= 0. The model was allowed to run over a time course of two hours. For this simulation,
the feedback loop on drug uptake aspects of the Ventilatory Depression Model (i. s. the
feedback of the effect of Ventilatory Depression 2060 on Device Model 5010), aid the
Sedation Model were disabled. Output of the model, when run, was plotted for various
parameters in Figures 6 and 7.
Figure 6 shows the output of the model as run in the absence of patient selflimiting
inhalation of opioid (i.e. with the Ventilatory Depression Model and the Sedation
Model disabled). Figure 6 shows the time course of drug in the inhaler (Formulation In
Inhaler 3020 - line 1), and in the lungs (Formulation in Lungs 3040 - line 2) i
absence of the self-limiting aspects of the invention. The amount of drug in the inhaler
dropped steadily over the first 10 minutes of simulation, at a rate Inhalation 3030.
n the
The
amount of drug in the lungs reflected the net processes of inhalation of drug into the
lungs, and absorption of drug from the lungs into the systemic circulation.
Figure 7 shows Ventilatory Depression 2060 over time, for the same simulation*
(Ventilatory Depression Model and Sedation Model disabled). The graph output
indicated that patient's ventilation dropped to approximately 25% of baseline ventilation
in this simulation. The Ventilatory depression persisted for approximately 5-10 mijiutes.
The drop in ventilation was reversed as carbon dioxide built up in the patient's pl&sma,
and, at the same rate, the patient's lungs (not simulated), counteracting the depressant
effect of the opioid on ventilation. This drop in ventilation exposed the patient to risk
from injury from hypoxia. .
• • •
(c) Output of the model when run with Ventilatoiy Depression Model enabled
The simulation used in (b) was modified by enabling the Ventilatoiy Depression
Model, and run again with the same initial parameters of Formulation In Inhaler 3020 F= 5
milliliters at time 0. Output of various parameters were plotted over time. Figure 8 shows
Formulation hi Inhaler 3020 (line 1), depicting the amount of drug that is left in the
inhaler, and Formulation la Lungs 3040 (line 2), depicting the amount of drug in the
lungs, in the presence of ventilatory depression, one of the two self-limiting aspects of I
invention (the other being sedation). As compared to Example 2(b), as expected, it took
longer to inhale the drug when the simulation was run with the Ventilatory Depression
Model enabled - inhalation of drug in Figure 8 took place over approximately 17 minutes
as opposed to the 10 minutes in Figure 6. This was due to a reduction in ventilation
caused by ventilatory depression, which limited the patient's exposure to the opioid. This
reduction in ventilation was best illustrated in Figure 9, which plotted Ventilatqry
Depression 2060 over time for the same simulation. Ventilatory Depression 2060 was
depressed by 50% in Figure 9. When compared with the simulation shown in Figure 7,
the patient was breathing half as much (in Figure 9) as when simulation was run with the
Ventilatory Depression Model deactivated (in Figure 7). This simulation shows that me
change in ventilation caused by the self-limitation of opioid uptake offers considerable
safety to the patient.
(d) Output of the model when run with Ventilatory Depression Model and Sedation
Model enabled
The same simulation (Formulation hi Inhaler 3020 = 5 milliliters at time = 0) was
run, this time with both the Ventilatory Depression Model 5030 and the Sedation Model
5040 enabled. Output of various parameters were plotted, over time. Figure 10 shows the
time course of Formulation hi Inhaler 3020 (Line 1) and Formulation In Lungs 3040
(Line 2) in the presence of ventilatory depression and sedation. As seen in the figure^
after 8 minutes drag inhalation stopped completely. The reason was that the patient has
become sedated, and could no longer hold the inhaler to the mouth (simulated here a£
Sedation State 1040 turning from 0 to 1). At this time, approximately 2 milliliter£
remained in Formulation In Inhaler 3020, and therefore, approximately 40% of the opioid
dose remained in the inhaler and was not inhaled. Figure 11 plots Ventilatory Depression
2060 during the time course of this simulation. The maximum depression of ventilation
in Figure 11 was approximately 60%. When compared with Figure 9, the improved; safety
from the opioid-induced sedation is evident.
Thus, Example 2, as illustrated in Figures 5 through 11, demonstrate* through
simulation the effects and advantages of the self-limiting system of opioid delivery, as
described herein.
Example 3: Administration of two opioids
In this simulation, the model parameters do not reflect any specific opioids, but
have been adjusted to demonstrate clearly the self-limiting aspect of the proposed system
of opioid delivery. The simulation models and measures the same variables, this time for
an opioid composition comprising of two different opioids with different
pharmacoldnetics.
(a) Building a two opioid model.
Figure 12 addresses how two opioids are combined into a single opioid
concentration for the model. In the two opioid simulation, Rapid Opioid In Effect Site
12010 represents the concentration of rapid onset opioid; Slow Opioid In Effect Site
12020 represents the slow onset opioid. Each of these is determined in parallel and in the
same manner as in the one opioid model (Example 2). However, each is determined
separately, then combined to determine Combined Opioid Effect Site Concentration
12030. Combined Opioid Effect Site Concentration 12030 is calculated using the known
relative potency of each opioid, Relative Potency 12040. Combined Opioid Effec Site
Concentration 12030 is equal to, and depicted as, Opioid in effect Site 1010 in th two
opioid models illustrated in Figures 13 and 17.
Figure 13 illustrates the algorithm for the two opioid model simulation. It
encompasses: a Device Model 13010, equivalent to and illustrated as Device Model 5010
and as described in Examples 1 and 2; a Pharmacokinetic Model 13020 comprising a
combination of two instances of the Pharmacokinetic Model 5020 (one for the irapid
opioid, and one for the slow opioid), each as illustrated in Figure 4 and Figure 5, aijid as
described in Examples 1 and 2, and each running in parallel, then combined using the
Two Drug Model 13050, as described in Figure 12; a Ventilatory Depression Model
5030, as illustrated in Figure 2 and Figure 5, and as described in Examples 1 and 2; and a
Sedation Model, 5040, as illustrated in Figure 2, Figure 5, and as described in Examples 1
and 2.
The model shown in figure 13 can also be ^described by the following
mathematical model, as represented in the Stella programming language (source code)|
