U.S. patent application number 16/414350 was filed with the patent office on 2019-09-12 for intranasal dhe for the treatment of headache.
The applicant listed for this patent is Satsuma Pharmaceuticals, Inc.. Invention is credited to Shunji Haruta, John Kollins, Salvador Rico, Nikhilesh N. Singh.
Application Number | 20190275036 16/414350 |
Document ID | / |
Family ID | 52424045 |
Filed Date | 2019-09-12 |
United States Patent
Application |
20190275036 |
Kind Code |
A1 |
Haruta; Shunji ; et
al. |
September 12, 2019 |
Intranasal DHE for the Treatment of Headache
Abstract
Presented herein are powder formulations comprising
dihydroergotamine (DHE), or a pharmaceutically acceptable salt
thereof. In addition to such formulations, also presented herein
are methods comprising intranasally administering powder
formulations comprising dihydroergotamine, or a pharmaceutically
acceptable salt thereof. The presented methods can be used for
treating headache, for example, for rapid onset treatment of
headache, including migraine, e.g. acute treatment of migraine with
or without aura.
Inventors: |
Haruta; Shunji;
(Kagoshima-ken, JP) ; Singh; Nikhilesh N.; (Mill
Valley, CA) ; Kollins; John; (San Francisco, CA)
; Rico; Salvador; (Berkeley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Satsuma Pharmaceuticals, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
52424045 |
Appl. No.: |
16/414350 |
Filed: |
May 16, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15023206 |
Mar 18, 2016 |
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PCT/IB2014/002706 |
Sep 24, 2014 |
|
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16414350 |
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61881947 |
Sep 24, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0043 20130101;
A61P 25/06 20180101; A61K 31/4985 20130101; A61K 47/22 20130101;
A61K 31/522 20130101; A61P 43/00 20180101; A61K 47/38 20130101;
A61K 45/06 20130101; A61K 31/48 20130101; A61K 9/146 20130101; A61K
47/02 20130101; A61K 31/48 20130101; A61K 2300/00 20130101; A61K
31/522 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61K 47/38 20060101 A61K047/38; A61K 47/22 20060101
A61K047/22; A61K 47/02 20060101 A61K047/02; A61K 9/00 20060101
A61K009/00; A61K 45/06 20060101 A61K045/06; A61K 31/48 20060101
A61K031/48; A61K 9/14 20060101 A61K009/14; A61K 31/522 20060101
A61K031/522 |
Claims
1. A pharmaceutical nasal dosage form, comprising:
dihydroergotamine or a pharmaceutically acceptable salt thereof and
at least one pharmaceutically acceptable excipient for treating
migraine with or without aura in a human subject, wherein said
pharmaceutical nasal dosage form is provided in a pre-primed nasal
device.
2. The pharmaceutical nasal dosage form of claim 1, wherein said
pharmaceutical nasal dosage form requires less than about 15
minutes to administer an effective dose of dihydroergotamine.
3. The pharmaceutical nasal dosage form of claim 2, wherein said
pharmaceutical nasal dosage form requires a single spray or two
sprays to administer said effective dose of dihydroergotamine.
4. The pharmaceutical nasal dosage form of claim 2, wherein said
effective dose of dihydroergotamine is from about 0.5 mg to about 2
mg.
5. The pharmaceutical nasal dosage form of claim 1, wherein said
dihydroergotamine or said pharmaceutically acceptable salt thereof
is present from about 0.5 mg to about 10 mg.
6. The pharmaceutical nasal dosage form of claim 1, wherein said
dihydroergotamine or said pharmaceutically acceptable salt thereof
is present from about 1.5 mg to about 6 mg.
7. The pharmaceutical nasal dosage form of claim 1, wherein said
pharmaceutical nasal dosage form comprises said pharmaceutically
acceptable salt of dihydroergotamine that is dihydroergotamine
mesylate.
8. The pharmaceutical nasal dosage form of claim 1, wherein said
pharmaceutically acceptable excipient comprises microcrystalline
cellulose.
9. The pharmaceutical nasal dosage form of claim 8, wherein said
microcrystalline cellulose is present in an amount of about 15% to
99% of a total weight of said pharmaceutical nasal dosage form.
10. The pharmaceutical nasal dosage form of claim 8, wherein said
microcrystalline cellulose component has a mean particle size
diameter of about 100 .mu.m or less.
11. The pharmaceutical nasal dosage form of claim 8, wherein said
microcrystalline cellulose component has a mean particle size
diameter of about 30 .mu.m or less.
12. A method comprising administering a pharmaceutical nasal dosage
form of dihydroergotamine or a pharmaceutically acceptable salt
thereof and at least one pharmaceutically acceptable excipient,
wherein said pharmaceutical nasal dosage form is administered using
a pre-primed nasal device and requires less than four sprays to
administer an effective dose of dihydroergotamine for treating
migraine with or without aura in a human subject.
13. The method of claim 12, wherein said pharmaceutical nasal
dosage form requires less than about 15 minutes for said
administration.
14. The method of claim 12, wherein said effective dose is from
about 0.5 mg to about 2 mg of dihydroergotamine.
15. The method of claim 12, wherein said effective dose is from
about 1.5 mg to about 6 mg of dihydroergotamine.
16. The method of claim 12, wherein said administration comprises
two sprays.
17. The method of claim 12, wherein said pharmaceutically
acceptable excipient comprises microcrystalline cellulose.
18. The method of claim 12, wherein said pharmaceutical nasal
dosage form upon intranasal administration to a human subject
provides at least about 10% higher AUC.sub.0-t, AUC.sub.0-inf, or
AUC.sub.0-30 min, compared to a corresponding liquid form.
19. The method of claim 12, wherein said pharmaceutical nasal
dosage form upon intranasal administration to a human subject
provides at least about 10% reduction in time required to achieve
C.sub.max or a plasma concentration of at least about 700 pg/ml,
compared to a corresponding liquid form.
20. The method of claim 12, wherein said pharmaceutical nasal
dosage form upon intranasal administration to a human subject
provides at least one of the following pharmacokinetic parameters:
C.sub.max of at least 900 pg/mL; AUC.sub.0-t of at least 1000
pg*hr/mL; and AUC.sub.0-inf of at least 5000 pg*hr/mL.
Description
1. CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/023,206 filed Mar. 18, 2016, which is
National Stage Entry of PCT/IB2014/002706 filed Sep. 24, 2014,
which claims the benefit of U.S. Provisional Patent Application
Ser. No. 61/881,947, filed Sep. 24, 2013, each of which is entirely
incorporated herein by reference.
2. BACKGROUND
[0002] Migraine is a very common, often debilitating, form of
headache. Typically the headache is unilateral (affecting one half
of the head) and pulsating in nature. In addition to head pain,
associated symptoms may include nausea, vomiting, photophobia,
(increased sensitivity to light), and phonophobia (increased
sensitivity to sound). Migraines can also be associated with
"auras," which are transient visual, sensory, language, or motor
disturbances often manifest as flashes of colored or blinking
lights that occur shortly before the onset of head pain.
[0003] Symptomatic treatment of migraine generally involves
administration of triptans, such as sumatriptan or zolmitriptan, or
ergot alkaloids, such as ergotamine or dihydroergotamine. While
various routes of administration of these drugs for the treatment
of migraine have been utilized, there still exists a need for
easily administrable, fast-acting drug formulations and treatments
for the amelioration of migraine symptoms.
3. SUMMARY OF THE INVENTION
[0004] The inventive embodiments provided in this Summary of the
Invention are meant to be illustrative only and to provide an
overview of selective embodiments disclosed herein. The Summary of
the Invention, being illustrative and selective, does not limit the
scope of any claim, does not provide the entire scope of inventive
embodiments disclosed or contemplated herein, and should not be
construed as limiting or constraining the scope of this disclosure
or any claimed inventive embodiment.
[0005] The pharmacokinetic data disclosed herein (e.g., C.sub.max,
T.sub.max, AUC.sub.0-t, AUC.sub.0-480 minutes, AUC.sub.0-inf,
T.sub.1/2) can be measured from a primate, preferably a monkey, and
preferably a Cynomolgus monkey, after a powder formulation
disclosed herein is administered. Alternatively, the
pharmacokinetic data disclosed herein (e.g., C.sub.max, T.sub.max,
AUC.sub.0-t, AUC.sub.0-480 minutes, AUC.sub.0-inf, T.sub.1/2) can
be measured from a human subject after a powder formulation
disclosed herein is administered.
[0006] Presented herein are powder formulations comprising
dihydroergotamine (DHE), or a pharmaceutically acceptable salt
thereof. In addition to such formulations, also presented herein
are methods comprising intranasally administering powder
formulations comprising dihydroergotamine, or a pharmaceutically
acceptable salt thereof. In some cases, the formulation is not a
liquid solution or a liquid spray formulation.
[0007] The presented methods can be used for treating headache, for
example, for rapid onset treatment of headache, including migraine,
e.g. acute treatment of migraine with or without aura.
[0008] The presented formulations can comprise a) dihydroergotamine
(DHE) or a pharmaceutically acceptable salt thereof, wherein the
total dose of DHE administered is 0.1-10.0 mg; b) a
microcrystalline cellulose comprises at least 15% of the total
weight of the formulation. In some cases, a mean T.sub.max of DHE
after administration of the powder formulation is about 1-120
minutes. The presented methods can comprise: intranasally
administering to a human a powder formulation comprising: a)
dihydroergotamine (DHE) or a pharmaceutically acceptable salt
thereof, wherein the total dose of DHE administered is 0.1-10.0 mg;
b) a microcrystalline cellulose comprises at least 15% of the total
weight of the formulation.
[0009] The presented formulations and methods may further comprise
at least one of the following: a) wherein a mean T.sub.max of DHE
after administration of the powder formulation is about 1 to about
120 minutes; b) wherein a (AUC.sub.0-30
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 2.5%; c) wherein a (AUC.sub.0-30
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 2.5% to 25%; d) wherein a
(AUC.sub.0-60 min/AUC.sub.0-inf).times.100% of DHE after
administration of the powder formulation is greater than 10%; e)
wherein a (AUC.sub.0-60 min/AUC.sub.0-inf).times.100% of DHE after
administration of the powder formulation is greater than 10% to
45%; f) wherein a (AUC.sub.0-120 min/AUC.sub.0-inf).times.100% of
DHE after administration of the powder formulation is greater than
25%; g) wherein a (AUC.sub.0-120 min/AUC.sub.0-inf).times.100% of
DHE after administration of the powder formulation is greater than
25% to 75%; h) wherein when the powder formulation is administered
to a primate, preferably a monkey, and preferably a Cynomolgus
monkey, a (AUC.sub.0-30 min/AUC.sub.0-inf).times.100% is greater
than 10%; i) wherein when the powder formulation is administered to
a primate, preferably a monkey, and preferably a Cynomolgus monkey,
a (AUC.sub.0-60 min/AUC.sub.0 inf).times.100% is greater than 20%;
j) wherein when the powder formulation is administered to a
primate, preferably a monkey, and preferably a Cynomolgus monkey, a
(AUC.sub.0-120 min/AUC.sub.0-inf).times.100% is greater than 40%.
The mean T.sub.max after administration of the powder formulation
can be measured from a primate, preferably a monkey, and preferably
a Cynomolgus monkey.
[0010] In some embodiments, a (AUC.sub.0-30
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 2.5%, for example, greater than
2.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or 30%. In some
embodiments, the (AUC.sub.0-30 min/AUC.sub.0-inf).times.100% of DHE
after administration of the powder formulation is greater than 2.5%
to 75%, for example, 2.5% to 50%, 2.5% to 25%, 2.5% to 15%, or 2.5%
to 5%. In some embodiments, a (AUC.sub.0-60
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 5%, for example, greater than
5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, or 60%. In some embodiments, the (AUC.sub.0-60
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 5% to 75%, for example, 5% to
50%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to 45%, 10%
to 25%, 10% to 15%, 15% to 50%, 15% to 25%, or 25% to 50%. In some
embodiments, a (AUC.sub.0-120 min/AUC.sub.0-inf).times.100% of DHE
after administration of the powder formulation is greater than 5%,
for example, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some
embodiments, the (AUC.sub.0-120 min/AUC.sub.0-inf).times.100% of
DHE after administration of the powder formulation is greater than
15% to 75%, for example, 15% to 75%, 15% to 50%, 15% to 25%, 25% to
75%, 25% to 50%, or 50% to 75%.
[0011] In some embodiments, when the powder formulation is
administered to a primate, preferably a monkey, and preferably a
Cynomolgus monkey, a (AUC.sub.0-30 min/AUC.sub.0-inf).times.100% of
DHE after administration of the powder formulation is greater than
2.5%, for example, greater than 2.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 25%, or 30%. In some embodiments, the (AUC.sub.0-30
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 2.5% to 75%, for example, 2.5%
to 50%, 2.5% to 25%, 2.5% to 15%, or 2.5% to 5%. For example, the
(AUC.sub.0-30 min/AUC.sub.0-inf).times.100% of DHE after
administration of the powder formulation is about 10%. In some
embodiments, when the powder formulation is administered to a
primate, preferably a monkey, and preferably a Cynomolgus monkey, a
(AUC.sub.0-60 min/AUC.sub.0-inf).times.100% of DHE after
administration of the powder formulation is greater than 5%, for
example, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, or 60%. In some embodiments, the
(AUC.sub.0-60 min/AUC.sub.0-inf).times.100% of DHE after
administration of the powder formulation is greater than 5% to 75%,
for example, 5% to 50%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to
50%, 10% to 45%, 10% to 25%, 10% to 15%, 15% to 50%, 15% to 25%, or
25% to 50%. For example, the (AUC.sub.0-60
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is about 20%. In some embodiments, when the
powder formulation is administered to a primate, preferably a
monkey, and preferably a Cynomolgus monkey, a (AUC.sub.0-120
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 5%, for example, greater than
5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, or 75%. In some embodiments, the (AUC.sub.0-120
min/AUC.sub.0-inf).times.100% of DHE after administration of the
powder formulation is greater than 15% to 75%, for example, 15% to
75%, 15% to 50%, 15% to 25%, 25% to 75%, 25% to 50%, or 50% to 75%.
For example, the (AUC.sub.0-120 min/AUC.sub.0-inf).times.100% of
DHE after administration of the powder formulation is about
40%.
[0012] The presented formulations can comprise a) dihydroergotamine
(DHE) or a pharmaceutically acceptable salt thereof, wherein the
total dose of DHE administered is 0.1-10.0 mg; b) a
microcrystalline cellulose comprises at least 15% of the total
weight of the formulation. In some cases, a mean T.sub.max of DHE
after administration of the powder formulation is about 1-120
minutes. The presented methods can comprise: intranasally
administering to a human a powder formulation comprising: a)
dihydroergotamine (DHE) or a pharmaceutically acceptable salt
thereof, wherein the total dose of DHE administered is 0.1-10.0 mg;
b) a microcrystalline cellulose comprises at least 15% of the total
weight of the formulation; wherein a mean T.sub.max of DHE after
administration of the powder formulation is about 1-120 minutes.
The mean T.sub.max after administration of the powder formulation
can be measured from a human subject.
[0013] In one embodiment, the methods and formulations comprise a
mean T.sub.max of DHE after administration of the formulation of at
least about 1 minutes, for example, at least about 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,
40, 45, 50, 60, 90, or 120 minutes. The mean T.sub.max of DHE after
administration of the formulation can be about 1 to about 120
minutes, for example, about 1-120 minutes, about 1-90 minutes,
about 1-60 minutes, about 1-50 minutes, 1-40 minutes, 1-30 minutes,
1-20 minutes, 1-10 minutes, 1-5 minutes, about 1-2 minutes, about
5-120 minutes, about 5-90 minutes, about 5-60 minutes, about 5-50
minutes, 5-40 minutes, 5-30 minutes, 5-25 minutes, 5-20 minutes,
5-10 minutes, about 10-120 minutes, about 10-90 minutes, about
10-60 minutes, about 10-50 minutes, 10-40 minutes, 10-30 minutes,
10-20 minutes, about 20-120 minutes, about 20-90 minutes, about
20-60 minutes, about 20-50 minutes, 20-40 minutes, 20-30 minutes,
about 30-120 minutes, about 30-90 minutes, about 30-60 minutes,
about 30-50 minutes, 30-40 minutes, about 40-120 minutes, about
40-90 minutes, about 40-60 minutes, 40-50 minutes, about 50-120
minutes, about 50-90 minutes, about 50-60 minutes, about 60-120
minutes, about 60-90 minutes, or about 90-120 minutes. The mean
T.sub.max after administration of the powder formulation can be
measured from a primate, preferably a monkey, and preferably a
Cynomolgus monkey.
[0014] In another embodiment, the methods and formulations comprise
a mean T.sub.max of DHE after administration of the formulation of
at least about 1 minute, for example, at least about 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,
40, 45, 50, 60, 90, or 120 minutes. The mean T.sub.max of DHE after
administration of the formulation can be about 1 to about 120
minutes, for example, about 1-120 minutes, about 1-90 minutes,
about 1-60 minutes, about 1-50 minutes, 1-40 minutes, 1-30 minutes,
1-20 minutes, 1-10 minutes, 1-5 minutes, about 1-2 minutes, about
5-120 minutes, about 5-90 minutes, about 5-60 minutes, about 5-50
minutes, 5-40 minutes, 5-30 minutes, 5-25 minutes, 5-20 minutes,
5-10 minutes, about 10-120 minutes, about 10-90 minutes, about
10-60 minutes, about 10-50 minutes, 10-40 minutes, 10-30 minutes,
10-20 minutes, about 20-120 minutes, about 20-90 minutes, about
20-60 minutes, about 20-50 minutes, 20-40 minutes, 20-30 minutes,
about 30-120 minutes, about 30-90 minutes, about 30-60 minutes,
about 30-50 minutes, 30-40 minutes, about 40-120 minutes, about
40-90 minutes, about 40-60 minutes, 40-50 minutes, about 50-120
minutes, about 50-90 minutes, about 50-60 minutes, about 60-120
minutes, about 60-90 minutes, or about 90-120 minutes. The mean
T.sub.max after administration of the powder formulation can be
measured from a human subject.
[0015] In another embodiment, the methods and formulations comprise
a mean C.sub.max of DHE after administration of the formulation of
at least about 0.01 ng/mL, for example, at least about 0.01, 0.1,
0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4,
4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,
80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 ng/mL. The mean
C.sub.max of DHE after administration of the formulation can be
about 0.1 to about 150 ng/mL, for example, about 0.1-150, 0.1-130,
0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10, 0.1-5, 0.1-1.0,
0.1-0.5, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30, 1-10, 1-5,
5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-150, 10-130,
10-110, 10-90, 10-70, 10-50, 10-30, 30-150, 30-130, 30-110, 30-90,
30-70, 30-50, 50-150, 50-130, 50-110, 50-90, 50-70, 70-150, 70-130,
70-110, 70-90, 90-150, 90-130, 90-110, 110-150, 110-130, or 130-150
ng/mL. The mean C.sub.max after administration of the powder
formulation can be measured from a primate, preferably a monkey,
and preferably a Cynomolgus monkey.
