U.S. patent application number 16/240639 was filed with the patent office on 2019-07-11 for intranasal delivery of dihydroergotamine by precision olfactory device.
The applicant listed for this patent is Impel Neuropharma, Inc.. Invention is credited to Christopher Fuller, John D. Hoekman, Kelsey H. Satterly, Stephen B. Shrewsbury, Scott Youmans.
Application Number | 20190209463 16/240639 |
Document ID | / |
Family ID | 67140390 |
Filed Date | 2019-07-11 |
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United States Patent
Application |
20190209463 |
Kind Code |
A1 |
Hoekman; John D. ; et
al. |
July 11, 2019 |
INTRANASAL DELIVERY OF DIHYDROERGOTAMINE BY PRECISION OLFACTORY
DEVICE
Abstract
Methods are provided for acutely treating migraine headache with
or without aura. The methods comprise administering to a subject
with migraine headache an effective dose of a liquid pharmaceutical
composition comprising dihydroergotamine (DHE) or a salt thereof,
wherein the dose is administered by an intranasal delivery device
that provides, following intranasal administration, (a) a mean peak
plasma DHE concentration (C.sub.max) of at least 750 pg/ml, (b)
with a mean time to C.sub.max (T.sub.max) of DHE of less than 45
minutes, and (c) a mean plasma AUC.sub.0-inf of DHE of at least
2500 pg*hr/ml. Also provided are kits for acutely treating migraine
with or without aura in which a liquid pharmaceutical composition
comprising DHE or DHE salt is contained within a sealed vial that
is attachable to a precision intranasal olfactory delivery device
packaged therewith.
Inventors: |
Hoekman; John D.; (Seattle,
WA) ; Satterly; Kelsey H.; (Seattle, WA) ;
Shrewsbury; Stephen B.; (Fallbrook, CA) ; Youmans;
Scott; (Bothell, WA) ; Fuller; Christopher;
(Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Impel Neuropharma, Inc. |
Seattle |
WA |
US |
|
|
Family ID: |
67140390 |
Appl. No.: |
16/240639 |
Filed: |
January 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62643657 |
Mar 15, 2018 |
|
|
|
62613939 |
Jan 5, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/26 20130101;
A61M 15/0065 20130101; A61M 11/08 20130101; A61M 15/002 20140204;
A61K 9/0043 20130101; A61M 15/0028 20130101; A61P 25/06 20180101;
A61M 15/08 20130101; A61K 31/522 20130101; A61M 15/009 20130101;
A61K 31/48 20130101; A61M 2205/8225 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/48 20060101 A61K031/48; A61K 31/522 20060101
A61K031/522; A61K 47/26 20060101 A61K047/26; A61M 15/08 20060101
A61M015/08; A61M 15/00 20060101 A61M015/00; A61P 25/06 20060101
A61P025/06 |
Claims
1. A method of acutely treating migraine headache with or without
aura, comprising: administering to a subject with migraine headache
an effective dose of a liquid pharmaceutical composition comprising
dihydroergotamine (DHE) or salt thereof, wherein the effective dose
is administered by an intranasal delivery device that provides,
following intranasal administration, (a) a mean peak plasma DHE
concentration (C.sub.max) of at least 750 pg/ml, (b) with a mean
time to C.sub.max (T.sub.max) of DHE of less than 45 minutes, and
(c) a mean plasma AUC.sub.0-inf of DHE of at least 2500
pg*hr/ml.
2. The method of claim 1, wherein the effective dose is (i) no more
than 2.0 mg DHE or salt thereof, (ii) less than 2.0 mg DHE or salt
thereof, (iii) 1.2-1.8 mg DHE or salt thereof, (iv) 1.4-1.6 mg DHE
or salt thereof, or (v) about 1.45 mg DHE or salt thereof.
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. The method of claim 1, wherein the effective dose is
administered (i) as a plurality of divided doses or (ii) as two
divided doses, optionally wherein each of the divided doses is
administered to each nostril.
8. (canceled)
9. (canceled)
10. The method of claim 7, wherein the effective dose is
administered (i) over no more than 1 minute, (ii) over no more than
45 seconds, or (iii) over no more than 30 seconds.
11. (canceled)
12. (canceled)
13. The method of claim 7, wherein the volume of liquid composition
administered per divided dose is (i) 140-250 .mu.L, (ii) 175
.mu.L-225 .mu.L, or (iii) about 200 .mu.L.
14. (canceled)
15. (canceled)
16. The method of claim 1, wherein the liquid composition comprises
a salt of DHE.
17. The method of claim 16, wherein the liquid composition
comprises DHE mesylate at a concentration of 2.5-7.5 mg/ml, 3.5-6.5
mg/ml or 4.0 mg/ml.
18. (canceled)
19. (canceled)
20. (canceled)
21. The method of claim 1, wherein the liquid composition further
comprises caffeine, optionally caffeine at a concentration of 10
mg/ml.
22. (canceled)
23. The method of claim 1, wherein the liquid composition further
comprises dextrose, optionally dextrose at a concentration of 50
mg/ml.
24. (canceled)
25. The method of claim 1, wherein the liquid composition comprises
4.0 mg/ml DHE mesylate, 10.0 mg/ml caffeine, and 50 mg/ml
dextrose.
26. The method of claim 1, wherein, following administration of the
effective dose, the mean C.sub.max of DHE is at least 1000 pg/ml,
or at least 1200 pg/ml.
27. (canceled)
28. The method of claim 1, wherein, following administration of the
effective dose, the mean plasma AUC.sub.0-inf of DHE is at least
3000 pg*hr/ml, at least 4000 pg*hr/ml, at least 5000 pg*hr/ml, or
at least 6000 pg*hr/ml.
29. (canceled)
30. (canceled)
31. (canceled)
32. The method of claim 1, wherein, following administration of the
effective dose, the mean peak plasma concentration (C.sub.max) of
8'-OH-DHE is at least 50 pg/ml or at least 55 pg/ml.
33. (canceled)
34. The method of claim 1, wherein, following administration of the
effective dose, the mean plasma AUC.sub.0-inf of 8'-OH-DHE is at
least 1000 pg*hr/ml.
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
45. (canceled)
46. The method of claim 1, wherein the subject has (i) migraine
headache with aura, (ii) migraine headache without aura, (iii)
onset of at least one prodromal symptom of migraine, (iv)
menstrual-associated migraine, or (v) migraine that does not
respond to triptan drugs.
47. (canceled)
48. (canceled)
49. (canceled)
50. (canceled)
51. The method of claim 1, wherein the subject self-administers the
liquid pharmaceutical composition or a care-giver of the subject
administers the liquid pharmaceutical composition to the
subject.
52. In a method of acutely treating migraine headache with or
without aura by intranasal administration of dihydroergotamine
(DHE) or salt thereof, the improvement comprising: administering a
dose of a liquid pharmaceutical composition comprising
dihydroergotamine (DHE) or salt thereof by an intranasal delivery
device that provides, following intranasal administration, (a) a
mean peak plasma DHE concentration (C.sub.max) of at least 750
pg/ml, (b) with a mean time to C.sub.max (T.sub.max) of DHE of less
than 45 minutes, and (c) a mean plasma AUC.sub.0-inf of DHE of at
least 2500 pg*hr/ml.
53. (canceled)
54. (canceled)
55. (canceled)
56. A kit for acutely treating migraine with or without aura,
comprising: a vial, within which is sealably contained at least one
effective dose of a liquid pharmaceutical composition comprising
dihydroergotamine (DHE) or salt thereof, and a device, wherein the
vial is configured to be attachable to the device, and wherein the
device, upon attachment of the vial, is a manually actuated,
metered-dose, propellant-driven intranasal administration device
capable of providing, after intranasal administration of a dose of
liquid pharmaceutical composition, (a) a mean peak plasma DHE
concentration (C.sub.max) of at least 750 pg/ml, (b) with a mean
time to C.sub.max (T.sub.max) of DHE of less than 45 minutes, and
(c) a mean plasma AUC.sub.0-inf of DHE of at least 2500
pg*hr/ml.
57. (canceled)
58. (canceled)
59. (canceled)
60. (canceled)
61. (canceled)
62. (canceled)
63. (canceled)
64. (canceled)
65. (canceled)
66. (canceled)
67. (canceled)
68. (canceled)
69. (canceled)
70. (canceled)
71. A device for delivering an intranasal dosage form comprising: a
housing that is configured to be held by a user, the housing
comprising an upper portion and an actuator grip configured to move
relative to the upper portion of the housing when a force is
applied to the actuator grip by the user; a canister containing a
propellant, wherein the canister is configured to release at least
a portion of the propellant upon actuation of the canister; a dose
chamber in fluid communication with the canister and configured to
receive the intranasal dosage form and the propellant; and a nozzle
disposed at a distal end of the dose chamber, the nozzle configured
to be inserted into a nostril of the user.
72. The device of claim 71, further comprising a junction that
couples the canister and the dose chamber, the junction comprising
a first branch configured to couple to the canister, a second
branch configured to couple to a vial containing the intranasal
dosage form, and a third branch configured to couple to the nozzle,
optionally further comprising a one-way valve positioned within the
second branch and configured to prevent released propellant in the
first branch from entering the second branch.
73. (canceled)
74. The device of claim 72, further comprising an extension spring
that is coupled to the housing at a first end and to the actuator
grip at a second end, wherein the spring is configured to increase
a force threshold to actuate the canister.
75. The device of claim 74, wherein the force threshold to actuate
the canister is greater than a force threshold to actuate a dose
pump of a vial containing the intranasal dosage form, such that the
force applied to the actuator grip by the user causes the
intranasal dosage form to enter the dose chamber before the
released propellant enters the dose chamber.
76. The device of claim 75, wherein the actuator grip comprises a
guiding feature that is configured to envelop at least a portion of
the canister, optionally wherein the guiding feature extends along
a length of the canister and captures a first end of the canister
opposite of a second end of the canister that is configured to
release the at least portion of the propellant.
77. (canceled)
78. The device of claim 76, wherein when the force is applied by
the user, the guiding feature is configured to transmit the force
to the canister, thereby actuating the canister.
79. (canceled)
80. The device of claim 71, further comprising a diffuser
positioned at a first end of the dose chamber such that the
released propellant is configured to pass through the diffuser,
optionally wherein the diffuser is configured to convert liquid
propellant into gaseous propellant as the released propellant
passes through the diffuser.
81. (canceled)
82. (canceled)
83. The device of claim 71, wherein the dose chamber is further
configured to sequentially receive the intranasal dosage form
followed by the propellant.
84. (canceled)
Description
1. CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to US provisional
application Nos. 62/643,657, filed Mar. 15, 2018, and 62/613,939,
filed Jan. 5, 2018, each of which is incorporated herein by
reference in its entirety.
2. BACKGROUND
[0002] Dihydroergotamine (DHE), a semisynthetic derivative of the
ergot alkaloid ergotamine, has been approved for over 70 years for
the treatment of migraines. The exact mechanism of action of DHE is
not known, but DHE is known to act as a serotonin receptor agonist,
cause vasoconstriction of intracranial blood vessels, and interact
centrally with dopamine and adrenergic receptors.
[0003] The oral bioavailability of DHE is poor, and DHE is commonly
administered parenterally as the mesylate salt by subcutaneous,
intramuscular or intravenous injection, and where approved, by
nasal spray. Because migraine headaches are episodic and occur
unpredictably, administration by nasal spray is far more convenient
for treatment of acute migraine than is administration by
injection. However, the previously approved nasal spray drug-device
combination product provides only 32% of the bioavailability of the
intravenous injection, and variable efficacy (among other factors)
has led to its withdrawal from market in the EU and other
countries, although it remains available in the United States.
