U.S. patent application number 16/192337 was filed with the patent office on 2019-03-21 for unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration.
The applicant listed for this patent is InCarda Therapeutics, Inc.. Invention is credited to Luiz BELARDINELLI, Prashanti MADHAVAPEDDI, Rangachari NARASIMHAN, Carlos SCHULER.
Application Number | 20190083396 16/192337 |
Document ID | / |
Family ID | 64096874 |
Filed Date | 2019-03-21 |
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United States Patent
Application |
20190083396 |
Kind Code |
A1 |
SCHULER; Carlos ; et
al. |
March 21, 2019 |
UNIT DOSES, AEROSOLS, KITS, AND METHODS FOR TREATING HEART
CONDITIONS BY PULMONARY ADMINISTRATION
Abstract
Methods of treating a heart condition include administering by
inhalation an effective amount of at least one antiarrhythmic
pharmaceutical agent to a patient in need thereof. Nebulized drug
product and kits are also contemplated.
Inventors: |
SCHULER; Carlos;
(Kensington, CA) ; NARASIMHAN; Rangachari;
(Saratoga, CA) ; BELARDINELLI; Luiz; (Palo Alto,
CA) ; MADHAVAPEDDI; Prashanti; (Fremont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
InCarda Therapeutics, Inc. |
Newark |
CA |
US |
|
|
Family ID: |
64096874 |
Appl. No.: |
16/192337 |
Filed: |
November 15, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2018/032092 |
May 10, 2018 |
|
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16192337 |
|
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62504292 |
May 10, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0078 20130101;
A61M 15/00 20130101; A61K 31/7076 20130101; A61K 31/435 20130101;
A61P 9/06 20180101; A61K 9/008 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61M 11/00 20060101 A61M011/00; A61P 9/06 20060101
A61P009/06; A61K 31/7076 20060101 A61K031/7076 |
Claims
1. A method of treating atrial arrhythmia comprising administering
a pharmaceutical composition via inhalation to a subject in need
thereof, said pharmaceutical composition comprising a
therapeutically effective amount of an antiarrhythmic agent,
wherein said antiarrhythmic agent is selected from the group
consisting of: class I, class II, class III, and class IV
antiarrhythmics, a salt and a solvate thereof, and any combination
thereof, and wherein a concentration of said antiarrhythmic agent
in said pharmaceutical composition is about 20 to about 60
mg/mL.
2. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has a maximum .DELTA.QRS of
from about 1 to about 100 msec in said subject as measured by
electrocardiography.
3. The method of claim 3, wherein said maximum .DELTA.QRS is from
about 3 to about 20 msec.
4. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has said maximum .DELTA.QRS
same as or greater than a maximum .DELTA.QRS achieved by a second
amount of said antiarrhythmic agent when administered intravenously
to said subject as measured by electrocardiography, wherein said
therapeutically effective amount is less than half of said second
amount.
5. The method of claim 1, wherein said concentration of said
antiarrhythmic agent is about 30 to about 50 mg/mL.
6. The method of claim 1, wherein said concentration of said
antiarrhythmic agent is about 45 mg/mL.
7. The method of claim 1, wherein said concentration of said
antiarrhythmic agent is 45 mg/mL.
8. The method of claim 1, wherein said pharmaceutical composition
comprises about 60 to about 130 mg of said antiarrhythmic
agent.
9. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has a T.sub.max of from about
0.2 to about 5 minutes in said subject.
10. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has a C.sub.max of from about
50 to about 1000 ng/mL in said subject.
11. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has a AUC.sub.Last of from
about 100 to about 10000 hr*ng/mL in said subject.
12. The method of claim 11, wherein said AUC.sub.Last is from about
200 to about 2000 hr*ng/mL.
13. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has a distribution t.sub.1/2 of
from about 0.1 to about 15 minutes in said subject.
14. The method of claim 13, wherein said distribution t.sub.1/2 is
from about 3 to about 5 minutes.
15. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has an elimination t.sub.1/2 of
from about 1 to about 25 hours in said subject.
16. The method of claim 15, wherein said elimination t.sub.1/2 is
from about 8.5 to about 10.5 hours.
17. The method of claim 1, wherein the administering comprises
aerosolizing said pharmaceutical composition using a jet
nebulizer.
18. The method of claim 17, wherein said aerosolizing occurs at
room temperature.
19. The method of claim 1, wherein said administering is conducted
via up to six inhalations.
20. The method of claim 1, wherein said administering takes about 1
to about 10 min.
21. The method of claim 1, wherein said pharmaceutical composition
comprises an aerosol of said aerosolized antiarrhythmic agent that
comprises particles having a mass median aerodynamic diameter less
than 4 .mu.m.
22. The method of claim 1, wherein said therapeutically effective
amount of said antiarrhythmic agent has an estimated total lung
dose (eTLD) of about 30 to about 90 mg when administered to a
subject via inhalation.
23. The method of claim 1, wherein said antiarrhythmic agent
comprises flecainide acetate.
24. The method of claim 1, wherein said pharmaceutical composition
further comprises a pH buffer prepared from acetic acid.
25. The method of claim 1, wherein a pH of said pharmaceutical
composition is from 5.0 to 6.5.
26. The method of claim 1, wherein said pharmaceutical composition
comprises a racemic mixture of flecainide.
27. The method of claim 1, wherein said atrial arrhythmia comprises
tachycardia.
28. The method of claim 27, wherein said tachycardia is selected
from the group consisting of: supraventricular tachycardia,
paroxysmal supraventricular tachycardia, atrial fibrillation,
paroxysmal atrial fibrillation, acute episodes in persistent and
permanent atrial fibrillation, atrial flutter, paroxysmal atrial
flutter, and lone atrial fibrillation.
Description
CROSS-REFERENCE
[0001] This application is a continuation of PCT Application No.
PCT/US2018/032092, filed May 10, 2018, which claims the benefit of
U.S. Provisional Application No. 62/504,292, filed May 10, 2017,
each of which is incorporated herein by reference in its
entirety.
BACKGROUND
1. Field of the Invention
[0002] The present invention relates to compositions, unit doses,
aerosols, and kits for treating certain heart conditions by
pulmonary administration and methods thereof.
2. Background Art
[0003] Cardiac arrhythmia (also dysrhythmia) is a term for any of a
large and heterogeneous group of conditions in which there is
abnormal electrical activity in the heart. The heart beat may be
too fast or too slow, and may be regular or irregular.
[0004] Atrial arrhythmia therapy is a field with a high level of
unmet clinical need. Many drugs used today have been on the market
since the early 1980s and 1990s and are mostly inadequate due to
either lack of efficacy or a side-effect profile that is often
cardiac related, that necessitates extensive monitoring of the
patient.
[0005] What is needed for fast and safe cardioversion (resolution
of arrhythmia) is therapy that:
[0006] (a) has little to no risk of acceleration of ventricular
rate before cardioversion;
[0007] (b) slows atrio-ventribular (AV) conduction so that there is
ventricular rate control and cardioversion at the same time;
[0008] (c) has minimal to no effect in prolonging the QRS interval
above the upper range of normal value (about 120 milliseconds) and
should have a low risk of torsade de pointes; and
[0009] (d) has minimal to no negative inotropic effect; it should
have only mild negative chronotropic effect, without the risk of
severe bradycardia when the patient reverts to sinus rhythm.
[0010] None of the current approved drug products exhibit these
characteristics. High oral and intravenous (IV) doses required to
compensate for absorption, metabolism, and dilution result in blood
high blood concentrations for an extended period of time that can
cause the dangerous adverse cardiac events like pro-arrhythmias, QT
prolongation, and torsade de pointes. FELDMAN et al., "Analysis of
Coronary Response to Various Doses of Intracoronary Nitroglycerin,"
Circulation, 66:321-327 (1982); and BARBATO et al., "Adrenergic
Receptors in Human Atherosclerotic Coronary Arteries," Circulation,
111:288-294 (2005). Comorbid conditions also limit use of ideal
drugs in some patients, for example the case with intravenous
adenosine. GAGLIONE et al., "Is There Coronary Vasoconstriction
after Intracoronary Beta-adrenergic Blockade in Patients with
Coronary Artery Disease," J Am Coll Cardiol, 10:299-310 (1987).
Drugs like verapamil and diltiazem injections are second line of
therapy requiring close monitoring of patients. NOGUCHI et al.,
"Effects of Intracoronary Propranolol on Coronary Blood Flow and
Regional Myocardial Function in Dogs," Eur J Pharmacol.,
144(2):201-10 (1987); and ZALEWSKI et al., "Myocardial Protection
during Transient Coronary Artery Occlusion in Man: Beneficial
Effects of Regional Beta-adrenergic Blockade," Circulation,
73:734-73 (1986).
[0011] Paroxysmal atrial fibrillation (PAF) is a subset of the
overall atrial fibrillation (AF) population and is estimated to be
25-30% of the overall AF population. About 2.5 million patients are
affected by AF in the United States. The population of PAF patients
is estimated to be 900,000 to 1.5 million worldwide.
[0012] Paroxysmal supraventricular tachycardia (PSVT) is a type of
arrhythmia that affects about 500,000 to 600,000 patients in the
United States.
[0013] Ablation techniques, e.g., RF ablation, are often used to
treat arrhythmias. But ablation is expensive with the cost
typically ranging from about $25,000 to $36,000 per procedure.
Despite the high expense, ablation may not completely correct the
arrhythmia. Often, multiple ablation procedures are required to
achieve a satisfactory therapeutic result.
[0014] Oral medications, e.g., pills, tend to require high doses
and long time for onset of action. The oral dose for heart
medications generally tends to be well over 1 mg. High doses
increase the likelihood of side effects and drug-drug interactions
as these patients typically take multiple medications. The time for
onset for oral cardiovascular medications tends to be around 60
minutes. Oral antiarrhythmic medications have been predominantly
developed for prevention whereas treatment being given
intravenously.
[0015] Intravenous injection usually requires a hospital setting
for administering a medicine and typically involves a visit to the
emergency room (ER). These overheads result in this therapy being
expensive compared to therapies where the patients can
self-administer their medicines. Intravenous injection requires a
dose that is higher than what is actually needed in the heart to
compensate for dilution and metabolism. Drug injected by IV passes
through the right side of the heart and then the lungs before
reaching the left side of the heart. See FIG. 1. The drug remains
in the blood stream at a high concentration bathing all the organs
and tissues with this drug in a high concentration, until the drug
gets excreted through the kidneys or through other metabolic routes
(e.g., hepatic). As a result, IV drugs may cause unwanted side
effects. Drugs administered via the IV route are significantly
diluted in the venous blood volume and lungs before reaching the
cardiac circulation.
[0016] Injecting a drug to the heart directly is usually a
last-resort taken by a cardiologist as a life saving measure in an
emergency. The doses of the drugs injected directly into the heart
in this manner are usually less than their IV and/or oral
doses.
[0017] In some cases, an unplanned surgery is necessary to save the
patient's life. Of course, unplanned surgeries are expensive and
risky to the patient.
[0018] Cardiac arrhythmias are associated with disabling symptoms
like tightness around the chest, palpitations, feeling tired,
shortness of breath, and sometimes chest pain.
[0019] In view of the above, arrhythmias frequently result in
emergency room (ER) visits, where intravenous drugs are
administered, sometimes necessitating an extended stay in the
hospital and in some cases also leading to unplanned invasive
procedures. Pipeline Insights: Antiarrhythmics, Datamonitor (June
2006); and TWISS et al., "Efficacy of Calcium Channel Blockers as
Maintenance Therapy for Asthma," British J of Clinical Pharmacology
(November 2001).
[0020] There remains, however, a need for improved compositions and
methods for treating heart conditions. Accordingly, there also
remains a need for methods of making these compositions.
SUMMARY
[0021] Accordingly, the present invention provides compositions,
unit doses, aerosols, kits, and methods for treating certain heart
conditions. Other features and advantages of the present invention
will be set forth in the description of invention that follows, and
in part will be apparent from the description or may be learned by
practice of the invention. The invention will be realized and
attained by the compositions and methods particularly pointed out
in the written description and claims hereof.
[0022] A first embodiment of the present invention is directed to a
method of treating atrial arrhythmia. The method comprises
administering an effective amount of at least one antiarrhythmic
pharmaceutical agent to a patient in need thereof, such that the at
least one antiarrhythmic pharmaceutical agent first enters the
heart through the pulmonary vein to the left atrium.
[0023] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, e.g., tachycardia. The method
comprises administering by inhalation (e.g., oral inhalation) an
effective amount of at least one antiarrhythmic pharmaceutical
agent to a patient in need thereof, wherein an amount of the at
least one antiarrhythmic pharmaceutical agent peaks in the coronary
circulation of the heart at a time ranging from 10 seconds to 30
minutes from administration (e.g., initiation of the administration
or end of the administration). In some cases, coronary circulation
can be a coronary artery or a coronary vein, including coronary
sinus.
[0024] In yet another aspect, the present invention is directed to
a method of self-diagnosing and treating atrial arrhythmia. The
method comprises self-diagnosing atrial arrhythmia by detecting at
least one of shortness of breath, heart palpitations, and above
normal heart rate. The method also comprises self-administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent within two hours, one hour,
30 minutes, or 15 minutes of the self-diagnosing.
[0025] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein an electrophysiologic effect is observed, via
electrocardiography, at a time ranging from 10 seconds to 30
minutes from the administration.
[0026] In still another aspect, the present invention is directed
to a method of treating atrial arrhythmia, comprising administering
by inhalation (e.g., oral inhalation) an effective amount of at
least one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein a cardiac score from a monitor implementing an
arrhythmia detection algorithm shows a transition from an
arrhythmic state to normal sinus rhythm in the patient at a time
ranging from 10 seconds to 30 minutes from the administration.
[0027] In yet another aspect, the present invention is directed to
a method of treating atrial arrhythmia, comprising administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein a short form-36 quality of life score of the
patient improves at a time ranging from 10 seconds to 30 minutes
from the administration.
[0028] In another aspect, the present invention is directed to a
unit dose comprising a unit dose receptacle and a composition
within the unit dose receptacle. The composition comprises at least
one antiarrhythmic pharmaceutical agent in an amount less than or
equal to an amount of the same at least one antiarrhythmic
pharmaceutical agent administered intravenously in the arm to
achieve a minimum effective amount in the coronary circulation, and
a pharmaceutically acceptable excipient.
[0029] In still another aspect, the present invention is directed
to an aerosol comprising particles having a mass median aerodynamic
diameter less than 10 .mu.m. The particles comprise at least one
antiarrhythmic pharmaceutical agent in an amount less than or equal
to an amount of the same at least one antiarrhythmic pharmaceutical
agent administered intravenously in the arm to achieve a minimum
effective amount in the coronary circulation, and a
pharmaceutically acceptable excipient.
[0030] Yet another aspect of the present invention is directed to a
kit. The kit comprises a container containing at least one
antiarrhythmic pharmaceutical agent and an aerosolization
device.
[0031] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering an
effective amount of at least one antiarrhythmic pharmaceutical
agent to a patient in need thereof, such that the at least one
antiarrhythmic pharmaceutical agent first enters the heart through
the pulmonary vein to the left atrium. In some cases, an amount of
the at least one antiarrhythmic pharmaceutical agent peaks in the
coronary circulation of the heart at a time ranging from 10 seconds
to 30 minutes from the administration. In some cases, the amount of
the at least one antiarrhythmic pharmaceutical agent in the
coronary circulation of the heart peaks at a time ranging from 2
minutes to 8 minutes from the administration. In some cases, the
amount of the at least one antiarrhythmic pharmaceutical agent in
the coronary circulation of the heart ranges from 0.1 mg/L to 60
mg/L at 2.5 minutes after the administration. In some cases, the
amount of the at least one antiarrhythmic pharmaceutical agent in
the coronary circulation of the heart is less than 0.1 mg/L at 30
minutes after the administration. In some cases, the effective
amount is an effective amount for only one pass through the heart.
In some cases, 10% to 60% of the nominal dose of the administered
at least one antiarrhythmic pharmaceutical agent reaches the
coronary circulation. In some cases, an amount of administered
antiarrhythmic pharmaceutical agent entering the patient ranges
from 0.1 mg to 200 mg. In some cases, a nominal amount of the at
least one antiarrhythmic pharmaceutical agent administered via
inhalation (e.g., oral inhalation) is less than or equal to an
amount of the same antiarrhythmic pharmaceutical agent administered
intravenously in the arm to achieve the same amount in the coronary
circulation. In some cases, the administering comprises 1 to 6
inhalations.
[0032] In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one member selected from
class Ia, class Ib, class Ic, class II, class III, class IV, and
class V antiarrhythmics. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ia
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class Ia antiarrhythmic
selected from quinidine, procainamide, and disopyramide. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class Ib antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class Ib antiarrhythmic selected from lidocaine, tocainide,
phenytoin, moricizine, and mexiletine. In some cases, the at least
one antiarrhythmic pharmaceutical agent comprises at least one
class Ic antiarrhythmic. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ic
antiarrhythmic selected from flecainide, propafenone, and
moricizine. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class II
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class II antiarrhythmic
selected from propranolol, acebutolol, soltalol, esmolol, timolol,
metoprolol, and atenolol. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class
III antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class III
antiarrhythmic selected from amiodarone, sotalol, bretylium,
ibutilide, methanesulfonamide, vernakalant, and dofetilide. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class IV antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class IV antiarrhythmic selected from bepridil, nitrendipine,
amlodipine, isradipine, nifedipine, nicardipine, verapamil, and
diltiazem. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class V antiarrhythmic.
In some cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class V antiarrhythmic selected from digoxin
and adenosine.
[0033] In some cases, the atrial arrhythmia comprises tachycardia.
In some cases, the atrial arrhythmia comprises supraventricular
tachycardia. In some cases, the atrial arrhythmia comprises
paroxysmal supraventricular tachycardia. In some cases, the atrial
arrhythmia comprises atrial fibrillation. In some cases, the atrial
arrhythmia comprises paroxysmal atrial fibrillation. In some cases,
the atrial arrhythmia comprises of acute episodes in persistent and
permanent atrial fibrillation. In some cases, the atrial arrhythmia
comprises atrial flutter. In some cases, the atrial arrhythmia
comprises paroxysmal atrial flutter. In some cases, the atrial
arrhythmia comprises lone atrial fibrillation. In some cases, the
administering comprises administering a liquid comprising the at
least one antiarrhythmic pharmaceutical agent. In some cases, the
administering comprises administering a powder comprising the at
least one antiarrhythmic pharmaceutical agent. In some cases, the
administering comprises administering a condensation aerosol
comprising the at least one antiarrhythmic pharmaceutical agent. In
some cases, the administering comprises administering a composition
compns1ng the at least one antiarrhythmic pharmaceutical agent,
wherein the composition is not a condensation aerosol.
[0034] In some cases, the pulmonary administration comprises
nebulizing a solution comprising the at least one antiarrhythmic
pharmaceutical agent. In some cases, the nebulizing comprises
nebulizing with a vibrating mesh nebulizer. In some cases, the
nebulizing comprises nebulizing with a jet nebulizer. In some
cases, the nebulizing comprises nebulizing with a breach-activated
nebulizer. In some cases, the nebulizing comprises forming droplets
having a mass median aerodynamic diameter of less than 10 .mu.m. In
some cases, the pulmonary administration comprises administering a
dry powder comprising the at least one antiarrhythmic
pharmaceutical agent. In some cases, the dry powder comprises
particles having a mass median aerodynamic diameter of less than 10
.mu.m. In some cases, the dry powder is administered via an active
dry powder inhaler. In some cases, the dry powder is administered
via a passive dry powder inhaler. In some cases, the pulmonary
administration comprises administering the at least one
antiarrhythmic pharmaceutical agent via a metered dose inhaler. In
some cases, the metered dose inhaler forms particles having a mass
median aerodynamic diameter of less than 10 .mu.m. In some cases,
the metered dose inhaler contains the at least one antiarrhythmic
pharmaceutical agent formulated in a carrier selected from
hydrofluoroalkane and chlorofluorocarbon. In some cases, the
treating comprises acute treatment after detection of atrial
arrhythmia. In some cases, the patient has normal sinus rhythm
within 10 minutes of initiating the administering.
[0035] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein an amount of the at least one antiarrhythmic
pharmaceutical agent peaks in the coronary circulation of the heart
at a time ranging from 10 seconds to 30 minutes from the
administration. In some cases, the amount of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart peaks at a time ranging from 2 minutes to 8 minutes from
the administration. In some cases, the amount of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart ranges from 0.1 mg/L to 60 mg/L at 2.5 minutes after the
administration. In some cases, the amount of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart is less than 0.1 mg/L at 30 minutes after the
administration. In some cases, the effective amount is an effective
amount for only one pass through the heart. In some cases, 10% to
60% of the nominal dose of the administered at least one
antiarrhythmic pharmaceutical agent reaches the coronary
circulation. In some cases, an amount of administered
antiarrhythmic pharmaceutical agent entering the patient ranges
from 0.1 mg to 200 mg. In some cases, a nominal amount of the at
least one antiarrhythmic pharmaceutical agent administered via
inhalation (e.g., oral inhalation) is less than or equal to an
amount of the same antiarrhythmic pharmaceutical agent administered
intravenously in the arm to achieve the same amount in the coronary
circulation. In some cases, the administering comprises 1 to 6
inhalations.