[0016] In another embodiment, the methods and formulations comprise
a mean C.sub.max of DHE after administration of the formulation of
at least about 0.01 ng/mL, for example, at least about 0.01, 0.1,
0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4,
4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,
80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 ng/mL. The mean
C.sub.max of DHE after administration of the formulation can be
about 0.1 to about 150 ng/mL, for example, about 0.1-150, 0.1-130,
0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10, 0.1-5, 0.1-1.0,
0.1-0.5, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30, 1-10, 1-5,
5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-150, 10-130,
10-110, 10-90, 10-70, 10-50, 10-30, 30-150, 30-130, 30-110, 30-90,
30-70, 30-50, 50-150, 50-130, 50-110, 50-90, 50-70, 70-150, 70-130,
70-110, 70-90, 90-150, 90-130, 90-110, 110-150, 110-130, or 130-150
ng/mL. The mean C.sub.max after administration of the powder
formulation can be measured from a human subject.
[0017] In another embodiment, the methods and formulations comprise
a mean AUC.sub.0-inf of DHE after administration of the formulation
of at least about 0.5 ngh/mL, for example, at least about 0.5, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,
200, 300, 400, 500, 600, or 700 ngh/mL. The mean AUC.sub.0-inf of
DHE after administration of the formulation can be about 0.5 to
about 700 ngh/mL, for example, about 0.5-700, 0.5-500, 0.5-300,
0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20, 0.5-10, 0.5-5, 0.5-2,
0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60, 1-40, 1-20, 1-10,
1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60, 10-40, 10-20,
20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40, 40-700,
40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,
60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,
100-300, 300-700, 300-500, or 500-700 ngh/mL. The mean
AUC.sub.0-inf after administration of the powder formulation can be
measured fr from a primate, preferably a monkey, and preferably a
Cynomolgus monkey.
[0018] In another embodiment, the methods and formulations comprise
a mean AUC.sub.0-inf of DHE after administration of the formulation
of at least about 0.5 ngh/mL, for example, at least about 0.5, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,
200, 300, 400, 500, 600, or 700 ngh/mL. The mean AUC.sub.0-inf of
DHE after administration of the formulation can be about 0.5 to
about 700 ngh/mL, for example, about 0.5-700, 0.5-500, 0.5-300,
0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20, 0.5-10, 0.5-5, 0.5-2,
0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60, 1-40, 1-20, 1-10,
1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60, 10-40, 10-20,
20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40, 40-700,
40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,
60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,
100-300, 300-700, 300-500, or 500-700 ngh/mL. The mean
AUC.sub.0-inf after administration of the powder formulation can be
measured from a human subject.
[0019] In another embodiment, the methods and formulations comprise
a mean AUC.sub.0-t of DHE after administration of the formulation
of at least about 0.5 ngh/mL, for example, at least about 0.5, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,
200, 300, 400, 500, 600, or 700 ngh/mL. The mean AUC.sub.0-inf of
DHE after administration of the formulation can be about 0.5 to
about 700 ngh/mL, for example, about 0.5-700, 0.5-500, 0.5-300,
0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20, 0.5-10, 0.5-5, 0.5-2,
0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60, 1-40, 1-20, 1-10,
1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60, 10-40, 10-20,
20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40, 40-700,
40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,
60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,
100-300, 300-700, 300-500, or 500-700 ngh/mL. The mean
AUC.sub.0-inf after administration of the powder formulation can be
measured from a primate, preferably a monkey, and preferably a
Cynomolgus monkey. The measurement can be taken 5, 10, 20, 30, 60,
90, 120, 180, 240, 300, 360, 420, or 480 minutes.
[0020] In another embodiment, the methods and formulations comprise
a mean AUC.sub.0-t of DHE after administration of the formulation
of at least about 0.5 ngh/mL, for example, at least about 0.5, 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,
200, 300, 400, 500, 600, or 700 ngh/mL. The mean AUC.sub.0-inf of
DHE after administration of the formulation can be about 0.5 to
about 700 ngh/mL, for example, about 0.5-700, 0.5-500, 0.5-300,
0.5-100, 0.5-80, 0.5-60, 0.5-40, 0.5-20, 0.5-10, 0.5-5, 0.5-2,
0.5-1, 1-700, 1-500, 1-300, 1-100, 1-80, 1-60, 1-40, 1-20, 1-10,
1-5, 10-700, 10-500, 10-300, 10-100, 10-80, 10-60, 10-40, 10-20,
20-700, 20-500, 20-300, 20-100, 20-80, 20-60, 20-40, 40-700,
40-500, 40-300, 40-100, 40-80, 40-60, 60-700, 60-500, 60-300,
60-100, 60-80, 80-700, 80-500, 80-300, 80-100, 100-700, 100-500,
100-300, 300-700, 300-500, or 500-700 ngh/mL. The mean
AUC.sub.0-inf after administration of the powder formulation can be
measured from a human subject. The measurement can be taken 5, 10,
20, 30, 60, 90, 120, 180, 240, 300, 360, 420, or 480 minutes.
[0021] In another embodiment, the methods and formulations comprise
a mean T.sub.1/2 of DHE after administration of the formulation of
at least about 10 minutes, for example, at least about 10, 20, 30,
40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, or 300 minutes.
The mean T.sub.1/2 of DHE after administration of the formulation
can be about 10 to about 300 minutes, for example, about 10-300,
10-250, 10-200, 10-150, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20,
20-300, 20-250, 20-200, 20-150, 20-120, 20-100, 20-80, 20-60,
20-40, 40-300, 40-250, 40-200, 40-150, 40-120, 40-100, 40-80,
40-60, 60-300, 60-250, 60-200, 60-150, 60-120, 60-100, 60-80,
80-300, 80-250, 80-200, 80-150, 80-120, 80-100, 100-300, 100-250,
100-200, 100-150, 100-120, 120-300, 120-250, 120-200, 120-150,
150-300, 150-250, 150-200, 200-300, 200-250, or 250-300 minutes.
For example, the mean T.sub.1/2 of DHE after administration of the
formulation is about 100 to about 300 minutes. The mean T.sub.1/2
after administration of the powder formulation can be measured from
a monkey (e.g., Cynomolgus monkeys).
[0022] In another embodiment, the methods and formulations comprise
a mean T.sub.1/2 of DHE after administration of the formulation of
at least about 10 minutes, for example, at least about 10, 20, 30,
40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, or 300 minutes.
The mean T.sub.1/2 of DHE after administration of the formulation
can be about 10 to about 300 minutes, for example, about 10-300,
10-250, 10-200, 10-150, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20,
20-300, 20-250, 20-200, 20-150, 20-120, 20-100, 20-80, 20-60,
20-40, 40-300, 40-250, 40-200, 40-150, 40-120, 40-100, 40-80,
40-60, 60-300, 60-250, 60-200, 60-150, 60-120, 60-100, 60-80,
80-300, 80-250, 80-200, 80-150, 80-120, 80-100, 100-300, 100-250,
100-200, 100-150, 100-120, 120-300, 120-250, 120-200, 120-150,
150-300, 150-250, 150-200, 200-300, 200-250, or 250-300 minutes.
For example, the mean T.sub.1/2 of DHE after administration of the
formulation is about 100 to about 300 minutes. The mean T.sub.1/2
after administration of the powder formulation can be measured from
a human subject.
[0023] In another aspect, the methods presented herein comprising
intranasally administering to a human a powder formulation
comprising dihydroergotamine (DHE) or a pharmaceutically acceptable
salt thereof. wherein the method further comprises at least one of
the following: wherein a mean T.sub.max of DHE after administration
of the formulation is about 2 to about 50 minutes; b) wherein a
mean C.sub.max of DHE after administration of the formulation is
about 0.1 to about 150 ng/mL; c) wherein a mean AUC.sub.0-inf of
DHE after administration of the formulation is about 1 to about 700
ngh/mL; d) wherein a mean T.sub.1/2 of DHE after administration of
the formulation is about 100 to about 300 minutes. In one
embodiment, the mean T.sub.max of DHE after administration of the
formulation is about 2 to about 50 minutes. In another embodiment,
the mean C.sub.max of DHE after administration of the formulation
is about 0.1 to about 150 ng/mL. In another embodiment, the mean
AUC.sub.0-inf of DHE after administration of the formulation is
about 1 to about 700 ngh/mL. In another embodiment, the mean
T.sub.1/2 of DHE after administration of the formulation is about
100 to about 300 minutes. The mean T.sub.max, C.sub.max,
AUC.sub.0-inf, and/or T.sub.1/2 after administration of the powder
formulation can be measured from a primate, preferably a monkey,
and preferably a Cynomolgus monkey.
[0024] In another aspect, the methods presented herein comprising
intranasally administering to a human a powder formulation
comprising dihydroergotamine (DHE) or a pharmaceutically acceptable
salt thereof. wherein the method further comprises at least one of
the following: wherein a mean T.sub.max of DHE after administration
of the formulation is about 2 to about 50 minutes; b) wherein a
mean C.sub.max of DHE after administration of the formulation is
about 0.1 to about 150 ng/mL; c) wherein a mean AUC.sub.0-inf of
DHE after administration of the formulation is about 1 to about 700
ngh/mL; d) wherein a mean T.sub.1/2 of DHE after administration of
the formulation is about 100 to about 300 minutes. In one
embodiment, the mean T.sub.max of DHE after administration of the
formulation is about 2 to about 50 minutes. In another embodiment,
the mean C.sub.max of DHE after administration of the formulation
is about 0.1 to about 150 ng/mL. In another embodiment, the mean
AUC.sub.0-inf of DHE after administration of the formulation is
about 1 to about 700 ngh/mL. In another embodiment, the mean
T.sub.1/2 of DHE after administration of the formulation is about
100 to about 300 minutes. The mean T.sub.max, C.sub.max,
AUC.sub.0-inf, and/or T.sub.1/2 after administration of the powder
formulation can be measured from a human subject.
[0025] In one case, the mean T.sub.max of DHE is about 10 to about
30 minutes, the mean C.sub.max of DHE is about 0.5 to about 6
ng/mL, the mean AUC.sub.0-inf of DHE is about 1 to about 15 ngh/mL,
and the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. In
another case, the mean T.sub.max of DHE is about 10 to about 50
minutes, the mean C.sub.max of DHE is about 1 to about 15 ng/mL,
the mean AUC.sub.0-inf of DHE is about 10 to about 50 ngh/mL, and
the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. In
another case, the mean T.sub.max of DHE is about 10 to about 50
minutes, the mean C.sub.max of DHE is about 2 to about 20 ng/mL,
the mean AUC.sub.0-inf of DHE is about 15 to about 110 ngh/mL, and
the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. In
another case, the mean T.sub.max of DHE is about 10 to about 50
minutes, the mean C.sub.max of DHE is about 2 to about 50 ng/mL,
the mean AUC.sub.0-inf of DHE is about 15 to about 200 ngh/mL, and
the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. The
mean T.sub.max, C.sub.max, AUC.sub.0-inf, and/or T.sub.1/2 after
administration of the powder formulation can be measured from a
primate, preferably a monkey, and preferably a Cynomolgus
monkey.
[0026] In one case, the mean T.sub.max of DHE is about 10 to about
30 minutes, the mean C.sub.max of DHE is about 0.5 to about 6
ng/mL, the mean AUC.sub.0-inf of DHE is about 1 to about 15 ngh/mL,
and the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. In
another case, the mean T.sub.max of DHE is about 10 to about 50
minutes, the mean C.sub.max of DHE is about 1 to about 15 ng/mL,
the mean AUC.sub.0-inf of DHE is about 10 to about 50 ngh/mL, and
the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. In
another case, the mean T.sub.max of DHE is about 10 to about 50
minutes, the mean C.sub.max of DHE is about 2 to about 20 ng/mL,
the mean AUC.sub.0-inf of DHE is about 15 to about 110 ngh/mL, and
the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. In
another case, the mean T.sub.max of DHE is about 10 to about 50
minutes, the mean C.sub.max of DHE is about 2 to about 50 ng/mL,
the mean AUC.sub.0-inf of DHE is about 15 to about 200 ngh/mL, and
the mean T.sub.1/2 of DHE is about 100 to about 300 minutes. The
mean T.sub.max, C.sub.max, AUC.sub.0-inf, and/or T.sub.1/2 after
administration of the powder formulation can be measured from a
human subject.
[0027] In some cases, the powder formulation is administered such
that the intersubject variability in DHE C.sub.max is less than
30%. For example, the intersubject variability in DHE C.sub.max is
less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the powder
formulation is administered such that the intersubject variability
in DHE T.sub.max is less than 30%. For example, the intersubject
variability in DHE T.sub.max is less than 30%, 25%, 20%, 15%, 10%,
or 5%. In some cases, the powder formulation is administered such
that the intersubject variability in DHE AUC.sub.0-inf is less than
30%. For example, the intersubject variability in DHE AUC.sub.0-inf
is less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the
powder formulation is administered such that the intersubject
variability in DHE T.sub.1/2 is less than 30%. For example, the
intersubject variability in DHE T.sub.1/2 is less than 30%, 25%,
20%, 15%, 10%, or 5%. The intersubject variability in DHE
T.sub.max, C.sub.max, AUC.sub.0-inf, and/or T.sub.1/2 after
administration of the powder formulation can be measured from
primates, preferably monkeys, and preferably a Cynomolgus
monkeys.
[0028] In some cases, the powder formulation is administered such
that the intersubject variability in DHE C.sub.max is less than
30%. For example, the intersubject variability in DHE C.sub.max is
less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the powder
formulation is administered such that the intersubject variability
in DHE T.sub.max is less than 30%. For example, the intersubject
variability in DHE T.sub.max is less than 30%, 25%, 20%, 15%, 10%,
or 5%. In some cases, the powder formulation is administered such
that the intersubject variability in DHE AUC.sub.0-inf is less than
30%. For example, the intersubject variability in DHE AUC.sub.0-inf
is less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the
powder formulation is administered such that the intersubject
variability in DHE T.sub.1/2 is less than 30%. For example, the
intersubject variability in DHE T.sub.1/2 is less than 30%, 25%,
20%, 15%, 10%, or 5%. The intersubject variability in DHE
T.sub.max, C.sub.max, AUC.sub.0-inf, and/or T.sub.1/2 after
administration of the powder formulation can be measured from human
subjects.
[0029] In another embodiment, the powder formulation comprises DHE
mesylate. For example, the powder formulation comprises DHE
mesylate, microcrystalline cellulose, and tribasic calcium
phosphate.
[0030] The methods and formulations may further comprise a
microcrystalline cellulose component with a mean particle size
diameter of about 100 .mu.m or less. The microcrystalline cellulose
component may have a mean particle size diameter of less than about
100 .mu.m, for example, about 95, 90, 85, 80, 75, 70, 65, 60, 55,
50, 45, 40, 35, 30, 25, 20, 15, 10, 5 .mu.m or less.
[0031] The microcrystalline cellulose component may comprise a
first microcrystalline cellulose portion with a mean particle
diameter size of about 30 .mu.m or less, and a second
microcrystalline cellulose portion with a mean particle size
diameter of about 30 to about 100 m. The first microcrystalline
cellulose portion may have a mean particle diameter size of about m
or less, for example, 30-25, 30-20, 30-15, 30-10, 30-5, 25-20,
25-15, 25-10, 25-5, 20-15, 20-10, 20-5, 15-10, 15-5 or 10-5 .mu.m.
In a specific embodiment, the first microcrystalline cellulose
portion has a mean particle diameter size of about 15-30 .mu.m. In
another specific embodiment, the first microcrystalline cellulose
portion has a mean particle diameter size of about 18-20 .mu.m. In
yet another specific embodiment, the first microcrystalline
cellulose portion has a mean particle diameter size of about 20
.mu.m. The second microcrystalline cellulose portion may have a
mean particle diameter size of about 30 to about 100 .mu.m, for
example, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-90, 40-80,
40-70, 40-60, 40-50, 50-90, 50-80, 50-70, 50-60, 60-90, 60-80,
60-70, 70-90, 70-80, or 80-90 .mu.m. In a specific embodiment, the
second microcrystalline cellulose portion has a mean particle
diameter size of about 45-65 .mu.m. In another specific embodiment,
the second microcrystalline cellulose portion has a mean particle
diameter size of about 45-55 .mu.m. In another specific embodiment,
the second microcrystalline cellulose portion has a mean particle
diameter size of about 50-55 .mu.m. In yet another specific
embodiment, the second microcrystalline cellulose portion has a
mean particle diameter size of about 50 .mu.m.
[0032] In one embodiment, the first microcrystalline cellulose
portion has a mean particle diameter size of about 15 to about 30
.mu.m and the second microcrystalline cellulose portion has a mean
particle diameter size of about 45 to about 65 .mu.m. In another
embodiment, the first microcrystalline cellulose portion has a mean
particle size of about 20 .mu.m and the second microcrystalline
cellulose portion has a mean particle size diameter of about 50 to
about 55 .mu.m. In yet another embodiment, the first
microcrystalline cellulose portion has a mean particle diameter
size of about 20 .mu.m, and the second microcrystalline cellulose
portion has a mean particle size diameter of about 50 .mu.m. In
some cases, the microcrystalline cellulose component is
substantially free of particles with a mean particle diameter size
of about 31 to about 44 .mu.m. The method of claim 4, wherein the
microcrystalline cellulose component is substantially free of
particles with a mean particle diameter size of about 31 to about
49 .mu.m. In some cases, substantially free of particles with a
mean particle diameter size means less than 15%, 10%, 5%, or 2% of
all the particles fall into the given range.
[0033] In another aspect, the microcrystalline cellulose component
may comprise at least about 5% of the total weight of the powder
formulation, for example, at least about 5%, 6%, 7%, 8%, 9%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, 90%, 95% or 95% of the total weight of the powder
formulation. The microcrystalline cellulose component may comprise
about 15% to about 99% of the total weight of the powder
formulation, for example, about 15%-99%, 20%-99%, 30%-99%, 40-99%,
50-99%, 60-99%, 70-99%, 80-99%, 90-99%, 15%-90%, 20%-90%, 30%-90%,
40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 15%-80%, 20%-80%, 30%-80%,
40-80%, 50-80%, 60-80%, 70-80%, 15%-70%, 20%-70%, 30%-70%, 40-70%,
50-70%, 60-70%, 15%-60%, 20%-60%, 30%-60%, 40-60%, 50-60%, 15%-50%,
20%-50%, 30%-50%, 40-50%, 15%-40%, 20%-40%, 30%-40%, 15%-30%,
20%-30%, or 15-20% of the total weight of the powder
formulation.
[0034] In one embodiment, the first microcrystalline cellulose
component comprises about 10 to about 90% of the total weight of
the powder formulation, for example, about 10%-90%, 15%-90%,
20%-90%, 30%-90%, 40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 10%-80%,
15%-80%, 20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70-80%, 10%-70%,
15%-70%, 20%-70%, 30%-70%, 40-70%, 50-70%, 60-70%, 10%-60%,
15%-60%, 20%-60%, 30%-60%, 40-60%, 50-60%, 10%-50%, 15%-50%,
20%-50%, 30%-50%, 40-50%, 10%-40%, 15%-40%, 20%-40%, 30%-40%,
10%-30%, 15%-30%, 20%-30%, 10%-20%, 15-20%, or 10%-15% of the total
weight of the powder formulation. In one embodiment, the first
microcrystalline cellulose component comprises about 70% to about
90% of the total weight of the powder formulation. In another
embodiment, the first microcrystalline cellulose component
comprises about 70% to about 90% of the total weight of the powder
formulation.
[0035] In one embodiment, the second microcrystalline cellulose
component comprises about 5% to about 15% of the total weight of
the powder formulation, for example, about 5%-15%, 5%-10%, or
10%-15% of the total weight of the powder formulation. In one
embodiment, the second microcrystalline cellulose component
comprises about 10% of the total weight of the powder formulation.
