U.S. patent application number 16/420051 was filed with the patent office on 2019-09-05 for intranasal epinephrine formulations and methods for the treatment of disease.
The applicant listed for this patent is Aegis Therapeutics, LLC, ARS PHARMACEUTICALS INC.. Invention is credited to Robert G. BELL, Richard LOWENTHAL, Edward T. MAGGIO, Pratik SHAH.
Application Number | 20190269782 16/420051 |
Document ID | / |
Family ID | 67548575 |
Filed Date | 2019-09-05 |
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United States Patent
Application |
20190269782 |
Kind Code |
A1 |
LOWENTHAL; Richard ; et
al. |
September 5, 2019 |
INTRANASAL EPINEPHRINE FORMULATIONS AND METHODS FOR THE TREATMENT
OF DISEASE
Abstract
Drug products adapted for nasal delivery comprising formulations
with epinephrine and devices comprising such formulations are
provided. Methods of treating anaphylaxis with epinephrine products
are also provided.
Inventors: |
LOWENTHAL; Richard; (San
Diego, CA) ; MAGGIO; Edward T.; (San Diego, CA)
; BELL; Robert G.; (San Diego, CA) ; SHAH;
Pratik; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARS PHARMACEUTICALS INC.
Aegis Therapeutics, LLC |
San Diego
San Diego |
CA
CA |
US
US |
|
|
Family ID: |
67548575 |
Appl. No.: |
16/420051 |
Filed: |
May 22, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2019/016918 |
Feb 6, 2018 |
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16420051 |
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15890131 |
Feb 6, 2018 |
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PCT/US2019/016918 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/7016 20130101;
A61K 9/0056 20130101; A61K 31/485 20130101; A61K 47/26 20130101;
A61K 9/0043 20130101; A61K 9/006 20130101; A61K 9/0048
20130101 |
International
Class: |
A61K 47/26 20060101
A61K047/26; A61K 31/7016 20060101 A61K031/7016; A61K 31/485
20060101 A61K031/485 |
Claims
1. A nasal spray pharmaceutical formulation comprising between
about 0.40 mg and about 2.4 mg of epinephrine, or a salt thereof,
in a single dose of the nasal spray pharmaceutical formulation;
wherein the nasal spray pharmaceutical formulation is an aqueous
solution; and wherein intranasal administration of a single dose of
the nasal spray pharmaceutical formulation to a subject provides
intramuscular (IM)-injection-like pharmacokinetics of epinephrine
when IM-injection is administered in the lateral thigh, or
subcutaneous (SC)-injection-like absorption of epinephrine when
SC-injection is administered into the subcutaneous layer of the
deltoid region in the upper arm.
2. The nasal spray pharmaceutical formulation of claim 1, wherein
intranasal administration of a single dose of the nasal spray
pharmaceutical formulation to a subject provides subcutaneous
(SC)-like absorption of epinephrine and the SC pharmacokinetic
profile has a C.sub.max of at least 100 pg/mL and AUC.sub.0-240 min
of 150 h*pg/mL.
3. The nasal spray pharmaceutical formulation of claim 1, wherein
intranasal administration of a single dose of the nasal spray
pharmaceutical formulation to a subject provides one or more of the
following pharmacokinetic features: both the mean AUC.sub.0-20 min
and AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.3 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.3 mg intramuscular injection yields;
a mean t.sub.max of less than 45 minutes; or IM-injection like
absorption under optimal dosing conditions in the thigh.
4. The nasal spray pharmaceutical formulation of claim 3, wherein a
single dose of the nasal spray pharmaceutical formulation comprises
about 1.0 mg of epinephrine, or a salt thereof; dodecyl maltoside;
water; and one or more ingredients selected from benzalkonium
chloride, sodium chloride, pH adjusting agents, and
ethylenediaminetetraacetic acid (EDTA), or a salt thereof.
5. The nasal spray pharmaceutical formulation of claim 1, wherein
intranasal administration of a single dose of the nasal spray
pharmaceutical formulation to a subject provides one or more of the
following pharmacokinetic features: both the mean AUC.sub.0-20 min
and AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.15 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.15 mg intramuscular injection
yields; a mean t.sub.max of less than 45 minutes; or IM-injection
like absorption under optimal dosing conditions in the thigh.
6. The nasal spray pharmaceutical formulation of claim 5, wherein a
single dose of the nasal spray pharmaceutical formulation comprises
between about 0.5 mg and about 0.7 mg of epinephrine, or a salt
thereof dodecyl maltoside; water; and one or more ingredients
selected from benzalkonium chloride, sodium chloride, pH adjusting
agents, and ethylenediaminetetraacetic acid (EDTA), or a salt
thereof.
7. The nasal spray pharmaceutical formulation of claim 1, wherein
intranasal administration of a single dose of the nasal spray
pharmaceutical formulation to a subject provides one or more of the
following pharmacokinetic features: both the mean AUC.sub.0-20 min
and AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.5 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.5 mg intramuscular injection yields;
a mean t.sub.max of less than 45 minutes; or IM-injection like
absorption under optimal dosing conditions in the thigh.
8. The nasal spray pharmaceutical formulation of claim 7, wherein a
single dose of the nasal spray pharmaceutical formulation comprises
between about 1.3 mg and about 1.5 mg of epinephrine, or a salt
thereof dodecyl maltoside; water; and one or more ingredients
selected from benzalkonium chloride, sodium chloride, pH adjusting
agents, and ethylenediaminetetraacetic acid (EDTA), or a salt
thereof.
9. The nasal spray pharmaceutical formulation of claim 1, wherein a
single dose of the nasal spray pharmaceutical formulation comprises
between about 0.4 mg and about 2.40 mg of epinephrine, or a salt
thereof, between about 0.1 and about 0.50 mg dodecyl maltoside;
water; and one or more ingredients selected from sodium chloride,
pH adjusting agents, and EDTA, or a salt thereof.
10. The nasal spray pharmaceutical formulation of claim 1, wherein
a single dose of the nasal spray pharmaceutical formulation
comprises between about 0.5 mg and about 2.0 mg per dose
epinephrine, or a salt thereof a combination of dodecyl maltoside
and benzalkonium chloride; water; sodium chloride; optional pH
adjusting agents; and ethylenediaminetetraacetic acid (EDTA), or a
salt thereof.
11. The nasal spray pharmaceutical formulation of claim 10,
wherein: the pH adjustment agent is an acid, a base, a buffer, or a
combination thereof and the nasal spray pharmaceutical formulation
has a pH between about 2.0 and about 6.0.
12. The nasal spray pharmaceutical formulation of claim 10,
wherein: the ethylenediaminetetraacetic acid (EDTA) or a salt
thereof is disodium EDTA.
13. The nasal spray pharmaceutical formulation of claim 1, wherein:
a single dose comprises between about 50 .mu.L and about 200 .mu.L
of the nasal spray pharmaceutical formulation.
14. The nasal spray pharmaceutical formulation of claim 1, wherein:
a single dose comprises about 100 .mu.L of the nasal spray
pharmaceutical formulation.
15. A method for administering epinephrine, or a salt thereof, to a
subject with an acute hypersensitivity reaction comprising the
intranasal administration of epinephrine, or a salt thereof, in an
aqueous nasal spray pharmaceutical formulation, wherein: a single
dose of the aqueous nasal spray pharmaceutical formulation
comprises between about 0.40 mg and about 2.0 mg of epinephrine, or
a salt thereof; intranasal administration a single dose of the
nasal spray pharmaceutical formulation provides a plasma
epinephrine concentration in a subject that is efficacious for the
treatment of an acute hypersensitivity reaction in the subject; and
intranasal administration of a single dose of the nasal spray
pharmaceutical formulation to a subject provides intramuscular
(IM)-injection-like pharmacokinetics of epinephrine when
IM-injection is administered in the lateral thigh, or subcutaneous
(SC)-injection-like absorption of epinephrine when SC-injection is
administered into the subcutaneous layer of the deltoid region in
the upper arm.
16. The method of claim 15, wherein: a single dose of the aqueous
nasal spray pharmaceutical formulation comprises between about 0.40
mg and about 2.0 mg of epinephrine, or a salt thereof; dodecyl
maltoside; water; and one or more ingredients selected from
benzalkonium chloride, sodium chloride, pH adjusting agents, and
ethylenediaminetetraacetic acid (EDTA), or a salt thereof.
17. The method of claim 15, wherein: a single dose of the aqueous
nasal spray pharmaceutical formulation comprises between about 0.40
mg and about 2.0 mg of epinephrine, or a salt thereof; a
combination of dodecyl maltoside and benzalkonium chloride; water;
and one or more ingredients selected from sodium chloride, pH
adjusting agents, and EDTA, or a salt thereof.
18. The method of claim 17, wherein: wherein intranasal
administration of a single dose of the aqueous nasal spray
pharmaceutical formulation to the subject provides one or more of
the following pharmacokinetic features: both a mean AUC.sub.0-20
min and mean AUC.sub.0-t that are at least 80% of the mean
AUC.sub.0-20 min and mean AUC.sub.0-t that a 0.3 mg intramuscular
injection of epinephrine provides; a mean C.sub.max that is at
least 80% of the C.sub.max and no more than 150% of the C.sub.max
that a 0.3 mg intramuscular injection of epinephrine provides; a
mean t.sub.max of less than 45 minutes; and intramuscular
(IM)-injection like absorption of epinephrine under optimal dosing
conditions in the thigh.
19. The method of claim 17, wherein: wherein intranasal
administration of a single dose of the aqueous nasal spray
pharmaceutical formulation to the subject provides one or more of
the following pharmacokinetic features: both a mean AUC.sub.0-20
min and mean AUC.sub.0-t that are at least 80% of the mean
AUC.sub.0-20 min and mean AUC.sub.0-t that a 0.15 mg intramuscular
injection of epinephrine provides; a mean C.sub.max that is at
least 80% of the C.sub.max and no more than 150% of the C.sub.max
that a 0.15 mg intramuscular injection of epinephrine provides; a
mean t.sub.max of less than 45 minutes; and intramuscular
(IM)-injection like absorption of epinephrine under optimal dosing
conditions in the thigh.
20. The method of claim 17, wherein: wherein intranasal
administration of a single dose of the aqueous nasal spray
pharmaceutical formulation to the subject provides one or more of
the following pharmacokinetic features: both a mean AUC.sub.0-20
min and mean AUC.sub.0-t that are at least 80% of the mean
AUC.sub.0-20 min and mean AUC.sub.0-t that a 0.5 mg intramuscular
injection provides; a mean C.sub.max that is at least 80% of the
C.sub.max and no more than 150% of the C.sub.max that a 0.5 mg
intramuscular injection provides; a mean t.sub.max of less than 45
minutes; and intramuscular (IM)-injection like absorption under
optimal dosing conditions in the thigh.
Description
CROSS REFERENCE
[0001] This application is a continuation of International
Application No. PCT/US2019/016918 filed on Feb. 6, 2018, which
claims the benefit of U.S. patent application Ser. No. 15/890,131
filed on Feb. 6, 2018; and U.S. Provisional Patent Application No.
62/784,057 filed on Dec. 21, 2018; each of which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] Described herein are intranasal (IN) epinephrine
formulations and methods of using such formulations in the
treatment of conditions or diseases.
BACKGROUND OF THE INVENTION
[0003] Anaphylaxis is a medical emergency that may require
resuscitation measures such as airway management, supplemental
oxygen, large volumes of intravenous fluids, and close monitoring.
Administration of epinephrine is the treatment of choice. A need
exists for needle-free and non-invasive methods of dosing
epinephrine. Provided herein are methods, formulations, and devices
for the treatment of anaphylaxis and other conditions.
SUMMARY OF THE INVENTION
[0004] Disclosed herein are methods, pharmaceutical formulations of
epinephrine and methods of use thereof in the treatment of
conditions such as type-1 hypersensitivity reactions (systemic
allergic reaction), asthma, and cardiac arrest.
[0005] Anaphylaxis is a severe, potentially life-threatening type-1
hypersensitivity reaction (systemic allergic reaction) that affects
many body systems, with rapid onset typically averaging between
about 5 to 30 minutes after intravenous exposure to an antigen and
about 2 hours after oral exposure. Anaphylaxis results from the
release of inflammatory mediators and cytokines from mast cells and
basophils, typically due to an immunologic reaction, but sometimes
due to non-immunologic mechanisms. The most common areas of the
body affected include: skin (80-90%), respiratory (70%),
gastrointestinal (30-45%), heart and vasculature (10-45%), and
central nervous system (10-15%) with usually two or more being
involved in a single episode.
[0006] Anaphylaxis is a medical emergency that may require
resuscitation measures such as airway management, supplemental
oxygen, large volumes of intravenous fluids, and close monitoring.
Administration of epinephrine is the treatment of choice with
antihistamines and steroids (for example, dexamethasone) often used
as adjuncts. Due to concerns of biphasic anaphylaxis, a period of
in-hospital observation for between 2 and 24 hours is often
required for people once they have returned to normal.
[0007] Epinephrine (adrenaline,
(R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-1,2-diol) is the
primary treatment for anaphylaxis with no absolute contraindication
to its use. Currently epinephrine is administered as a solution
given by injection, preferably into the mid anterolateral thigh as
soon as anaphylaxis is suspected. The injection may be repeated
every 5 to 15 minutes if there is insufficient response. A second
dose is needed in 16-35% of episodes, but more than two doses are
rarely required. The intramuscular route is preferred over
subcutaneous administration because the latter may have delayed
epinephrine absorption. However, while only minor adverse effects
from epinephrine are reported (tremors, anxiety, headaches, and
palpitations) there have been numerous reports of the highly
variable exposures from injection products depending on the
location of the injection (intramuscular or subcutaneous), and
other factors such as body mass index (BMI).
[0008] There is a significant need in the medical community to
develop products that will help improve the clinical management of
anaphylaxis in an out-of-hospital setting. While epinephrine is
effective when delivered by intramuscular injection, there is
published evidence that the pharmacokinetics are highly variable
depending on the site of the injection, whether intramuscular or
subcutaneous. There have also been significant product quality
problems with approved auto-injectors that utilize complex
technologies, resulting in many recalls for these products by the
FDA in the United States. Epinephrine auto-injectors, such as
EpiPen.RTM., are also cumbersome to carry, and require training and
time to properly administer in a potentially life-threatening
situation.
[0009] The need for alternative, needle-free and non-invasive
methods for dosing epinephrine are well-documented, as many
patients have a fear of injection and, as a result, are reluctant
to use an auto-injector of any kind. Further, the auto-injectors
are large and burdensome, so many patients in need do not have an
epinephrine injector in their presence at all times. There is also
a well-documented reluctance to self-administer a dose in public
settings.
[0010] Thus, there is a need for improved or alternative methods of
dosing epinephrine in an emergency situation, as well as improved
or alternative formulations and devices. Desirable improvements
include: individually and in combinations, convenience (intranasal
versus intramuscular), more rapid administration, more reliable,
more consistent dosing, needleless, more discrete to dose in
public, and administrable by an untrained individual or
non-professional.
[0011] Accordingly, provided herein are methods, formulations, and
devices for the treatment of anaphylaxis and other conditions
comprising administering an intranasal formulation of epinephrine
using a small compact unit dose sprayer device.
[0012] In one aspect, described herein is a nasal spray
pharmaceutical formulation comprising between about 0.40 mg and
about 2.4 mg of epinephrine, or a salt thereof. In another aspect,
described herein is a nasal spray pharmaceutical formulation
comprising between about 0.40 mg and about 2.4 mg of epinephrine,
or a salt thereof, in a single dose of the nasal spray
pharmaceutical formulation. In another aspect, described herein is
a nasal spray pharmaceutical formulation comprising between about
0.40 mg and about 2.4 mg of epinephrine, or a salt thereof, in a
single dose nasal spray pharmaceutical formulation. In some
embodiments, the nasal spray pharmaceutical formulation comprises
between about 0.40 mg and about 2.0 mg of epinephrine, or a salt
thereof. In some embodiments, the nasal spray pharmaceutical
formulation comprises between about 0.40 mg and about 1.8 mg of
epinephrine, or a salt thereof. In some embodiments, a single dose
of the nasal spray pharmaceutical formulation comprises between
about 0.5 mg and about 2.0 mg of epinephrine, or a salt thereof. In
some embodiments, a single dose of the nasal spray pharmaceutical
formulation comprises between about 0.5 mg and about 1.5 mg of
epinephrine, or a salt thereof. In some embodiments, a single dose
of the nasal spray pharmaceutical formulation comprises between
about 0.5 mg and about 0.7 mg of epinephrine, or a salt thereof. In
some embodiments, a single dose of the nasal spray pharmaceutical
formulation comprises about 1.0 mg of epinephrine, or a salt
thereof. In some embodiments, a single dose of the nasal spray
pharmaceutical formulation comprises between about 1.3 mg and about
1.5 mg of epinephrine, or a salt thereof. In some embodiments,
intranasal administration of a single dose of the nasal spray
pharmaceutical formulation to a subject provides a plasma
epinephrine concentration that are efficacious for the treatment of
an acute hypersensitivity reaction. In some embodiments, the nasal
spray pharmaceutical formulation is an aqueous solution, aqueous
suspension, aqueous emulsion, non-aqueous solution, non-aqueous
suspensions, non-aqueous emulsion, or dry powder.
[0013] In one aspect, described herein is a nasal spray formulation
comprising between about 0.40 mg and about 2.4 mg per dose of
epinephrine, or a salt thereof, dispensed from the device. In some
embodiments, described herein is a nasal spray formulation
comprising between about 0.5 mg and about 2.0 mg of epinephrine, or
a salt thereof, per dose dispensed from the device; between about
0.5 mg and about 1.5 mg of epinephrine, or a salt thereof, per dose
dispensed from the device; between about 0.5 mg and about 0.7 mg of
epinephrine, or a salt thereof, per dose dispensed from the device;
about 1.0 mg of epinephrine, or a salt thereof, per dose dispensed
from the device; or between about 1.3 mg and about 1.5 mg of
epinephrine, or a salt thereof, per dose dispensed from the device.
In some embodiments, a single dose of the the nasal spray
formulation when administered intranasally provides plasma
epinephrine concentrations that are efficacious for the treatment
of an acute hypersensitivity reaction. In some embodiments, the
epinephrine or salt thereof is present in the pharmaceutical
formulation in an amount efficacious for the treatment of an acute
hypersensitivity reaction. In some embodiments, the nasal spray
formulation is an aqueous solution, aqueous suspension, aqueous
emulsion, non-aqueous solution, non-aqueous suspension or
non-aqueous emulsion.
[0014] In some embodiments, the nasal spray formulation comprises
between about 1 mg/mL and about 40 mg/mL of epinephrine, or a salt
thereof, per dose. In some embodiments, the nasal spray formulation
comprises between about 5 mg/mL and about 40 mg/mL of epinephrine,
or a salt thereof, per dose. In some embodiments, the nasal spray
formulation comprises between about 1 mg/mL and about 20 mg/mL of
epinephrine, or a salt thereof, per dose. In some embodiments, the
nasal spray formulation comprises between about 3 mg/mL and about
20 mg/mL of epinephrine, or a salt thereof, per dose. In some
embodiments, the nasal spray formulation comprises between about 3
mg/mL and about 15 mg/mL of epinephrine, or a salt thereof, per
dose. In some embodiments, the nasal spray formulation comprises
about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7
mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11
mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15
mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19
mg/mL, or about 20 mg/mL of epinephrine, or a salt thereof, per
dose. In some embodiments, a dose of the nasal spray formulation
comprises about 100 .mu.L of the nasal spray epinephrine
formulation described herein.
[0015] In some embodiments, a nasal spray formulation described
herein comprises about 1 mg/mL to about 40 mg/mL of epinephrine, or
a salt thereof. In some embodiments, a nasal spray formulation
described herein comprises about 1 mg/mL to about 20 mg/mL of
epinephrine, or a salt thereof. In some embodiments, a nasal spray
formulation described herein comprises about 1 mg/mL to about 18
mg/mL of epinephrine, or a salt thereof. In some embodiments, a
nasal spray formulation described herein comprises about 1 mg/mL,
about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6
mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL,
about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL,
about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL,
about 19 mg/mL, or about 20 mg/mL of epinephrine, or a salt
thereof. In some embodiments, a nasal spray formulation described
herein comprises about 3 mg/mL, about 5 mg/mL, about 6 mg/mL, about
6.5 mg/mL, about 7 mg/mL, about 7.5 mg/mL, about 8 mg/mL, about 8.5
mg/mL, about 9 mg/mL, about 9.5 mg/mL, about 10 mg/mL, about 10.5
mg/mL, about 11 mg/mL, about 11.5 mg/mL, about 12 mg/mL, about 12.5
mg/mL, about 13 mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 14.5
mg/mL, or about 15 mg/mL of epinephrine, or a salt thereof. In some
embodiments, a nasal spray formulation described herein comprises
about 10 mg/mL of epinephrine, or a salt thereof. In some
embodiments, a nasal spray formulation described herein comprises
about 6 mg/mL to about 8 mg/mL of epinephrine, or a salt thereof.
In some embodiments, a nasal spray formulation described herein
comprises about 13 mg/mL to about 15 mg/mL of epinephrine, or a
salt thereof. In some embodiments, a dose of the nasal spray
formulation comprises about 100 .mu.l of the nasal spray
epinephrine formulation described herein.
[0016] In some embodiments, a dose of about 100 .mu.L of the nasal
spray formulation described herein comprises 1 mg/mL to about 40
mg/mL of epinephrine, or a salt thereof. In some embodiments, a
dose of about 100 .mu.L of the nasal spray formulation described
herein comprises 1 mg/mL to 20 mg/mL of epinephrine, or a salt
thereof. In some embodiments, a dose of about 100 .mu.L of the
nasal spray formulation described herein comprises 3 mg/mL, 3.5
mg/mL, 4 mg/mL, 4.5 mg/mL, 5 mg/mL, 6 mg/mL, 6.5 mg/mL, 7 mg/mL,
7.5 mg/mL, 8 mg/mL, 8.5 mg/mL, 9 mg/mL, 9.5 mg/mL, 10 mg/mL, 10.5
mg/mL, 11 mg/mL, 11.5 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5
mg/mL, 14 mg/mL, 14.5 mg/mL, or 15 mg/mL of epinephrine, or a salt
thereof.
[0017] In some embodiments, the nasal spray formulation comprises
one or more absorption enhancers.
[0018] In some embodiments, the nasal spray formulation provides
intramuscular (IM)-injection-like pharmacokinetics when
IM-injection is dosed in the lateral thigh, or subcutaneous
(SC)-like absorption or in between.
[0019] In some embodiments, the nasal spray formulation provides
intramuscular (IM)-injection-like absorption.
[0020] In some embodiments, the nasal spray formulation provides
subcutaneous (SC)-like absorption and the SC pharmacokinetic
profile has a C.sub.max of at least 100 pg/mL and AUC.sub.0-240 min
of 150 h*pg/mL.
[0021] In some embodiments, intranasal administration of a single
dose of the nasal spray pharmaceutical formulation to a subject
provides intramuscular (IM)-injection-like absorption.
[0022] In some embodiments, the nasal spray formulation when
administered to a subject yields one or more of the following
pharmacokinetic features: both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.3 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the Cmax that a 0.3 mg intramuscular injection yields; a
mean t.sub.max of less than 45 minutes; or IM-injection like
absorption under optimal dosing conditions in the thigh. In some
embodiments, the nasal spray formulation when administered to a
subject yields one or more of the following pharmacokinetic
features: both the mean AUC.sub.0-20 min and AUC.sub.0-t are at
least 80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.3 mg
intramuscular injection yields; a mean Cmax that is at least 80% of
the C.sub.max and no more than 150% of the Cmax that a 0.3 mg
intramuscular injection yields; a mean t.sub.max of less than 45
minutes; and IM-injection like absorption under optimal dosing
conditions in the thigh.
[0023] In some embodiments, the nasal spray formulation when
administered to a subject yields one or more of the following
pharmacokinetic features: both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.15 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the Cmax that a 0.15 mg intramuscular injection yields; a
mean t.sub.max of less than 45 minutes; or IM-injection like
absorption under optimal dosing conditions in the thigh. In some
embodiments, the nasal spray formulation when administered to a
subject yields one or more of the following pharmacokinetic
features: both the mean AUC.sub.0-20 min and AUC.sub.0-t are at
least 80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.15 mg
intramuscular injection yields; a mean C.sub.max that is at least
80% of the C.sub.max and no more than 150% of the Cmax that a 0.15
mg intramuscular injection yields; a mean t.sub.max of less than 45
minutes; and IM-injection like absorption under optimal dosing
conditions in the thigh.
[0024] In some embodiments, the nasal spray formulation when
administered to a subject yields one or more of the following
pharmacokinetic features: both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.5 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the Cmax that a 0.5 mg intramuscular injection yields; a
mean t.sub.max of less than 45 minutes; or IM-injection like
absorption under optimal dosing conditions in the thigh. In some
embodiments, the nasal spray formulation when administered to a
subject yields one or more of the following pharmacokinetic
features: both the mean AUC.sub.0-20 min and AUC.sub.0-t are at
least 80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.5 mg
intramuscular injection yields; a mean C.sub.max that is at least
80% of the C.sub.max and no more than 150% of the C.sub.max that a
0.5 mg intramuscular injection yields; a mean t.sub.max of less
than 45 minutes; and IM-injection like absorption under optimal
dosing conditions in the thigh.
[0025] In some embodiments, the nasal spray formulation comprises
between about 0.5 and about 1.1 molar equivalents of acid to each
mole of epinephrine. In some embodiments, the acid is adipic acid,
ammonium chloride, citric acid, acetic acid, hydrochloric acid,
lactic acid, phosphoric acid, propionic acid, sulfuric acid or
tartaric acid. In some embodiments, the acid is hydrochloric acid.
In some embodiments, no base is added to the nasal spray
formulation during its preparation. In some embodiments, the nasal
spray formulation has a pH between about 2.0 and about 6.0. In some
embodiments, the nasal spray formulation has a pH of about 4.0.
[0026] In some embodiments, the nasal spray formulation comprises
between about 5 mg/mL and about 40 mg/mL per dose epinephrine, or a
salt thereof. In some embodiments, the nasal spray formulation
comprises between about 0.9 mg and about 2.40 mg per dose dispensed
from the device of epinephrine, or a salt thereof. In some
embodiments, the nasal spray formulation comprises between about
0.5 mg and about 2.0 mg per dose dispensed from the device of
epinephrine, or a salt thereof. In some embodiments, the nasal
spray formulation comprises between about 0.9 mg and about 1.5 mg
per dose dispensed from the device of epinephrine, or a salt
thereof. In some embodiments, the nasal spray formulation comprises
between about 0.75 mg and about 1.5 mg per dose dispensed from the
device of epinephrine, or a salt thereof. In some embodiments, the
nasal spray formulation comprises between about 0.45 mg and about
1.15 mg per dose dispensed from the device of epinephrine, or a
salt thereof. In some embodiments, the nasal spray formulation
comprises between about 1.0 mg and about 2.0 mg per dose dispensed
from the device of epinephrine, or a salt thereof. In some
embodiments, the nasal spray formulation comprises between about
0.5 mg and about 2.0 mg of epinephrine, or a salt thereof, per dose
dispensed from the device. In some embodiments, the nasal spray
formulation comprises between about 0.5 mg and about 1.5 mg of
epinephrine, or a salt thereof, per dose dispensed from the device.
In some embodiments, the nasal spray formulation comprises between
about 0.5 mg and about 0.7 mg of epinephrine, or a salt thereof,
per dose dispensed from the device. In some embodiments, the nasal
spray formulation comprises about 1.0 mg of epinephrine, or a salt
thereof, per dose dispensed from the device. In some embodiments,
the nasal spray formulation comprises between about 1.3 mg and
about 1.5 mg of epinephrine, or a salt thereof, per dose dispensed
from the device.
[0027] In some embodiments, the nasal spray pharmaceutical
formulation comprises one or more absorption enhancement agents;
and optionally one or more agents selected from isotonicity agents;
stabilizing agents; preservatives; taste-masking agents; viscosity
modifiers; antioxidants; buffers and pH adjustment agents; wherein
the pH of the nasal spray pharmaceutical formulation is between
about 2.0 and about 6.0.