[0036] In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one member selected from
class Ia, class Ib, class Ic, class II, class III, class IV, and
class V antiarrhythmics. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ia
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class Ia antiarrhythmic
selected from quinidine, procainamide, and disopyramide. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class Ib antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class Ib antiarrhythmic selected from lidocaine, tocainide,
phenytoin, moricizine, and mexiletine. In some cases, the at least
one antiarrhythmic pharmaceutical agent comprises at least one
class Ic antiarrhythmic. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ic
antiarrhythmic selected from flecainide, propafenone, and
moricizine. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class II
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class II antiarrhythmic
selected from propranolol, acebutolol, soltalol, esmolol, timolol,
metoprolol, and atenolol. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class
III antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class III
antiarrhythmic selected from amiodarone, sotalol, bretylium,
ibutilide, methanesulfonamide, vernakalant, and dofetilide. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class IV antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class IV antiarrhythmic selected from bepridil, nitrendipine,
amlodipine, isradipine, nifedipine, nicardipine, verapamil, and
diltiazem. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class V antiarrhythmic.
In some cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class V antiarrhythmic selected from digoxin
and adenosine.
[0037] In some cases, the atrial arrhythmia comprises tachycardia.
In some cases, the atrial arrhythmia comprises supraventricular
tachycardia. In some cases, the atrial arrhythmia comprises
paroxysmal supraventricular tachycardia. In some cases, the atrial
arrhythmia comprises atrial fibrillation. In some cases, the atrial
arrhythmia comprises paroxysmal atrial fibrillation. In some cases,
the atrial arrhythmia comprises of acute episodes in persistent and
permanent atrial fibrillation. In some cases, the atrial arrhythmia
comprises atrial flutter. In some cases, the atrial arrhythmia
comprises paroxysmal atrial flutter. In some cases, the atrial
arrhythmia comprises lone atrial fibrillation.
[0038] In some cases, the administering comprises administering a
liquid comprising the at least one antiarrhythmic pharmaceutical
agent. In some cases, the administering comprises administering a
powder comprising the at least one antiarrhythmic pharmaceutical
agent. In some cases, the administering comprises administering a
condensation aerosol comprising the at least one antiarrhythmic
pharmaceutical agent. In some cases, the administering comprises
administering a composition comprising the at least one
antiarrhythmic pharmaceutical agent, wherein the composition is not
a condensation aerosol. In some cases, the pulmonary administration
comprises nebulizing a solution comprising the at least one
antiarrhythmic pharmaceutical agent. In some cases, the nebulizing
comprises nebulizing with a vibrating mesh nebulizer. In some
cases, the nebulizing comprises nebulizing with a jet nebulizer. In
some cases, the nebulizing comprises forming droplets having a mass
median aerodynamic diameter of less than 10 .mu.m. In some cases,
the pulmonary administration comprises administering a dry powder
comprising the at least one antiarrhythmic pharmaceutical agent. In
some cases, the dry powder comprises particles having a mass median
aerodynamic diameter of less than 10 .mu.m. In some cases, the dry
powder is administered via an active dry powder inhaler. In some
cases, the dry powder is administered via a passive dry powder
inhaler. In some cases, the pulmonary administration comprises
administering the at least one antiarrhythmic pharmaceutical agent
via a metered dose inhaler. In some cases, the metered dose inhaler
forms particles having a mass median aerodynamic diameter of less
than 10 .mu.m. In some cases, the metered dose inhaler contains the
at least one antiarrhythmic pharmaceutical agent formulated in a
carrier selected from hydrofluroalkane and chloroflurocarbon.
[0039] In some cases, the treating comprises acute treatment after
detection of atrial arrhythmia. In some cases, the patient has
normal sinus rhythm within 30 minutes of initiating the
administration. In some cases, the patient has normal sinus rhythm
within 10 minutes of initiating the administration.
[0040] In another aspect, the present invention is directed to a
method of self-diagnosing and treating atrial arrhythmia,
comprising: self-diagnosing atrial arrhythmia by detecting at least
one of shortness of breath, heart palpitations, and above normal
heart rate; and self-administering by inhalation (e.g., oral
inhalation) an effective amount of at least one antiarrhythmic
pharmaceutical agent within two hours of the self-diagnosing. In
some cases, the self-administering occurs within one hour of the
self-diagnosing. In some cases, the self-administering occurs
within 30 minutes of the self-diagnosing. In some cases, the
self-administering occurs within 15 minutes of the self-diagnosing.
In some cases, the self-administering continues until the patient
no longer detects the at least one of shortness of breath, heart
palpitations, and above normal heart rate.
[0041] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein an electrophysiologic effect is observed, via
electrocardiography, at a time ranging from 10 seconds to 30
minutes from the administration. In some cases, the
electrophysiologic effect comprises a transition from arrhythmia to
a normal sinus rhythm. In some cases, the electro physiologic
effect comprises a transition from an absence of a P wave to a
presence of a P wave.
[0042] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein a cardiac score from a monitor implementing an
arrhythmia detection algorithm shows a transition from an
arrhythmic state to normal sinus rhythm in the patient at a time
ranging from 10 seconds to 30 minutes from the administration. In
some cases, the monitor comprises a Holter monitor, telemetry, and
mobile ECG.
[0043] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering by
inhalation (e.g., oral inhalation) an effective amount of at least
one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein a short form-36 quality of life score of the
patient improves at a time ranging from 10 seconds to 30 minutes
from the administration.
[0044] In another aspect, the present invention is directed to a
unit dose comprising: a unit dose receptacle; a composition within
the unit dose receptacle, the composition comprising: at least one
antiarrhythmic pharmaceutical agent in an amount less than or equal
to an amount of the same at least one antiarrhythmic pharmaceutical
agent administered intravenously in the arm to achieve a minimum
effective amount in the coronary circulation; and a
pharmaceutically acceptable excipient. In some cases, the
composition comprises a solution. In some cases, the composition
comprises a solution having a tonicity that ranges from isotonic to
physiologic isotonicity. In some cases, the composition comprises
an aqueous solution. In some cases, the composition comprises a
non-aqueous solution. In some cases, the composition further
comprises a pH buffer. In some cases, the composition further
comprises a pH buffer selected from citrate, phosphate, phthalate,
and lactate. In some cases, the composition consists essentially of
the at least one antiarrhythmic pharmaceutical agent and water. In
some cases, the composition consists essentially of the at least
one antiarrhythmic pharmaceutical agent, water, and a pH buffer. In
some cases, the composition has a pH ranging from 3.5 to 8.0.
[0045] In some cases, the pharmaceutically acceptable excipient
comprises hydrofluoroalkane. In some cases, the pharmaceutically
acceptable excipient comprises chlorofluoralkane. In some cases,
the composition is substantially preservative-free. In some cases,
the at least one antiarrhythmic pharmaceutical agent comprises at
least one member selected from class Ia, class Ib, class Ic, class
II, class III, class IV, and class V antiarrhythmics. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class Ia antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class Ia antiarrhythmic selected from quinidine, procainamide,
and disopyramide, and pharmaceutically acceptable salts thereof. In
some cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class Ib antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class Ib antiarrhythmic selected from lidocaine, tocainide,
phenytoin, moricizine, and mexiletine, and pharmaceutically
acceptable salts thereof. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ic
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class Ic antiarrhythmic
selected from flecainide, propafenone, and moricizine, and
pharmaceutically acceptable salts thereof. In some cases, the at
least one antiarrhythmic pharmaceutical agent comprises at least
one class II antiarrhythmic. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class II
antiarrhythmic selected from propranolol, acebutolol, soltalol,
esmolol, timolol, metoprolol, and atenolol, and pharmaceutically
acceptable salts thereof. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class
III antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class III
antiarrhythmic selected from amiodarone, sotalol, bretylium,
ibutilide, methanesulfonamide, vernakalant, and dofetilide, and
pharmaceutically acceptable salts thereof. In some cases, the at
least one antiarrhythmic pharmaceutical agent comprises at least
one class IV antiarrhythmic. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class IV
antiarrhythmic selected from bepridil, nimodipine, nisoldipine,
nitrendipine, amlodipine, isradipine, nifedipine, nicardipine,
verapamil, and diltiazem, and pharmaceutically acceptable salts
thereof. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class V antiarrhythmic.
In some cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class V antiarrhythmic selected from digoxin
and adenosine, and pharmaceutically acceptable salts thereof. In
some cases, the receptacle comprises 0.1 mg to 200 mg of the at
least one antiarrhythmic pharmaceutical agent. In some cases, the
unit dose is substantially tasteless.
[0046] In another aspect, the present invention is directed to an
aerosol comprising particles having a mass median aerodynamic
diameter less than 10 .mu.m, wherein the particles comprise: at
least one antiarrhythmic pharmaceutical agent in an amount less
than or equal to an amount of the same at least one antiarrhythmic
pharmaceutical agent administered intravenously in the arm to
achieve a minimum effective amount in the coronary circulation; and
a pharmaceutically acceptable excipient.
[0047] In some cases, the particles comprise a nebulized solution.
In some cases, the particles comprise a nebulized aqueous solution.
In some cases, the particles further comprise a pH buffer. In some
cases, the particles further comprise a pH buffer selected from
citrate, phosphate, phthalate, and lactate. In some cases, the
particles consist essentially of the at least one antiarrhythmic
pharmaceutical agent and water. In some cases, the particles
consist essentially of the at least one antiarrhythmic
pharmaceutical agent, water, and a pH buffer. In some cases, the
particles have a pH ranging from 3.5 to 8.0. In some cases, the
particles are substantially preservative-free.
[0048] In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one member selected from
class Ia, class Ib, class Ic, class II, class III, class IV, and
class V antiarrhythmics. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ia
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class Ia antiarrhythmic
selected from quinidine, procainamide, and disopyramide. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class Ib antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class Ib antiarrhythmic selected from lidocaine, tocainide,
phenytoin, moricizine, and mexiletine. In some cases, the at least
one antiarrhythmic pharmaceutical agent comprises at least one
class Ic antiarrhythmic. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class Ic
antiarrhythmic selected from flecainide, propafenone, and
moricizine. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class II
antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class II antiarrhythmic
selected from propranolol, acebutolol, soltalol, esmolol, timolol,
metoprolol, and atenolol. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class
III antiarrhythmic. In some cases, the at least one antiarrhythmic
pharmaceutical agent comprises at least one class III
antiarrhythmic selected from amiodarone, sotalol, bretylium,
ibutilide, methanesulfonamide, vernakalant, and dofetilide. In some
cases, the at least one antiarrhythmic pharmaceutical agent
comprises at least one class IV antiarrhythmic. In some cases, the
at least one antiarrhythmic pharmaceutical agent comprises at least
one class IV antiarrhythmic selected from bepridil, nimodipine,
nisoldipine, nitrendipine, amlodipine, isradipine, nifedipine,
nicardipine, verapamil, and diltiazem. In some cases, the at least
one antiarrhythmic pharmaceutical agent comprises at least one
class V antiarrhythmic. In some cases, the at least one
antiarrhythmic pharmaceutical agent comprises at least one class V
antiarrhythmic selected from digoxin and adenosine. In some cases,
the aerosol is substantially tasteless.
[0049] In another aspect, the present invention is directed to a
kit, comprising: a container containing at least one antiarrhythmic
pharmaceutical agent; and an aerosolization device. In some cases,
the aerosolization device comprises a nebulizer. In some cases, the
aerosolization device comprises a vibrating mesh nebulizer. In some
cases, the aerosolization device comprises a jet nebulizer. In some
cases, the aerosolization device comprises a dry powder inhaler. In
some cases, the aerosolization device comprises an active dry
powder inhaler. In some cases, the aerosolization device comprises
a passive dry powder inhaler. In some cases, the aerosolization
device comprises a metered dose inhaler. In some cases, an amount
of the at least one antiarrhythmic pharmaceutical agent is
sufficient to produce an electrophysiologic effect with a minimum
of one pass through the heart. In some cases, the effective amount
of the at least one antiarrhythmic pharmaceutical agent is
sub-therapeutic when diluted by overall blood volume.
[0050] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering to
one or more pulmonary veins through pulmonary airways and through
use of an aerosolization device an effective amount of at least one
antiarrhythmic pharmaceutical agent selected from a group
consisting of class I, class II, class III, and class IV
antiarrhythmics, to a patient in need thereof, wherein the
effective amount of the at least one antiarrhythmic pharmaceutical
agent is a total amount from 0.1 mg to 200 mg administered over
multiple inhalations, wherein the at least one antiarrhythmic
pharmaceutical agent level peaks in a coronary circulation of the
heart at a time between 30 seconds and 20 minutes from the
pulmonary administration, and wherein the patient's sinus rhythm is
restored to normal within 30 minutes of initiating the
administration.
[0051] In some cases, the concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart ranges between 0.1 mg/L and 60 mg/L at 2.5 minutes after
pulmonary administration, and the concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart is less than 0.1 mg/L at 30 minutes after pulmonary
administration, or wherein 10% to 60% of a nominal dose of the
administered at least one antiarrhythmic pharmaceutical agent
reaches the coronary circulation. In some cases, the concentration
of the at least one antiarrhythmic pharmaceutical agent in the
coronary circulation of the heart is between 0.1 mg/L and 20 mg/L
at 2.5 minutes after pulmonary administration, and the
concentration of the at least one antiarrhythmic pharmaceutical
agent in the coronary circulation of the heart is less than 0.1
mg/L at 30 minutes after pulmonary administration, or wherein
between 5% and 60% of a nominal dose of the administered at least
one antiarrhythmic pharmaceutical agent reaches the coronary
circulation. In some cases, the method comprises pulmonary
administration of the at least one antiarrhythmic in up to 6
inhalations. In some cases, the atrial arrhythmia comprises
tachycardia. In some cases, the tachycardia comprises
supraventricular tachycardia, paroxysmal supraventricular
tachycardia, atrial fibrillation, paroxysmal atrial fibrillation,
acute episodes in persistent and permanent atrial fibrillation,
atrial flutter, paroxysmal atrial flutter or lone atrial
fibrillation. In some cases, the method comprises administering a
liquid, dry powder, or nebulized droplets comprising the at least
one antiarrhythmic pharmaceutical agent, wherein the powder or
nebulized droplets have a mass median aerodynamic diameter of less
than 10 .mu.m.
[0052] In some cases, the antiarrhythmic pharmaceutical agent is a
class I antiarrhythmic. In some cases, the class I antiarrhythmic
is a class Ia, Ib, or Ic antiarrhythmic. In some cases, the
antiarrhythmic pharmaceutical agent is a class II antiarrhythmic.
In some cases, the class II antiarrhythmic is esmolol HCl. In some
cases, dosage of the esmolol HCl is between 0.5 and 0.75 mg/kg body
weight. In some cases, the antiarrhythmic pharmaceutical agent is a
class IV antiarrhythmic. In some cases, the class IV antiarrhythmic
is diltiazem. In some cases, dosage of the diltiazem is 0.25 mg/kg
body weight. In some cases, the at least one antiarrhythmic
pharmaceutical agent level peaks in the coronary circulation of the
heart at a time between 1 minute and 10 minutes. In some cases, the
aerosolization device is a nebulizer configured to administer the
at least one antiarrhythmic pharmaceutical agent in a liquid
pharmaceutical formulation, wherein the aerosolization occurs at
room temperature. In some cases, the at least one antiarrhythmic
pharmaceutical agent is self-administered by the patient.
[0053] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering to
one or more pulmonary veins through pulmonary airways and through
use of an aerosolization device an effective amount of at least one
antiarrhythmic pharmaceutical agent selected from a group
consisting of class I, class II, class III, and class IV
antiarrhythmics, to a patient in need thereof, wherein the patient
self-administers and self-titrates an effective inhaled dose of at
least one antiarrhythmic pharmaceutical agent for a conversion of
atrial arrhythmia to normal sinus rhythm, wherein the at least one
antiarrhythmic pharmaceutical agent level peaks in a coronary
circulation of the heart at a time between 30 seconds and 20
minutes from the pulmonary administration, and wherein the
patient's sinus rhythm is restored to normal within 30 minutes of
initiating the administration.
[0054] In some cases, the concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart ranges between 0.1 mg/L and 60 mg/L at 2.5 minutes after
pulmonary administration, and the concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart is less than 0.1 mg/L at 30 minutes after pulmonary
administration, or wherein 10% to 60% of the nominal dose of the
administered at least one antiarrhythmic pharmaceutical agent
reaches the coronary circulation.
[0055] In some cases, the concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart is between 0.1 mg/L and 20 mg/L at 2.5 minutes after
pulmonary administration, and the concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart is less than 0.1 mg/L at 30 minutes after pulmonary
administration, or wherein between 5% and 60% of the nominal dose
of the administered at least one antiarrhythmic pharmaceutical
agent reaches the coronary circulation. In some cases, the method
comprises pulmonary administration of the at least one
antiarrhythmic in up to 6 inhalations.
[0056] In some cases, the atrial arrhythmia comprises tachycardia.
In some cases, the tachycardia comprises supraventricular
tachycardia, paroxysmal supraventricular tachycardia, atrial
fibrillation, paroxysmal atrial fibrillation, acute episodes in
persistent and permanent atrial fibrillation, atrial flutter,
paroxysmal atrial flutter or lone atrial fibrillation. In some
cases, the method comprises administering a liquid, dry powder, or
nebulized droplets comprising the at least one antiarrhythmic
pharmaceutical agent, wherein the dry powder or nebulized droplets
have a mass median aerodynamic diameter of less than 10 .mu.m.
[0057] In some cases, the antiarrhythmic pharmaceutical agent is a
class I antiarrhythmic. In some cases, the class I antiarrhythmic
is a class Ia, Ib, or Ic antiarrhythmic. In some cases, the
antiarrhythmic pharmaceutical agent is a class II antiarrhythmic.
In some cases, the class II antiarrhythmic is esmolol HCl. In some
cases, the effective inhaled dose of the esmolol HCl is between 0.5
and 0.75 mg/kg body weight. In some cases, the antiarrhythmic
pharmaceutical agent is a class IV antiarrhythmic. In some cases,
the class IV antiarrhythmic is diltiazem. In some cases, the
effective inhaled dose of the diltiazem is 0.25 mg/kg body weight.
In some cases, the at least one antiarrhythmic pharmaceutical agent
level peaks in the coronary circulation of the heart at a time
between 1 minute and 10 minutes. In some cases, the aerosolization
device is a nebulizer configured to administer the at least one
antiarrhythmic pharmaceutical agent in a liquid pharmaceutical
formulation, wherein the aerosolization occurs at room
temperature.
[0058] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising: administering to
one or more pulmonary veins through pulmonary airways by inhalation
(e.g., oral inhalation) an effective amount of at least one
antiarrhythmic pharmaceutical agent selected from a group
consisting of class I, class II, class III, and class IV
antiarrhythmics, to a subject in need thereof, wherein the
effective amount of the at least one antiarrhythmic pharmaceutical
agent is a total amount from 0.1 mg to 200 mg and has: i) a
T.sub.max of from about 0.1 minute to about 30 minutes; ii) a
C.sub.max of from about 10 ng/mL to about 5000 ng/mL; iii) an
AUC.sub.Last of from about 100 hr*ng/mL to about 10000 hr*ng/mL;
iv) a distribution t.sub.1/2 of from about 0.1 minute to about 15
minutes; v) an elimination t.sub.1/2 of from about 1 hour to about
25 hours; vi) a .DELTA.QRS of from about 0.01 msec to about 100
msec; or any combination thereof.
[0059] In some cases, the at least one antiarrhythmic
pharmaceutical agent is administered over multiple inhalations. In
some cases, the at least one antiarrhythmic pharmaceutical agent is
administered in up to 6 inhalations. In some cases, the subject's
sinus rhythm is restored to normal within 30 minutes of initiating
the administration. In some cases, the at least one antiarrhythmic
pharmaceutical agent level peaks in a coronary circulation of the
heart at a time between 30 seconds and 20 minutes from the
administration. In some cases, concentration of the at least one
antiarrhythmic pharmaceutical agent in the coronary circulation of
the heart ranges between 0.1 mg/L and 60 mg/L at 2.5 minutes after
the administration. In some cases, concentration of the at least
one antiarrhythmic pharmaceutical agent in the coronary circulation
of the heart is less than 0.1 mg/L at 30 minutes after the
administration. In some cases, 5% to 60% of a nominal dose of the
administered at least one antiarrhythmic pharmaceutical agent
reaches the coronary circulation. In some cases, the effective
amount of the at least one antiarrhythmic pharmaceutical agent has
a T.sub.max of from about 0.1 minute to about 30 minutes. In some
cases, the effective amount of the at least one antiarrhythmic
pharmaceutical agent has a T.sub.max of from about 1 minute to
about 5 minutes. In some cases, the effective amount of the at
least one antiarrhythmic pharmaceutical agent has a T.sub.max of
from about 0.1 minute to about 3 minutes. In some cases, the
effective amount of the at least one antiarrhythmic pharmaceutical
agent has a T.sub.max of from about 0.2 minute to about 5 minutes.