Brain_CO2_2040(t) = Brain_C02_2040(t - dt) + (Brain_Plasma_CO2_Equilibration_2020) * -
INIT Brain_C02_2040 = BaseIine_C02_2071
INFLOWS:
Brain_Plasma_CO2_Equih'bration_2020 = keO_C02_2073*(Plasma_CO2_2020-
Brain_CO2_2040)
Forraulation_in_Inhaler_3020(t) = Formdation_in_Inhaler_3020(t- dt) + (Fill_In|aler_3010 -
Iahalation_I_3031 - Inhalation_2_3032) * dt
INIT FonnuMon_inJnhaler_3020 = 0
INFLOWS:
Fill_Inhaler_3010 = if time = 0 then Dose_3050/DT else 0
OUTFLOWS:
inhalation_l_3031 = if Sedation_State_1040 = 0 then 0.25*VentilatoryvDepression else 0
Inhalation_2_3032 = if Sedation_State_1040 = 0 then 0.25*Ventilatory_Depression_2060 else
Opioid_inJ3ffect_Site_1010(t) = Opioid_in_Effect_Site_1010(t - dt)
INIT Opioid_in_Effect_Site_1010 = 0
Plasma_CO2_2020(t) = Plasma_CO2_2020(t - dt) + (CO2_Production_2010 -
Brain_Plasma_CO2_EquM>ration_2020 - CO2_Elimination_2050) * dt
INIT Plasma_CO2_2020 = Baseline_CO2_2071
INFLOWS:
C02_Production_2010 = { Place right hand side of equation here... }
OUTFLOWS:
Brain_Plasma_CO2_Equilibration_2020 = keO_CO2_2073*(Plasma_CO2_2020-
Braui_CO2_2040)
C02_Eh'mination_2050 = Plasma_CO2_2020*kelC02_2072*Ventilatory_Depression_2060
RapidJDrag_Effect_Site(t) == Rapid_Drag_Effect_Site(t - dt)+
(Rapid_Drug_Plasma_Effect_Site_Equilibration) * dt
JNTT RapidJDmg_Effect__Site = 0
INFLOWS:
Rapid_Drug_Plasma_Effect_Site_Equilibration = (Rapid_Drug_In_Plasma-
RapidJDrugr_Effect_Site)*.693/l
Rapid_Drug_In_Plasma(t) = Rapid_Drug_In_Plasma(t - dt) 4- (Rapid_Drug_Absorption -
Rapid_Drug_Clearance - Rapid_Drug_Piasma_Effect_Site_EquiKbration) * dt
INIT Rapid_DragJn_Plasma = 0
INFLOWS:
Rapid_Drug_Absorption = Rapid_Fonnulation_in_Lung.693/l Rapid_Drag_Concentratio
OUTFLOWS:
Rapid_Drug_Clearance = Rapid_Drug_In_Plasma.693/10 ®
Rapid_Drug_Plasma_Effect_Site_Equilibration=(Rapid_Drag_In_Plasma-
Rapid_Drug_Effect_Site)*.693/l
Rapid_Fornmlation_i[i_Limg(t) = Rapid_Formulation_in_Lang(t - dt) + (Inhalation_l_3031
Rapid_Drug_Absorption) * dt
INTT Rapid_Formulation_in_Lung = 0
INFLOWS:
inhalation_l_3031 = if Sedation_State_1040 = 0 then 0.25*Ventilatory_Depression else 0
OUTFLOWS:
Rapid_Drug_Absorption = Rapid_Fonriulation_iaJLung*.693/l *Rapid_Drug_Concentrati
Sedation_State_1040(t) = Sedation_State_1040(t- dt) + (Sedation_Evaluator_1030) * dt
INIT Sedation_State_1040 = 0
INFLOWS:
Sedation_Evaluator_1030 = i^Opioid_in_Effect_Site_1010>Sedation_Threshhold_1020)
elseO
Slow_Drug_Effect_Site(t) = Slow_Drug_Effect_Site(t - dt) +
(Slow_Drug_Plasma_EfFect_Site_Equilibration) dt
INIT Slow_Drag_Effect_Site = 0
INFLOWS:
hen 1
Slow_Drug_Plasma_Effect_Site_EquiIibration = (Slbw_Drug_In_Plasma-
SlowJDrug_Effect_Site)*.693/10
Slow_Drug_Ih_Plasma(t) = Slow_Drag_In_Plasma(t - dt) + (Slow_Drag_Absorption -
Slow_Drug_Clearance - SIow_Drug_Plasma_Effect_Site_Equilibration) * dt
INIT Slow_Drug_In_Plasma = 0
INFLOWS:
Slow_Dnig_Absorption = Slow_Fonnulation_In_Lung*.693/12*Slow_Drag_Concentration
OUTFLOWS:
Slow_Drug_aearance = Slow_Drug_In_Plasma*.693/300
SIow_Drag_Plasma_Effect_Site_Equilibration = (Slow_Drug_In_Plasma-
Slow_Drug_Efifect_Site).693/10
Slow_Formuktion_Ih_Lung(t) = Siow_Formulation_Li_Lung(t - dt) + (Jnhalation_2_3032 -
Slow_Drag_Absorption) dt s
INTT Slow_Fonnulation_In_Lung = 0
INFLOWS:
Inhalation_2_3032 = if Sedation_State_1040 = 0 then 0.25*Ventilatory_Depression_2060 else (|)
OUTFLOWS:
Slow_Drag_Absorption = Slow_Formulation_In_Luiig*.693/12*Slow_Drug_Coiiceiitration
Baseline_CO2_2071 =40
C50_2074 = .3
Dose_3050 = 5
F_2076 = 4
Gamma_2075 = 1.2
keO_CO2_2073 = 0.92
kelCO2_2072 = 0.082
Opioid_in_EfFect_Site_1010 = Rapid_Drug_Effect_Site+Slow_Drug_Effect_Site
Rapid_Drug_Concentration = 1
Sedation_Threshhold_1020=1.5
Slow_Drug_Concentration =1
Ventilatory_Depression__206Q = (1-
OpioidJn_Effect_Site_1010^aimna_2075/(C50^
ma_2075))*(Brain_C02_2040/BaseIine_CO2_2071)AFJ076
.
(b) Output of mo"del when run with. Ventilatory Depression Model and Sedation model
enabled
The same simulation (Formulation In Inhaler 3020 = 5 milliliters at time = 0| was
run in the two opioid model as illustrated in Example 3(a) and Figure 13. Figure 14
shows the time course of Formulation In Inhaler 3020 (Line 1), Formulation In ping
(Rapid Opioid) 3040 (Line 2), and Formulation In Lung (Slow Opioid) 3040 (Line 3), in
the presence of ventilatory depression and sedation. The simulation showed that, over 12
minutes of run, the drug was inhaled by the patient. The rate of fall in the amount of] drug
in the inhaler was not perfectly linear, reflecting the slowed breathing with opioidinduced
ventilatory depression. After approximately 12 minutes, the patient stopped
inhaling more opioid, reflecting opioid-induced sedation. The rapidly acting opioia was
quickly taken up into the systemic circulation, which limited how much accumulated in
the lung, and produced a quick drop in concentration in the lung when the patient sto sped
inhaling more opioid. The slowly acting opioid was taken up slowly by the lung, uhich
permitted more drag to accumulate in the lung during inhalation^ and the administration
of opioid into the systemic circulation for over two hours following the end of opioid
delivery to the patient.
Figure 15 shows different variables for the same simulation. In Figure 15, line 1
indicates the rapidly acting opioid concentration in the effect site (Rapid Drug Effect
Site), over time, and demonstrates the rapid rise owing to quick absorption and rapid
plasma-effect site equilibration, and a rapid drop owing to rapid metabolism. Line 2 is the
slowly acting opioid concentration in the effect site (Slow Drag Effect Site), over time,
and demonstrated a slow rise in concentration owing to slow absorption and slow plasmaeffect
site equilibration, and a slow decrease over time owing to slow metabolism. Lrie 3
shows the combined concentration of rapid and slow onset drug (Combined Opioid EJfect
Site Concentration) As can be seen, the combination reaches a peak during the
administration of the first opioid.
Figure 15 and Figure 14 show different variables for the same simulation run[ on
the same X axis (time). One can therefore refer back to Figure 14 to see that the patient
stopped self-administering drug at approximately 12 minutes. When Figure 14 is
interposed with Figure 15, we can see that this reflected the patients' response to the
rapidly acting opioid, as the concentration of the slowly acting opioid was negligible at 12
minutes. However•, the overall opioid concentration remained fairly steady over time.
This reflected the slowly acting opioid gradually replacing the rapid acting opioip in
Opioid In The Effect Site as the rapidly acting opioid was eliminated from the system
through Rapid Drug Clearance.
Figure 16 shows the time course of Ventilatory Depression 2060 during and after
delivery of opioids with the two-opioid delivery system, in the same simulation