[0028] In some embodiments, the nasal spray pharmaceutical
formulation has a pH between about 3.0 and about 5.0. In some
embodiments, the nasal spray pharmaceutical formulation has a pH of
about 4.0. In some embodiments, the nasal spray pharmaceutical
formulation comprises pH adjustment agents. In some embodiments,
the pH adjustment agent is an acid, a base, a buffer, or a
combination thereof. In some embodiments, the acid is adipic acid,
ammonium chloride, citric acid, acetic acid, hydrochloric acid,
lactic acid, phosphoric acid, propionic acid, sulfuric acid or
tartaric acid; the base is sodium hydroxide, sodium citrate, sodium
bicarbonate, sodium carbonate; and the buffer is a phosphate
buffer, acetate buffer, or citrate buffer. In some embodiments, the
nasal spray pharmaceutical formulation comprises between about 0.5
and about 1.1 molar equivalents of acid to each mole of
epinephrine. In some embodiments, the acid is hydrochloric
acid.
[0029] In some embodiments, the nasal spray formulation comprises
one or more absorption enhancers selected from dodecyl maltoside,
benzalkonium chloride, oleic acid, or salt thereof, polysorbate 20,
polysorbate 80, and sodium lauryl sulfate.
[0030] In some embodiments, the formulation comprises one or more
absorption enhancers selected from alcohol, aprotinin, benzalkonium
chloride, benzyl alcohol, capric acid, ceramides, cetylpyridinium
chloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl,
dimethyl sulfoxide, glyceryl monooleate, glycofurol, glycofurol,
glycosylated sphingosines, glycyrrhetinic acids,
2-hydroxypropyl-.beta.-cyclodextrin, laureth-9, lauric acid,
lauroyl carnitine, lysophosphatidylcholine, menthol, poloxamer 407
or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl
myristate, isopropyl palmitate, lanolin, light mineral oil,
linoleic acid, menthol, myristic acid, myristyl alcohol, oleic
acid, or salt thereof, oleyl alcohol, palmitic acid, polysorbate
20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers,
polyoxylglycerides, pyrrolidone, quillaia saponin, salicylic acid,
sodium salt, .beta.-sitosterol .beta.-D-glucoside, sodium lauryl
sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid,
taurodihydrofusidic acid, thymol, tricaprylin, triolein, and
alkylsaccharides.
[0031] In some embodiments, the formulation comprises one or more
absorption enhancers selected from dodecyl maltoside, benzalkonium
chloride, oleic acid, or salt thereof, polysorbate 20, polysorbate
80, and sodium lauryl sulfate.
[0032] In some embodiments, the one or more absorption enhancers
are: about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside; or
about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride; or about
0.001 (w/v) to about 1% (w/v) oleic acid, or salt thereof; or a
combination of about 0.005% (w/v) to about 2.5% (w/v) dodecyl
maltoside and about 0.001 (w/v) to about 1% (w/v) benzalkonium
chloride; or a combination of about 0.005% (w/v) to about 2.5%
(w/v) dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v)
oleic acid, or salt thereof or a combination of about 0.001 (w/v)
to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to
about 1% (w/v) oleic acid, or salt thereof.
[0033] In some embodiments, the one or more absorption enhancers
are: about 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride;
or about 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride; or
about 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride;
wherein the benzalkonium chloride is the sole absorption
enhancement agent in the formulation or is in present in the
formulation with one or more additional absorption enhancement
agents.
[0034] In some embodiments, the formulation comprises a
preservative. In some embodiments, the preservative is benzalkonium
chloride.
[0035] In some embodiments, the nasal spray pharmaceutical
formulation comprises an isotonicity agent. In some embodiments,
the isotonicity agent is dextrose, glycerin, mannitol, potassium
chloride, or sodium chloride. In some embodiments, the isotonicity
agent is sodium chloride.
[0036] In some embodiments, the nasal spray formulation
additionally comprises a stabilizing agent. In some embodiments,
the stabilizing agent is ethylenediaminetetraacetic acid (EDTA) or
a salt thereof. In some embodiments, the EDTA is disodium EDTA. In
some embodiments, the nasal spray formulation comprises from about
0.001% (w/v) to about 1% (w/v) of disodium EDTA.
[0037] In some embodiments, the nasal spray formulation
additionally comprises a preservative. In some embodiments, the
preservative is benzalkonium chloride.
[0038] In some embodiments, the nasal spray formulation comprises
one or more absorption enhancers selected from alkylglycosides,
benzalkonium chloride, oleic acid, or salt thereof, polysorbate 20,
polysorbate 80, sodium lauryl sulfate, cyclodextrins, medium and
long chain fatty acids, or salts thereof, saturated and unsaturated
fatty acids, or salts thereof, alcohol, glycerin, propylene glycol,
PEG 300/400, and benzyl alcohol.
[0039] In some embodiments, the nasal spray formulation further
comprises an antioxidant. In some embodiments, the nasal spray
formulation further comprises an antioxidant selected from alpha
tocopherol, arachidonic acid, ascorbic acid, ascorbyl palmitate,
benzethonium chloride, benzethonium bromide, benzalkonium chloride,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
capric acid, caproic acid, carbon dioxide, cetylpyridium chloride,
chelating agents, chitosan derivatives, citric acid monohydrate,
dodecyl dimethyl aminopropionate, enanthic acid, erythorbic acid,
ethyl oleate, fumaric acid, glycerol oleate, glyceryl monostearate,
lauric acid, limonene, linolenic acid, lysine, malic acid, menthol,
methionine, monothioglycerol, myristic acid, oleic acid, palmitic
acid, pelargonic acid, peppermint oil, phosphoric acid,
polysorbates, potassium metabisulfite, propionic acid, propyl
gallate, sodium ascorbate, sodium bisulfite, sodium caprate, sodium
desoxycholate, sodium deoxyglycolate, sodium formaldehyde
sulfoxylate, sodium glycocholate, sodium hydroxybenzoyal amino
caprylate, sodium lauryl sulfate, sodium metabisulfite, sodium
sulfite, sodium taurocholate, sodium thiosulfate, stearic acid,
sulfur dioxide and a combination thereof.
[0040] In some embodiments, the nasal spray formulation further
comprises synergists with the antioxidants selected from citric
acid monohydrate, tartaric acid, thymol, tocopherol (alpha
tocopherol), tocopherasol, vitamin E and vitamin E polyethylene
glycol succinate and a combination thereof.
[0041] In some embodiments, the nasal spray formulation further
comprises permeation enhancers selected from alcohol, arachidonic
acid, benzethonium chloride, benzethonium bromide, benzalkonium
chloride, capric acid, caproic acid, carvone, cetylpyridium
chloride, chitosans, citric acid,
6-cyclohexyl-1-hexyl-.beta.-D-maltopyranoside,
n-decyl-.beta.-D-maltopyranoside, dimethyl sulfoxide, dodecyl
dimethyl aminopropionate, 1-O-n-Dodecyl-.beta.-D-maltopyranoside,
dodecylpolyethyleneglycolether, edetate disodium dihydrate,
enanthic acid, glyceryl monooleate, glyceryl monostearate,
glycofurol, isopropyl myristate, isopropyl palmitate, pelargonic
acid, lanolin, lauric acid, light mineral oil, limonene, linoleic
acid, lysine, menthol, myristic acid, myristyl alcohol, oleic acid,
oleyl alcohol, palmitic acid, peppermint oil, polyoxyethylene alkyl
ethers, polyoxylglycerides, polysorbates, pyrrolidone, sodium
caprate, sodium desoxycholate, sodium deoxyglycolate, sodium
glycocholate, sodium hydroxybenzoyal amino caprylate, sodium lauryl
sulfate, sodium taurocholate, stearic acid, thymol, tricaprylin,
triolein, undecylenic acid, and a combination thereof.
[0042] In some embodiments, the nasal spray formulation comprises:
about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside; about
0.001 (w/v) to about 1% (w/v) benzalkonium chloride; about 0.001
(w/v) to about 1% (w/v) oleic acid, or salt thereof; a combination
of about about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside
and about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride; a
combination of about 0.005% (w/v) to about 2.5% (w/v) dodecyl
maltoside and about 0.001 (w/v) to about 1% (w/v) oleic acid, or
salt thereof; or a combination of about 0.001 (w/v) to about 1%
(w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v)
oleic acid, or salt thereof: or a combination of about 0.001 (w/v)
to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to
about 1% (w/v) oleic acid, or salt thereof and 0.001% to 1% sodium
metabisulfite; or a combination of about 0.001 (w/v) to about 1%
(w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v)
oleic acid, or salt thereof and about 0.001% to 10% polysorbate 80
and 0.001% to 1% sodium metabisulfite; or a combination of about
0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001
(w/v) to about 1% (w/v) oleic acid, or salt thereof and about
0.001% to 10% polysorbate 80 and 0.001% to 1% sodium metabisulfite
and 0.001% to 1% citric acid.
[0043] In some embodiments, the nasal spray formulation comprises:
about 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride;
about 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride; or
about 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride;
wherein the benzalkonium chloride is the sole absorption
enhancement agent in the nasal spray formulation or is in present
in the formulation with one or more additional absorption
enhancement agents.
[0044] In some embodiments, the nasal spray formulation comprises:
about 0.001% to 1% of any one of the antioxidants described herein,
or a combination of any one of the antioxidants described
herein.
[0045] In some embodiments, the nasal spray formulation comprises a
buffering agent. Buffering agents include, but are not limited to,
adipic acid, boric acid, calcium carbonate, calcium hydroxide,
calcium lactate, calcium phosphate, tribasic, citric acid
monohydrate, dibasic sodium phosphate, diethanolamine, glycine,
maleic acid, malic acid, methionine, monobasic sodium phosphate,
monoethanolamine, monosodium glutamate, phosphoric acid, potassium
citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium
carbonate, sodium citrate dihydrate, sodium hydroxide, sodium
lactate, and triethanolamine.
[0046] In one aspect, provided herein is a method of treatment of a
condition mediated by adrenergic receptors comprising the
intranasal administration of any one of the formulations as
described herein. In some embodiments, the condition is chosen from
a type-1 hypersensitivity reaction (systemic allergic reaction), an
acute asthmatic attack, cardiac arrest, and Stokes-Adams Syndrome.
In some embodiments, the condition is a type-1 hypersensitivity
reaction (systemic allergic reaction). In some embodiments, the
type 1 hypersensitivity reaction is chosen from allergic asthma,
allergic conjunctivitis, allergic rhinitis, anaphylaxis,
angioedema, urticaria, eosinophilia, drug allergy and food allergy.
In some embodiments, the drug allergy is an antibiotic allergy.
[0047] In one aspect, described herein is a nasal spray formulation
comprising epinephrine or a salt thereof, which when administered
to a subject yields one or more of the following pharmacokinetic
features: both the mean AUC.sub.0-20 min and AUC.sub.0-t are at
least 80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.3 mg
intramuscular injection yields; a mean C.sub.max that is at least
80% of the C.sub.max and no more than 150% of the C.sub.max that a
0.3 mg intramuscular injection yields; a mean t.sub.max of less
than 45 minutes; or IM-injection like absorption under optimal
dosing conditions in the thigh. In another aspect, described herein
is a nasal spray formulation comprising epinephrine or a salt
thereof, which when administered to a subject yields one or more of
the following pharmacokinetic features: both the mean AUC.sub.0-20
min and AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.3 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.3 mg intramuscular injection yields;
a mean t.sub.max of less than 45 minutes; and IM-injection like
absorption under optimal dosing conditions in the thigh.
[0048] In another aspect, described herein is a nasal spray
formulation comprising epinephrine or a salt thereof, which when
administered to a subject yields one or more of the following
pharmacokinetic features: both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.15 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.15 mg intramuscular injection
yields; a mean t.sub.max of less than 45 minutes; or IM-injection
like absorption under optimal dosing conditions in the thigh. In
another aspect, described herein is a nasal spray formulation
comprising epinephrine or a salt thereof, which when administered
to a subject yields one or more of the following pharmacokinetic
features: both the mean AUC.sub.0-20 min and AUC.sub.0-t are at
least 80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.15 mg
intramuscular injection yields; a mean C.sub.max that is at least
80% of the C.sub.max and no more than 150% of the Cmax that a 0.15
mg intramuscular injection yields; a mean t.sub.max of less than 45
minutes; and IM-injection like absorption under optimal dosing
conditions in the thigh.
[0049] In yet another aspect, described herein is a nasal spray
formulation comprising epinephrine or a salt thereof, which when
administered to a subject yields one or more of the following
pharmacokinetic features: both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.5 mg intramuscular injection yields; a mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.5 mg intramuscular injection yields;
a mean t.sub.max of less than 45 minutes; or IM-injection like
absorption under optimal dosing conditions in the thigh.
[0050] In some embodiments, the nasal spray formulation is a
pharmaceutical formulation.
[0051] In some embodiments, the epinephrine or salt thereof is
present in the nasal spray formulation in an amount efficacious for
the treatment of an acute hypersensitivity reaction.
[0052] In some embodiments, intranasal administration of a single
dose of the nasal spray pharmaceutical formulation to a subject
provides a plasma epinephrine concentration that is efficacious for
the treatment of an acute hypersensitivity reaction. In some
embodiments, a single dose of the nasal spray pharmaceutical
formulation comprises between about 0.5 mg and about 2.0 mg of
epinephrine, or a salt thereof. In some embodiments, a single dose
of the nasal spray pharmaceutical formulation comprises between
about 0.5 mg and about 1.5 mg of epinephrine, or a salt thereof. In
some embodiments, a single dose of the nasal spray pharmaceutical
formulation comprises between about 0.5 mg and about 0.7 mg of
epinephrine, or a salt thereof. In some embodiments, a single dose
of the nasal spray pharmaceutical formulation comprises about 1.0
mg of epinephrine, or a salt thereof. In some embodiments, a single
dose of the nasal spray pharmaceutical formulation comprises
between about 1.3 mg and about 1.5 mg of epinephrine, or a salt
thereof. In some embodiments, the formulation is an aqueous
solution, aqueous suspension, aqueous emulsion, non-aqueous
solution, non-aqueous suspension, non-aqueous emulsion, pressurized
metered-dose inhalers or dry powder.
[0053] In some embodiments, the nasal spray formulation is an
aqueous solution, aqueous suspensions, aqueous emulsion,
non-aqueous solution, non-aqueous suspension or non-aqueous
emulsion.
[0054] In some embodiments, the nasal spray formulation has
intramuscular (IM)-injection-like pharmacokinetics when
IM-injection is dosed in the lateral thigh, or subcutaneous
(SC)-like absorption or in between.
[0055] In some embodiments, the nasal spray formulation has
subcutaneous (SC)-like absorption and the SC pharmacokinetic
profile has a Cmax of at least 100 pg/mL and AUC0-240 min of 150
h*pg/mL.
[0056] In some embodiments, the nasal spray formulation has
intramuscular (IM)-injection-like absorption.
[0057] In some embodiments, the nasal spray formulation comprises
an absorption enhancer.
[0058] In some embodiments, the nasal spray pharmaceutical
formulation comprises one or more absorption enhancement agents;
and optionally one or more agents selected from isotonicity agents;
stabilizing agents; preservatives; taste-masking agents; viscosity
modifiers; antioxidants; buffers and pH adjustment agents; wherein
the pH of the nasal spray pharmaceutical formulation is between
about 2.0 and about 6.0. In some embodiments, the nasal spray
pharmaceutical formulation has a pH between about 3.0 and about
5.0. In some embodiments, the nasal spray pharmaceutical
formulation has a pH of about 4.0.
[0059] In some embodiments, the nasal spray pharmaceutical
formulation comprises pH adjustment agents. In some embodiments,
the pH adjustment agent is an acid, a base, a buffer, or a
combination thereof. In some embodiments, the acid is adipic acid,
ammonium chloride, citric acid, acetic acid, hydrochloric acid,
lactic acid, phosphoric acid, propionic acid, sulfuric acid or
tartaric acid; the base is sodium hydroxide, sodium citrate, sodium
bicarbonate, sodium carbonate; and the buffer is a phosphate
buffer, acetate buffer, or citrate buffer.
[0060] In some embodiments, the nasal spray formulation comprises
between about 0.5 and about 1.1 molar equivalents of acid to each
mole of epinephrine. In some embodiments, the acid is adipic acid,
ammonium chloride, citric acid, acetic acid, hydrochloric acid,
lactic acid, phosphoric acid, propionic acid, sulfuric acid or
tartaric acid. In some embodiments, the acid is hydrochloric acid.
In some embodiments, no base is added to the formulation during its
preparation. In some embodiments, the nasal spray formulation has a
pH between about 2.0 and about 6.0. In some embodiments, the nasal
spray formulation has a pH of about 4.0.
[0061] In some embodiments, the nasal spray formulation comprises
between about 5 mg/mL and about 40 mg/mL per dose epinephrine, or a
salt thereof. In some embodiments, the nasal spray formulation
comprises between about 0.40 mg and about 2.40 mg per dose
dispensed from the device of epinephrine, or a salt thereof. In
some embodiments, the nasal spray formulation comprises between
about 0.9 mg and about 2.40 mg per dose dispensed from the device
of epinephrine, or a salt thereof. In some embodiments, the nasal
spray formulation comprises between about 0.5 mg and about 2.0 mg
per dose dispensed from the device of epinephrine, or a salt
thereof. In some embodiments, the nasal spray formulation comprises
between about 0.9 mg and about 1.5 mg per dose dispensed from the
device of epinephrine, or a salt thereof. In some embodiments, the
nasal spray formulation comprises between about 0.75 mg and about
1.5 mg per dose dispensed from the device of epinephrine, or a salt
thereof. In some embodiments, the nasal spray formulation comprises
between about 0.45 mg and about 1.15 mg per dose dispensed from the
device of epinephrine, or a salt thereof. In some embodiments, the
nasal spray formulation comprises between about 1.0 mg and about
2.0 mg per dose dispensed from the device of epinephrine, or a salt
thereof.
[0062] In some embodiments, the nasal spray formulation comprises
one or more absorption enhancers selected from alcohol, aprotinin,
benzalkonium chloride, benzyl alcohol, capric acid, ceramides,
cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic
acid, decanoyl, dimethyl sulfoxide, glyceryl monooleate,
glycofurol, glycofurol, glycosylated sphingosines, glycyrrhetinic
acids, 2-hydroxypropyl-.beta.-cyclodextrin, laureth-9, lauric acid,
lauroyl carnitine, lysophosphatidylcholine, menthol, poloxamer 407
or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl
myristate, isopropyl palmitate, lanolin, light mineral oil,
linoleic acid, menthol, myristic acid, myristyl alcohol, oleic
acid, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80,
propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides,
pyrrolidone, quillaia saponin, salicylic acid, sodium salt,
.beta.-sitosterol .beta.-D-glucoside, sodium lauryl sulfate,
sucrose cocoate, taurocholic acid, taurodeoxycholic acid,
taurodihydrofusidic acid, thymol, tricaprylin, triolein, and
alkylsaccharides.
[0063] In some embodiments, the nasal spray formulation comprises
one or more absorption enhancers selected from dodecyl maltoside,
benzalkonium chloride, oleic acid, or salt thereof, polysorbate 20,
polysorbate 80, and sodium lauryl sulfate.
[0064] In some embodiments, the nasal spray formulation comprises:
about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside; about
0.001 (w/v) to about 1% (w/v) benzalkonium chloride; about 0.001
(w/v) to about 1% (w/v) oleic acid, or salt thereof; a combination
of about about 0.005% (w/v) to about 2.5% (w/v) dodecyl maltoside
and about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride; a
combination of about 0.005% (w/v) to about 2.5% (w/v) dodecyl
maltoside and about 0.001 (w/v) to about 1% (w/v) oleic acid, or
salt thereof; or a combination of about 0.001 (w/v) to about 1%
(w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v)
oleic acid, or salt thereof and about 0.001 to 1% of an antioxidant
(e.g. sodium metabisulfite). In some embodiments, the nasal spray
formulation comprises: about 0.005% (w/v) to about 2.5% (w/v)
dodecyl maltoside; about 0.001 (w/v) to about 1% (w/v) benzalkonium
chloride; about 0.001 (w/v) to about 1% (w/v) oleic acid, or salt
thereof, a combination of about 0.005% (w/v) to about 2.5% (w/v)
dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v)
benzalkonium chloride; a combination of about 0.005% (w/v) to about
2.5% (w/v) dodecyl maltoside and about 0.001 (w/v) to about 1%
(w/v) oleic acid, or salt thereof, or a combination of about 0.001
(w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v)
to about 1% (w/v) oleic acid, or salt thereof. In some embodiments,
the nasal spray formulation comprises: about 0.005% (w/v) to about
0.08% (w/v) benzalkonium chloride; about 0.01% (w/v) to about 0.06%
(w/v) benzalkonium chloride; or about 0.01% (w/v) to about 0.04%
(w/v) benzalkonium chloride; wherein the benzalkonium chloride is
the sole absorption enhancement agent in the nasal spray
formulation or is in present in the formulation with one or more
additional absorption enhancement agents.
[0065] In some embodiments, the nasal spray formulation
additionally comprises a stabilizing agent. In some embodiments,
the stabilizing agent is ethylenediaminetetraacetic acid (EDTA) or
a salt thereof. In some embodiments, the EDTA is disodium EDTA. In
some embodiments, the EDTA is present in an amount that is from
about 0.001% to about 1%.
[0066] In some embodiments, the nasal spray formulation
additionally comprises a preservative. In some embodiments, the
preservative is benzalkonium chloride.
[0067] In one aspect, described herein is a method of treatment of
a condition mediated by adrenergic receptors comprising the
intranasal administration of any one of the formulation described
herein. In some embodiments, the condition is chosen from a type-1
hypersensitivity reaction (systemic allergic reaction), an acute
asthmatic attack, cardiac arrest, and Stokes-Adams Syndrome. In
some embodiments, the condition is a type-1 hypersensitivity
reaction (systemic allergic reaction). In some embodiments, the
type 1 hypersensitivity reaction is chosen from allergic asthma,
allergic conjunctivitis, allergic rhinitis, anaphylaxis,
angioedema, urticaria, eosinophilia, drug allergy and food allergy.
In some embodiments, the drug allergy is an antibiotic allergy.
[0068] In another aspect, described herein is a method of treatment
of anaphylaxis comprising the intranasal administration of an
intranasal formulation of epinephrine in an amount less than about
2.0 mg. In some embodiments, the nasal pharmaceutical formulation
comprises between about 0.5 mg and about 1.5 mg of epinephrine, or
a salt thereof. In some embodiments, the nasal pharmaceutical
formulation comprises between about 0.5 mg and about 0.7 mg of
epinephrine, or a salt thereof. In some embodiments, the nasal
pharmaceutical formulation comprises about 1.0 mg of epinephrine,
or a salt thereof. In some embodiments, the nasal pharmaceutical
formulation comprises between about 1.3 mg and about 1.5 mg of
epinephrine, or a salt thereof.
[0069] In some embodiments of the methods of treatments, the
intranasal formulation comprises: one or more absorption
enhancement agents; an isotonicity agent; a stabilizing agent; a
preservative; an optional antioxidant; and optional pH adjustment
agents. In some embodiments of the methods of treatment, the one or
more absorption enhancement agents are selected from: dodecyl
maltoside; benzalkonium chloride; oleic acid, or salt thereof;
sodium laural sulfate; a combination of dodecyl maltoside and
benzalkonium chloride; a combination of dodecyl maltoside and oleic
acid, or salt thereof, and a combination of benzalkonium chloride
and oleic acid, or salt thereof. In some embodiments of the methods
of treatment, the one or more absorption enhancement agents are
selected from: about 0.005% (w/v) to about 2.5% (w/v) dodecyl
maltoside; about 0.001 (w/v) to about 1% (w/v) benzalkonium
chloride; about 0.001 (w/v) to about 1% (w/v) oleic acid, or salt
thereof; a combination of about 0.005% (w/v) to about 2.5% (w/v)
dodecyl maltoside and about 0.001 (w/v) to about 1% (w/v)
benzalkonium chloride; a combination of about 0.005% (w/v) to about
2.5% (w/v) dodecyl maltoside and about 0.001 (w/v) to about 1%
(w/v) oleic acid, or salt thereof, or a combination of about 0.001
(w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v)
to about 1% (w/v) oleic acid, or salt thereof. In some embodiments
of the methods of treatment, the formulation comprises: about
0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride; about
0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride; or about
0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride; wherein the
benzalkonium chloride is the sole absorption enhancement agent in
the formulation or is in present in the formulation with one or
more absorption enhancement agents. In some embodiments of the
methods of treatment, the isotonicity agent is sodium chloride. In
some embodiments of the methods of treatment, the stabilizing agent
is EDTA. In some embodiments of the methods of treatment, the
stabilizing agent is EDTA in an amount from about 0.001% (w/v) to
about 1% (w/v). In some embodiments of the methods of treatment,
the preservative is benzalkonium chloride. In some embodiments of
the methods of treatment, the preservative is benzalkonium chloride
in an amount from about 0.001% (w/v) to about 1% (w/v).
[0070] Articles of manufacture, which include packaging material, a
nasal spray formulation described herein within the packaging
material, and a label that indicates that the nasal spray
formulation is used for the treatment of any of the conditions
described herein (e.g. anaphylaxis) are provided.
[0071] Other objects, features and advantages of the compositions
and methods described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the instant disclosure will become apparent to those
skilled in the art from this detailed description.
BRIEF DESCRIPTION OF FIGURES
[0072] FIG. 1 shows the area under the plasma concentration versus
time curve at time 0-120 minutes (AUC.sub.0-120 min) of epinephrine
absorption at different dosages and routes of administration as
disclosed in Srisawat et al., "A preliminary study of intranasal
epinephrine administration as a potential route for anaphylaxis
treatment," Asian Pac J Allergy Immunol, 2016 Mar.; 34(1):38-43,
discussed below.
[0073] FIG. 2 shows the plasma epinephrine concentration versus
time plots after administrations of IN saline, IN epinephrine at 5
mg, and IM epinephrine at 0.3 mg, as disclosed in Srisawat et
al.
[0074] FIG. 3 shows the mean plasma epinephrine concentrations
above baseline (pg/mL) vs. time (min) curves from the first
clinical study described in Example 2A comparing 0.3 mg epinephrine
IM and IN; the curve with squared represents IM, and the curve with
circles, IN.
[0075] FIG. 4 shows the mean plasma epinephrine concentrations
above baseline (pg/mL) vs. time (min) curves from the second
clinical study described in Example 2B comparing 0.5, 1.0, and 2.0
mg epinephrine IN. The curve with circles represents 0.5 mg; the
curve with triangles, 1.0 mg, and the curve with squares, 2.0
mg.
[0076] FIG. 5 shows the first 30 minutes of the mean plasma
epinephrine concentrations above baseline (pg/mL) vs. time (min)
curves from the second clinical study described in Example 2B
comparing 0.5, 1.0, and 2.0 mg IN epinephrine. The curve with
circles represents 0.5 mg; the curve with triangles, 1.0 mg, and
the curve with squares, 2.0 mg.
[0077] FIG. 6 repeats the data from FIG. 4 and overlays it with the
mean plasma concentration vs. time curve for IM epinephrine from
the first clinical study described in Example 2A.
[0078] FIG. 7 repeats the data from FIG. 5 and overlays it with the
first 30 minutes of the mean plasma concentration vs. time curve
for IM epinephrine from the first clinical study described in
Example 2A.
[0079] FIG. 8 shows the mean plasma epinephrine concentrations
above baseline (pg/mL) vs. time (min) curves from the comparative
bioavailability portion of the second clinical study described in
Example 2B, comparing 1.0 mg epinephrine IN (curve w/ circles) to
0.3 mg epinephrine IM (epinephrine auto injector, curve w/
triangles).
[0080] FIG. 9 shows the first 30 minutes of the mean plasma
epinephrine concentrations above baseline (pg/mL) vs. time (min)
curves from the comparative bioavailability portion of the second
clinical study described in Example 2B, comparing 1.0 mg
epinephrine IN (curve w/circles) to 0.3 mg epinephrine IM
(EpiPen.RTM., curve w/ triangles).