In some cases, the effective amount of the at least one
antiarrhythmic pharmaceutical agent has a C.sub.max of from about
50 ng/mL to about 500 ng/mL. In some cases, the effective amount of
the at least one antiarrhythmic pharmaceutical agent has a
C.sub.max of from about 100 ng/mL to about 250 ng/mL. In some
cases, the effective amount of the at least one antiarrhythmic
pharmaceutical agent has an AUC.sub.Last of from about 100 hr*ng/mL
to about 10000 hr*ng/mL. In some cases, the effective amount of the
at least one antiarrhythmic pharmaceutical agent has an
AUC.sub.Last of from about 200 ng/mL to about 2000 hr*ng/mL. In
some cases, the effective amount of the at least one antiarrhythmic
pharmaceutical agent has an AUC.sub.Last of from about 500 ng/mL to
about 800 hr*ng/mL. In some cases, the effective amount of the at
least one antiarrhythmic pharmaceutical agent has an AUC.sub.Last
of from about 400 ng/mL to about 600 hr*ng/mL. In some cases, the
effective amount of the at least one antiarrhythmic pharmaceutical
agent has a distribution t.sub.1/2 of from about 0.1 minute to
about 15 minutes. In some cases, the effective amount of the at
least one antiarrhythmic pharmaceutical agent has a distribution
t.sub.1/2 of from about 3 minute to about 4 minutes. In some cases,
the effective amount of the at least one antiarrhythmic
pharmaceutical agent has a distribution t.sub.1/2 of from about 3
minute to about 5 minutes. In some cases, the effective amount of
the at least one antiarrhythmic pharmaceutical agent has an
elimination t.sub.1/2 of from about 1 hour to about 25 hours. In
some cases, the effective amount of the at least one antiarrhythmic
pharmaceutical agent has an elimination t.sub.1/2 of from about 8.5
hour to about 10.5 hours. In some cases, the effective amount of
the at least one antiarrhythmic pharmaceutical agent has a
.DELTA.QRS of from about 0.01 msec to about 100 msec. In some
cases, the effective amount of the at least one antiarrhythmic
pharmaceutical agent has a .DELTA.QRS of from about 1 msec to about
10 msec. In some cases, the effective amount of the at least one
antiarrhythmic pharmaceutical agent has a .DELTA.QRS of from about
5 msec to about 20 msec. In some cases, the effective amount of the
at least one antiarrhythmic pharmaceutical agent delivered through
the pulmonary airways by inhalation has a higher ratio of the
maximum .DELTA.QRS to the C.sub.max as compared to that provided by
intravenous delivery of an effective amount of the at least one
antiarrhythmic pharmaceutical agent. In some cases, the ratio of
the maximum .DELTA.QRS to the C.sub.max provided by the effective
amount of the at least one antiarrhythmic pharmaceutical agent
delivered through the pulmonary airways by inhalation is at least 2
folds greater than that provided by intravenous delivery of an
effective amount of the at least one antiarrhythmic pharmaceutical
agent. In some cases, the atrial arrhythmia comprises tachycardia.
In some cases, the tachycardia comprises supraventricular
tachycardia, paroxysmal supraventricular tachycardia, atrial
fibrillation, paroxysmal atrial fibrillation, acute episodes in
persistent and permanent atrial fibrillation, atrial flutter,
paroxysmal atrial flutter, or lone atrial fibrillation. In some
cases, the method comprises administering a liquid, dry powder,
extruded droplets, or nebulized droplets comprising the at least
one antiarrhythmic pharmaceutical agent, wherein the powder or
nebulized droplets have a mass median aerodynamic diameter of less
than 10 .mu.m. In some cases, the antiarrhythmic pharmaceutical
agent is a class I antiarrhythmic. In some cases, the class I
antiarrhythmic is a class Ia, Ib, or Ic antiarrhythmic. In some
cases, the class Ic antiarrhythmic is flecainide. In some cases,
the antiarrhythmic pharmaceutical agent is a class II
antiarrhythmic. In some cases, the class II antiarrhythmic is
esmolol HCl. In some cases, dosage of the esmolol HCl is between
0.5 and 0.75 mg/kg body weight. In some cases, the antiarrhythmic
pharmaceutical agent is a class IV antiarrhythmic. In some cases,
the class IV antiarrhythmic is diltiazem. In some cases, dosage of
the diltiazem is 0.25 mg/kg body weight. In some cases, the at
least one antiarrhythmic pharmaceutical agent is aerosolized in a
nebulizer. In some cases, the nebulizer is a breath-activated
nebulizer. In some cases, the nebulizer is a breath-actuated
nebulizer. In some cases, the nebulizer is configured to administer
a liquid pharmaceutical formulation of the at least one
antiarrhythmic pharmaceutical agent. In some cases, the
aerosolization occurs at room temperature. In some cases, the at
least one antiarrhythmic pharmaceutical agent is self-administered
by the subject. In some cases, the T.sub.max, the C.sub.max, the
AUC.sub.Last, the distribution t.sub.1/2, the elimination
t.sub.1/2, or the maximum .DELTA.QRS of the effective amount of the
at least one antiarrhythmic agent is measured in a human PK/PD
study. In some cases, the human PK/PD study is a single-dose PK/PD
study. In some cases, the human PK/PD study is a multi-dose (e.g.,
escalating dose) PK/PD study.
[0060] In another aspect, disclosed herein is a method of treating
a heart condition, comprising administering a pharmaceutically
effective amount of an antiarrhythmic pharmaceutical agent via
inhalation to a patient in need thereof, wherein T.sub.max of the
pharmaceutically effective amount of the antiarrhythmic
pharmaceutical agent after inhalation is from about 0.1 minute to
about 30 minutes; C.sub.max of the pharmaceutically effective
amount of the antiarrhythmic pharmaceutical agent after inhalation
is from about 10 ng/mL to about 5000 ng/mL; or AUC.sub.Last of the
pharmaceutically effective amount of the antiarrhythmic
pharmaceutical agent after inhalation is from about 100 hr*ng/mL to
about 10000 hr*ng/mL. In some cases, the T.sub.max is from about
0.1 minute to about 5 minutes, the C.sub.max is from about 50 ng/mL
to about 500 ng/mL, or the AUC.sub.Last is from about 200 hr*ng/mL
to about 2000 hr*ng/mL. In some cases, the T.sub.max is from about
0.1 minute to about 5 minutes and the C.sub.max is from about 50
ng/mL to about 500 ng/mL. In some cases, the T.sub.max is from
about 0.1 minute to about 5 minutes and the AUC.sub.Last is from
about 200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, the
C.sub.max is from about 50 ng/mL to about 500 ng/mL, and the
AUC.sub.Last is from about 200 hr*ng/mL to about 2000 hr*ng/mL. In
some cases, the antiarrhythmic pharmaceutical agent is a class I,
class II, class III, or class IV antiarrhythmic. In some cases, the
antiarrhythmic pharmaceutical agent comprises a class Ic
antiarrhythmic. In some cases, the antiarrhythmic pharmaceutical
agent comprises flecainide or a pharmaceutically acceptable salt
thereof. In some cases, the method comprises administering 20 mg to
100 mg of flecainide or a pharmaceutically acceptable salt thereof
via inhalation to the patient in need thereof. In some cases, the
method comprises administering 0.25 mg/kg body weight to 1.5 mg/kg
body weight of flecainide or a pharmaceutically acceptable salt
thereof via inhalation to the patient in need thereof. In some
cases, the antiarrhythmic pharmaceutical agent is delivered over
two or more inhalations. In some cases, time between the two or
more inhalations is from about 0.1 to 10 minutes.
[0061] In another aspect, disclosed herein is a nebulized drug
product, comprising a pharmaceutically effective amount of an
antiarrhythmic pharmaceutical agent, wherein T.sub.max of the
pharmaceutically effective amount of the antiarrhythmic
pharmaceutical agent after inhalation is from about 0.1 minute to
about 30 minutes; C.sub.max of the pharmaceutically effective
amount of the antiarrhythmic pharmaceutical agent after inhalation
is from about 10 ng/mL to about 5000 ng/mL; or AUC.sub.Last of the
pharmaceutically effective amount of the antiarrhythmic
pharmaceutical agent after inhalation is from about 100 hr*ng/mL to
about 10000 hr*ng/mL. In some cases, the T.sub.max is from about
0.1 minute to about 5 minutes, the C.sub.max is from about 50 ng/mL
to about 500 ng/mL, or the AUC.sub.Last is from about 200 hr*ng/mL
to about 2000 hr*ng/mL. In some cases, the T.sub.max is from about
0.1 minute to about 5 minutes and the C.sub.max is from about 50
ng/mL to about 500 ng/mL. In some cases, the T.sub.max is from
about 0.1 minute to about 5 minutes and the AUC.sub.Last is from
about 200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, the
C.sub.max is from about 50 ng/mL to about 500 ng/mL, and the
AUC.sub.Last is from about 200 hr*ng/mL to about 2000 hr*ng/mL. In
some cases, the antiarrhythmic pharmaceutical agent is a class I,
class II, class III, or class IV antiarrhythmic. In some cases, the
antiarrhythmic pharmaceutical agent comprises a class Ic
antiarrhythmic. In some cases, the antiarrhythmic pharmaceutical
agent comprises flecainide or a pharmaceutically acceptable salt
thereof. In some cases, the nebulized drug product comprises 20 mg
to 100 mg of flecainide or a pharmaceutically acceptable salt
thereof.
[0062] In another aspect, disclosed herein is a method of
manufacturing a formulation for the treatment of a heart condition,
comprising a pharmaceutically effective amount of an antiarrhythmic
pharmaceutical agent, wherein T.sub.max of the pharmaceutically
effective amount of the antiarrhythmic pharmaceutical agent after
nebulization and inhalation of the formulation by a patient in need
thereof is from about 0.1 minute to about 30 minutes; C.sub.max of
the pharmaceutically effective amount of the antiarrhythmic
pharmaceutical agent after nebulization and inhalation of the
formulation by a patient in need thereof is from about 10 ng/mL to
about 5000 ng/mL; or AUC.sub.Last of the pharmaceutically effective
amount of the antiarrhythmic pharmaceutical agent after
nebulization and inhalation of the formulation by a patient in need
thereof is from about 100 hr*ng/mL to about 10000 hr*ng/mL. In some
cases, the T.sub.max is from about 0.1 minute to about 5 minutes,
the C.sub.max is from about 50 ng/mL to about 500 ng/mL, or the
AUC.sub.Last is from about 200 hr*ng/mL to about 2000 hr*ng/mL. In
some cases, the T.sub.max is from about 0.1 minute to about 5
minutes and the C.sub.max is from about 50 ng/mL to about 500
ng/mL. In some cases, the T.sub.max is from about 0.1 minute to
about 5 minutes and the AUC.sub.Last is from about 200 hr*ng/mL to
about 2000 hr*ng/mL. In some cases, the C.sub.max is from about 50
ng/mL to about 500 ng/mL, and the AUC.sub.Last is from about 200
hr*ng/mL to about 2000 hr*ng/mL. In some cases, the antiarrhythmic
pharmaceutical agent is a class I, class II, class III, or class IV
antiarrhythmic. In some cases, the antiarrhythmic pharmaceutical
agent comprises a class Ic antiarrhythmic. In some cases, the
antiarrhythmic pharmaceutical agent comprises flecainide or a
pharmaceutically acceptable salt thereof. In some cases, the
antiarrhythmic pharmaceutical agent is delivered over two or more
inhalations. In some cases, time between the two or more
inhalations is from about 0.1 to 10 minutes.
[0063] In another aspect, disclosed herein is a nebulized drug
product, comprising a pharmaceutically effective amount of an
antiarrhythmic pharmaceutical agent for use in treating a heart
condition, wherein T.sub.max of the pharmaceutically effective
amount of the antiarrhythmic pharmaceutical agent after inhalation
is from about 0.1 minute to about 30 minutes; C.sub.max of the
pharmaceutically effective amount of the antiarrhythmic
pharmaceutical agent after inhalation is from about 10 ng/mL to
about 5000 ng/mL; or AUC.sub.Last of the pharmaceutically effective
amount of the antiarrhythmic pharmaceutical agent after inhalation
is from about 100 hr*ng/mL to about 10000 hr*ng/mL. In some cases,
the T.sub.max is from about 0.1 minute to about 5 minutes, the
C.sub.max is from about 50 ng/mL to about 500 ng/mL, or the
AUC.sub.Last is from about 200 hr*ng/mL to about 2000 hr*ng/mL. In
some cases, the T.sub.max is from about 0.1 minute to about 5
minutes and the C.sub.max is from about 50 ng/mL to about 500
ng/mL. In some cases, the T.sub.max is from about 0.1 minute to
about 5 minutes and the AUC.sub.Last is from about 200 hr*ng/mL to
about 2000 hr*ng/mL. In some cases, the C.sub.max is from about 50
ng/mL to about 500 ng/mL, and the AUC.sub.Last is from about 200
hr*ng/mL to about 2000 hr*ng/mL. In some cases, the antiarrhythmic
pharmaceutical agent is a class I, class II, class III, or class IV
antiarrhythmic. In some cases, the antiarrhythmic pharmaceutical
agent comprises a class Ic antiarrhythmic. In some cases, the
antiarrhythmic pharmaceutical agent comprises flecainide or a
pharmaceutically acceptable salt thereof. In some cases, the
nebulized drug product comprises 20 mg to 100 mg of flecainide or a
pharmaceutically acceptable salt thereof.
INCORPORATION BY REFERENCE
[0064] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] The present invention is further described in the
description of invention that follows, in reference to the noted
plurality of non-limiting drawings, wherein:
[0066] FIG. 1 shows how prior art intravenous drug passes through
the heart and lungs before reaching coronary arteries, hence
coronary circulation.
[0067] FIG. 2A shows how inhaled drug of the present invention
passes through directly from the lungs to the left atrium, left
ventricle and then into the coronary arteries.
[0068] FIG. 2B shows how inhaled drug of the present invention
passes through the pulmonary vein to the left atrium.
[0069] FIG. 3 shows that molecules with high Log-P values and those
that have high lipid solubility are likely to exhibit faster
absorption through the lung.
[0070] FIG. 4 shows a six compartment PK-PD model to compare
intravenous and pulmonary delivery.
[0071] FIG. 5 shows the results of a simulation comparing
intravenous and pulmonary delivery of verapamil.
[0072] FIG. 6 shows the results of a simulation comparing
intravenous and pulmonary delivery of lidocaine.
[0073] FIG. 7 shows a representative study outline: effects of
flecainide (FLE, n=2), diltiazem (DIL, n=2), and dofetilide (DOF,
n=2) on induced atrial-fibrillation. NSR: normal sinus rhythm.
[0074] FIG. 8 shows a representative study outline: dose-response
of intratracheal (IT) esmolol HCL (ESM, n<=2) or adenosine (ADN,
n<=2) on induced supra-ventricular tachycardia (SVT). NSR:
normal sinus rhythm. IV: intravenous
[0075] FIG. 9 shows an ECG trace showing Dog in Afib prior to
dosing of either vehicle or test article.
[0076] FIG. 10 shows an ECG trace showing Dog continues to be in
Afib after pulmonary administration of vehicle (water, 3 ml).
[0077] FIG. 11 shows an ECG trace showing the Afib converting into
normal sinus rhythm when a dog was administered 4 mg/kg body weight
of Flecainide acetate by intra-tracheal instillation.
[0078] FIG. 12 shows an ECG trace showing Afib converting as soon
as dosing occurred at 2 mg/kg body weight of flecainide
acetate.
[0079] FIG. 13 shows an ECG trace showing Afib converting after
administration of diltiazem HCl at 0.25 mg/kg body weight.
[0080] FIG. 14 shows results from a supraventricular tachycardia
model in which PR interval and Mean Arterial blood pressure (MAP)
change in time after pulmonary administration of pulmonary
diltiazem 0.25 mg/kg.
[0081] FIG. 15 shows results from the supraventricular tachycardia
model in which PR interval and Mean Arterial blood pressure (MAP)
change in time after intravenous administration of pulmonary
diltiazem 0.25 mg/kg.
[0082] FIG. 16 shows results from the supraventricular tachycardia
model showing effect on PR interval over time of 0.5 mg/kg body
weight of esmolol HCl administered via the lung (IT).
[0083] FIG. 17 shows results from the supraventricular tachycardia
model showing period of AV block induced by esmolol 0.5 mg/kg
administered via the lung.
[0084] FIG. 18 shows results from the supraventricular tachycardia
model showing period of AV block induced by esmolol 0.5 mg/kg
administered via the lung.
[0085] FIG. 19 shows results from the supraventricular tachycardia
model showing effect on PR interval over time of 0.5 mg/kg body
weight of esmolol HCl administered via the lung (IT).
[0086] FIG. 20 shows results from the supraventricular tachycardia
model showing period of AV block induced by esmolol 0.75 mg/kg
administered via the lung.
[0087] FIG. 21 shows the design for the Phase 1 clinical study.
[0088] FIG. 22 shows the time course of the changes in the heart
rate (.DELTA.HR) relative to the baseline (pre-dose) following oral
inhalation of 20 mg eTLD (estimated Total Lung Dose) of flecainide
acetate solution and placebo in subjects of Cohort 1. Values are
the mean.+-.standard error of the mean (SEM).
[0089] FIG. 23 shows the changes in heart rate (.DELTA.HR)
following inhalation of 40 mg eTLD of flecainide acetate and
placebo solutions in subjects of Cohort 2 relative to pre-dose
values. Values are the mean.+-.SEM.
[0090] FIG. 24 shows the heart rate (bpm) of subjects in Cohort 5
following oral inhalation (IH) of flecainide acetate solution (30
mg eTLD) and administration of flecainide acetate solution by IV (2
mg/kg). Values are the mean.+-.standard deviation (SD).
[0091] FIG. 25A shows changes in systolic blood pressure (BP) from
subjects of Cohort 1 following inhalation of 20 mg eTLD of
flecainide acetate and placebo solutions.
[0092] FIG. 25B shows changes in diastolic BP from subjects of
Cohort 1 following inhalation of 20 mg eTLD of flecainide acetate
and placebo solutions.
[0093] FIG. 26A shows changes in systolic BP from subjects of
Cohort 2 following inhalation of 40 mg eTLD of flecainide acetate
and placebo solutions.
[0094] FIG. 26B shows changes in diastolic BP from subjects of
Cohort 2 following inhalation of 40 mg eTLD of flecainide acetate
and placebo solutions.
[0095] FIG. 27A shows changes in systolic BP from subjects of
Cohort 5 following single dose administration of inhaled (IH)
flecainide (30 mg eTLD) and IV flecainide (2 mg/kg). Values are the
mean.+-.SD.
[0096] FIG. 27B shows changes in diastolic BP from subjects of
Cohort 5 following single dose administration of inhaled (IH)
flecainide (30 mg eTLD) and IV flecainide (2 mg/kg). Values are the
mean.+-.SD.
[0097] FIG. 28 shows mean venous plasma concentration-time curves
following inhalation of 20 mg eTLD, 30 mg eTLD, and 40 mg eTLD of
flecainide acetate solution.
[0098] FIG. 29A shows the mean venous plasma concentration-time
curve following administration of flecainide acetate solution by IV
(2 mg/kg). Data points represent the mean.+-.SD.
[0099] FIG. 29B shows mean venous plasma concentration-time curves
following administration of flecainide acetate solution by
inhalation (IH; 30 mg eTLD) or IV (2 mg/kg). Data points represent
the mean.+-.SD.
[0100] FIG. 30 shows the time course of the changes in PR interval
duration (.DELTA.PR) relative to the baseline (pre-dose) following
oral inhalation of 20 mg eTLD of flecainide acetate solution and
acetate buffer (placebo). Values are the mean.+-.SEM; n=6
(flecainide), n=2 (placebo).
[0101] FIG. 31 shows the time course of the changes in QRS interval
duration (.DELTA.QRS) relative to the baseline (pre-dose) following
oral inhalation of 20 mg eTLD of flecainide acetate solution and
placebo. Values are the mean.+-.SEM; n=6 (flecainide), n=2
(placebo).
[0102] FIG. 32 shows the time course of the changes in QRS interval
duration (.DELTA.QRS) relative to the baseline (pre-dose) following
oral inhalation of 40 mg eTLD of flecainide acetate solution and
placebo. Values are the mean.+-.SEM; n=10 (flecainide), n=4
(placebo).
[0103] FIG. 33A shows selected digitized electrocardiographic (ECG)
tracings from lead V5 depicting the P-, QRS- and T-wave complexes
recorded prior to (pre-dose) and at various times after (post-dose)
completion of inhalation of 40 mg eTLD of flecainide. Denoted in
each panel are the values of the QRS interval duration in
milliseconds (QRSd, ms) and R-wave amplitude in microvolts (QRSa,
.mu.V).
[0104] FIG. 33B shows bar graphs summarizing the time course of
changes in QRS interval duration measured from ECGs at the
respective times and obtained from the same subject in FIG. 13A. *
p<0.05.
[0105] FIG. 33C shows bar graphs summarizing the time course of
changes in R-wave amplitude measured from ECGs at the respective
times and obtained from the same subject in FIG. 13A. *
p<0.05.
[0106] FIG. 34 shows the changes in QRS interval duration
(.DELTA.QRS) relative to the baseline (pre-dose) in subjects of
Cohort 5 (IV-inhalation crossover) following A) administration of
flecainide acetate solution by IV (2 mg/kg; *10 min infusion,
intraventricular conduction delay lasted 5-10 min) and B) oral
inhalation of 30 mg eTLD of flecainide acetate solution (**4 min
inhalation).
[0107] FIG. 35 shows the time course of the changes in the QTcF
interval duration (.DELTA.QTcF) relative to the baseline (pre-dose)
following oral inhalation of 20 mg eTLD of flecainide acetate
solution and placebo. Values are the mean.+-.SEM; n=6 (flecainide),
n=2 (placebo).
[0108] FIG. 36 shows ECG tracings recorded from a subject
administered flecainide (2 mg/kg) by IV. Small arrows on the
electrogram indicate the T-wave.
[0109] FIG. 37 shows venous plasma concentrations of flecainide
administered IV or orally at the time of cardioversion of atrial
fibrillation (AF) in patients with recent onset AF (left panel),
following oral inhalation of 40 mg eTLD of flecainide acetate
solution by healthy volunteers (center panel), and at the time of
conversion of AF to NSR in dogs following intratracheal (IT)
instillation of 0.75 mg/kg of flecainide (right panel). LV=Left
Ventricle; * Mean.+-.SD of plasma concentration (.times.1.96-fold)
extrapolated from animal studies in dogs at time of
cardioversion.
[0110] FIG. 38 shows comparative .DELTA.QRS interval prolongation
(msec) associated with the administration of flecainide or
vemakalant at the time of cardioversion of AF in patients with
recent onset AF and following oral inhalation of 30 mg eTLD of
flecainide acetate solution by healthy volunteers.