For example, in particular embodiments, the first microcrystalline
cellulose portion comprises about 8% to about 90% of the total
weight of the formulation, and the second microcrystalline
cellulose portion comprises about 10% of the total weight of the
formulation. In another certain embodiment, the first
microcrystalline cellulose portion is about 5% to about 90% of the
total weight of the powder formulation, and the second
microcrystalline portion is about 10% of the total weight of the
powder formulation.
[0036] In another aspect, the methods and formulations may further
comprise a fluidizing agent. For example, the fluidizing agent is
tribasic calcium phosphate. The tribasic calcium phosphate can be
about 0.1% to about 5.0% of the total weight of the powder
formulation, for example about 0.1%-5%, 0.1%-4%, 0.1%-3%, 0.1%-2%,
0.1%-1%, 0.1%-0.5%, 0.5%-5%, 0.5%-4%, 0.5%-3%, 0.5%-2%, 0.5%-1%,
1%-5%, 1%-4%, 1%-3%, 1%-2%, 2%-5%, 2%-4%, 2%-3%, 3%-5%, 3%-4%, or
4%-5% of the total weight of the powder formulation. In one
embodiment, the tribasic calcium phosphate is about 0.5% to about
1.0% of the total weight of the powder formulation. In another
embodiment, the tribasic calcium phosphate is about 0.5% to about
1.5% of the total weight of the powder formulation. In another
embodiment, the tribasic calcium phosphate is about 0.8% of the
total weight of the powder formulation.
[0037] In another aspect, the methods and formulations may further
comprise at least one of the following: an adenosine receptor
antagonist, a phosphodiesterase inhibitor, an acetylcholinesterase
inhibitor, a vasodilator, xanthine, caffeine, paraxanthine,
theobromine, and theophylline. For example, the methods and
formulations further comprise caffeine. The caffeine can be at
least about 1% of the total weight of the powder formulation, for
example about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or more of the total weight
of the powder formulation. The caffeine can be about 1% to 60% of
the total weight of the powder formulation, for example, about
1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-20%, 1%-10%, 1%-5%, 10%-60%,
10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-60%, 20%-50%, 20%-40%,
20%-30%, 30%-60%, 30%-50%, 30%-40%, 40%-60%, 40%-50%, or 50%-60% of
the total weight of the powder formulation. In another embodiment,
the powder formulation comprises about 5% to 10% caffeine. In a
particular embodiment, the caffeine is anhydrous caffeine. In
another embodiment, the powder formulation comprises about 10% to
15% caffeine.
[0038] In another aspect, a total dose of the powder formulation
administered can be at least about 0.1 mg, for example, at least
about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5,
3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, or 25 mg. The total dose of the
powder formulation administered can be about 0.1 to about 25 mg,
for example, about 0.1-25.0 mg, about 0.1-20.0 mg, about 0.1-15.0
mg, about 0.1-10.0 mg, about 0.1-5.0 mg, about 0.1-2.0 mg, about
0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-25.0 mg, about 0.2-20.0 mg,
about 0.2-15.0 mg, about 0.2-10.0 mg, about 0.2-5.0 mg, about
0.2-2.0 mg, about 0.2-1.0 mg, about 0.2-0.5 mg, about 0.5-25.0 mg,
about 0.5-20.0 mg, about 0.5-15.0 mg, about 0.5-10.0 mg, about
0.5-5.0 mg, about 0.5-2.0 mg, about 0.5-1.0 mg, about 1.0-25.0 mg,
about 1.0-20.0 mg, about 1.0-15.0 mg, about 1.0-10.0 mg, about
1.0-5.0 mg, about 1.0-2.0 mg, about 2.0-25.0 mg, about 2.0-20.0 mg,
about 2.0-15.0 mg, about 2.0-10.0 mg, about 2.0-5.0 mg, about
5.0-25.0 mg, about 5.0-20.0 mg, about 5.0-15.0 mg, about 5.0-10.0
mg, about 10.0-25.0 mg, about 10.0-20.0 mg, about 10.0-15.0 mg,
about 15.0-25.0 mg, or about 15.0-20.0 mg. For example, the total
dose of the powder formulation administered is about 25 mg.
[0039] In another aspect, the powder formulation comprises a total
dose of DHE administered of at least about 0.1 mg, for example, at
least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2,
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10
mg. The powder formulation may comprise a total dose of DHE
administered of about 0.1 to about 10.0 mg, for example, about
0.1-10.0 mg, about 0.1-9.0 mg DHE, about 0.1-8.0 mg DHE, about
0.1-7.0 mg DHE, about 0.1-6.0 mg DHE, about 0.1-5.0 mg, about
0.1-4.0 mg DHE, about 0.1-3.0 mg DHE, about 0.1-2.0 mg, about
0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-10.0 mg, about 0.2-9.0 mg
DHE, about 0.2-8.0 mg DHE, about 0.2-7.0 mg DHE, about 0.2-6.0 mg
DHE, about 0.2-5.0 mg, about 0.2-4.0 mg DHE, about 0.2-3.0 mg DHE,
about 0.2-2.0 mg, about 0.2-1.0 mg, about 0.2-0.5 mg, about
0.5-10.0 mg, about 0.5-9.0 mg DHE, about 0.5-8.0 mg DHE, about
0.5-7.0 mg DHE, about 0.5-6.0 mg DHE, about 0.5-5.0 mg, about
0.5-4.0 mg DHE, about 0.5-3.0 mg DHE, about 0.5-2.0 mg, about
0.5-1.0 mg, about 1.0-10.0 mg, about 1.0-5.0 mg, about 1.0-4.0 mg
DHE, about 1.0-3.0 mg DHE, about 1.0-2.0 mg, about 2.0-10.0 mg,
about 2.0-9.0 mg DHE, about 2.0-8.0 mg DHE, about 2.0-7.0 mg DHE,
about 2.0-6.0 mg DHE, about 2.0-5.0 mg, about 2.0-4.0 mg DHE, about
2.0-3.0 mg DHE, about 5.0-10.0 mg, about 5.0-9.0 mg DHE, about
5.0-8.0 mg DHE, about 5.0-7.0 mg DHE, about 5.0-6.0 mg DHE, about
6.0-10.0 mg, about 6.0-9.0 mg DHE, about 6.0-8.0 mg DHE, about
6.0-7.0 mg DHE, about 7.0-10.0 mg, about 7.0-9.0 mg DHE, about
7.0-8.0 mg DHE, about 8.0-10.0 mg, about 8.0-9.0 mg DHE, or about
9.0-10.0 mg DHE. For example, the total dose of DHE administered of
about 0.5 mg. In certain embodiments, the total dose of DHE
administered is 0.1-5.0 mg. In certain other embodiments, the total
amount of DHE administered is 0.5-5.0 mg. In certain other
embodiments, the total amount of DHE administered is 0.5-3.0 mg. In
certain other embodiments, the total amount of DHE administered is
1.0-2.0 mg.
[0040] In some embodiments, the powder formulation has an angle of
repose about 53.degree. or less, for example, about 53.degree.,
52.degree., 51.degree., 50.degree., 48.degree., 46.degree.,
44.degree., 42.degree., 40.degree., 38.degree., 36.degree.,
34.degree., 32.degree., 30.degree., 28.degree., 26.degree.,
24.degree., 22.degree., 20.degree. or less.
[0041] Presented herein are methods and formulations used for
treating headache. For example, the methods and formulations are
used for treating migraine. In some cases, the methods of treating
migraine are methods for the acute treatment of migraine headaches
with or without aura.
[0042] In one embodiment, at least a portion of the powder
formulation is administered to a single nostril of the human. In
another embodiment, at least a portion of the powder formulation is
administered to each nostril of the human. For example, in a
specific embodiment of the method, about half of the formulation is
administered to one nostril and about half of the formulation is
administered to the other nostril of the human.
4. BRIEF DESCRIPTION OF DRAWINGS
[0043] FIG. 1 presents pharmacokinetic profiles of DHE intranasal
powder formulations, including comparisons with Migranal nasal
spray, in monkey.
[0044] FIG. 2 presents pharmacokinetic profiles of DHE intranasal
powder formulations, including comparisons with Migranal nasal
spray, in monkey from 0 to 3 hours.
[0045] FIG. 3 presents a comparison of DHE intranasal powder
formulations and Migranal nasal spray AUC from 0-30 minutes.
[0046] FIG. 4 presents pharmacokinetic profiles of caffeine vs.
non-caffeine containing DHE intranasal powder formulations (0.5 mg
DHE dose).
[0047] FIG. 5 presents pharmacokinetic profiles of 1 mg DHE powder
formulation administered to a single nostril vs. 1 mg DHE powder
formulation administered to both nostrils ("double nostril"; 0.5 mg
DHE dose/nostril).
[0048] FIG. 6 presents plasma DHE concentrations in monkeys over
480 minutes after the tested administrations.
5. DETAILED DESCRIPTION
[0049] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
the ordinary skill in the art to which this invention belongs.
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
formulations or unit doses herein, some methods and materials are
now described. Unless mentioned otherwise, the techniques employed
or contemplated herein are standard methodologies. The materials,
methods and examples are illustrative only and not limiting.
[0050] The details of one or more inventive embodiments are set
forth in the accompanying drawings, the claims, and the description
herein. Other features, objects, and advantages of the inventive
embodiments disclosed and contemplated herein can be combined with
any other embodiment unless explicitly excluded.
[0051] Unless otherwise indicated, open terms for example
"contain," "containing," "include," "including," and the like mean
comprising.
[0052] The singular forms "a", "an", and "the" are used herein to
include plural references unless the context clearly dictates
otherwise. Accordingly, unless the contrary is indicated, the
numerical parameters set forth in this application are
approximations that may vary depending upon the desired properties
sought to be obtained by the present invention.
[0053] Unless otherwise indicated, some embodiments herein
contemplate numerical ranges. When a numerical range is provided,
unless otherwise indicated, the range includes the range endpoints.
Unless otherwise indicated, numerical ranges include all values and
subranges therein as if explicitly written out. Unless otherwise
indicated, any numerical ranges and/or values herein can be at
80-125% of the numerical ranges and/or values.
[0054] Unless otherwise indicated, "mean particle diameter" can
refer to the particle size distribution of a powder in its
non-aggregated state. Primary particle diameter can be determined
using a laser-diffraction particle size distribution analyzer. In
some embodiments, the particle size analyzer can be Mastersizer
2000 manufactured by Malvern Instruments Limited.
[0055] The pharmacokinetic data disclosed herein (e.g., C.sub.max,
T.sub.max, AUC.sub.0-t, AUC.sub.0-480 minutes, AUC.sub.0-inf,
T.sub.1/2) can be measured from a primate, preferably a monkey, and
preferably a Cynomolgus monkey, after a powder formulation
disclosed herein is administered. Alternatively, the
pharmacokinetic data disclosed herein (e.g., C.sub.max, T.sub.max,
AUC.sub.0-t, AUC.sub.0-480 minutes, AUC.sub.0-inf, T.sub.1/2) can
be measured from a human subject after a powder formulation
disclosed herein is administered.
[0056] Presented herein are formulations comprising
dihydroergotamine (DHE), or a pharmaceutically acceptable salt
thereof. Also presented herein are methods for treating headache,
for example, methods of treating migraine in a subject, e.g. in a
human, comprising intranasally administering particular
formulations comprising dihydroergotamine, or a pharmaceutically
acceptable salt thereof, to a subject, e.g. a human, having a
headache, for example, a migraine, wherein the formulation is not a
liquid solution or a liquid spray formulation. For example,
presented herein are methods for rapid onset treatment of headache,
including migraine, e.g. acute treatment of migraine with or
without aura, comprising intranasally administering the
formulations presented herein. Unless noted, such formulations are
referred to herein as powder formulations.
[0057] Intranasal administration, as used herein in the context of
the powder formulations presented herein, unless otherwise noted,
refers to administration whereby at least 95.+-.5% of the powder
formulation is administered to the nasal cavity as measured by
multiple path particle dosimetry (MPPD) model analysis, a
computational model used to estimate human airway particle
dosimetry (see, e.g., Anjilvel, S. and Asgharian, B. (1995) Fundam.
Appl. Toxicol. 28, 41-50; and National Institute for Public Health
and the Environment (RIVM) (2002) Multiple Path Particle Dosimetry
Model (MPPD v 1.0): A Model for Human and Rat Airway Particle
Dosimetry. Bilthoven, The Netherlands. RIVA Report 650010030), or
via an Andersen Cascade Impactor.
[0058] Generally, not less than 90% of the particles in the powder
formulations presented herein have a diameter less than 150 .mu.m,
and not more than 5% of the particles in the powder formulations
have a diameter less than 10 .mu.m. In addition, generally, the
overall mean particle size of the particles in the powder
formulations presented herein about 15 to about 30 .mu.m, about 18
to about 25 .mu.m, about 18 to about 20 .mu.m, or about 20
.mu.m.
[0059] In a particular aspect, presented herein is a method of
treating headache, for example treating migraine e.g., a method for
acute treatment of migraine with or without aura, comprising
intranasally administering to a human having a headache, e.g., a
migraine, a formulation comprising DHE, or a pharmaceutically
acceptable salt thereof, e.g., DHE mesylate, microcrystalline
cellulose, and tribasic calcium phosphate, wherein the formulation
is not a liquid solution or a liquid spray formulation. Unless
noted, such formulations are referred to herein as powder
formulations. In a specific aspect, provided herein are methods of
treating headache, including migraine, comprising intranasally
administering powder formulations comprising dihydroergotamine or a
pharmaceutically acceptable salt thereof, e.g., dihydroergotamine
mesylate, microcrystalline cellulose with a mean particle diameter
size of about 100 .mu.m or less, and tribasic calcium phosphate.
Throughout, unless otherwise noted, "about" means within +10% of a
value. For example, if it is stated that a component makes up
"about 70%" of a mixture, it is implied that the component makes up
within a range of 63% and 77% of the mixture. In addition, in
instances wherein "about" is used, it is to be understood that
embodiments involving the exact value associated with "about" are
also contemplated. For example, when an embodiment recites "about
0.5 mg DHE," an embodiment reciting "0.5 mg DHE" is also
contemplated and is described herein.
[0060] In yet another aspect, provided herein are methods of
treating headache, including migraine, comprising intranasally
administering powder formulations comprising dihydroergotamine or a
pharmaceutically acceptable salt thereof, e.g., dihydroergotamine
mesylate, a microcrystalline cellulose portion with a mean particle
size diameter of about 50-55 m, e.g., 50 .mu.m, comprising about
10% of the total weight of the powder formulation, a
microcrystalline cellulose portion with a mean particle size of
about 20 .mu.m comprising about 3 to about 90%, e.g., 8 to about
90%, of the total weight of the powder formulation and, optionally,
a fluidizing agent. In certain embodiments, the powder formulations
utilized as part of the methods further comprise caffeine, e.g.,
anhydrous caffeine. Throughout, unless otherwise noted, percent (%)
weight, in the context of the powder formulations presented herein,
refers to weight per weight percent (%) (W/W %).
[0061] In another aspect, presented herein are powder formulations
that can be utilized in conjunction with the methods of treating
headache, including migraine. In a certain aspect, presented herein
are powder formulations comprising dihydroergotamine or a
pharmaceutically acceptable salt thereof. In a specific aspect,
provided herein are powder formulations comprising: a)
dihydroergotamine or a pharmaceutically acceptable salt thereof,
e.g., dihydroergotamine mesylate; b) microcrystalline cellulose,
e.g., a microcrystalline cellulose with a mean particle diameter
size of about 100 .mu.m or less; and c) tribasic calcium phosphate.
In yet another aspect, provided herein are powder formulations
comprising dihydroergotamine, or a pharmaceutically acceptable salt
thereof, e.g., dihydroergotamine mesylate a microcrystalline
cellulose portion with a mean particle size diameter of about 50-55
.mu.m, e.g., 50 .mu.m, comprising about 10% of the total weight of
the powder formulation, a microcrystalline cellulose portion with a
mean particle size of about 20 .mu.m comprising about 3% to about
90%, e.g., about 8 to about 90%, of the total weight of the powder
formulation and, optionally, a fluidizing agent. In certain
embodiments, the powder formulations further comprise caffeine,
e.g., anhydrous caffeine.
[0062] In certain embodiments, greater than or equal to about 90%
of the particles in the powder formulation have a diameter less
than 150 .mu.m. In other embodiments the overall mean particle size
of the formulation is about 15 to about 30 .mu.m, about 18 to about
25 .mu.m, about 18 to about 20 .mu.m, or about 20 .mu.m. In further
embodiments, less than or equal to about 5% of the particles in the
powder formulation have a diameter less than 10 .mu.m. In yet other
embodiments, greater than or equal to about 90% of the particles in
the power formulation have a diameter less than 150 .mu.m; and the
overall mean particle size of the formulation is about 15 to about
30 .mu.m, about 18 to about 25 .mu.m, about 18 to about 20 .mu.m,
or about 20 .mu.m; and less than or equal to about 5% of the
particles in the powder formulation have a diameter less than 10
.mu.m.
5.1 Dihydroergotamine
[0063] Dihydroergotamine (DHE) is an ergot alkaloid having a
structure as follows:
##STR00001##
[0064] The methods and formulations presented herein can utilize
DHE and any pharmaceutically acceptable salt, hydrate, polymorph,
isomer, diastereomer, prodrug, metabolite, ion pair complex, or
chelate thereof.
[0065] In certain embodiments, the methods and formulations
presented herein comprise a pharmaceutically acceptable salt of
DHE. In embodiments wherein a pharmaceutically acceptable salt of
DHE is utilized, the pharmaceutically acceptable salt of DHE may be
used instead of or in addition to DHE in any or all of the methods
and compositions presented herein.
[0066] A pharmaceutically acceptable salt of DHE can be formed
using a pharmaceutically acceptable non-toxic acid or base,
including an inorganic acid or base, or an organic acid or base. In
specific embodiments, a pharmaceutically acceptable salt of DHE
that can be utilized in connection with the methods and
formulations presented herein is a pharmaceutically acceptable salt
derived from acids including, but not limited to, the following:
acetic, alginic, anthranilic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,
galacturonic, gluconic, glucuronic, glutamic, glycolic,
hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,
mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phenylacetic, phosphoric, propionic, salicylic, stearic, succinic,
sulfanilic, sulfuric, tartaric acid, or p-toluenesulfonic acid. In
one embodiment the pharmaceutically acceptable salt of DHE is a
salt of methanesulfonic acid. An alternative nomenclature of the
methanesulfonic acid salt of DHE is DHE mesylate.
[0067] For further description of pharmaceutically acceptable salts
that can be used in the methods described herein see, for example,
S. M. Barge et al., "Pharmaceutical Salts," 1977, J. Pharm. Sci.
66:1-19, which is incorporated herein by reference in its
entirety.
[0068] The mean particle size of the DHE or pharmaceutically
acceptable salt of DHE, e.g, DHE mesylate, utilized can be less
than about 100 .mu.m, for example, about 95, 90, 85, 80, 75, 70,
65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 .mu.m or less.