DETAILED DESCRIPTION
[0081] Disclosed herein are methods and formulations useful for the
treatment of anaphylaxis and other conditions, comprising
administering an intranasal formulation of epinephrine. Also
provided are devices adapted for nasal delivery of a pharmaceutical
formulation to a patient, including single, bi- and multidose
delivery comprising a therapeutically effective amount of
epinephrine and pharmaceutically acceptable salts thereof.
[0082] Intranasal epinephrine has a long history of use in low
doses as a decongestant and as a vasoconstrictor, often formulated
combination with anaesthetic, in sinus and nasal surgery.
Historically, epinephrine has been difficult to formulate as an
intranasal solution for systemic delivery. See, e.g., Srisawat C et
al., "A preliminary study of intranasal epinephrine administration
as a potential route for anaphylaxis treatment," Asian Pac J
Allergy Immunol, 2016 Mar.; 34(1):38-43. Srisawat showed that
significant systemic absorption of epinephrine via the IN route was
observed only at 5 mg (see FIG. 1) and the pharmacokinetic
parameters of IN epinephrine even at 5 mg were also not
significantly different from those of the IM epinephrine group (see
Table 1, below).
TABLE-US-00001 TABLE 1 Intramuscular and Intranasal Administraton
of Epinephrine (from Srisawat (2016). Intramuscular (IM) Intranasal
(IN) Mean .+-. SD Epinephrine 0.3 mg Epinephrine 5 mg
C.sub.baseline (pg/mL) 35 .+-. 23 8 .+-. 6 C.sub.max (pg/mL) 309
.+-. 88 386 .+-. 152 T.sub.max (min) 67 .+-. 43 70 .+-. 17
AUC.sub.0-120 min 18.3 .+-. 9.3 19.4 .+-. 12.1 (ng * min/mL)
[0083] FIG. 1 is reproduced from Srisawat C et al. and demonstrates
that Srisawat et al. observed no blood level of epinephrine at the
intranasal dose level of 2.5 mg and below.
[0084] Furthermore, FIG. 2 shows that even at a dose of 5 mg,
Srisawat was not able to make an intranasal formulation that could
achieve a higher plasma concentration than intramuscular
epinephrine delivered by auto injector at any time point before
about 60 minutes, thus absorption during the critical early time
points was delayed when rapid absorption is needed to stop the
systemic allergic reaction (anaphylaxis). This is potentially
detrimental in serious conditions such as anaphylaxis where
immediate treatment, and thus injection-like pharmacokinetics, are
desirable. The PK profile of IM injection into the thigh is
considered the optimal dosing method by literature given that the
higher vascularity of the leg muscle allows for more rapid
absorption and distribution of the epinephrine providing a rapid
increase in plasma levels to stop the anaphylaxis reaction much
sooner than other routes of administration. FIG. 2 also shows that
Srisawat's 5 mg formulation, in contrast to intramuscular
epinephrine delivered by auto injector, cleared from the plasma
almost entirely in about two hours. Finally, epinephrine is known
to be associated with dose-related cardiac side effects including
myocardial infarction, at doses as low as 0.3 to 0.5 mg
intramuscularly; accordingly, doses as high as 5 mg would likely be
risky in the general population if nasal conditions existed that
may allow excessive absorption. Thus, lower dose preparations that
would avoid such risks are preferred as a safer nasal
preparation.
[0085] Disclosed herein are intranasal formulations of epinephrine,
and nasal spray devices comprising the formulations, that solve the
problems of past attempts. Various aspects may contribute to the
success of the formulations, devices, and methods of use disclosed
herein.
[0086] For example, in certain embodiments, formulating epinephrine
in an aqueous solution with the appropriate addition of molar
equivalents of acid to each mole of said epinephrine helps to
solubilize and stabilize the epinephrine. This allows the
formulation to avoid the use of buffering agents commonly used in
aqueous pharmaceutical compositions for injection, including
phosphate, acetate, and citrate buffers, which are sometimes
avoided in the nasal formulations disclosed herein. Other salts of
epinephreine, such as epinephrine acetate, epinephrine
hydrochloride, epinephrine tartrate, epinephrine bitartrate,
epinephrine hydrogen tartrate and epinephrine borate can also be
used to formulate aqueous solutions of epinephrine.
[0087] Certain embodiments of the formulations, devices, and
methods of use disclosed herein offer advantages over epinephrine
formulated in other ways. Epinephrine is considered a narrow
therapeutic index drug. As a sympathomimetic catecholamine,
epinephrine has a narrow therapeutic index and serious adverse
reactions including cardiovascular and cerebrovascular reactions
can be associated with its use. Nevertheless, the use epinephrine
for this indication is life saving and the benefits of using it
outweigh the potential safety risks. Intranasal delivery and
formulation are suited for the safe, painless delivery of drugs
such as epinephrine by consistent content uniformity, delivery
amount and absorption, thereby minimizing serious adverse reactions
including cardiovascular and cerebrovascular reactions that can be
associated with its use via injection mechanisms. Shot weights have
low variability and consistently deliver the labeled dose.
[0088] In one aspect, described herein is a pharmaceutical
composition comprising: a) epinephrine; and b) an alkylglycoside;
wherein the pharmaceutical composition is formulated for
administration into the circulatory system of a subject via the
intranasal, inhalation, or pulmonary, administration route. In some
embodiments, described herein is a pharmaceutical composition
comprising: a) epinephrine; and b) an alkylglycoside; wherein the
pharmaceutical composition is a liquid formulated for intranasal
delivery.
[0089] In some embodiments, the alkylglycoside has an alkyl chain
including between 8 to 20 carbons. In some embodiments, the
alkylglycoside is selected from the group consisting of undecyl
maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl
maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and
sucrose mono-tetradecanoate. In some embodiments, the
alkylglycoside is dodecyl-beta-D-maltoside. In some embodiments,
the alkylglycoside concentration is between about 0.001% and 10.0%
(w/v). In some embodiments, the alkylglycoside concentration is
between about 0.05% and 0.5% (w/v).
[0090] In some embodiments, the composition further comprises a
membrane penetration-enhancing agent. In some embodiments, the
membrane penetration-enhancing agent is a surfactant, a bile salt,
a phospholipid, an alcohol, an enamine, a long-chain amphipathic
molecule, a small hydrophobic molecule, sodium or a salicylic acid
derivative, a glycerol ester of acetoacetic acid, a cyclodextrin, a
medium-chain or long chain fatty acids, a chelating agent, an amino
acid or salt thereof, an enzyme or combination thereof. In some
embodiments, the membrane penetration-enhancing agent is selected
from the group consisting of citric acid, sodium citrate, propylene
glycol, glycerin, ascorbic acid, sodium metabisulfite,
ethylenediaminetetraacetic acid (EDTA) disodium, benzalkonium
chloride, hydroxyquinolone, sodium hydroxide, and combinations
thereof. In some embodiments, the membrane penetration-enhancing
agent is selected from the group consisting of citric acid, sodium
citrate, propylene glycol, glycerin, ascorbic acid, sodium
metabisulfite, ethylenediaminetetraacetic acid (EDTA) disodium,
benzalkonium chloride, sodium hydroxide, and combinations thereof.
In some embodiments, membrane penetration-enhancing agent is
benzalkonium chloride, EDTA, or a combination thereof.
[0091] In some embodiments, the composition provides a C.sub.max
for the epinephrine in a subject that is about 2 fold or greater as
compared to administration without alkylglycoside.
[0092] In some embodiments, the composition provides a Tmax for the
epinephrine in a subject that is about 2 fold or less as compared
to administration without alkylglycoside.
[0093] In some embodiments, the composition provides a Tmax for the
epinephrine of about 0.3 hours or less in a subject.
[0094] In some embodiments, the composition has a pH of about 2.0
to 6.0. In some embodiments, the composition has a pH of about 2.0
to 5.0.
[0095] In another aspect, described herein is a method of
increasing the bioavailability of epinephrine in a subject
comprising administering to a subject a pharmaceutical composition
comprising epinephrine and an alkylglycoside, thereby increasing
the bioavailability of the epinephrine in the subject; wherein the
pharmaceutical composition is formulated for administration into
the circulatory system of a subject via the intranasal, inhalation,
or pulmonary, administration route. In some embodiments, described
herein is a method of increasing the bioavailability of epinephrine
in a subject comprising administering to a subject a pharmaceutical
composition comprising epinephrine and an alkylglycoside, thereby
increasing the bioavailability of the epinephrine in the subject;
wherein the pharmaceutical composition is a liquid formulated for
intranasal delivery.
[0096] In some embodiments, increasing the bioavailabilty of
epinephrine permits for lower dose amounts of epeinpehrine to be
delivered intrasally and be efficacious for treating anaphylaxis.
In some embodiments, exposure to larger doses of epinephrine can
result in an epinephrine overdose. There is increased interest and
need in developing alternative non-invasive epinephrine dosage
forms that provide epinephrine plasma concentrations equivalent to
those obtained by epinephrine auto-injectors, available in a range
of doses, have a long shelf-life, and be free from needle anxiety,
the possibility of administration error, unintentional injection
and injury. Epinephrine nasal dosage forms described herein offer
the potential of being user-friendly, non-invasive alternatives for
the first-aid emergency treatment of anaphylaxis in community
settings.
[0097] In some embodiments, the alkylglycoside has an alkyl chain
including between 8 to 20 carbons. In some embodiments, the
alkylglycoside is selected from the group consisting of undecyl
maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl
maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and
sucrose mono-tetradecanoate. In some embodiments, the
alkylglycoside is dodecyl-beta-D-maltoside. In some embodiments,
the alkylglycoside concentration is between about 0.001% and 10.0%
(w/v). In some embodiments, the alkylglycoside concentration is
between about 0.05% and 0.5% (w/v).
[0098] In some embodiments, the composition further comprises a
membrane penetration-enhancing agent. In some embodiments, the
membrane penetration-enhancing agent is a surfactant, a bile salt,
a phospholipid, an alcohol, an enamine, a medium and/or long-chain
amphipathic molecules, a small hydrophobic molecule, sodium or a
salicylic acid derivative, a glycerol ester of acetoacetic acid, a
cyclodextrin, a medium-chain or long chain fatty acids, a chelating
agent, an amino acid or salt thereof, an enzyme or combination
thereof. In some embodiments, the membrane penetration-enhancing
agent is selected from the group consisting of citric acid, sodium
citrate, propylene glycol, glycerin, ascorbic acid, sodium
metabisulfite, ethylenediaminetetraacetic acid (EDTA) disodium,
benzalkonium chloride, sodium hydroxide, and combinations thereof.
In some embodiments, the membrane penetration-enhancing agent is
benzalkonium chloride, EDTA, or a combination thereof.
[0099] In some embodiments, the composition provides a C.sub.max
for the epinephrine in the subject that is about 2 fold or greater
as compared to administration without alkylglycoside.
[0100] In some embodiments, the composition provides a Tmax for the
epinephrine in the subject that is about 2 fold or less as compared
to administration without alkylglycoside.
[0101] In some embodiments, the composition provides a Tmax for the
epinephrine of about 0.3 hours or less in the subject.
[0102] In some embodiments, the composition has a pH of about 2.0
to 6.0. In some embodiments, the composition has a pH of about 2.0
to 5.0.
[0103] In some embodiments, compositions described here are liquid
compositions suitable for intranasal administration.
[0104] In one aspect, the invention provides a method of increasing
absorption of epinephrine into the circulatory system of a subject
by administering, via the nasal, inhalation or pulmonary delivery
route a composition comprising: (a) epinephrine; (b) an absorption
increasing amount of a suitable nontoxic, nonionic alkylglycoside
having a hydrophobic alkyl group joined by a linkage to a
hydrophilic saccharide; and (c) a mucosal delivery-enhancing
agent.
[0105] The term, "mucosal delivery-enhancing agent" includes agents
which enhance the release or solubility (e.g., from a formulation
delivery vehicle), diffusion rate, penetration capacity and timing,
uptake, residence time, stability, effective half-life, peak or
sustained concentration levels, clearance and other desired mucosal
delivery characteristics (e.g., as measured at the site of
delivery, or at a selected target site of activity such as the
bloodstream or central nervous system) of a compound(s) (e.g.,
biologically active compound). Enhancement of mucosal delivery can
occur by any of a variety of mechanisms, including, for example, by
increasing the diffusion, transport, persistence or stability of
the compound, increasing membrane fluidity, modulating the
availability or action of calcium and other ions that regulate
intracellular or paracellular permeation, solubilizing mucosal
membrane components (e.g., lipids), changing non-protein and
protein sulfhydryl levels in mucosal tissues, increasing water flux
across the mucosal surface, modulating epithelial junction
physiology, reducing the viscosity of mucus overlying the mucosal
epithelium, reducing mucociliary clearance rates, and other
mechanisms.
[0106] Exemplary mucosal delivery enhancing agents include the
following agents and any combinations thereof: [0107] (a) an
aggregation inhibitory agent; [0108] (b) a charge-modifying agent;
[0109] (c) a pH control agent; [0110] (d) a degradative enzyme
inhibitory agent; [0111] (e) a mucolytic or mucus clearing agent;
[0112] (f) a ciliostatic agent; [0113] (g) a membrane
penetration-enhancing agent selected from: [0114] (i) a surfactant;
[0115] (ii) a bile salt; [0116] (ii) a phospholipid additive, mixed
micelle, liposome, or carrier; [0117] (iii) an alcohol; [0118] (iv)
an enamine; [0119] (v) an NO donor compound; [0120] (vi) a
long-chain amphipathic molecule; [0121] (vii) a small hydrophobic
penetration enhancer; [0122] (viii) sodium or a salicylic acid
derivative; [0123] (ix) a glycerol ester of acetoacetic acid;
[0124] (x) a cyclodextrin or beta-cyclodextrin derivative; [0125]
(xi) a medium-chain fatty acid; [0126] (xii) a chelating agent;
[0127] (xiii) an amino acid or salt thereof; [0128] (xiv) an
N-acetylamino acid or salt thereof, [0129] (xv) an enzyme
degradative to a selected membrane component; [0130] (ix) an
inhibitor of fatty acid synthesis; [0131] (x) an inhibitor of
cholesterol synthesis; and [0132] (xi) any combination of the
membrane penetration enhancing agents recited in (i)-(x); [0133]
(h) a modulatory agent of epithelial junction physiology; [0134]
(i) a vasodilator agent; [0135] (j) a selective transport-enhancing
agent; and [0136] (k) a stabilizing delivery vehicle, carrier,
mucoadhesive, support or complex-forming species with which the
compound is effectively combined, associated, contained,
encapsulated or bound resulting in stabilization of the compound
for enhanced nasal mucosal delivery, wherein the formulation of the
compound with the intranasal delivery-enhancing agents provides for
increased bioavailability of the compound in a blood plasma of a
subject.
[0137] Additional mucosal delivery-enhancing agents include, for
example, citric acid, sodium citrate, propylene glycol, glycerin,
ascorbic acid (e.g., L-ascorbic acid), sodium metabisulfite,
ethylenediaminetetraacetic acid (EDTA) disodium, benzalkonium
chloride, sodium hydroxide, and mixtures thereof. For example, EDTA
or its salts (e.g., sodium or potassium) are employed in amounts
ranging from about 0.01% to 2% by weight of the composition
containing alkylsaccharide preservative.
[0138] In yet another aspect, described herein is a pharmaceutical
composition having a suitable nontoxic, nonionic alkylglycoside
having a hydrophobic alkyl group joined by a linkage to a
hydrophilic saccharide in combination with a mucosal
delivery-enhancing agent selected from: [0139] (a) an aggregation
inhibitory agent; [0140] (b) a charge-modifying agent; [0141] (c) a
pH control agent; [0142] (d) a degradative enzyme inhibitory agent;
[0143] (e) a mucolytic or mucus clearing agent; [0144] (f) a
ciliostatic agent; [0145] (g) a membrane penetration-enhancing
agent selected from: [0146] (i) a surfactant; [0147] (ii) a bile
salt; [0148] (ii) a phospholipid additive, mixed micelle, liposome,
or carrier; [0149] (iii) an alcohol; [0150] (iv) an enamine; [0151]
(v) an NO donor compound; [0152] (vi) a long-chain amphipathic
molecule; [0153] (vii) a small hydrophobic penetration enhancer;
[0154] (viii) sodium or a salicylic acid derivative; [0155] (ix) a
glycerol ester of acetoacetic acid; [0156] (x) a cyclodextrin or
beta-cyclodextrin derivative; [0157] (xi) a medium-chain or long
chain fatty acid; [0158] (xii) a chelating agent; [0159] (xiii) an
amino acid or salt thereof; [0160] (xiv) an N-acetylamino acid or
salt thereof; [0161] (xv) an enzyme degradative to a selected
membrane component; [0162] (ix) an inhibitor of fatty acid
synthesis; [0163] (x) an inhibitor of cholesterol synthesis; and
[0164] (xi) any combination of the membrane penetration enhancing
agents recited in (i)-(x); [0165] (h) a modulatory agent of
epithelial junction physiology; [0166] (i) a vasodilator agent;
[0167] (j) a selective transport-enhancing agent; and [0168] (k) a
stabilizing delivery vehicle, carrier, mucoadhesive, support or
complex-forming species with which the compound is effectively
combined, associated, contained, encapsulated or bound resulting in
stabilization of the compound for enhanced nasal mucosal delivery,
wherein the formulation of the compound with the intranasal
delivery-enhancing agents provides for increased bioavailability of
the compound in a blood plasma of a subject.
[0169] In another embodiment, described herein is a method of
administering an alkylglycoside composition by administering a
therapeutically effective amount of at least one alkyglycoside
having an alkyl chain length from about 12 to about 14 carbon
atoms, at least one saccharide with an antibacterial activity, and
epinephrine.
[0170] In one aspect, provided herein is an antibacterial
alkylsaccharide composition, which includes
n-dodecyl-4-O-.alpha.-D-glucopyranosyl-.beta.-D-glucopyranoside or
n-tetradecyl-4-O-.alpha.-D-glucopyranosyl-.beta.-D-glucopyranoside.
[0171] Accordingly, provided herein is Embodiment 1, a nasal spray
formulation comprising between about 0.40 mg and about 2.40 mg per
dose dispensed from the device of epinephrine, or a salt thereof.
Alternative Embodiment 1, a nasal spray formulation comprising
between about 0.40 mg and about 2.0 mg per dose dispensed from the
device of epinephrine, or a salt thereof.
Embodiment 2
[0172] The nasal spray formulation as recited in Embodiment 1,
wherein the formulation is a pharmaceutical formulation.
Embodiment 3
[0173] The nasal spray formulation as recited in Embodiment 2,
wherein the epinephrine or salt thereof is present in the
pharmaceutical formulation in an amount efficacious for the
treatment of an acute hypersensitivity reaction.
Embodiment 4
[0174] The nasal spray formulation as recited in any of Embodiments
1-3, wherein the formulation is aqueous.
Embodiment 5
[0175] The nasal spray formulation as recited in any of Embodiments
1-4, wherein the formulation comprises an absorption enhancer. In
alternative Embodiment 5, the nasal spray formulation as recited in
any of Embodiments 1-4, wherein the formulation comprises one or
more absorption enhancers.
Embodiment 6
[0176] The nasal spray formulation as recited in any of Embodiments
1-5, wherein the formulation has intramuscular (IM)-injection-like
or subcutaneous (SQ)-like absorption, or in between.
Embodiment 7
[0177] The nasal spray formulation as recited in Embodiment 6,
wherein has intramuscular (IM)-injection-like absorption.
Embodiment 8
[0178] The nasal spray formulation as recited in Embodiment 6,
wherein the formulation has subcutaneous (SC)-like absorption.
Embodiment 9
[0179] The nasal spray formulation as recited in Embodiment 8 where
the SC pharmacokinetic profile has a C.sub.max of at least 100
pg/mL and AUC.sub.0-240 min of 150 h*pg/mL.
Embodiment 10
[0180] The nasal spray formulation as recited in any of Embodiments
1-9, wherein the formulation, when administered to a subject,
yields one or more of the following pharmacokinetic features:
[0181] both the mean AUC.sub.0-20 min and AUC.sub.0-t are at least
80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.3 mg
intramuscular injection yields; [0182] a mean C.sub.max that is at
least 80% of the C.sub.max and no more than 150% of the C.sub.max
that a 0.3 mg intramuscular injection yields; [0183] a mean
t.sub.max of less than 45 minutes; and [0184] IM-injection like
absorption under optimal dosing conditions in the thigh.
Embodiment 11
[0185] The nasal spray formulation as recited in any of Embodiments
1-9, wherein the formulation, when administered to a subject,
yields one or more of the following pharmacokinetic features:
[0186] both the mean AUC.sub.0-20 min and AUC.sub.0-t are at least
80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.15 mg
intramuscular injection yields; [0187] a mean C.sub.max that is at
least 80% of the C.sub.max and no more than 150% of the C.sub.max
that a 0.15 mg intramuscular injection yields; [0188] a mean tmax
of less than 45 minutes; and [0189] IM-injection like absorption
under optimal dosing conditions in the thigh.
Embodiment 12
[0190] The nasal spray formulation as recited in any of Embodiments
1-9, wherein the formulation, when administered to a subject,
yields one or more of the following pharmacokinetic features:
[0191] both the mean AUC.sub.0-20 min and AUC.sub.0-t are at least
80% of the AUC.sub.0-20 min and AUC.sub.0-t that a 0.5 mg
intramuscular injection yields; [0192] a mean C.sub.max that is at
least 80% of the C.sub.max and no more than 150% of the C.sub.max
that a 0.5 mg intramuscular injection yields; [0193] a mean tmax of
less than 45 minutes; and [0194] IM-injection like absorption under
optimal dosing conditions in the thigh.
Embodiment 13
[0195] The nasal spray formulation as recited in Embodiment 1-12,
wherein the formulation, when administered to a subject, yields a
t.sub.max of less than 40 minutes, a t.sub.max of less than 35
minutes, a t.sub.max of between 30 and 45 minutes, a t.sub.max of
between 30 and 40 minutes, or a t.sub.max of between 30 and 35
minutes. Alternative Embodiment 13. The nasal spray formulation as
recited in Embodiment 1-12, wherein the formulation, when
administered to a subject, yields a t.sub.max of less than 40
minutes, a t.sub.max of less than 35 minutes, a t.sub.max of
between 15 and 45 minutes, a t.sub.max of between 20 and 45
minutes, a t.sub.max of between 25 and 45 minutes, a t.sub.max of
between 30 and 45 minutes, a t.sub.max of between 30 and 40
minutes, a t.sub.max of between 30 and 35 minutes, a t.sub.max of
between 15 and 20 minutes, a t.sub.max of between 15 and 25
minutes, or a t.sub.max of between 15 and 30 minutes.
Embodiment 14
[0196] The nasal spray formulation as recited in any of Embodiments
1-13, wherein the formulation comprises less than one molar
equivalents of acid to each mole of epinephrine.
Embodiment 15
[0197] The nasal spray formulation as recited in any of Embodiments
1-13, wherein the formulation comprises between about 0.5 and about
1.1 molar equivalents of acid to each mole of epinephrine.
Embodiment 16
[0198] The nasal spray formulation as recited in either of
Embodiments 14 and 15, wherein the acid is hydrochloric acid.
Alternative Embodiment 16, The nasal spray formulation as recited
in either of Embodiments 14 and 15, wherein the acid is acetic
acid, adipic acid, ammonium chloride, boric acid, citric acid,
hydrochloric acid, lactic acid, phosphoric acid, propionic acid,
sulfuric acid, or tartaric acid.
Embodiment 17
[0199] The nasal spray formulation as recited in any of Embodiments
1-16, wherein the formulation has a pH between about 3.0 and about
6.0. Alternative Embodiment 17. The nasal spray formulation as
recited in any of Embodiments 1-16, wherein the formulation has a
pH between about 2.0 and about 6.0.
Embodiment 18
[0200] The nasal spray formulation as recited in Embodiment 17,
wherein the formulation has a pH between about 3.5 and about
5.0.
Embodiment 19
[0201] The nasal spray formulation as recited in Embodiment 17,
wherein the formulation has a pH between about 4.0 and about
4.5.
Embodiment 20
[0202] The nasal spray formulation as recited in Embodiment 17,
wherein the formulation has a pH of about 4.5.
Embodiment 21
[0203] The nasal spray formulation as recited in Embodiment 17,
wherein the formulation has a pH of about 4.0.
Embodiment 22
[0204] The nasal spray formulation as recited in any of Embodiments
1-21, wherein the formulation comprises between about 5 mg/mL and
about 40 mg/mL epinephrine, or a salt thereof. Alternative
Embodiment 22. The nasal spray formulation as recited in any of
Embodiments 1-21, wherein the formulation comprises between about 3
mg/mL and about 40 mg/mL epinephrine, or a salt thereof.
Embodiment 23
[0205] The nasal spray formulation as recited in any of Embodiments
1-22, wherein the formulation comprises between about 0.9 mg and
about 2.4 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 24
[0206] The nasal spray formulation as recited in any of Embodiments
1-22, wherein the formulation comprises between about 0.5 mg and
about 2.0 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 25
[0207] The nasal spray formulation as recited in any of Embodiments
1-22, wherein, the formulation comprises between about 0.75 mg and
about 1.5 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 26
[0208] The nasal spray formulation as recited in any of Embodiments
1-22, wherein the formulation comprises between about 0.9 mg and
about 1.15 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 27
[0209] The nasal spray formulation as recited in any of Embodiments
1-22, wherein the formulation comprises about 1.0 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 28
[0210] The nasal spray formulation as recited in any of Embodiments
1-22, wherein the formulation comprises between about 0.45 mg and
about 1.15 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 29
[0211] The nasal spray formulation as recited in any of Embodiments
1-22, wherein the formulation comprises between about 1.0 mg and
about 2.0 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 30
[0212] The nasal spray formulation as recited in any of Embodiments
1-29, wherein the formulation additionally comprises a stabilizing
agent.
Embodiment 31
[0213] The nasal spray formulation as recited in Embodiment 30,
wherein the stabilizing agent is ethylenediaminetetraacetic acid
(EDTA) or a salt thereof.
Embodiment 32
[0214] The nasal spray formulation as recited in Embodiment 31,
wherein the EDTA is disodium EDTA.
Embodiment 33
[0215] The nasal spray formulation as recited in Embodiment 31 or
32, wherein the EDTA is present in an amount that is from 5% to 15%
of the amount of the epinephrine, both measured in mmol.
Alternative Embodiment 33. The nasal spray formulation as recited
in Embodiment 31 or 32, wherein the EDTA is present in an amount
that is from 0.001% (w/v) to 1% (w/v).
Embodiment 34
[0216] The nasal spray formulation as recited in Embodiment 31 or
32, wherein the mmol of EDTA is about 10% of the mmol of the
epinephrine.
Embodiment 35
[0217] The nasal spray formulation as recited in any of Embodiments
1-34, wherein the formulation additionally comprises a
preservative.
Embodiment 36
[0218] The nasal spray formulation as recited in Embodiment 35,
wherein the preservative is benzalkonium chloride.
Embodiment 37
[0219] The nasal spray formulation as recited in any of Embodiments
1-34, wherein the formulation additionally comprises an absorption
enhancer.
Embodiment 38
[0220] The nasal spray formulation as recited in Embodiment 37,
wherein the absorption enhancer is an alkylsaccharide.
Embodiment 39
[0221] The nasal spray formulation as recited in Embodiment 38,
wherein the absorption enhancer is dodecyl maltoside.
Embodiment 40
[0222] The nasal spray formulation as recited in Embodiment 39,
wherein the formulation comprises about 0.005% (w/v) to about 2.5%
(w/v) dodecyl maltoside.
Embodiment 41
[0223] The nasal spray formulation as recited in Embodiment 40,
wherein the formulation comprises about 0.1% (w/v) to about 0.5%
(w/v) dodecyl maltoside.