[0004] There is, therefore, a need for an intranasal DHE product
that provides increased bioavailability and reduced variability in
systemically delivered dose for treatment of migraine.
3. SUMMARY
[0005] We designed a manually actuated, propellant-driven,
intranasal administration device that can reproducibly deliver
metered doses of liquid pharmaceutical compositions beyond the
nasal valve to more distal regions of the nasal cavity. We tested
the device in a Phase I clinical trial that compared the
bioavailability of (i) dihydroergotamine (DHE) mesylate
administered as a single divided 1.45 mg intranasal dose using our
Precision Olfactory Delivery (POD.RTM.) Device ("INP104"); (ii) a
2.0 mg dose of DHE mesylate administered intranasally using
Migranal.RTM. Nasal Spray according to the US FDA approved product
label; and (iii) a 1.0 mg intravenous injection of DHE mesylate for
injection (D.H.E.45.RTM.), in healthy adult subjects.
[0006] As described in detail in Example 2, INP104 provided 4-fold
higher mean maximal plasma concentration, nearly 3-fold higher mean
systemic drug exposure, and reached maximal DHE plasma
concentration faster than Migranal.RTM.. The higher maximal plasma
concentration and systemic drug exposure were achieved with a lower
administered dose of the identical formulation of DHE mesylate,
1.45 mg for INP104 versus 2.0 mg for Migranal.RTM., and without
requiring a 15-minute wait between administration of divided
sub-doses, as required for Migranal.RTM.. In addition, systemic
delivery of DHE was more consistent with INP104 than with
Migranal.RTM., with lower coefficient of variation (CV %) in DHE
AUC.sub.0-inf and C.sub.max observed across subjects.
[0007] Accordingly, in a first aspect, methods are provided for
acutely treating migraine headache with or without aura. The
methods comprise administering to a subject with migraine headache
an effective dose of a liquid pharmaceutical composition comprising
dihydroergotamine (DHE) or a salt thereof, wherein the dose is
administered by an intranasal delivery device that provides,
following intranasal administration, (a) a mean peak plasma DHE
concentration (C.sub.max) of at least 750 pg/ml, (b) with a mean
time to C.sub.max (T.sub.max) of DHE of less than 45 minutes, and
(c) a mean plasma AUC.sub.0-inf of DHE of at least 2500
pg*hr/ml.
[0008] In various embodiments, the dose is no more than 2.0 mg DHE
or salt thereof, less than 2.0 mg DHE or salt thereof, 1.2-1.8 mg
DHE or salt thereof, or 1.4-1.6 mg DHE or salt thereof. In a
particular embodiment, the dose is about 1.45 mg DHE or salt
thereof.
[0009] In a variety of embodiments, the dose is administered as a
plurality of divided doses. In certain embodiments, the dose is
administered as two divided doses. In a particular embodiment, one
divided dose is administered to each nostril. In typical divided
dose embodiments, the dose is administered over no more than 1
minute, over no more than 45 seconds, or over no more than 30
seconds. In various embodiments, the volume of liquid composition
administered per divided dose is 140-250 .mu.L, 175 .mu.L-225
.mu.L, about 200 .mu.L, or about 180 .mu.L.
[0010] In typical embodiments, the liquid composition comprises a
salt of DHE. In currently preferred embodiments, the liquid
composition comprises DHE mesylate. In certain embodiments, the
liquid composition comprises DHE mesylate at a concentration of
2.5-7.5 mg/ml, 3.5-6.5 mg/ml, or more particularly, 4.0 mg/ml DHE
mesylate.
[0011] In some embodiments, the liquid composition further
comprises caffeine. In particular embodiments, the liquid
composition comprises caffeine at a concentration of 10 mg/ml. In
some embodiments, the liquid composition further comprises
dextrose, and in certain embodiments, dextrose at a concentration
of 50 mg/ml. In specific embodiments, the liquid composition
comprises 4.0 mg/ml DHE mesylate, 10.0 mg/ml caffeine, and 50 mg/ml
dextrose.
[0012] In various embodiments, following administration of the
dose, the mean C.sub.max of DHE is at least 1000 pg/ml, or at least
1200 pg/ml. In various embodiments, following administration of the
dose, the mean plasma AUC.sub.0-inf of DHE is at least 3000
pg*hr/ml, 4000 pg*hr/ml, 5000 pg*hr/ml, or 6000 pg*hr/ml.
[0013] In some embodiments, following administration of the dose,
the mean peak plasma concentration (C.sub.max) of 8'-OH-DHE is at
least 50 pg/ml or at least 55 pg/ml. In some embodiments, following
administration of the dose, the mean plasma AUC.sub.0-inf of
8'-OH-DHE is at least 1000 pg*hr/ml.
[0014] In typical embodiments, the intranasal delivery device is a
manually actuated, propellant-driven, metered-dose intranasal
administration device. In some embodiments, prior to first manual
actuation, the liquid pharmaceutical composition and propellant are
not in contact within the device. In certain embodiments, the
liquid pharmaceutical composition is contained in a vial and the
propellant is contained in a canister. The canister may further be
a pressurized canister. In currently preferred embodiments, between
successive manual actuations, the liquid pharmaceutical composition
in the vial and propellant in the canister are not in contact
within the device.
[0015] In certain of these embodiments, each manual actuation
brings a metered volume of liquid pharmaceutical composition and a
separately metered volume of propellant into contact within a dose
chamber of the device. In specific embodiments, contact of
propellant with liquid pharmaceutical composition within the dose
chamber of the device creates a spray of liquid pharmaceutical
composition as the formulation is expelled through a nozzle of the
device. In particular embodiments, the nozzle has a plurality of
lumens, and the spray is ejected simultaneously through a plurality
of nozzle lumens. In some embodiments, the propellant is a
hydrofluoroalkane propellant, and in specific embodiments, the
propellant is hydrofluoroalkane-134a.
[0016] In various embodiments, prior to first actuation, the vial
is nonintegral to the device and is configured to be attachable
thereto. In some of these embodiments, the vial is configured to be
threadably attachable to the device.
[0017] In some embodiments, the subject has migraine headache with
aura. In some embodiments, the subject has migraine headache
without aura. In some embodiments, the subject has had onset of at
least one prodromal symptom of migraine. In a variety of
embodiments, the subject has menstrual-associated migraine. In
certain embodiments, the subject has triptan-resistant
migraine.
[0018] In typical embodiments, the subject self-administers the
liquid pharmaceutical composition.
[0019] In a second, related, aspect, improved methods of acutely
treating migraine headache with or without aura by intranasal
administration of dihydroergotamine (DHE) or salt thereof are
provided. In this aspect, the improvement comprises administering a
dose of a liquid pharmaceutical composition comprising
dihydroergotamine (DHE) or salt thereof by an intranasal delivery
device that provides, following intranasal administration, (a) a
mean peak plasma DHE concentration (C.sub.max) of at least 750
pg/ml, (b) with a mean time to C.sub.max (T.sub.max) of DHE of less
than 45 minutes, and (c) a mean plasma AUC.sub.0-inf of DHE of at
least 2500 pg*hr/ml.
[0020] In typical embodiments of this aspect, the intranasal
delivery device is a manually actuated, metered-dose,
propellant-driven intranasal administration device as used in
methods of the first aspect. In certain embodiments, contact of
propellant with liquid pharmaceutical composition within a dose
chamber of the device ejects a spray of liquid pharmaceutical
composition through a nozzle of the device. In specific
embodiments, the nozzle has a plurality of lumens, and the spray is
ejected simultaneously through a plurality of nozzle lumens.
[0021] In another aspect, kits are provided for acutely treating
migraine with or without aura. The kits comprise a vial, within
which is sealably contained at least one effective dose of a liquid
pharmaceutical composition comprising dihydroergotamine (DHE) or
salt thereof, and a device, wherein the vial is configured to be
attachable to the device, and wherein the device, upon attachment
of the vial, is a manually actuated, metered-dose,
propellant-driven intranasal administration device capable of
providing, after intranasal administration of a dose of liquid
pharmaceutical composition, (a) a mean peak plasma DHE
concentration (C.sub.max) of at least 750 pg/ml, (b) with a mean
time to C.sub.max (T.sub.max) of DHE of less than 45 minutes, and
(c) a mean plasma AUC.sub.0-inf of DHE of at least 2500
pg*hr/ml.
[0022] In some embodiments, the device within the kit comprises a
canister, wherein the canister is a pressurized canister containing
propellant.
[0023] In certain of these embodiments, following attachment of the
vial to the device and prior to first manual actuation, the liquid
pharmaceutical composition and propellant are not in contact within
the device. In some embodiments, between successive manual
actuations, the liquid pharmaceutical composition in the vial and
propellant in the canister are not in contact within the device. In
typical embodiments, each manual actuation brings a metered volume
of liquid pharmaceutical composition and a separately metered
volume of propellant into contact within a dose chamber of the
device, and contact of propellant with liquid pharmaceutical
composition within the dose chamber of the device creates a spray
of liquid pharmaceutical composition as the formulation is expelled
through a nozzle of the device.
[0024] In some currently preferred embodiments, the liquid
pharmaceutical composition within the vial comprises a salt of DHE.
In certain embodiments, the liquid composition comprises DHE
mesylate. In particular embodiments, the liquid composition
comprises DHE mesylate at a concentration of 2.5-7.5 mg/ml, or
about 4.0 mg/ml DHE mesylate. In specific embodiments, the liquid
composition comprises 4.0 mg/ml DHE mesylate, 10.0 mg/ml caffeine,
and 50 mg/ml dextrose.
[0025] In various kit embodiments, the vial contains no more than 2
ml of liquid pharmaceutical composition. In some embodiments, the
vial contains approximately 1 ml of liquid pharmaceutical
composition.
[0026] In some embodiments, the pressurized canister contains an
amount of propellant sufficient to administer no more than 1 dose
of liquid pharmaceutical composition.
[0027] Other features and advantages of the present disclosure will
become apparent from the following detailed description, including
the drawings. It should be understood, however, that the detailed
description and the specific examples are provided for illustration
only, because various changes and modifications within the spirit
and scope of the invention will become apparent to those skilled in
the art from the detailed description.
4. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 shows a cross section of an embodiment of a handheld,
manually actuated, metered-dose, propellant-driven intranasal
administration device useful for precision olfactory delivery of
dihydroergotamine (DHE).
[0029] FIG. 2 shows a cross section of the in-line nasal delivery
device of FIG. 1 in the stages of rest and actuation. FIG. 2A shows
the in-line nasal delivery device at rest with FIG. 2B showing the
actuation of the pump and FIG. 2C showing actuation of the
propellant valve.
[0030] FIG. 3 shows a cross section of another implementation of
the in-line nasal delivery device.
[0031] FIG. 4 shows a cross section of the diffuser as seated
within the device.
[0032] FIG. 5A shows an exploded view of the dose chamber and the
Y-junction unassembled.
[0033] FIG. 5B shows an exploded view of the dose chamber and
Y-junction in cooperation.
[0034] FIG. 6 shows arrows representing both dose and propellant
flow.
[0035] FIG. 7 shows the actuator grip and conical spring
arrangement.
[0036] FIG. 8 shows a cross section of the optional nose cone and a
side elevation of the optional nose cone.
[0037] FIGS. 9A and 9B illustrate the device used in the phase I
clinical trial described in Example 2, with further description of
the numbered parts set forth in Table 1.
[0038] FIGS. 10A and 10B plot plasma concentrations of DHE versus
time as measured in the phase I comparative bioavailability
clinical trial described in Example 2, with FIG. 10A plotting data
from 0 to 8 hours and FIG. 10B plotting data from 0 to 24
hours.