Figure 16 illustrates an initial decrease in ventilation to approximately 60% of baseline.
As mentioned previously (in the description for Figure 11), this is well tolerated] by
patients. As the CO2 builds up, ventilation was stimulated. Note that there was very little
decrease in ventilation after this initial drop. The reason is that there is now adequate CO2
accumulation in the patient to continue driving ventilation.
As demonstrated by figures 13, 14, and 15, in the two drug embodiment of me
device, the first drug acts as a 'probe' of the patient's sensitivity to opioids, and limits the
dose of both the first and the second opioid. In this manner, the patient can receive an
slowly acting opioid without receiving an excessive dose. A combination of two opioids,
one of them fast acting, can therefore be used to increase the safety profile of either
opioid alone, or, more particularly, of the slow acting opioid.
Example 4: Alfentanil and Morphine as examples of opioids in the two drug model
This example shows an application of Example 3 to two specific drugs, name
alfentanil and morphine, wherein alfentanil is the rapidly acting opioid and morphine is
the slowly acting opioid.
Figure 17 encompasses: a Device Model 17010, comprising 2 Device Modbl
5010's, as described in Figure 5 and explained in Example 1, and each running in parallel,
but each modified and re-labeled for the specific known parameters of the opioids
alfentanil and morphine; a Ventilatory Depression Model 5030, as described in Figure 2,
a Sedation Model 5040, as described in Figure 1, and a Two Drug Model, 17050, ajs
described in figure 12 but re-labeled to reflect the specific drags alfentanil and morphine^
Figure 17 exposes all of the parameters 2070 of the ventilatory depression model, 1703d39
The; parameters 4080 of the pharmacokinetic models for morphine and alfentanil, 17020,
are now fully exposed: Alfentanil and morphine are each represented by a 3 compartment
mammillary model with an effect site. .
The model shown in figure 17 can also be described by the following
mathematical model, as represented in the Stella programming language. The constants
for alfentanil arid morphine are based on existing literature for these drugs.
Alfentanttjnjnhaler(t) = Alfentana_in_Inhaler(t - dt) + (- InhaIe_Alfentanil) * dt
INIT Alfentanil_in_Inhaler = Alferitanil_Dose _ ug
OUTFLOWS:
Innale_Alfentanil = If Sedation_State = 0 then
Alfentanfl_Dose__ug/Dose_Duratioii*Ventilatory_Depressioii else 0
Alfentanfljn_Lung(t) = Alfentanil_in_Lung(t - dt) + (Inhale_Alfentanil - AlfentanilJJptake
INTT Alfentanil_in_Lung = 0
INFLOWS:
Inhale_Alfentanil = If Sedation_State = 0 then
Alfentanil Dose ug/Dose Duration Ventilatory Depression else 0
OUTFLOWS:
Alfentanil_Uptake = Alfentanil_in_Limg.693/Alfentaiul_Absorption_Half_Life
Alfentanil_Xl(t) = AlfentaniI_Xl(t - dt) + (Alfentanil_CI2 + Alfentanil_CB
Alfentanil_Uptake - AlfentaniI_Cll) dt
INIT Alfentanil_Xl = 0
INFLOWS:
Alfentanil_C12 = Alfentanil_X2 Alfentanil_K21-Alfentanil_Xl*AIfentanil_K12
Alfentanil_CB = Alfentanil_X3*Alfentanil_K3 l-Alfentanil_Xl*Alfentanil_K13
AlfentaniI_CLe = Alfentanil_Xeffect*Alfentanil_KeOAlfentanil_
Xl *Alfentanil_KeO*.001/Alfentanil_Vl
Alfentanil_Uptake = Alfentanu_inJLung*.693/Alfentanil_Absorption_Half_Life
OUTFLOWS:
Alfentanil_Cll = Alfentanil_Xl*Alfentanil_K10
Alfentanil_X2(t) = Alfentanil__X2(t - dt) + (- Alfentanil_C12) * dt
INIT Alfentanil X2=0
dt
OUTFLOWS:
AlfentaniI_C12 = AIfentanil_X2*Alfentanil_K21-Alfentanil_Xl*Alfentanil_K12
Alfentanil_X3(t) =. Alfentanil_X3(t - dt) + (- Alfentanil_C13) * dt
INIT Alfentanil_X3 = 0
OUTFLOWS:
Alfentarul_C13 = AJfentanil_X3*AlfentanU_K31-Alfentanil_Xl*Alfentanil_K13
Alfentanil_Xeffect(t) = Alfentanil_Xeffect(t - dt) + (- Alfentanil_CLe) * dt
INIT Alfentanil_Xeflfect = 0
OUTFLOWS:
Alfentanil_CLe = Alfentanil_Xeffect*Alfentaml_KeOAIfentanil_
Xl*Alfentaml_KeO*.001/Alfentanil_Vl
Morphine_in_Inhaler(t) = Moiprtine_in_Inhaler(t - dt) + (- Inhale_Morphine) * dt ®
INTT Morphine_in_lnhaler = Moiphine_Dose__mg* 1000
OUTFLOWS:
Inhale_Morphine = If sedation_state = 0 then
Morphine_Dose__rng*1000/Dose_Duration*Ventilatory_Depressionelse 0
Morphine_in_Lung(t) = Morphine_in_Lung(t - dt) + (Innale_Morphine - Morphine_Uptake) * cit
INTT Morphine_in_Lung = 0
INFLOWS:
Inhale_Morphiae = If sedation_state = 0 then
Morphine_Dose__mg*1000/Dose_Duration*VentiIatory_Depression else 0
OUTFLOWS:
Morphine_Uptake = Morphine_in_Liing*.693/Morphine_Absorption_Half_Life
Morphine_Xl(t) = Morphine_Xl(t - dt) + (Morphine_C12 + Morphine_C13 + Morphine_CLe +
Morphine_Uptake - Morphine_Cll) * dt
INIT Morphine_Xl = 0
INFLOWS:
Morphrne_C12 = Morphine_X2*Moiphine_K21-Morphine_Xl*Morphine_K12
Moiphine_Q3=Morphine_X3*Moiphine_Ol-Morphine_Xl*Morphine_K13
Morphine_CLe = Morphine_Xeffect*Morphine_KeOMorphineJX:
Morphine_KeO*.001/Morphine_Vl
Morphinejjptake = Mo^hine_in_Limg*.693/MorphinejVbsorption_HaIf_Life
OUTFLOWS:
Morphine_Cll = MorphineJQ*Morphine_K10
*
Morphine_X2(t) = Morphine_X2(t - dt) + (- Morphine_C12) * dt
INIT Morphine_X2 = 0
OUTFLOWS:
Morphine_C12 = MorpIrme_X2*Morphiae_K21-Morphir^_Xl*]V[orphineJK:i2
Morphine_X3(t) = Morphine_X3(t - dt) + (- Morphine_CI3) * dt
INrr Morphine_X3 = 0
OUTFLOWS:
Morphine_C13 = Morphine_X3*Morphine_K31-Morphirie_Xl*Morpliine_K13
Morphine_XetTect(t)=Morphine_Xet&ct(t - dt) 4- (- Morphine_CLe) * dt
INTT Morpbrne_XerTect = 0
OUTFLOWS:
Morphine_CLe = Morphine_Xeffect*Morplrine_KeOMorphine_
Xl*Morpliine_KeO*.OOl/Morp1iine_Vl
PaCO2(t) =PaCO2(t - dt) + (CO2_Accuraulation - CO2Equilb) * dt
INTT PaCO2 = PaCO2@0
INFLOWS:
CO2_Accumulation = KelCO2*PaC02@0-KfilC02*VentilatotyJDepression*PaCO2
OUTFLOWS:
CO2Equilb = keOCO2*(PaCO2-PeCX)2)
PeCO2(t) =PeC02(t - dt) + (CO2Equilb) * dt
INIT PeCO2 = PaOO2@0
INFLOWS:
GO2Equilb = teOCO2*(PaC02-PeCO2)
Sedation_State(t) = Sedation_State(t - dt) + (Sedation_Evaluator) * dt
INIT Sedation_State = 0
INFLOWS:
SedationJBvaluator = if Combined_Opioid_Effeci_Site_Concentration 0 else 1
Alfentanil_Absorption_Half_Life = 1
Alfentanil_Ce = Alfentanil_Xeffect/.001
Alfentanil_Cp = Alfentanil_X l/Alfentanil_Vl
AlfentanilJDose ug = 1500
AlfentanOjaO = 0.090957
Alfentanil_K12 = 0.655935
Alfentanil_K13 = 0.112828
Alfentanil_K21= 0.214
AlfentanilJOl = 0.017
Alfentauil_KeO = 0.77
Alfentanil_Vl = 2.18
C50 = l.l
Combined_Opioid_EfFeci_Site_Concentratioa = Alfailaiul_Ce/60+Morphine_Ce/70
Dose_Duration= 12
F = 4
Gamma =1.2
keOCO2 = 0.92
KelCO2 = 0.082
Moiphine_Absorption_Half_Life = 2
Moq3hine_Ce=Moiphine_Xefiect/.001
Morphine_Qp=Morphine_X 1 /Moiphine_Vl
Morphine_D6se__mg = 20
Morphine_K10 = 0.070505618
Moiphine_K12 = 0.127340824
Moiphme_K13 = 0.018258427
Moiphine_K21 = 0.025964108
Moiphine_K31 =0.001633166
MorphineJKeO == 0.005
MoiphineJVl = 17.8
PaCO2@0 = 40
Sedation_Threshold= 1.5