Embodiment 42
[0224] The nasal spray formulation as recited in Embodiment 41,
wherein the formulation comprises about 0.25% (w/v) dodecyl
maltoside. Alternative Embodiment 42. The nasal spray formulation
as recited in Embodiment 41, wherein the formulation comprises
about 0.25% (w/v) dodecyl maltoside and about 0.001 (w/v) to about
1% (w/v) benzalkonium chloride. Alternative Embodiment 42. The
nasal spray formulation as recited in Embodiment 41, wherein the
formulation comprises about 0.25% (w/v) dodecyl maltoside and about
0.001 (w/v) to about 1% (w/v) Oleic acid, or salt thereof.
Alternative Embodiment 42. The nasal spray formulation as recited
in Embodiment 41, wherein the formulation comprises about 0.25%
(w/v) dodecyl maltoside, about 0.001 to about 1% (w/v) benzalkonium
chloride and about 0.001 to about 1% (w/v) oleic acid, or salt
thereof.
Embodiment 43a
[0225] In certain embodiments, the formulation comprises between
about 0.75 mg and about 1.5 mg per dose dispensed from the device
of epinephrine, or a salt thereof, and when administered as a nasal
spray to a subject yields one or more of the following
pharmacokinetic features: [0226] both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.3 mg intramuscular injection yields; [0227] a
mean C.sub.max that is at least 80% of the C.sub.max and no more
than 150% of the C.sub.max that a 0.3 mg intramuscular injection
yields; [0228] a mean tmax of less than 45 minutes; and [0229]
IM-injection like absorption under optimal dosing conditions in the
thigh.
Embodiment 43b
[0230] In certain embodiments, the formulation comprises between
about 0.5 mg and about 1.15 mg per dose dispensed from the device
of epinephrine, or a salt thereof, and when administered as a nasal
spray to a subject yields one or more of the following
pharmacokinetic features: [0231] Both the mean AUC.sub.0-20 min and
AUC.sub.0-t is at least 80% of the AUC.sub.0-20 min and AUC.sub.0-t
that a 0.15 mg intramuscular injection yields; [0232] A mean
C.sub.max that is at least 80% of the C.sub.max and no more than
150% of the C.sub.max that a 0.15 mg intramuscular injection
yields; [0233] A mean tmax of less than 45 minutes [0234]
IM-injection like absorption under optimal dosing conditions in the
thigh.
Embodiment 43c
[0235] In certain embodiments, the formulation comprises between
about 1.0 mg and about 2.0 mg per dose dispensed from the device of
epinephrine, or a salt thereof, and when administered as a nasal
spray to a subject yields one or more of the following
pharmacokinetic features: [0236] both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.5 mg intramuscular injection yields; [0237] a
mean C.sub.max that is at least 80% of the C.sub.max and no more
than 150% of the C.sub.max that a 0.5 mg intramuscular injection
yields; [0238] a mean tmax of less than 45 minutes; and [0239]
IM-injection like absorption under optimal dosing conditions in the
thigh.
[0240] Also provided are embodiments wherein any of Embodiments
43a, 43b, and 43c comprise one or more of the limitations recited
above in Embodiments 2-22 and 30-42.
[0241] Also provided herein is Embodiment 44, a nasal spray
formulation comprising epinephrine, or a salt thereof, which when
administered to a subject, yields one or more of the following
pharmacokinetic features: [0242] both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.3 mg intramuscular injection yields; [0243] a
mean C.sub.max that is at least 80% of the Cmax and no more than
150% of the C.sub.max that a 0.3 mg intramuscular injection yields;
[0244] a mean t.sub.max of less than 45 minutes; and [0245]
IM-injection like absorption under optimal dosing conditions in the
thigh.
[0246] Also provided herein is Embodiment 45, a nasal spray
formulation comprising epinephrine, or a salt thereof, which when
administered to a subject, yields one or more of the following
pharmacokinetic features: [0247] both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.15 mg intramuscular injection yields; [0248] a
mean C.sub.max that is at least 80% of the C.sub.max and no more
than 150% of the C.sub.max that a 0.15 mg intramuscular injection
yields; [0249] a mean t.sub.max of less than 45 minutes; and [0250]
IM-injection like absorption under optimal dosing conditions in the
thigh,
[0251] Also provided herein is Embodiment 46, a nasal spray
formulation comprising epinephrine, or a salt thereof, which when
administered to a subject, yields one or more of the following
pharmacokinetic features: [0252] both the mean AUC.sub.0-20 min and
AUC.sub.0-t are at least 80% of the AUC.sub.0-20 min and
AUC.sub.0-t that a 0.5 mg intramuscular injection yields; [0253] a
mean C.sub.max that is at least 80% of the C.sub.max and no more
than 150% of the C.sub.max that a 0.5 mg intramuscular injection
yields; [0254] a mean t.sub.max of less than 45 minutes; and [0255]
IM-injection like absorption under optimal dosing conditions in the
thigh.
Embodiment 47
[0256] The nasal spray formulation as recited in any of Embodiments
45-46, comprising between about 0.4 mg and about 2.40 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 48
[0257] The nasal spray formulation as recited in Embodiment 47,
wherein the formulation is a pharmaceutical formulation.
Embodiment 49
[0258] The nasal spray formulation as recited in Embodiment 48,
wherein the epinephrine or salt thereof is present in the
pharmaceutical formulation in an amount efficacious for the
treatment of an acute hypersensitivity reaction.
Embodiment 50
[0259] The nasal spray formulation as recited in any of Embodiments
44-49, wherein the formulation is aqueous.
Embodiment 51
[0260] The nasal spray formulation as recited in any of Embodiments
44-50, wherein the formulation has intramuscular
(IM)-injection-like or subcutaneous (SQ)-like absorption.
Embodiment 52
[0261] The nasal spray formulation as recited in Embodiment 51,
wherein the formulation has intramuscular (IM)-injection-like
absorption.
Embodiment 53
[0262] The nasal spray formulation as recited in Embodiment 51,
wherein the formulation has subcutaneous (SQ)-like absorption.
Embodiment 54
[0263] The nasal spray formulation as recited in Embodiment 1-51
where the SC pharmacokinetic profile has a C.sub.max of at least
100 pg/mL and AUC.sub.0-240 min of 150 h*pg/mL.
Embodiment 55
[0264] The nasal spray formulation as recited in any of Embodiments
44-54, wherein the formulation comprises between about 5 mg/mL and
about 40 mg/mL of epinephrine, or a salt thereof.
Embodiment 56
[0265] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises between about 0.9 mg and
about 2.4 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 57
[0266] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises between about 0.5 mg and
about 2.0 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 58
[0267] The nasal spray formulation as recited in any of Embodiments
44-55, wherein, the formulation comprises between about 0.75 mg and
about 1.5 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 59
[0268] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises between about 0.9 mg and
about 1.15 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 60
[0269] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises about 1.0 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 61
[0270] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises between about 0.45 mg and
about 1.15 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 62
[0271] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises between about 0.5 mg and
about 2.0 mg per dose dispensed from the device of epinephrine, or
a salt thereof.
Embodiment 63
[0272] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises about 0.5 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 64
[0273] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises about 0.75 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 65
[0274] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises about 1.0 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 66
[0275] The nasal spray formulation as recited in any of Embodiments
44-55, wherein the formulation comprises about 1.5 mg per dose
dispensed from the device of epinephrine, or a salt thereof.
Embodiment 67
[0276] The nasal spray formulation as recited in any of Embodiments
44-66, wherein the formulation comprises less than one molar
equivalents of acid to each mole of epinephrine.
Embodiment 68
[0277] The nasal spray formulation as recited in any of Embodiments
44-66, wherein the formulation comprises between about 0.5 and
about 1.1 molar equivalents of acid to each mole of
epinephrine.
Embodiment 69
[0278] The nasal spray formulation as recited in either of
Embodiments 66 and 67, wherein the acid is a strong acid. Strong
acids include hydrochloric acid, phosphoric acid, and sulfuric
acid.
Embodiment 70
[0279] The nasal spray formulation as recited in Embodiment 69,
wherein the acid is hydrochloric acid.
Embodiment 71
[0280] The nasal spray formulation as recited in any of Embodiments
44-70, wherein no base is added to the formulation during its
preparation.
Embodiment 72
[0281] The nasal spray formulation as recited in any of Embodiments
44-71, wherein the formulation has a pH between about 3.0 and about
6.0. Alternative embodiment Embodiment 72. The nasal spray
formulation as recited in any of Embodiments 44-71, wherein the
formulation has a pH between about 2.0 and about 6.0.
Embodiment 73
[0282] The nasal spray formulation as recited in Embodiment 72,
wherein the formulation has a pH between about 3.5 and about
5.0.
Embodiment 74
[0283] The nasal spray formulation as recited in Embodiment 72,
wherein the formulation has a pH between about 4.0 and about
4.5.
Embodiment 75
[0284] The nasal spray formulation as recited in Embodiment 72,
wherein the formulation has a pH of about 4.5.
Embodiment 76
[0285] The nasal spray formulation as recited in Embodiment 72,
wherein the formulation has a pH of about 4.0.
Embodiment 77
[0286] The nasal spray formulation as recited in any of Embodiments
44-76, wherein the formulation additionally comprises a stabilizing
agent.
Embodiment 78
[0287] The nasal spray formulation as recited in Embodiment 77,
wherein the stabilizing agent is ethylenediaminetetraacetic acid
(EDTA) or a salt thereof.
Embodiment 79
[0288] The nasal spray formulation as recited in Embodiment 78,
wherein the EDTA is disodium EDTA.
Embodiment 80
[0289] The nasal spray formulation as recited in Embodiment 78,
wherein the EDTA is present in an amount that is from 5% to 15% of
the amount of the epinephrine, both measured in mmol. Alternative
Embodiment 80. The nasal spray formulation as recited in Embodiment
78, wherein the EDTA is present in an amount that is from about
0.001% (w/v) to about 1% (w/v).
Embodiment 81
[0290] The nasal spray formulation as recited in Embodiment 79,
wherein the mmol of EDTA is about 10% of the mmol of the
epinephrine.
Embodiment 82
[0291] The nasal spray formulation as recited in any of Embodiments
44-81, wherein the formulation additionally comprises a
preservative.
Embodiment 83
[0292] The nasal spray formulation as recited in Embodiment 82,
wherein the preservative is benzalkonium chloride.
Embodiment 84
[0293] The nasal spray formulation as recited in any of Embodiments
44-83, wherein the formulation additionally comprises an absorption
enhancer. In alternative Embodiment 84, The nasal spray formulation
as recited in any of Embodiments 44-83, wherein the formulation
additionally comprises one or more absorption enhancers.
Embodiment 85
[0294] The nasal spray formulation as recited in Embodiment 84,
wherein the absorption enhancer is an alkylsaccharide. In
alternative Embodiment 85, The nasal spray formulation as recited
in Embodiment 84, wherein the absorption enhancer is an
alkylsaccharide and/or benzalkonium chloride.
Embodiment 86
[0295] The nasal spray formulation as recited in Embodiment 85,
wherein the absorption enhancer is dodecyl maltoside. In
alternative Embodiment 86, The nasal spray formulation as recited
in Embodiment 85, wherein the absorption enhancer is dodecyl
maltoside, benzalkonium chloride, or a combination of dodecyl
maltoside and benzylalkonium chloride.
Embodiment 87
[0296] The nasal spray formulation as recited in Embodiment 86,
wherein the formulation comprises about 0.005% (w/v) to about 2.5%
(w/v) dodecyl maltoside.
Embodiment 88
[0297] The nasal spray formulation as recited in Embodiment 87,
wherein the formulation comprises about 0.1% (w/v) to about 0.5%
(w/v) dodecyl maltoside.
Embodiment 89
[0298] The nasal spray formulation as recited in Embodiment 88,
wherein the formulation comprises about 0.25% (w/v) dodecyl
maltoside. Also provided is Embodiment 90, a method of treatment of
a condition mediated by adrenergic receptors comprising the
intranasal administration of the formulation as recited in any of
Embodiments 1-89 above.
Embodiment 91
[0299] The method as recited in Embodiment 90, wherein the
condition is chosen from a type-1 hypersensitivity reaction
(systemic allergic reaction), an acute asthmatic attack, cardiac
arrest, and Stokes-Adams Syndrome.
Embodiment 92
[0300] The method as recited in Embodiment 91, wherein the
condition is a type-1 hypersensitivity reaction (systemic allergic
reaction).
Embodiment 93
[0301] The method as recited in Embodiment 92, wherein the type-1
hypersensitivity reaction (systemic allergic reaction) is chosen
from allergic asthma, allergic conjunctivitis, allergic rhinitis,
anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy and
food allergy.
Embodiment 94
[0302] The method as recited in Embodiment 93, wherein the drug
allergy is an antibiotic allergy.
Embodiment 95
[0303] Also provided herein is a method of treatment of a systemic
allergic reaction and anaphylaxis comprising the intranasal
administration of an unbuffered intranasal formulation of
epinephrine in an amount less than about 2.0 mg.
[0304] Also provided are embodiments wherein Embodiment 95
comprises one or more of the limitations recited above in
Embodiments 2-22, 25-28, 30-55, 58-61, and 63-89.
Embodiment 96
[0305] A pharmaceutical composition comprising: a) epinephrine; and
b) an alkylglycoside; wherein the composition is formulated for
administration into the circulatory system of a subject via the
intranasal, inhalation, or pulmonary administration route.
Alternative Embodiment 96. A pharmaceutical composition comprising:
a) epinephrine; and b) an alkylglycoside; wherein the composition
is a liquid formulated for intranasal delivery.
Embodiment 97
[0306] The pharmaceutical composition of Embodiment 96, wherein the
alkylglycoside has an alkyl chain including between 8 to 20
carbons.
Embodiment 98
[0307] The pharmaceutical composition of Embodiment 97, wherein the
alkylglycoside is selected from the group consisting of undecyl
maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl
maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and
sucrose mono-tetradecanoate.
Embodiment 99
[0308] The pharmaceutical composition of Embodiment 98, wherein the
alkylglycoside is dodecyl-beta-D-maltoside.
Embodiment 100
[0309] The pharmaceutical composition of Embodiment 96, wherein the
alkylglycoside concentration is between about 0.001% and 10.0%
(w/v).
Embodiment 101
[0310] The pharmaceutical composition of Embodiment 100, wherein
the alkylglycoside concentration is between about 0.05% and 0.5%
(w/v).
Embodiment 102
[0311] The pharmaceutical composition of Embodiment 96, wherein the
composition further comprises a membrane penetration-enhancing
agent. The pharmaceutical composition of Embodiment 96, wherein the
composition further comprises a membrane penetration-enhancing
agent, pH modifier, buffering agents, isotonicity agent,
antioxidant, chelator, preservative, or a combination thereof.
Embodiment 103
[0312] The pharmaceutical composition of Embodiment 102, wherein
the membrane penetration-enhancing agent is a surfactant, a bile
salt, a phospholipid, an alcohol, an enamine, a medium and/or
long-chain amphipathic molecule, a small hydrophobic molecule,
sodium or a salicylic acid derivative, a glycerol ester of
acetoacetic acid, a cyclodextrin, a medium-chain or long chain
fatty acid, a chelating agent, an amino acid or salt thereof, an
enzyme or combination thereof.
Embodiment 104
[0313] The pharmaceutical composition of Embodiment 102, wherein
the membrane penetration-enhancing agent is selected from the group
consisting of citric acid, sodium citrate, propylene glycol,
glycerin, ascorbic acid, sodium metabisulfite,
ethylenediaminetetraacetic acid (EDTA) disodium, benzalkonium
chloride, sodium hydroxide, and combinations thereof.
Embodiment 105
[0314] The pharmaceutical composition of Embodiment 102, wherein
the membrane penetration-enhancing agent is benzalkonium chloride,
EDTA, or a combination thereof.
Embodiment 106
[0315] The pharmaceutical composition of Embodiment 96, wherein the
composition provides a C.sub.max for the epinephrine in a subject
that is about 2 fold or greater as compared to administration
without alkylglycoside.
Embodiment 107
[0316] The pharmaceutical composition of Embodiment 96, wherein the
composition provides a Tmax for the epinephrine in a subject that
is about 2 fold or less as compared to administration without
alkylglycoside.
Embodiment 108
[0317] The pharmaceutical composition of Embodiment 96, wherein the
composition provides a Tmax for the epinephrine of about 0.3 hours
or less in a subject.
Embodiment 109
[0318] The pharmaceutical composition of Embodiment 96, wherein the
composition has a pH of about 2.0 to 5.0.
Embodiment 110
[0319] A method of increasing the bioavailability of epinephrine in
a subject comprising administering to a subject a composition
comprising epinephrine and an alkylglycoside, thereby increasing
the bioavailability of the epinephrine in the subject, wherein the
composition is administered into the circulatory system of the
subject via the intranasal, inhalation, or pulmonary administration
route. Alternative Embodiment 110. A method of increasing the
bioavailability of epinephrine in a subject comprising
administering to a subject a composition comprising epinephrine and
an alkylglycoside, thereby increasing the bioavailability of the
epinephrine in the subject, wherein the composition is a liquid
composition administered intranasally.
Embodiment 111
[0320] The method of Embodiment 110, wherein the alkylglycoside has
an alkyl chain including between 8 to 20 carbons.
Embodiment 112
[0321] The method of Embodiment 111, wherein the alkylglycoside is
selected from the group consisting of undecyl maltoside, dodecyl
maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose
mono-dodecanoate, sucrose mono-tridecanoate, and sucrose
mono-tetradecanoate.
Embodiment 113
[0322] The method of Embodiment 112, wherein the alkylglycoside is
dodecyl-beta-D-maltoside.
Embodiment 114
[0323] The method of Embodiment 110, wherein the alkylglycoside
concentration is between about 0.001% and 10.0% (w/v).
Embodiment 115
[0324] The method of Embodiment 114, wherein the alkylglycoside
concentration is between about 0.05% and 0.5% (w/v).
Embodiment 116
[0325] The method of Embodiment 110, wherein the composition
further comprises a membrane penetration-enhancing agent.
Embodiment 117
[0326] The method of Embodiment 116, wherein the membrane
penetration-enhancing agent is a surfactant, a bile salt, a
phospholipid, an alcohol, an enamine, a long-chain amphipathic
molecule, a small hydrophobic molecule, sodium or a salicylic acid
derivative, a glycerol ester of acetoacetic acid, a cyclodextrin, a
medium-chain fatty acid, a chelating agent, an amino acid or salt
thereof, an enzyme or combination thereof.
Embodiment 118
[0327] The method of Embodiment 117, wherein the membrane
penetration-enhancing agent is selected from the group consisting
of citric acid, sodium citrate, propylene glycol, glycerin,
ascorbic acid, sodium metabisulfite, ethylenediaminetetraacetic
acid (EDTA) disodium, benzalkonium chloride, sodium hydroxide, and
combinations thereof.
Embodiment 119
[0328] The method of Embodiment 116, wherein the membrane
penetration-enhancing agent is benzalkonium chloride, EDTA, or a
combination thereof.
Embodiment 120
[0329] The method of Embodiment 110, wherein the composition
provides a C.sub.max for the epinephrine in the subject that is
about 2 fold or greater as compared to administration without
alkylglycoside.
Embodiment 121
[0330] The method of Embodiment 110, wherein the composition
provides a Tmax for the epinephrine in the subject that is about 2
fold or less as compared to administration without
alkylglycoside.
Embodiment 122
[0331] The method of Embodiment 110, wherein the composition
provides a Tmax for the epinephrine of about 0.3 hours or less in
the subject.
Embodiment 123
[0332] The method of Embodiment 110, wherein the composition has a
pH of about 2.0 to 6.0. Alternative Embodiment 123. The method of
Embodiment 110, wherein the composition has a pH of about 2.0 to
5.0.
Definitions
[0333] As used herein, the following terms have the meanings
indicated.
[0334] When ranges of values are disclosed, and the notation "from
n.sub.1 . . . to n.sub.2" or "between n.sub.1 . . . and n.sub.2" is
used, where n.sub.1 and n.sub.2 are the numbers, then unless
otherwise specified, this notation is intended to include the
numbers themselves and the range of numbers between them. This
range may be integral or continuous between and including the end
values. By way of example, the range "from 2 to 6 carbons" is
intended to include two, three, four, five, and six carbons, since
carbons come in integer units. Compare, by way of example, the
range "from 1 to 3 .mu.M (micromolar)," which is intended to
include 1 .mu.M, 3 .mu.M, and everything in between to any number
of significant figures (e.g., 1.255 .mu.M, 2.1 .mu.M, 2.9999 .mu.M,
etc.).
[0335] The term "about," as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as
variable within a range. When no range, such as a margin of error
or a standard deviation to a mean value given in a chart or table
of data, is recited, the term "about" should be understood to mean
the greater of the range which would encompass the recited value
and the range which would be included by rounding up or down to
that figure as well, considering significant figures, and the range
which would encompass the recited value plus or minus 20%.
[0336] "Weight per volume" or "w/v" refers to the mass in grams of
a dissolved solute divided by the volume in milliliters of the
entire solution. Typically, weight by volume is expressed as a
percentage.
[0337] The term "absorption enhancer," as used herein, refers to a
functional excipient included in formulations to improve the
absorption of an active agent such as a pharmacologically active
drug. This term usually refers to an agent whose function is to
increase absorption by enhancing nasal mucous-membrane permeation,
rather than increasing solubility. As such, such agents are
sometimes called permeation enhancers or penetration enhancers. In
particular, absorption enhancers described herein may improve
paracellular transport (i.e., passage through intercellular spaces
and tight junctions), transcellular transport (i.e., passive
diffusion or active transport across cellular membranes), or
transcytosis (i.e., cellular vesicular uptake). Ozsoy et al.,
Molecules 14:3754-79, 2009.
[0338] Examples of absorption enhancers include alcohol, aprotinin,
benzalkonium chloride, benzyl alcohol, capric acid, ceramides,
cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic
acid, decanoyl, dimethyl sulfoxide, glyceryl monooleate,
glycofurol, glycofurol, glycosylated sphingosines, glycyrrhetinic
acids, 2-hydroxypropyl-.beta.-cyclodextrin, laureth-9, lauric acid,
lauroyl carnitine, sodium lauryl sulfate, lysophosphatidylcholine,
menthol, poloxamer 407 or F68, poly-L-arginine,
polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl
palmitate, lanolin, light mineral oil, linoleic acid, menthol,
myristic acid, myristyl alcohol, oleic acid, or salt thereof, oleyl
alcohol, palmitic acid, polysorbate 80, propylene glycol,
polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone,
quillaia saponin, salicylic acid, sodium salt, .beta.-sitosterol
.beta.-D-glucoside, sucrose cocoate, taurocholic acid,
taurodeoxycholic acid, taurodihydrofusidic acid, thymol,
tricaprylin, triolein, and alkylsaccharides, and combinations
thereof, including but not limited to dodecyl maltoside,
dodecyl-.beta.-D-maltoside, tetradecyl maltoside,
tetradecyl-.beta.-D-maltoside and sucrose dodecanoate.
Alkylsaccharides (e.g., nonionic alkylsaccharide surfactants such
as alkylglycosides and sucrose esters of fatty acids that consist
of an aliphatic hydrocarbon chain coupled to a sugar moiety by a
glycosidic or ester bond, respectively), cyclodextrins (cyclic
oligosaccharides composed of six or more monosaccharide units with
a central cavity, which form inclusion complexes with hydrophobic
molecules and they have primarily been used to increase drug
solubility and dissolution and to enhance low molecular weight drug
absorption), chitosans (linear cationic polysaccharides produced
from the deacetylation of chitin), and bile salts and their
derivatives (such as sodium glycocholate, sodium taurocholate, and
sodium taurodihydrofusidate) tend to be amongst the best-tolerated
absorption enhancers. See, e.g., Aungst B J, AAPS Journal
14(1):10-8, 2011; and Maggio, E T, Excipients and Food Chem.
5(2):100-12, 2014. Due to their chemical properties, certain
absorption enhancers can function as preservatives and/or cationic
surfactants in certain circumstances, depending on concentration in
the formulation and other factors.
[0339] Described herein are compositions comprising epinephrine and
at least one absorption enhancer and/or preservative and/or
surfactant wherein the at least one absorption enhancer and/or
preservative and/or surfactant comprises at least one
alkylglycoside and/or at least one saccharide alkyl ester.
[0340] As used herein, the term "alkylsaccharide" (also referred to
herein as "alkylglycoside") refers to a type of an absorption
enhancer. As used herein, an alkylsaccharide refers to any sugar
joined by a linkage to any hydrophobic alkyl, as is known in the
art. Alkylsaccharides include, but are not limited to:
alkylsaccharides, such as octyl-, nonyl-, decyl-, undecyl-,
dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-,
heptadecyl-, and octadecyl-.alpha.- or .beta.-D-maltoside,
-glucoside or -sucroside; alkyl thiomaltosides, such as heptyl,
octyl, dodecyl-, tridecyl-, and tetradecyl-.beta.-D-thiomaltoside;
alkyl thioglucosides, such as heptyl- or octyl 1-thio .alpha.- or
.beta.-D-glucopyranoside; alkyl thiosucroses; alkyl maltotriosides;
long chain aliphatic carbonic acid amides of sucrose
.beta.-amino-alkyl ethers; derivatives of palatinose and
isomaltamine linked by amide linkage to an alkyl chain; derivatives
of isomaltamine linked by urea to an alkyl chain; long chain
aliphatic carbonic acid ureides of sucrose .beta.-amino-alkyl
ethers; and long chain aliphatic carbonic acid amides of sucrose
.beta.-amino-alkyl ethers. The hydrophobic alkyl can be chosen of
any desired size, depending on the hydrophobicity desired and the
hydrophilicity of the saccharide moiety. For example, one preferred
range of alkyl chains is from about 9 to about 24 carbon atoms. An
even more preferred range is from about 9 to about 16 or about 14
carbon atoms. Similarly, some preferred saccharides include
maltose, sucrose, and glucose linked by glycosidic linkage to an
alkyl chain of 9, 10, 12, 13, 14, 16, 18, 20, 22, or 24 carbon
atoms, e.g., nonyl-, decyl-, dodecyl- and tetradecyl sucroside,
glucoside, and maltoside, etc. The alkyl chain of an
alkylsaccharide is often linked to the saccharide via a glycosidic
bond, and accordingly, alkylsaccharides are often interchangeably
referred to as alkylglycosides.
[0341] Any "suitable" alkylglycoside means one that fulfills the
characteristics contemplated herein, i.e., that the alkylglycoside
be nontoxic and nonionic, and that it increases the absorption of a
compound (e.g. epinephrine) when it is administered with the
compound via the nasal delivery route.
[0342] As use herein, a "saccharide" is inclusive of
monosaccharides, oligosaccharides or polysaccharides in straight
chain or ring forms, or a combination thereof to form a saccharide
chain. Oligosaccharides are saccharides having two or more
monosaccharide residues. The saccharide can be chosen, for example,
from any currently commercially available saccharide species or can
be synthesized. Some examples of the many possible saccharides to
use include glucose, maltose, maltotriose, maltotetraose, sucrose
and trehalose. Preferable saccharides include maltose, sucrose and
glucose.
[0343] In some embodiments, described herein are composition that
include at least one alkylglycoside and/or saccharide alkyl ester
and epinephrine, methods of administering and using the
compositions via the nasal delivery route, and methods of
ameliorating a disease state in a subject by administration of such
compositions.
[0344] In some embodiments, described herein is a method of
administering a composition having at least one alkylglycoside
and/or saccharide alkyl ester admixed, mixed, or blended with
epinephrine and administered or delivered to a subject, wherein the
alkyl has from about 10 to 24, 10 to 20, 10 to 16, or 10 to 14
carbon atoms, wherein the at least one alkylglycoside and/or
saccharide alkyl ester increases the stability and bioavailability
of the therapeutic agent.
[0345] In some embodiments, alkylsaccharides contemplated have a
hydrophobic alkyl group linked to a hydrophilic saccharide. The
linkage between the hydrophobic alkyl group and the hydrophilic
saccharide can include, among other possibilities, a glycosidic,
thioglycosidic (Horton), amide (Carbohydrates as Organic Raw
Materials, F. W. Lichtenthaler ed., VCH Publishers, New York,
1991), ureide (Austrian Pat. 386,414 (1988); Chem. Abstr.