The mean particle size of the DHE or pharmaceutically acceptable
salt of DHE, e.g, DHE mesylate, utilized can be about 5-100 .mu.m,
for example, for example, about 5-90, 5-80, 5-70, 5-60, 5-50, 5-40,
5-30, 5-20, 5-10, 10-90, 10-80, 10-70, 10-60, 10-50, 10-40, 10-30,
10-20, 20-90, 20-80, 20-70, 20-60, 20-50, 20-40, 20-30, 30-90,
30-80, 30-70, 30-60, 30-50, 30-40, 40-90, 40-80, 40-70, 40-60,
40-50, 50-90, 50-80, 50-70, 50-60, 60-90, 60-80, 60-70, 70-90,
70-80, or 80-90 .mu.m. The mean particle size of the DHE or
pharmaceutically acceptable salt of DHE, e.g, DHE mesylate,
utilized can be about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0,
9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 .mu.m. Moreover,
generally, not less than 90% of the DHE or pharmaceutically
acceptable salt of DHE, e.g., DHE mesylate, particles in the powder
formulations presented herein have a diameter less than 150 .mu.m,
and not more than 5% of the particles in the powder formulation
have a diameter less than 5 .mu.m. In addition, generally, the
overall mean particle size of the DHE particles in the powder
formulations presented herein about 15 to about 30 .mu.m, about 18
to about 25 .mu.m, about 18 to about 20 .mu.m, or about 20
.mu.m.
[0069] In some embodiments, the total weight of the powder
formulation comprises about 0.4 to about 46%, or about 0.4 to about
23% or about 0.4 to about 9%, or about 2 to about 9%, or about 4 to
about 9% of DHE. In other embodiments, the total weight of the
powder formulation comprises about 0.3 to about 37%, or about 0.3
to about 18% or about 0.3 to about 7%, or about 2 to about 7%, or
about 3 to about 9% of DHE or a pharmaceutically acceptable salt
thereof.
5.2 Methods of Treating Headache
[0070] Presented herein are methods for treating headache, for
example, methods of treating migraine in a subject, e.g. in a
human, comprising intranasally administering particular
formulations comprising dihydroergotamine, or a pharmaceutically
acceptable salt thereof, to a subject, e.g. a human, having a
headache, for example, a migraine. For example, presented herein
are methods for rapid onset treatment of headache, including
migraine, e.g. acute treatment of migraine with or without aura,
comprising intranasally administering the formulations presented
herein.
[0071] In a particular aspect, provided herein are methods of
treating headache, including migraine, comprising intranasally
administering powder formulations comprising dihydroergotamine or a
pharmaceutically acceptable salt thereof. In a specific aspect,
provided herein are methods of treating headache, including
migraine, comprising intranasally administering powder formulations
comprising dihydroergotamine or a pharmaceutically acceptable salt
thereof, e.g., dihydroergotamine mesylate, microcrystalline
cellulose with a mean particle diameter size of about 100 .mu.m or
less, and tribasic calcium phosphate. In yet another aspect,
provided herein are methods of treating headache, including
migraine, comprising intranasally administering powder formulations
comprising dihydroergotamine or a pharmaceutically acceptable salt
thereof, e.g., dihydroergotamine mesylate a microcrystalline
cellulose portion with a mean particle size diameter of about 50-55
.mu.m, e.g., about 50 .mu.m, comprising about 10% of the total
weight of the powder formulation, a microcrystalline cellulose
portion with a mean particle size of about 20 .mu.m comprising
about 3 to about 90%, e.g., about 8 to about 90%, of the total
weight of the powder formulation and, optionally, a fluidizing
agent. In certain embodiments, the powder formulations utilized as
part of the methods further comprise caffeine, e.g., anhydrous
caffeine.
[0072] In certain embodiments, the headache treated by the methods
provided herein is a cluster headache, chronic daily headache, or
migraine, including adult migraine or pediatric migraine. The
migraine can be migraine with aura or migraine without aura. In
particular embodiments, the methods presented herein are methods
for acute treatment of a human having a migraine with or without
aura. In other embodiments, the methods presented herein are
methods for chronic treatment of migraine with or without aura.
[0073] "Treating," as used herein, refers to the amelioration of at
least one symptom of the disorder being treated. Thus, the methods
of treating headache, for example migraine, presented herein
ameliorate at least one symptom of the headache, for example
migraine. In certain embodiments, the methods of treating headache,
for example migraine, presented herein reduce at least one symptom
of the headache, for example migraine. In other embodiments, the
methods of treating headache, for example migraine, presented
herein eliminate at least one symptom of the headache, for example,
migraine.
[0074] Symptoms of headache, e.g., cluster headache, chronic daily
headache or migraine, include pain. Symptoms of migraine can also
include, for example, nausea, vomiting, photophobia, phonophobia,
osmophobia (aversion to, or hypersensitivity to, odors), vertigo,
and/or allodynia. In certain embodiments, the methods of treating
headache, for example migraine, presented herein ameliorate at
least one such symptom of the headache, for example migraine. In
particular embodiments, the methods of treating headache, for
example migraine, presented herein reduce at least one such symptom
of the headache, for example migraine. In other particular
embodiments, the methods of treating headache, for example
migraine, presented herein eliminate at least one such symptom of
the headache, for example, migraine.
[0075] In specific embodiments, the methods of treating migraine
ameliorate at least one of pain, nausea, phonophobia or
photophobia. In other specific embodiments, such methods ameliorate
at least two, three or all four of said symptoms.
[0076] In some embodiments, the headache has a severity of more
than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a scale of 0
to 10. In certain embodiments, the methods of treating a headache,
for example migraine, presented herein ameliorate at least one
symptom of a headache, for example a migraine, having a severity of
more than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a scale
of 0 to 10. In certain embodiments, the methods of treating
headache, for example migraine, presented herein reduce the
severity of a headache, for example a migraine, having a severity
of more than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a
scale of 0 to 10.
[0077] In certain embodiments, the intensity of headache pain, for
example, pain associated with migraine, can be measured according
to a 4-point severity scale (0=no pain, 1=mild, 2=moderate,
3=severe). In certain embodiments, the methods of treating
headache, for example migraine, presented herein reduce the
severity of headache pain, for example pain associated with
migraine, by at least one point on such a 4-point severity
scale.
[0078] In certain embodiments, the methods of treating migraine
presented herein ameliorate at least one symptom of the migraine,
e.g., ameliorate at least one of pain, nausea, phonophobia, or
photophobia. The symptom or symptoms can, for example, be evaluated
via a four point severity scale as follows: 0=none 1=mild symptom,
not interfering with normal daily activities 2=moderate symptom,
causing some restriction to normal activities 3=severe, leading to
inability to perform normal daily activities. Alternatively, or
additionally, a symptom or symptoms, including the four listed
above, can be evaluated via a four-point functional disability
scale that assesses the level of impairment a symptom has on a
patient's ability to perform usual daily activities, as follows:
0=not at all impaired 1=slightly impaired 2=moderately impaired
3=severely or completely impaired See, Cephalalgia 1991;
11:1-12.
[0079] In certain embodiments, the methods of treating headache,
for example migraine, presented herein ameliorate at least one
symptom of the headache, for example migraine, within 10, 15, 20,
25, 30 or 45 minutes of intranasally administering a powder
formulation presented herein. In other embodiments, the methods of
treating headache, for example migraine, presented herein
ameliorate at least one symptom of the headache, for example
migraine, within 1, 1.5, 2, 2.5, 3, or 4 hours of intranasally
administering a powder formulation presented herein. In particular
embodiments, methods of treating headache, for example migraine,
presented herein the amelioration of at least one symptom of the
headache, for example migraine, is sustained for about 3, 4, 5, 6,
8, 12, 18, 36, or 48 hours.
[0080] With respect to the microcrystalline cellulose component of
the powder formulations presented herein, generally, acceptable
microcrystalline cellulose can include microcrystalline cellulose
obtained by decomposing cellulose materials such as pulp by either
or both of acid and alkaline hydrolyses, then purifying the
hydrolysate, and crushing or grinding it before, during, or after
drying. Microcrystalline cellulose of particular mean particle
diameter size can be obtained, for example, via appropriate
processing, e.g., via fine grinding using a high-speed rotary
impact mill or air attrition mill as necessary, and size sorting.
In certain embodiments, microcrystalline cellulose components
utilized as part of the microcellulose of the powder formulations
presented herein can include products available under the trade
names of Ceolus.RTM. PH-F20JP, Ceolus.RTM. PH-301,
Ceolus.RTM.PH-101, Ceolus.RTM. PH-102, and Ceolus.RTM. PH-302
(available from Asahi Kasei Corporation), and Avicel.RTM. PH-105,
Avicel.RTM.PH-101, Avicel.RTM.PH-102, Avicel.RTM.PH-301, and
Avicel.RTM.PH-302 (available from FMC Biopolymer Corporation). In a
particular embodiment, powder formulations that can be used in
conjunction with the methods and compositions presented herein can
comprise Ceolus.RTM. PH-F20JP and Ceolus.RTM. PH-301.
[0081] Mean particle size diameters, for example, the mean particle
size diameters of the microcrystalline portions of the powder
formulations described herein, can be determined using standard
techniques, for example, via a laser-diffraction particle size
distribution analyzer or via sorting methods. The mean particle
diameter size refers to a diameter that divides particles into two
groups of equal numbers: a group with greater diameters and a group
with smaller diameters. The mean diameter size determined using a
laser-diffraction particle size distribution analyzer corresponds
to 50% volume in a determined cumulative particle size distribution
curve. The mean particle diameter size can, for example, be
determined by a sorting method that corresponds to 50 (W/W) % on a
cumulative particle size distribution curve that can be obtained by
sorting an appropriate amount of the particle being assessed, for
an appropriate time, e.g., ten minutes, on an electromagnetic sieve
shaker, using standard sieves and weighing the sample remaining on
each sieve.
[0082] With respect to tribasic calcium phosphate (also known as
hydroxyapatite), any pharmaceutically acceptable tribasic calcium
phosphate can be used in conjunction with the methods and
compositions presented herein. In certain embodiments, the tribasic
calcium phosphate utilized has an average particle diameter of
about 10-100 .mu.m, for example, about 10 to 75 .mu.m, about 10 to
50 .mu.m, about 10-30 .mu.m, or about 10 .mu.m. Moreover,
generally, not less than 90% of the tribasic calcium phosphate
particles in the powder formulations presented herein have a
diameter less than 150 .mu.m, and not more than 5% of the particles
in the powder formulation have a diameter less than 10 .mu.m. In
addition, generally, the overall mean particle size of the tribasic
calcium phosphate particles in the powder formulations presented
herein about 15 to about 30 .mu.m, about 18 to about 25 .mu.m,
about 18 to about 20 .mu.m, or about 20 .mu.m.
[0083] In certain embodiments, greater than or equal to about 90%
of the tribasic calcium phosphate particles have a diameter less
than 150 .mu.m. In other embodiments the overall mean particle size
of the tribasic calcium phosphate particles is about 15 to about 30
.mu.m, about 18 to about 25 .mu.m, about 18 to about 20 .mu.m, or
about 20 .mu.m. In further embodiments, less than or equal to about
5% of the tribasic calcium phosphate particles have a diameter less
than 10 .mu.m. In yet other embodiments, for the tribasic calcium
phosphate particles, greater than or equal to about 90% of the
particles have a diameter less than 150 .mu.m; and the overall mean
particle size is about 15 to about 30 .mu.m, about 18 to about 25
.mu.m, about 18 to about 20 .mu.m, or about 20 .mu.m; and less than
or equal to about 5% of the particles have a diameter less than 10
.mu.m.
[0084] The powder formulations described herein can be made using
standard techniques. For example, the components of the powder
formulations can be mixed while applying a shearing force, e.g.,
via a high shear mixer/stirrer. Alternatively, for example, the
components of the powder formulations can be homogeneously mixed
using, e.g., a mortar or V-blender. The order of mixing is not
critical to the production process. See Example 1, below, for
representative, non-limited examples of methods for the production
of powder formulations as presented herein.
[0085] The powder formulations can be intranasally administered
utilizing any techniques known in the art. For example, the
formulations can be administered utilizing a dispenser, for example
a single use dispenser or a multi-use dispenser. In certain
embodiments the powder formulations are administered using a device
such as, for example, a device as described in US 2011/0045088 or
in WO 2012/105236, each of which is incorporated herein by
reference for its disclosure of devices that can be utilized to
intranasally administer powder formulations to a primate, for
example, to a human. In specific embodiments, the device used to
administer the powder formulation is a Fit-lizer.TM. (SNBL, LTD)
intranasal dispenser device.
[0086] In certain specific embodiments, the powder formulations
presented herein are encapsulated prior to administration. For
example, the powder formulations presented herein can be
encapsulated in unit dose form. In certain embodiments, the
encapsulated powder formulations are released from the capsule
prior to administration. In other embodiments, the powder
formulations are released from the capsule upon administration.
Powder formulations can, for example, be intranasally administered
utilizing devices designed to accept and delivery powder
formulations that have been encapsulated. In certain embodiments,
the fill weight of the capsule comprises an appropriate excess
amount of the powder formulation such that the desired dose is
administered, taking into account the particular administration
device being utilized.
[0087] In one aspect, presented herein is a method of treating
headache comprising: intranasally administering to a human having a
headache a powder formulation comprising: a) DHE, or a
pharmaceutically acceptable salt thereof, wherein the total dose of
DHE being administered is about 0.1-10.0 mg; b) a microcrystalline
cellulose component with a mean particle size diameter of about 100
.mu.m or less; and c) tribasic calcium phosphate. Herein, unless
otherwise noted, "the total dose of DHE being administered" and
like phrasing means the total amount of parent DHE in the DHE form,
e.g., amount of DHE free base in a pharmaceutically acceptable DHE
salt, being administered. In a particular embodiment, the powder
formulation comprises DHE mesylate, and the total amount of DHE
free base of the DHE mesylate being administered is about 0.1-10.0
mg.
[0088] In certain embodiments of such a method, the powder
formulation is administered to a single nostril of the human having
a headache. In other embodiments of the method, a portion of the
powder formulation is administered to each nostril of the human.
For example, in a specific embodiment of the method, about half of
the powder formulation is administered to one nostril and about
half of the powder formulation is administered to the other nostril
of the human having a headache.
[0089] In another aspect, presented herein is a method of treating
migraine comprising: intranasally administering to a human having a
migraine a powder formulation comprising: a) DHE, or a
pharmaceutically acceptable salt thereof, wherein the total dose of
DHE being administered is about 0.1-10.0 mg; b) a microcrystalline
cellulose component with a mean particle size diameter of about 100
.mu.m or less; and c) tribasic calcium phosphate. In a particular
embodiment, the powder formulation comprises DHE mesylate. In
certain embodiments of the method, the powder formulation is
administered to a single nostril of the human having a migraine. In
other embodiments of the method, a portion of the powder
formulation is administered to each nostril of the human having a
migraine. For example, in a specific embodiment, about half of the
powder formulation is administered to one nostril and about half of
the powder formulation is administered to the other nostril of the
human having a migraine.
[0090] In yet another embodiment of such a method of treating
headache, including migraine, the microcrystalline cellulose
component of the formulation comprises a first microcrystalline
cellulose portion with a mean particle diameter size of about 30
.mu.m or less, and a second microcrystalline cellulose portion with
a mean particle size diameter of about 30-100 .mu.m. In a
particular embodiment of such a method, the first microcrystalline
cellulose portion has a mean particle diameter size of about 15-30
.mu.m. In a specific embodiment of such a method, the first
microcrystalline cellulose portion has a mean particle diameter
size of about 18-20 .mu.m. In yet another specific embodiment of
such a method, the first microcrystalline cellulose portion has a
mean particle diameter size of about 20 .mu.m. In another
particular embodiment of such a method, the second microcrystalline
cellulose portion has a mean particle diameter size of about 45-65
.mu.m. In a specific embodiment of such a method, the second
microcrystalline cellulose portion has a mean particle diameter
size of about 45-55 .mu.m. In another specific embodiment of such a
method, the second microcrystalline cellulose portion has a mean
particle diameter size of about 50-55 .mu.m. In another specific
embodiment of such a method, the second microcrystalline cellulose
portion has a mean particle diameter size of about 50 .mu.m. In yet
another embodiment of such a method, the first microcrystalline
cellulose portion has a mean particle diameter size of about 20
.mu.m, and the second microcrystalline cellulose portion has a mean
particle size diameter of about 50 .mu.m. In yet other embodiments
of such a method, the first microcrystalline cellulose portion has
a mean particle diameter size of about 30 .mu.m or less, for
example, about 15-30 .mu.m, about 18-20 .mu.m, or about 20 .mu.m,
and the second microcrystalline cellulose portion has a mean
particle diameter size of about 45-65 .mu.m, about 45-55 .mu.m,
about 50-55 .mu.m, or about 50 .mu.m. In instances wherein the
method is a method for treating migraine, the method can, in
certain embodiments, be a method for the acute treatment of
migraine with or without aura.
[0091] In certain embodiments of such methods of treating headache,
including migraine, the microcrystalline cellulose component of the
powder formulation comprises about 10 to about 99%, e.g., about 15
to about 99%, of the total weight of the formulation. In other
embodiments, the microcrystalline cellulose component of the powder
formulation comprises about 53 to about 99%, about 76 to about 99%,
about 76 to about 97%, about 90 to about 97%, or about 90 to about
95% of the total weight of the formulation. In some embodiments,
the microcrystalline cellulose component of the powder formulation
comprises about 10 to about 98%, about 18 to about 98%, about 18 to
about 91%, about 67 to about 91%, or about 67 to about 83%. In
further embodiments, the microcrystalline cellulose component of
the powder formulation comprises about 53%, about 76%, about 90%,
about 95%, about 97%, or about 99% of the total weight of the
formulation. In other embodiments, the microcrystalline cellulose
component of the powder formulation comprises about 10%, about 18%,
about 66%, about 83%, about 91%, or about 98% of the total weight
of the formulation.
[0092] For example, in particular embodiments, the first
microcrystalline cellulose portion comprises about 3.0 to about
90%, e.g., about 8.0 to about 90%, of the total weight of the
formulation, and the second microcrystalline cellulose portion
comprises about 10% of the total weight of the formulation. In
other embodiments, the first microcrystalline cellulose portion
comprises about comprises about 43 to about 89%, about 66 to about
89%, about 66 to about 87%, about 80 to about 87%, or about 80 to
about 85% of the total weight of the formulation, of the total
weight of the formulation, and the second microcrystalline
cellulose portion comprises about 10% of the total weight of the
formulation. In some embodiments, the microcrystalline cellulose
component of the powder formulation comprises about 1 to about 88%,
about 8 to about 88%, about 8 to about 81%, about 57 to about 81%,
or about 57 to about 83%, and the second microcrystalline cellulose
portion comprises about 10% of the total weight of the formulation.
In further embodiments, the microcrystalline cellulose component of
the powder formulation comprises about 43%, about 66%, about 80%,
about 85%, about 87%, or about 89% of the total weight of the
formulation, and the second microcrystalline cellulose portion
comprises about 10% of the total weight of the formulation. In
other embodiments, the microcrystalline cellulose component of the
powder formulation comprises about 1%, about 8%, about 57%, about
73%, about 81%, or about 88% of the total weight of the
formulation, and the second microcrystalline cellulose portion
comprises about 10% of the total weight of the formulation.
[0093] In certain embodiments of the methods of treating headache,
including migraine, the tribasic calcium phosphate comprises about
0.5-1.0% of the total weight of the formulation. In specific
embodiments of the methods of treating headache, including
migraine, the tribasic calcium phosphate comprises about 0.8% of
the total weight of the formulation.
[0094] In another aspect, the powder formulations utilized as part
of the methods of treating headache, including migraine, further
comprise caffeine, for example, anhydrous caffeine In specific
embodiments, the powder formulations utilized as part of the
methods of treating headache, including migraine, comprise about
1-60%, about 1-25%, about 10-60%, or about 10-25% caffeine, for
example, anhydrous caffeine. In other embodiments, the powder
formulations utilized as part of the methods of treating headache,
including migraine, comprise about 1%, about 5%, about 6%, about
10%, about 12%, about 20%, about 23%, about 39%, about 48%, about
50%, or about 58% caffeine.