[0039] FIGS. 11A and 11B plot plasma concentrations of the
8'-OH-DHE metabolite of DHE versus time as measured in the phase I
comparative bioavailability clinical trial described in Example 2,
with FIG. 11A plotting data from 0 to 8 hours and FIG. 11B plotting
data from 0 to 24 hours.
[0040] FIG. 12A shows a cross section of an alternate
implementation of the in-line nasal delivery device.
[0041] FIG. 12B shows a zoomed-in view of the cross section of FIG.
12A.
[0042] FIG. 13A shows a cross section of the diffuser as seated
within the device, according to an additional embodiment.
[0043] FIG. 13B shows an exploded view of the nozzle and the
Y-junction, according to an additional embodiment.
[0044] FIG. 14 illustrates the nose cone, according to an
additional embodiment.
5. DETAILED DESCRIPTION
5.1. Definitions
[0045] Unless defined otherwise, all technical and scientific terms
used herein have the meaning commonly understood by a person
skilled in the art to which this invention belongs.
5.2. Other Interpretational Conventions
[0046] Ranges: throughout this disclosure, various aspects of the
invention are presented in a range format. Ranges include the
recited endpoints. It should be understood that the description in
range format is merely for convenience and brevity and should not
be construed as an inflexible limitation on the scope of the
invention. Accordingly, the description of a range should be
considered to have specifically disclosed all the possible
subranges as well as individual numerical values within that range.
For example, description of a range such as from 1 to 6 should be
considered to have specifically disclosed subranges such as from 1
to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to
6 etc., as well as individual numbers within that range, for
example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of
the breadth of the range.
[0047] Unless specifically stated or apparent from context, as used
herein the term "or" is understood to be inclusive.
[0048] Unless specifically stated or apparent from context, as used
herein, the terms "a", "an", and "the" are understood to be
singular or plural. That is, the articles "a" and "an" are used
herein to refer to one or to more than one (i.e., to at least one)
of the grammatical object of the article. By way of example, "an
element" means one element or more than one element.
[0049] In this disclosure, "comprises," "comprising," "containing,"
"having," "includes," "including," and linguistic variants thereof
have the meaning ascribed to them in U.S. Patent law, permitting
the presence of additional components beyond those explicitly
recited.
[0050] Unless specifically stated or otherwise apparent from
context, as used herein the term "about" is understood as within a
range of normal tolerance in the art, for example within 2 standard
deviations of the mean and is meant to encompass variations of
.+-.20% or .+-.10%, more preferably .+-.5%, even more preferably
.+-.1%, and still more preferably .+-.0.1% from the stated
value.
5.3. Summary of Experimental Observations
[0051] We designed a manually actuated, propellant-driven,
intranasal administration device that can reproducibly deliver
metered doses of liquid pharmaceutical compositions beyond the
nasal valve to more distal regions of the nasal cavity. We tested
the device in a Phase I clinical trial designed to compare the
bioavailability of (i) dihydroergotamine (DHE) mesylate
administered as a single divided 1.45 mg intranasal dose using this
Precision Olfactory Delivery (POD.TM.) Device ("INP104"); (ii) a
2.0 mg dose of DHE mesylate administered intranasally using
Migranal.RTM. Nasal Spray according to the US FDA approved product
label; and (iii) a 1.0 mg intravenous injection of DHE mesylate for
injection (D.H.E.45.RTM.), in healthy adult subjects.
[0052] As described in detail in Example 2, INP104 provided nearly
3-fold higher mean systemic drug exposure, nearly 4-fold higher
mean maximal plasma concentration, and reached maximal DHE plasma
concentration faster than Migranal.RTM.. The higher systemic drug
exposure and higher maximal plasma concentration were achieved with
a lower administered dose of the identical formulation of DHE
mesylate, 1.45 mg for INP104 versus 2.0 mg for Migranal.RTM., and
without requiring a 15-minute wait between administration of
divided sub-doses, as required for Migranal.RTM..
[0053] In addition, systemic delivery of DHE was more consistent
with INP104 than with Migranal.RTM., with lower variation observed
across subjects for both AUC.sub.0-inf and C.sub.max
parameters.
[0054] Although bolus intravenous administration of 1 mg DHE
mesylate provided greater than 10-fold higher C.sub.max than 1.45
mg DHE mesylate administered intranasally by INP104, the high
C.sub.max achieved with intravenous administration is known to be
correlated with adverse events ("AE"s), specifically nausea, and IV
DHE mesylate is most commonly administered with an anti-emetic.
Within 20-30 minutes following administration, DHE plasma
concentrations achieved through INP104 intranasal administration
were essentially indistinguishable from concentrations achieved by
intravenous administration. Thus, despite a greater than 10-fold
higher C.sub.max, bolus intravenous administration of 1 mg DHE
mesylate provided less than 2-fold greater systemic drug delivery,
measured as AUC.sub.0-inf, as compared to INP104 intranasal
delivery.
[0055] The 8'OH-DHE metabolite of DHE is known to be active, and to
contribute to the long-lasting effect of DHE on migraine. We found
that intranasal administration of 1.45 mg DHE mesylate by INP104
provides equivalent systemic exposure to the active metabolite of
DHE as bolus intravenous administration of 1.0 mg DHE mesylate. In
contrast, the 8'-OH DHE metabolite could be detected in only a
minority of subjects administered Migranal.RTM..
5.4. Methods of Treating Migraine with or without Aura
[0056] Accordingly, in a first aspect, methods are provided for
acutely treating migraine headache with or without aura.
[0057] The methods comprise administering to a subject with
migraine headache an effective dose of a liquid pharmaceutical
composition comprising dihydroergotamine (DHE) or a salt thereof,
wherein the dose is administered by an intranasal delivery device
that provides, following intranasal administration, (a) a mean peak
plasma DHE concentration (C.sub.max) of at least 750 pg/ml, (b)
with a mean time to C.sub.max (T.sub.max) of DHE of less than 45
minutes, and (c) a mean plasma AUC.sub.0-inf of DHE of at least
2500 pg*hr/ml.
5.4.1. Effective Dose
[0058] In various embodiments, the dose is no more than 2.0 mg DHE
or salt thereof. In typical embodiments, the dose is less than 2.0
mg DHE or DHE salt.
[0059] In certain embodiments, the dose is 1.2-1.8 mg DHE or salt
thereof, 1.4-1.6 mg DHE or salt thereof, or 1.4-1.5 mg DHE or salt
thereof. In some embodiments, the dose is about 1.2, 1.25, 1.3,
1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, or 1.7 mg DHE or salt
thereof. In a currently preferred embodiment, the dose is about
1.45 mg DHE or salt thereof.
[0060] In some embodiments, the dose is administered as a single
undivided dose. In these embodiments, the dose is administered to
either the left or right nostril.
[0061] In other embodiments, the dose is administered as a
plurality of divided doses. In some of these embodiments, the dose
is administered as 2, 3, or 4 divided doses. In particular
embodiments, the dose is administered as 2 divided doses. In
currently preferred embodiments, the dose is administered as 2
divided doses, with one divided dose administered to each
nostril.
[0062] In embodiments in which the dose is administered as a
plurality of divided doses, the entire effective dose is typically
administered over no more than 1 minute--that is, all of the
plurality of divided doses are administered within 1 minute of
administration of the first divided dose. In certain divided dose
embodiments, the dose is administered over no more than 45 seconds.
In certain divided dose embodiments, the dose is administered over
no more than 30 seconds.
[0063] In embodiments in which the dose is administered as a
plurality of divided doses, the volume of liquid composition
administered per divided dose is typically 140-250 .mu.L. In
certain embodiments, the volume of liquid composition administered
per divided dose is 145 .mu.L-225 .mu.L. In some embodiments, the
volume of liquid composition administered per divided dose is 175
.mu.L-225 .mu.L. In particular embodiments, the volume of liquid
composition administered per divided dose is about .about.180 .mu.L
or .about.200 .mu.L.
5.4.2. Liquid Pharmaceutical Composition
[0064] The liquid pharmaceutical composition comprises
dihydroergotamine (DHE) or salt thereof.
[0065] In typical embodiments, the liquid pharmaceutical
composition comprises a salt of DHE. In preferred embodiments, the
liquid composition comprises DHE mesylate.
[0066] Dihydroergotamine mesylate--ergotamine hydrogenated in the
9,10 position as the mesylate salt--is known chemically as
ergotaman-3',6',18-trione,
9,10-dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl)-,
(5'.alpha.)-, monomethane-sulfonate. Its molecular weight is 679.80
and its empirical formula is
C.sub.33H.sub.37N.sub.5O.sub.5.CH.sub.4O.sub.3S. The structure is
shown in formula (I) below:
##STR00001##
[0067] In typical embodiments, the liquid pharmaceutical
composition comprises DHE mesylate at a concentration of at least 1
mg/ml, 1.5 mg/ml, 2.0 mg/ml, 2.5 mg/ml, 3.0 mg/ml, 3.5 mg/ml, 4.0
mg/ml, 4.5 mg/ml or 5.0 mg/ml. In some embodiments, the liquid
pharmaceutical composition comprises DHE mesylate at a
concentration of 2.5-7.5 mg/ml. In certain embodiments, the liquid
pharmaceutical composition comprises 3.0-5.0 mg/ml or 3.5-6.5 mg/ml
DHE mesylate. In particular embodiments, the liquid pharmaceutical
composition comprises 4.0 mg/ml DHE mesylate.
[0068] In some embodiments, the composition further comprises
caffeine. In particular embodiments, the composition comprises
caffeine at a concentration of 1 mg/ml-20 mg/ml, 5 mg/ml-15 mg/ml,
or 7.5 mg/ml-12.5 mg/ml. In particular embodiments, the composition
comprises 10.0 mg/ml caffeine.
[0069] In some embodiments, the composition further comprises
dextrose. In certain embodiments, the composition comprises
dextrose at a concentration of 5 mg/ml, 10 mg/ml, 15 mg/ml, 20
mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, or 50
mg/ml. In some embodiments, the composition comprises dextrose at a
concentration of at least 50 mg/ml.
[0070] In various currently preferred embodiments, the liquid
pharmaceutical composition comprises 4.0 mg/ml DHE mesylate, 10.0
mg/ml caffeine, and 50 mg/ml dextrose.
5.4.3. Systemic Delivery
[0071] The methods comprise administering to a subject with
migraine headache an effective dose of a liquid pharmaceutical
composition comprising dihydroergotamine (DHE) or a salt thereof,
wherein the dose is administered by an intranasal delivery device
that provides, following intranasal administration, (a) a mean peak
plasma DHE concentration (C.sub.max) of at least 750 pg/ml, (b)
with a mean time to C.sub.max (T.sub.max) of DHE of less than 45
minutes, and (c) a mean plasma AUC.sub.0-inf of DHE of at least
2500 pg*hr/ml.
[0072] In various embodiments, the mean peak plasma DHE
concentration (C.sub.max) achieved following administration of a
dose, whether administered as an undivided dose or a plurality of
divided doses, is at least 750 pg/ml, 800 pg/ml, 900 pg/ml, 1000
pg/ml, 1100 pg/ml, or 1200 pg/ml. In some embodiments, the mean DHE
C.sub.max achieved following administration of a dose is at least
1250, 1300, 1350, 1400, 1450 or 1500 pg/ml. In certain embodiments,
the mean DHE C.sub.max achieved following administration of a dose
is at least 750 pg/ml, 800 pg/ml, 900 pg/ml, 1000 pg/ml, 1100
pg/ml, or 1200 pg/ml. In certain embodiments, the mean DHE
C.sub.max achieved following administration of a dose is at least
1250, 1300, 1350, 1400, 1450 or 1500 pg/ml. In particular
embodiments, the mean DHE C.sub.max achieved following
administration of a dose is 1000-1500 pg/ml, 1100-1400 pg/ml, or
1200-1300 pg/ml.