110:137536p (1989); see Gruber, H. and Greber, G., "Reactive
Sucrose Derivatives" in Carbohydrates as Organic Raw Materials, pp.
95-116) or ester linkage (Sugar Esters: Preparation and
Application, J. C. Colbert ed., (Noyes Data Corp., New Jersey),
(1974)). Further, preferred glycosides can include maltose,
sucrose, and glucose linked by glycosidic linkage to an alkyl chain
of about 9-16 carbon atoms, e.g., nonyl-, decyl-, dodecyl- and
tetradecyl sucroside, glucoside, and maltoside. These compositions
are amphipathic and nontoxic, because they degrade to an alcohol
and an oligosaccharide.
[0346] The above examples are illustrative of the types of
glycosides contemplated, but the list is not exhaustive.
Derivatives of the above compounds which fit the criteria described
herein are also contemplated when choosing an alkylsaccharide.
[0347] In some embodiments, membrane penetration-enhancing agents
contemplated serve as anti-bacterial agents. An agent is an
"anti-bacterial" agent or substance if the agent or its equivalent
destroy bacteria, or suppress bacterial growth or reproduction.
[0348] The term "active ingredient" or "pharmaceutically active
compound" is defined in the context of a "formulation" and is
intended to mean a component of a pharmaceutical formulation that
provides the primary pharmacological effect, as opposed to an
"inactive ingredient" which would generally be recognized as
providing no pharmaceutical benefit.
[0349] The term "actuation," as used herein, refers to operation of
the device such that the pharmaceutical formulation is delivered
therefrom.
[0350] The term "antimicrobial preservative," as used herein,
refers to a pharmaceutically acceptable excipient with
antimicrobial properties which is added to a pharmaceutical
formulation to maintain microbiological stability. Antimicrobial
preservatives include, but are not limited to, antibacterial
agents, antifungal agents, antioxidants, and preservatives.
[0351] The term "AUC," as used herein, refers to the area under the
drug plasma concentration-time curve. The term "AUC.sub.0-t," as
used herein, refers to the area under the drug plasma
concentration-time curve from t=0 to the last measured or
measurable concentration. The term "AUC.sub.0-.infin.," or
equivalently, "AUC.sub.0-inf," as used herein, refers to the area
under the drug plasma concentration-time curve extrapolated to
infinity (Go).
[0352] As used here, the term "benzalkonium chloride" ("BZK")
refers to a member of the class of quaternary ammonium compounds
having the following structure:
##STR00001##
in which n is an integer. Benzalkonium chloride is a mixture of
alkylbenzyl dimethylammonium chlorides, where a mixture of more
than one n is used. In certain embodiments, n is 8, 10, 12, 14, 16,
or 18. In other embodiments, n is 10, 12, or 14. In some
embodiments, a mixture of n is 10, 12 and/or 14 predominate. In
some embodiments, a mixture of n is 10, 12, 14 and/or 16
predominate. In some embodiments, benzalkonium chloride functions
as a preservative (even in low amounts), an antiseptic, a
disinfectant, a solubilizing and wetting agent, and/or a cationic
surfactant. In some cases, benzalkonium chloride refers to a type
of an absorption enhancer.
[0353] The term "bioavailability (F)," as used herein, refers to
the fraction of a dose of drug that is absorbed from its site of
administration and reaches, in an unchanged form, the systemic
circulation. The term "absolute bioavailability" is used when the
fraction of absorbed drug is related to its IV bioavailability. It
may be calculated using the following formula:
F = AUC extravascular AUC intravenous .times. Dose intravenous Dose
extravascular ##EQU00001##
[0354] The term "relative bioavailability (F.sub.rel)" is used to
compare two different extravascular routes of drug administration
and it may be calculated using the following formula:
F rel = AUC extravascular 1 AUC extravascular 2 .times. Dose
extravascular 2 Dose extravascular 1 ##EQU00002##
[0355] The term "clearance (CL)," as used herein, refers to the
rate at which a drug is eliminated divided by its plasma
concentration, giving a volume of plasma from which drug is
completely removed per unit of time. CL is equal to the elimination
rate constant (2) multiplied by the volume of distribution
(V.sub.d), wherein "V.sub.d" is the fluid volume that would be
required to contain the amount of drug present in the body at the
same concentration as in the plasma. The term "apparent clearance
(CL/F)," as used herein, refers to clearance that does not take
into account the bioavailability of the drug. It is the ratio of
the dose over the AUC.
[0356] The term "C.sub.max," as used herein, refers to the maximum
observed plasma concentration.
[0357] The term "coefficient of variation (CV)," as used herein,
refers to the ratio of the sample standard deviation to the sample
mean. It is often expressed as a percentage.
[0358] The term "confidence interval," as used herein, refers to a
range of values which will include the true average value of a
parameter a specified percentage of the time.
[0359] The term "device," as used herein, refers to an apparatus
capable of delivering a drug to patient in need thereof.
[0360] The term "delivery time," as used herein, refers to the
amount of time that elapses between a determination made by a
healthcare professional, or an untrained individual that an
individual is in need of nasal delivery of epinephrine and
completion of the delivery.
[0361] The term "disease," as used herein, is intended to be
generally synonymous, and is used interchangeably with, the terms
"disorder," "syndrome," and "condition" (as in medical condition),
in that all reflect an abnormal condition of the human or animal
body or of one of its parts that impairs normal functioning, is
typically manifested by distinguishing signs and symptoms, and
causes the human or animal to have a reduced duration or quality of
life.
[0362] As used herein, the "dose dispensed from the device" is
typically measured in the nasal spray setting by the difference in
weight of a device before and after actuation to release a dose of
the formulation contained therein. The volume of liquid formulation
and weight in milligrams of the active moiety contained therein may
be determined by standard calculations.
[0363] The term "elimination rate constant (4" as used herein,
refers to the fractional rate of drug removal from the body. This
rate is constant in first-order kinetics and is independent of drug
concentration in the body. .lamda. is the slope of the plasma
concentration-time line (on a logarithmic y scale). The term
".lamda..sub.z," as used herein, refers to the terminal phase
elimination rate constant, wherein the "terminal phase" of the drug
plasma concentration-time curve is a straight line when plotted on
a semi-logarithmic graph. The terminal phase is often called the
"elimination phase" because the primary mechanism for decreasing
drug concentration during the terminal phase is drug elimination
from the body. The distinguishing characteristic of the terminal
elimination phase is that the relative proportion of drug in the
plasma and peripheral volumes of distribution remains constant.
During this "terminal phase" drug returns from the rapid and slow
distribution volumes to the plasma, and is permanently removed from
the plasma by metabolism or renal excretion.
[0364] The term "equal," as used herein, means essentially the same
as (i.e., negligibly different from) in quantity, amount, value,
degree, or size. The term "equal" may, in certain embodiments,
include "bioequivalent," but the terms are not coterminous.
[0365] The term "bioequivalent," as used herein, describes the
relationship between a reference and a putative equivalent or
alternative drug, and per 21 C.F.R. .sctn. 320.1, means that there
is no significant difference in the rate and extent to which the
active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug
action when administered at the same molar dose under similar
conditions in an appropriately designed study. Rate and extent of
absorption may be determined from, or informed by, C.sub.max and
AUC, respectively. In certain embodiments, statistical criteria may
be used, e.g., between 80% and 125% of a reference value, or 90%
CI.
[0366] The term "molar equivalent," as used herein, refers to an
amount of epinephrine that is equimolar to a specified amount of
acid.
[0367] The term "excipient," as used herein, refers to a natural or
synthetic substance formulated alongside the active ingredient of a
medication. An excipient is included in a formulation for a variety
of reasons such as, but not limited to, long-term stabilization,
bulking up solid formulations, or to confer a therapeutic
enhancement on the active ingredient in the final dosage form, such
as facilitating drug absorption, reducing viscosity, or enhancing
solubility.
[0368] The term "filled," as used herein, refers to an association
between a device and a pharmaceutical formulation, for example,
when a pharmaceutical formulation described herein comprising a
therapeutically effective amount of epinephrine is present within a
reservoir that forms a part of a device described herein.
[0369] The term "formulation," with or without the modifier
"pharmaceutical," as used herein, refers to a composition
comprising at least one physiologically active ingredient (e.g., a
drug); including but not limited to, salts, solvates and hydrates
of epinephrine and related compounds described herein, whereby the
formulation is amenable to use for a specified, efficacious outcome
in a mammal (for example, without limitation, a human).
[0370] The term "pharmaceutical formulation," as used herein, alone
or in combination, refers to a formulation that is suited for use
for treatment (or in certain embodiments, prevention) of a disease
in a subject.
[0371] The term "hydrate," as used herein, refers to epinephrine
described herein or a salt thereof that further includes a
stoichiometric or non-stoichiometric amount of water bound by
non-covalent intermolecular forces.
[0372] The term "in need of treatment" and the term "in need
thereof" when referring to treatment are used interchangeably and
refer to a judgment made by a caregiver (e.g. physician, nurse,
nurse practitioner, that a patient will benefit from treatment.
[0373] As used herein, an "intramuscular (IM) injection" of
epinephrine is typically administered via an IM epinephrine
delivered by auto injector in the thigh, e.g., in the vestus
lateralis muscle (referred to herein as "optimal dosing conditions
in the thigh"). As such, when comparing pharmacokinetic parameters
yielded by IM epinephrine injection to those yielded by IN
epinephrine administration, the comparison should be assumed to be
as if the IM injection were in the thigh, which is the optimal
dosing method for epinephrine. In one embodiment, IM epinephrine
injection is achieved with EpiPen.RTM. Auto-Injector (0.3 mg/0.3 mL
epinephrine injection, USP, pre-filled auto-injector; Mylan
Specialty L.P.).
[0374] As used herein, an "subcutaneous (SQ) injection" of
epinephrine is typically administered by injection into the
subcutaneous layer of the deltoid region in the upper arm. Simons
et al. Epinephrine absorption in adults: Intramuscular versus
subcutaneous injection. J Allergy. Clin. Immunol. 2001;
108:871-3.
[0375] As used herein, two embodiments are "mutually exclusive"
when one is defined to be something which is different than the
other. For example, an embodiment wherein the concentration of
epinephrine is specified to be 5 mg/mL is mutually exclusive with
an embodiment wherein the amount of epinephrine is specified to be
10 mg/mL. However, an embodiment wherein the amount of epinephrine
is specified to be 5 mg/mL is not mutually exclusive with an
embodiment in which less than about 10% of the pharmaceutical
formulation leaves the nasal cavity via drainage into the
nasopharynx or externally.
[0376] The term "pharmaceutically acceptable," as used herein,
refers to a component of a formulation, often referred to as a
carrier or excipient, that is compatible with the other ingredients
of the formulation and not overly deleterious to the recipient
thereof.
[0377] The term "pre-primed," as used herein, refers to a device,
such as a nasal spray which can deliver a formulation to a patient
in need thereof with the first actuation of the spray pump, i.e.,
without the need to prime the pump prior to dosing, such as by
actuating the pump one or more times until a spray appears.
[0378] The term "prone," as used herein, refers to a patient who is
lying face down.
[0379] As used herein, the term "protective packaging" refers to
overwrap.
[0380] The term "solvate," as used herein, refers to epinephrine
described herein or a salt, thereof, that further includes a
stoichiometric or non-stoichiometric amount of a solvent bound by
non-covalent intermolecular forces. Preferred solvents are
volatile, non-toxic, and/or acceptable for administration to humans
in trace amounts.
[0381] The term "storage-stable," as used herein, refers to a
formulation in which at least about 90% to 115% of the active
ingredient remains within acceptable regulatory specifications
after storage of the formulation at specified temperature and
humidity for a specified time, for example, for at least 12 months
at 25.degree. C. and 60% relative humidity and about six months at
about 40.degree. C. and about 75% relative humidity.
[0382] The term "subject," as used herein, is intended to be
synonymous with "patient," and refers to any mammal (preferably
human) afflicted with a condition likely to benefit from treatment
with a therapeutically effective amount epinephrine, e.g., a
subject experiencing a type-1 hypersensitivity reaction (systemic
allergic reaction) such as anaphylaxis.
[0383] The term "supine," as used herein, refers to a patient who
is lying face up.
[0384] The term "nostril," as used herein, is synonymous with
"naris."
[0385] The term "therapeutically effective amount" or
"therapeutically effective dose," as used herein, refers to the
amount or dose of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
or individual that is being sought by a researcher, healthcare
provider or individual. A therapeutically effective amount may, but
need not necessarily, eliminate one, more, or all symptoms of a
disease, disorder, or condition being treated. A therapeutically
effective amount may also prevent disease progression or the
appearance of further symptoms.
[0386] The term "t.sub.1/2" or "half-life," as used herein, refers
to the amount of time required for half of a drug or other analyte
of interest (for example, an adrenergic receptor agonist) to be
eliminated from the body or the time required for a drug
concentration to decline by half.
[0387] The term "tonicity agent," as used herein, refers to a
compound which modifies the osmolality of a formulation, for
example, to render it isotonic. Tonicity agents include, dextrose,
lactose, sodium chloride, calcium chloride, magnesium chloride,
sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene
glycol, hydroxyethyl starch, glycine and the like. In some
embodiments, formulations contemplated herein include one or more
tonicity agents selected from dextrose, glycerin, mannitol,
potassium chloride and sodium chloride. In some embodiments,
formulations contemplated herein include sodium chloride as a
tonicity agent.
[0388] The term "tomography," as used herein, refers to a process
of imaging by sections. The images may be looked at individually,
as a series of two-dimensional slices or together, as a
computer-generated three-dimensional representation.
[0389] The term "T.sub.max," as used herein, refers to the time,
from administration, for a drug or other analyte to reach maximum
drug plasma concentration (C.sub.max).
Epinephrine
[0390] The term "epinephrine" as used herein refers to the compound
(R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-1,2-diol, also known
as adrenaline, shown below and having the following structure,
elemental makeup, molecular weight, and CAS Registry Number:
##STR00002##
The term include any metabolite, salt, ester, hydrate, anhydride,
solvate, isomer, isotope, enantiomer, free acid form, free base
form, crystalline form, co-crystalline form, complexes, amorphous
form, pro-drug (including ester pro-drug) form, racemate,
polymorph, chelate, isomer, tautomer, or optically active form
thereof, or mixture of any two or more of the foregoing.
[0391] Provided are drug products adapted for nasal delivery of
epinephrine, including formulations and devices. Epinephrine acts
by binding to a variety of adrenergic receptors. Epinephrine is a
nonselective agonist of all adrenergic receptors, including the
major subtypes .alpha.1, .alpha.2, .beta.1, .beta.2, and .beta.3.
Its actions vary by tissue type and tissue expression of adrenergic
receptors. For example, high levels of epinephrine causes smooth
muscle relaxation in the airways but causes contraction of the
smooth muscle that lines most arterioles.
[0392] Provided are formulations, devices adapted for nasal
delivery of a formulation to a patient, kits comprising the
foregoing, and methods of using the same in treatment, each
comprising a therapeutically effective amount of epinephrine.
[0393] Epinephrine may be present in the formulations administered
herein at concentrations between 1 mg/mL and 40 mg/mL, for example,
at concentrations of about 5 mg/mL, about 10 mg/mL, or about 20
mg/mL.
[0394] Epinephrine may be present in the formulations administered
herein at doses between 0.1 mg and 4 mg, for example, at doses of
about 0.5 mg, about 1.0 mg, or about 2.0 mg. These doses may be
scaled based on molecular weight of a counterion if a salt is used
to prepare the formulation.
[0395] Epinephrine may optionally exist as a pharmaceutically
acceptable salt including pharmaceutically acceptable acid addition
salts prepared from pharmaceutically acceptable non-toxic acids
including inorganic and organic acids. Representative acids
include, but are not limited to, acetic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,
fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,
isethionic, lactic, maleic, malic, mandelic, methanesulfonic,
mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as
those pharmaceutically acceptable salts listed by Berge et al.,
Journal of Pharmaceutical Sciences, 66:1-19 (1977). The acid
addition salts may be obtained as the direct products of compound
synthesis. In the alternative, the free base may be dissolved in a
suitable solvent containing the appropriate acid and the salt
isolated by evaporating the solvent or otherwise separating the
salt and solvent. Due to the perceived insolubility of epinephrine
base, finished dosage forms of epinephrine used in healthcare
(solutions, aerosols, etc.) are typically salts, e.g.
hydrochloride, bitartrate, or borate salts. In certain embodiments,
formulations contemplated herein include a salt form of epinephrine
that is epinephrine acetate, epinephrine hydrochloride, epinephrine
tartrate, epinephrine bitartrate, epinephrine hydrogen tartrate or
epinephrine borate.
[0396] Accordingly, provided herein are pharmaceutical formulations
for intranasal administration comprising epinephrine. In certain
embodiments, the formulation is an aqueous solution. In certain
embodiments, the formulation comprises, per dose, between about 25
and about 250 .mu.L of the aqueous solution. In certain
embodiments, the formulation comprises, per dose, between about 50
and about 250 .mu.L of the aqueous solution. In certain
embodiments, the formulation comprises, per dose, between about 50
and about 200 .mu.L of the aqueous solution. In certain
embodiments, the formulation comprises, per dose, not more than
about 140 .mu.L. In certain embodiments, the formulation comprises,
per dose, not more than about 100 .mu.L. In certain embodiments,
the formulation comprises, per dose, about 100 .mu.L. The
formulation may comprise, per dose, about 25 .mu.L, about 50 .mu.L,
about 75 .mu.L, about 100 .mu.l, about 125 .mu.L, about 150 .mu.L,
about 175 .mu.L, about 200 .mu.L, or about 250 .mu.L, of the
aqueous solution.
[0397] The pharmaceutical formulations for intranasal
administration comprising epinephrine described herein bypass
potential metabolic conversion in the gastrointestinal tract and
hepatic first-pass metabolism, and reach the systemic circulation
in a pharmacologically active form. Epinephrine is extensively
metabolized after oral administration by the
catechol-O-methyltransferase in the gastrointestinal tract and by
monoamine oxidase in the gastrointestinal tract and in the liver.
Avoiding first pass clearance assures that more of the epinephrine
that is administered will be available to treat anaphylaxis. By
avoiding first pass liver clearance, the bioavailability of the
epinephrine is increased.
Formulations
[0398] Also provided are pharmaceutical formulations comprising
epinephrine. Certain embodiments of the present disclosure include
a method of producing a formulation comprising admixing epinephrine
and a pharmaceutically acceptable carrier. Pharmaceutical
formulations are applied directly to the nasal cavity using the
devices described herein. In the case of a spray, this may be
achieved for example by means of a metering atomizing spray pump,
e.g. a single, bi-dose or multiuse spray device, with or without a
propellant.
[0399] Liquid preparations include solutions, suspensions and
emulsions, for example, water, or water-ethanol, or water-propylene
glycol solutions. Typically, the formulation is an aqueous liquid
solution. Additional ingredients in liquid preparations may include
preservatives, stabilizing agents, tonicity agents, absorption
enhancers, pH-adjusting agents, antioxidants, buffers,
sweetners/flavoring agents/task-masking agents, and optionally
other ingredients. Ingredients in liquid preparations may serve
different functions. The function(s) of a particular ingredient
will depend on a number of factors including, but not limited to,
presence or absence of other ingredients, concentration(s), and
other factors.
[0400] Preservatives include: benzalkonium chloride, methylparaben,
sodium benzoate, benzoic acid, phenyl ethyl alcohol, and the like,
and mixtures thereof. Due to their chemical properties, certain
preservatives can function as a surfactants and/or absorption
enhancers in certain circumstances, depending on concentration in
the formulation and other factors.
[0401] Other preservatives include: alcohol, benzalkonium chloride,
benzethonium chloride, benzoic acid, benzyl alcohol, boric acid,
bronopol, butylated hydroxyanisole (BHA), butylene glycol,
butylparaben, calcium acetate, calcium chloride, calcium lactate,
carbon dioxide, bentonite, cetrimide, cetylpyridinium chloride,
chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric
acid monohydrate, cresol, dimethyl ether, ethylparaben, glycerin,
hexetidine, imidurea, magnesium trisilicate, isopropyl alcohol,
lactic acid, methylparaben, monothioglycerol, parabens (methyl,
ethyl and propyl), pentetic acid, phenol, phenoxyethanol,
phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate,
phenylmercuric nitrate, potassium benzoate, potassium
metabisulfite, potassium sorbate, propionic acid, propyl gallate,
propylene glycol, propylparaben, propylparaben sodium, sodium
acetate, sodium benzoate, sodium borate, sodium lactate, sodium
metabisulfite, sodium propionate, sodium sulfite, sorbic acid,
sulfobutyletherb-cyclodextrin, sulfur dioxide, edetic acid,
thimerosal, and xylitol.
[0402] In some embodiments, preservatives include, but are not
limited to, antibacterial agents, antifungal agents, and
antioxidants.
[0403] Antibacterial agents include, but are not limited to,
chlorocresol, diazolidinyl urea, dimethyl sulfoxide, glacial acetic
acid, imidurea, iodine/edetic acid, phenylmercuric acetate,
phenylmercuric borate, phenylmercuric hydroxide, potassium sorbate,
sodium hydroxide, sorbic acid, thymol, antiseptics, and
disinfectants.
[0404] Antifungal agents include, but are not limited to, benzoic
acid, butylene glycol, butylparaben, chlorocresol, coconut oil,
dimethyl sulfoxide, ethylparaben, glacial acetic acid, imidurea,
methylparabens, phenylmercuric acetate, phenylmercuric borate,
phenylmercuric hydroxide, potassium sorbate, propylparaben, sodium
propionate, sodium thiosulfate, thymol, and vanillin.
[0405] Surfactants include but are not limited to: Polysorbate 80
NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4)
sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate,
polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4)
sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate,
polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20
sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate,
sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate,
sorbitan tristearate, and the like, and mixtures thereof. Due to
their chemical properties, certain surfactants can function as a
preservatives and/or absorption enhancers in certain circumstances,
depending on concentration in the formulation and other
factors.
[0406] Surfactants include but are not limited to: cationic,
anionic, nonionic and zwitterionic surfactants.
[0407] Surfactants also include: anionic surfactants (e.g.
carboxylates sulphonates, petroleum sulphonates,
alkylbenzenesulphonates, naphthalenesulphonates, olefin
sulphonates, alkyl sulphates, sulphates, sulphated natural oils and
fats, sulphated esters, sulphated alkanolamides, alkylphenols,
ethoxylated and sulphated), nonionic surfactants (e.g. ethoxylated
aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters,
polyethylene glycol esters, anhydrosorbitol ester and it's
ethoxylated derivatives, glycol esters of fatty acids, carboxylic
amides, monoalkanolamine condensates, polyoxyethylene fatty acid
amides), cationic surfactants (e.g. quaternary ammonium salts,
amines with amide linkages, polyoxyethylene alkyl and alicyclic
amines, 4.n,n,n',n' tetrakis substituted ethylenediamines, 2-alkyl
1-hydroxethyl 2-imidazolines), amphoteric surfactants (amphoteric
surfactants contains both an acidic and a basic hydrophilic moiety
in their surface e.g., n-coco 3-aminopropionic acid/sodium salt,
n-tallow 3-iminodipropionate, disodium salt, n-carboxymethyl n
dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n
hydroxyethylglycine, sodium salt, etc.).
[0408] Antioxidants include, but are not limited to, tocopherol,
arachidonic acid, ascorbic acid, ascorbyl palmitate, benzethonium
chloride, benzethonium bromide, benzalkonium chloride, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), capric acid,
caproic acid, carbon dioxide, cetylpyridium chloride, chelating
agents, chitosan derivatives, citric acid monohydrate, dodecyl
dimethyl aminopropionate, enanthic acid, erythorbic acid, ethyl
oleate, fumaric acid, glycerol oleate, glyceryl monostearate,
lauric acid, limonene, linolenic acid, lysine, malic acid, menthol,
methionine, monothioglycerol, myristic acid, oleic acid, or salt
thereof, palmitic acid, pelargonic acid, peppermint oil, phosphoric
acid, polysorbates, potassium metabisulfite, propionic acid, propyl
gallate, sodium ascorbate, sodium bisulfate, sodium caprate, sodium
desoxycholate, sodium deoxyglycolate, sodium formaldehyde
sulfoxylate, sodium glycocholate, sodium hydroxybenzoyal amino
caprylate, sodium lauryl sulfate, sodium metabisulfite, sodium
sulfite, sodium taurocholate, sodium thiosulfate, stearic acid,
sulfur dioxide and a combination thereof.
[0409] Buffers include, but are not limited to, phosphate buffers,
acetate buffers, and citrate buffers.
[0410] In some embodiments, the nasal spray formulation comprises a
buffering agent. Buffering agents include, but are not limited to,
adipic acid, boric acid, calcium carbonate, calcium hydroxide,
calcium lactate, calcium phosphate, tribasic, citric acid
monohydrate, dibasic sodium phosphate, diethanolamine, glycine,
maleic acid, malic acid, methionine, monobasic sodium phosphate,
monoethanolamine, monosodium glutamate, phosphoric acid, potassium
citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium
carbonate, sodium citrate dihydrate, sodium hydroxide, sodium
lactate, and triethanolamine.
[0411] Isotonicity agents include sodium chloride, calcium
chloride, magnesium chloride, sorbitol, sucrose, dextrose, lactose,
mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl
starch, glycerine, glycine, and the like, and mixtures thereof. In
certain embodiments, the isotonicity agent is chosen from dextrose,
glycerin, mannitol, potassium chloride, and sodium chloride. In
certain embodiments, the isotonicity agent is sodium chloride. In
certain embodiments, the formulations disclosed herein contain
sodium chloride in an amount sufficient to cause the final
composition to have a nasally acceptable osmolality, preferably
240-350 mOsm/kg. In certain embodiments, the formulations contain
0.3-1.9% sodium chloride.
[0412] Sweetners/flavoring agents/task-masking agents include, but
are not limited to, sucrose, dextrose, lactose, sucralose,
acesulfame-K, aspartame, saccharin, sodium saccharin, citric acid,
aspartic acid, eucalyptol, mannitol, glycerin, xylitol, menthol,
glycyrrhizic acid, cinnamon oils, oil of wintergreen, peppermint
oils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus
oil such as lemon oil, orange oil, grape and grapefruit oil, fruit
essences including apple, peach, pear, strawberry, raspberry,
cherry, plum, pineapple, apricot, etc. and combinations thereof. In
some embodiments, the formulations contain from about 0.0001
percent to about 1 percent of a sweetener/flavoring
agent/task-masking agent, and may be present at lower or higher
amounts as a factor of one or more of potency of the effect on
flavor, solubility of the flavorant, effects of the flavorant on
solubility or other physicochemical or pharmacokinetic properties
of other formulation components, or other factors.
[0413] In certain embodiments, the pharmaceutical formulation
additionally comprises an isotonicity agent. The intranasal
formulation may comprise between about 0.2% (w/v) and about 1.2%
(w/v) isotonicity agent, such as about 0.2% (w/v), about 0.3%
(w/v), about 0.4% (w/v), about 0.5% (w/v), about 0.6% (w/v), about
0.7% (w/v), about 0.8% (w/v), about 0.9% (w/v), about 1.0% (w/v),
about 1.1% (w/v), or about 1.2% (w/v). The intranasal formulation
may comprise more than about 0.1% (w/v) isotonicity agent. The
intranasal formulation may comprise less than about 1.2% (w/v)
isotonicity agent. In other embodiments, the intranasal formulation
may comprise between about 0.2% (w/v) and about 1.9% (w/v)
isotonicity agent, such as about 0.2% (w/v), about 0.3% (w/v),
about 0.4% (w/v), about 0.5% (w/v), about 0.6% (w/v), about 0.7%
(w/v), about 0.8% (w/v), about 0.9% (w/v), about 1.0% (w/v), about
1.1% (w/v), about 1.2% (w/v), about 1.3% (w/v), about 1.4% (w/v),
about 1.5% (w/v), about 1.6% (w/v), about 1.7% (w/v), about 1.8%
(w/v), or about 1.9% (w/v). The intranasal formulation may comprise
less than about 1.9% (w/v) isotonicity agent.