[0095] While the particle size of the caffeine utilized as part of
the powder formulations described herein is not particularly
critical, the mean particle size of the caffeine, e.g., anhydrous
caffeine, is generally about 10-100 .mu.m, for example, about 10 to
75 .mu.m, about 10 to 50 .mu.m, about 10-30 .mu.m, about 10-20
.mu.m, about 15-20 .mu.m, about 10 .mu.m, about 15 .mu.m, about 16
.mu.m, about 17 .mu.m, about 18 .mu.m, about 19 .mu.m, or about 20
.mu.m. Moreover, generally, not less than 90% of the caffeine,
e.g., anhydrous caffeine, particles in the powder formulations
presented herein have a diameter less than 150 .mu.m, and not more
than 5% of the caffeine particles in the powder formulation have a
diameter less than 10 .mu.m. In addition, generally, the overall
mean particle size of the caffeine, e.g., anhydrous caffeine,
particles in the powder formulations presented herein about 15 to
about 30 .mu.m, about 18 to about 25 .mu.m, about 18 to about 20
.mu.m, or about 20 .mu.m.
[0096] In particular embodiments of such methods of treating
headache, including migraine, the total dose of DHE administered is
about 0.1-5.0 mg. In certain other embodiments, the total dose of
DHE administered is about 0.5-5.0 mg. In certain other embodiments,
the total dose of DHE administered is about 0.5-3.0 mg. In certain
other embodiments, the total dose of DHE administered is about
1.0-2.0 mg. In particular embodiments of such methods, the total
dose of DHE administered is about 0.1 mg, about 0.5 mg, about 1.0
mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about
5.0 mg, about 7.5 mg, or about 10.0 mg. In certain embodiments, the
total dose is administered into a single nostril. In other
embodiments, a portion of the total dose is administered into each
nostril. In yet other embodiments, about half of the total dose is
administered into one nostril and the remaining half is
administered into the other nostril.
[0097] In specific embodiments of such a method of treating
headache, including migraine, the total amount of the powder
formulation administered is 5, 10, 15, 20, 25, 30, 35, 40, 45, or
50 mg. In certain embodiments, the total amount of the powder
formulation is administered into a single nostril. In other
embodiments, a portion of the total amount of the powder
formulation is administered into each nostril. In yet other
embodiments, about half of the total amount of the powder
formulation is administered into one nostril and the remaining half
is administered into the other nostril.
[0098] In particular embodiments wherein such methods of treating
headache are methods of treating migraine, the methods can include
a method for the acute treatment of migraine with or without
aura.
[0099] In certain embodiments, the methods of treating headache,
including migraine, comprise administering the powder formulation
such that the mean T.sub.max of DHE is about 10-50 minutes. In
other embodiments, the mean T.sub.max of DHE is about 10-30
minutes. In further embodiments, the mean T.sub.max of DHE is about
5-50 minutes. In yet further embodiments, the mean T.sub.max of DHE
is about 5-30 minutes. In further embodiments, the mean T.sub.max
of DHE is about 2-50 minutes. In yet further embodiments, the mean
T.sub.max of DHE is about 2-30 minutes. In other embodiments, the
methods of treating headache, including migraine, comprise
administering the powder formulation such that the mean C.sub.max
of DHE is about 0.5-100 ng/mL. In yet other embodiments, such
methods of treating headache, including migraine, utilizing about
0.1-1.0 mg DHE comprise administering the powder formulation such
that the mean AUC.sub.0-inf of DHE is about 1-500 ngh/mL. In
further embodiments, the mean AUC.sub.0-30 min of DHE is about
1-500 ngh/mL. In yet other embodiments, the methods of treating
headache, including migraine, comprise administering the powder
formulation such that the mean T.sub.1/2 of DHE is about 110-260
minutes. In yet other embodiments, the methods of treating
headache, including migraine, comprise administering the
intersubject variability in DHE C.sub.max is less than 30%.
[0100] In a particular aspect, presented herein is a method of
treating headache, including migraine, comprising: intranasally
administering to a human having a headache, e.g., migraine, a
powder formulation comprising: a) DHE, or a pharmaceutically
acceptable salt thereof, wherein the total dose of DHE being
administered is about 0.1-2.0 mg; b) a microcrystalline cellulose
component comprising a first microcrystalline cellulose portion
with a mean particle size of about 30 .mu.m or less, for example,
about 15-30 .mu.m, about 18-20 .mu.m, or about 20 .mu.m, and a
second microcrystalline cellulose portion with a mean particle size
diameter of about 45-65 .mu.m, about 45-55 .mu.m, about 50-55
.mu.m, or about 50 .mu.m, wherein the first microcrystalline
cellulose portion comprises about 45 to about 90%, e.g., about 50
to about 90%, of the total weight of the formulation, and the
second microcrystalline portion comprises about 10% of the total
weight of the formulation; and c) tribasic calcium phosphate
comprising about 0.5-1.0%, e.g., about 0.8%, of the total weight of
the formulation.
[0101] In a specific embodiment of such a method, the powder
formulation comprises DHE mesylate. In another specific embodiment
of such a method, the powder formulation is administered to a
single nostril of the human having a headache, e.g., migraine. In
yet another specific embodiment of such a method, a portion of the
powder formulation is administered to each nostril of the human
having a headache, e.g. headache. For example, in a specific
embodiment, about half of the powder formulation is administered to
one nostril and about half of the powder formulation is
administered to the other nostril of the human having a headache,
e.g. headache.
[0102] In instances wherein such a method is a method of treating
migraine, the method can be a method of acute treatment of migraine
with or without aura.
[0103] In yet another particular embodiment of such a method of
treating headache, including migraine, the powder formulation
further comprises caffeine, for example, about 1-25% caffeine,
e.g., anhydrous caffeine.
[0104] In specific embodiments of such a method of treating
headache, including migraine, the total amount of the powder
formulation administered is 5, 10, 15, 20, 25, 30, 35, 40, 45, or
50 mg. In certain embodiments, the total amount of the powder
formulation is administered into a single nostril. In other
embodiments, a portion of the total amount of the powder
formulation is administered into each nostril. In yet other
embodiments, about half of the total amount of the powder
formulation is administered into one nostril and the remaining half
is administered into the other nostril.
[0105] In a particular embodiment of such a method of treating
headache, including migraine utilizing a powder formulation
comprising about 0.1-2.0 mg DHE, the powder formulation is
administered such that the mean T.sub.max of DHE is about 10-50
minutes. In another embodiment, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-50
minutes. In another embodiment, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-30
minutes. In another particular embodiment, the powder formulation
is administered such that the mean C.sub.max of DHE is about 0.5-40
ng/mL. In yet another particular embodiment, the powder formulation
is administered such that the mean AUC.sub.0-inf of DHE is about
1-200 ngh/mL. In another specific embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.1/2 of DHE is about 100-300
minutes. In still another embodiment of such a method of treating
headache, including migraine, the intersubject variability in DHE
C.sub.max is less than 30%.
[0106] In another particular aspect, presented herein is a method
of treating headache, including migraine, comprising: intranasally
administering to a human having a headache, e.g., migraine, a
powder formulation comprising: a) DHE, or a pharmaceutically
acceptable salt thereof, e.g., DHE mesylate, wherein the total dose
of DHE administered is about 0.1 mg; b) a microcrystalline
cellulose component comprising a first microcrystalline cellulose
portion with a mean particle size of about 30 .mu.m or less, for
example, about 15-30 .mu.m, about 18-20 .mu.m, or about 20 .mu.m,
and a second microcrystalline cellulose portion with a mean
particle size diameter of about 45-65 .mu.m, for example, about
45-55 .mu.m or about 50-55 .mu.m, e.g., about 50 .mu.m, wherein the
first microcrystalline cellulose portion comprises about 80 to
about 90%, e.g., about 85 to about 90%, of the total weight of the
formulation, and the second microcrystalline portion comprises
about 10% of the total weight of the formulation; and c) tribasic
calcium phosphate comprising about 0.5-1.0%, e.g., about 0.8%, of
the total weight of the formulation. In yet another particular
embodiment of such a method of treating headache, including
migraine, the powder formulation further comprises caffeine, for
example, about 1-2% caffeine, e.g. anhydrous caffeine.
[0107] In another specific embodiment of such a method, the powder
formulation is administered to a single nostril of the human having
a migraine. In yet another specific embodiment of such a method, a
portion of the powder formulation is administered to each nostril
of the human having a headache, e.g., migraine. For example, in a
specific embodiment, about half of the powder formulation is
administered to one nostril and about half of the powder
formulation is administered to the other nostril of the human
having a headache, e.g., migraine. In specific embodiments of such
a method of treating headache, including migraine, the total amount
of the powder formulation administered is about 5, 10, 15, 20, 25,
30, 35, 40, 45, or 50 mg, into a single or into both nostrils.
[0108] In instances wherein such a method is a method of treating
migraine, the method can be acute treatment of migraine with or
without aura.
[0109] In a particular embodiment of such a method of treating
headache, including migraine, utilizing a powder formulation
comprising about 0.1 mg DHE, the powder formulation is administered
such that the mean T.sub.max of DHE is about 10-30 minutes. In
another embodiment, the powder formulation is administered such
that the mean T.sub.max of DHE is about 2-50 minutes. In another
embodiment, the powder formulation is administered such that the
mean T.sub.max of DHE is about 2-30 minutes. In another particular
embodiment of such a method of treating headache, including
migraine, the powder formulation is administered such that the mean
C.sub.max of DHE is about 0.1-6 ng/mL. In another embodiment of
such a method of treating headache, including migraine, the powder
formulation is administered such that the mean AUC.sub.0-inf of DHE
is about 1-15 ngh/mL. In another embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.1/2 of DHE is about 100-300
minutes. In yet another particular embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-30
minutes, the mean C.sub.max of DHE is about 0.1-6 ng/mL, the mean
AUC.sub.0-inf of DHE is about 1-15 ngh/mL, and the mean T.sub.1/2
of DHE is about 100-300 minutes. In still another embodiment of
such a method of treating headache, including migraine, the
intersubject variability in DHE C.sub.max is less than 30%.
[0110] In yet another aspect, presented herein is a method of
treating headache, including migraine, comprising: intranasally
administering to a human having a headache, e.g, migraine, a powder
formulation comprising: a) DHE, or a pharmaceutically acceptable
salt thereof, e.g., DHE mesylate, wherein the total dose of DHE
being administered is about 0.5 mg; b) a microcrystalline cellulose
component comprising a first microcrystalline cellulose portion
with a mean particle size of about 30 .mu.m or less, for example,
about 15-30 .mu.m, about 18-20 .mu.m, or about 20 .mu.m, and a
second microcrystalline cellulose portion with a mean particle size
diameter of about 45-65 .mu.m, for example, about 45-55 .mu.m or
about 50-55 .mu.m, e.g., about 50 .mu.m, wherein the first
microcrystalline cellulose portion comprises about 75 to about 90%,
e.g., about 80 to about 90%, of the total weight of the
formulation, and the second microcrystalline portion comprises
about 10% of the total weight of the formulation; and c) tribasic
calcium phosphate comprising about 0.5-1.0%, e.g., about 0.8%, of
the total weight of the formulation. In yet another particular
embodiment of such a method of treating headache, including
migraine, the powder formulation further comprises caffeine, for
example, about 5-10% caffeine, e.g. anhydrous caffeine.
[0111] In another specific embodiment of such a method, the powder
formulation is administered to a single nostril of the human having
a headache, e.g., migraine. In yet another specific embodiment of
such a method, a portion of the powder formulation is administered
to each nostril of the human having a headache, e.g., migraine. For
example, in a specific embodiment, about half of the powder
formulation is administered to one nostril and about half of the
powder formulation is administered to the other nostril of the
human having a headache, e.g., migraine. In specific embodiments of
such a method of treating headache, including migraine, the total
amount of the powder formulation administered is about 5, 10, 15,
20, 25, 30, 35, 40, 45, or 50 mg, into a single or into both
nostrils.
[0112] In a specific embodiment of such a method, the method is a
method for the acute treatment of migraine with or without
aura.
[0113] In a particular embodiment of such a method of treating
headache, including migraine, comprises utilizing a powder
formulation comprising about 0.5 mg DHE, the powder formulation is
administered such that the mean T.sub.max of DHE is about 10-50
minutes. In another embodiment, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-50
minutes. In another embodiment, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-30
minutes. In another particular embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean C.sub.max of DHE is about 1.0-15
ng/mL. In another embodiment of such a method of treating headache,
including migraine, the powder formulation is administered such
that the mean AUC.sub.0-inf of DHE is about 10-50 ngh/mL. In
another embodiment of such a method of treating headache, including
migraine, the powder formulation is administered such that the mean
T.sub.1/2 of DHE is about 100-300 minutes. In yet another
particular embodiment of such a method of treating headache,
including migraine, the powder formulation is administered such
that the mean T.sub.max of DHE is about 2-50 minutes, the mean
C.sub.max of DHE is about 1.0-15 ng/mL, the mean AUC.sub.0-inf of
DHE is about 10-50 ngh/mL, and the mean T.sub.1/2 of DHE is about
100-300 minutes. In still another embodiment of such a method of
treating headache, including migraine, the intersubject variability
in DHE C.sub.max is less than 30%.
[0114] In yet another aspect, presented herein is a method of
treating headache, including migraine, comprising: intranasally
administering to a human having a headache, e.g., migraine a powder
formulation comprising: a) DHE, or a pharmaceutically acceptable
salt thereof, e.g., DHE mesylate, wherein the total dose of DHE
being administered is about 1.0 mg; b) a microcrystalline cellulose
component comprising a first microcrystalline cellulose portion
with a mean particle size of about 30 .mu.m or less, for example,
about 15-30 .mu.m, about 18-20 .mu.m, or about 20 .mu.m, and a
second microcrystalline cellulose portion with a mean particle size
diameter of about 45-65 .mu.m, for example, about 45-55 .mu.m or
about 50-55 .mu.m, e.g., about 50 .mu.m, wherein the first
microcrystalline cellulose portion comprises about 65 to about 90%,
e.g., about 70 to about 90%, of the total weight of the
formulation, and the second microcrystalline portion comprises
about 10% of the total weight of the formulation; and c) tribasic
calcium phosphate comprising about 0.5-1.0%, e.g., about 0.8%, of
the total weight of the formulation. In yet another particular
embodiment of such a method of treating migraine, the powder
formulation further comprises caffeine, for example, about 10-15%
caffeine, e.g. anhydrous caffeine.
[0115] In another specific embodiment of such a method, the powder
formulation is administered to a single nostril of the human having
a headache, e.g., migraine. In yet another specific embodiment of
such a method, a portion of the powder formulation is administered
to each nostril of the human having a headache, e.g., migraine. For
example, in a specific embodiment, about half of the powder
formulation is administered to one nostril and about half of the
powder formulation is administered to the other nostril of the
human having a migraine. In specific embodiments of such a method
of treating headache, including migraine, the total amount of the
powder formulation administered is about 5, 10, 15, 20, 25, 30, 35,
40, 45, or 50 mg, into a single or into both nostrils.
[0116] In a specific embodiment of such a method, the method is a
method for the acute treatment of migraine with or without
aura.
[0117] In a particular embodiment of such a method of treating
headache, including migraine, utilizing a powder formulation
comprising about 1.0 mg DHE, the powder formulation is administered
such that the mean T.sub.max of DHE is about 10-50 minutes. In
another embodiment, the powder formulation is administered such
that the mean T.sub.max of DHE is about 2-50 minutes. In another
embodiment, the powder formulation is administered such that the
mean T.sub.max of DHE is about 2-30 minutes. In another particular
embodiment of such a method of treating headache, including
migraine, the powder formulation is administered such that the mean
C.sub.max of DHE is about 2.0-20 ng/mL. In another embodiment of
such a method of treating headache, including migraine, the powder
formulation is administered such that the mean AUC.sub.0-inf of DHE
is about 15-110 ngh/mL. In another embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.1/2 of DHE is about 100-300
minutes. In yet another particular embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-50
minutes, the mean C.sub.max of DHE is about 2.0-20 ng/mL, the mean
AUC.sub.0-inf of DHE is about 15-110 ngh/mL, and the mean T.sub.1/2
of DHE is about 100-300 minutes. In still another embodiment of
such a method of treating migraine, the intersubject variability in
DHE C.sub.max is less than 30%.
[0118] In yet another aspect, presented herein is a method of
treating headache, including migraine, comprising: intranasally
administering to a human having a migraine a powder formulation
comprising: a) DHE, or a pharmaceutically acceptable salt thereof,
e.g., DHE mesylate, wherein the total dose of DHE is about 2.0 mg;
b) a microcrystalline cellulose component comprising a first
microcrystalline cellulose portion with a mean particle size of
about 30 .mu.m or less, for example, about 15-30 .mu.m, about 18-20
.mu.m, or about 20 .mu.m, and a second microcrystalline cellulose
portion with a mean particle size diameter of about 45-65 .mu.m,
for example, about 45-55 .mu.m or about 50-55 .mu.m, e.g., about 50
.mu.m, wherein the first microcrystalline cellulose portion
comprises about 45 to about 80%, e.g., about 50 to about 80%, of
the total weight of the formulation, and the second
microcrystalline portion comprises about 10% of the total weight of
the formulation; and c) tribasic calcium phosphate comprising about
0.5-1.0%, e.g., about 0.8%, of the total weight of the formulation.
In yet another particular embodiment of such a method of treating
headache, including migraine, the powder formulation further
comprises caffeine, for example, about 20-30% caffeine, e.g.
anhydrous caffeine.
[0119] In another specific embodiment of such a method, the powder
formulation is administered to a single nostril of the human having
a headache, e.g., migraine. In yet another specific embodiment of
such a method, a portion of the powder formulation is administered
to each nostril of the human having a headache, e.g., migraine. For
example, in a specific embodiment, about half of the powder
formulation is administered to one nostril and about half of the
powder formulation is administered to the other nostril of the
human having a headache, e.g, migraine. In specific embodiments of
such a method of treating headache, including migraine, the total
amount of the powder formulation administered is about 5, 10, 15,
20, 25, 30, 35, 40, 45, or 50 mg, into a single or into both
nostrils.
[0120] In a specific embodiment of such a method, the method is a
method for the acute treatment of migraine with or without
aura.
[0121] In a particular embodiment of such a method of treating
headache, including migraine, utilizing a powder formulation
comprising about 2.0 mg DHE, the powder formulation is administered
such that the mean T.sub.max of DHE is about 10-50 minutes. In
another embodiment, the powder formulation is administered such
that the mean T.sub.max of DHE is about 2-50 minutes. In another
embodiment, the powder formulation is administered such that the
mean T.sub.max of DHE is about 2-30 minutes. In another particular
embodiment of such a method of treating headache, including
migraine, the powder formulation is administered such that the mean
C.sub.max of DHE is about 2.0-50 ng/mL. In another embodiment of
such a method of treating headache, including migraine, the powder
formulation is administered such that the mean AUC.sub.0-inf of DHE
is about 15-200 ngh/mL. In another embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.1/2 of DHE is about 100-300
minutes. In yet another particular embodiment of such a method of
treating headache, including migraine, the powder formulation is
administered such that the mean T.sub.max of DHE is about 2-50
minutes, the mean C.sub.max of DHE is about 2.0-50 ng/mL, the mean
AUC.sub.0-inf of DHE is about 15-200 ngh/mL, and the mean T.sub.1/2
of DHE is about 100-300 minutes. In still another embodiment of
such a method of treating headache, including migraine, the
intersubject variability in DHE C.sub.max is less than 30%.