[0073] In various embodiments, the mean time to C.sub.max
(T.sub.max) of DHE following administration is less than 55
minutes. In typical embodiments, the DHE T.sub.max is less than 50
minutes, 45 minutes, 40 minutes, or 35 minutes. In some
embodiments, the T.sub.max of DHE following administration is 30-50
minutes, or 35-45 minutes. In particular embodiments, the DHE
T.sub.max is no more than 35 minutes, 40 minutes, or 45
minutes.
[0074] In various embodiments, the mean plasma AUC.sub.0-inf of DHE
following administration is at least 3000 pg*hr/ml, 4000 pg*hr/ml,
5000 pg*hr/ml, or 6000 pg*hr/ml. In various embodiments, the mean
plasma AUC.sub.0-inf of DHE following administration is at least
7000 pg*hr/ml, 8000 pg*hr/ml, 9000 pg*hr/ml, or 10,000 pg*hr/ml. In
some embodiments, the mean plasma AUC.sub.0-inf of DHE following
administration is at least 5000, 5100, 5200, 5300, 5400, 5500,
5600, 5700, 5800, 5900, or 6000 pg*hr/ml. In some embodiments, the
mean plasma AUC.sub.0-inf of DHE following administration is
greater than 6000, 5900, 5800, 5700, 5600, 5500, 5400, 5300, 5200,
5100 or 5000 pg*hr/ml.
[0075] In various embodiments, following administration of the
dose, the mean peak plasma concentration (C.sub.max) of 8'-OH-DHE
is at least 50 pg/ml. In certain embodiments, the mean C.sub.max of
8'-OH-DHE is at least 55 pg/ml.
[0076] In various embodiments, following administration of the
dose, the mean plasma AUC.sub.0-inf of 8'-OH-DHE is at least 500
pg*hr/ml. In some embodiments, the mean plasma AUC.sub.0-inf of
8'-OH-DHE is at least 600 pg*hr/ml, 700 pg*hr/ml, 800 pg*hr/ml, 900
pg*hr/ml, or even at least 1000 pg*hr/ml. In certain embodiments,
the mean plasma AUC.sub.0-inf of 8'-OH-DHE is at least 1100
pg*hr/ml, 1200 pg*hr/ml, 1250 pg*hr/ml, 1300 pg*hr/ml, 1400
pg*hr/ml, or 1500 pg*hr/ml.
5.4.4. Migraine
[0077] The methods described herein are used to acutely treat
migraine headache, with or without aura.
[0078] In various embodiments, the subject has had onset of at
least one prodromal symptom of migraine, without onset of headache
pain. In certain embodiments, the subject has had onset of at least
one prodromal symptom selected from neck stiffness, facial
paresthesia, photosensitivity, acoustic sensitivity, and visual
aura.
[0079] In various embodiments, the subject has had onset of at
least one symptom associated with acute migraine. In certain
embodiments, the subject has had onset of at least one symptom
selected from visual aura; headache pain, including dull,
throbbing, or pulsing pain; photosensitivity; acoustic sensitivity;
nausea; vomiting. Visual aura and headache pain may be unilateral
or bilateral, focal or diffuse.
[0080] In various embodiments, administration is performed within 5
minutes, 10 minutes, 15 minutes, or 30 minutes of onset of at least
one prodromal symptom. In various embodiments, administration is
performed within 5 minutes, 10 minutes, 15 minutes, or 30 minutes
of onset of at least one acute symptom.
[0081] In typical embodiments, the subject performs the
administration (self-administration). In some embodiments, the
administration is performed by another individual, such as a
parent, guardian, caregiver, or medical professional.
[0082] In some embodiments, migraine to be treated is associated
with menstruation. In some embodiments, migraine to be treated has
proven resistant to triptans.
[0083] In various embodiments, the methods are used for acute
treatment of cluster headaches rather than migraine.
5.4.5. Device
[0084] In the methods described herein, the dose is administered by
an intranasal delivery device that provides, following intranasal
administration, (a) a mean peak plasma DHE concentration
(C.sub.max) of at least 750 pg/ml, (b) with a mean time to
C.sub.max (T.sub.max) of DHE of less than 45 minutes, and (c) a
mean plasma AUC.sub.0-inf of DHE of at least 2500 pg*hr/ml.
[0085] 5.4.5.1. Compound Delivery Device
[0086] In various embodiments, the intranasal administration device
is a "compound delivery device" as described in U.S. Pat. No.
9,550,036, the disclosure of which is incorporated herein by
reference in its entirety.
[0087] 5.4.5.2. Medical Unit Dose Container Device
[0088] In various embodiments, the intranasal administration device
is a "medical unit dose container" device as described in WO
2014/179228, the disclosure of which is incorporated herein by
reference in its entirety.
[0089] 5.4.5.3. Manually Activated, Propellant-Driven, Metered-Dose
Device
[0090] In typical embodiments, the intranasal delivery device is a
manually actuated, propellant-driven, metered-dose intranasal
administration device.
[0091] In currently preferred embodiments, the liquid
pharmaceutical composition and propellant are not in contact within
the device prior to first manual actuation, and, optionally, not in
contact within the device between successive manual actuations. In
such embodiments, the device typically comprises a vial and a
canister, wherein the liquid pharmaceutical composition is
contained in the vial and the propellant is contained in the
canister. Typically, the canister is a pressurized canister of
propellant. In typical embodiments, the propellant is a
hydrofluoroalkane propellant suitable for pharmaceutical use. In
specific embodiments, the propellant is hydrofluoroalkane-134a.
[0092] In various embodiments, each manual actuation brings a
metered volume of liquid pharmaceutical composition and a
separately metered volume of propellant into contact within a dose
chamber of the device. Contact of propellant with liquid
pharmaceutical composition within the dose chamber of the device
propels the dose towards the nozzle of the device, creating a spray
as the dose is expelled through the nozzle of the device. In
particularly preferred embodiments, the nozzle has a plurality of
lumens, and the spray is ejected simultaneously through a plurality
of nozzle lumens.
[0093] As discussed in further detail below with respect to kits,
in some embodiments the vial is nonintegral to the device and is
configured to be attachable thereto. In particular embodiments, the
vial is configured to be threadably attachable to the device.
[0094] 5.4.5.3.1. In-Line Nasal Delivery Device
[0095] In certain currently preferred embodiments, the manually
actuated, propellant-driven metered-dose intranasal administration
device is an "in-line nasal delivery device" as described in WO
2017/044897, the disclosure of which is incorporated herein by
reference in its entirety.
[0096] Typically, in these embodiments the device delivers at least
a portion of the dose of liquid pharmaceutical composition to the
nasal cavity beyond the nasal valve, including delivery to the
turbinates and/or the olfactory region. In certain embodiments, the
device delivers at least 25%, 30%, 40%, 50%, 60%, or 70% of the
dose of liquid pharmaceutical composition beyond the nasal valve.
In certain embodiments, the device delivers liquid pharmaceutical
composition so that at least 25%, 30%, 40%, 50%, 60%, or 70% of the
dose of liquid pharmaceutical composition is brought into contact
with the upper third of the nasal cavity (nasal epithelium) of the
subject.
[0097] As shown in FIG. 1, the in-line nasal delivery device 1
includes a housing 10, diffuser 20, tip 35, nozzle 40, dose chamber
45, an actuator 50, and a pump 25 to move the liquid pharmaceutical
composition into the dose chamber 45. In one series of embodiments,
the in-line nasal device 1 is associated and cooperative with a
propellant canister 5, a propellant valve 15, and a vial 30 of
liquid pharmaceutical composition cooperative with the pump 25 to
move the liquid pharmaceutical composition into the dose chamber
45.
[0098] In one series of embodiments, the diffuser 20 is a frit 21
(not shown in FIG. 1). The diffuser provides for the conversion of
the liquefied propellant in the propellant canister 5 to gas and/or
an increase in temperature of the propellant.
[0099] In one series of embodiments, the propellant valve 15 is a
metered dose propellant valve 16.
[0100] In one series of embodiments, the liquid pharmaceutical
composition is supplied in the form of a sealed vial 30, e.g., of
glass. In one series of embodiments, the vial 30 has a neck 31 (not
shown) that is sealed by a removable closure 32 (not shown), for
example but not limited to sealed with a plastic cover, crimped
metal seal, and rubber stopper (for stability and sterility
purposes). When the closure 32 is removed, the device 1 can be
engaged with the vial 30. In one series of embodiments, device 1
can be engaged with vial 30 by cooperation with the neck 31 of the
vial 30. In a related aspect, further discussed below, sealed vial
30 and device 1 can be co-packaged into a kit to be assembled at
time of use.
[0101] In certain embodiments, vial 30 is a 3.5-mL amber glass
vial.
[0102] A pump 25 moves the liquid pharmaceutical composition into
the dose chamber 45.
[0103] The propellant canister 5 is a canister of a compressed gas
or a liquefied propellant. Compressed gases include but are not
limited to compressed air and compressed hydrocarbons. In one
series of embodiments, the compressed gas is nitrogen or carbon
dioxide. Liquefied propellants include but are not limited to
chlorofluorocarbons and hydrofluoroalkanes. In a preferred
embodiment, propellant canister 5 contains HFA-134a.
[0104] The canister 5 will generally be provided with a propellant
valve 15 by which the gas flow can be controlled.
[0105] The tip 35 includes a nozzle 40. In one series of
embodiments, the nozzle 40 has a plurality of nozzle openings 41
(not shown) (synonymously, nozzle lumens). Through the plurality of
nozzle openings 41, the liquid pharmaceutical composition and
propellant is delivered to the nasal cavity.
[0106] Actuation of the propellant canister 5 is effectively
coordinated with actuation of the pump 25 for the vial 30 for the
liquid pharmaceutical composition. The arrangement may be such that
actuation of the vial 30 for the liquid pharmaceutical composition
causes actuation of the propellant canister 5. FIG. 2 shows the
device 1 at rest (FIG. 2A) and in actuation (FIGS. 2B and 2C).
[0107] As an example, the staging of the device 1 actuation is as
follows. The housing 10 is compressed to prime the propellant
canister 5. When the housing 10 is compressed, an actuator 50
remains stationary in the housing 10 while the propellant canister
5 and the vial 30 move towards the actuator 50. At this time, the
propellant valve 15 associated with the propellant canister 5 is
not actuated by compression. The actuator 50 acts upon the pump 25
compressing the pump 25 and the liquid pharmaceutical composition
from the vial 30 is moved into the dose chamber 45. After a
majority of the liquid pharmaceutical composition has moved into
the dose chamber 45, the actuator 50 acts upon the propellant valve
15 and the propellant valve 15 begins to compress. The continued
depression of the actuator 50 releases the propellant from the
propellant canister 5. The propellant pushes the liquid
pharmaceutical composition as it exits the device 1 through the
nozzle openings (lumens) 41 (not shown) of the nozzle 40 located in
the tip 35. The actuator 50 provides for first actuation of the
pump 25, then once the pump 25 bottoms out, the continued
depression of the actuator 50 provides for release of the
propellant from the canister 5.
[0108] In an alternative implementation of the device 1 (not
shown), the device 1 does not include a diffuser 20. In such
embodiments, the device typically incorporates another type of dose
retaining valve.
[0109] FIG. 3 shows yet another implementation of the device 100.