VentilatoryJDepression^l-
CombinedJ pioidJEffeciJSit Concentration
Site_ConcentrationAGanima))*(PeCO2/PaC02@0)AF
The simulation was run with a starting parameter of 700 meg of bioavailable
alfentanil and 67 meg of bioavailable morphine in the inhaler at time 0 (Alfentanil hi
Inhaler = 700 meg at time = 0; Morphine In Inhaler = 67 meg at time 0). Figure 18 and
19 shows the concentrations of various parameters when the simulation was run. Figure
18 showed concentration of alfentanil (in ng/ml, line 1), morphine (in ng/ml, line 2) and
combined opioid (in ng/ml of fentanyl equivalents, line 3) over time (in minutes) at the
effect site following inhalation of the combined product. In this ^example, drug
administration has terminated after 90% of the inhaled drug was delivered because of
patient sedation. As can be seen, the alfentanil concentration rises quickly in the effect
site (line 1) producing a rapid drug effect. The morphine drug effect rises quite slowly in
the effect site (line 2), producing a slowly rising drug effect. Line 3 is shows the
combined opioid effect site concentrations, where each drug has been adjusted for its
potency relative to fentanyl. All three lines have different Y scales, as can be seen on the
Y axis, to normalize the effect site concentrations for relative potency. As can be seen in
line 3, the highest opioid exposure occurs at the time of inhalation, and is almost entirely
due to the alfentanil. However, as the alfentanil washes out of the effect site, it is almost
exactly replaced by the influx of morphine into the effect site. A concentration at the site
of effect of less than 25 ng/ml on the alfentanil scale (equivalent to 37.5 ng/ml on the
morphine scale and 0.5 ng/ml on the fentanyl scale due to their relative potency) is
considered sub-therapeutic; a patient will typically feel analgesic effects between 50
ng/ml and 100 ng/ml (on the alfentanil scale), side effects between 75 and 125 ng/ml (on
the alfentanil scale) and toxic effects above 125 ng/ml (on the alfentanil scale).
Figure 19 showed the ventilatory depression from the inhalation of an alfentanil
morphine combination opioid delivery system. As shown in figure 19, the ventilation
decreases to about 65% of baseline during drug administration, and then recovers to
approximately 80% of baseline as CO2 accumulates. Ventilation is maintained at 80% of
baseline throughout the next 4 hours, as the morphine effect is sustained.
As demonstrated in figures 17,18, and 19, in the alfentanil morphine combination
opioid delivery system, based on simulations using parameter values taken from the
literature, the patient self-limiting opioid delivery system prevents administration of a
toxic dose of opioid, and provides for the safe delivery of a slowly acting opioid by
combining the slowly acting opioid with a rapidly acting opioid, and using the effects of
the rapidly acting opioid to limit the total opioid exposure. ;
Example 5: Clinical testing of Fentanvl preparations in human subjects ;