[0414] In certain embodiments, the formulation additionally
comprises an absorption enhancer. In certain embodiments, the
pharmaceutical formulation comprises between about 0.005% (w/v) to
about 2.5% (w/v) of the absorption enhancer. In certain
embodiments, the pharmaceutical formulation comprises between about
0.05% (w/v) to about 2.5% (w/v) of the absorption enhancer. In
certain embodiments, the pharmaceutical formulation comprises
between about 0.1% (w/v) to about 0.5% (w/v) of the absorption
enhancer. In certain embodiments, the pharmaceutical formulation
comprises about 0.25% (w/v) of the absorption enhancer. In certain
embodiments, the pharmaceutical formulation comprises about 0.18%
(w/v) of the absorption enhancer.
[0415] In certain embodiments, the absorption enhancer is selected
from benzalkonium chloride, cyclodextrins, chitosan, deoxycholic
acid, an alkylsaccharide (e.g., a nonionic alkylsaccharide
surfactant such as an alkylglycoside and a sucrose ester of fatty
acids that consists of an aliphatic hydrocarbon chain coupled to a
sugar moiety by a glycosidic or ester bond, respectively), fusidic
acid derivatives, glycocholic acid, laureth-9,
phosphatidylcholines, taurocholic acid, taurodihydrofusidic acid,
microspheres and liposomes, and bile salts. In certain embodiments,
the absorption enhancer is benzalkonium chloride. The formulation
may comprise about 0.01% (w/v) to about 1% (w/v) benzalkonium
chloride. In certain embodiments, the pharmaceutical formulation
comprises about 0.005% (w/v) to about 0.015% (w/v) benzalkonium
chloride. In certain embodiments, the pharmaceutical formulation
comprises about 0.01% (w/v), about 0.02% (w/v), about 0.03% (w/v),
or about 0.04% (w/v) of benzalkonium chloride. In certain
embodiments, the pharmaceutical formulation comprises about 0.01%
(w/v) benzalkonium chloride. In certain embodiments, the
pharmaceutical formulation comprises about 0.02% (w/v) benzalkonium
chloride. In certain embodiments, the pharmaceutical formulation
comprises about 0.04% benzalkonium chloride.
[0416] In certain embodiments, the pharmaceutical formulation
comprises benzalkonium chloride in an amount between about 0.001%
(w/v) and about 1% (w/v). In certain other embodiments, the
pharmaceutical formulation comprises benzalkonium chloride in an
amount between about 0.001% (w/v) and about 0.5% (w/v). In certain
other embodiments, the pharmaceutical formulation comprises
benzalkonium chloride in an amount between about 0.001% (w/v) and
about 0.2% (w/v). In some embodiments, the pharmaceutical
formulation comprises 0.001% (w/v), 0.003% (w/v), 0.005% (w/v),
0.007% (w/v), 0.009% (w/v), 0.01% (w/v), 0.02% (w/v), 0.03% (w/v),
0.04% (w/v), 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.08% (w/v),
0.09% (w/v), 0.1% (w/v), 0.11% (w/v), 0.12% (w/v), 0.13% (w/v),
0.14% (w/v), 0.15% (w/v), 0.16% (w/v), 0.17% (w/v), 0.18% (w/v),
0.19% (w/v), 0.2% (w/v), 0.31% (w/v), 0.22% (w/v), 0.23% (w/v),
0.24% (w/v), 0.25% (w/v), 0.26% (w/v), 0.27% (w/v), 0.28% (w/v),
0.29% (w/v), 0.3% (w/v), 0.31% (w/v), 0.32% (w/v), 0.33% (w/v),
0.34% (w/v), 0.35% (w/v), 0.36% (w/v), 0.37% (w/v), 0.38% (w/v),
0.39% (w/v), 0.4% (w/v), 0.41% (w/v), 0.42% (w/v), 0.43% (w/v),
0.44% (w/v), 0.45% (w/v), 0.46% (w/v), 0.47% (w/v), 0.48% (w/v),
0.49% (w/v), 0.5% (w/v), 0.51% (w/v), 0.52% (w/v), 0.53% (w/v),
0.54% (w/v), 0.55% (w/v), 0.56% (w/v), 0.57% (w/v), 0.58% (w/v),
0.59% (w/v), 0.6% (w/v), 0.61% (w/v), 0.62% (w/v), 0.63% (w/v),
0.64% (w/v), 0.65% (w/v), 0.66% (w/v), 0.67% (w/v), 0.68% (w/v),
0.69% (w/v), 0.7% (w/v), 0.71% (w/v), 0.72% (w/v), 0.73% (w/v),
0.74% (w/v), 0.75% (w/v), 0.76% (w/v), 0.77% (w/v), 0.78% (w/v),
0.79% (w/v), 0.8% (w/v), 0.81% (w/v), 0.82% (w/v), 0.83% (w/v),
0.84% (w/v), 0.85% (w/v), 0.86% (w/v), 0.87% (w/v), 0.88% (w/v),
0.89% (w/v), 0.9% (w/v), 0.91% (w/v), 0.92% (w/v), 0.93% (w/v),
0.94% (w/v), 0.95% (w/v), 0.96% (w/v), 0.97% (w/v), 0.98% (w/v),
0.99% (w/v), or 1% (w/v) benzalkonium chloride.
[0417] In certain embodiments, the absorption enhancer is an
alkylsaccharide. In certain embodiments, the alkylsaccharide is
chosen from dodecyl maltoside, tetradecyl maltoside (TDM) and
sucrose dodecanoate.
[0418] In certain embodiments, the alkylsaccharide is dodecyl
maltoside (the alkylglycoside
1-O-n-dodecyl-.beta.-D-maltopyranoside, alternately referred to as
lauryl-.beta.-D-maltopyranoside, dodecyl maltopyranoside, and DDM;
C.sub.24H.sub.46Q.sub.11, often referred to by the trade name
Intravail.RTM.). Alkylsaccharides are used in commercial food and
personal care products and have been designated Generally
Recognized as Safe (GRAS) substances for food applications. They
are non-irritating enhancers of transmucosal absorption that are
odorless, tasteless, non-toxic, non-mutagenic, and non-sensitizing
in the Draize test up to a 25% concentration. Alkylsaccharides
increase absorption by increasing paracellular permeability, as
indicated by a decrease in transepithelial electrical resistance;
they may also increase transcytosis. The effect is short-lived.
Other alkylsaccharides include tetradecyl maltoside (TDM) and
sucrose dodecanoate.
[0419] In certain embodiments, an intranasal formulation comprises
between about 0.05% (w/v) and about 2.5% (w/v) Intravail.RTM.. In
certain embodiments, an intranasal formulation comprises between
about 0.1% (w/v) and about 0.5% (w/v) Intravail.RTM.. In certain
embodiments, an intranasal formulation comprises between about
0.15% (w/v) and about 0.35% (w/v) Intravail.RTM.. In certain
embodiments, an intranasal formulation comprises between about
0.15% (w/v) and about 0.2% (w/v) Intravail.RTM.. In certain
embodiments, an intranasal formulation comprises about 0.18% (w/v)
Intravail.RTM.. In certain embodiments, an intranasal formulation
comprises about 0.2% (w/v) to about 0.3% (w/v) Intravail.RTM.. In
certain embodiments, an intranasal formulation comprises about
0.25% (w/v) Intravail.RTM..
[0420] In certain embodiments, the absorption enhancer is
Intravail.RTM. (dodecyl maltoside).
[0421] In certain embodiments, the absorption enhancer in the
intranasal formulation is a combination of dodecyl maltoside and
benzalkonium chloride. While the use of dodecyl maltoside or
benzalkonium chloride as an absorption enhancer in the intranasal
formulations described herein provides bioavailability of intransal
epinephrine, the combination of dodecyl maltoside and benzalkonium
chloride as absorption enhancers in the intranasal formulations
described herein provides pharmacokinetics that closely match
pharmacokinetics obtained through intramuscular injection of
epinephrine.
[0422] In certain embodiments, each dose dispensed from the device
of the pharmaceutical formulation comprises between about 0.4 mg
and about 2.40 mg per dose epinephrine, or a salt thereof, and
between 0.1 and 0.50 mg Intravail.RTM. (dodecyl maltoside).
[0423] In certain embodiments, each dose dispensed from the device
of the formulation comprises between about 0.5 mg and about 2.0 mg
per dose epinephrine, or a salt thereof, and about between 0.1 and
0.50 mg Intravail.RTM. (dodecyl maltoside).
[0424] In certain embodiments, each dose dispensed from the device
of the formulation comprises between about 0.75 mg and about 1.5 mg
per dose epinephrine, or a salt thereof, and between 0.1 and 0.50
mg Intravail.RTM. (dodecyl maltoside).
[0425] In certain embodiments, each dose dispensed from the device
of the formulation comprises between about 0.9 mg and about 1.15 mg
per dose epinephrine, or a salt thereof, and about 0.25 mg
Intravail.RTM. (dodecyl maltoside).
[0426] In certain embodiments, each dose dispensed from the device
of the formulation comprises about 1.0 mg per dose epinephrine, or
a salt thereof, and about 0.25 mg Intravail.RTM. (dodecyl
maltoside).
[0427] In certain embodiments, the pharmaceutical formulation
additionally comprises a chealating agent or antioxidant
(stabilizing agent) to improve stability. In certain embodiments,
the chealating/stabilizing agent is EDTA.
[0428] Examples of additional stabilizing agents include: acacia,
agar, albumin, alginic acid, aluminum stearate, ammonium alginate,
ascorbic acid, ascorbyl palmitate, bentonite, butylated
hydroxytoluene (BHT), calcium alginate, calcium stearate,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
carrageenan, cellulose, microcrystalline, carboxymethylcellulose
sodium, ceratonia, colloidal silicon dioxide, cyclodextrins,
diethanolamine, edetates, ethylcellulose, ethylene glycol
palmitostearate, glycerin monostearate, guar gum, hectorite,
hydroxpropyl betadex, hydroxypropyl cellulose, hypromellose,
inulin, invert sugar, lauric acid, lecithin, magnesium aluminum
silicate, mineral oil and lanolin alcohols, monoethanolamine,
pectin, pentetic acid, phospholipids, polacrilin potassium,
poloxamer, polyvinyl alcohol, potassium alginate, potassium
chloride, povidone, propyl gallate, propylene glycol, propylene
glycol alginate, raffinose, sodium acetate, sodium alginate, sodium
borate, sodium stearyl fumarate, sorbitol, stearyl alcohol,
sulfobutylether b-cyclodextrin, tagatose, trehalose,
triethanolamine, white wax, xanthan gum, xylitol, yellow wax, and
zinc acetate.
[0429] Examples of additional chelating agents include: citric acid
monohydrate, disodium edetate, edetate calcium disodium, edetic
acid, fumaric acid, malic acid, maltol, pentetic acid, sodium
edetate, and trisodium edetate.
[0430] In certain embodiments, the pharmaceutical formulation
comprises benzalkonium chloride. In certain embodiments, the
pharmaceutical formulation comprises about 0.005% (w/v) to about 1%
(w/v) benzalkonium chloride.
[0431] In its capacity as a surfactant, benzalkonium chloride can
affect the surface tension of droplets from a delivered nasal spray
plume, producing spherical or substantially spherical particles
having a narrow droplet size distribution (DSD), as well as the
viscosity of a liquid formulation.
[0432] In certain embodiments, the absorption enhancer is an
alkylsaccharide, for example, a nonionic alkylsaccharide surfactant
such as an alkylglycoside and a sucrose ester of fatty acids that
consists of an aliphatic hydrocarbon chain coupled to a sugar
moiety by a glycosidic or ester bond, respectively. In certain
embodiments, the absorption enhancer is an alkylmaltoside (e.g., a
tetradecyl maltoside (TDM), a dodecyl maltoside (DDM), etc.). In
certain embodiments, the absorption enhancer is sucrose
dodecanoate. Alkylsaccharides are used in commercial food and
personal care products and have been designated Generally
Recognized as Safe (GRAS) substances for food applications. They
are non-irritating enhancers of transmucosal absorption that are
odorless, tasteless, non-toxic, non-mutagenic, and non-sensitizing
in the Draize test up to a 25% concentration. Without being bound
to any theory, it is believed that alkylsaccharides increase
absorption by increasing paracellular permeability, as indicated by
a decrease in transepithelial electrical resistance; they may also
increase transcytosis. The effect may be short-lived. In its
capacity as an absorption enhancer, alkylmaltosides (e.g., a
tetradecyl maltoside (TDM), a dodecyl maltoside (DDM), etc.) can
affect the surface tension of droplets from a delivered nasal spray
plume, producing spherical or substantially spherical particles
having a narrow droplet size distribution (DSD), as well as the
viscosity of a liquid formulation.
[0433] In certain embodiments, the absorption enhancer is the
alkylsaccharide 1-O-n-dodecyl-.beta.-D-maltopyranoside (alternately
referred to as lauryl-.beta.-D-maltopyranoside, dodecyl
maltopyranoside, dodecyl maltoside, and DDM;
C.sub.24H.sub.46Q.sub.11; often referred to by the trade name
Intravail.RTM.). In certain embodiments, an intranasal formulation
comprises about 0.01% (w/v) to about 2.5% (w/v) DDM. In certain
embodiments, an intranasal formulation comprises about 0.1% (w/v)
to about 0.5% (w/v) DDM. In certain embodiments, an intranasal
formulation comprises about 0.15% (w/v) to about 0.35% (w/v) DDM.
In certain embodiments, an intranasal formulation comprises about
0.15% (w/v) to about 0.2% (w/v) DDM. In certain embodiments, an
intranasal formulation comprises about 0.18% (w/v) DDM. In certain
embodiments, an intranasal formulation comprises about 0.2% (w/v)
to about 0.3% (w/v) DDM. In certain embodiments, an intranasal
formulation comprises about 0.25% (w/v) DDM.
[0434] In sugar chemistry, an anomer is either of a pair of cyclic
stereoisomers (designated .alpha. or .beta.) of a sugar or
glycoside, differing only in configuration at the hemiacetal (or
hemiketal) carbon, also called the anomeric carbon or reducing
carbon. If the structure is analogous to one with the hydroxyl
group on the anomeric carbon in the axial position of glucose, then
the sugar is an alpha anomer. If, however, that hydroxyl is
equatorial, the sugar is a beta anomer. For example,
.alpha.-D-glucopyranose and .beta.-D-glucopyranose, the two cyclic
forms of glucose, are anomers. Likewise, alkylglycosides occur as
anomers. For example, dodecyl .beta.-D-maltoside and dodecyl
.alpha.-D-maltoside are two cyclic forms of dodecyl maltoside. The
two different anomers are two distinct chemical structures, and
thus have different physical and chemical properties. In one aspect
of the invention, the alkylglycoside of the present invention is a
.beta. anomer. In an exemplary aspect, the alkylglycoside is a
.beta. anomer of an alkylmaltoside, such as
tetradecyl-.beta.-D-maltoside (TDM).
[0435] In some embodiments, the alkylglycoside used is a
substantially pure alkylglycoside. As used herein a "substantially
pure" alkylglycoside refers to one anomeric form of the
alkylglycoside (either the .alpha. or .beta. anomeric forms) with
less than about 2% of the other anomeric form, preferably less than
about 1.5% of the other anomeric form, and more preferably less
than about 1% of the other anomeric form. In one aspect, a
substantially pure alkylgycoside contains greater than 98% of
either the .alpha. or .beta. anomer. In another aspect, a
substantially pure alkylgycoside contains greater than 99% of
either the .alpha. or .beta. anomer. In another aspect, a
substantially pure alkylgycoside contains greater than 99.5% of
either the .alpha. or .beta. anomer. In another aspect, a
substantially pure alkylgycoside contains greater than 99.9% of
either the .alpha. or .beta. anomer.
[0436] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; and one or more ingredients selected from
absorption enhancers, chealating agents, antioxidants, stabilizing
agents, surfactants, isotonicity agents, and pH adjusting
agents.
[0437] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; and one or more ingredients selected from
alkylglycosides, chitosan, alkylcyclodextrins, benzalkonium
chloride, sodium chloride, and EDTA.
[0438] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; and one or more ingredients selected from
dodecyl maltoside (DDM), tetradecyl maltoside (TDM), benzalkonium
chloride, sodium chloride, hydrochloric acid, and EDTA. In certain
other embodiments, described herein is an aqueous formulation
suitable for intranasal administration comprising: epinephrine;
water; and one or more ingredients selected from dodecyl maltoside
(DDM), benzalkonium chloride, sodium chloride, and EDTA.
[0439] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; dodecyl maltoside (DDM); and one or more
ingredients selected from benzalkonium chloride, sodium chloride,
pH adjusting agents, and EDTA.
[0440] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; benzalkonium chloride; and one or more
ingredients selected from dodecyl maltoside (DDM), sodium chloride,
pH adjusting agents, and EDTA.
[0441] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; dodecyl maltoside (DDM) or benzalkonium
chloride or a combination of dodecyl maltoside (DDM) and
benzalkonium chloride; and one or more additional ingredients
selected from sodium chloride, pH adjusting agents, and EDTA.
[0442] pH adjusting agents include acids described herein (e.g.
hydrochloric acid, citric acid), buffers (e.g. phosphate, acetate,
and citrate buffers), and bases (e.g. sodium hydroxide, sodium
citrate, sodium bicarbonate, sodium carbonate).
[0443] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
about 0.5% (w/v) to about 2.5% (w/v) epinephrine; water; and one or
more ingredients selected from: about 0.05% (w/v) to about 2.5%
(w/v) dodecyl maltoside (DDM); about 0.005% (w/v) to about 1% (w/v)
benzalkonium chloride; about 0.2% (w/v) to about 1.2% (w/v) sodium
chloride, optional hydrochloric acid or sodium hydroxide in a
sufficient amount to adjust the pH to a final pH of about 4.0 to
about 5.0; and about 0.05% (w/v) to about 2.0% (w/v) EDTA.
[0444] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising: i)
about 0.5% (w/v) to about 2.5% (w/v) epinephrine; ii) water; iii)
about 0.05% (w/v) to about 2.5% (w/v) dodecyl maltoside (DDM) or
about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride, or a
combination of about 0.05% (w/v) to about 2.5% (w/v) dodecyl
maltoside (DDM) and about 0.005% (w/v) to about 1% (w/v)
benzalkonium chloride; and iv) one or more ingredients selected
from a) about 0.2% (w/v) to about 1.2% (w/v) sodium chloride; b)
optional hydrochloric acid or sodium hydroxide in an amount
sufficient to adjust the pH to a final pH of about 4.0 to about
5.0; and c) about 0.05% (w/v) to about 2.0% (w/v) EDTA.
[0445] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising: i)
about 0.9% (w/v) to about 2.0% (w/v) epinephrine; ii) water; iii)
about 0.05% (w/v) to about 2.5% (w/v) dodecyl maltoside (DDM), or
about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride, or a
combination of about 0.05% (w/v) to about 2.5% (w/v) dodecyl
maltoside (DDM) and about 0.005% (w/v) to about 1% (w/v)
benzalkonium chloride; and iv) one or more ingredients selected
from a) about 0.2% (w/v) to about 1.2% (w/v) sodium chloride; b)
optional hydrochloric acid or sodium hydroxide hydrochloric acid in
an amount sufficient to adjust the pH to a final pH of about 4.0 to
about 5.0; and c) about 0.05% (w/v) to about 2.0% (w/v) EDTA.
[0446] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
about 0.5% (w/v) to about 2.5% (w/v) epinephrine; water; about
0.05% (w/v) to about 2.5% (w/v) dodecyl maltoside (DDM); about
0.005% (w/v) to about 1% (w/v) benzalkonium chloride; about 0.2%
(w/v) to about 1.2% (w/v) sodium chloride, hydrochloric acid in a
sufficient amount to adjust the pH to a final pH of about 4.0 to
about 5.0; and about 0.05% (w/v) to about 2.0% (w/v) EDTA.
[0447] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; one or more absorption enhancement agents; an
isotonicity agent; a stabilizing agent; a preservative; and
optional pH adjustment agents to adjust pH to pH 3 to 6. In certain
embodiments, described herein is an aqueous formulation suitable
for intranasal administration comprising: epinephrine; water; one
or more absorption enhancement agents (e.g. dodecyl maltoside;
benzalkonium chloride; or a combination of dodecyl maltoside and
benzalkonium chloride); an isotonicity agent (e.g. sodium
chloride); a stabilizing agent (e.g. EDTA or disodium EDTA); a
preservative (e.g. benzalkonium chloride); and optional pH
adjustment agents to adjust pH to pH 3 to 6. In certain
embodiments, described herein is an aqueous formulation suitable
for intranasal administration comprising: epinephrine; water; one
or more absorption enhancement agents (e.g. dodecyl maltoside;
benzalkonium chloride; or a combination of dodecyl maltoside and
benzalkonium chloride); an isotonicity agent (e.g. sodium
chloride); a stabilizing agent (e.g. EDTA or disodium EDTA); a
preservative (e.g. benzalkonium chloride); an antioxidant; a
buffering agent; and optional pH adjustment agents to adjust pH to
pH 3 to 6.
[0448] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
epinephrine; water; dodecyl maltoside or benzalkonium chloride or a
combination of dodecyl maltoside and benzalkonium chloride; sodium
chloride; EDTA or disodium EDTA; and optional pH adjustment agents
to adjust pH to pH 3 to 6.
[0449] In certain embodiments, described herein is an aqueous
formulation suitable for intranasal administration comprising:
about 0.5% (w/v) to about 2.5% (w/v) epinephrine; water; about
0.05% (w/v) to about 2.5% (w/v) dodecyl maltoside or about 0.005%
(w/v) to about 1% (w/v) benzalkonium chloride or a combination of
about 0.05% (w/v) to about 2.5% (w/v) dodecyl maltoside and about
0.005% (w/v) to about 1% (w/v) benzalkonium chloride; about 0.2%
(w/v) to about 1.2% (w/v) sodium chloride; about 0.05% (w/v) to
about 2.0% (w/v) EDTA or disodium EDTA; and optional pH adjustment
agents to adjust pH to pH 3 to 6.
[0450] In some embodiments, a 100 .mu.L sample of the aqueous
formulation suitable for intranasal administration comprises less
than about 2.5 mg of epinephrine. In some embodiments, a 100 .mu.L
sample of the aqueous formulation suitable for intranasal
administration comprises about 0.5 mg to about 2.5 mg of
epinephrine. In some embodiments, a 100 .mu.L sample of the aqueous
formulation suitable for intranasal administration comprises about
0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg,
about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4
mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about
1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg,
about 2.4 mg, or about 2.5 mg of epinephrine.
Nasal Drug Delivery Devices and Kits
[0451] Also provided are nasal drug delivery devices comprising a
formulation described herein. In certain embodiments, the device is
pre-primed. In certain embodiments, the device can be primed before
use. In certain embodiments, the device can be actuated with one
hand.
[0452] Nasal delivery is considered an attractive, safe, and
easy-to-administer route for needle-free, systemic drug delivery,
especially when rapid absorption and effect are desired. In
addition, nasal delivery may help address issues related to poor
bioavailability, slow absorption, drug degradation, and adverse
events (AEs) in the gastrointestinal tract and avoids the
first-pass metabolism in the liver.
[0453] Liquid nasal formulations are mainly aqueous solutions, but
suspensions, emulsions, liposomes, and microspheres can also be
delivered. Other liquid formulations can comprise liposomes,
microspheres, mixed aqueous-organic formulations, non-aqueous
formulations, dry powder and retentive formulations (gels). In
traditional spray pump systems, antimicrobial preservatives are
typically required to maintain microbiological stability in liquid
formulations. Metered spray pumps have dominated the nasal drug
delivery market since they were introduced. The pumps typically
deliver 100 .mu.L (25-250 .mu.L) per spray, and they offer high
reproducibility of the emitted dose and plume geometry in in vitro
tests.
[0454] Examples of standard metered spray pumps include those
offered by Aptar Pharma, Inc., such as the multi-dose "classic
technology platform" nasal spray devices, and by BD
Medical-Pharmaceutical Systems, such as the Accuspray.TM. system.
Such devices comprise a reservoir which holds multiple doses of the
nasal spray formulation (e.g., 50, 100, 150, 200, 60, or 120
doses), a closure (e.g., screw, crimp, or snap-on), and an actuator
which delivers anywhere from 45 to 1000 .mu.L (e.g. 50, 100, 140,
150, or 200 .mu.L) of fluid per actuation to comprise a single
dose. The actuator may be configured to count doses, deliver gel
formulations, deliver in an upside-down configuration, etc.
[0455] In traditional multi-use spray pump systems, antimicrobial
preservatives are typically required to maintain microbiological
stability in liquid formulations. However, preservative-free
systems are also available, e.g. the Advanced Preservative Free
(APF) system from Aptar, which is vented, contains a filter
membrane for air flow which prevents contamination, has a
metal-free fluid path for oxidizing formulations, and can be used
in any orientation. Additional nasal spray devices from Aptar and
others are optimized with dispenser tips that prevent clogging
(useful for high-viscosity and high-volatile formulations),
actuators that do not need re-priming after long periods of disuse,
etc. Additional nasal spray devices are propellant driven. Yet
additional nasal spray devices include dry powder inhalers.
[0456] The particle size and plume geometry can vary within certain
limits and depend on the properties of the pump, the formulation,
the orifice of the actuator, and the force applied. The droplet
size distribution of a nasal spray is a critical parameter, since
it significantly influences the in vivo deposition of the drug in
the nasal cavity. The droplet size is influenced by the actuation
parameters of the device and the formulation. The prevalent median
droplet size should be between about 30 and about 100 .mu.m. If the
droplets are too large (>about 120 .mu.m), deposition takes
place mainly in the anterior parts of the nose, and if the droplets
are too small (<about 10 .mu.m), they can possibly be inhaled
and reach the lungs and oral cavity, which should be avoided
because of safety reasons. In its capacity as a surfactant,
benzalkonium chloride and alkylmaltosides (e.g., a tetradecyl
maltoside (TDM), a dodecyl maltoside (DDM), etc.) can affect the
surface tension of droplets from a delivered nasal spray plume,
producing spherical or substantially spherical particles having a
narrow droplet size distribution (DSD), as well as the viscosity of
a liquid formulation.
[0457] Plume geometry, droplet size and DSD of the delivered plume
subsequent to spraying may be measured under specified experimental
and instrumental conditions by appropriate and validated and/or
calibrated analytical procedures known in the art. These include
photography, laser diffraction, and impaction systems (cascade
impaction, NGI). Plume geometry, droplet size and DSD can affect
pharmacokinetic outcomes such as C.sub.max, T.sub.max, and dose
proportionality.
[0458] Droplet size distribution can be controlled in terms of
ranges for the D10, D50, D90, span RD90-D10)/D501, and percentage
of droplets less than 10 mm. In certain embodiments, the
formulation will have a narrow DSD. In certain embodiments, the
formulation will have a D(v,50) of 30-70 .mu.m and a D(v,
90)<100 .mu.m.
[0459] In certain embodiments, the percent of droplets less than 10
.mu.m will be less than 10%. In certain embodiments, the percent of
droplets less than 10 .mu.m will be less than 5%. In certain
embodiments, the percent of droplets less than 10 .mu.m will be
less than 2%. In certain embodiments, the percent of droplets less
than 10 .mu.m will be less than 1%.
[0460] In certain embodiments, the formulation when dispensed by
actuation from the device will produce a uniform circular plume
with an ovality ratio close to 1. Ovality ratio is calculated as
the quotient of the maximum diameter (D.sub.max) and the minimum
diameter (D.sub.min) of a spray pattern taken orthogonal to the
direction of spray flow (e.g., from the "top"). In certain
embodiments, the ovality ratio is less than .+-.2.0. In certain
embodiments, the ovality ratio is less than .+-.1.5. In certain
embodiments, the ovality ratio is less than .+-.1.3. In certain
embodiments, the ovality ratio is less than .+-.1.2. In certain
embodiments, the ovality ratio is less than .+-.1.1.