The device 100 can deliver a single or multiple dose from a vial 30
or other container. The device 100 allows for multiple doses to be
delivered from the vial 30, or a single dose. For example, the vial
30 may contain a volume of liquid pharmaceutical composition for
multiple doses, while the user may decide to only deliver a single
dose from the vial 30. The liquid pharmaceutical composition may be
a drug, active pharmaceutical ingredient, or a pharmaceutical
formulation.
[0110] Initially, the vial 30 may be separate from the rest of the
assembled device 100. At the time of use, the device 100 and vial
30 are taken out of their respective packaging. Prior to use, the
vial 30 will generally be sealed. In the embodiment where the vial
30 is covered by a plastic cover, metal seal and stopper, the
plastic cover and metal seal are pulled away from the top of the
vial 30, and the rubber stopper is removed from the vial 30. The
vial 30 may be screwed into a pump fitment 180 located at the base
of the device 100. For example, but not limitation, the vial 30 may
have female threads which can be screwed into male threads on a
pump fitment 180, or vice versa. The vial 30 may contain, for
example but not limited to, inclusive of end points, 2-3 ml, in
another embodiment 2-2.5 ml of liquid pharmaceutical
composition.
[0111] As shown in FIG. 3, the device 100 includes a housing 110.
The housing 110 contains components of the device 100 including the
Y-junction 120. The Y-junction 120 has three branches radiating
from a common base. The Y-junction and its three branches may be a
molded component. The Y-junction 120 establishes both fluid and gas
paths within the device 100, and connects the metered dose pump
130, the dose chamber 150, and the propellant canister 140 when the
propellant canister 140 is assembled with the device.
[0112] As shown in FIG. 3, for use of the device 100, the user will
generally orient the device 100 with the propellant canister 140
assembled and located at the top and the vial 30 assembled and
located at the bottom. Housed within the device's 100 housing 110,
the optional check-valve 160 (attached to the metered dose pump 130
stem) press fits into a receiving hub of a first branch of the
Y-junction 120. An internal bore provides fluid communication from
the metered dose pump 130, through the optional check-valve 160 and
to a third branch of the Y-junction 120, which connects to the dose
chamber 150. In one series of embodiments, the check valve 160 is
an elastomeric component that installs within a plastic housing
between the metered dose pump 130 and the Y-junction 120. The
optional check valve 160: (a) reduces or eliminates dose leakage
which could occur through the metered dose pump 130 if the pump
stem was depressed and the propellant canister 140 was actuated;
(b) allows for improved consistency in dose delivery by the device
100; and/or provides that liquid pharmaceutical composition is not
pushed back down the internal dose loading channel 230 of the
Y-junction 120 and into the metered dose pump 130.
[0113] When oriented as to be used in operation, housed within the
device's 100 housing 110, towards the top of the device 100, the
propellant canister 140 press fits into a second branch of the
Y-junction 120, establishing the gas path through internal bores,
through the diffuser 170 and to the dose chamber 150.
[0114] In this implementation of the device 100, the diffuser 170
is annular. As shown in FIG. 4, the annular diffuser 170 sits
inside a bore on the back end of the dose chamber 150. The external
diameter of the annular diffuser 170 is in a compression fit with
the dose chamber 150. In other embodiments, not shown, the annular
diffuser is fixed to the dose chamber using means other to or in
addition to compression fit.
[0115] An internal dose loading channel 230 which is molded as a
portion of the Y-junction 120 fits into the inner bore of the
annual diffuser 170 when the dose chamber 150 is installed onto the
Y-junction 120. The inner diameter of the annular diffuser 170 is
in compression with the internal dose loading channel 230 portion
of the Y-junction 120. The annular diffuser 170 is seated between
the outer wall of the internal dose loading channel 230 and the
inner wall of the dose chamber 150, sealing against both of those
surfaces to form the bottom of the dose chamber 150. Additional
embodiments of the diffuser 170, dose chamber 150, and Y-junction
120 are discussed with regards to FIGS. 12-13.
[0116] In one series of embodiments, the diffuser 170 is a frit 171
(not shown). In other embodiments, the diffuser 170 is a component
that is homogenously or heterogeneously porous. In some
embodiments, the diffuser 170 may be a disk-shaped member. The
diffuser 170: (a) provides for the conversion of the liquefied
propellant in the propellant canister 140 to gas; (b) provides an
increase in temperature of the propellant; (c) acts to prevent the
propellant from flowing back into the device 100; (d) acts to
prevent the liquid pharmaceutical composition from flowing back
into the device 100; and/or (e) acts to allows gas flow into the
dose chamber 150 while preventing the liquid pharmaceutical
composition from leaking out. The diffuser may be made of a porous
polymer material.
[0117] The relationship in operation of the device 100 between the
liquid pharmaceutical composition, the diffuser 170, the inner dose
loading tube 230, the dose chamber 150 and the Y-junction 120 are
shown at least in FIG. 6. In operation, the liquid pharmaceutical
composition being loaded into the dose chamber 150 takes the less
restrictive route, flowing out of the vial 30 and filling the dose
chamber 150 rather than loading backwards through the diffuser 170
and into the delivery path of the propellant of the Y-junction 120.
In operation of the device 100, the staging of operation and the
amount of time required for operation of the device allows the
diffuser 170 to restrict liquid pharmaceutical composition from
flowing back into the Y-junction 120 for the period of time needed,
as the propellant canister 140 is activated after liquid
pharmaceutical composition loading. During proper device 100 use,
the entire actuation of the device 100, including metered dose pump
130 and propellant canister 140, is approximately a second or less
than a second. The loaded dose in the dose chamber 150 does not
have enough time to flow backwards into the Y-junction 120.
Immediately after the dose chamber 150 is full, the propellant
expels the liquid pharmaceutical composition from the device
100.
[0118] On the third leg of the Y-junction 120 at a 45-degree angle,
the dose chamber 150 press fits into the Y-junction 120, completing
the flow paths for both gas and fluid through the device. In one
series of embodiments, the angle is 30 degrees, 35 degrees, 40
degrees, 45 degrees, 50 degrees, 55 degrees, 60 degrees, inclusive
of endpoints and intervening degrees.
[0119] The Y-junction 120 may contain engagement ribs (not shown)
to help secure and position the assembly within the housing 110 of
the device 100.
[0120] The device 100 includes a pump fitment 180. The pump fitment
180 secures the metered dose pump 130 to the vial 30 and holds both
components in place during device 100 use. One series of
embodiments of the pump fitment 180 is that it consists of
engagement ribs that retain it within the housing 110, provide
vertical displacement, and prevent rotation during installation of
the vial 30.
[0121] The device 100 includes a dose chamber 150. The dose chamber
150 receives and stores the liquid pharmaceutical composition that
has been pushed out of the inner tube of the Y-junction 120. When
the propellant canister 140 is actuated, the Y-junction 120 and
dose chamber 150 are pressurized and the propellant gas expels the
liquid pharmaceutical composition out of the dose chamber 150. As
shown in FIGS. 5A and 5B, the dose chamber 150 is press fit into
the Y-junction 120. The nozzle 190 is installed into the end of the
dose chamber 150 opposite where it is press fit into the Y-junction
120.
[0122] The nozzle 190 is installed into the distal end (end
opposite where the dose chamber 150 is press fit into the
Y-junction 120) of the dose chamber 150, forming a liquid and
gas-tight seal around the outer diameter. During actuation of the
device 100, propellant evacuates liquid pharmaceutical composition
from the dose chamber 150, pushing it out the nozzle 190.
[0123] The nozzle 190 forms the narrow plume angle (for example, an
angle of 1 to 40 degrees, including endpoints and angles
intermittent there between; in one series of embodiments the angle
is 5 degrees, 10 degrees, 15 degrees, 20 degrees, 25 degrees, 30
degrees, 35 degrees) multi-stream deposition. The nozzle 190 and
resultant angle of the plume produced promotes delivery of the
liquid pharmaceutical composition to the olfactory region of the
user's nasal cavity.
[0124] In this implementation, as shown in FIG. 8, the device 100
may include an optional nose cone 200. The external geometries of
the nose cone 200 assist in providing proper alignment of the
device 100 during insertion into the nose. The diametrically
opposed flat sides aid with placement against the septum of either
naris, with the depth stop providing correct depth of insertion.
The nose cone 200 adds redundancy to nozzle 190 retention through
mechanical interference incorporated into the design. As shown in
FIG. 3 and FIG. 8, there is an opening in the nose cone 200 which
aligns with the nozzle 190. The nose cone 200 is not part of the
pressurized flow path.
[0125] The housing 110 represents the body of the device 100. The
housing 110 includes two different "clamshells" concealing the
components of the device 100 and retaining all components to ensure
functionality. The housing 110 houses the metered dose pump 130 and
pump fitment 180, the actuator grip 210, the Y-junction 120, the
propellant canister 140, and the dose chamber 150. The nose cone
200 engages onto the outer geometry of the housing 110, or may be
optionally integrated into the design of the clamshells. An
additional embodiment of the nose cone 200 is discussed with
regards to FIG. 14. The housing 110 is designed to assemble easily
through the use of, for example but not limited to, mattel pins,
snaps, post or screws, or a combination thereof, molded into the
geometry.
[0126] The actuator grip 210 provides for actuation displacement by
the user. The actuator grip 210 is composed of two parts, actuator
grip A and actuator grip B and surround the Y-junction 120 and
reside within the housing 110. FIG. 7 shows two finger grip notches
215 are designed into the actuator grip 210 to allow the user to
engage the device 100 with the fingers, for example but not limited
to, the index and middle finger. These finger grip notches 215
allow the user to apply downward movement leading to device 100
actuation.
[0127] The metered dose pump 130 draws liquid pharmaceutical
composition up from the vial 30 to the Y-junction 120. The metered
dose pump 130 may utilize a custom pump fitment 180 to promote
functionality within the device 100, and allow attachment of the
vial 30 via threads. The metered dose pump 130 may deliver, for
example but not limited to, volumes of 130 .mu.l, 140 .mu.l, 150
.mu.l, 160 .mu.l, 170 .mu.l, 180 .mu.l, 190 .mu.l, 200 .mu.l, or
230 .mu.l during actuation. Commercially available metered dose
pumps 130 can be used.
[0128] For the device 100 to consistently deliver liquid
pharmaceutical composition, the metered dose pump 130 must first
deliver liquid pharmaceutical composition, followed by propellant
canister 140 actuation to expel the liquid pharmaceutical
composition. As shown in FIG. 7, one manner in which to accomplish
this is via a conical spring 220 between the propellant canister
140 and Y-junction 120 to create the necessary propellant canister
140 actuation force resulting in the correct order of actuation
between the metered dose pump 130 and propellant canister 140. In
one implementation, a conical spring 220 is used, although this
force is not limited to being produced by a conical spring 220 as
other mechanisms can be used. In one series of embodiments, the
conical spring 220 has a near zero preload, with a k value of about
25.5 lbf in and a maximum load of 3.2 lbf. Selection of the spring
or mechanism will include the considerations of: (a) providing for
proper device 100 staging; (b) physical space in the device 100;
and/or (c) and user feedback regarding how stiff of a conical
spring 220 still allows a variety of users to activate the device
100.
[0129] The conical spring 220 is installed inline between the
propellant canister 140 and Y-junction 120. The actuator grip 210
physically holds the propellant canister 140. The user activates
the device 100 by, for example, applying an in-line force acting
down from the actuator grips 210, and up from the vial 30. This
force simultaneously acts to activate both the metered dose pump
130 and the propellant canister 140. The conical spring 220 acts in
parallel to the internal propellant canister metering valve spring,
increasing the necessary force required to activate the propellant
canister 140. By choosing the conical spring 220 such that the
necessary force required to actuate the propellant canister 140 is
in excess of the maximum necessary force required to completely
actuate the metered dose pump 130, the device 100 provides that
dose is loaded into the dose chamber 150 before propellant gas
begins to expel liquid pharmaceutical composition from the device
100.