fa) Method of Preparation of Free and Liposome Encapsulated Fentanyl Preparation^.
Preparations containing a mixture of free fentanyl and liposome encapsulated
fentanyl were prepared by mixing an ethanolic phase with an aqueous phase. The
ethanolic phase comprised ethanol, fentanyl citrate, phosphatidylcholine and cholesterol.
The aqueous phase comprised water for injection. Before mixing, both phases were
heated to a temperature of about 56 to 60 degrees centigrade. The two phases were mixed
and the mixture was stirred for a further 10 minutes at 56-60 degrees centigrade. The
mixture was then allowed to cool to room temperature over approximately two hours.
Typically, each ml of the final aqueous formulation contained 500 meg fentanyl, 40 rag
phosphatidylcholine, 4 mg cholesterol, and 100 mg ethanol. After filling, preparations
were autoclaved for final sterilization. Final preparations contained between 35 to 45
of the fentanyl as free drug with the remainder in the encapsulated fraction.
(b) Treatment protocol
The procedure of the following example shows how the administration of] a
mixture of free and liposome encapsulated fentanyl through the lungs of a patient delivers
therapeutically effective concentrations to the bloodstream and that side effects of
hypoxia are generally (but not always) preceded by somnolence, dizziness or sedation
during the administration period.
Healthy volunteer subjects were treated with single or multiple doses of a mixture
of free and liposome encapsulated fentanyl using the AeroEclipse™ Nebulizer breatiiactuated
unit with compressed air set at 8 litres/minute. During each dosing period the
nebulizer was charged with a 3 ml of the mixture of free (40%) and liposome
encapsulated (60%) fentanyl and the subjects were instructed to inhale nebulized drug
until the device no longer generated aerosol for inhalation. Subjects that become drowsy,
sleepy or dizzy during the inhalation period were encouraged to continue to selfadminister
the drug until the nebulizer was no longer generated aerosol. Plasma samples
were collected through the administration period and for tile 12 hours following initiation
of administration to monitor plasma fentanyl concentrations. Patients were monitored for
any adverse events, including changes in respiratory rate and hypoxia.
Control subjects were given intravenous fentanyl.
(c) Measurement of maximum plasma concentration and end of dose plasma
concentration
In order to determine whether patients could prevent toxic levels of drug by selflimiting
the drug before a toxic effect was exhibited, maximum plasma concent -ation
(Cmax) was plotted against plasma concentration at end of dosing (Ceod) (Figure 20A).
Ceod was found in most cases to be within 80% of Cmax, indicating that the max mum
concentration of opioid was not significantly higher than the concentration at the time the
subject stopped taking the opioid. This is in stark contrast to the control subjects (figure
20B) where patients given intravenous fentanyl exhibited Cmax concentrations
significantly higher than Ceod. This indicates an increased safety in titration of drug by
the subjects, since the concentration (and resulting toxic effects) of the opioid will not
increase significantly after the subject stops taking the opioid. This indicates that, in an
inhaled opioid formulation of the disclosed concentration over a relatively long period of
time (2-20 minutes), if the "end of dose" amount is non-toxic, the maximum
concentration of opioid taken by the subject is likely also non-toxic.
(d) Determination of time points for side effects and toxic effects
In order for subjects to effectively self-titrate, side effects of the drug such as
drowsiness, dizziness or ventilatory depression should occur before the onset of toxic
effects. Toxic effects were denned in this experiment as blood hypoxia resulting in a
blood oxygen saturation lower than 90% of normal for the subject. In order to deteimine
whether side effects occur before toxic effects, time to a side effect, and time to a toxic
effect, were plotted against time to end of dose (Figure 21). For any end of dose time,
time to side effect was equal or shorter than time to toxic effect, indicating that
drowsiness, dizziness or ventilatory depression always took place before or at the time of
toxic effect.