[0461] The details and mechanical principles of particle generation
for different types of nasal aerosol devices has been described.
See, Vidgren and Kublik, Adv. Drug Deliv. Rev. 29:157-77, 1998.
Traditional spray pumps replace the emitted liquid with air, and
preservatives are therefore required to prevent contamination.
However, driven by the studies suggesting possible negative effects
of preservatives, pump manufacturers have developed different spray
systems that avoid the need for preservatives. These systems use a
collapsible bag, a movable piston, or a compressed gas to
compensate for the emitted liquid volume (on the World Wide Web at
aptar.com and on the World Wide Web at rexam.com). The solutions
with a collapsible bag and a movable piston compensating for the
emitted liquid volume offer the additional advantage that they can
be emitted upside down, without the risk of sucking air into the
dip tube and compromising the subsequent spray. This may be useful
for some products where the patients are bedridden and where a
head-down application is recommended. Another method used for
avoiding preservatives is that the air that replaces the emitted
liquid is filtered through an aseptic air filter. In addition, some
systems have a ball valve at the tip to prevent contamination of
the liquid inside the applicator tip. More recently, pumps have
been designed with side-actuation. The pump was designed with a
shorter tip to avoid contact with the sensitive mucosal surfaces.
New designs to reduce the need for priming and re-priming, and
pumps incorporating pressure point features to improve the dose
reproducibility and dose counters and lock-out mechanisms for
enhanced dose control and safety are available (on the World Wide
Web at rexam.com and on the World Wide Web at aptar.com).
[0462] Traditional, simple single, bi-dose and multi-use
metered-dose spray pumps require priming and some degree of
overfill to maintain dose conformity for the labeled number of
doses. They are well suited for drugs to be administered daily over
a prolonged duration, but due to the priming procedure and limited
control of dosing, unless a specialty device is selected, they are
less suited for drugs with a narrow therapeutic window of time in
which to use the device, particularly if they are not used often.
For expensive drugs and drugs intended for single administration or
sporadic use and where tight control of the dose and formulation is
of importance, single-dose (UDS) or bi-dose spray (BDS) devices are
preferred (on the World Wide Web at aptar.com). A simple variant of
a single-dose spray device (MAD.TM.) is offered by LMA (LMA, Salt
Lake City, Utah, USA; on the World Wide Web at lmana.com). A
nosepiece with a spray tip is fitted to a standard syringe. The
liquid drug to be delivered is first drawn into the syringe and
then the spray tip is fitted onto the syringe. This device has been
used in academic studies to deliver, for example, a topical steroid
in patients with chronic rhinosinusitis and in a vaccine study. A
pre-filled device based on the same principle for one or two doses
(Accuspray.TM., Becton Dickinson Technologies, Research Triangle
Park, N.C., USA; on the World Wide Web at bdpharma.com) is used to
deliver the influenza vaccine FluMist.TM. (on the World Wide Web at
flumist.com), approved for both adults and children in the US
market. A similar device for two doses was marketed by a Swiss
company for delivery of another influenza vaccine a decade ago.
[0463] Pre-primed single- and bi-dose devices are also available,
and consist of a reservoir, a piston, and a swirl chamber (see,
e.g., the UDS UnitDose.TM. and BDS BiDose.TM. devices from Aptar,
formerly Pfeiffer). The spray is formed when the liquid is forced
out through the swirl chamber. These devices are held between the
second and the third fingers with the thumb on the actuator. A
pressure point mechanism incorporated in some devices secures
reproducibility of the actuation force and emitted plume
characteristics. Currently, marketed nasal migraine drugs like
Imitrex.RTM. (on the World Wide Web at gsk.com) and Zomig.RTM. (on
the World Wide Web at az.com; Pfeiffer/Aptar single-dose device),
the marketed influenza vaccine Flu-Mist (on the World Wide Web at
flumist.com; Becton Dickinson single-dose spray device), and the
intranasal formulation of naloxone for opioid overdose rescue,
Narcan Nasal.RTM. (on the World Wide Web at narcan.com; Adapt
Pharma) are delivered with this type of device.
[0464] In certain embodiments, the 90% confidence interval for dose
delivered per actuation is .+-.about 2%. In certain embodiments,
the 95% confidence interval for dose delivered per actuation is
.+-.about 2.5%.
[0465] Historically, intranasal administration of drugs in large
volume, such as from syringes adapted with mucosal atomizer devices
(MADs), has encountered difficulty due to the tendency of some of
the formulation to drip back out of the nostril or down the
nasopharynx. Accordingly, in certain embodiments, upon nasal
delivery of said pharmaceutical formulation to said patient, less
than about 20% of said pharmaceutical formulation leaves the nasal
cavity via drainage into the nasopharynx or externally. In certain
embodiments, upon nasal delivery of said pharmaceutical formulation
to said patient, less than about 10% of said pharmaceutical
formulation leaves the nasal cavity via drainage into the
nasopharynx or externally. In certain embodiments, upon nasal
delivery of said pharmaceutical formulation to said patient, less
than about 5% of said pharmaceutical formulation leaves the nasal
cavity via drainage into the nasopharynx or externally.
[0466] Current container closure system designs for inhalation
spray drug products include both pre-metered and device-metered
presentations using mechanical or power assistance and/or energy
from patient inspiration for production of the spray plume.
Pre-metered presentations contain previously measured doses or a
dose fraction in some type of units (e.g., single or multiple
blisters or other cavities) that are subsequently inserted into the
device during manufacture or by the patient before use. Typical
device-metered units have a reservoir containing formulation
sufficient for multiple doses that are delivered as metered sprays
by the device itself when activated by the patient.
[0467] With aseptic techniques, the use of preservatives may not be
required in pre-primed devices, but overfill is required resulting
in a waste fraction similar to the metered-dose, multi-dose sprays.
To emit 100 .mu.L, a volume of 125 .mu.L is filled in the device
(Pfeiffer/Aptar single-dose device) used for the intranasal
migraine medications Imitrex.TM. (sumatriptan) and Zomig.TM.
(zolmitriptan) and about half of that for a bi-dose design. Sterile
drug products may be produced using aseptic processing or terminal
sterilization. Terminal sterilization usually involves filling and
sealing product containers under high-quality environmental
conditions. Products are filled and sealed in this type of
environment to minimize the microbial and particulate content of
the in-process product and to help ensure that the subsequent
sterilization process is successful. In most cases, the product,
container, and closure have low bioburden, but they are not
sterile. The product in its final container is then subjected to a
sterilization process such as heat, irradiation, or chemical (gas).
In an aseptic process, the drug product, container, and closure are
first subjected to sterilization methods separately, as
appropriate, and then brought together. Because there is no process
to sterilize the product in its final container, it is critical
that containers be filled and sealed in an efficient quality
environment. Aseptic processing involves more variables than
terminal sterilization. Before aseptic assembly into a final
product, the individual parts of the final product generally can be
subjected to various sterilization processes. For example, glass
containers are subjected to dry heat; rubber closures are subjected
to moist heat; and liquid dosage forms are subjected to filtration.
Each of these manufacturing processes requires validation and
control.
[0468] Devices recited herein may employ any of the pharmaceutical
formulations, and are useful in the methods disclosed herein.
[0469] Accordingly, provided herein are devices adapted for nasal
delivery of a pharmaceutical formulation to a patient, comprising a
reservoir with a therapeutically effective amount of
epinephrine.
[0470] In certain embodiments, epinephrine is the only
pharmaceutically active compound in the pharmaceutical
formulation.
[0471] In certain embodiments, the volume of the pharmaceutical
formulation in the reservoir is not more than about 140 .mu.L.
[0472] In certain embodiments, the volume of the pharmaceutical
formulation in the reservoir is above about 125 .mu.L and less than
140 .mu.L.
[0473] In certain embodiments, about 100 .mu.L of the
pharmaceutical formulation in the reservoir is delivered to the
patient in one actuation.
[0474] In some embodiments, about 100 .mu.L of the pharmaceutical
formulation in the reservoir is delivered to the patient in one
actuation and comprises less than about 2.5 mg of epinephrine. In
some embodiments, about 100 .mu.L of the pharmaceutical formulation
in the reservoir is delivered to the patient in one actuation and
comprises about 0.5 mg to about 2.5 mg of epinephrine. In some
embodiments, about 100 .mu.L of the pharmaceutical formulation in
the reservoir is delivered to the patient in one actuation and
comprises about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg,
about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3
mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about
1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg,
about 2.3 mg, about 2.4 mg, or about 2.5 mg of epinephrine.
[0475] In certain embodiments, the pharmaceutical formulation
further comprises one or more excipients selected from water, EDTA,
and sodium chloride. In certain embodiments, the pharmaceutical
formulation further comprises benzalkonium chloride.
[0476] In some embodiments, about 100 .mu.l of the acqueous
pharmaceutical formulation in the reservoir is delivered to the
patient in one actuation and comprises epinephrine,
dodeclymaltoside or benzalkonium chloride or a combination of
dodeclymaltoside and benzalkonium chloride, EDTA, and NaCl.
[0477] In certain embodiments, the pharmaceutical formulation is
substantially free of antimicrobial preservatives.
[0478] In certain embodiments, the pharmaceutical formulation
further comprises a compound which acts as a preservative,
absorption enhancer and/or a cationic surfactant; an isotonicity
agent; a stabilizing agent; and an amount of acid or base
sufficient to achieve a pH of about 3.5 to about 6.0. The use of
absorption enhancers, such as alkylsaccharides, cyclodextrins, and
chitosans may increase the rate at which epinephrine is absorbed.
In general, absorption enhancers provide improved pharmacokinetic
outcomes such as increased C.sub.max, reduced T.sub.max, and dose
proportionality compared to both intramuscular formulations and
intranasal formulations that do not contain an absorption enhancer.
Without being bound to any theory, such absorption enhancers
typically operate by affecting two primary mechanisms for nasal
absorption: paracellular transport via opening of tight junctions
between cells, and transcellular transport or transcytosis through
cells via vesicle carriers.
[0479] Some absorption enhancing excipients can alter the
paracellular and/or transcellular pathways, others can extend
residence time in the nasal cavity or prevent metabolic changes.
Without an absorption enhancer, the molecular-weight limit for
nasal absorption is about 1 kDa, while administration of drugs in
conjunction with absorption enhancers can enable the absorption of
molecules from 1-30 kDa. Intranasal administration of most
absorption enhancers, however, can cause nasal mucosa damage.
Maggio, J. Excipients and Food Chem. 5(2):100-12, 2014. Examples of
absorption enhancers include aprotinin, benzalkonium chloride,
benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride,
chitosan, cyclodextrins, deoxycholic acid, decanoyl carnitine,
EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol,
glycosylated sphingosines, glycyrrhetinic acids,
2-hydroxypropyl-.beta.-cyclodextrin, laureth-9, lauric acid,
lauroyl carnitine, lauryl sulfate, lysophosphatidylcholine,
menthol, poloxamer 407, poloxamer F68, poly-L-arginine,
polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol,
quillaia saponin, salicylic acid,
.beta.-sitosterol-.beta.-D-glucoside, sucrose cocoate, taurocholic
acid, taurodeoxycholic acid, taurodihydrofusidic acid, and
alkylsaccharides, such as dodecyl maltoside, tetradecyl maltoside
and sucrose dodecanoate.
[0480] Epinephrine may optionally exist as pharmaceutically
acceptable salts including pharmaceutically acceptable acid
addition salts prepared from pharmaceutically acceptable non-toxic
acids including inorganic and organic acids. Representative acids
include, but are not limited to, acetic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,
fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,
isethionic, lactic, maleic, malic, mandelic, methanesulfonic,
mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. The
acid addition salts may be obtained as the direct products of
compound synthesis. In the alternative, the free base may be
dissolved in a suitable solvent containing the appropriate acid and
the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent. The salt may form solvates with
standard low molecular weight solvents using methods known to the
skilled artisan.
[0481] In certain embodiments, the device is filled with the
pharmaceutical formulation using sterile filling.
[0482] In certain embodiments, the pharmaceutical formulation is
chemically storage-stable for about twelve months at about
25.degree. C. and about 60% relative humidity and about six months
at about 40.degree. C. and about 75% relative humidity.
[0483] In some embodiments, intranasal epinephrine is delivered as
an aqueous solution, aqueous suspension, aqueous emulsion,
non-aqueous solution, non-aqueous suspensions, non-aqueous
emulsion, a solution with halogenated hydrocarbon propellant(s), or
as a dry powder. In some embodiments, aqueous formulations are
sprayed into the nostril. In some embodiments, aqueous formulations
are aerosolized by liquid nebulizers employing either hydraulic or
ultrasonic atomization. Propellant-based systems may use suitable
pressurized metered-dose inhalers (pMDIs). Dry powders may use dry
powder inhaler devices (DPIs), which are capable of dispersing the
drug substance effectively.
[0484] Propellants typically used include chlorofluorocarbons,
hydrochlorofluorocarbons, hydrofluorocarbons, hydrocarbons, and
compressed gases.
[0485] In some embodiments, intranasal epinephrine is delivered as
a nasal aerosol produced by a nasal pressurized metered-dose
inhalers (pMDIs). In some embodiments, the pMDI is a
hydrofluoroalkane (HFA)-based pMDI for nasal use. Like spray pumps,
nasal pMDIs produce a localized deposition on the anterior
non-ciliated epithelium of the nasal vestibule and in the anterior
parts of the narrow nasal valve, but due to quick evaporation of
the spray delivered with a pMDI, noticeable "drip-out" may be less
of an issue.
[0486] In some embodiments, epinephrine is delivered with a
nebulizer. Nebulizers use compressed gasses (air, oxygen, and
nitrogen) or ultrasonic or mechanical power to break up medical
solutions and suspensions into small aerosol droplets that can be
directly inhaled into the nose. The smaller particles and slow
speed of the nebulized aerosol increase penetration to the target
sites in the middle and superior meatuses and the paranasal
sinuses.
[0487] In some embodiments, epinephrine is delivered with a
pulsating aerosol generated via a perforated vibrating membrane. In
some embodiments, the pulsation membrane nebulizer is VibrENT (PART
Pharma GmbH). In some embodiments, epinephrine is delivered with a
pulsating aerosol in combination with breathing techniques
[0488] In some embodiments, epinephrine is delivered with
Bi-Directional.TM. delivery technology (e.g. Bi-Directional.TM.
Exhalation Delivery Systems (EDS); OptiNose).
[0489] In some embodiments, epinephrine is delivered with an
atomizer. In some embodiments, the atomizer is a handheld
battery-driven atomizer intended for nasal drug delivery. In some
embodiments, the atomizer atomizes liquids by producing a vortical
flow on the droplets as they exit the device. Such devices include
the ViaNase atomizer (by Kurve Technology Inc., Lynnwood, Wash.,
USA). In some embodiments, the atomizer is a nasal atomizer driven
by highly pressurized nitrogen gas.
[0490] In some embodiments, intranasal epinephrine is delivered
with a nasal powder device. In some embodiments, the nasal powder
device is a nasal powder inhaler, nasal powder sprayer, or nasal
powder insufflator. Powder sprayers typically have a compressible
compartment to provide a pressure that when released creates a
plume of powder particles fairly similar to that of a liquid spray.
Breath-actuated inhalers require the user to use his or her own
breath to inhale the powder into the nostril from a blister or
capsule. Nasal insufflator devices consist of a mouthpiece and a
nosepiece that are fluidly connected. Delivery occurs when the
subject exhales into the mouthpiece to close the velum, and the
airflow carries the powder particles into the nose through the
device nosepiece.
[0491] In some embodiments, the nasal powder inhaler is a blister
based powder inhaler. Typically, the blister is pierced before use
and the device nosepiece placed into one nostril. The subject
closes the other nostril with the finger and inhales the powder
into the nose. Representative devises include
BiDose.TM./Prohaler.TM., and Twin-Lizer.TM..
[0492] Representative nasal powder sprayers include, but are not
limited to, UnidoseDP.TM. Fit-Lizer.TM., Monopowder.TM.,
SoluVent.TM.)
[0493] In some embodiments, the nasal powder sprayer is a
capsule-based, single-dose powder devices. In one such embodiment,
the capsule-based, single-dose powder device consist of a chamber
that cuts off the top and bottom of the capsule when inserted. A
plastic chamber is compressed by hand, compressed air passes
through a one-way valve and the capsule during actuation, and the
powder is emitted.
[0494] In some embodiments, the nasal powder sprayer consists of an
air-filled compartment that is compressed until a pin ruptures a
membrane to release pressure that emits a plume of powder.
[0495] In some embodiments, the nasal powder sprayer consists of a
plunger that when pressed creates a positive pressure that ruptures
a membrane to expel the powder.
[0496] In some embodiments, the nasal powder insufflator requires
the subject to blow into one end of the tube while the other end is
inserted into the vestibule of the nostril.
[0497] In some embodiments, intranasal epinephrine is delivered
with a breath-powered Bi-Directional.TM. delivery device. A
breathpowered Bi-Directional.TM. nasal delivery device utilizes the
exhaled breath to deliver the drug into the nose. Breath-powered
Bi-Directional.TM. devices consist of a mouthpiece and a sealing
nosepiece with an optimized frusto-conical shape and comfortable
surface that mechanically expands the first part of the nasal
valve. The user slides a sealing nosepiece into one nostril until
it forms a seal with the flexible soft tissue of the nostril
opening, at which point, it mechanically expands the narrow
slit-shaped part of the nasal triangular valve. The user then
exhales through an attached mouthpiece. When exhaling into the
mouthpiece against the resistance of the device, the soft palate
(or velum) is automatically elevated by the positive oropharyngeal
pressure, isolating the nasal cavity from the rest of the
respiratory system. Owing to the sealing nosepiece, the dynamic
pressure that is transferred from the mouth through the device to
the nose further expands the slit-like nasal passages. This
"breath-powered" mechanism enables release of liquid or powder
particles into an air stream that enters one nostril, passes
entirely around the nasal septum, and exits through the opposite
nostril. Actuation of drug release in devices employing this
approach use manual triggering or mechanisms automatically
triggered by flow and/or pressure.
Single-Dose Devices
[0498] In certain embodiments, the device is a single-dose device,
wherein the pharmaceutical formulation is present in one reservoir,
and wherein the therapeutically effective amount of the epinephrine
is delivered essentially by one actuation of the device.
[0499] Also provided herein is a single-use, pre-primed device
adapted for nasal delivery of a pharmaceutical formulation to a
patient by one actuation of the device into one nostril of the
patient, having a single reservoir comprising about 100 .mu.L of a
pharmaceutical formulation as disclosed herein.
[0500] In certain embodiments, the device is actuatable with one
hand.
[0501] In certain embodiments, the delivery time is less than about
30 seconds. In certain embodiments, the delivery time is less than
about 25 seconds. In certain embodiments, the delivery time is less
than about 20 seconds. In certain embodiments, the delivery time is
less than about 15 seconds.
[0502] In certain embodiments, the 90% confidence interval for dose
delivered per actuation is .+-.about 2%. In certain embodiments,
the 95% confidence interval for dose delivered per actuation is
.+-.about 2.5%.
[0503] In certain embodiments, upon nasal delivery of the
formulation to the patient, less than about 20%, less than about
15%, less than about 10%, or less than about 5%, of the formulation
leaves the nasal cavity via drainage into the nasopharynx or
externally, as provided above.
[0504] In certain embodiments, said formulation is chemically
storage-stable for about twelve months at about 25.degree. C. and
about 60% relative humidity and/or about six months at about
40.degree. C. and about 75% relative humidity.
Bi-Dose Devices
[0505] In certain embodiments, said device is a bi-dose device,
wherein a first volume of said formulation is present in a first
reservoir and a second volume of said formulation is present in a
second reservoir, and wherein said therapeutically effective amount
is delivered essentially by a first actuation of said device into a
first nostril of said patient and a second actuation of said device
into a second nostril of said patient.
[0506] In certain embodiments, said first volume and said second
volume combined is equal to not more than about 380 .mu.L.
[0507] In certain embodiments, about 100 .mu.L of said first volume
of said formulation is delivered by said first actuation.
[0508] In certain embodiments, about 100 .mu.L of said second
volume of said formulation is delivered by said second
actuation.
[0509] In certain embodiments, said bi-dose device is actuatable
with one hand.
[0510] In certain embodiments, the delivery time is less than about
30 seconds. In certain embodiments, the delivery time is less than
about 25 seconds. In certain embodiments, the delivery time is less
than about 20 seconds. In certain embodiments, the delivery time is
less than about 15 seconds.
[0511] In certain embodiments, the 90% confidence interval for dose
delivered per actuation is .+-.about 2%. In certain embodiments,
the 95% confidence interval for dose delivered per actuation is
.+-.about 2.5%.
[0512] In certain embodiments, upon nasal delivery of the
formulation to the patient, less than about 20%, less than about
15%, less than about 10%, or less than about 5%, of the formulation
leaves the nasal cavity via drainage into the nasopharynx or
externally.
[0513] Also provided are embodiments wherein any embodiment above
may be combined with any one or more of these embodiments, provided
the combination is not mutually exclusive.
Indications
[0514] Also provided are formulations and devices for use in
treating conditions mediated by adrenergic receptors, and/or one or
more symptoms thereof, and methods of treatment of such conditions
comprising administering the formulations and using the devices
disclosed herein.
[0515] In certain embodiments, the condition is (1) treatment of
acute hypersensitivity, such as a type-1 hypersensitivity reaction
(for example such as an anaphylactoid reaction (systemic allergic
reaction) to foods, drugs, animal serums, insect bites and stings,
and other allergens, see below), (2) treatment of acute asthmatic
attacks to relieve bronchospasm not controlled by inhalation or
subcutaneous administration of other solutions of the drug, (3)
treatment and prophylaxis of cardiac arrest and/or attacks of
transitory atrioventricular (A-V) heart block with syncopal
seizures (Stokes-Adams Syndrome), (4) to increase mean arterial
blood pressure in adult patients with hypotension associated with
septic shock, (5) for induction and maintenance of mydriasis during
intraocular surgery.
[0516] In certain embodiments, the type-1 hypersensitivity reaction
(systemic allergic reaction) is chosen from allergic asthma,
allergic conjunctivitis, allergic rhinitis (hay fever),
anaphylaxis, angioedema, urticaria (hives), eosinophilia,
antibiotic allergy (e.g. to penicillin or cephalosporin), and food
allergy (e.g. to peanuts or shellfish).
[0517] In certain embodiments, the type-1 hypersensitivity reaction
(systemic allergic reaction) is anaphylaxis.
[0518] Symptoms of anaphylaxis include hives, generalized itching,
nasal congestion, wheezing, difficulty breathing, cough, cyanosis,
lightheadedness, dizziness, confusion, slurred speech, rapid pulse,
palpitations, nausea and vomiting, abdominal pain or cramping, skin
redness or inflammation, nasal flaring, and intercostal
retractions.
[0519] In certain embodiments, the symptom of the type-1
hypersensitivity reaction (systemic allergic reaction) is chosen
from generalized hives (urticatria), itching (pruritis), flushing,
swelling (angioedema) of the afflicted tissues, a burning sensation
of the skin (common in those with angioedema), swelling of the
tongue or throat, respiratory symptoms such as shortness of breath,
wheezes, or stridor shortness of breath, coronary artery spasm,
myocardial infarction, dysrhythmia, or cardiac arrest (those with
underlying coronary disease are at greater risk of cardiac
effects), tachycardia, bradycardia, and a Bezold-Jarisch
reflex.
[0520] In certain embodiments, the type-1 hypersensitivity reaction
(systemic allergic reaction) is caused by stinging insects (e.g.,
order Hymenoptera, which include bees, wasps, hornets, yellow
jackets and fire ants), biting insects (e.g., triatoma,
mosquitoes), allergen immunotherapy, foods, drugs, diagnostic
testing substances (e.g. radiocontrast media) and other allergens,
as well as idiopathic anaphylaxis or exercise-induced
anaphylaxis.
[0521] In certain embodiments, the cardiac arrest is
out-of-hospital cardiac arrest.
[0522] Also provided are embodiments wherein any embodiment above
may be combined with any one or more of these embodiments, provided
the combination is not mutually exclusive.
Examples
[0523] The following examples are provided for illustrative
purposes only and not to limit the scope of the claims provided
herein.
Example 1. Epinephrine Formulations for Clinical Use
[0524] A representative procedure for the preparation of
formulations for clinical use is described. The Formulation
Excipient Solution (FES) can be made in advance (up to 7 days) and
stored at room temperature. The epinephrine stock solution (ESS)
should be made fresh within 72 hours of dosing, protected from
light and excessive oxidation and stored at 2-8.degree. C. until 2
hours before use. A mixture of equal volumes of sterile filtered
FES and ESS will result in a solution of epinephrine,
dodecylmaltoside (DDM), EDTA, benzalkonium chloride (BZK) in saline
for use in the clinical protocols below.
[0525] A 200 mL batch of Formulation Excipient Solution (FES) is
prepared by weighing 0.80 g (0.75-0.85 g) of EDTA into a 200 mL
volumetric flask and dissolving in .about.150 mL of Sterile Saline;
weighing 1.00 g (0.95-1.05 g) of Intravail.RTM. DDM, quantitatively
transferring to the EDTA solution, and mixing until dissolved
(solution should be clear and colorless); if necessary, using
gentle heating (40-60.degree. C.) aid solution, then cooling to
room temperature once dissolved; adding the desired amount of a BZK
solution (or adding BZK as a solid) and adding to the mixing
Intravail.RTM./EDTA mixture; adding the appropriate amount of 1 N
HCl to attain a pH of 4 (e.g. approximately 20 mL), and diluting QS
to volume with Sterile Saline, and stirring until the mixture is
uniform. The pH of the FES solution may be measured and
recorded.
[0526] Epinephrine Stock Solution (ESS) 10 mg/mL should be freshly
prepared, protected from light (e.g. with foil, the use of brown
colored lights, etc.), and use within 72 hours of dosing. To
formulate a 100 mL batch of final 10 mg/mL product: ensure 100 mL
volumetric flask is wrapped in foil prior to adding FES Solution;
add 50 mL of FES Solution to each of two foil wrapped 100 mL flasks
(50 mL per flask); weigh and add 1.0 g (0.95-1.05 g) of epinephrine
(E4250 Sigma Aldrich) into each of the two 100 mL flasks; mix each
until uniform; measure the pH of each flask and record.
[0527] Final Dosing Formulations (FDF) are prepared by filling
appropriate sprayers capable of delivering 100 .mu.L per spray with
appropriate amounts of ESS (e.g. about 5.0 mL of ESS for Aptar
multi-dose spray devices or about 125 .mu.L of ESS for uni-dose
spray devices).
[0528] Representative epinephrine formulations for clinical use are
presented in Table 2, Table 3, and Table 4.