[0111] FIGS. 39-67 refer to data obtained in pigs. FIG. 39 shows
flecainide venous and left ventricular chamber (LV) plasma levels
at different time points following intravenous administration of
2.0 mg/kg over 2 min.
[0112] FIG. 40 shows flecainide venous and LV plasma levels at
different time points following intratracheal instillation of 0.75
mg/kg.
[0113] FIG. 41 shows flecainide venous and LV plasma levels at
different time points following intratracheal instillation of 1.5
mg/kg.
[0114] FIG. 42 shows the effects of intravenous administration of
flecainide (2.0 mg/kg) on heart rate (primary vertical axis) and LV
plasma levels (secondary vertical axis) at different time
points.
[0115] FIG. 43 shows the effects of intravenous administration of
flecainide (2.0 mg/kg) on mean arterial blood pressure (MAP;
primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0116] FIG. 44 shows the effects of intravenous administration of
flecainide (2.0 mg/kg) on the PR interval duration (primary
vertical axis) and LV plasma levels (secondary vertical axis) at
different time points.
[0117] FIG. 45 shows the effects of intravenous administration of
flecainide (2.0 mg/kg) on QRS interval duration (primary vertical
axis) and LV plasma levels (secondary vertical axis) at different
time points.
[0118] FIG. 46 shows the effects of intravenous administration of
flecainide (2.0 mg/kg) on the QTc interval duration (primary
vertical axis) and LV plasma levels (secondary vertical axis) at
different time points.
[0119] FIG. 47 shows the effects of intravenous administration of
flecainide (2.0 mg/kg) on the JTc interval duration (primary
vertical axis) and LV plasma levels (secondary vertical axis) at
different time points.
[0120] FIG. 48 shows the effects of intratracheal instillation of
the lower dose of flecainide (0.75 mg/kg) on heart rate (primary
vertical axis) and LV plasma levels (secondary vertical axis) at
different time points.
[0121] FIG. 49 shows the effects of intratracheal instillation of
the lower dose of flecainide (0.75 mg/kg) on MAP (primary vertical
axis) and LV plasma levels (secondary vertical axis) at different
time points.
[0122] FIG. 50 shows the effects of intratracheal instillation of
the lower dose of flecainide (0.75 mg/kg) on the PR interval
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0123] FIG. 51 shows the effects of intratracheal instillation of
the lower dose of flecainide (0.75 mg/kg) on QRS interval duration
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0124] FIG. 52 shows the effects of intratracheal instillation of
the lower dose of flecainide (0.75 mg/kg) on the QTc interval
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0125] FIG. 53 shows the effects of intratracheal instillation of
the lower dose of flecainide (0.75 mg/kg) on the JTc interval
(primary vertical axis) and LV plasma level (secondary vertical
axis) at different time points.
[0126] FIG. 54 shows the effects of intratracheal instillation of
the higher dose of flecainide (1.5 mg/kg) on heart rate (primary
vertical axis) and LV plasma levels (secondary vertical axis) at
different time points.
[0127] FIG. 55 shows the effects of intratracheal instillation of
the higher dose of flecainide (1.5 mg/kg) on MAP (primary vertical
axis) and LV plasma levels (secondary vertical axis) at different
time points.
[0128] FIG. 56 shows the effects of intratracheal instillation of
the higher dose of flecainide (1.5 mg/kg) on the PR interval
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0129] FIG. 57 shows the effects of intratracheal instillation of
the higher dose of flecainide (1.5 mg/kg) on QRS interval duration
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0130] FIG. 58 shows the effects of intratracheal instillation of
the higher dose of flecainide (1.5 mg/kg) on the QTc interval
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0131] FIG. 59 shows the effects of intratracheal instillation of
the higher dose of flecainide (1.5 mg/kg) on the JTc interval
(primary vertical axis) and LV plasma levels (secondary vertical
axis) at different time points.
[0132] FIG. 60 shows the protocol and a representative example of
induction of atrial fibrillation (AF) to test conversion by IT
flecainide.
[0133] FIG. 61 shows a summary of the data from experiments
evaluating the effects of intratracheal instillation of flecainide
(1.5 mg/kg) on AF duration (n=3).
[0134] FIG. 62A shows the effects of slow versus rapid infusion of
IV administered flecainide on the venous plasma levels of
flecainide.
[0135] FIG. 62B shows the effects of slow versus rapid infusion of
IV administered flecainide on the QRS interval duration.
[0136] FIG. 62C shows the correlation between venous plasma levels
of slowly versus rapidly infused, IV administered flecainide and
QRS widening.
[0137] FIG. 63 shows catheter placement in anesthetized Yorkshire
pigs.
[0138] FIG. 64 shows AF duration was correlated with IT flecainide
dose.
[0139] FIG. 65 shows representative electrograms demonstrating AF
conversion at 5 min after IT flecainide (1.5 mg/kg) (lower panel)
compared to no conversion by 10 min after no drug (upper
panel).
[0140] FIG. 66A shows the plasma concentration of flecainide
reached levels required for conversion of AF to NSR within 10 min
after IT flecainide (0.75 mg/kg and 1.5 mg/kg).
[0141] FIG. 66B shows the plasma concentrations of flecainide at
the time of conversion of AF to NSR following IT instillation of
flecainide (0.75 mg/kg and 1.5 mg/kg).
[0142] FIG. 67 shows the reduction in the dominant frequency of AF
by IT flecainide (0.75 mg/kg and 1.5 mg/kg).
[0143] FIGS. 68A-71 refer to data obtained in dogs. FIG. 68A shows
a representative ECG demonstrating AF prior to dosing.
[0144] FIG. 68B shows a representative ECG demonstrating
persistence of AF after IT instillation of vehicle.
[0145] FIG. 68C shows a representative ECG demonstrating AF prior
to dosing.
[0146] FIG. 68D shows a representative ECG demonstrating conversion
of AF to NSR following IT flecainide (0.75 mg/kg).
[0147] FIG. 69 shows a summary of the changes in blood pressure,
ventricular rate, and LV dP/dT.sub.max (the maximal rate of rise of
LV pressure) upon conversion of AF to NSR following administration
of flecainide via IV or IT.
[0148] FIG. 70 shows the variations in plasma concentrations of
flecainide in the left ventricular chamber (LV), pulmonary artery
(PA), and femoral vein (VEN) based on the route of delivery (IT and
IV) of flecainide. Note that following IV infusion, the
concentrations of flecainide in the PA were transiently higher
(2.1- to 3.5-fold)* than those in the LV. After IT instillation of
flecainide, its concentrations were transiently higher (1.4- to
3.2-fold)* in the LV chamber than in the PA (*between 1 to 3 min
after administration of flecainide).
[0149] FIG. 71 shows the time course of the ratios of the plasma
concentrations of flecainide in the pulmonary artery (PA) and left
ventricular chamber (LV) following IV or IT administration.
[0150] FIGS. 72-87B refer to data obtained in human subjects. FIG.
72 shows the effects of postural changes and inhalation of
flecainide or placebo (n=3) on heart rate (HR) at different time
points.
[0151] FIG. 73 shows the effects of intravenously delivered (IV)
flecainide on systolic blood pressure and heart rate in 6 subjects
at different time points.
[0152] FIG. 74 shows the effects of inhaled flecainide on systolic
blood pressure and heart rate in 6 subjects at different time
points.
[0153] FIG. 75A shows systolic and diastolic blood pressures
following flecainide intravenous delivery in 6 subjects.
[0154] FIG. 75B shows systolic and diastolic blood pressures
following flecainide inhalation (IH) administration in 6
subjects.
[0155] FIGS. 76A and 76B show venous plasma concentration-time
curves of the per-protocol population and post-hoc population
following oral inhalation of 20, 40, and 60 mg eTLD flecainide,
respectively.
[0156] FIGS. 77A and 77B show venous plasma concentration-time
curves following intravenous infusion and inhalation of flecainide,
respectively.
[0157] FIG. 78 shows venous plasma concentration-time curve
following flecainide IV infusion (normalized to 30 mg eTLD dose)
and oral inhalation.
[0158] FIG. 79 shows time course of changes in QRS interval
duration with flecainide or placebo.
[0159] FIGS. 80A and 80B show time courses of changes in QRS
interval duration following flecainide via IV infusion and oral
inhalation, respectively.
[0160] FIG. 81 shows time course of changes in PR interval duration
with flecainide or placebo.
[0161] FIGS. 82A and 82B show time courses of changes in PR
interval following flecainide IV infusion and oral inhalation,
respectively.
[0162] FIG. 83 shows relationship between peak venous plasma
concentrations of flecainide (C.sub.max) and the magnitude of
maximal QRS prolongation.
[0163] FIGS. 84A and 84B show time courses of changes in plasma
concentrations of flecainide and QRS duration with flecainide IV
infusion and oral inhalation, respectively.
[0164] FIG. 85 shows non-steady state relationships between plasma
concentration of flecainide and QRS duration following flecainide
IV infusion and oral inhalation, respectively.
[0165] FIG. 86 shows non-steady state relationships between plasma
concentrations of flecainide and QRS duration following flecainide
IV infusion and oral inhalation in subjects with near-equal .DELTA.
QRS values.
[0166] FIG. 87A shows baseline (pre-dose) values of heart rate,
systolic blood pressure (BP), and diastolic BP in Periods 1 and 2
of 6 subjects in Part B study.
[0167] FIG. 87B shows baseline (pre-dose) values of QRS complexes
and PR intervals in Periods 1 and 2 of 6 subjects in Part B
study.
DETAILED DESCRIPTION
[0168] It is to be understood that unless otherwise indicated the
present invention is not limited to specific formulation
components, drug delivery systems, manufacturing techniques,
administration steps, or the like, as such may vary. In this
regard, unless otherwise stated, a reference to a compound or
component includes the compound or component by itself, as well as
the compound or component in combination with other compounds or
components, such as mixtures of compounds.
[0169] Before further discussion, a definition of the following
terms will aid in the understanding of the present invention.
[0170] As used herein, the singular forms "a," "an," and "the"
include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to "an antiarrhythmic
pharmaceutical agent" includes not only a single active agent but
also a combination or mixture of two or more different active
agents.
[0171] Reference herein to "one embodiment," "one version," or "one
aspect" shall include one or more such embodiments, versions or
aspects, unless otherwise clear from the context.
[0172] As used herein, the term "solvate" is intended to include,
but not be limited to, pharmaceutically acceptable solvates.
[0173] As used herein, the term "pharmaceutically acceptable
solvate" is intended to mean a solvate that retains one or more of
the biological activities and/or properties of the antiarrhythmic
pharmaceutical agent and that is not biologically or otherwise
undesirable. Examples of pharmaceutically acceptable solvates
include, but are not limited to, antiarrhythmic pharmaceutical
agents in combination with water, isopropanol, ethanol, methanol,
DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations
thereof.
[0174] As used herein, the term "salt" is intended to include, but
not be limited to, pharmaceutically acceptable salts.
[0175] As used herein, the term "pharmaceutically acceptable salt"
is intended to mean those salts that retain one or more of the
biological activities and properties of the free acids and bases
and that are not biologically or otherwise undesirable.
Illustrative examples of pharmaceutically acceptable salts include,
but are not limited to, sulfates, pyrosulfates, bisulfates,
sulfites, bisulfites, phosphates, monohydrogenphosphates,
dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,
bromides, iodides, acetates, propionates, decanoates, caprylates,
acrylates, formates, isobutyrates, caproates, heptanoates,
propiolates, oxalates, malonates, succinates, suberates, sebacates,
fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,
benzoates, chlorobenzoates, methylbenzoates, di nitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
xylenesulfonates, phenylacetates, phenyipropionates,
phenylbutyrates, citrates, lactates, .gamma.-hydroxybutyrates,
glycolates, tartrates, methanesulfonates, propanesulfonates,
naphthalene-1-sulfonates, naphthalene-2-sulfonates, and
mandelates.
[0176] If the antiarrhythmic pharmaceutical agent is a base, the
desired salt may be prepared by any suitable method known in the
art, including treatment of the free base with an inorganic acid,
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like, or with an organic acid, such
as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,
salicylic acid, pyranosidyl acids such as glucuronic acid and
galacturonic acid, alpha-hydroxy acids such as citric acid and
tartaric acid, amino acids such as aspartic acid and glutamic acid,
aromatic acids such as benzoic acid and cinnamic acid, sulfonic
acids such as p-toluenesulfonic acid and ethanesulfonic acid, or
the like.
[0177] If the antiarrhythmic pharmaceutical agent is an acid, the
desired salt may be prepared by any suitable method known in the
art, including treatment of the free acid with an inorganic or
organic base, such as an amine (primary, secondary or tertiary), an
alkali metal or alkaline earth metal hydroxide, or the like.
Illustrative examples of suitable salts include organic salts
derived from amino acids such as glycine and arginine, ammonia,
primary, secondary and tertiary amines, and cyclic amines such as
piperidine, morpholine and piperazine, and inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron,
copper, zinc, aluminum and lithium.
[0178] The term "about" in relation to a reference numerical value
can include a range of values plus or minus 10% from that value.
For example, the amount "about 10" includes amounts from 9 to 11,
including the reference numbers of 9, 10, and 11. The term "about"
in relation to a reference numerical value can also include a range
of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%
from that value.
[0179] As used herein, "atrial arrhythmia" can mean an arrhythmia
that affects at least one atrium and does not include bradycardia.
For instance, atrial arrhythmia may originate in and affect at
least one atrium.
[0180] As used herein, "tachycardia" can mean an arrhythmia in
which the heart beat is too fast, e.g., faster than normal. For
instance, tachycardia may involve a resting heart rate of over 100
beats per minute, such as greater than 110, greater than 120, or
greater than 130 beats minute.
[0181] As used herein, the phrase "heart rhythm arrhythmia" can
mean an arrhythmia in which the heart beat is irregular.
[0182] As used herein, the "amount of the at least one
antiarrhythmic pharmaceutical agent in blood in the coronary
circulation of the heart" may be measured by extracting a sample
from any vascular region of the coronary circulation of the heart
(e.g., arteries, veins, including coronary sinus) by using a
cannula. The amount of antiarrhythmic pharmaceutical agent in the
sample may then be determined by known means, such as bioanalytical
techniques that employ analytical equipment such as LC-MS/MS. Thus,
the amount of antiarrhythmic pharmaceutical agent in the blood in
the heart may be measured for any particular time.
[0183] As used herein, the terms "treating" and "treatment" can
refer to reduction in severity and/or frequency of symptoms,
elimination of symptoms and/or underlying cause, reduction in
likelihood of the occurrence of symptoms and/or underlying cause,
and/or remediation of damage. Thus, "treating" a patient with an
active agent as provided herein includes prevention of a particular
condition, disease, or disorder in a susceptible individual as well
as treatment of a clinically symptomatic individual.
[0184] As used herein, "nominal amount" can refer to the amount
contained within the unit dose receptacle(s) that are
administered.
[0185] As used herein, "effective amount" can refer to an amount
covering both therapeutically effective amounts and
prophylactically effective amounts.
[0186] As used herein, a "therapeutically effective amount" of an
active agent refers to an amount that is effective to achieve a
desired therapeutic result. A therapeutically effective amount of a
given active agent will typically vary with respect to factors such
as the type and severity of the disorder or disease being treated
and the age, gender, and weight of the patient. In some cases,
"inhalation" (e.g., "oral inhalation") can refer to inhalation
delivery of a therapeutically effective amount of a pharmaceutical
agent contained in one unit dose receptacle, which, in some
instance, can require one or more breaths, like 1, 2, 3, 4, 5, 6,
7, 8, 9, or more breaths. For example, if the effective amount is
90 mg, and each unit dose receptacle contains 30 mg, the delivery
of the effective amount can require 3 inhalations.
[0187] Unless otherwise specified, the term "therapeutically
effective amount" can include a "prophylactically effective
amount," e.g., an amount of active agent that is effective to
prevent the onset or recurrence of a particular condition, disease,
or disorder in a susceptible individual.
[0188] As used herein, the phrase "minimum effective amount" can
mean the minimum amount of a pharmaceutical agent necessary to
achieve an effective amount.
[0189] As used herein, "mass median diameter" or "MMD" can refer to
the median diameter of a plurality of particles, typically in a
polydisperse particle population, e.g., consisting of a range of
particle sizes. MMD values as reported herein are determined by
laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany),
unless the context indicates otherwise. For instance, for powders
the samples are added directly to the feeder funnel of the Sympatec
RODOS dry powder dispersion unit. This can be achieved manually or
by agitating mechanically from the end of a VIBRI vibratory feeder
element. Samples are dispersed to primary particles via application
of pressurized air (2 to 3 bar), with vacuum depression (suction)
maximized for a given dispersion pressure. Dispersed particles are
probed with a 632.8 nm laser beam that intersects the dispersed
particles' trajectory at right angles. Laser light scattered from
the ensemble of particles is imaged onto a concentric array of
photomultiplier detector elements using a reverse-Fourier lens
assembly. Scattered light is acquired in time-slices of 5 ms.
Particle size distributions are back-calculated from the scattered
light spatial/intensity distribution using a proprietary
algorithm.
[0190] As used herein, "geometric diameter" can refer to the
diameter of a single particle, as determined by microscopy, unless
the context indicates otherwise.
[0191] As used herein, "mass median aerodynamic diameter" or "MMAD"
can refer to the median aerodynamic size of a plurality of
particles or particles, typically in a polydisperse population. The
"aerodynamic diameter" can be the diameter of a unit density sphere
having the same settling velocity, generally in air, as a powder
and is therefore a useful way to characterize an aerosolized powder
or other dispersed particle or particle formulation in terms of its
settling behavior. The aerodynamic diameter encompasses particle or
particle shape, density, and physical size of the particle or
particle. As used herein, MMAD refers to the median of the
aerodynamic particle or particle size distribution of aerosolized
particles determined by cascade impaction, unless the context
indicates otherwise.
[0192] As used herein, the term "emitted dose" or "ED" can refer to
an indication of the delivery of particles from an aerosolization
device after an actuation or dispersion event from a unit dose
receptacle or reservoir. ED is defined as the ratio of the dose
delivered by an inhaler device to the nominal dose (e.g., the mass
of powder or liquid per unit dose placed into a suitable inhaler
device prior to firing). The ED is an experimentally determined
amount, and may be determined using an in vitro system that mimics
patient dosing. For instance, to determine an ED value for a dry
powder, a nominal dose of dry powder is placed into a
Turbospin.RTM. DPI device (PH&T, Italy), described in U.S. Pat.
Nos. 4,069,819 and 4,995,385, which are incorporated herein by
reference in their entireties. The Turbospin.RTM. DPI is actuated,
dispersing the powder. The resulting aerosol cloud is then drawn
from the device by vacuum (30 L/min) for 2.5 seconds after
actuation, at which point it is captured on a tared glass fiber
filter (Gelman, 47 mm diameter) attached to the device mouthpiece.
The amount of powder that reaches the filter constitutes the
delivered dose. For example, for a capsule containing 5 mg of dry
powder, capture of 4 mg of powder on the tared filter would
indicate an ED of 80% (=4 mg (delivered dose)/5 mg (nominal
dose)).
[0193] As used herein, "passive dry powder inhaler" can refer to an
inhalation device that relies upon a patient's inspiratory effort
to disperse and aerosolize a pharmaceutical composition contained
within the device in a reservoir or in a unit dose form and does
not include inhaler devices which comprise a means for providing
energy, such as pressurized gas and vibrating or rotating elements,
to disperse and aerosolize the drug composition.
[0194] As used herein, "active dry powder inhaler" can refer to an
inhalation device that does not rely solely on a patient's
inspiratory effort to disperse and aerosolize a pharmaceutical
composition contained within the device in a reservoir or in a unit
dose form and does include inhaler devices that comprise a means
for providing energy to disperse and aerosolize the drug
composition, such as pressurized gas and vibrating or rotating
elements.
[0195] By a "pharmaceutically acceptable" component is meant a
component that is not biologically or otherwise undesirable, e.g.,
the component may be incorporated into a pharmaceutical formulation
of the invention and administered to a patient as described herein
without causing any significant undesirable biological effects or
interacting in a deleterious manner with any of the other
components of the formulation in which it is contained. When the
term "pharmaceutically acceptable" is used to refer to an
excipient, it is generally implied that the component has met the
required standards of toxicological and manufacturing testing or
that it is included on the Inactive Ingredient Guide prepared by
the U.S. Food and Drug Administration.
[0196] As used herein, "P wave" can represent the wave generated by
the electrical depolarization of the atria (right and left), and is
usually 0.08 to 0.1 seconds (80-100 ms) in duration.
[0197] As used herein, "short form-36 quality of life" can mean the
Short Form 36 (SF-36) survey of patient health (updated August
2005). The SF-36 consists of eight scaled scores, which are the
sums of the questions in their section. Each scale is directly
transformed into a 0-100 scale on the assumption that each question
carries equal weight. The eight sections are: (1) vitality; (2)
physical functioning; (3) bodily pain; (4) general health
perceptions; (5) physical role functioning; (6) emotional role
functioning; (7) social role functioning; and (8) mental health. It
can also refer to any Quality of Life questionnaire for AF
sympotoms.
[0198] As used herein, "preservative" can mean cresols and
benzoates. Thus, "substantially preservative-free" can mean that a
composition does not include a substantial amount of any cresols
and/or benzoates. For instance, "substantially preservative-free"
compositions can comprise less than 1 wt %, such as less than 0.5
wt %, less than 0.4 wt %, less than 0.3 wt %, less than 0.2 wt %,
or less than 0.1 wt %, of preservative. Of course,
"preservative-free" can mean that no preservative is present.