(e) Determination of.correlation between toxic effect and side effect.
In order for subjects to effectively self-titrate, a toxic effect should be almost
always preceded by a side effect causing (or signaling) the cessation of administration of
drug. Figure 22 shows, for the total population of the study, that side effect is closely
correlated to toxic effect, indicating that it is extremely likely that a subject exhibiting a
toxic effect will have also exhibited a side effect.
This example shows, in a controlled trial of human subjects, that (1) a toxic ef
is almost always preceded by a side effect, and that (2) Cmax of inhaled opioid, in the
dose profile given in Ms example, is approximately Geod. Therefore, a subject who
stops administration of opioid when a side effect is felt will likely not reach opioid
concentration levels required for toxic effect.

WE CLAIM:
1. An opioid formulation for use in a method of providing analgesia to a patient;
wherein the formulation comprises of at least one rapid-onset opioid; of atleast one sustained relief opioid and a pharmaceuticaHy acceptable carrier as herein described, wherein the rapid-onset opioid is chosen from fentanyl, alfentanil, sufentanil and remifentanil, preferably from fentanyl and alfentanil,
wherein the concentration and type of each opioid in the formulation is selected so that, during inhalation, analgesia is achieved before the onset of said side effect, and the onset of said side effect occurs before the onset of toxicity, and so that the maximum total opioid plasma concentration does not reach toxic levels, whereby the onset of said side effect can be used by the patient to terminate inhalation to avoid toxicity,
wherein the said formulation is dispensed by the pulmonary drug delivery device at a mass medium aerodynamic diameter of from 1 to 5 microns;
wherein the ratio of concentration of total sustained-effect opioid to concentration of total rapid-onset opioid is from 1:2 to 6:1 and the said one sustained-effect opioid is liposomally encapsulated fentanyl and the rapid-onset opioid is fentanyl.
2. The formulation as claimed in claim 1 wherein the formulation is dispensed by the pulmonary drug delivery device at a mass medium aerodynamic diameter of from 1 to 3 microns.
3. The formulation as claimed in claim 2 wherein the formulation is dispensed by the pulmonary drug delivery device at a mass medium aerodynamic diameter of from 1.5 to 2 microns.