TABLE-US-00002 TABLE 2 Representative Epinephrine Formulations for
Clinical Use. Ingredients Quantity per mL (-)-Epinephrine 3 5 10 10
10 20 USP (mg) DDM (mg) 2.5 2.5 2.5 2.5 2.5 2.5 Disodium 2.0 2.0
2.0 2.0 2.0 2.0 EDTA USP (mg) BZK USP (mg) 0.1 0.2 0.2 0.4 0.6 0.2
Sodium 8.23 8.23 8.23 8.23 8.23 8.23 chloride USP (mg) 1N HCl (mL)
0.051 0.051 0.051 0.051 0.051 0.051 0.1N HCl Adjust to Adjust to
Adjust to Adjust to Adjust to Adjust to and/or 0.1 pH 3.8-4.2 pH
3.8-4.2 pH 3.8-4.2 pH 3.8-4.2 pH 3.8-4.2 pH 3.8-4.2 NaOH Purified
water, QS to 1 mL QS to 1 mL QS to 1 mL QS to 1 mL QS to 1 mL QS to
1 mL Millipore, Type I
TABLE-US-00003 TABLE 3 Representative Epinephrine Formulations for
Clinical Use. Ingredients Quantity per mL (-)-Epinephrine 3 5 6.5
10 13 15 20 USP (mg) DDM (mg) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Disodium
EDTA 2.0 2.0 2.0 2.0 2.0 2.0 2.0 USP (mg) BZK USP (mg) 0.4 0.4 0.4
0.4 0.4 0.4 0.4 Sodium chloride 8.23 8.23 8.23 8.23 8.23 8.23 8.23
USP (mg) 1N HCl (mL) 0.051 0.051 0.051 0.051 0.051 0.051 0.051 0.1N
HCl and/or Adjust to Adjust to Adjust Adjust Adjust to Adjust to
Adjust to 0.1 NaOH pH 3.8-4.2 pH 3.8-4.2 to pH to pH pH 3.8-4.2 pH
3.8-4.2 pH 3.8-4.2 3.8-4.2 3.8-4.2 Purified water, QS to 1 mL QS to
1 mL QS to 1 mL QS to 1 mL QS to 1 mL QS to 1 mL QS to 1 mL
Millipore, Type I
TABLE-US-00004 TABLE 4 Representative Epinephrine Formulations for
Clinical Use. Ingredients Quantity per mL (-)-Epinephrine USP 10 10
10 10 10 10 10 10 (mg) Dodecylmaltoside 2.5 2.5 2.5 2.5 2.5 2.5 2.5
2.5 (DDM) (mg) Disodium EDTA USP 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
(mg) Benzalkonium Chloride 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 USP (mg)
Sodium chloride USP 8.23 8.23 8.23 8.23 8.23 8.23 8.23 8.23 (mg)
Butylated -- 0.1 0.1 -- -- -- -- -- hydroxyanisole (BHA) (mg)
Citric acid -- -- 0.42 -- 4.2 -- 4.2 -- monohydrate (mg)
Isoascorbic Acid (mg) -- -- -- 0.1 0.1 -- -- D-.alpha.-Tocopherol
-- -- -- -- -- 5.0 5.0 -- polyethylene glycol 1000 succinate (mg)
Sodium metabisulfite -- -- -- -- -- -- -- 0.05 (mg) 1N HCl 0.051 mL
0.051 mL 0.051 mL 0.051 mL 0.051 mL 0.051 mL 0.051 mL 0.051 mL 0.1N
HCl Adjust Adjust Adjust Adjust Adjust Adjust Adjust Adjust to pH
to pH to pH to pH to pH to pH to pH to pH 3.8-4.2 3.8-4.2 3.8-4.2
3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 0.1 NaOH Adjust Adjust
Adjust Adjust Adjust Adjust Adjust Adjust to pH to pH to pH to pH
to pH to pH to pH to pH 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2 3.8-4.2
3.8-4.2 3.8-4.2 3.8-4.2 Purified water, QS to 1 mL QS to 1 mL QS to
1 mL QS to 1 mL QS to 1 mL QS to 1 mL QS to QS to Millipore, Type I
1 mL 1 mL
Example 2: Clinical Protocols
[0529] The following clinical protocols were carried out, or may be
carried out, in healthy human volunteers to assess the safety,
optimal dosing, and pharmacokinetics of intranasal epinephrine.
Example 2A: First Clinical Study
[0530] Objective.
[0531] The primary objective of this study was to assess the
comparative bioavailability of epinephrine after intranasal
administration and intramuscular administration as intramuscular
epinephrine delivered by auto injector in healthy volunteers under
fasted conditions. A secondary objective was to evaluate the safety
and tolerability of intranasal (IN) epinephrine in healthy
volunteers.
[0532] Study Design.
[0533] A Phase 1, open-label, randomized, single-dose,
two-treatment, crossover study was carried out that consisted of a
screening period, baseline period, and an open-label treatment
period. In the screening period, subjects underwent screening
within 21 days prior to entering into the open-label treatment
phase of the study. In the baseline period, within 24 hours of
dosing, initial assessments were taken; in some cases, screening
and baseline visits could be combined if all assessments are done
within 24 hours of dosing.
[0534] In the Open-Label Treatment Period, twelve (12) eligible
subjects were randomized after an overnight fast to receive single
0.3 mg doses of intranasal epinephrine and intramuscular
epinephrine delivered by auto injector. Blood samples were
collected for 360 minutes after dosing. Treatments were separated
by a minimum 24 hours wash out period. Safety assessments were
performed on each study day and subjects released after discharge
assessments on Day 1. Subjects were followed for 6 hours after the
administration of the last dose of study drug.
[0535] Plasma samples from all subjects that completed two periods
of the study were analyzed. Blood samples for the measurement of
plasma concentrations of epinephrine, norepinephrine and
dihydroxyphenylglycol (DHPG) (metabolite) were collected before (0,
pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120,
150, 180, 240 and 360 minutes after dosing. Actual blood collection
times can vary as follows: 1).+-.1 minutes for the 2 to 20 minute
samples, 2).+-.2 minutes for the 25 to 90 minute samples, and
3).+-.5 minutes for the 120 to 360 minute samples. Actual sampling
times were recorded.
[0536] Study Drugs and Administration.
[0537] Each 100 .mu.L IN dose of intranasal epinephrine formulation
contained, in addition to 0.3 mg epinephrine, 0.25% (w/v)
dodecylmaltoside (0.25 mg), 0.04% (w/v) benzalkonium chloride (BZK)
(0.04 mg), ethylenediaminetetraacetic acid (EDTA) in 10 mM pH 4.0
acetate buffer. The intramuscular epinephrine delivered by auto
injector delivered 0.3 mg epinephrine by intramuscular
injection.
[0538] Subjects were fasted prior to administration of either IN or
IM epinephrine. Each 100 .mu.L spray was administered to the left
nostril via a commercially-available multiple dose nasal spray
device marketed by Aptar Pharma. Priming of the device (activation
5 times) was done in a hood or priming box within 30 minutes prior
to dosing the subject.
[0539] Participants.
[0540] The study included healthy male adult volunteers (up to 12)
between the ages of 18 and 55 years, inclusive, who gave written,
informed consent. Other inclusion criteria included: body weight
more than 50 kg; mass index between 18 and 28 kg/(height in
m).sup.2 (BMI), inclusive; no medical history of hypertension and
cardiovascular disease; blood pressure and heart rate within normal
range at screening and baseline; no clinically significant abnormal
findings in medical history, on physical examination,
electrocardiogram (QTcF<450 msec), or clinical laboratory
results during screening; and agreement to remain confined in house
until study end and willing to comply with all required study
procedures.
[0541] Exclusion criteria included: history of clinically
significant gastrointestinal, renal, hepatic, neurologic,
hematologic, endocrine, oncologic, respiratory, immunologic,
psychiatric, or cardiovascular disease, severe seasonal or
non-seasonal allergies, nasal polyps, no nasal piercings, or any
nasal passage abnormality that could interfere with nasal spray
administration, or any other condition which, in the opinion of the
Principal Investigator, would jeopardize the safety of the subject
or impact the validity of the study results; smoked within 6 months
prior to screening; significant traumatic injury, major surgery or
open biopsy within 30 days prior to study screening; history of
allergic or adverse responses to epinephrine or any comparable or
similar product; an abnormal diet (such as one that severely
restricts specific basic food groups [e.g., ketogenic diet], limits
calories [e.g., fast], and/or requires the use of daily supplements
as a substitute for the foods typically eaten at mealtimes), during
the four (4) weeks preceding the study; donation of blood or plasma
within 30 days of the first dose of study drug; participation in a
clinical trial within 30 days prior to the first dose of study drug
(non-interventional trial acceptable); inadequate or difficult
venous access that could jeopardize the quality or timing of the PK
samples; positive blood screen for HIV, Hepatitis B surface antigen
(HbSAg), or Hepatitis C, or a positive urine screen for alcohol
(saliva test may be utilized at baseline), drugs of abuse, or
cotinine.
[0542] Additionally, during the study, subjects were not permitted:
to take OTC products, including vitamins and supplements, for the
seven (7) days preceding the study; to use any prescription
medication within 14 days prior to the first dose of study drug or
during the study unless approved by the Principal Investigator and
medical monitor; to use oral and/or nasal decongestants within 14
days prior to the first dose of study drug or during the study; to
smoke or use tobacco products for six (6) months prior to the first
dose of Study Drug and for the duration of the study; or to engage
in strenuous exercise during the confinement period of the
study.
[0543] Safety.
[0544] Adverse events were collected and reviewed to evaluate the
safety and tolerability of intranasal (IN) epinephrine. Other
safety measures included vital sign measurement. Objective
evaluations of nasal irritation were assessed after each
administration of study drug using a 6-point (0.fwdarw.5) score.
The scoring was done by a trained observer based on an assessment
of the nasal mucosa prior to dosing (baseline) and at 30 (.+-.5
min) minutes, and 1 (.+-.10 min), 2 (.+-.15 min), 4 (.+-.30 min),
and 6 (.+-.30 min) hours post dose. Irritation was assessed by
evaluating the degree of mucosal inflammation and bleeding. The
subjects were required to report any incident of bleeding or
inflammation in-between the actual evaluation time points.
[0545] An unconstrained visual analog scale (VAS) that consists of
a 10 cm (100 mm) horizontal straight line was used to assess acute
pain following each administration of the intranasal intranasal
(IN) epinephrine drug product. The ends of the scale were defined
as extreme limits of pain sensation: 0=no pain, 10=extreme pain.
The subjects were asked to mark a point on the scale which best
describes their intensity of pain and discomfort just prior to
dosing (baseline) and at 15 (.+-.2 min) and 30 (.+-.5 min) minutes,
and 1 (.+-.10 min) hour post dose. The location of the marking at
each time point was measured and noted as the reported score.
[0546] Pharmacokinetic Analysis.
[0547] Pharmacokinetic parameters for epinephrine, norepinephrine
and DHPG will be calculated using non-compartmental analysis were
calculated: maximum plasma concentration (C.sub.max), time to
C.sub.max (t.sub.max), area under the curve to the final time with
a concentration equal to or greater than the lower limit of
quantitation [AUC.sub.(0-t)] and to infinity [AUC.sub.(inf)],
elimination rate constant (.lamda.z) and half-life (t.sub.1/2),
and, for epinephrine only, clearance (CL/F) and volume of
distribution (Vz/F) uncorrected for bioavailability (F).
[0548] Non-GCP pharmacokinetic analysis was performed using
WinNonlin version 7.0. The lower limit of bioanalytical
quantification was 20 pg/mL. Plasma concentration designated as BLQ
were given a value of 20 pg/mL. The pharmacokinetic parameters
C.sub.max, AUC.sub.(0-t), and AUC.sub.(inf) for epinephrine,
norepinephrine and DHPG were compared among treatments using an
analysis of variance (ANOVA) model with treatment, period,
sequence, and subject within sequence as the classification
variables using the natural logarithms of the data. Baseline
corrected C.sub.max was calculated from the uncorrected
C.sub.max-PreDose concentration. Baseline corrected AUC.sub.0-t was
calculated from the uncorrected AUC.sub.0-t-PreDose concentration x
t.sub.last. Confidence intervals (90%) were constructed for the
geometric mean ratios, intranasal-to-intramuscular epinephrine of
the three parameters using the log-transformed data and the two
one-sided t-tests procedure. The point estimates and confidence
limits will be exponentiated back to the original scale.
Comparability between intranasal (IN) epinephrine and intramuscular
epinephrine was assessed from the geometric mean ratios and 90%
confidence intervals for the three parameters.
[0549] Results.
[0550] Mean plasma concentration of epinephrine from IN
administration remained significantly below that of epinephrine
from intramuscular epinephrine delivered by auto injector
throughout the study, as shown in FIG. 3. Intranasal administration
of epinephrine using the above intranasal epinephrine formulation
resulted in significantly lower exposure (C.sub.max and
AUC.sub.0-t) of the parent compound epinephrine compared to
intramuscular epinephrine delivered by auto injector, as shown
below in Table 5. There were no related adverse events reported.
The pH was between 3 and 4.
TABLE-US-00005 TABLE 5 Intramuscular and Intranasal Administraton
of Epinephrine. Intramuscular 0.3 mg Intranasal 0.3 mg C.sub.max
AUC.sub.0-t t.sub.max C.sub.max AUC.sub.0-t t.sub.max (pg/mL) (hr *
pg/mL) (min) (pg/mL) (hr * pg/mL) (min) Mean 333 19878 18 83 8932
53 SD 196 6051 53 6385 Min 71 7493 6 19 767 2 Median 311 19606 20
83 7771 23 Max 729 30381 45 222 23011 240 CV % 59 30 64 71
Geometric 280 18854 69 6619 Mean CV % 72 38 73 117 Geometric
Mean
Example 2B: Second Clinical Study
[0551] Objective.
[0552] The primary objectives of this study were to determine the
optimal dose of a formulation of intranasal epinephrine (IN-Epi) to
be used in a study of, and in that study to assess, the comparative
bioavailability of epinephrine after intranasal administration and
intramuscular administration by injection (EpiPen.RTM.) injection
in healthy volunteers under fasted conditions. A secondary
objective was to evaluate the safety and tolerability of the
formulation of intranasal epinephrine in healthy volunteers.
[0553] Study Design.
[0554] A Phase 1, dose escalation followed by a 12 subject
open-label, randomized, single-dose, two-treatment, two-period,
crossover studies was conducted as follows.
[0555] A dose escalation in three subjects was conducted to
determine the optimal dose of epinephrine. In the Screening Period,
subjects underwent screening within 28 days prior to entering into
the study. Three (3) subjects were subsequently enrolled and
received IN-Epi doses of 0.5 mg, 1.0 mg and 2.0 mg epinephrine by
IN administration (formulated at pH 5.5 to 6.0) after an overnight
fast. Blood samples were collected for 360 minutes after dosing.
Treatments were separated by a minimum 24 hours wash out
period.
[0556] Thereafter, comparative bioavailabilty of the intranasal
formulation to intramuscular injection was assessed in twelve
subjects in an open-label, randomized, single-dose, two-treatment,
two-period, crossover study that consisted of a screening period,
baseline period, and an open-label treatment period. In the
Screening Period, subjects underwent screening within 28 days prior
to entering into the study. In the Open-Label Treatment Period,
twelve (12) eligible subjects were randomized to 1.0 mg of IN-Epi
or a 0.3 mg dose of epinephrine injection by IM administration
(EpiPen.RTM.) after an overnight fast to receive single doses.
Blood samples are collected for 360 minutes after dosing.
Treatments are separated by a minimum 24 hours wash out period.
[0557] Safety assessments were performed at each of the study day
and subjects could be released after discharge assessment. Subjects
were followed for 6 hours after the administration of the last dose
of study drug.
[0558] The study was carried out in part as disclosed above. For
all parts of the study, the following procedures were performed as
follows.
[0559] Study Drugs and Administration.
[0560] Each 100 .mu.L IN dose of epinephrine formulation contained,
in addition to 0.5 mg, 1.0 mg, or 2.0 mg (5 mg/mL, 10 mg/mL, or 20
mg/mL) of IN-Epi, 0.25% (w/v) dodecylmaltoside (0.25 mg), 0.04%
(w/v) benzalkonium chloride (BZK) (0.04 mg), and
Ethylenediaminetetraacetic acid (EDTA) in 0.9% (w/v) saline, at pH
4.5 (3.5 to 5.0). The commercially available EpiPen.RTM. delivers
0.3 mg epinephrine by intramuscular injection.
[0561] Subjects were fasted prior to administration of either IN or
IM epinephrine. Each 100 .mu.L spray was administered to the left
nostril via a commercially-available multiple dose nasal spray
device marketed by Aptar Pharma. Priming of the device (activation
5 times) was done in a hood or priming box within 30 minutes prior
to dosing the subject.
[0562] Participants.
[0563] A total of fifteen (15) males were enrolled in the study.
Plasma samples from all subjects that complete the study were
analyzed. Blood samples for the measurement of plasma
concentrations of epinephrine were collected before (0, pre-dose)
and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180,
240 and 360 minutes after dosing. Actual blood collection times
could vary as follows: 1).+-.1 minutes for the 2 to 20 minute
samples, 2).+-.2 minutes for the 25 to 90 minute samples, and
3).+-.5 minutes for the 120 to 360 minute samples.
[0564] Inclusion criteria.
[0565] Participants: were male, between ages 18 and 30, inclusive;
gave written informed consent; had body weight more than 50 kg and
mass index between 18 and 28 kg/m.sup.2, inclusive; had no
family/medical history of hypertension and cardiovascular disease
within the past 10 years; have blood pressure within normal range
(i.e. <140/90 mmHg) at screening; had no clinically significant
abnormal findings in the medical history, on physical examination,
electrocardiogram (QTcF<450 msec), or clinical laboratory
results during screening; and agreed to remain confined in house
during appropriate study times and willing to comply with all
required study procedures.
[0566] Exclusion Criteria.
[0567] Exclusion criteria included history of clinically
significant gastrointestinal, renal, hepatic, neurologic,
hematologic, endocrine, oncologic, pulmonary, immunologic,
psychiatric, or cardiovascular disease, severe seasonal or non
seasonal allergies, nasal polyps, or any nasal passage abnormality
that could interfere with nasal spray administration, or any other
condition which, in the opinion of the Principal Investigator,
would jeopardize the safety of the subject or impact the validity
of the study results; had smoked within 6 months prior to
screening; significant traumatic injury, major surgery or open
biopsy within 30 days prior to study screening; history of allergic
or adverse responses to epinephrine or any comparable or similar
product; had been on an abnormal diet (such as one that severely
restricts specific basic food groups [e.g., ketogenic diet], limits
calories [e.g., fast], and/or required the use of daily supplements
as a substitute for the foods typically eaten at mealtimes), during
the four (4) weeks preceding the study; donated blood or plasma
within 30 days of the first dose of study drug; participation in a
clinical trial within 30 days prior to the first dose of study
drug; inadequate or difficult venous access that may jeopardize the
quality or timing of the PK samples; positive blood screen for HIV,
Hepatitis B surface antigen (HbSAg), or Hepatitis C, or a positive
urine screen for alcohol, drugs of abuse, or cotinine.
[0568] Additionally, during the study, subjects were not permitted:
to take OTC products, including vitamins and supplements, for the
seven (7) days preceding the study; to use any prescription
medication within 14 days prior to the first dose of study drug or
during the study unless approved by the Principal Investigator and
medical monitor; to use oral and/or nasal decongestants within 14
days prior to the first dose of study drug or during the study; to
smoke or use tobacco products for six (6) months prior to the first
dose of Study Drug and for the duration of the study; or to engage
in strenuous exercise during the confinement period of the
study.
[0569] Safety.
[0570] Adverse events were collected and were or will be reviewed
to evaluate the safety and tolerability of IN-Epi. Other safety
measures will include vital sign measurements.
[0571] Objective evaluations of nasal irritation were assessed
after each administration of study drug using a 6-point
(0.fwdarw.5) score. The scoring was done by a medically trained
observer based on an assessment of the nasal mucosa prior to dosing
(baseline) and at 30 (.+-.5 min) minutes, and 1 (.+-.10 min), 2
(.+-.15 min), 4 (.+-.30 min), and 6 (.+-.30 min) hours post dose.
Irritation was assessed by evaluating the degree of mucosal
inflammation and bleeding. Subjects were also required to report
any incident of bleeding or inflammation in-between the actual
evaluation time points.
[0572] An unconstrained visual analog scale (VAS) that consists of
a 10 cm (100 mm) horizontal straight line was used to assess acute
pain following each administration of the IN-Epi drug product. The
ends of the scale were defined as extreme limits of pain sensation:
0=no pain, 10=extreme pain. Subjects were asked to mark a point on
the scale which best describes their intensity of pain and
discomfort just prior to dosing (baseline) and at 15 (.+-.2 min)
and 30 (.+-.5 min) minutes, and 1 (.+-.10 min) hour post dose. The
location of the marking at each time point was measured and noted
as the reported score.
[0573] Pharmacokinetic Analysis.
[0574] Pharmacokinetic parameters for epinephrine were calculated
using non-compartmental analysis: maximum plasma concentration
(C.sub.max), time to C.sub.max (t.sub.max), area under the curve to
the final time with a concentration equal to or greater than the
lower limit of quantitation [AUC.sub.(0-t)] and to infinity
[AUC.sub.(inf)], elimination rate constant (.lamda.z) and half-life
(t.sub.1/2), and, for epinephrine only, clearance (CL/F) and volume
of distribution (Vz/F) uncorrected for bioavailability (F).
[0575] Pharmacokinetic parameters C.sub.max, AUC.sub.(0-t), and
AUC.sub.(inf) for epinephrine were compared among treatments using
an analysis of variance (ANOVA) model with treatment, period,
sequence, and subject within sequence as the classification
variables using the natural logarithms of the data. Confidence
intervals (90%) were constructed for the geometric mean ratios,
IN-Epi-to-EpiPen.RTM., of the three parameters using the
log-transformed data and the two one-sided t-tests procedure. The
point estimates and confidence limits were exponentiated back to
the original scale. Comparability between IN and IM epinephrine
were assessed from the geometric mean ratios and 90% confidence
intervals for the three parameters.
[0576] Results.
[0577] Results for the dose escalation portion of the study are
given below in Table 6 and in FIGS. 4, 5, 6, and 7. Intranasal
formulations of epinephrine formulated as disclosed above at doses
of 0.5, 1.0, and 2.0 mg in saline at pH 4.0 (3.5-5.0 acceptable)
were administered to three subjects. Table 6 below gives the mean
pharmacokinetic parameters for the three doses.
TABLE-US-00006 TABLE 6 Mean pharmacokinetic parameters for three
doses of intranasal epinephrine. 0.5 mg 1.0 mg 2.0 mg AUC.sub.0-t
AUC.sub.0-t AUC.sub.0-t t.sub.max C.sub.max (min * t.sub.max
C.sub.max (min * t.sub.max C.sub.max (min * (min) (pg/mL) pg/mL)
(min) (pg/mL) pg/mL) (min) (pg/mL) pg/mL) Mean 28.3 234 24000 12.7
586 43900 12.5 2470 166000 SD 27.4 22.4 5090 6.43 369 18400 2.5
1370 80800 CV % 96.8 9.55 21.2 50.8 63 41.8 20 55.4 48.7 Geo Mean
21.1 234 23600 11.7 468 41100 12.3 2230 154000
[0578] As can be seen, T.sub.max was lower, and C.sub.max and AUC
higher, for all doses of intranasal epinephrine than in the
previous study. These trends were more marked with increasing dose.
In particular, the 1.0 and 2.0 mg formulations each exhibited a
T.sub.max that was lower than intramuscular epinephrine delivered
by auto injector as used in the previous study, and a C.sub.max
that was higher. AUC for all intranasal formulations was higher
than for intramuscular epinephrine delivered by auto injector for
all doses.
[0579] FIGS. 4 and 5 show the mean time-vs-concentration curves for
the 0.5, 1.0, and 2.0 mg intranasal formulations of epinephrine.
FIGS. 6 and 7 duplicate the data in FIGS. 4 and 5, but overlay it
on the epinephrine auto injector data from Study 2A to illustrate
the pharmacokinetic differences between, for example, the 1.0 and
2.0 mg intranasal doses of epinephrine and intramuscular
epinephrine auto injector. These figures also provide a relevant
contrast to FIG. 3, where intranasal epinephrine was formulated in
acetate buffer at pH 3-4.
[0580] The results from the dose escalation portion of the study
show, in contrast to previous studies, that epinephrine can be
formulated to achieve significant bioavailability. At certain
doses, the pharmacokinetics of intranasal epinephrine so formulated
appears superior to intramuscular epinephrine delivered by auto
injector, achieving a rapid, IM-injection-like rate of absorption
in the first 20 minutes.
[0581] Results for the portion of the study comparing
bioavailability of IN to IM injection are given below in Tables
7-9c and in FIGS. 8 and 9. Intranasal epinephrine formulated as
disclosed above at a dose of 1.0 mg in saline at approximately pH
4.0 was administered to twelve subjects; a further twelve were
administered intramuscular epinephrine delivered by auto injector
(0.3 mg) in the thigh. Table 7 below shows mean PK parameters for
IN and IM epinephrine formulated as disclosed above.
TABLE-US-00007 TABLE 7 Mean PK parameters for IN and IM
epinephrine. Intranasal 1.0 mg IM Injection Thigh 0.3 mg C.sub.max
AUC.sub.0-t t.sub.max C.sub.max AUC.sub.0-t t.sub.max (pg/mL) (min
* pg/mL) (min) (pg/mL) (min * pg/mL) (min) N 12 12 12 12 12 12 Min
182 28102 6 64 16318 20 Max 484 70450 150 560 66792 61 Geo 305
44221 25 236 45294 25 Mean CV 30 28 161 64 48 183 % Geo Mean
[0582] FIGS. 8 and 9 also demonstrate that the plasma time vs.
concentration curve for 1.0 mg IN epinephrine is very similar to
that for 0.3 mg. IM epinephrine (EpiPen.RTM.) administered in the
thigh.
[0583] Table 8 below shows C.sub.max and partial AUC data comparing
the IM and IN routes. Ratio of intranasal as a percent of reference
for AUCs are given. The data below demonstrate that 1.0 mg
intranasal epinephrine can be formulated to be highly similar to or
better than a 0.3 mg intramuscular injection of epinephrine.
TABLE-US-00008 TABLE 8 Comparison of Key Pharmacokinetic Parameters
between Intranasal and Intramuscular Administration---Ratio Defined
as Intranasal/Intramuscular with 90% Confidence Interval. 90%
Confidence Interval Dependent Ratio % Ref Lower Upper C.sub.max 129
90 185 AUC.sub.0-t 98 78 122 AUC.sub.0-21/2 85 60 120 AUC.sub.0-5
74 50 109 AUC.sub.0-71/2 73 46 116 AUC.sub.0-10 79 48 130
AUC.sub.0-15 93 57 150 AUC.sub.0-20 102 64 163
[0584] Tables 9a-9c below show comparisons of 9a) the median
t.sub.max, 9b) the distribution of t.sub.max values, and 9c) the
percent of subjects with t.sub.max satisfying the stated condition
between intranasal and intramuscular epinephrine.
TABLE-US-00009 TABLE 9a Distribution of tmax Values Resulting After
Intranasal and Intramuscular Administration. t.sub.max (minutes)
Percentile Intranasal Intramuscular 25% 9 6 Median (50%) 20 35 75%
79 60
TABLE-US-00010 TABLE 9b t.sub.max Values Listed in Ascending Order
After Intranasal and Intramuscular Administration. Intranasal
Intramuscular t.sub.max (minutes) 6 4 8 6 8 6 9 6 10 6 20 25 20 25
20 35 20 45 20 60 45 60 79 60
TABLE-US-00011 TABLE 9c Percent of Subjects with t.sub.max
Satisfying Stated Condition After Intranasal and Intramuscular
Administration. Percent of Subjects Number of Subjects Intra-
Intra- t.sub.max Condition (Min.) Intranasal muscular Intranasal
muscular Less than 40 min. 83% 67% 10 8 Less than 35 min. 83% 58%
10 7 Between 30 and 45 min. 8% 17% 1 2 Between 30 and 40 min. 0% 8%
0 1 Between 30 and 35 min. 0% 8% 0 1
[0585] IN-Epi appeared to be safe and well-tolerated, and
demonstrated PK parameters equivalent to and in some aspects (e.g.
C.sub.max) are better than epinephrine auto injector.
[0586] Additionally, throughout the study, no significant PK
differences were observed between 1.0 mg IN epinephrine and the 0.3
mg. IM epinephrine.
Other Embodiments
[0587] Also provided are embodiments wherein any embodiment above
can be combined with any one or more of these embodiments, provided
the combination is not mutually exclusive. Also provided herein are
uses in the treatment of indications or one or more symptoms
thereof as disclosed herein, and uses in the manufacture of
medicaments for the treatment of indications or one or more
symptoms thereof as disclosed herein, equivalent in scope to any
embodiment disclosed above, or any combination thereof that is not
mutually exclusive. The methods and uses may employ any of the
devices disclosed herein, or any combination thereof that is not
mutually exclusive, or any of the pharmaceutical formulations
disclosed herein, or any combination thereof that is not mutually
exclusive.
[0588] Although the present invention has been described with
reference to specific details of certain embodiments thereof in the
above examples, it will be understood that modifications and
variations are encompassed within the spirit and scope of the
invention.
* * * * *