[0199] As used herein, "substantially tasteless" can mean a
composition that has substantially little to no taste upon initial
ingestion.
[0200] As an overview, the present invention relates to methods of
treating atrial arrhythmia. The methods may comprise administering
an effective amount of at least one antiarrhythmic pharmaceutical
agent to a patient in need thereof, such that the at least one
antiarrhythmic pharmaceutical agent first enters the heart through
the pulmonary veins to the left atrium.
[0201] In one aspect, a method of treating atrial arrhythmia
comprises administering by inhalation an effective amount of at
least one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein an amount of the at least one antiarrhythmic
pharmaceutical agent peaks in the coronary circulation of the heart
at a time ranging from 10 seconds to 30 minutes from the
administration.
[0202] In yet another aspect, the present invention is directed to
a method of self-diagnosing and treating atrial arrhythmia. The
method comprises self-diagnosing atrial arrhythmia by detecting at
least one of shortness of breath, heart palpitations, and above
normal heart rate. The method also comprises self-administering by
inhalation an effective amount of at least one antiarrhythmic
pharmaceutical agent within two hours, one hour, 30 minutes, or 15
minutes of the self-diagnosing. In some cases, the method comprises
self-administering by inhalation an effective amount of at least
one antiarrhythmic pharmaceutical agent within 15 minutes of the
self-diagnosing.
[0203] In another aspect, a method of treating atrial arrhythmia
comprises administering by inhalation an effective amount of at
least one antiarrhythmic pharmaceutical agent to a patient in need
thereof, wherein an electrophysiologic effect is observed, via
electrocardiography, at a time ranging from 10 seconds to 30
minutes from the administration.
[0204] In still another aspect, a method of treating atrial
arrhythmia comprises administering by inhalation an effective
amount of at least one antiarrhythmic pharmaceutical agent to a
patient in need thereof, wherein a cardiac score from a monitor
implementing an arrhythmia detection algorithm shows a transition
from an arrhythmic state to normal sinus rhythm in the patient at a
time ranging from 10 seconds to 30 minutes from the
administration.
[0205] In yet another aspect, a method of treating atrial
arrhythmia comprises administering by inhalation an effective
amount of at least one antiarrhythmic pharmaceutical agent to a
patient in need thereof, wherein a short form-36 quality of life
score of the patient improves at a time ranging from 10 seconds to
30 minutes from the administration.
[0206] In another aspect, a unit dose comprises a unit dose
receptacle and a composition within the unit dose receptacle. The
composition comprises at least one antiarrhythmic pharmaceutical
agent in an amount less than or equal to an amount of the same at
least one antiarrhythmic pharmaceutical agent administered
intravenously in the arm to achieve a minimum effective amount in
the coronary circulation, and a pharmaceutically acceptable
excipient.
[0207] In still another aspect, an aerosol comprises particles
having a mass median aerodynamic diameter less than 10 .mu.m. The
particles comprise at least one antiarrhythmic pharmaceutical agent
in an amount less than or equal to an amount of the same at least
one antiarrhythmic pharmaceutical agent administered intravenously
in the arm to achieve a minimum effective amount in the coronary
circulation, and a pharmaceutically acceptable excipient.
[0208] In yet another aspect, a kit comprises a container
containing at least one antiarrhythmic pharmaceutical agent and an
aerosolization device.
[0209] In certain embodiments, the present invention includes
"pharmaco-rescue-therapies" to provide fast cardioversion in
patients with atrial arrhythmias like Paroxysmal Ventricular
Tachycardia (PSVT), and Paroxysmal Atrial Fibrillation (PAF). The
pharmaco-rescue-therapies are usually intended for
self-administration of the medicine by inhalation.
[0210] Inhalation is the shortest route for a drug to reach the
heart, next only to intracardiac injection, as shown in FIGS. 2A
and 2B. Drugs delivered by inhalation generally exhibit "pulsatile
pharmacokinetics" of transient high drug concentrations, followed
by dilution to sub-therapeutic levels.
[0211] Thus, in some embodiments, the present invention involves a
rapid acting inhaled product with a fast onset of action compared
to oral medicine. The product is expected to be at least as fast as
intravenous medicine. In some embodiments, an amount of the at
least one antiarrhythmic pharmaceutical agent peaks in the coronary
circulation of the heart at a time ranging from 10 seconds to 30
minutes, such as 30 seconds to 20 minutes, 1 minute to 10 minutes,
2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the
administration. In certain embodiments, an electrophysiologic
effect is observed, via electrocardiography, at a time ranging from
10 seconds to 30 minutes, such as 30 seconds to 20 minutes, 1
minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5
minutes, from the administration. In some embodiments, a cardiac
score from a device with an arrhythmia detection algorithm shows a
transition from an arrhythmic state to normal sinus rhythm in the
patient at a time ranging from 10 seconds to 30 minutes, such as 30
seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8
minutes, or 2.5 minutes to 5 minutes, from the administration. In
some embodiments, a short form-36 quality of life score of the
patient improves at a time ranging from 10 seconds to 30 minutes,
such as 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes
to 8 minutes, or 2.5 minutes to 5 minutes, from the administration.
In certain embodiments, the patient has normal sinus rhythm within
30 minutes, such as within 10 minutes, of initiating the
administering.
[0212] In some aspects, the present invention involves low doses
that are safe and effective. Other aspects typically involve low
premature metabolism and low drug-drug interaction.
[0213] The present invention includes non-invasive drug delivery to
the heart. The lung is shortest route for drug to heart with
minimal dilution next to intra-cardiac injection. Drugs delivered
via the lung have a fast onset action compared to those delivered
via the oral route. Pipeline Insights: Antiarrhythmics, Datamonitor
(June 2006). Pulmonary drug delivery to the heart is at least
equivalent to a portable intravenous injection. Inhaled drugs
(e.g., verapamil, diltiazem, lidocaine, ibutilide, procainamide,
and propafenone) are expected to exhibit "pulsatile
pharmacokinetics" of transient high drug concentrations, followed
by dilution to sub-therapeutic levels.
[0214] Existing cardiovascular drugs tend to be small molecules
with high lipid solubility. These lipid soluble molecules (e.g.,
diltiazem, verapamil, ibutilide, propafenone) are expected to have
a high pulmonary bioavailability and fast rate of pulmonary
absorption. This ensures that they reach the heart through the
pulmonary veins.
[0215] The pulsatile pharmacokinetic behavior of the drugs show
that the drug is diluted within a few seconds of reaching effective
concentrations in the heart and is diluted to sub-therapeutic
levels in the volume of the blood. This characteristic will
minimize drug-drug interactions that produce significant
toxicological responses normally seen at steady state.
[0216] Thus, in certain embodiments, the present invention relates
to achieving transient high drug concentrations in the heart that
effect rate and rhythm changes in the heart within a short period
of time allowing for treatment of episodic arrhythmias such as
paroxysmal atrial arrhythmias.
[0217] The results of the invention are surprising and unexpected.
In this regard, the antiarrhythmic pharmaceutical agents pass
through the lungs quickly. For instance, verapamil and diltiazem
will ionize if in salt form, so the base will pass through the
lungs quickly. In some aspects, the methods of the present
invention take advantage of fast onset of action, high drug
bioavailability, and fast absorption through the lung. Most
cardiovascular drugs are small molecules that have high lipid
solubility and are therefore expected to have high pulmonary
bioavailability and a fast rate of absorption. FIG. 3 shows the
log-p values and lipid solubility of exemplary cardiovascular
molecules along with their expected high pulmonary
bioavailability.
[0218] Another reason why the results of the present invention are
surprising and unexpected involves the rate at which the
antiarrhythmic pharmaceutical agents pass through the heart. While
a skilled artisan might expect the rate to be too fast, modeling
indicates that the drug will not pass through the heart too fast.
Thus, a therapeutic effect is achieved despite fast pass-through
and despite only one pass-through at therapeutic levels.
[0219] In view of the above, in one or more embodiments of the
invention, a composition comprises an antiarrhythmic pharmaceutical
agent. Examples of antiarrhythmic pharmaceutical agents include,
but are not limited to, class Ia (sodium channel blockers,
intermediate association/dissociation), class Ib (sodium channel
blockers, fast association/dissociation), class Ic (sodium channel
blocker, slow association/dissociation), class II (beta blockers),
class III (potassium channel blockers), class IV (calcium channel
blockers), and class V (unknown mechanisms) antiarrhythmics.
[0220] Class Ia antiarrhythmics include, but are not limited to,
quinidine, procainamide, and disopyramide, and pharmaceutically
acceptable salts thereof. Class Ib antiarrhythmics include, but are
not limited to, lidocaine, tocainide, phenytoin, moricizine, and
mexiletine, and pharmaceutically acceptable salts thereof. Class Ic
antiarrhythmics include, but are not limited to, flecainide,
propafenone, and moricizine, and pharmaceutically acceptable salts
thereof. Class II antiarrhythmics include, but are not limited to,
propranolol, acebutolol, soltalol, esmolol, timolol, metoprolol,
and atenolol, and pharmaceutically acceptable salts thereof. Class
III antiarrhythmics include, but are not limited to, amiodarone,
sotalol, bretylium, ibutilide, E-4031 (methanesulfonamide),
vernakalant, and dofetilide, and pharmaceutically acceptable salts
thereof. Class IV antiarrhythmics include, but are not limited to,
bepridil, nitrendipine, amlodipine, isradipine, nifedipine,
nicardipine, verapamil, and diltiazem, and pharmaceutically
acceptable salts thereof. Class V antiarrhythmics include, but are
not limited to, digoxin and adenosine, and pharmaceutically
acceptable salts thereof.
[0221] The present invention also includes derivatives of the above
antiarrhythmic pharmaceutical agents such as solvates, salts,
solvated salts, esters, amides, hydrazides, N-alkyls, and/or
N-amino acyls. The derivatives of the antiarrhythmic pharmaceutical
agents can be pharmaceutically acceptable derivatives. Examples of
ester derivatives include, but are not limited to, methyl esters,
choline esters, and dimethylaminopropyl esters. Examples of amide
derivatives include, but are not limited to, primary, secondary,
and tertiary amides. Examples of hydrazide derivatives include, but
are not limited to, N-methylpiperazine hydrazides. Examples of
N-alkyl derivatives include, but are not limited to,
N',N',N'-trimethyl and N',N'-dimethylaminopropyl succininimidyl
derivatives of antiarrhythmic pharmaceutical agent methyl esters.
Examples of N-aminoacyl derivatives include, but are not limited
to, N-ornithyl-, N-diaminopropionyl-, N-lysil-, N-hexamethyllysil-,
and N-piperdine-propionyl- or
N',N'-methyl-1-piperazine-propionyl-antiarrhythmic pharmaceutical
agent methyl esters.
[0222] The antiarrhythmic pharmaceutical agents may exist as single
stereoisomers, racemates, and/or mixtures of enantiomers, and/or
diastereomers. All such single stereoisomers, racemates, and
mixtures thereof are intended to be within the scope of the present
invention. These various forms of the compounds may be
isolated/prepared by methods known in the art.
[0223] The antiarrhythmic pharmaceutical agents of the present
invention may be prepared in a racemic mixture (e.g., mixture of
isomers) that contains more than 50%, preferably at least 75%, and
more preferably at least 90% of the desired isomer (e.g., 80%
enantiomeric or diastereomeric excess). According to particularly
preferred embodiments, the compounds of the present invention are
prepared in a form that contains at least 95% (90% e.e. or d.e.),
even more preferably at least 97.5% (95% e.e. or d.e.), and most
preferably at least 99% (98% e.e. or d.e.) of the desired isomer.
Compounds identified herein as single stereoisomers are meant to
describe compounds used in a form that contains more than 50% of a
single isomer. By using known techniques, these compounds may be
isolated in any of such forms by slightly varying the method of
purification and/or isolation from the solvents used in the
synthetic preparation of such compounds.
[0224] The pharmaceutical composition according to one or more
embodiments of the invention may comprise one or more
antiarrhythmic pharmaceutical agents and, optionally, one or more
other active ingredients and, optionally, one or more
pharmaceutically acceptable excipients. For example, the
pharmaceutical composition may comprise neat particles of
antiarrhythmic pharmaceutical agent (e.g., particles containing
only the antiarrhythmic pharmaceutical agent), may comprise neat
particles of antiarrhythmic pharmaceutical agent together with
other particles, and/or may comprise particles comprising
antiarrhythmic pharmaceutical agent and one or more active
ingredients and/or one or more pharmaceutically acceptable
excipients.
[0225] Thus, the pharmaceutical composition according to one or
more embodiments of the invention may, if desired, contain a
combination of antiarrhythmic pharmaceutical agent and one or more
additional active agents. Examples of additional active agents
include, but are not limited to, agents that may be delivered
through the lungs.
[0226] Additional active agents may comprise, for example,
hypnotics and sedatives, psychic energizers, tranquilizers,
respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson
agents (dopamine antagnonists), analgesics, anti-inflammatories,
antianxiety drugs (anxiolytics), appetite suppressants,
antimigraine agents, muscle contractants, additional
anti-infectives (antivirals, antifungals, vaccines) antiarthritics,
antimalarials, antiemetics, anepileptics, cytokines, growth
factors, anti-cancer agents, antithrombotic agents,
antihypertensives, cardiovascular drugs, antiarrhythmics,
antioxidants, anti-asthma agents, hormonal agents including
contraceptives, sympathomimetics, diuretics, lipid regulating
agents, antiandrogenic agents, antiparasitics, anticoagulants,
neoplastics, antineoplastics, hypoglycemics, nutritional agents and
supplements, growth supplements, antienteritis agents, vaccines,
antibodies, diagnostic agents, and contrasting agents. The
additional active agent, when administered by inhalation, may act
locally or systemically.
[0227] The additional active agent may fall into one of a number of
structural classes, including but not limited to small molecules,
peptides, polypeptides, proteins, polysaccharides, steroids,
proteins capable of eliciting physiological effects, nucleotides,
oligonucleotides, polynucleotides, fats, electrolytes, and the
like.
[0228] Examples of additional active agents suitable for use in
this invention include but are not limited to one or more of
calcitonin, amphotericin B, erythropoietin (EPO), Factor VIII,
Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony
stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase
inhibitor, elcatonin, granulocyte macrophage colony stimulating
factor (GMCSF), growth hormone, human growth hormone (HGH), growth
hormone releasing hormone (GHRH), heparin, low molecular weight
heparin (LMWH), interferon alpha, interferon beta, interferon
gamma, interleukin-1 receptor, interleukin-2, interleukin-1
receptor antagonist, interleukin-3, interleukin-4, interleukin-6,
luteinizing hormone releasing hormone (LHRH), factor IX, insulin,
pro-insulin, insulin analogues (e.g., mono-acylated insulin as
described in U.S. Pat. No. 5,922,675, which is incorporated herein
by reference in its entirety), amylin, C-peptide, somatostatin,
somatostatin analogs including octreotide, vasopressin, follicle
stimulating hormone (FSH), insulin-like growth factor (IGF),
insulintropin, macrophage colony stimulating factor (M-CSF), nerve
growth factor (NGF), tissue growth factors, keratinocyte growth
factor (KGF), glial growth factor (GGF), tumor necrosis factor
(TNF), endothelial growth factors, parathyroid hormone (PTH),
glucagon-like peptide thymosin alpha 1, IIb/IIa inhibitor, alpha-1
antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors,
bisphosponates, respiratory syncytial virus antibody, cystic
fibrosis transmembrane regulator (CFFR) gene, deoxyribonuclease
(DNase), bactericidal/permeability increasing protein (BPI),
anti-CMV antibody, 13-cis retinoic acid, oleandomycin,
troleandomycin, roxithromycin, clarithromycin, davercin,
azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin,
midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin,
and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin,
levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin,
norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin,
sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin,
tosufloxacin, prulifloxacin, irloxacin, pazufloxacin,
clinafloxacin, and sitafloxacin, teicoplanin, rampolanin,
mideplanin, colistin, daptomycin, gramicidin, colistimethate,
polymixins such as polymixin B, capreomycin, bacitracin, penems;
penicillins including penicllinase-sensitive agents like penicillin
G, penicillin V, penicillinase-resistant agents like methicillin,
oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram
negative microorganism active agents like ampicillin, amoxicillin,
and hetacillin, cillin, and galampicillin; antipseudomonal
penicillins like carbenicillin, ticarcillin, azlocillin,
mezlocillin, and piperacillin; cephalosporins like cefpodoxime,
cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin,
cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole,
cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin,
cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile,
cefepime, cefixime, cefonicid, cefoperazone, cefotetan,
cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams
like aztreonam; and carbapenems such as imipenem, meropenem,
pentamidine isethiouate, lidocaine, metaproterenol sulfate,
beclomethasone diprepionate, triamcinolone acetamide, budesonide
acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn
sodium, ergotamine tartrate and where applicable, analogues,
agonists, antagonists, inhibitors, and pharmaceutically acceptable
salt forms of the above. In reference to peptides and proteins, the
invention is intended to encompass synthetic, native, glycosylated,
unglycosylated, pegylated forms, and biologically active fragments,
derivatives, and analogs thereof.
[0229] Additional active agents for use in the invention can
further include nucleic acids, as bare nucleic acid molecules,
vectors, associated viral particles, plasmid DNA or RNA or other
nucleic acid constructions of a type suitable for transfection or
transformation of cells, e.g., suitable for gene therapy including
antisense. Further, an active agent may comprise live attenuated or
killed viruses suitable for use as vaccines. Other useful drugs
include those listed within the Physician's Desk Reference (most
recent edition), which is incorporated herein by reference in its
entirety.
[0230] When a combination of active agents is used, the agents may
be provided in combination in a single species of pharmaceutical
composition or individually in separate species of pharmaceutical
compositions.
[0231] The amount of antiarrhythmic pharmaceutical agent in the
pharmaceutical composition may vary. The amount of antiarrhythmic
pharmaceutical agent(s) is typically at least about 5 wt %, such as
at least about 10 wt %, at least about 20 wt %, at least about 30
wt %, at least about 40 wt %, at least about 50 wt %, at least
about 60 wt %, at least about 70 wt %, or at least about 80 wt %,
of the total amount of the pharmaceutical composition. The amount
of antiarrhythmic pharmaceutical agent(s) generally varies between
about 0.1 wt % to 100 wt %, such as about 5 wt % to about 95 wt %,
about 10 wt % to about 90 wt %, about 30 wt % to about 80 wt %,
about 40 wt % to about 70 wt %, or about 50 wt % to about 60 wt
%.
[0232] As noted above, the pharmaceutical composition may include
one or more pharmaceutically acceptable excipient. Examples of
pharmaceutically acceptable excipients include, but are not limited
to, lipids, metal ions, surfactants, amino acids, carbohydrates,
buffers, salts, polymers, and the like, and combinations
thereof.
[0233] Examples of lipids include, but are not limited to,
phospholipids, glycolipids, ganglioside GM1, sphingomyelin,
phosphatidic acid, cardiolipin; lipids bearing polymer chains such
as polyethylene glycol, chitin, hyaluronic acid, or
polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and
polysaccharides; fatty acids such as palmitic acid, stearic acid,
and oleic acid; cholesterol, cholesterol esters, and cholesterol
hemisuccinate.
[0234] In one or more embodiments, the phospholipid comprises a
saturated phospholipid, such as one or more phosphatidylcholines.
Exemplary acyl chain lengths are 16:0 and 18:0 (e.g., palmitoyl and
stearoyl). The phospholipid content may be determined by the active
agent activity, the mode of delivery, and other factors.
[0235] Phospholipids from both natural and synthetic sources may be
used in varying amounts. When phospholipids are present, the amount
is typically sufficient to coat the active agent(s) with at least a
single molecular layer of phospholipid. In general, the
phospholipid content ranges from about 5 wt % to about 99.9 wt %,
such as about 20 wt % to about 80 wt %.
[0236] Generally, compatible phospholipids can comprise those that
have a gel to liquid crystal phase transition greater than about
40.degree. C., such as greater than about 60.degree. C., or greater
than about 80.degree. C. The incorporated phospholipids may be
relatively long chain (e.g., C.sub.16-C.sub.22) saturated lipids.
Exemplary phospholipids useful in the present invention include,
but are not limited to, phosphoglycerides such as
dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,
diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine,
diphosphatidyl glycerols, short-chain phosphatidylcholines,
hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid
KG, Ludwigshafen, Germany), long-chain saturated
phosphatidylethanolamines, long-chain saturated
phosphatidylserines, long-chain saturated phosphatidylglycerols,
long-chain saturated phosphatidylinositols, phosphatidic acid,
phosphatidylinositol, and sphingomyelin.
[0237] Examples of metal ions include, but are not limited to,
divalent cations, including calcium, magnesium, zinc, iron, and the
like. For instance, when phospholipids are used, the pharmaceutical
composition may also comprise a polyvalent cation, as disclosed in
WO 01/85136 and WO 01/85137, which are incorporated herein by
reference in their entireties. The polyvalent cation may be present
in an amount effective to increase the melting temperature
(T.sub.m) of the phospholipid such that the pharmaceutical
composition exhibits a T.sub.m which is greater than its storage
temperature (T.sub.m) by at least about 20.degree. C., such as at
least about 40.degree. C. The molar ratio of polyvalent cation to
phospholipid may be at least about 0.05:1, such as about 0.05:1 to
about 2.0:1 or about 0.25:1 to about 1.0:1. An example of the molar
ratio of polyvalent cation:phospholipid is about 0.50:1. When the
polyvalent cation is calcium, it may be in the form of calcium
chloride. Although metal ion, such as calcium, is often included
with phospholipid, none is required.
[0238] As noted above, the pharmaceutical composition may include
one or more surfactants. For instance, one or more surfactants may
be in the liquid phase with one or more being associated with solid
particles or particles of the composition. By "associated with" it
is meant that the pharmaceutical compositions may incorporate,
adsorb, absorb, be coated with, or be formed by the surfactant.