4. The formulation as claimed in any of claims 1 to 3 wherein the maximum total opioid plasma concentration at the onset of side effect is no less than 66% of the maximum total opioid plasma concentration.
5. The formulation as claimed in claim 4 wherein the maximum total opioid plasma concentration at the onset of side effect is no less than 80% of the maximum total opioid plasma concentration
6. The formulation as claimed in claim 1 wherein the ratio of concentration of liposomally encapsulated fentanyl to fentanyl is from 1:1 to 5:1
7. The formulation as claimed in claim 1 wherein the ratio of concentration of liposomally encapsulated fentanyl to fentanyl is from 2:1 to 4:1.
8. The formulation as claimed in claim 1 wherein the ratio of concentration of liposomally encapsulated fentanyl to fentanyl is from 3:1.
9. The opioid formulation as claimed in claim 1 wherein the total opioid concentration is from 250 to 1500 mcg/ml.
10. The opioid formulation as claimed in claim 9 containing liposomally encapsulated fentanyl in a concentration of from 100 to 750 mcg/ml.
11. The opioid formulation as claimed in claim 9 containing fentanyl in a concentration of from 100 to 750 mcg/ml.
12. The opioid formulation as claimed in claim 1 wherein the total opioid concentration is 500 mcg/ml, the fentanyl concentration is 200 mcg/ml and the liposomally encapsulated fentanyl concentration is 300 mcg/ml.