[0130] In another embodiment, an extension spring is used in lieu
of a conical spring. The extension spring is discussed with regards
to FIG. 12A.
[0131] During device 100 actuation, the metered dose pump 130 draws
liquid pharmaceutical composition up from the vial 30 at the bottom
of the device 100 via the Y-junction 120, through the internal dose
loading channel 230 and into the dose chamber 150. The internal
dose loading channel 230 provides a clear route for the liquid
pharmaceutical composition to be loaded ahead of the diffuser 170,
without needed to physically pass through the porous material of
the diffuser 170. As shown in FIG. 6, small arrow heads represent
the flow of the propellant while large arrow heads represent the
flow of the liquid pharmaceutical composition. Priming shots may be
required to completely fill the metered dose pump 130 and internal
dose loading channel 230 of the Y-junction 120 prior to user
dosing. An optional dose cap (not shown) may cover the nose cone
200 of the device 100 and captures the priming shots while also
providing a means of visual indication to the user that the device
is primed.
[0132] In the second stage of device 100 actuation, once the dose
chamber 150 has been filled, the propellant canister 140 releases
propellant which enters through the top of the Y-junction 120,
following the path shown by smaller arrow heads in FIG. 6. The
propellant flows physically through the porous material of the
diffuser 170, which promotes the vaporization of the propellant.
The diffuser 170 and the path along which the propellant travels
(shown by the arrow heads in FIG. 6) convert liquid propellant into
gas propellant, resulting in expansion and propulsion of the
propellant. The propellant first contacts the liquid pharmaceutical
composition at the proximal (distal being closer to the nozzle 190,
proximal being farther away from the nozzle 190) face of the
diffuser 170 as seated in the device 100. As the propellant
continues to expand, it pushes the liquid pharmaceutical
composition forward (toward the nozzle 190) in the dose chamber
150, exiting though the nozzle 190 at the end of the dose chamber
150.
[0133] The propellant canister 140 provides the propulsive energy
for the device 100. The stem of the propellant valve seats into the
top receiver of the Y-junction 120. During use, the user presses
down on the actuator grips 210 which pulls the propellant canister
140 body down, actuating the propellant valve. This releases a
metered volume of liquid propellant. As the propellant vaporizes
and expands, the liquid pharmaceutical composition is forced toward
the distal end of dose chamber 150 and out through the nozzle
190.
[0134] As a non-limiting example of propellant, the propellant
canister 140 uses HFA 134A as the propellant for the system. Other
propellants are envisioned. There are commercially available
propellant canisters 140.
[0135] In certain embodiments, the device, propellant canister, and
vial containing liquid pharmaceutical composition are provided
separately, optionally co-packaged into a kit, and thereafter
assembled for use. In certain embodiments, propellant canister 140
is provided assembled within device 100 and the vial containing
liquid pharmaceutical composition is provided separately,
optionally with the device (with integrated canister) and vial
co-packaged into a kit. In some embodiments, the device, propellant
canister, and vial containing liquid pharmaceutical composition are
provided to the user fully assembled.
[0136] 5.4.5.3.2. Alternate in-Line Nasal Delivery Device
[0137] In certain embodiments, the device comprises the following
parts; part numbering is as depicted in FIGS. 9A and 9B.
TABLE-US-00001 TABLE 1 Clinical Trial Device PART PART COMPONENT ID
NAME MATERIAL Device 1 Y-Junction PP 2 Diffuser PE 3 Dose Chamber
PP 4 Metering Pump POM; PE Medium Density; Chlorobutyl Rubber PP;
White Masterbatch Colorant Stainless Steel; PE (HDPE + LDPE) 5
Finger Grip (right) ABS 6 Clamshell (right) ABS 7 Clamshell (left)
ABS 8 Propellant Canister Propellant: HFA Canister: Anodized
Aluminum HFA Metering Valve: Anodized Aluminum; Polyester;
Stainless Steel; EF327 Seat and Gasket 9 Nozzle LCP 10 Check Valve
Silicone 11 Check Valve PP Adapter 12 Finger Grip (left) ABS 13
Extension Spring Stainless Steel 14 Nose Cone ABS Drug 15 Drug Vial
3.5 ml amber glass vial container
ABBREVIATIONS
[0138] ABS=acrylonitrile butadiene styrene; CMO=contract
manufacturing organization; HDPE=high density polyethylene;
HFA=hydrofluoroalkane-134a; LCP=liquid crystal polymer; LDPE=low
density polyethylene; PE=polyethylene; POM=polyacetal copolymer;
PP=polypropylene
[0139] The vial contains liquid pharmaceutical composition in an
amount sufficient for at least one total dose of DHE, or salt
thereof, to be delivered by the device, in a single undivided or a
plurality of divided doses. In particular embodiments, the vial
contains liquid pharmaceutical composition in an amount sufficient
for at most one total dose of DHE, or salt thereof, to be delivered
by the device, in a single undivided or a plurality of divided
doses.
[0140] In various embodiments, the propellant canister contains
pressurized propellant in an amount sufficient for optional priming
of the device followed by delivery of at least one total dose of
DHE, or salt thereof, to be delivered by the device, in a single
undivided or a plurality of divided doses. In particular
embodiments, the propellant canister contains pressurized
propellant in an amount sufficient for optional priming of the
device followed by delivery of at most one total dose of DHE, or
salt thereof, to be delivered by the device, in a single undivided
or a plurality of divided doses.
[0141] In some embodiments, with each actuation, a minority of the
pressurized liquid hydrofluoroalkane is converted to gaseous
hydrofluoroalkane. In certain embodiments, the quantity of
pressurized liquid hydrofluoroalkane is sufficient to permit a
predetermined number of device actuations. In some of these
embodiments, the quantity is sufficient to permit 2, 3, 4, 5, 6, 7
or 8 actuations. In some embodiments, the quantity is sufficient to
permit 10, 11, 12, 13, 14, 15, or even 20 actuations. In certain
embodiments, a majority of the pressurized liquid hydrofluoroalkane
is converted to gaseous hydrofluoroalkanes after 2, 3, 4, 5, 6, 7,
or 8 actuations. In certain embodiments, a majority of the
pressurized liquid hydrofluoroalkane is converted to gaseous
hydrofluoroalkanes after 10, 11, 12, 13, 14, 15, or 20
actuations.
[0142] 5.4.5.3.3. Alternate in-Line Nasal Delivery Device
[0143] FIG. 12A shows a cross section of an alternate
implementation of the in-line nasal delivery device 1200. The
in-line nasal delivery device 1200 may be an embodiment of the
in-line nasal delivery device 100. For example, the device 1200 may
use the same or similar components as the device 100, as described
with regards to FIGS. 3-9. Additionally, components of device 1200
and device 100 may be used interchangeably or in some combination
thereof. In the embodiment of FIG. 12A, the device 1200 includes a
housing 12110, a Y-junction 12120, a metered dose pump 12130, a
propellant canister 12140, a dose chamber 12150 (shown in FIG.
13A), a check valve 12160, a diffuser 12170 (shown in FIG. 13A), a
pump fitment 12180, a nozzle (not shown), a nose cone 12200, and an
actuator grip 12210. The housing 12110 includes an upper portion
1205 and a bottom portion 1210. The device 1200 additionally
includes an extension spring 1215 and a check valve adapter
1220.
[0144] Similar to the actuator grip 210 described with regards to
FIG. 3, the actuator grip 12210 provides for actuation displacement
by the user. The actuator grip 12210 surrounds the Y-junction 12120
and resides within the housing 12110. FIG. 12A shows two finger
grip notches 12215 that are designed into the actuator grip 12210
to allow the user to engage the device 1200 with the fingers, for
example but not limited to, the index and middle finger. The finger
grip notches 12215 allow the user to engage or grip the device in
order to cause device 1200 actuation.
[0145] More specifically, the actuator grip 12210 includes a
guiding feature 1225 that extends along a length of the housing
12110 behind (as illustrated in FIG. 12A) the propellant canister
12140 and captures an end of the propellant canister 12140. In the
illustrated example, the end is the bottom of the propellant
canister 12140, which is opposite from the end containing the valve
for propellant dispersal. The guiding feature 1225 may capture the
end of the propellant canister 12140 by folding above or adhering
to the end. The propellant canister 12140 is nested within the
guiding feature 1225 such that the guiding feature 1225 securely
supports the propellant canister 12140. By enveloping a portion of
the propellant canister 12140, the guiding feature 1225 is securely
coupled to a larger, more rigid surface area of the propellant
canister 12140 than when coupled to a narrow surface, such as the
propellant valve 15 in the embodiment of device 1. In this
configuration, as the user applies downward movement via the finger
grip notches 12215 to actuate the device 1200, the guiding feature
1225 transmits the downward force to the propellant canister 12140,
thereby actuating the propellant canister 12140. The guiding
feature 1225 actuates the propellant canister 12140 in a stable
manner and is less likely to lose its physical coupling to the
propellant canister 12140.
[0146] In one embodiment, the propellant canister 12140 is entirely
enclosed within the housing 12110. In one specific embodiment, the
propellant canister 12140 is enclosed by the upper portion of the
housing 1205, which may be formed during manufacturing from at
least two separate parts. The Y-junction 12120 is fixed in place
with the bottom housing portion 1210, with the guiding feature 1225
extending upward to establish the position of the propellant
canister 12140 with respect to the Y-junction 12120. This structure
ensures that the propellant canister 12140 moves relative to the
Y-junction 12120 during actuation, to which it is fluidly
coupled.
[0147] In a similar manner to the conical spring 220 described with
regards to FIG. 7, the extension spring 1215 creates an actuation
force that ensures a desired order of actuation between the metered
dose pump 12130 and the propellant canister 12140. Specifically,
during device actuation, the metered dose pump 12130 first delivers
liquid pharmaceutical composition to the dose chamber 12150,
followed by propellant canister 12140 actuation to expel the liquid
pharmaceutical composition. The force of the extension spring 1215
is established to both provide proper order of actuation and enable
ease of actuation by users.
[0148] The extension spring 1215 is coupled to the housing upper
portion 1205 and the actuator grip 12210. As illustrated in FIG.
12A, a first end of the extension spring 1215 couples to a boss
1230 on the housing upper portion 1205, and a second end of the
extension spring 1215 couples to a boss 1235 on the actuator grip
12210. In the embodiment of FIG. 12A, the housing upper portion
1205 and the actuator grip 12210 translate relative to one another
during actuation of the device 1200. The extension spring 1215 is
coupled to each component such that the extension spring 1215
creates a resisting force when the housing upper portion 1205 and
the actuator grip 12210 translate away from each other. As
previously described, the user activates the device 1200 by, for
example, applying an in-line force acting down from the actuator
grips 12210, and up from the vial containing the pharmaceutical
composition. This applied force actuates both the metered dose pump
12130 of the vial and the propellant canister 12140. As the applied
force on the extension spring 1215 increases, a threshold (higher)
force to actuate the propellant canister 12140 is achieved after a
threshold (lower) force to actuate the metered dose pump 12130 is
achieved, such that the applied force first exceeds the threshold
force of the metered dose pump 12130. In this configuration,
actuation of the device 1200 first activates the metered dose pump
12130 and then activates the propellant canister 12140 such that
dose is loaded into the dose chamber 12150 before propellant begins
to expel liquid pharmaceutical composition from the device
1200.