Surfactants include, but are not limited to, fluorinated and
nonfluorinated compounds, such as saturated and unsaturated lipids,
nonionic detergents, nonionic block copolymers, ionic surfactants,
and combinations thereof. It should be emphasized that, in addition
to the aforementioned surfactants, suitable fluorinated surfactants
are compatible with the teachings herein and may be used to provide
the desired preparations.
[0239] Examples of nonionic detergents include, but are not limited
to, sorbitan esters including sorbitan trioleate (Span.TM. 85),
sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate,
polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20)
sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl
polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether,
glycerol esters, and sucrose esters. Other suitable nonionic
detergents can be easily identified using McCutcheon's Emulsifiers
and Detergents (McPublishing Co., Glen Rock, N.J.), which is
incorporated herein by reference in its entirety.
[0240] Examples of block copolymers include, but are not limited
to, diblock and triblock copolymers of polyoxyethylene and
polyoxypropylene, including poloxamer 188 (Pluronic.TM. F-68),
poloxamer 407 (Pluronic.TM. F-127), and poloxamer 338.
[0241] Examples of ionic surfactants include, but are not limited
to, sodium sulfosuccinate, and fatty acid soaps.
[0242] Examples of amino acids include, but are not limited to
hydrophobic amino acids. Use of amino acids as pharmaceutically
acceptable excipients is known in the art as disclosed in WO
95/31479, WO 96/32096, and WO 96/32149, which are incorporated
herein by reference in their entireties.
[0243] Examples of carbohydrates include, but are not limited to,
monosaccharides, disaccharides, and polysaccharides. For example,
monosaccharides such as dextrose (anhydrous and monohydrate),
galactose, mannitol, D-mannose, sorbitol, sorbose and the like;
disaccharides such as lactose, maltose, sucrose, trehalose, and the
like; trisaccharides such as raffinose and the like; and other
carbohydrates such as starches (hydroxyethylstarch), cyclodextrins,
and maltodextrins.
[0244] Examples of buffers include, but are not limited to, tris or
citrate.
[0245] Examples of acids include, but are not limited to,
carboxylic acids.
[0246] Examples of salts include, but are not limited to, sodium
chloride, salts of carboxylic acids, (e.g., sodium citrate, sodium
ascorbate, magnesium gluconate, sodium gluconate, tromethamine
hydrochloride, etc.), ammonium carbonate, ammonium acetate,
ammonium chloride, and the like.
[0247] Examples of organic solids include, but are not limited to,
camphor, and the like.
[0248] The pharmaceutical composition of one or more embodiments of
the present invention may also include a biocompatible, such as
biodegradable polymer, copolymer, or blend or other combination
thereof. In this respect useful polymers comprise polylactides,
polylactide-glycolides, cyclodextrins, polyacrylates,
methylcellulose, carboxymethylcellulose, polyvinyl alcohols,
polyanhydrides, polylactams, polyvinyl pyrrolidones,
polysaccharides (dextrans, starches, chitin, chitosan, etc.),
hyaluronic acid, proteins, (albumin, collagen, gelatin, etc.).
Those skilled in the art will appreciate that, by selecting the
appropriate polymers, the delivery efficiency of the composition
and/or the stability of the dispersions may be tailored to optimize
the effectiveness of the antiarrhythmic pharmaceutical
agent(s).
[0249] For solutions, the compositions may include one or more
osmolality adjuster, such as sodium chloride. For instance, sodium
chloride may be added to solutions to adjust the osmolality of the
solution. In one or more embodiments, an aqueous composition
consists essentially of the antiarrhythmic pharmaceutical agent,
the osmolality adjuster, and water.
[0250] Solutions may also comprise a buffer or a pH adjusting
agent, typically a salt prepared from an organic acid or base.
Representative buffers comprise organic acid salts of citric acid,
lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric
acid, succinic acid, acetic acid, or phthalic acid, Tris,
tromethamine hydrochloride, or phosphate buffers. Thus, the buffers
include citrates, phosphates, phthalates, and lactates.
[0251] Besides the above mentioned pharmaceutically acceptable
excipients, it may be desirable to add other pharmaceutically
acceptable excipients to the pharmaceutical composition to improve
particle rigidity, production yield, emitted dose and deposition,
shelf-life, and patient acceptance. Such optional pharmaceutically
acceptable excipients include, but are not limited to: coloring
agents, taste masking agents, buffers, hygroscopic agents,
antioxidants, and chemical stabilizers. Further, various
pharmaceutically acceptable excipients may be used to provide
structure and form to the particle compositions (e.g., latex
particles). In this regard, it will be appreciated that the
rigidifying components can be removed using a post-production
technique such as selective solvent extraction.
[0252] The pharmaceutical compositions of one or more embodiments
of the present invention can lack taste. In this regard, although
taste masking agents are optionally included within the
composition, the compositions often do not include a taste masking
agent and lack taste even without a taste masking agent.
[0253] The pharmaceutical compositions may also include mixtures of
pharmaceutically acceptable excipients. For instance, mixtures of
carbohydrates and amino acids are within the scope of the present
invention.
[0254] The compositions of one or more embodiments of the present
invention may take various forms, such as solutions, dry powders,
reconstituted powders, suspensions, or dispersions comprising a
non-aqueous phase, such as propellants (e.g., chlorofluorocarbon,
hydrofluoroalkane).
[0255] The solutions of the present invention are typically clear.
In this regard, many of the antiarrhythmic pharmaceutical agents of
the present invention are water soluble.
[0256] In some embodiments, the isotonicity of the solution ranges
from isotonic to physiologic isotonicity. Physiologic isotonicity
is the isotonicity of physiological fluids.
[0257] The compositions typically have a pH ranging from 3.5 to
8.0, such as from 4.0 to 7.5, or 4.5 to 7.0, or 5.0 to 6.5.
[0258] For dry powders, the moisture content is typically less than
about 15 wt %, such as less than about 10 wt %, less than about 5
wt %, less than about 2 wt %, less than about 1 wt %, or less than
about 0.5 wt %. Such powders are described in WO 95/24183, WO
96/32149, WO 99/16419, WO 99/16420, and WO 99/16422, which are
incorporated herein by reference in their entireties.
[0259] In one version, the pharmaceutical composition comprises
antiarrhythmic pharmaceutical agent incorporated into a
phospholipid matrix. The pharmaceutical composition may comprise
phospholipid matrices that incorporate the active agent and that
are in the form of particles that are hollow and/or porous
microstructures, as described in the aforementioned WO 99/16419, WO
99/16420, WO 99/16422, WO 01/85136, and WO 01/85137, which are
incorporated herein by reference in their entireties. The hollow
and/or porous microstructures are useful in delivering the
antiarrhythmic pharmaceutical agent to the lungs because the
density, size, and aerodynamic qualities of the hollow and/or
porous microstructures facilitate transport into the deep lungs
during a user's inhalation. In addition, the phospholipid-based
hollow and/or porous microstructures reduce the attraction forces
between particles, making the pharmaceutical composition easier to
deagglomerate during aerosolization and improving the flow
properties of the pharmaceutical composition making it easier to
process.
[0260] In one version, the pharmaceutical composition is composed
of hollow and/or porous microstructures having a bulk density less
than about 1.0 g/cm.sup.3, less than about 0.5 g/cm.sup.3, less
than about 0.3 g/cm.sup.3, less than about 0.2 g/cm.sup.3, or less
than about 0.1 g/cm.sup.3. By providing low bulk density particles
or particles, the minimum powder mass that can be filled into a
unit dose container is reduced, which eliminates the need for
carrier particles. That is, the relatively low density of the
powders of one or more embodiments of the present invention
provides for the reproducible administration of relatively low dose
pharmaceutical compounds. Moreover, the elimination of carrier
particles will potentially reduce throat deposition and any "gag"
effect or coughing, since large carrier particles, e.g., lactose
particles, will impact the throat and upper airways due to their
size.
[0261] In some aspects, the present invention involves high
rugosity particles. For instance, the particles may have a rugosity
of greater than 2, such as greater than 3, or greater than 4, and
the rugosity may range from 2 to 15, such as 3 to 10.
[0262] In one version, the pharmaceutical composition is in dry
powder form and is contained within a unit dose receptacle which
may be inserted into or near the aerosolization apparatus to
aerosolize the unit dose of the pharmaceutical composition. This
version is useful in that the dry powder form may be stably stored
in its unit dose receptacle for a long period of time. In some
examples, pharmaceutical compositions of one or more embodiments of
the present invention may be stable for at least 2 years. In some
versions, no refrigeration is required to obtain stability. In
other versions, reduced temperatures, e.g., at 2-8.degree. C., may
be used to prolong stable storage. In many versions, the storage
stability allows aerosolization with an external power source.
[0263] It will be appreciated that the pharmaceutical compositions
disclosed herein may comprise a structural matrix that exhibits,
defines or comprises voids, pores, defects, hollows, spaces,
interstitial spaces, apertures, perforations or holes. The absolute
shape (as opposed to the morphology) of the perforated
microstructure is generally not critical and any overall
configuration that provides the desired characteristics is
contemplated as being within the scope of the invention.
Accordingly, some embodiments comprise approximately spherical
shapes. However, collapsed, deformed or fractured particles are
also compatible.
[0264] In one version, the antiarrhythmic pharmaceutical agent is
incorporated in a matrix that forms a discrete particle, and the
pharmaceutical composition comprises a plurality of the discrete
particles. The discrete particles may be sized so that they are
effectively administered and/or so that they are available where
needed. For example, for an aerosolizable pharmaceutical
composition, the particles are of a size that allows the particles
to be aerosolized and delivered to a user's respiratory tract
during the user's inhalation.
[0265] The matrix material may comprise a hydrophobic or a
partially hydrophobic material. For example, the matrix material
may comprise a lipid, such as a phospholipid, and/or a hydrophobic
amino acid, such as leucine or tri-leucine. Examples of
phospholipid matrices are described in WO 99/16419, WO 99/16420, WO
99/16422, WO 01/85136, and WO 01/85137 and in U.S. Pat. Nos.
5,874,064; 5,855,913; 5,985,309; 6,503,480; and 7,473,433, and in
U.S. Published App. No. 20040156792, all of which are incorporated
herein by reference in their entireties. Examples of hydrophobic
amino acid matrices are described in U.S. Pat. Nos. 6,372,258;
6,358,530; and 7,473,433, which are incorporated herein by
reference in their entireties.
[0266] When phospholipids are utilized as the matrix material, the
pharmaceutical composition may also comprise a polyvalent cation,
as disclosed in WO 01/85136 and WO 01/85137, which are incorporated
herein by reference in their entireties.
[0267] According to another embodiment, release kinetics of the
composition containing antiarrhythmic pharmaceutical agent(s) is
controlled. According to one or more embodiments, the compositions
of the present invention provide immediate release of the
antiarrhythmic pharmaceutical agent(s). Alternatively, the
compositions of other embodiments of the present invention may be
provided as non-homogeneous mixtures of active agent incorporated
into a matrix material and unincorporated active agent in order to
provide desirable release rates of antiarrhythmic pharmaceutical
agent According to this embodiment, antiarrhythmic pharmaceutical
agents formulated using the emulsion-based manufacturing process of
one or more embodiments of the present invention have utility in
immediate release applications when administered to the respiratory
tract. Rapid release is facilitated by: (a) the high specific
surface area of the low density porous powders; (b) the small size
of the drug crystals that are incorporated therein, and; (c) the
low surface energy of the particles.
[0268] Alternatively, it may be desirable to engineer the particle
matrix so that extended release of the active agent(s) is effected.
This may be particularly desirable when the active agent(s) is
rapidly cleared from the lungs or when sustained release is
desired. For example, the nature of the phase behavior of
phospholipid molecules is influenced by the nature of their
chemical structure and/or preparation methods in spray-drying
feedstock and drying conditions and other composition components
utilized. In the case of spray-drying of active agent(s)
solubilized within a small unilamellar vesicle (SUV) or
multilamellar vesicle (MLV), the active agent(s) are encapsulated
within multiple bilayers and are released over an extended
time.
[0269] In contrast, spray-drying of a feedstock comprised of
emulsion droplets and dispersed or dissolved active agent(s) in
accordance with the teachings herein leads to a phospholipid matrix
with less long-range order, thereby facilitating rapid release.
While not being bound to any particular theory, it is believed that
this is due in part to the fact that the active agent(s) are never
formally encapsulated in the phospholipid, and the fact that the
phospholipid is initially present on the surface of the emulsion
droplets as a monolayer (not a bilayer as in the case of
liposomes). The spray-dried particles prepared by the
emulsion-based manufacturing process of one or more embodiments of
the present invention often have a high degree of disorder. Also,
the spray-dried particles typically have low surface energies,
where values as low as 20 mN/m have been observed for spray-dried
DSPC particles (determined by inverse gas chromatography). Small
angle X-ray scattering (SAXS) studies conducted with spray-dried
phospholipid particles have also shown a high degree of disorder
for the lipid, with scattering peaks smeared out, and length scales
extending in some instances only beyond a few nearest
neighbors.
[0270] It should be noted that a matrix having a high gel to liquid
crystal phase transition temperature is not sufficient in itself to
achieve sustained release of the active agent(s). Having sufficient
order for the bilayer structures is also important for achieving
sustained release. To facilitate rapid release, an emulsion-system
of high porosity (high surface area), and minimal interaction
between the drug substance and phospholipid may be used. The
pharmaceutical composition formation process may also include the
additions of other composition components (e.g., small polymers
such as Pluronic F-68; carbohydrates, salts, hydrotropes) to break
the bilayer structure are also contemplated.
[0271] To achieve a sustained release, incorporation of the
phospholipid in bilayer form may be used, especially if the active
agent is encapsulated therein. In this case increasing the T.sub.m
of the phospholipid may provide benefit via incorporation of
divalent counterions or cholesterol. As well, increasing the
interaction between the phospholipid and drug substance via the
formation of ion-pairs (negatively charged active+steaylamine,
positively charged active+phosphatidylglycerol) would tend to
decrease the dissolution rate. If the active is amphiphilic,
surfactant/surfactant interactions may also slow active
dissolution.
[0272] The addition of divalent counterions (e.g., calcium or
magnesium ions) to long-chain saturated phosphatidylcholines
results in an interaction between the negatively charged phosphate
portion of the zwitterionic headgroup and the positively charged
metal ion. This results in a displacement of water of hydration and
a condensation of the packing of the phospholipid lipid headgroup
and acyl chains. Further, this results in an increase in the Tm of
the phospholipid. The decrease in headgroup hydration can have
profound effects on the spreading properties of spray-dried
phospholipid particles on contact with water. A fully hydrated
phosphatidylcholine molecule will diffuse very slowly to a
dispersed crystal via molecular diffusion through the water phase.
The process is exceedingly slow because the solubility of the
phospholipid in water is very low (about 10.sup.-10 mol/L for
DPPC). Prior art attempts to overcome this phenomenon include
homogenizing the crystals in the presence of the phospholipid. In
this case, the high degree of shear and radius of curvature of the
homogenized crystals facilitates coating of the phospholipid on the
crystals. In contrast, "dry" phospholipid powders according to one
or more embodiments of this invention can spread rapidly when
contacted with an aqueous phase, thereby coating dispersed crystals
without the need to apply high energies.
[0273] For example, upon reconstitution, the surface tension of
spray-dried DSPC/Ca mixtures at the air/water interface decreases
to equilibrium values (about 20 mN/m) as fast as a measurement can
be taken. In contrast, liposomes of DSPC decrease the surface
tension (about 50 mN/m) very little over a period of hours, and it
is likely that this reduction is due to the presence of hydrolysis
degradation products such as free fatty acids in the phospholipid.
Single-tailed fatty acids can diffuse much more rapidly to the
air/water interface than can the hydrophobic parent compound.
Hence, the addition of calcium ions to phosphatidylcholines can
facilitate the rapid encapsulation of crystalline drugs more
rapidly and with lower applied energy.
[0274] In another version, the pharmaceutical composition comprises
low density particles achieved by co-spray-drying nanocrystals with
a perfluorocarbon-in-water emulsion. The nanocrystals may be formed
by precipitation and may, e.g., range in size from about 45 .mu.m
to about 80 .mu.m. Examples of perfluorocarbons include, but are
not limited to, perfluorohexane, perfluorooctyl bromide,
perfluorooctyl ethane, perfluorodecalin, perfluorobutyl ethane.
[0275] In accordance with the teachings herein the particles may be
provided in a "dry" state. That is, in one or more embodiments, the
particles will possess a moisture content that allows the powder to
remain chemically and physically stable during storage at ambient
or reduced temperature and remain dispersible. In this regard,
there is little or no change in primary particle size, content,
purity, and aerodynamic particle size distribution.
[0276] As such, the moisture content of the particles is typically
less than about 10 wt %, such as less than about 6 wt %, less than
about 3 wt %, or less than about 1 wt %. The moisture content is,
at least in part, dictated by the composition and is controlled by
the process conditions employed, e.g., inlet temperature, feed
concentration, pump rate, and blowing agent type, concentration and
post drying. Reduction in bound water leads to significant
improvements in the dispersibility and flowability of phospholipid
based powders, leading to the potential for highly efficient
delivery of powdered lung surfactants or particle composition
comprising active agent dispersed in the phospholipid. The improved
dispersibility allows simple passive DPI devices to be used to
effectively deliver these powders.
[0277] Yet another version of the pharmaceutical composition
includes particle compositions that may comprise, or may be
partially or completely coated with, charged species that prolong
residence time at the point of contact or enhance penetration
through mucosae. For example, anionic charges are known to favor
mucoadhesion while cationic charges may be used to associate the
formed particle with negatively charged bioactive agents such as
genetic material. The charges may be imparted through the
association or incorporation of polyanionic or polycationic
materials such as polyacrylic acids, polylysine, polylactic acid,
and chitosan.
[0278] In some versions, the pharmaceutical composition comprises
particles having a mass median diameter less than about 20 .mu.m,
such as less than about 10 .mu.m, less than about 7 .mu.m, or less
than about 5 .mu.m. The particles may have a mass median
aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m,
such as about 1.5 .mu.m to about 5 .mu.m, or about 2 .mu.m to about
4 .mu.m. If the particles are too large, a larger percentage of the
particles may not reach the lungs. If the particles are too small,
a larger percentage of the particles may be exhaled.
[0279] Unit doses of the pharmaceutical compositions may be placed
in a container. Examples of containers include, but are not limited
to, syringes, capsules, blow fill seal, blisters, vials, ampoules,
or container closure systems made of metal, polymer (e.g., plastic,
elastomer), glass, or the like. For instance, the vial may be a
colorless Type I borosilicate glass ISO 6R 10 mL vial with a
chlorobutyl rubber siliconized stopper, and rip-off type aluminum
cap with colored plastic cover.
[0280] The container may be inserted into an aerosolization device.
The container may be of a suitable shape, size, and material to
contain the pharmaceutical composition and to provide the
pharmaceutical composition in a usable condition. For example, the
capsule or blister may comprise a wall which comprises a material
that does not adversely react with the pharmaceutical composition.
In addition, the wall may comprise a material that allows the
capsule to be opened to allow the pharmaceutical composition to be
aerosolized. In one version, the wall comprises one or more of
gelatin, hydroxypropyl methylcellulose (HPMC),
polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar,
aluminum foil, or the like. In one version, the capsule may
comprise telescopically adjoining sections, as described for
example in U.S. Pat. No. 4,247,066 which is incorporated herein by
reference in its entirety. The size of the capsule may be selected
to adequately contain the dose of the pharmaceutical composition.
The sizes generally range from size 5 to size 000 with the outer
diameters ranging from about 4.91 mm to 9.97 mm, the heights
ranging from about 11.10 mm to about 26.14 mm, and the volumes
ranging from about 0.13 mL to about 1.37 mL, respectively. Suitable
capsules are available commercially from, for example, Shionogi
Qualicaps Co. in Nara, Japan and Capsugel in Greenwood, S.C. After
filling, a top portion may be placed over the bottom portion to
form a capsule shape and to contain the powder within the capsule,
as described in U.S. Pat. Nos. 4,846,876 and 6,357,490, and in WO
00/07572, which are incorporated herein by reference in their
entireties. After the top portion is placed over the bottom
portion, the capsule can optionally be banded.
[0281] For solutions, the amount of the composition in the unit
dose typically ranges from about 0.5 ml to about 15 ml, such as
about 2 ml to about 15 ml, from about 3 ml to about 10 ml, about 4
ml to about 8 ml, or about 5 ml to about 6 ml.
[0282] The compositions of the present invention may be made by any
of the various methods and techniques known and available to those
skilled in the art.
[0283] For instance, a solution of antiarrhythmic pharmaceutical
agent may be made using the following procedure. Typically,
manufacturing equipment is sterilized before use. A portion of the
final volume, e.g., 70%, of solvent, e.g., water for injection, may
be added into a suitable container. Antiarrhythmic pharmaceutical
agent may then be added. The antiarrhythmic pharmaceutical agent
may be mixed until dissolved. Additional solvent may be added to
make up the final batch volume. The batch may be filtered, e.g.,
through a 0.2 nm filter into a sterilized receiving vessel. Filling
components may be sterilized before use in filling the batch into
vials, e.g., 10 ml vials.