13. An opioid formulation as claimed in any one of claims 1 to 12 as and when used in the manufacture of a medicament for providing analgesia to a patient.



Documents:

4177-delnp-2005-abstract.pdf

4177-DELNP-2005-Assignment-(11-06-2009).pdf

4177-DELNP-2005-Assignment-(29-06-2009).pdf

4177-DELNP-2005-Assignment-11-04-2008.pdf

4177-DELNP-2005-Claims-(26-06-2009).pdf

4177-delnp-2005-claims.pdf

4177-DELNP-2005-Correspondence-Others-(11-06-2009).pdf

4177-DELNP-2005-Correspondence-Others-(26-06-2009).pdf

4177-DELNP-2005-Correspondence-Others-(29-06-2009).pdf

4177-DELNP-2005-Correspondence-Others-11-04-2008.pdf

4177-delnp-2005-correspondence-others.pdf

4177-DELNP-2005-Correspondence-PO-(11-06-2009).pdf

4177-delnp-2005-description (complete).pdf

4177-delnp-2005-drawings.pdf

4177-DELNP-2005-Form-1-(11-06-2009).pdf

4177-delnp-2005-form-1.pdf

4177-delnp-2005-form-18.pdf

4177-delnp-2005-form-2.pdf

4177-DELNP-2005-Form-26-(11-06-2009).pdf

4177-DELNP-2005-Form-26-11-04-2008.pdf

4177-delnp-2005-form-3.pdf

4177-delnp-2005-form-5.pdf

4177-DELNP-2005-Others-Documents-(11-06-2009).pdf

4177-delnp-2005-pct-210.pdf

4177-delnp-2005-pct-237.pdf

4177-delnp-2005-pct-308.pdf

4177-delnp-2005-pct-311.pdf

4177-DELNP-2005-Petition-137-(29-06-2009).pdf


Patent Number 235496
Indian Patent Application Number 4177/DELNP/2005
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 06-Jul-2009
Date of Filing 15-Sep-2005
Name of Patentee YM BIOSCIENCES INC.
Applicant Address 5045 ORBITOR DRIVE.BLDG.11.SUITE 400, MISSISSAUGA, L4W 4Y4,CANADA
Inventors:
# Inventor's Name Inventor's Address
1 HUNG ORLANDA RICARDO 933 GREENWOOD AVENUE, HALIFAX, NOVA SCOTIA B3H 3L1,CANADA.
2 SHAFER, STEVEN, LOUIS 531 SULLIVAN DRIVE, MOUNTAIN VIEW, CA94041, U.S.A.
3 PLIURA, DIANA, HELEN 5032 BRANDY LANE COURT MISSISSAUGA, ONTARIO L5M 5A2 CANADA.
PCT International Classification Number A61K 9/12
PCT International Application Number PCT/CA2004/000303
PCT International Filing date 2004-03-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/450,333 2003-02-28 U.S.A.