[0122] In one aspect, presented herein is a method of treating
headache, including migraine, comprising: intranasally
administering to a human having a headache a powder formulation
comprising: a) DHE, or a pharmaceutically acceptable salt thereof,
wherein the total dose of DHE being administered is about 0.1-10.0
mg; b) a microcrystalline cellulose component comprising a first
microcrystalline cellulose portion with a mean particle size
diameter of about 30 .mu.m or less, for example, about 15-30 .mu.m,
about 18-20 .mu.m, or about 20 .mu.m, and a second microcrystalline
cellulose portion with a mean particle size diameter of about 45-65
.mu.m, for example, about 45-55 .mu.m or about 50-55 .mu.m, e.g.,
about 50 .mu.m, wherein the first microcrystalline cellulose
portion comprises about 3 to about 90%, e.g., about 8 to about 90%,
of the total weight of the powder formulation of the total weight
of the formulation, and the second microcrystalline portion
comprises about 10% of the total weight of the formulation.
[0123] In a particular embodiment of such a method of treating
headache, including treating migraine, the powder formulation
comprises DHE mesylate. In certain embodiments of such a method,
the powder formulation is administered to a single nostril of the
human having a headache, including migraine. In other embodiments
of such a method, a portion of the powder formulation is
administered to each nostril of the human having a headache, e.g.,
migraine. For example, in a specific embodiment of such a method,
about half of the powder formulation is administered to one nostril
and about half of the powder formulation is administered to the
other nostril of the human having a headache, e.g., migraine.
[0124] In particular embodiments of such methods of treating
headache, including migraine, the total dose of DHE administered is
about 0.1-5.0 mg. In certain other embodiments, the total dose of
DHE administered is about 0.5-5.0 mg. In certain other embodiments,
the total dose of DHE administered is about 0.5-3.0 mg. In certain
other embodiments, the total dose of DHE administered is about
1.0-2.0 mg. In particular embodiments of such methods, the total
dose of DHE administered is about 0.1 mg, about 0.5 mg, about 1.0
mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about
5.0 mg, about 7.5 mg, or about 10.0 mg. In certain embodiments, the
total dose is administered into a single nostril. In other
embodiments, a portion of the total dose is administered into each
nostril. In yet other embodiments, about half of the total dose is
administered into one nostril and the remaining half is
administered into the other nostril.
[0125] In specific embodiments of such a method of treating
headache, including migraine, the total amount of the powder
formulation administered is 5, 10, 15, 20, 25, 30, 35, 40, 45, or
50 mg. In certain embodiments, the total amount of the powder
formulation is administered into a single nostril. In other
embodiments, a portion of the total amount of the powder
formulation is administered into each nostril. In yet other
embodiments, about half of the total amount of the powder
formulation is administered into one nostril and the remaining half
is administered into the other nostril.
[0126] In certain embodiments of such methods of treating headache,
including migraine, the powder formulation further comprises a
fluidizing agent. Fluidizing agents include but are not limited to
tribasic calcium phosphate, talc, silicon dioxide, and magnesium
stearate. In some embodiments, the fluidizing agent is tribasic
calcium phosphate. In certain embodiments, the tribasic calcium
phosphate comprises about 0.5-1.0% of the total weight of the
formulation. In specific embodiments of the methods of treating
migraine, the tribasic calcium phosphate comprises about 0.8% of
the total weight of the formulation.
[0127] In certain other embodiments, the powder formulations
utilized as part of such methods of treating headache, including
migraine, further comprise caffeine, for example, anhydrous
caffeine In specific embodiments, the powder formulations utilized
as part of the methods of treating migraine comprise about 1-60%
caffeine, for example, anhydrous caffeine.
[0128] In particular embodiments, such methods are methods for the
acute treatment of migraine with or without aura.
[0129] In certain embodiments, such methods of treating headache,
including migraine, comprise administering the powder formulation
such that the mean T.sub.max of DHE is about 10-50 minutes. In
another embodiment, the powder formulation is administered such
that the mean T.sub.max of DHE is about 2-50 minutes. In another
embodiment, the powder formulation is administered such that the
mean T.sub.max of DHE is about 2-30 minutes. In other embodiments,
such methods of treating headache, e.g., migraine, comprise
administering the powder formulation such that the mean C.sub.max
of DHE is about 0.5-100 ng/mL. In yet other embodiments, the
methods of treating headache, including migraine, comprise
administering the powder formulation such that the mean
AUC.sub.0-inf of DHE is about 4-500 ngh/mL. In yet other
embodiments, the methods of treating headache, including migraine,
comprise administering the powder formulation such that the mean
T.sub.1/2 of DHE is about 110-260 minutes. In yet other
embodiments, the methods of treating headache, including migraine,
comprise administering the intersubject variability in DHE
C.sub.max is less than 30%.
[0130] In yet another aspect, presented herein are methods for
treating headache, including migraine, comprising intranasally
administering to a human having a headache, e.g., a migraine, a
powder formulation comprising: a) DHE, or a pharmaceutically
acceptable salt thereof, e.g., DHE mesylate; b) a microcrystalline
cellulose component comprising a first microcrystalline cellulose
portion having a mean particle diameter size of less than about 30
.mu.m (e.g., about 15-30 .mu.m, about 15-20 .mu.m, about 18-20
.mu.m, or about 20 .mu.m), and a second microcrystalline cellulose
portion having a mean particle diameter size of about 45-65 .mu.m
(e.g., about 45-55 .mu.m, about 50-55 .mu.m, or about 50 .mu.m); c)
tribasic calcium phosphate; and, optionally d) caffeine, for
example anhydrous caffeine, wherein the powder formulation contains
the parameters of any of the representative DHE powder formulations
presented, below, in Table 1.
TABLE-US-00001 TABLE 1 w/w % of total powder formulation DHE Dose
1.sup.st MCC 2.sup.nd MCC (mg) portion portion TCP Caffeine 0.1-10
38-94 5-15 0.5-1.5 0 0.1-2.sup. 75-94 5-15 0.5-1.5 0 1-5 60-90 5-15
0.5-1.5 0 1-2 74-90 5-15 0.5-1.5 0 0.1 73-94 5-15 0.5-1.5 0 0.5
76-92 5-15 0.5-1.5 0 1.0 74-90 5-15 0.5-1.5 0 2.0 69-85 5-15
0.5-1.5 0 5.0 55-71 5-15 0.5-1.5 0 8.0 41-57 5-15 0.5-1.5 0 10.0
32-48 5-15 0.5-1.5 0 0.1-10 4-89 5-15 0.5-1.5 1-58 0.1-2.sup. 57-88
5-15 0.5-1.5 1-23 1-5 8-57 5-15 0.5-1.5 12-58 1-2 57-73 5-15
0.5-1.5 12-23 0.1 .sup. 76-93.5 5-15 0.5-1.5 0.5-2.sup. 0.5 .sup.
66-89.5 5-15 0.5-1.5 2.5-10 1.0 54-85 5-15 0.5-1.5 5-20 2.0 29-75
5-15 0.5-1.5 10-40 5.0 1-46 5-15 0.5-1.5 25-59 8.0 0.3-32 5-15
0.5-1.5 25-56 10.0 0.1-12 5-15 0.5-1.5 25-47 0.1-10 38-94 10
0.5-1.5 0 0.1-2.sup. 75-94 10 0.5-1.5 0 1-5 60-90 10 0.5-1.5 0 1-2
74-90 10 0.5-1.5 0 0.1 73-94 10 0.5-1.5 0 0.5 76-92 10 0.5-1.5 0
1.0 74-90 10 0.5-1.5 0 2.0 69-85 10 0.5-1.5 0 5.0 55-71 10 0.5-1.5
0 8.0 41-57 10 0.5-1.5 0 10.0 32-48 10 0.5-1.5 0 0.1-10 4-89 10
0.5-1.5 1-58 0.1-2.sup. 57-88 10 0.5-1.5 1-23 1-5 8-57 10 0.5-1.5
12-58 1-2 57-73 10 0.5-1.5 12-23 0.1 .sup. 76-93.5 10 0.5-1.5
0.5-2.sup. 0.5 .sup. 66-89.5 10 0.5-1.5 2.5-10 1.0 54-85 10 0.5-1.5
5-20 2.0 29-75 10 0.5-1.5 10-40 5.0 1-46 10 0.5-1.5 25-59 8.0
0.3-32 10 0.5-1.5 25-56 10.0 0.1-12 10 0.5-1.5 25-47 0.1-10 38-94
5-15 0.8 0 0.1-2.sup. 75-94 5-15 0.8 0 1-5 60-90 5-15 0.8 0 1-2
74-90 5-15 0.8. 0 0.1 73-94 5-15 0.8 0 0.5 76-92 5-15 0.8 0 1.0
74-90 5-15 0.8 0 2.0 69-85 5-15 0.8 0 5.0 55-71 5-15 0.8 0 8.0
41-57 5-15 0.8 0 10.0 32-48 5-15 0.8 0 0.1-10 4-89 5-15 0.8 1-58
0.1-2.sup. 57-88 5-15 0.8 1-23 1-5 8-57 5-15 0.8 12-58 1-2 57-73
5-15 0.8 12-23 0.1 .sup. 76-93.5 5-15 0.8 0.5-2.sup. 0.5 .sup.
66-89.5 5-15 0.8 2.5-10 1.0 54-85 5-15 0.8 5-20 2.0 29-75 5-15 0.8
10-40 5.0 1-46 5-15 0.8 25-59 8.0 0.3-32 5-15 0.8 25-56 10.0 0.1-12
5-15 0.8 25-47 0.1-10 38-94 10 0.8 0 0.1-2.sup. 75-94 10 0.8 0 1-5
60-90 10 0.8 0 1-2 74-90 10 0.8 0 0.1 73-94 10 0.8 0 0.5 76-92 10
0.8 0 1.0 74-90 10 0.8 0 2.0 69-85 10 0.8 0 5.0 55-71 10 0.8 0 8.0
41-57 10 0.8 0 10.0 32-48 10 0.8 0 0.1-10 4-89 10 0.8 1-58
0.1-2.sup. 57-88 10 0.8 1-23 1-5 8-57 10 0.8 12-58 1-2 57-73 10 0.8
12-23 0.1 .sup. 76-93.5 10 0.8 0.5-2.sup. 0.5 .sup. 66-89.5 10 0.8
2.5-10 1.0 54-85 10 0.8 5-20 2.0 29-75 10 0.8 10-40 5.0 1-46 10 0.8
25-59 8.0 0.3-32 10 0.8 25-56 10.0 0.1-12 10 0.8 25-47 MCC =
microcrystalline cellulose TCP = tribasic calcium phosphate
6. EXAMPLES
6.1 Example 1: Preparation of DHE Powder Formulations
[0131] 6.1.1 Preparation of 0.1 mg DHE Powder Formulation
[0132] Powder formulations comprising 0.1 mg DHE were prepared as
described herein.
[0133] Materials.
[0134] Dihydroergotamine mesylate (99.7% purity; primary particle
distribution: Dv10: 5.3 .mu.m; Dv50: 17.7 .mu.m; Dv90: 69.3 .mu.m;
"DvX" refers to the maximum particle diameter below which X % of
the sample exists; for example, "Dv10" refers to the maximum
particle diameter below which 10% of the sample exists);
microcrystalline cellulose, Ceolus.RTM. PH-F20JP (nominal particle
size: 20 .mu.m, less than 1% retained when sieved through mesh size
400; Asahi Kasei Chemicals Corporation); Microcrystalline
cellulose, Ceolus.RTM. PH-301 (nominal particle size: 50 .mu.m,
less than 1% retained when sieved through mesh size 60 and less
than 30% retained when sieved through mesh size 200; Asahi Kasei
Chemicals Corporation); Tribasic calcium phosphate
(Ca.sub.5(OH)(PO.sub.4).sub.3; Mallinckrodt Chemicals); HPMC
capsule, size 2, Quali-V (Qualicaps Co., Ltd).
[0135] Procedure.
[0136] Two hundred-fifty mg Ceolus.RTM. PH-301 and 1110 mg
Ceolus.RTM.PH-F20JP were combined in a glass vial and mixed with
vigorous shaking for approximately 10 minutes. Twenty mg tribasic
calcium phosphate was then added and mixed with vigorous shaking
for approximately 10 minutes. Ten mg dihydroergotamine mesylate was
then added and mixed with vigorous shaking for approximately 10
minutes. An additional 1110 mg Ceolus.RTM. PH-F20JP was then added
and mixed with vigorous shaking for approximately 10 minutes. The
resulting DHE powder formulation was encapsulated into the HPMC
capsules (25 mg/capsule.+-.1 mg) and the length of each capsule was
adjusted to 17.8.+-.0.4 mm using a capsule sizer.
[0137] 6.1.2 Preparation of 0.5 mg DHE Powder Formulation
[0138] Powder formulations comprising 0.5 mg DHE were prepared as
described herein.
[0139] Materials.
[0140] Dihydroergotamine mesylate (99.7% purity; primary particle
distribution: Dv10: 5.3 .mu.m; Dv50: 17.7 .mu.m; Dv90: 69.3 .mu.m);
microcrystalline cellulose, Ceolus.RTM. PH-F20JP (nominal particle
size: 20 .mu.m, less than 1% retained when sieved through mesh size
400; Asahi Kasei Chemicals Corporation); Microcrystalline
cellulose, Ceolus.RTM. PH-301 (nominal particle size: 50 .mu.m,
less than 1% retained when sieved through mesh size 60 and less
than 30% retained when sieved through mesh size 200; Asahi Kasei
Chemicals Corporation); Tribasic calcium phosphate
(Ca.sub.5(OH)(PO.sub.4).sub.3; Mallinckrodt Chemicals); HPMC
capsule, size 2, Quali-V (Qualicaps Co., Ltd).
[0141] Procedure.
[0142] Sixty mg Ceolus.RTM. PH-301 and 261.6 mg Ceolus.RTM.
PH-F20JP were combined in a glass vial and mixed with vigorous
shaking for approximately 10 minutes. 4.8 mg tribasic calcium
phosphate was then added and mixed with vigorous shaking for
approximately 10 minutes. Twelve mg dihydroergotamine mesylate was
then added and mixed with vigorous shaking for approximately 10
minutes. An additional 261.6 mg Ceolus.RTM. PH-F20JP was then added
and mixed with vigorous shaking for approximately 10 minutes. The
resulting DHE powder formulation was encapsulated into the HPMC
capsules (25 mg/capsule.+-.1 mg) and the length of each capsule was
adjusted to 17.8.+-.0.4 mm using a capsule sizer. Similar
procedures were also utilized to yield capsules with 1.5 mg.+-.0.5
mg of such a 0.5 mg DHE powder formulation per capsule.
[0143] 6.1.3 Preparation of 1.0 mg DHE Powder Formulation
[0144] Powder formulations comprising 1.0 mg DHE were prepared as
described herein.
[0145] Materials.
[0146] Dihydroergotamine mesylate (99.7% purity; primary particle
distribution: Dv10: 5.3 .mu.m; Dv50: 17.7 .mu.m; Dv90: 69.3 .mu.m);
microcrystalline cellulose, Ceolus.RTM. PH-F20JP (nominal particle
size: 20 .mu.m, less than 1% retained when sieved through mesh size
400; Asahi Kasei Chemicals Corporation); Microcrystalline
cellulose, Ceolus.RTM. PH-301 (nominal particle size: 50 .mu.m,
less than 1% retained when sieved through mesh size 60 and less
than 30% retained when sieved through mesh size 200; Asahi Kasei
Chemicals Corporation); Tribasic calcium phosphate
(Ca.sub.5(OH)(PO.sub.4).sub.3; Mallinckrodt Chemicals); HPMC
capsule, size 2, Quali-V (Qualicaps Co., Ltd).
[0147] Procedure.
[0148] Sixty mg Ceolus.RTM. PH-301 and 255.6 mg Ceolus.RTM.
PH-F20JP were combined in a glass vial and mixed with vigorous
shaking for approximately 10 minutes. 4.8 mg tribasic calcium
phosphate was then added and mixed with vigorous shaking for
approximately 10 minutes. Twenty-four mg dihydroergotamine mesylate
was then added and mixed with vigorous shaking for approximately 10
minutes. An additional 255.6 mg Ceolus.RTM.PH-F20JP was then added
and mixed with vigorous shaking for approximately 10 minutes. The
resulting DHE powder formulation was encapsulated into the HPMC
capsules (25 mg/capsule.+-.1 mg) and the length of each capsule was
adjusted to 17.8.+-.0.4 mm using a capsule sizer.
[0149] 6.1.4 DHE Powder Formulations
[0150] Presented below, in Table 2, are representative DHE powder
formulations that can be utilized in the methods of treating
headache, including migraine, presented herein. Such formulations
can be produced, for example, following procedures as described in
the preceding examples. The total amount of such formulations can
be administered intranasally into a single nostril, or,
alternatively, a portion can be administered into each nostril; for
example, about one-half of the total can be administered into each
nostril.
TABLE-US-00002 TABLE 2 Components 0.1 mg 0.5 mg 1.0 mg 2.0 mg 5.0
mg DHE DHE DHE DHE DHE dose dose dose dose dose mg DHE 0.116 0.58
1.16 2.32 5.80 mesylate MCC (Ceolus 22.184 21.72 21.14 19.98 16.50
PH-F20JP) MCC (Ceolus 2.50 2.50 2.50 2.50 2.50 PH-301 Tribasic 0.20
0.20 0.20 0.20 0.20 calcium phosphate Total unit 25 25 25 25 25
dose wt Units: mg DHE--dihydroergotamine mesylate MCC (Ceolus
PH-F20JP)--Microcrystalline cellulose nominal particle size 20
.mu.m; less than 1% retained when sieved through mesh size 400. MCC
(Ceolus PH 301)--Microcrystalline cellulose nominal particle size
50 .mu.m; less than 1% retained when sieved through mesh size 60
and less than 30% retained when sieved through mesh size 200.
[0151] 6.1.5 DHE Powder Formulations Comprising Caffeine
[0152] Presented below, in Table 3, are representative DHE powder
formulations comprising caffeine that can be utilized in the
methods of treating headache, including migraine, presented herein.
Such caffeine-containing formulations can be produced, for example,
following procedures similar to those described in the preceding
examples. The total amount of such formulations can be administered
intranasally into a single nostril, or, alternatively, a portion
can be administered into each nostril; for example, about one-half
of the total can be administered into each nostril.