[0284] As an example, the above-noted sterilizing may include the
following. A 5 liter type 1 glass bottle and lid may be placed in
an autoclave bag and sterilized at elevated temperature, e.g.,
121.degree. C. for 15 minutes, using an autoclave. Similarly, vials
may be placed into suitable racks, inserted into an autoclave bag,
and sterilized at elevated temperature, e.g., 121.degree. C. for 15
minutes, using an autoclave. Also similarly, stoppers may be placed
in an autoclave bag and sterilized at elevated temperature, e.g.,
121.degree. C. for 15 minutes, using an autoclave. Before
sterilization, sterilizing filters may be attached to tubing, e.g.,
a 2 mm length of 7 mm.times.13 mm silicone tubing. A filling line
may be prepared by placed in an autoclave bag and sterilized at
elevated temperature, e.g., 121.degree. C. for 15 minutes, using an
autoclave.
[0285] The above-noted filtration may involve filtration into a
laminar flow work area. The receiving bottle and filters may be set
up in the laminar flow work area.
[0286] The above-noted filling may also be conducted under laminar
flow protection. The filling line may be unwrapped and placed into
the receiving bottle. The sterilized vials and stoppers may be
unwrapped under laminar flow protection. Each vial may be filled,
e.g., to a target fill of 5 g, and stoppered. A flip off collar may
be applied to each vial. The sealed vials may be inspected for vial
leakage, correct overseals, and cracks.
[0287] In certain cases, the antiarrhythmic pharmaceutical agent
may be in a solution. In particular examples, the solution is an
aqueous solution. In other examples, the antiarrhythmic
pharmaceutical agent can be present at a concentration from about 1
mg/mL to about 60 mg/mL, such as 1 mg/mL to 5 mg/mL, 1 mg/ml to 10
mg/mL, 1 mg/ml to 15 mg/mL, 1 mg/mL to 20 mg/mL, 1 mg/mL to 25
mg/mL, 1 mg/mL to 30 mg/mL, 1 mg/mL to 35 mg/mL, 1 mg/mL to 40
mg/mL, 1 mg/mL to 45 mg/mL, 1 mg/mL to 50 mg/mL, 1 mg/mL to 55
mg/mL, 5 mg/ml to 10 mg/mL, 5 mg/ml to 15 mg/mL, 5 mg/mL to 20
mg/mL, 5 mg/mL to 25 mg/mL, 5 mg/mL to 30 mg/mL, 5 mg/mL to 35
mg/mL, 5 mg/mL to 40 mg/mL, 5 mg/mL to 45 mg/mL, 5 mg/mL to 50
mg/mL, 5 mg/mL to 55 mg/mL, 5 mg/mL to 60 mg/mL; 10 mg/ml to 15
mg/mL, 10 mg/mL to 20 mg/mL, 10 mg/mL to 25 mg/mL, 10 mg/mL to 30
mg/mL, 10 mg/mL to 35 mg/mL, 10 mg/mL to 40 mg/mL, 10 mg/mL to 45
mg/mL, 10 mg/mL to 50 mg/mL, 10 mg/mL to 55 mg/mL, 10 mg/mL to 60
mg/mL, 15 mg/mL to 20 mg/mL, 15 mg/mL to 25 mg/mL, 15 mg/mL to 30
mg/mL, 15 mg/mL to 35 mg/mL, 15 mg/mL to 40 mg/mL, 15 mg/mL to 45
mg/mL, 15 mg/mL to 50 mg/mL, 15 mg/mL to 55 mg/mL, 15 mg/mL to 60
mg/mL, 20 mg/mL to 25 mg/mL, 20 mg/mL to 30 mg/mL, 20 mg/mL to 35
mg/mL, 20 mg/mL to 40 mg/mL, 20 mg/mL to 45 mg/mL, 20 mg/mL to 50
mg/mL, 20 mg/mL to 55 mg/mL, 20 mg/mL to 60 mg/mL, 25 mg/mL to 30
mg/mL, 25 mg/mL to 35 mg/mL, 25 mg/mL to 40 mg/mL, 25 mg/mL to 45
mg/mL, 25 mg/mL to 50 mg/mL, 25 mg/mL to 55 mg/mL, 25 mg/mL to 60
mg/mL, 30 mg/mL to 35 mg/mL, 30 mg/mL to 40 mg/mL, 30 mg/mL to 45
mg/mL, 30 mg/mL to 50 mg/mL, 30 mg/mL to 55 mg/mL, 30 mg/mL to 60
mg/mL, 35 mg/mL to 40 mg/mL, 35 mg/mL to 45 mg/mL, 35 mg/mL to 50
mg/mL, 35 mg/mL to 55 mg/mL, 35 mg/mL to 60 mg/mL, 40 mg/mL to 45
mg/mL, 40 mg/mL to 50 mg/mL, 40 mg/mL to 55 mg/mL, 40 mg/mL to 60
mg/mL, 45 mg/mL to 50 mg/mL, 45 mg/mL to 55 mg/mL, 45 mg/mL to 60
mg/mL, 50 mg/mL to 55 mg/mL, 50 mg/mL to 60 mg/mL, or 55 mg/mL to
60 mg/mL. In yet other embodiments, the antiarrhythmic
pharmaceutical agent is be present at about 30 mg/mL, 31 mg/mL, 32
mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36 mg/mL, 37 mg/ml, 38 mg/mL,
39 mg/mL, 40 mg/mL, 41 mg/mL, 42 mg/mL, 43 mg/mL, 44 mg/mL, 45
mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49 mg/mL, 50 mg/mL, 51 mg/mL,
52 mg/mL, 53 mg/mL, 54 mg/mL, or 55 mg/mL.
[0288] As another example, an antiarrhythmic may be prepared by
lyophilizing the antiarrhythmic to form a powder for storage. The
powder is then reconstituted prior to use. This technique may be
used when the antiarrhythmic is unstable in solution.
[0289] In some cases, the lyophilized powder can be reconstituted
in a suitable solvent such that the antiarrhythmic pharmaceutical
agent is present at a concentration from about 1 mg/mL to about 60
mg/mL, such as 1 mg/mL to 5 mg/mL, 1 mg/ml to 10 mg/mL, 1 mg/ml to
15 mg/mL, 1 mg/mL to 20 mg/mL, 1 mg/mL to 25 mg/mL, 1 mg/mL to 30
mg/mL, 1 mg/mL to 35 mg/mL, 1 mg/mL to 40 mg/mL, 1 mg/mL to 45
mg/mL, 1 mg/mL to 50 mg/mL, 1 mg/mL to 55 mg/mL, 5 mg/ml to 10
mg/mL, 5 mg/ml to 15 mg/mL, 5 mg/mL to 20 mg/mL, 5 mg/mL to 25
mg/mL, 5 mg/mL to 30 mg/mL, 5 mg/mL to 35 mg/mL, 5 mg/mL to 40
mg/mL, 5 mg/mL to 45 mg/mL, 5 mg/mL to 50 mg/mL, 5 mg/mL to 55
mg/mL, 5 mg/mL to 60 mg/mL; 10 mg/ml to 15 mg/mL, 10 mg/mL to 20
mg/mL, 10 mg/mL to 25 mg/mL, 10 mg/mL to 30 mg/mL, 10 mg/mL to 35
mg/mL, 10 mg/mL to 40 mg/mL, 10 mg/mL to 45 mg/mL, 10 mg/mL to 50
mg/mL, 10 mg/mL to 55 mg/mL, 10 mg/mL to 60 mg/mL, 15 mg/mL to 20
mg/mL, 15 mg/mL to 25 mg/mL, 15 mg/mL to 30 mg/mL, 15 mg/mL to 35
mg/mL, 15 mg/mL to 40 mg/mL, 15 mg/mL to 45 mg/mL, 15 mg/mL to 50
mg/mL, 15 mg/mL to 55 mg/mL, 15 mg/mL to 60 mg/mL, 20 mg/mL to 25
mg/mL, 20 mg/mL to 30 mg/mL, 20 mg/mL to 35 mg/mL, 20 mg/mL to 40
mg/mL, 20 mg/mL to 45 mg/mL, 20 mg/mL to 50 mg/mL, 20 mg/mL to 55
mg/mL, 20 mg/mL to 60 mg/mL, 25 mg/mL to 30 mg/mL, 25 mg/mL to 35
mg/mL, 25 mg/mL to 40 mg/mL, 25 mg/mL to 45 mg/mL, 25 mg/mL to 50
mg/mL, 25 mg/mL to 55 mg/mL, 25 mg/mL to 60 mg/mL, 30 mg/mL to 35
mg/mL, 30 mg/mL to 40 mg/mL, 30 mg/mL to 45 mg/mL, 30 mg/mL to 50
mg/mL, 30 mg/mL to 55 mg/mL, 30 mg/mL to 60 mg/mL, 35 mg/mL to 40
mg/mL, 35 mg/mL to 45 mg/mL, 35 mg/mL to 50 mg/mL, 35 mg/mL to 55
mg/mL, 35 mg/mL to 60 mg/mL, 40 mg/mL to 45 mg/mL, 40 mg/mL to 50
mg/mL, 40 mg/mL to 55 mg/mL, 40 mg/mL to 60 mg/mL, 45 mg/mL to 50
mg/mL, 45 mg/mL to 55 mg/mL, 45 mg/mL to 60 mg/mL, 50 mg/mL to 55
mg/mL, 50 mg/mL to 60 mg/mL, or 55 mg/mL to 60 mg/mL. In yet other
embodiments, after reconstitution of a lyophilized powder the
antiarrhythmic pharmaceutical agent is present at about 30 mg/mL,
31 mg/mL, 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36 mg/mL, 37
mg/ml, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL, 42 mg/mL, 43 mg/mL,
44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49 mg/mL, 50
mg/mL, 51 mg/mL, 52 mg/mL, 53 mg/mL, 54 mg/mL, or 55 mg/mL.
[0290] The solvent for the solution to be lyophilized may comprise
water. The solution may be excipient-free. For instance, the
solution may be cryoprotectant-free.
[0291] In one or more embodiments, a suitable amount (e.g., 120 g
per liter of final solution) of drug substance may be dissolved,
e.g., in about the 75% of the theoretical total amount of water for
injection under nitrogen bubbling. The dissolution time may be
recorded and appearance may be evaluated.
[0292] Then, the dilution to the final volume with WFI may be
carried out. Final volume may be checked. Density, pH, endotoxin,
bioburden, and content by UV may be measured both before and after
sterile filtration.
[0293] The solution may be filtered before lyophilizing. For
instance, a double 0.22 .mu.m filtration may be performed before
filling. The filters may be tested for integrity and bubble point
before and after the filtration.
[0294] Pre-washed and autoclaved vials may be aseptically filled
using an automatic filling line to a target of 5 ml per vial and
then partially stoppered. In process check for fill volumes may be
done by checking the fill weight every 15 minutes.
[0295] The lyophilizing is generally conducted within about 72
hours, such as within about 8 hours, or within about 4 hours, of
the dissolving.
[0296] In one or more embodiments, the lyophilizing comprises
freezing the solution to form a frozen solution. The frozen
solution is typically held at an initial temperature ranging from
about -40.degree. C. to about -50.degree. C., such as about
-45.degree. C. During the initial temperature period, the pressure
around the frozen solution is typically atmospheric pressure. The
initial temperature period typically ranges from about 1 hour to
about 4 hours, such about 1.5 hours to about 3 hours, or about 2
hours.
[0297] The lyophilizing may further comprise raising a temperature
of the frozen solution to a first predetermined temperature, which
may range from about 10.degree. C. to about 20.degree. C., such as
about 15.degree. C. The time for the heat ramp from the initial
temperature to the first predetermined temperature generally ranges
from about 6 hours to about 10 hours, such as about 7 hours to
about 9 hours.
[0298] During the first predetermined temperature period, the
pressure around the solution typically ranges from about 100
.mu.bar to about 250 .mu.bar, such as about 150 .mu.bar to about
225 .mu.bar. The solution may be held at the first predetermined
temperature for a period ranging from about 20 hours to about 30
hours, such as from about 24 hours.
[0299] The lyophilizing may still further comprise raising a
temperature of the solution to a second predetermined temperature,
which may range from about 25.degree. C. to about 35.degree. C.,
such as about 30.degree. C. During the second predetermined
temperature period, the pressure around the frozen solution
typically ranges from about 100 .mu.bar to about 250 .mu.bar, such
as about 150 .mu.bar to about 225 .mu.bar. The solution may be held
at the second predetermined temperature for a period ranging from
about 10 hours to about 20 hours.
[0300] In view of the above, the lyophilization cycle may comprise
a freezing ramp, e.g., from 20.degree. C. to -45.degree. C. in 65
minutes, followed by a freeze soak, e.g., at -45.degree. C. for 2
hours. Primary drying may be accomplished with a heating ramp,
e.g., from -45.degree. C. to 15.degree. C. in 8 hours, followed by
a temperature hold, e.g., at 15.degree. C. for 24 hours at a
pressure of 200 .mu.bar. Secondary drying may be accomplished with
a heating ramp, e.g., from 15.degree. C. to 30.degree. C. in 15
minutes, followed by a temperature hold at 30.degree. C. for 15
hours at a pressure of 200 .mu.bar. At the end of the
lyophilization cycle, the vacuum may be broken with sterile
nitrogen, and the vials may be automatically stoppered.
[0301] The water content of the lyophilized powder is typically
less than about 7 wt %, such as less than about 5 wt %, less than
about 4 wt %, less than about 3 wt %, less than about 2 wt %, or
less than about 1 wt %.
[0302] The powder is capable of being reconstituted with water at
25.degree. C. and 1.0 atmosphere and with manual agitation, in less
than about 60 seconds, such as less than about 30 seconds, less
than about 15 seconds, or less than about 10 seconds.
[0303] The powder typically has a large specific surface area that
facilitates reconstitution. The specific surface area typically
ranges from about 5 m.sup.2/g to about 20 m.sup.2/g, such as about
8 m.sup.2/g to 15 m.sup.2/g, or about 10 m.sup.2/g to 12
m.sup.2/g.
[0304] Upon reconstitution with water, the antiarrhythmic
pharmaceutical agent solution typically has a pH that ranges from
about 2.5 to about 7, such as about 3 to about 6.
[0305] For dry powders, the composition may be formed by spray
drying, lyophilization, milling (e.g., wet milling, dry milling),
and the like.
[0306] In spray drying, the preparation to be spray dried or
feedstock can be any solution, coarse suspension, slurry, colloidal
dispersion, or paste that may be atomized using the selected spray
drying apparatus. In the case of insoluble agents, the feedstock
may comprise a suspension as described above. Alternatively, a
dilute solution and/or one or more solvents may be utilized in the
feedstock. In one or more embodiments, the feed stock will comprise
a colloidal system such as an emulsion, reverse emulsion
microemulsion, multiple emulsion, particle dispersion, or
slurry.
[0307] In one version, the antiarrhythmic pharmaceutical agent and
the matrix material are added to an aqueous feedstock to form a
feedstock solution, suspension, or emulsion. The feedstock is then
spray dried to produce dried particles comprising the matrix
material and the antiarrhythmic pharmaceutical agent. Suitable
spray-drying processes are known in the art, for example as
disclosed in WO 99/16419 and U.S. Pat. Nos. 6,077,543; 6,051,256;
6,001,336; 5,985,248; and 5,976,574, which are incorporated herein
by reference in their entireties.
[0308] Whatever components are selected, the first step in particle
production typically comprises feedstock preparation. If a
phospholipids-based particle is intended to act as a carrier for
the antiarrhythmic pharmaceutical agent, the selected active
agent(s) may be introduced into a liquid, such as water, to produce
a concentrated suspension. The concentration of antiarrhythmic
pharmaceutical agent and optional active agents typically depends
on the amount of agent required in the final powder and the
performance of the delivery device employed (e.g., the fine
particle dose for a metered dose inhaler (MDI) or a dry powder
inhaler (DPI)).
[0309] Any additional active agent(s) may be incorporated in a
single feedstock preparation and spray dried to provide a single
pharmaceutical composition species comprising a plurality of active
agents. Conversely, individual active agents could be added to
separate stocks and spray dried separately to provide a plurality
of pharmaceutical composition species with different compositions.
These individual species could be added to the suspension medium or
dry powder dispensing compartment in any desired proportion and
placed in the aerosol delivery system as described below.
[0310] Polyvalent cation may be combined with the antiarrhythmic
pharmaceutical agent suspension, combined with the phospholipid
emulsion, or combined with an oil-in-water emulsion formed in a
separate vessel. The antiarrhythmic pharmaceutical agent may also
be dispersed directly in the emulsion.
[0311] For example, polyvalent cation and phospholipid may be
homogenized in hot distilled water (e.g., 70.degree. C.) using a
suitable high shear mechanical mixer (e.g., Ultra-Turrax model T-25
mixer) at 8000 rpm for 2 to 5 min. Typically, 5 to 25 g of
fluorocarbon is added dropwise to the dispersed surfactant solution
while mixing. The resulting polyvalent cation-containing
perfluorocarbon in water emulsion may then be processed using a
high pressure homogenizer to reduce the particle size. Typically,
the emulsion is processed for five discrete passes at 12,000 to
18,000 PSI and kept at about 50.degree. C. to about 80.degree.
C.
[0312] When the polyvalent cation is combined with an oil-in-water
emulsion, the dispersion stability and dispersibility of the spray
dried pharmaceutical composition can be improved by using a blowing
agent, as described in WO 99/16419, which is incorporated herein by
reference in its entirety. This process forms an emulsion,
optionally stabilized by an incorporated surfactant, typically
comprising submicron droplets of water immiscible blowing agent
dispersed in an aqueous continuous phase. The blowing agent may be
a fluorinated compound (e.g., perfluorohexane, perfluorooctyl
bromide, perfluorooctyl ethane, perfluorodecalin, perfluorobutyl
ethane) which vaporizes during the spray-drying process, leaving
behind generally hollow, porous aerodynamically light particles.
Other suitable liquid blowing agents include nonfluorinated oils,
chloroform, Freon.RTM. fluorocarbons, ethyl acetate, alcohols,
hydrocarbons, nitrogen, and carbon dioxide gases. The blowing agent
may be emulsified with a phospholipid.
[0313] Although the pharmaceutical compositions may be formed using
a blowing agent as described above, it will be appreciated that, in
some instances, no additional blowing agent is required and an
aqueous dispersion of the antiarrhythmic pharmaceutical agent
and/or pharmaceutically acceptable excipients and surfactant(s) are
spray dried directly. In such cases, the pharmaceutical composition
may possess certain physicochemical properties (e.g., high
crystallinity, elevated melting temperature, surface activity,
etc.) that make it particularly suitable for use in such
techniques.
[0314] As needed, cosurfactants such as poloxamer 188 or span 80
may be dispersed into this annex solution. Additionally,
pharmaceutically acceptable excipients such as sugars and starches
can also be added.
[0315] The feedstock(s) may then be fed into a spray dryer.
Typically, the feedstock is sprayed into a current of warm filtered
air that evaporates the solvent and conveys the dried product to a
collector. The spent air is then exhausted with the solvent.
Commercial spray dryers manufactured by Buchi Ltd. or Niro Corp.
may be modified for use to produce the pharmaceutical composition.
Examples of spray drying methods and systems suitable for making
the dry powders of one or more embodiments of the present invention
are disclosed in U.S. Pat. Nos. 6,077,543; 6,051,256; 6,001,336;
5,985,248; and 5,976,574, which are incorporated herein by
reference in their entireties.
[0316] Operating conditions of the spray dryer such as inlet and
outlet temperature, feed rate, atomization pressure, flow rate of
the drying air, and nozzle configuration can be adjusted in order
to produce the required particle size, and production yield of the
resulting dry particles. The selection of appropriate apparatus and
processing conditions are within the purview of a skilled artisan
in view of the teachings herein and may be accomplished without
undue experimentation. Exemplary settings are as follows: an air
inlet temperature between about 60.degree. C. and about 170.degree.
C.; an air outlet between about 40.degree. C. to about 120.degree.
C.; a feed rate between about 3 mL/min to about 15 mL/min; an
aspiration air flow of about 300 L/min; and an atomization air flow
rate between about 25/min and about 50 L/min. The settings will, of
course, vary depending on the type of equipment used. In any event,
the use of these and similar methods allow formation of
aerodynamically light particles with diameters appropriate for
aerosol deposition into the lung.
[0317] Hollow and/or porous microstructures may be formed by spray
drying, as disclosed in WO 99/16419, which is incorporated herein
by reference. The spray-drying process can result in the formation
of a pharmaceutical composition comprising particles having a
relatively thin porous wall defining a large internal void. The
spray-drying process is also often advantageous over other
processes in that the particles formed are less likely to rupture
during processing or during deagglomeration.
[0318] Pharmaceutical compositions useful in one or more
embodiments of the present invention may alternatively be formed by
lyophilization. Lyophilization is a freeze-drying process in which
water is sublimed from the composition after it is frozen. The
lyophilization process is often used because biologics and
pharmaceuticals that are relatively unstable in an aqueous solution
may be dried without exposure to elevated temperatures, and then
stored in a dry state where there are fewer stability problems.
With respect to one or more embodiments of the instant invention,
such techniques are particularly compatible with the incorporation
of peptides, proteins, genetic material and other natural and
synthetic macromolecules in pharmaceutical compositions without
compromising physiological activity. Lyophilized cake containing a
fine foam-like structure can be micronized using techniques known
in the art to provide particles of the desired size.
[0319] The compositions of one or more embodiments of the present
invention may be administered by inhalation.
[0320] Moreover, the doses of composition that are inhaled are
typically much less than those administered by other routes and
required to obtain similar effects, due to the efficient targeting
of the inhaled composition to the heart.
[0321] In one or more embodiments of the invention, a
pharmaceutical composition comprising antiarrhythmic pharmaceutical
agent is administered to the lungs of a patient in need thereof.
For example, the patient may have been diagnosed with an
arrhythmia. Examples of arrhythmias include, but are not limited
to, tachycardia, supraventricular tachycardia (SVT), paroxysmal
supraventricular tachycardia (PSVT), atrial fibrillation (AF),
paroxysmal atrial fibrillation (PAF), persistent atrial
fibrillation, permanent atrial fibrillation, atrial flutter,
paroxysmal atrial flutter, and lone atrial fibrillation.