[0149] In some embodiments, the extension spring 1215 may be used
in lieu of or in addition to the conical spring 220. The
configuration of the extension spring may streamline the assembly
process of the device relative to the configuration of the conical
spring, as the conical spring may create a resisting force between
the propellant canister 140 and Y-junction 120 such that the
components are pushed apart during assembly, whereas the extension
spring may pull the components towards each other. In addition, the
configuration of the extension spring may prolong the shelf life
and overall lifetime of the device relative to the configuration of
the conical spring. This may be in part due to the press fit
between the stem of the propellant canister 140 and Y-junction 120
of the device 100, which may naturally relax over time and which
may be propagated by the resisting force of the conical spring
between the propellant canister 140 and Y-junction 120, potentially
furthering the decrease in durability of the press fit over
time.
[0150] The check valve adapter 1220 is an adapter that couples the
check valve 12160 and the Y-junction 12120. The check valve 12160
may be an embodiment of check valve 160. In the embodiment of FIGS.
12A-12B, the check valve adapter 1220 is a cylindrical component
having a first end that inserts into a channel of the Y-junction
12120 and mates with the check valve 12160 positioned within the
channel of the Y-junction 12120 and a second end that mates with
the metered dose pump 130. As illustrated in the zoomed-in view in
FIG. 12B, an end of the check valve 12160 comprises a flange that
is captured at an end of the channel of the Y-junction 12120 and
mates with a respective interface of the check valve adapter 1220.
The check valve 12160 and/or check valve adapter 1220 may be
secured at each end with an adhesive, ultrasonic welding, an
interference fit (e.g., press fit, friction fit, or similar), or
some combination thereof. The check valve adapter 1220 may augment
the function of the check valve 12160 by improving the seal between
the check valve 12160 and the Y-junction 12120. As discussed with
regards to FIG. 3, a check valve may: (a) reduce or eliminate dose
leakage which could occur through the metered dose pump if the pump
stem was depressed and the propellant canister was actuated; (b)
allow for improved consistency in dose delivery by the device;
and/or (c) provide that liquid pharmaceutical composition is not
pushed back down an internal dose loading channel of the Y-junction
and into the metered dose pump.
[0151] FIG. 13A shows a cross section of a diffuser 12170 as seated
within the device 1200, according to an additional embodiment. The
diffuser 12170 may be an embodiment of the diffuser 170. In this
implementation of the device 1200, the diffuser 12170 is annular.
As shown in FIG. 13A, the diffuser 12170 sits on a shelf 1305
inside a bore 1310 of the Y-junction 12120, and the dose chamber
12150 is inserted into the bore 1310 of the Y-junction 12120. The
diffuser 12170 is seated between the shelf of the bore of the
Y-junction 12120 and a bottom face of the dose chamber 12150,
sealing against both of those surfaces. The diffuser 12170 may
further be sealed along its inner diameter to the Y-junction 12120.
In this configuration, the diffuser 12170 creates an interference
seal along its inner diameter, its upper face, and its lower outer
edge (in contact with the shelf 1305). This configuration may allow
expansion of the diffuser 12170, for example, as propellant flows
through the diffuser 12170 due to changes in temperature or as a
result of device assembly. Sealing the diffuser 12170 along its
inner diameter may improve the consistency and/or quality of the
seal and/or performance of the diffuser 12170 relative to sealing
the diffuser 12170 along its top and bottom faces in a compression
fit, which could compress the diffusion path within (the path along
which propellant travels and is diffused). In this configuration,
variations in the manufacturing of the diffuser 12170 may be less
likely to affect the performance of the diffuser 12170. For
example, the tolerances of the outer diameter of the diffuser 12170
may not need to be as precisely controlled to prevent bending of
the diffuser 12170 such that flatness of the diffuser 12170 is
maintained to ensure a proper compression fit along its faces. In
some instances, the interference seal may or may not be liquid or
gas tight.
[0152] FIG. 13B shows an exploded view of the dose chamber 12150
and the Y-junction 12120, according to an additional embodiment.
FIG. 13B illustrates the bore 1310 and the shelf 1305 of the
Y-junction 12120. The dose chamber 12150 may include a chamfer 1315
around an outer edge of its bottom face such that the dose chamber
12150 may be easily inserted into the bore 1310. In alternate
embodiments, the configuration of the dose chamber 12150 and
Y-junction 12120 may be reversed such that the dose chamber 12150
includes a bore into which a diffuser and an end of the Y-junction
12120 is inserted.
[0153] FIG. 14 illustrates the nose cone 12200, according to an
additional embodiment. The nose cone 12200 may be an embodiment of
the nose cone 200. As previously described, the external geometries
of the nose cone 12200 assist in providing proper alignment of the
device 1200 during insertion into the nose. As shown in FIG. 14,
the nose cone 12200 comprises an opening 1405 that aligns with the
nozzle (not shown). The dose chamber 12150 (not shown in this view)
may be positioned between two bosses 1410a, 1410b that maintain the
alignment of the dose chamber 12150 and the nozzle within the nose
cone 12200. In the embodiment of FIG. 14, the nose cone 12200 is
integrated into the design of the clamshells. The nose cone 12200
and the clamshells may be molded together during manufacturing,
decreasing the overall part count of the device 1200 and enabling
easy assembly of the device 1200.
5.5. Kits
[0154] In another aspect, kits are provided for acutely treating
migraine with or without aura.
[0155] The kit comprises a vial and a device. The vial is sealed,
and sealably contains at least one effective dose of a liquid
pharmaceutical composition comprising dihydroergotamine (DHE) or
salt thereof. The vial is configured to be attachable to the
device. The device is reciprocally configured to receive the vial.
Upon attachment of the vial to the device by the user, the device
becomes a manually actuated, propellant-driven, metered-dose
intranasal administration device capable of providing, after
intranasal administration of a dose of liquid pharmaceutical
composition, (a) a mean peak plasma DHE concentration (C.sub.max)
of at least 750 pg/ml, (b) with a mean time to C.sub.max
(T.sub.max) of DHE of less than 45 minutes, and (c) a mean plasma
AUC.sub.0-inf of DHE of at least 2500 pg*hr/ml.
[0156] In typical embodiments, upon attachment of the vial to the
device, the device becomes a manually actuated, propellant-driven,
metered-dose intranasal administration device as described in
Section 5.3.5.3 above. In currently preferred embodiments, upon
attachment of the vial to the device, the device becomes a manually
actuated, propellant-driven, metered-dose intranasal administration
device as particularly described in Section 5.3.5.3.1 above. In
currently preferred embodiments, the propellant-containing canister
is a pressurized canister that is sealed within the device and is
not accessible to the user.
[0157] In various embodiments, the vial is a sealed glass vial. In
currently preferred embodiments, the vial is a 3.5-mL amber sealed
glass vial.
[0158] In typical embodiments, the liquid pharmaceutical
composition that is sealably contained within the vial is a liquid
pharmaceutical composition as described in Section 5.3.2 above. In
currently preferred embodiments, the vial comprises a liquid
pharmaceutical composition having the following composition: a
clear, colorless to faintly yellow solution in an amber glass vial
containing:
TABLE-US-00002 dihydroergotamine mesylate, USP 4.0 mg caffeine,
anhydrous, USP 10.0 mg dextrose, anhydrous, USP 50.0 mg carbon
dioxide, USP qs purified water, USP qs 1.0 mL.
[0159] The vial contains liquid pharmaceutical composition in an
amount sufficient for at least one total dose of DHE, or salt
thereof, to be delivered by the device, in a single undivided or a
plurality of divided doses. In particular embodiments, the vial
contains liquid pharmaceutical composition in an amount sufficient
for at most one total dose of DHE, or salt thereof, to be delivered
by the device, in a single undivided or a plurality of divided
doses.
[0160] In typical embodiments, the propellant canister within the
device that is co-packaged with the vial in the kit contains
pressurized propellant in an amount sufficient for optional priming
of the device followed by delivery of at least one total dose of
DHE, or salt thereof, to be delivered by the device either in a
single undivided or a plurality of divided doses. In particular
embodiments, the propellant canister contains pressurized
propellant in an amount sufficient for optional priming of the
device followed by delivery of at most one total dose of DHE, or
salt thereof, to be delivered by the device, in a single undivided
or a plurality of divided doses.
5.6. Experimental Examples
[0161] The invention is further described through reference to the
following experimental examples. These examples are provided for
purposes of illustration only, and are not intended to be
limiting.
5.6.1. Example 1: Reproducibility of Dose Delivery
[0162] Table 2 provides experimental data on one implementation of
the in-line device described in Section 5.3.5.1.1 above. As used in
Table 2, "dose" refers to a volume delivered in a single device
actuation.
TABLE-US-00003 TABLE 2 Dose Volume [.mu.L] Shot # Device 1 Device 2
Device 3 Device 4 Device 5 Device 6 1 190.6 193.7 185.3 199.2 199.2
145.1 2 181.4 205.5 178.9 167.7 167.7 141.7 3 183.1 188.5 173.3
165.6 165.6 138.5 4 183.2 193.3 145.8 164.6 164.6 136.6 185 uL +
10% 203.5 5 183.3 201.5 200.7 162.0 162.0 142.1 185 uL - 10% 166.5
6 185.8 207.7 166.3 179.4 179.4 138.9 185 uL + 15% 212.8 7 184.3
195.1 180.3 164.8 164.8 140.9 185 uL - 15% 157.3 8 183.3 205.4
175.3 164.9 164.9 142.0 9 180.5 178.1 172.0 164.1 164.1 141.8 10
179.7 204.0 178.0 170.6 170.6 143.9 Mean 183.5 197.3 175.6 170.3
170.3 141.2 StDev 3.1 9.3 14.0 11.3 11.3 2.5 Min 179.7 178.1 145.8
162.0 162.0 136.6 Max 190.6 207.7 200.7 199.2 199.2 145.1
5.6.2. Example 2: Phase I Clinical Trial
[0163] A Phase I clinical trial was conducted to compare the
bioavailability of dihydroergotamine (DHE) mesylate following (i)
single divided dose intranasal administration of INP104, a
drug-device combination employing a Precision Olfactory Delivery
(POD.RTM.) Device (Impel NeuroPharma, Seattle); (ii) intranasal
administration of Migranal.RTM. Nasal Spray (Valeant
Pharmaceuticals); and (iii) intravenous injection with D.H.E.
45.RTM. (Valeant Pharmaceuticals) in healthy adult subjects.
[0164] 5.6.2.1. Study Design
[0165] The study was a three-period, three-way, randomized,
open-label, single-dose, cross-over, comparative bioavailability
study.
[0166] Thirty-six subjects (approximately equal numbers of men and
women) were enrolled and randomized into the study. Twenty-eight
subjects completed the study. Treatment assignment was randomized
in a three-treatment, three-period balanced crossover study of six
sequences shown below, with a 7-day washout between treatments:
TABLE-US-00004 TABLE 3 Treatment Sequence 1 2 3 1 A B C 2 B C A 3 C
A B 4 A C B 5 B A C 6 C B A A = 1.45 mg INP104 B = 1.0 mg D.H.E.
45, IV C = 2 mg Migranal .RTM. Nasal Spray.
Subjects all received 10 mg IV metoclopramide 5-10 minutes prior to
each treatment.
[0167] INP104 was self-administered using the I123 POD.TM. Device
(Impel NeuroPharma, Seattle). The dose of DHE mesylate was divided,
with one spray in each nostril delivering a total target dose of
1.45 mg DHE mesylate.