TABLE-US-00003 TABLE 3 0.1 mg 0.5 mg 0.5 mg 1.0 mg 1.0 mg 2.0 mg
5.0 mg DHE DHE DHE DHE DHE DHE DHE Components dose dose dose dose
dose dose dose DHE 0.116 0.58 0.58 1.16 1.16 2.32 5.80 mesylate
Caffeine 0.29 1.45 1.25 2.9 2.5 5.8 14.5 anhydrous MCC (Ceolus
21.894 20.27 20.47 18.24 18.64 14.18 2.00 PH-F20JP) MCC (Ceolus
2.50 2.50 2.50 2.50 2.50 2.50 2.50 PH-301 Tribasic 0.20 0.20 0.20
0.20 0.20 0.20 0.20 calcium phosphate Total unit 25 25 25 25 25 25
25 dose wt Units: mgs DHE--dihydroergotamine mesylate MCC (Ceolus
PH-F20JP) - Microcrystalline cellulose nominal particle size 20 um;
less than 1% retained when sieved through mesh size 400. MCC
(Ceolus PH 301) - Microcrystalline cellulose nominal particle size
50 um; less than 1% retained when sieved through mesh size 60 and
less than 30% retained when sieved through mesh size 200
6.2 Example 2: Pharmacokinetic Study of Intranasal
Dihydroergotamine Formulations in Primates
[0153] The study described herein is designed to assess the
pharmacokinetics of plasma dihydroergotamine (DHE) and 8'-hydroxy
DHE levels after intranasal administration using DHE powder
formulations described herein, and to compare the pharmacokinetic
profiles achieved via intranasal administration of such
formulations with those of comparative DHE formulations
administered via various dosing routes.
[0154] The study utilizes Cynomolgus monkeys (Macaca fascicularis,
purpose bred) because the nasal cavity of such monkeys is
morphologically similar to that in humans, and is commonly used as
an experimental animal.
[0155] Methods.
[0156] Animals.
[0157] Six male Cynomolgus monkeys (Macaca fascicularis, purpose
bred), 4 to 6 years old are used, following accredited animal
welfare standards.
[0158] Test Powder Formulations.
[0159] Powder formulations containing 0.1 mg DHE, 0.5 mg DHE and
1.0 mg DHE, as described in the Examples, above, and summarized in
Table 3, above, are tested. With respect to the 0.5 mg DHE
formulation, a 25 mg single nostril dose is tested, as is a 12.5 mg
two-nostril dose (total dose=25 mg). Powder formulations containing
0.5 mg DHE containing 1.25 mg anhydrous caffeine and 1.0 mg DHE
containing 2.5 mg anhydrous caffeine, as summarized in Table xxx,
above, are also tested. With respect to each of the 0.5 mg DHE
formulations, a 25 mg single nostril dose is tested, as is a 12.5
mg two-nostril dose (total dose=25 mg). The powder formulations are
encapsulated as described in the Examples above, and are
administered using a Fit-lizer.TM. intranasal dispenser (SNBL,
LTD).
[0160] Comparative Formulations:
[0161] The following formulations and routes of administration are
tested for comparison purposes: IM DHE solution: 0.1 mg DHE
mesylate of solution of D.H.E. 45.RTM. (Valeant Pharmaceuticals
North America) for intramuscular (IM) administration; IV DHE
solution: 0.1 mL of D.H.E. 45.RTM. (Valeant Pharmaceuticals North
America) containing 0.1 mg DHE mesylate diluted with water for
injection to 1.0 mL; 0.5 mg IN DHE solution: 0.5 mg DHE mesylate
nasal spray (Migranal.RTM.; Valeant Pharmaceuticals North America);
1.0 mg IN DHE solution: 1.0 mg DHE mesylate nasal spray
(Migranal.RTM.; Valeant Pharmaceuticals North America); and 0.1 mg
IN DHE solution: 0.1 mg DHE mesylate (Migranal.RTM. diluted to 0.1
mg concentration with saline).
[0162] Dosing.
[0163] The dose levels of the DHE powder formulations are set at
levels equivalent to clinical doses of 0.1, 0.5, and 1.0 mg/body.
As comparisons, the doses of the comparative formulations include
ones set at the same levels as clinical doses of 1.0 mg/body for
injection (IV and IM) and 0.5 mg/nostril for intranasal
administration.
[0164] Powder DHE formulations are administered intranasally using
a Fit-lizer.RTM. dispenser as noted above, and administration is
confirmed by use of a breath monitoring device while holding the
other nostril closed.
[0165] Intranasal solutions are administered using a device
manually actuated to deliver substance, and administration is
confirmed by use of a breath monitoring device while holding the
other nostril closed.
[0166] Intramuscular injections are performed into the brachial
muscle using a disposable needle and syringe.
[0167] Intravenous injections are administered into the cephalic
vein of the forearm using a disposable needle and syringe.
Volume/amount administered per dose: 1.0 mL.
[0168] Sampling.
[0169] Blood sampling for pharmacokinetic analyses is performed
each dosing day. The sampling points are as follows: Before dosing,
2, 5, 10, 15, 20, 30, 45, 60, 120, 180, 240 and 480 minutes after
dosing (total: 13 points). In certain instances a 14.sup.th point
at 25 minutes after dosing is also performed. Blood is drawn from
the femoral vein with a syringe containing heparin sodium. The
blood is immediately cooled on ice, centrifuged (4.degree. C., 1710
cg, 3000 rpm, 15 minutes), and the plasma is stored in a deep
freezer (-70.degree. C. or below).
[0170] Pharmacokinetic Analysis.
[0171] An LC/MS/MS analytical method is utilized for determination
of DHE and 8'-hydroxy-DHE concentrations in plasma samples.
C.sub.max, T.sub.max, AUC.sub.0-t and T.sub.1/2 parameters are
measured.
[0172] 6.2.1 Results
[0173] Table 4 depicts the C.sub.max, T.sub.max, and AUC results
from intranasal dosing of cynomolgous monkeys with 0.5 mg DHE
mesylate nasal spray, that is, Migranal (liquid formulation) and
the DHE powder formulations described in Example 1. The
corresponding PK curves of DHE in monkey plasma after intranasal
dosing with 0.5 mg of Migranal and 0.1, 0.5 and 1.0 mg of the
intranasal DHE powder are shown in FIGS. 1 and 2. The data in Table
4 and FIGS. 1 and 2 show that the intranasal powder formulation
maintains a short T.sub.max (17.5-30 min) over all doses tested. In
this example, the AUC.sub.0-t (i.e., AUC.sub.0-480 minutes) is
tested 480 minutes after administration of the powder formulation
or Migranal. Additionally, the pharmacokinetic profile of IN powder
DHE is improved over the approved Migranal treatment. Specifically,
the T.sub.max values resulting from the IN powder are shorter than
that resulting from Migranal administration. Additionally, at the
same DHE dose of 0.5 mg, the IN powder produces a 30% increase in
DHE C.sub.max over Migranal. This improved PK is also reflected in
FIG. 3, which shows that the DHE AUC in the first 30 minutes
post-dosing is higher in monkeys when dosed with IN powder vs.
Migranal.
TABLE-US-00004 TABLE 4 PK parameters of DHE in cynomolgous monkeys
after intranasal dosing C.sub.max AUC.sub.0-t AUC.sub.0-inf
T.sub.max (ng/ml) (ng h/mL) (ng h/mL) (min) IN Powder (0.1 mg) 1.82
5.01 5.72 17.5 IN Powder (0.5 mg) 6.00 18.76 22.25 30.0 IN Powder
(1.0 mg) 7.59 27.90 33.96 29.0 Migranal (0.5 mg) 4.65 16.20 19.15
45.0
[0174] FIG. 4 shows a comparison of DHE pharmacokinetic plasma
concentration curves when dosed with DHE intranasal powder (0.5 mg
DHE) with and without caffeine. The results shown in FIG. 4 not
only demonstrate that the C.sub.max was increased upon the addition
of caffeine, but the T.sub.max was also lowered. Moreover, the
results in FIG. 5 demonstrate that splitting the dose of DHE
intranasal powder between two nostrils results in an increased DHE
C.sub.max compared to administration of the full dose in one
nostril. FIG. 6 presents plasma DHE concentrations in monkeys over
480 minutes after the tested administrations.
[0175] 6.2.2 Conclusions
[0176] The results of this example demonstrate that intranasal
administration of powder formulations of dihydroergotamine
described herein produce a rapid onset and good exposure to DHE in
primate plasma. When compared with the FDA approved Migranal
intranasal DHE formulation, the IN DHE powder formulations
presented herein produce higher C.sub.max values and shorter
T.sub.max values. Additionally, the exposure within the first 30
minutes post-administration is improved with the IN DHE powder
formulations. The improvement in these PK parameters is
particularly important in the treatment of migraine. Since DHE is
generally administered to relieve an already occurring migraine, a
faster onset and greater exposure to the drug in a short period of
time is an optimal pharmacokinetic profile. Lastly, the plasma
exposure to the drug is even further improved by adding caffeine to
the IN DHE powder formulation and/or splitting the dose between two
nostrils. These improvements in PK allow for administration of a
lower dose of DHE to achieve therapeutically effective plasma
levels.
6.3 Example 3: A Randomized, Open-Label, 5-Way Crossover Study to
Evaluate the Pharmacokinetics, Dose Proportionality, Safety, and
Tolerability of Single Doses of Dihydroergotamine 1, 1.5, 2 and 3
.mu.mg Intranasal Powder and Assess the Relative Bioavailability to
Dihydroergotamine 1 .mu.mg Administered Subcutaneously as a
Solution in Healthy Volunteers
[0177] The study described herein is designed to determine the
pharmacokinetic profile, dose-proportionality, safety and
tolerability of DHE intranasal powder 1 mg, 1.5 mg, 2 mg and 3 mg
in young healthy subjects and compare its bioavailability with DHE
1 mg administered subcutaneously as a solution. The
pharmacokinetics of DHE and its metabolite
(8'-.beta.-hydroxydihydroergotamine; 8'-.beta.-OH-DHE) are
characterized in this study.
[0178] Methodology.
[0179] This is a single-center, single-dose, randomized,
open-label, 5-way crossover, pharmacokinetic and safety study.
Thirty (30) eligible subjects, not less than 40% or more than 60%
of either gender, receive study medication in each of 5 treatment
periods. Subjects are randomly assigned to one of the 5 treatment
sequences in accordance with a predetermined randomization
schedule. The 5 treatment sequences are as follows in Table 5:
TABLE-US-00005 TABLE 5 Period 1 Period 2 Period 3 Period 4 Period 5
Sequence Treatment Treatment Treatment Treatment Treatment 1 A E B
C D 2 B A C D E 3 C B D E A 4 D C E A B 4 E D A B C Treatment A =
DHE 1 mg IN powder Treatment B = DHE 1.5 mg IN powder Treatment C =
DHE 2 mg IN powder Treatment D = DHE 3 mg IN powder Treatment E =
DHE 1 mg SC solution
[0180] During each treatment period, subjects are confined for 36
hours approximately. Subjects are admitted in the early evening
before dosing of the each treatment period (approximately 12 hours
before drug administration) and remain in the clinical research
unit until approximately 24 hours post-dose.
[0181] Study drug is administered in the morning, after an
overnight fast of at least 10 hours. Multiple blood samples for PK
analysis are drawn over 24 hours. A standardized lunch is provided
within 4 to 5 hours after dosing. A standardized dinner is provided
at approximately 1800 hours.
[0182] There is a washout period of not less than 7 days between
treatment periods. The duration of the washout period is measured
from the last day of the preceding period (approximately 24 hours
post-dose) to dosing day of the subsequent period.
[0183] A safety follow-up visit takes place 7.+-.2 days after the
last treatment period.
[0184] Patient Inclusion Criteria.
[0185] A subject is eligible for inclusion in this study only if
all of the following criteria apply: [0186] Young healthy males or
females, 18-45 years (inclusive) of age at the time of enrollment,
who have provided signed Informed Consent and, if applicable, HIPAA
authorization. [0187] Healthy as judged by a responsible physician
with no clinically significant abnormality identified on the
medical or laboratory evaluation, including 12-lead ECG. A subject
with a clinical abnormality or laboratory parameters outside the
reference range for this age group may be included only if the
Investigator considers that the finding will not introduce
additional risk factors and will not interfere with the study
procedures. [0188] Subjects with a body mass index (BMI) .gtoreq.18
and .ltoreq.32 kg/m.sup.2. [0189] Female subjects are included if
they are post-menopausal or sterilized; or if they are of
childbearing potential, they are not breastfeeding, have a negative
pregnancy test, have no intention of becoming pregnant during the
course of the study and are using adequate contraceptive drugs or
devices during the course of this study. Medically acceptable
methods of contraception that may be used by the subject and/or her
partner are: oral contraceptives, progestin injection or implants,
condom with spermicide, diaphragm with spermicide, IUD, vaginal
spermicidal suppository combined with another barrier method of
contraception (condom, diaphragm), hormonal patch and vaginal ring,
surgical sterilization of their partner(s) or abstinence. Females
using oral contraception must have started using the medication at
least 4 weeks prior to screening. Surgical sterilization of
partners must have occurred at least 6 weeks prior to screening.
[0190] Non-smokers (refrained from any tobacco usage, including
smokeless tobacco, nicotine patches, etc., for 6 months prior to
the administration of the study medication). [0191] Subjects with
intact nasal mucosa (no erythema, no inflammation, no ulceration,
no swelling, no bleeding, no atrophy (severe local dryness and/or
crusting), no septal perforation, and no other nasal conditions
that may interfere with IN dosing. [0192] Subjects who are willing
to abstain from alcohol for the 24 hours prior to first dose of
study drug until the end of the blood sampling period after the
last treatment period. [0193] Subjects who are willing and able to
comply with the requirements of the protocol and follow directions
from the clinic staff. [0194] Subjects who are willing to avoid the
consumption of grapefruit, pomelo and Seville orange products and
juices within 24 hours prior to dosing of study drug until the end
of the study.
[0195] Patient Exclusion Criteria.
[0196] A subject is excluded from this study if any of the
following criteria apply: [0197] Any clinically significant central
nervous system (e.g., seizures), cardiac, pulmonary, metabolic,
renal, hepatic or gastrointestinal conditions or history of such
conditions that, in the opinion of the investigator may place the
subject at an unacceptable risk as a participant in this trial or
may interfere with the absorption, distribution, metabolism or
excretion of drugs. [0198] Abnormal physical findings of clinical
significance at the screening examination or baseline which would
interfere with the objectives of the study. [0199] History of
serious adverse reactions or hypersensitivity to any drug, or who
are known to be allergic to any of the test product(s) or any
components in the test product(s) or history of hypersensitivity or
allergic reactions to any of the study preparations as described in
the Investigator's Brochure. [0200] Clinically significant abnormal
laboratory values (as determined by the Principal Investigator) at
the screening evaluation. [0201] 12 lead ECG obtained at screening
with: PR >240 msec, QRS>110 msec and QTc 430 msec,
bradycardia (<50 bpm) or clinically significant minor ST wave
changes on the screening ECG, or any other changes on the screening
ECG that would interfere with measurement of the QT interval.
[0202] History of orthostatic hypotension or orthostatic
hypertension present at screening. [0203] Presence of an acute
medical condition (e.g., diarrhea, fever, upper respiratory viral
infection) within 14 days of first dosing in this study that is
judged by the investigator to be clinically significant. [0204]
Presence or history of allergies requiring acute or chronic
treatment (except seasonal allergic rhinitis). [0205] Symptoms of a
significant somatic or mental illness in the four week period
preceding drug administration [0206] History or presence of
migraine attacks in the last year. [0207] Surgical interventions
within 6 months of the study. [0208] Has a positive pre-study
Hepatitis B surface antigen; positive hepatitis C (HCV) antibody or
detectable HCV ribonucleic acid (RNA); or positive HIV antibody
result. [0209] History of sensitivity to 5-HT.sub.1B/D receptor
agonists or to heparin (if the clinical research unit uses heparin
to maintain intravenous cannula patency). [0210] Use of any
prescription (e.g., ergotamine containing or ergot type medications
(e.g., dihydroergotamine), or another 5-HT.sub.1B/D receptor
agonists), or nonprescription medications, including vitamins and
natural, herbal and dietary supplements within 7 days or 5
half-lives (whichever is longer) prior to the first dose of study
medication, or use of St. John's Wort within 28 days prior to the
first dose of study medication. However, the Investigator and study
team can review medication use on a case by case basis to determine
if its use would compromise subject safety or interfere with study
procedures or data interpretation. By exception, the volunteer may
take paracetamol or acetaminophen (.ltoreq.2 g/day) or ibuprofen
(1600 mg/day) up to 48 hours prior to the first dose of study
medication. [0211] Subjects who use or have used other systemic
prescription medications, or any drugs (or herbal preparations)
known to inhibit CYP1A2 (for example fluvoxamine), CYP2D6 (for
example paroxetine, quinidine and fluoxetine), or CYP3A (for
example clarithromycin, itraconazole, ketoconazole, indinavir and
erythromycin) or induce CYP1A2 (for example rifampin) or CYP3A (for
example rifampin and carbamazepine) within 28 days prior to dosing.
[0212] History of drug abuse or dependence within 12 months of the
study. [0213] Has a history of regular alcohol consumption
averaging >14 drinks/week (1 drink (12 g alcohol)=5 ounces (150
ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of
80 proof distilled spirits) within 6 months of the screening visit.
[0214] Loss of 500 ml blood or more during the 3 month period
before the study, e.g. blood donor. [0215] The subject has a
positive pre-study alcohol or urine drug screen. A minimum list of
drugs that will be screened for include Amphetamines, Barbiturates,
Cocaine, Opiates, Cannabinoids and Benzodiazepines. (Suspected
false positive results may be repeated at the discretion of the
Principal Investigator.) [0216] Concurrent participation in another
drug research study or within 60 days of enrollment. [0217]
Considered by the Investigator to be unsuitable candidate for this
study.
[0218] Outcome Measures.
[0219] Pharmacokinetics.
[0220] Pharmacokinetic sample collection: a total of 20 blood
samples (6 mL each) are collected at the following times: 0
(pre-dose), 5, 10, 15, 20, 25, 30, 35, 40, and 45 minutes, and 1,
1.5, 2, 3, 4, 6, 8, 12, 18 and 24 hours post-dose.
[0221] Safety/Tolerability.
[0222] The following assessment and measurements are conducted
prior to dosing and/or at periodic intervals following dosing for
up to 24 hours. [0223] 1. Physical examination [0224] 2. Vitals
signs and body weight [0225] 3. 12-lead ECG [0226] 4. Blood tests
for hematology and biochemistry analysis [0227] 5. Urinalysis
[0228] 6. Adverse events (AEs) [0229] 7. Review of non-study
medications received [0230] 8. Subjective assessment of nasal
irritation: a questionnaire, answered by the subject, concerning
the presence of various symptoms related to the nose [0231] 9.
Brief Smell Identification Test (B-SIT.TM.), a standardized test of
olfactory function. [0232] 10. Objective assessment of nasal
irritation: a structures examination of the nasal cavity and
mucosal integrity. [0233] 11. Endoscopic examination of the nose if
any clinical significant abnormalities were observed in any of the
above 3 assessments. [0234] 12. Suicidal evaluation with the
Columbia Suicide-Severity Rating Scale (C-SSRS).
[0235] Main Statistical Methods.
[0236] Pharmacokinetics.
[0237] The following pharmacokinetic parameters are calculated for
both DHE and its major metabolite,
8'-.beta.-hydroxydihydroergotamine, using standard noncompartmental
analysis: [0238] 1. Area under the concentration-time curves
(AUC.sub.0-.infin., and AUC.sub.0-t) [0239] 2. Maximum observed
plasma concentration (C.sub.max) [0240] 3. Time to reach C.sub.max
(T.sub.max) [0241] 4. Terminal half-life (t.sub.1/2) [0242] 5.
Terminal rate constant (kel) [0243] 6. Ratio of AUC.sub.0-t to
AUC.sub.0-.infin., (AUC.sub.0-t/0-.infin.)
[0244] Statistical analyses are performed using SAS.RTM.. All PK
parameters are calculated using the actual post-dose blood sampling
times. Each time point is evaluated separately relative to the
baseline value. Descriptive statistics [N, mean, standard deviation
(SD), minimum, median, maximum and coefficient of variation (CV)]
are used to summarize the PK parameters for each treatment.
[0245] The study endpoints are: [0246] 1. Pharmacokinetics and dose
proportionality of DHE 1 mg, 1.5 mg, 2 mg and 3 mg intranasal
powder. Dose proportionality will be determined by comparing
AUC.sub.0-.infin., AUC.sub.0-t and C.sub.max as estimated from
plasma DHE and 8'-.beta.-OH-DHE concentration profiles (Treatments
A to D). [0247] 2. Pharmacokinetics of DHE 1 mg solution
administered subcutaneously (Treatment E). [0248] 3. Relative
bioavailability of the DHE 1 mg intranasal powder will be
determined by comparing the AUC.sub.0-t, AUC.sub.0-.infin. and
C.sub.max of the intranasal powder (Treatment A) to those of the
DHE 1 mg subcutaneous solution (Treatment E). [0249] 4. Safety and
tolerability of DHE in healthy adults following intranasal powder
administration (Treatments A to D). [0250] 5. Examination and
reporting of all safety measures (i.e. adverse events, vital signs
and lab parameters) for all treatments in the study.
[0251] The relative bioavailability of the DHE intranasal powder
vs. subcutaneous solution is determined by examining the 90%
confidence interval for the ratios of the test group (Treatment A)
mean ln-transformed AUC.sub.0-t, AUC.sub.0-.infin. and C.sub.max,
relative to the reference group means (Treatment E).
[0252] Dose proportionality within Treatments A and D, is assessed
by fitting the estimates of the ln-transformed parameters
AUC.sub.0-.infin., AUC.sub.0-t and C.sub.max for both dose levels
to the power model. Individual slopes are derived for each subject.
The power model is fitted with log (dose) at fixed effect and
subjects as a random effect. The estimated mean slope and 90%
confidence intervals are constructed for each parameter. The
primary criterion for dose proportionality for AUC.sub.0-.infin.,
AUC.sub.0-t and C.sub.max is the inclusion of 1 within the range of
the CIs, indicating the slope did not deviate significantly from
1.
[0253] Safety:
[0254] Safety analyses are conducted for the safety population
which is defined as any volunteer who received study
medication.
[0255] Safety labs including CBC, chemistry and urinalysis findings
are collected at baseline and end of each treatment period. Results
from laboratory analyses are tabulated using descriptive
statistics. A tabulation of by-volunteer abnormal/out-of-range
findings is provided and changes from baseline to End of Period in
all laboratory variables are tabulated.
[0256] A standard 12-lead ECG is obtained at screening, at the
beginning and at the end of each treatment period and in the safety
follow-up visit at the end of the study. A tabulation of
by-volunteer abnormal/out-of-range findings is provided and changes
from baseline to End of Study variables are tabulated.
6.4 Example 4: A Randomized, Open-Label, 5-Way Crossover Study to
Evaluate the Pharmacokinetics, Bioavailability, Safety, and
Tolerability of Single Doses of Dihydroergotamine 0.5 .mu.Mg and 1
.mu.Mg Intranasal Powder and Dihydroergotamine 0.5 .mu.Mg
Administered Intravenously, Intramuscularly and Intranasally as a
Solution in Healthy Volunteers
[0257] The study described herein is designed to determine the
pharmacokinetic profile of DHE and its 8'-hydroxy-DHE metabolite,
safety and tolerability of DHE intranasal powder 0.5 mg and 1 mg in
young healthy subjects and compare its bioavailability with DHE 0.5
mg administered intravenously, intramuscularly or as an intranasal
solution.
[0258] Methodology.
[0259] This is a single-center, single-dose, randomized,
open-label, 5-way crossover, pharmacokinetic and safety study.
Thirty (30) eligible subjects, not less than 40% or more than 60%
of either gender, receive study medication in each of 5 treatment
periods. Subjects are randomly assigned to one of the 5 treatment
sequences in accordance with a predetermined randomization
schedule. The 5 treatment sequences are as follows in Table 6:
TABLE-US-00006 TABLE 6 Period 1 Period 2 Period 3 Period 4 Period 5
Sequence Treatment Treatment Treatment Treatment Treatment 1 A E B
C D 2 B A C D E 3 C B D E A 4 D C E A B 4 E D A B C Treatment A =
DHE 0.5 mg IN powder Treatment B = DHE 1 mg IN powder Treatment C =
DHE 0.5 mg IN solution Treatment D = DHE 0.5 mg IM solution
Treatment E = DHE 0.5 mg IV solution
[0260] During each treatment period, subjects are confined for 36
hours approximately. Subjects are admitted in the early evening
before dosing of the each treatment period (approximately 12 hours
before drug administration) and remain in the clinical research
unit until approximately 24 hours post-dose.
[0261] Study drug is administered in the morning, after an
overnight fast of at least 10 hours. Multiple blood samples for PK
analysis are drawn over 24 hours. A standardized lunch is provided
within 4 to 5 hours after dosing. A standardized dinner is provided
at approximately 1800 hours.
[0262] There is a washout period of not less than 7 days between
treatment periods. The duration of the washout period is measured
from the last day of the preceding period (approximately 24 hours
post-dose) to dosing day of the subsequent period.
[0263] A safety follow-up visit takes place 7.+-.2 days after the
last treatment period.
[0264] Patient Inclusion Criteria.
[0265] A subject is eligible for inclusion in this study only if
all of the following criteria apply: [0266] Young healthy males or
females, 18-45 years (inclusive) of age at the time of enrollment,
who have provided signed Informed Consent and, if applicable, HIPAA
authorization. [0267] Healthy as judged by a responsible physician
with no clinically significant abnormality identified on the
medical or laboratory evaluation, including 12-lead ECG. A subject
with a clinical abnormality or laboratory parameters outside the
reference range for this age group may be included only if the
Investigator considers that the finding will not introduce
additional risk factors and will not interfere with the study
procedures. [0268] Subjects with a body mass index (BMI) .gtoreq.18
and .ltoreq.32 kg/m.sup.2. [0269] Female subjects are included if
they are post-menopausal or sterilized; or if they are of
childbearing potential, they are not breastfeeding, have a negative
pregnancy test, have no intention of becoming pregnant during the
course of the study and are using adequate contraceptive drugs or
devices during the course of this study. Medically acceptable
methods of contraception that may be used by the subject and/or her
partner are: oral contraceptives, progestin injection or implants,
condom with spermicide, diaphragm with spermicide, IUD, vaginal
spermicidal suppository combined with another barrier method of
contraception (condom, diaphragm), hormonal patch and vaginal ring,
surgical sterilization of their partner(s) or abstinence. Females
using oral contraception must have started using the medication at
least 4 weeks prior to screening. Surgical sterilization of
partners must have occurred at least 6 weeks prior to screening.
[0270] Non-smokers (refrained from any tobacco usage, including
smokeless tobacco, nicotine patches, etc., for 6 months prior to
the administration of the study medication). [0271] Subjects with
intact nasal mucosa (no erythema, no inflammation, no ulceration,
no swelling, no bleeding, no atrophy (severe local dryness and/or
crusting), no septal perforation, and no other nasal conditions
that may interfere with IN dosing. [0272] Subjects who are willing
to abstain from alcohol for the 24 hours prior to first dose of
study drug until the end of the blood sampling period after the
last treatment period. [0273] Subjects who are willing and able to
comply with the requirements of the protocol and follow directions
from the clinic staff. [0274] Subjects who are willing to avoid the
consumption of grapefruit, pomelo and Seville orange products and
juices within 24 hours prior to dosing of study drug until the end
of the study.
[0275] Patient Exclusion Criteria.
[0276] A subject is ineligible for inclusion in this study if any
of the following criteria apply: [0277] Any clinically significant
central nervous system (e.g., seizures), cardiac, pulmonary,
metabolic, renal, hepatic or gastrointestinal conditions or history
of such conditions that, in the opinion of the investigator may
place the subject at an unacceptable risk as a participant in this
trial or may interfere with the absorption, distribution,
metabolism or excretion of drugs. [0278] Abnormal physical findings
of clinical significance at the screening examination or baseline
which would interfere with the objectives of the study. [0279]
History of serious adverse reactions or hypersensitivity to any
drug, or who are known to be allergic to any of the test product(s)
or any components in the test product(s) or history of
hypersensitivity or allergic reactions to any of the study
preparations as described in the Investigator's Brochure. [0280]
Clinically significant abnormal laboratory values (as determined by
the Principal Investigator) at the screening evaluation. [0281] 12
lead ECG obtained at screening with: PR >240 msec, QRS>110
msec and QTc 430 msec, bradycardia (<50 bpm) or clinically
significant minor ST wave changes on the screening ECG, or any
other changes on the screening ECG that would interfere with
measurement of the QT interval. [0282] History of orthostatic
hypotension or orthostatic hypertension present at screening.
[0283] Presence of an acute medical condition (e.g., diarrhea,
fever, upper respiratory viral infection) within 14 days of first
dosing in this study that is judged by the investigator to be
clinically significant. [0284] Presence or history of allergies
requiring acute or chronic treatment (except seasonal allergic
rhinitis). [0285] Symptoms of a significant somatic or mental
illness in the four week period preceding drug administration
[0286] History or presence of migraine attacks in the last year.
[0287] Surgical interventions within 6 months of the study. [0288]
Has a positive pre-study Hepatitis B surface antigen; positive
hepatitis C (HCV) antibody or detectable HCV ribonucleic acid
(RNA); or positive HIV antibody result. [0289] History of
sensitivity to 5-HT.sub.1B/D receptor agonists or to heparin (if
the clinical research unit uses heparin to maintain intravenous
cannula patency). [0290] Use of any prescription (e.g., ergotamine
containing or ergot type medications (e.g., dihydroergotamine), or
another 5-HT.sub.1B/D receptor agonists), or nonprescription
medications, including vitamins and natural, herbal and dietary
supplements within 7 days or 5 half-lives (whichever is longer)
prior to the first dose of study medication, or use of St. John's
Wort within 28 days prior to the first dose of study medication.
However, the Investigator and study team can review medication use
on a case by case basis to determine if its use would compromise
subject safety or interfere with study procedures or data
interpretation. By exception, the volunteer may take paracetamol or
acetaminophen (.ltoreq.2 g/day) or ibuprofen (1600 mg/day) up to 48
hours prior to the first dose of study medication. [0291] Subjects
who use or have used other systemic prescription medications, or
any drugs (or herbal preparations) known to inhibit CYP1A2 (for
example fluvoxamine), CYP2D6 (for example paroxetine, quinidine and
fluoxetine), or CYP3A (for example clarithromycin, itraconazole,
ketoconazole, indinavir and erythromycin) or induce CYP1A2 (for
example rifampin) or CYP3A (for example rifampin and carbamazepine)
within 28 days prior to dosing. [0292] History of drug abuse or
dependence within 12 months of the study. [0293] Has a history of
regular alcohol consumption averaging >14 drinks/week (1 drink
(12 g alcohol)=5 ounces (150 ml) of wine or 12 ounces (360 ml) of
beer or 1.5 ounces (45 ml) of 80 proof distilled spirits) within 6
months of the screening visit. [0294] Loss of 500 ml blood or more
during the 3 month period before the study, e.g. blood donor.
[0295] The subject has a positive pre-study alcohol or urine drug
screen. A minimum list of drugs that will be screened for include
Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and
Benzodiazepines. (Suspected false positive results may be repeated
at the discretion of the Principal Investigator.) [0296] Concurrent
participation in another drug research study or within 60 days of
enrollment. [0297] Considered by the Investigator to be unsuitable
candidate for this study.
[0298] Outcome Measures.
[0299] Pharmacokinetics:
[0300] Pharmacokinetic sample collection: a total of 20 blood
samples (6 mL each) are collected at the following times: 0
(pre-dose and immediately post-dose in the IV arm), 5, 10, 15, 20,
25, 30, 35, 40, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 18
and 24 hours post-dose.
[0301] Safety/Tolerability:
[0302] The following assessment and measurements will be conducted
prior to dosing and/or at periodic intervals following dosing for
up to 24 hours. [0303] Physical examination [0304] Vitals signs and
body weight [0305] 12-lead ECG [0306] Blood tests for hematology
and biochemistry analysis [0307] Urinalysis [0308] Adverse events
(AEs) [0309] Review of non-study medications received [0310]
Subjective assessment of nasal irritation: a questionnaire,
answered by the subject, concerning the presence of various
symptoms related to the nose [0311] Brief Smell Identification Test
(B-SIT.TM.), a standardized test of olfactory function. [0312]
Objective assessment of nasal irritation: a structures examination
of the nasal cavity and mucosal integrity. [0313] Endoscopic
examination of the nose if any clinical significant abnormalities
were observed in any of the above 3 assessments. [0314] Suicidal
evaluation with the Columbia Suicide-Severity Rating Scale
(C-SSRS).
[0315] Main Statistical methods (including required subject number
requirement):
[0316] Pharmacokinetics.
[0317] The following pharmacokinetic parameters are calculated for
both DHE and its major metabolite,
8'-.beta.-hydroxydihydroergotamine, using standard noncompartmental
analysis: [0318] 1. Area under the concentration-time curves
(AUC.sub.0-.infin., and AUC.sub.0-t) [0319] 2. Maximum observed
plasma concentration (C.sub.max) [0320] 3. Time to reach C.sub.max
(T.sub.max) [0321] 4. Terminal half-life (t.sub.1/2) [0322] 5.
Terminal rate constant (kel) [0323] 6. Ratio of AUC.sub.0-t to
AUC.sub.0-.infin. (AUC.sub.0-t/0-.infin.)
[0324] Statistical analyses are performed using SAS.RTM.. Plasma
concentrations and pharmacokinetic parameters are summarized
descriptively by treatment group and time point, where appropriate.
All PK parameters are calculated using the actual post-dose blood
sampling times. Each time point is evaluated separately relative to
the baseline value. Descriptive statistics [N, mean, standard
deviation (SD), minimum, median, maximum and coefficient of
variation (CV)] are used to summarize the PK parameters for each
treatment.
[0325] The study endpoints are: [0326] 1. Pharmacokinetics and dose
proportionality of DHE 0.5 and 1 mg intranasal powder. Dose
proportionality is determined by comparing AUC.sub.0-.infin.,
AUC.sub.0-t and C.sub.max as estimated from plasma DHE and
8'-.beta.-OH-DHE concentration profiles (Treatments A and B).
[0327] 2. Pharmacokinetics of DHE 0.5 mg solution administered
intravenously, intramuscularly and intranasally (Treatments C, D
and E). [0328] 3. Absolute and relative bioavailability of the DHE
0.5 mg intranasal powder are determined by comparing the
AUC.sub.0-t, AUC.sub.0-.infin. and C.sub.max of the intranasal
powder (Treatment A) to those of the DHE 0.5 mg intravenous,
intramuscular and intranasal solutions (Treatments C, D and E).
[0329] 4. Safety and tolerability of DHE in healthy adults
following intranasal powder administration (Treatments A and B).
[0330] 5. Examination and reporting of all safety measures (i.e.
adverse events, vital signs and lab parameters) for all treatments
in the study.
[0331] The absolute and relative bioavailability of the DHE
intranasal powder vs. intravenous and intramuscular and intranasal
solution are determined by examining the 90% confidence interval
for the ratios of the test group (Treatment A) mean ln-transformed
AUC.sub.0-t, AUC.sub.0-.infin. and C.sub.max, relative to the
reference group means (Treatments C, D, and E).
[0332] Dose proportionality within Treatments A and B, are assessed
by fitting the estimates of the ln-transformed parameters
AUC.sub.0-.infin., AUC.sub.0-t and C.sub.max for both dose levels
to the power model. Individual slopes will be derived for each
subject. The power model is fitted with log (dose) at fixed effect
and subjects as a random effect. The estimated mean slope and 90%
confidence intervals are constructed for each parameter. The
primary criterion for dose proportionality for AUC.sub.0-.infin.,
AUC.sub.0-t and C.sub.max is the inclusion of 1 within the range of
the CIs, indicating the slope did not deviate significantly from
1.
[0333] Safety.
[0334] Safety analyses are conducted for the safety population
which is defined as any volunteer who received study
medication.
[0335] All adverse events reported during the study are listed,
documenting course, severity, possible relationship to study
medication and outcome. Verbatim terms on the case report forms are
classified to preferred terms and related system organ class using
the MedDRA dictionary. The preferred terms and system organ classes
are tabulated by treatment group and study period. All reported
adverse events are summarized by the number of volunteers reporting
adverse events, system organ class, preferred term, severity and
relationship to study drug. All adverse events are presented in
data listings indexed by volunteer.
[0336] Safety labs including CBC, chemistry and urinalysis findings
are collected at baseline and end of each treatment period. Results
from laboratory analyses are tabulated using descriptive
statistics. A tabulation of by-volunteer abnormal/out-of-range
findings is provided and changes from baseline to End of Period in
all laboratory variables are tabulated.
[0337] A standard 12-lead ECG is obtained at screening, at the
beginning and at the end of each treatment period and in the safety
follow-up visit at the end of the study. A tabulation of
by-volunteer abnormal/out-of-range findings is provided and changes
from baseline to End of Study variables are tabulated.
6.5 Example 5: Treatment of Migraine with Dihydroergotamine
Intranasal Powder Formulation
[0338] The DHE nasal powder formulation is indicated for rapid
onset treatment of acute migraine with or without aura. Patients
are instructed to use the product when they have an active migraine
headache. Specifically, prior to use, patients are instructed to
blow their nose gently to help open the nasal passages. If the
entire dose is to be delivered in a single nostril, the patient is
instructed to select the nostril with the better airflow. Some
physicians may consider using the DHE nasal powder in their office
or in a medical setting. The total amount of DHE in a single dose
ranges from about 0.1 to 10 mg. Typically, a patient receives a
dose of about 1.0 to 2.0 mg. DHE nasal powder with or without
caffeine may be administered to the patient.
[0339] DHE Nasal Powder Presentation.
[0340] The DHE nasal powder formulation is delivered using a
dispenser. The dispenser primarily consists of a squeeze bottle
with a nozzle approximately half an inch long. The squeeze bottle
functions as a pump and the nozzle, which normally holds the powder
at its base, also targets and guides the delivery of the powder
into the nostril. The squeeze bottle can be configured as a
disposable single-unit dose delivery system or a multiple dose
delivery. It can also be configured to be refilled with the powder
once the pre-filled dispenser is fully used. The dispenser
containing the formulation can also be configured to deliver each
dose in a single or a double puff without priming. The powder from
the dispenser can be administered in either nostril or both
nostrils.
[0341] Exclusions.
[0342] Patients are instructed not to use the product to prevent a
headache if they have no prodromal symptoms of migraine such as
changes in mental state including irritability or confusion, and
physical signs including thirst or diarrhea. Any migraine patient
who is pregnant or nursing, has any cardiovascular diseases, or
taking anti-HIV medications, or taking macrolide antibiotic such as
troleandomycin, clarithromycin or erythromycin is instructed not to
use the DHE nasal powder formulation. Similarly, migraine patients
taking triptans are instructed not to use the DHE nasal powder and
conversely, patients using the DHE nasal powder are instructed not
to simultaneously use triptans for the treatment of migraine.
INCORPORATION BY REFERENCE
[0343] Various references such as patents, patent applications, and
publications are cited herein, the disclosures of which are hereby
incorporated by reference herein in their entireties. In the event
of a conflict between a term herein and a term incorporated by
reference, the term herein controls.
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