[0168] The I123 POD Device is a handheld, manually actuated,
propellant-driven, metered-dose administration device intended to
deliver a drug formulation to the nasal cavity. Drug delivery to
the nasal cavity via the I123 POD Device is driven by
hydrofluoroalkane-134a (HFA) propellant. The I123 POD Device
functions as an intranasal delivery device; the HFA propellant in
the 1123 POD Device is not intended to deliver drug to the lungs
and does not contact the DHE formulation until the time of
delivery.
[0169] The INP104 drug component, DHE DP, is a 3.5-mL amber glass
vial filled with DHE mesylate 4 mg/mL. The formulation is identical
to that in the Migranal.RTM. Nasal Spray device: a clear, colorless
to faintly yellow solution in an amber glass vial containing:
TABLE-US-00005 dihydroergotamine mesylate, USP 4.0 mg caffeine,
anhydrous, USP 10.0 mg dextrose, anhydrous, USP 50.0 mg carbon
dioxide, USP qs purified water, USP qs 1.0 mL.
[0170] The DHE DP vial attaches to the I123 POD Device. The I123
POD Device may have a nominal output between 175 .mu.L/actuation
pump and 205 .mu.L/actuation pump (inclusive). In some embodiments,
the I123 POD Device may have a nominal output that is about 175,
176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,
189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,
202, 203, 204, or 205 .mu.L/actuation pump.
[0171] A single manual actuation of the device by the user results
in the operation of the metering pump to fill the dose chamber with
the DHE formulation and subsequent, but almost instantaneous,
activation of the propellant canister to expel the formulation
through the nozzle, as a spray, resulting in delivery to the nasal
cavity of the user. The device is designed to be disposed of after
successful single divided-dose drug delivery (1 spray per nostril).
Actuation of the I123 POD Device releases approximately 63 .mu.L of
HFA-134a propellant, similar to HFA exposure from metered-dose
inhalers.
[0172] D.H.E. 45.RTM. (Valeant Pharmaceuticals, NDA 005929) was
administered in a volume of 1 mL intravenously over 1 minute.
[0173] Migranal.RTM. (Valeant Pharmaceuticals, NDA 20148) Nasal
Spray (2 mg) was self-administered with equal dosing to both
nostrils. In accordance with the product label, one spray (0.5 mg)
was administered in each nostril initially, followed by an
additional spray (0.5 mg) in each nostril 15 minutes later.
[0174] 5.6.2.2. Pharmacokinetic Assessments
Sampling and Processing
[0175] Blood samples for PK analysis were obtained, according to
the clinical trial site's standard operating procedures (SOPs),
within 15 minutes prior to dosing and at 5, 10, 20, 30, 40 and 50
minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 8, 12, 24, 36 and 48
hours after dosing. For the Migranal.RTM. Nasal Spray dose, the PK
sampling timeclock was started following administration of the
first dose of Migranal.RTM. Nasal Spray.
Pharmacokinetic Analysis
[0176] Individual DHE and 8'-OH-DHE plasma concentration data were
listed for each individual and summarized by nominal sampling
time-point and administration method with descriptive statistics
(sample size [N], arithmetic mean, standard deviation [SD], median,
minimum, maximum and geometric mean). Individual and mean DHE and
8'-OH-DHE plasma concentration-time profiles for each
administration method were also graphed.
[0177] Pharmacokinetic parameters were computed from the individual
plasma DHE and 8'-OH-DHE concentrations using a non-compartmental
approach. Appropriate validated PK software (e.g., Phoenix
WinNonlin v6.3) was used. The parameters that were determined and
their definitions are provided in Table 4 below.
TABLE-US-00006 TABLE 4 C.sub.max Maximum observed drug
concentration. T.sub.max Time to maximum observed drug
concentration. If the maximum value occurs at more than one time-
point, T.sub.max is defined as the first time point with this
value. AUC.sub.0-t Area under the drug concentration-time curve,
calculated using linear-up log-down trapezoidal summation from time
zero to the time of the last Measurable concentration. k.sub.el
Apparent terminal elimination rate constant, calculated by linear
regression of the terminal linear portion of the log concentration
vs. time curve. AUC.sub.0-inf Area under the drug
concentration-time curve from time zero to infinity, calculated as
AUC.sub.0-t + Ct/k.sub.el. t.sub.1/2 Apparent elimination
half-life, calculated as ln(2)/k.sub.el. CL/F Apparent clearance
calculated as Dose/AUC.sub.0-inf. (CL for i.v.) Vz/F Apparent
volume of distribution at the terminal phase, (Vz for i.v.)
calculated as Dose/(.sub.el * AUC.sub.0-inf).
Statistical Methods for Pharmacokinetic Analyses
[0178] PK parameters were summarized by administration method using
descriptive statistics (arithmetic means, SD, coefficients of
variation [CV], sample size [N] minimum, maximum, median and
geometric mean). Geometric mean was calculated for AUC.sub.0-t,
AUC.sub.0-inf, and C.sub.max.
[0179] No value for k.sub.el, t.sub.1/2, AUC.sub.0-inf, CL/F, Vz/F,
as appropriate, were reported for cases that did not exhibit a
terminal log-linear phase in the concentration versus time profile
or did not contain sufficient data during this phase for parameter
estimation.
Statistical Analysis
[0180] A comparative bioavailability assessment was undertaken to
demonstrate (i) that the lower 90% confidence interval of the DHE
after INP104 to DHE after Migranal Nasal Spray geometric mean
ratios for C.sub.max and AUC (AUC.sub.0-t, AUC.sub.0-inf) is not
less than 80%, and (ii) the upper 90% confidence interval of the
DHE after INP104 to D.H.E. 45 Injection (IV) geometric mean ratios
for C.sub.max and AUC (AUC.sub.0-t, AUC.sub.0-inf) not greater than
125%--i.e., to demonstrate that exposure is equal to or greater
than 80% and equal to or less than 125% range observed between
Migranal Nasal Spray and D.H.E. 45 Injection (IV),
respectively.
[0181] For each comparator (Migranal Nasal Spray and D.H.E. 45
Injection (IV)), the following analysis methods were performed
independently. Analysis of variance (ANOVA) with effects for
sequence, subject nested within sequence, period, and treatment
were performed on the ln-transformed DHE and 8'OH-DHE AUC.sub.0-t,
AUC.sub.0-inf and C.sub.max. Each ANOVA included calculation of
least squares mean (LSM), the difference between administration
method LSM, and the standard error associated with the
difference.
[0182] Only subjects who had completed all three treatments and had
sufficient PK sample collection to generate the key PK parameters
(AUC.sub.0-t, AUC.sub.0-inf and C.sub.max) for each administration
method were included in the ANOVA analysis.
[0183] Ratios of geometric means were calculated using the
exponentiation of the difference between treatment LSM from the
analyses on the ln-transformed AUC.sub.0-t, AUC.sub.0-inf and
C.sub.max. These ratios were expressed as a percentage relative to
the reference (comparator) treatment, i.e. INP104 [test]/Comparator
[reference]. Consistent with the two one-sided tests for
bioequivalence, 90% confidence intervals were obtained for the
ratio of the geometric means for AUC.sub.0-t, AUC.sub.0-inf and
C.sub.max.
[0184] 5.6.2.3. Results: DHE and 8'OH-DHE Pharmacokinetics
[0185] The time course of plasma DHE concentrations is plotted in
FIGS. 10A and 10B, and initial summary statistics are provided in
Table 5 below.
TABLE-US-00007 TABLE 5 DHE pharmacokinetics Migranal .RTM. INP104
(2 mg (1.45 mg D.H.E. 45 .RTM. intranasal) intranasal) (1 mg IV)
AUC.sub.0-inf (pg*hr/ml) mean 2,248 6,291 10,053 [% CV] [68%] [44%]
[18%] (range) (444-7247) (978-10,445) C.sub.max (pg/ml) mean 318
1,258 14,460 [% CV] [83%] [54%] [34%] (range) (25.4-1190)
(270-2660) T.sub.max (min) mean 55 34 5 T.sub.max (hr) mean 0.92
0.57 0.08 (range) (0.5-3.08) (0.333-2.05)
[0186] As compared to Migranal Nasal Spray, INP104 provides nearly
3-fold higher mean systemic drug exposure, with an AUC.sub.0-inf of
6,291 pg*hr/ml as compared to 2,248 pg*hr/ml for Migranal.RTM..
INP104 also provides nearly 4-fold higher mean maximal plasma
concentration, with a C.sub.max of 1,258 pg/ml as compared to 318
pg/ml for Migranal.RTM.. Maximal DHE plasma concentration is
reached faster with INP104, with a mean T.sub.max of 34 minutes
versus 55 minutes for Migranal.RTM.. The higher systemic drug
exposure and higher maximal plasma concentration were achieved with
a lower administered dose of the identical formulation of DHE
mesylate, 1.45 mg for INP104 versus 2.0 mg for Migranal.RTM., and
without requiring a 15-minute wait between administration of
divided sub-doses, as required for Migranal.RTM..
[0187] In addition, systemic delivery of DHE was more consistent
with INP104 than with Migranal.RTM., with lower variation observed
across subjects for both AUC.sub.0-inf and C.sub.max parameters
(see Table 5 above for coefficients of variation).
[0188] Although bolus intravenous administration of 1 mg DHE
mesylate provided greater than 10-fold higher C.sub.max than 1.45
mg DHE mesylate administered intranasally by INP104, the high
C.sub.max achieved with intravenous administration is known to be
correlated with adverse events ("AE"s), specifically nausea, and IV
DHE mesylate (D.H.E. 45) is most commonly administered with an
anti-emetic. Within 20-30 minutes following administration, DHE
plasma concentrations achieved through INP104 intranasal
administration were essentially indistinguishable from
concentrations achieved by intravenous administration. Thus,
despite a greater than 10-fold higher C.sub.max, bolus intravenous
administration of 1 mg DHE mesylate provided less than 2-fold
greater systemic drug delivery, measured as AUC.sub.0-inf, as
compared to INP104 intranasal delivery.
[0189] The 8'OH-DHE metabolite of DHE is known to be active, and to
contribute to the long-lasting effect of DHE on migraine. The time
course of plasma 8'-OH-DHE concentrations is plotted in FIGS. 11A
and 11B. Initial summary statistics for plasma concentrations of
8'OH-DHE are provided in Table 6, below.
TABLE-US-00008 TABLE 6 8'OH-DHE pharmacokinetics Migranal .RTM.
INP104 (2 mg (1.45 mg D.H.E. 45 .RTM. intranasal) intranasal) (1 mg
IV) AUC.sub.0-inf 1113 [53%] 1063 [59%] 924 [63%] (pg*hr/ml) [% CV]
n = 6 n = 20 n = 28 C.sub.max .sup. 42 [35%] .sup. 58 [44%] 392
[26%] (pg/ml) [% CV] n = 8 n = 24 n = 28 T.sub.max 2.30 [57%] 1.43
[53%] 0.08 [8%].sup. (hr) n = 8 n = 24 n = 28
[0190] These data demonstrate that intranasal administration of
1.45 mg DHE by INP104 provides equivalent systemic exposure to the
active metabolite of DHE as bolus intravenous administration of 1.0
mg DHE. In addition, the metabolite was detected in only 8 subjects
after Migranal.RTM. intranasal delivery, versus 24 subjects
following intranasal administration of INP104.
6. INCORPORATION BY REFERENCE
[0191] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
by reference in their entirety.
7. EQUIVALENTS
[0192] While this invention has been disclosed with reference to
specific embodiments, it is apparent that other embodiments and
variations of this invention may be devised by others skilled in
the art without departing from the true spirit and scope of the
invention. The appended claims are intended to be construed to
include all such embodiments and equivalent variations.
* * * * *