[0322] Thus, the pharmaceutical compositions of one or more
embodiments of the present invention can be used to treat and/or
provide prophylaxis for a broad range of patients. A suitable
patient for, receiving treatment and/or prophylaxis as described
herein is any mammalian patient in need thereof, preferably such
mammal is a human. Examples of patients include, but are not
limited to, pediatric patients, adult patients, and geriatric
patients. In some embodiments, the composition is intended only as
a treatment for rapid resolution of symptoms and restoration of
normal sinus rhythm, and is not taken as a preventative, e.g., when
the patient is well, there is no need for drug--this can increase
the benefit-risk ratio of the therapy and overall safety due to the
sporadic or intermittent dosing, and the focus on reducing
disabling symptoms and restoring sinus rhythm only when needed.
[0323] The dosage necessary and the frequency of dosing of the
antiarrhythmic pharmaceutical agent depend on the composition and
concentration of the antiarrhythmic pharmaceutical agent within the
composition. In some cases, the dose is less than about 10%, 20%,
30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of its normal intravenous
dose. In some cases, the dose is about 5% to about 10%, is about
10% to about 20%, is about 20% to about 30%, is about 30% to about
40%, is about 50% to about 60%, is about 60% to about 70%, is about
70% to about 80%, is about 80% to about 90%, or is about 90% to
about 95% of the intravenous dose. The pulmonary dose is similar to
intracardiac doses. Inhalation avoids dilution of drug in the body
as compared to intravenous or oral dosing.
[0324] In some cases, the effective dosage administered
intravenously can be calculated based on the weight of the subject.
For example, in some cases, the effective dose administered
intravenously to a subject weighing 70 kg is 2 mg/kg (i.e., 140
mg).
[0325] Inhalation also avoids metabolism, such as hepatic
metabolism. For instance, calcium channel blockers, such as
diltiazem, undergo significant hepatic metabolism when taken
orally. Inhalation allows rapid delivery of the parent diltiazem
compound to the heart as a bolus. Surprisingly, administration by
inhalation of diltiazem via the inhalation route according to the
present invention converted atrial fibrillation to normal sinus
rhythm and reduced heart rate. Thus, administration by inhalation
of diltiazem can be useful for treating both atrial fibrillation
and supraventricular tachycardia (SVT). In contrast, administration
by IV of diltiazem is typically only used for converting SVT to
normal sinus rhythm and in atrial fibrillation to reduce heart rate
(not for converting to normal sinus rhythm).
[0326] Inhalation also avoids red blood cell metabolism. For
instance, the reduced dilution and short route associated with
inhalation reduces red blood cell metabolism of esmolol.
[0327] Inhalation may also avoid reduced blood pressure and
fainting. For instance, IV administration of beta blockers, such as
esmolol, may reduce mean arterial blood pressure (MAP). Inhalation
allows rapid delivery of esmolol without reducing MAP. As a result,
inhalation of beta blockers may result in an MAP of 10 mm Hg to 20
mm Hg greater than the MAP resulting from IV administration of the
same beta blocker.
[0328] With inhaled cardiotherapy the drug is directed to the heart
from the lungs as a bolus. So, the heart sees a high concentration.
The drug is rapidly diluted as it passes through the heart, but the
exposure time is sufficient for the desired pharmacological action.
Once the drug passes through the heart, the concentration of the
drug in the systemic circulation (e.g., peripheral venous blood) is
below the therapeutic concentration and is considered ineffective.
The therapeutic window is the range of dosage of a drug or of its
concentration in a bodily system that provides safe effective
therapy. Anything below the minimum amount is sub-therapeutic and
hence ineffective in that concentration. In view of the dilution,
unwanted side effects are minimized.
[0329] In one version, the antiarrhythmic may be administered
daily. In this version, the daily dosage of antiarrhythmic
pharmaceutical agent ranges from about 0.1 mg to about 600 mg, such
as about 0.5 mg to about 500 mg, about 1 mg to about 400 mg, about
2 mg to about 300 mg, and about 3 mg to about 200 mg. The amount of
antiarrhythmic pharmaceutical agent for the treatment of arrhythmia
can be at least about 0.1 mg, such as at least about 0.1, 0.2, 0.3,
0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5,
5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80,
90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, or
500 mg. The amount of antiarrhythmic pharmaceutical agent for the
treatment of arrhythmia can range about 0.01-500 mg, such as about
0.1-500, 0.1-450, 0.1-400, 0.1-350, 0.1-300, 0.1-250, 0.1-200,
0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10,
0.1-5, 0.1-1.0, 0.1-0.5, 1-500, 1-450, 1-400, 1-350, 1-300, 1-250,
1-200, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30, 1-10, 1-5,
5-500, 5-450, 5-400, 5-350, 5-300, 5-250, 5-200, 5-150, 5-130,
5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-500, 10-450, 10-400,
10-350, 10-300, 10-250, 10-200, 10-150, 10-130, 10-110, 10-90,
10-70, 10-50, 10-30, 30-500, 30-450, 30-400, 30-350, 30-300,
30-250, 30-200, 30-150, 30-130, 30-110, 30-90, 30-70, 30-50,
50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150,
50-130, 50-110, 50-90, 50-70, 70-500, 70-450, 70-400, 70-350,
70-300, 70-250, 70-200, 70-150, 70-130, 70-110, 70-90, 90-500,
90-450, 90-400, 90-350, 90-300, 90-250, 90-200, 90-150, 90-130,
90-110, 110-500, 110-450, 110-400, 110-350, 110-300, 110-250,
110-200, 110-150, 110-130, 130-500, 130-450, 130-400, 130-350,
130-300, 130-250, 130-200, 130-150, 150-500, 150-450, 150-400,
150-350, 150-300, 150-250, 150-200, 200-500, 200-450, 200-400,
200-350, 200-300, 200-250, 250-500, 250-450, 250-400, 250-350,
250-300, 300-500, 300-450, 300-400, 300-350, 350-500, 350-450,
350-400, 400-500, 400-450, or 450-500 mg. For example, the amount
of antiarrhythmic pharmaceutical agent for the treatment of
arrhythmia can range about from 0.1 to about 5 mg.
[0330] The dose may be administered during a single inhalation or
may be administered during several inhalations. The fluctuations of
antiarrhythmic pharmaceutical agent concentration can be reduced by
administering the pharmaceutical composition more often or may be
increased by administering the pharmaceutical composition less
often. Therefore, the pharmaceutical composition of one or more
embodiments of the present invention may be administered from about
four times daily to about once a month, such as about once daily to
about once every two weeks, about once every two days to about once
a week, and about once per week. The pharmaceutical composition can
also be administered to the patient on an as-needed basis.
[0331] For treating a patient suffering from an arrhythmia, the
amount per dose of antiarrhythmic pharmaceutical agent administered
may be an amount that is effective to treat the arrhythmia. The
amount of antiarrhythmic pharmaceutical agent for the treatment of
arrhythmia will generally be higher than that used for prevention,
and will typically range from about 0.001 mg/kg to 6 mg/kg, such as
from about 0.002 mg/kg to about 5 mg/kg, or from about 0.005 mg/kg
to about 4 mg/kg. In one exemplary treatment regimen, the
formulation in accordance with one or more embodiments of the
invention may be administered about 1 to about 4 times daily, such
as from about 2 to about 3 times daily. Generally, the dose of
antiarrhythmic pharmaceutical agent delivered to a patient will
range from about 0.1 mg to about 600 mg, such as from about 0.2 mg
to 500 mg daily, depending on the condition being treated, the age
and weight of the patient, and the like.
[0332] In some cases, the amount of antiarrhythmic pharmaceutical
agent for the treatment of arrhythmia can be at least about 0.001
mg/kg, such as at least about 0.001 mg/kg, 0.002 mg/kg, 0.003
mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.04
mg/kg, 0.06 mg/kg, 0.08 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4
mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1
mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg,
4.5 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg,
15 mg/kg, or 20 mg/kg. The amount of antiarrhythmic pharmaceutical
agent for the treatment of arrhythmia can range from about 0.001
mg/kg to 20 mg/kg, such as from about 0.001 mg/kg to about 0.01
mg/kg, from about 0.01 mg/kg to about 0.05 mg/kg, from about 0.05
mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.2 mg/kg,
from about 0.5 mg/kg to from about 0.1 mg/kg to about 1 mg/kg, from
about 0.1 mg/kg to about 2 mg/kg, from about 0.1 mg/kg to about 3
mg/kg, from about 0.3 mg/kg to about 1 mg/kg, from about 0.3 mg/kg
to about 2 mg/kg, from about 0.3 mg/kg to about 3 mg/kg, from about
0.5 mg/kg to about 1 mg/kg, from about 0.5 mg/kg to about 2 mg/kg,
from about 0.5 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to
about 6 mg/kg, from about 0.7 mg/kg to about 1 mg/kg, from about
0.7 mg/kg to about 2 mg/kg, from about 0.7 mg/kg to about 4 mg/kg,
from about 0.7 mg/kg to about 6 mg/kg, from about 1 mg/kg to about
2 mg/kg, from about 1 mg/kg to about 4 mg/kg, from about 1 mg/kg to
about 6 mg/kg, from about 1 mg/kg to about 8 mg/kg, from about 1
mg/kg to about 10 mg/kg, from about 1 mg/kg to about 15 mg/kg, from
about 1 mg/kg to about 20 mg/kg, from about 2 mg/kg to about 3
mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 2 mg/kg to
about 6 mg/kg, from about 2 mg/kg to about 8 mg/kg, from about 2
mg/kg to about 10 mg/kg, from about 2 mg/kg to about 15 mg/kg, from
about 2 mg/kg to about 20 mg/kg, from about 3 mg/kg to about 4
mg/kg, from about 3 mg/kg to about 5 mg/kg, from about 3 mg/kg to
about 6 mg/kg, from about 3 mg/kg to about 8 mg/kg, from about 3
mg/kg to about 10 mg/kg, from about 3 mg/kg to about 15 mg/kg, from
about 3 mg/kg to about 20 mg/kg, from about 4 mg/kg to about 5
mg/kg, from about 4 mg/kg to about 6 mg/kg, from about 4 mg/kg to
about 8 mg/kg, from about 4 mg/kg to about 10 mg/kg, from about 4
mg/kg to about 15 mg/kg, from about 4 mg/kg to about 20 mg/kg, from
about 6 mg/kg to about 8 mg/kg, from about 6 mg/kg to about 10
mg/kg, from about 6 mg/kg to about 15 mg/kg, from about 6 mg/kg to
about 20 mg/kg, from about 8 mg/kg to about 10 mg/kg, from about 8
mg/kg to about 15 mg/kg, from about 8 mg/kg to about 20 mg/kg, from
about 10 mg/kg to about 15 mg/kg, from about 10 mg/kg to about 20
mg/kg, or from about 15 mg/kg to about 20 mg/kg.
[0333] For instance, the present invention may involve a follow-up
inhalation if no cardioversion occurs after an initial inhalation.
Typically, if no cardioversion occurs within 30 minutes of the
initial inhalation, the follow-up dosage is higher or the same as
the initial dosage.
[0334] The dosing may be guided by how the patient feels. Also or
alternatively, dosing may be guided by using a portable/mobile ECG
device. For instance, the dosing may be guided by using a Holter
monitor.
[0335] In another version, the pharmaceutical composition is
administered prophylactically to a patient who is likely to develop
an arrhythmia. For example, a patient who has a history of
arrhythmias can be prophylactically treated with a pharmaceutical
composition comprising antiarrhythmic pharmaceutical agent to
reduce the likelihood of developing an arrhythmia.
[0336] The pharmaceutical composition may be administered to a
patient in any regimen which is effective to prevent an arrhythmia.
Illustrative prophylactic regimes include administering an
antiarrhythmic pharmaceutical agent as described herein 1 to 21
times per week.
[0337] While not wishing to be bound by theory, by providing the
antiarrhythmic pharmaceutical agent in accordance with one or more
embodiments of the invention, the systemic exposure of the
antiarrhythmic pharmaceutical agent can be reduced by avoiding
initial dilution. As noted above, the antiarrhythmic pharmaceutical
agent undergoes dilution as and after it passes through the heart.
Thus, the administration via inhalation of antiarrhythmic
pharmaceutical agent is believed to be safer than intravenous
delivery.
[0338] In another aspect, a method of administering comprises
administering to free breathing patients by way of an aerosol
generator device and/or system for administration of aerosolized
medicaments such as those disclosed in U.S. Published Application
Nos. 20050235987, 20050211253, 20050211245, 20040035413, and
20040011358, the disclosures of which are incorporated herein by
reference in their entireties.
[0339] In one version, the pharmaceutical composition may be
delivered to the lungs of a patient in the form of a dry powder.
Accordingly, the pharmaceutical composition comprises a dry powder
that may be effectively delivered to the deep lungs or to another
target site. This pharmaceutical composition is in the form of a
dry powder comprising particles having a size selected to permit
penetration into the alveoli of the lungs. In one version, the
pharmaceutical composition may be delivered by extruding a liquid
through micron or submicron-sized holes with subsequent Rayleigh
break-up into fine droplets.
[0340] In some instances, it is desirable to deliver a unit dose,
such as doses of 0.1 mg or 100 mg or greater of an antiarrhythmic
pharmaceutical agent to the lung in a single inhalation. The above
described phospholipid hollow and/or porous dry powder particles
allow for doses of about 5 mg or greater, often greater than about
10 mg, sometimes greater than about 15 mg, sometimes greater than
about 20 mg, sometimes greater than about 25 mg, and sometimes
greater than about 30 mg, to be delivered in a single inhalation
and in an advantageous manner. Alternatively, a dosage may be
delivered over two or more inhalations, such as 1 to 6, 1 to 5, or
1 to 4, inhalations. For example, a 10 mg dosage may be delivered
by providing two unit doses of 5 mg each, and the two unit doses
may be separately inhaled. In certain embodiments, the overall dose
of the antiarrhythmic pharmaceutical agent ranges from 0.1 mg to
200 mg, such as 0.5 mg to 150 mg, or 1 mg to 100 mg.
[0341] In some cases, a dosage may be delivered over two or more
inhalations, such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, 75, 80, 85, 90, 95 or 100 inhalations. A dosage may also be
delivered over 1 to 100 inhalations, such as 1-3, 1-4, 1-5, 1-6,
1-10, 1-20, 1-50, 1-80, 1-100, 2-5, 2-6, 2-10, 2-20, 2-50, 2-100,
5-10, 5-20, 5-50, 5-100, 10-20, 10-50, 10-100, 20-50, 20-100, or
50-100 inhalations. For example, a 10 mg dosage may be delivered by
providing two unit doses of 5 mg each, and the two unit doses may
be separately inhaled. In certain embodiments, the overall dose of
the antiarrhythmic pharmaceutical agent ranges from about 0.01-500
mg, such as about 0.1-500, 0.1-450, 0.1-400, 0.1-350, 0.1-300,
0.1-250, 0.1-200, 0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70,
0.1-50, 0.1-30, 0.1-10, 0.1-5, 0.1-1.0, 0.1-0.5, 1-500, 1-450,
1-400, 1-350, 1-300, 1-250, 1-200, 1-150, 1-130, 1-110, 1-90, 1-70,
1-50, 1-30, 1-10, 1-5, 5-500, 5-450, 5-400, 5-350, 5-300, 5-250,
5-200, 5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-500,
10-450, 10-400, 10-350, 10-300, 10-250, 10-200, 10-150, 10-130,
10-110, 10-90, 10-70, 10-50, 10-30, 30-500, 30-450, 30-400, 30-350,
30-300, 30-250, 30-200, 30-150, 30-130, 30-110, 30-90, 30-70,
30-50, 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200,
50-150, 50-130, 50-110, 50-90, 50-70, 70-500, 70-450, 70-400,
70-350, 70-300, 70-250, 70-200, 70-150, 70-130, 70-110, 70-90,
90-500, 90-450, 90-400, 90-350, 90-300, 90-250, 90-200, 90-150,
90-130, 90-110, 110-500, 110-450, 110-400, 110-350, 110-300,
110-250, 110-200, 110-150, 110-130, 130-500, 130-450, 130-400,
130-350, 130-300, 130-250, 130-200, 130-150, 150-500, 150-450,
150-400, 150-350, 150-300, 150-250, 150-200, 200-500, 200-450,
200-400, 200-350, 200-300, 200-250, 250-500, 250-450, 250-400,
250-350, 250-300, 300-500, 300-450, 300-400, 300-350, 350-500,
350-450, 350-400, 400-500, 400-450, or 450-500 mg. For example, the
amount of antiarrhythmic pharmaceutical agent for the treatment of
arrhythmia can range about from 0.1 to about 5 mg. In some
instances the antiarrhythmic agent can be administered as-needed
titrating the dosage to effect.
[0342] The time for dosing is typically short. For nebulizers the
dosing time usually ranges from 1 minute to 20 minutes, such as
from 2 minutes to 15 minutes, or from 3 minutes to 10 minutes.
Regarding dry powders, for a single capsule, the total dosing time
is normally less than about 1 minute. Thus, the time for dosing may
be less than about 5 min, such as less than about 4 min, less than
about 3 min, less than about 2 min, or less than about 1 min.
[0343] In certain embodiments, the present invention is directed to
a method of diagnosis by a health care provider followed by
treatment of atrial arrhythmia. In certain embodiments, the present
invention is directed to a method of self-diagnosing and treating
atrial arrhythmia. The method comprises diagnosing or
self-diagnosing atrial arrhythmia by detecting at least one of
shortness of breath, heart palpitations, and above normal heart
rate. The method also comprises self-administering by inhalation an
effective amount of at least one antiarrhythmic pharmaceutical
agent within two hours, such as within one hour, 30 minutes, or
within 15 minutes, of the self-diagnosing.
[0344] In certain embodiments, the patient can self-titrate. For
example, the patient can self-administer, e.g., by using a
nebulizer, until disabling symptoms disappear. In some cases, the
self-administering continues until the patient no longer feels
heart palpitations, or until the patient detects the restoration of
normal sinus rhythm using a portable/mobile ECG device (which can
be worn by the patient, such as a watch; or otherwise carried by
the patient, such as an over the skin patch or an implantable
device connected to a smart phone or watch).
[0345] The time for onset of action is also typically short. For
instance, the patient may have normal sinus rhythm within 20
minutes of initiating the administering, such as within 15 minutes,
within 10 minutes, or within 5 minutes of initiating the
administering. The rapid onset of action is advantageous because
the longer a patient has had arrhythmia, the longer it typically
takes to convert the patient to normal sinus rhythm.
[0346] In some embodiments, the method of the present invention
allows the patient to avoid other therapies, such as ablation
and/or electrical cardioversion. In other embodiments, the method
of the present invention is used in combination with other
therapies, such as before or after electrical cardioversion and/or
ablation therapy.
[0347] The dispersions or powder pharmaceutical compositions may be
administered using an aerosolization device. The aerosolization
device may be a nebulizer, a metered dose inhaler, a liquid dose
instillation device, or a dry powder inhaler. The aerosolization
device may comprise the extrusion of the pharmaceutical preparation
through micron or submicron-sized holes with subsequent Rayleigh
break-up into fine droplets. The pharmaceutical composition may be
delivered by a nebulizer as described in WO 99/16420, by a metered
dose inhaler as described in WO 99/16422, by a liquid dose
instillation apparatus as described in WO 99/16421, and by a dry
powder inhaler as described in U.S. Published Application Nos.
20020017295 and 20040105820, WO 99/16419, WO 02/83220, and U.S.
Pat. No. 6,546,929, which are incorporated herein by reference in
their entireties. As such, an inhaler may comprise a canister
containing the particles or particles and propellant, and wherein
the inhaler comprises a metering valve in communication with an
interior of the canister. The propellant may be a
hydrofluoroalkane.
[0348] The formulations of the present invention may be
administered with nebulizers, such as that disclosed in PCT WO
99/16420, the disclosure of which is hereby incorporated in its
entirety by reference, in order to provide an aerosolized
medicament that may be administered to the pulmonary air passages
of a patient in need thereof. Nebulizers are known in the art and
could easily be employed for administration of the claimed
formulations without undue experimentation. Breath activated or
breath-actuated nebulizers, as well as those comprising other types
of improvements which have been, or will be, developed are also
compatible with the formulations of the present invention and are
contemplated as being within the scope thereof.
[0349] In some cases, the nebulizer is a breath activated or
breath-actuated nebulizer. In some cases, the nebulizer is a
hand-held inhaler device (e.g., AeroEclipse.RTM. II Breath Actuated
Nebulizer (BAN)). In some cases, the nebulizer has a compressed air
source. In some cases, the nebulizer converts liquid medication
into an aerosol. In some cases, the nebulizer converts liquid
medication into an aerosol by extruding the pharmaceutical
preparation through micron or submicron-sized holes. In some cases,
the nebulizer converts liquid medication into an aerosol so it can
be inhaled into the lungs. In some cases, the nebulizer is a small
volume nebulizer. In some cases, the nebulizer is a small volume
jet nebulizer. In some cases, aerosolized medication is only
produced when inhaled through the device. In some cases, the
medication is contained in the cup between breaths or during breaks
in treatment. In some cases, the medication is contained in the cup
until ready to be inhaled.
[0350] Nebulizers impart energy into a liquid pharmaceutical
formulation to aerosolize the liquid, and to allow delivery to the
pulmonary system, e.g., the lungs, of a patient. A nebulizer
comprises a liquid delivery system, such as a container having a
reservoir that contains a liquid pharmaceutical formulation. The
liquid pharmaceutical formulation generally comprises an active
agent that is either in solution or suspended within a liquid
medium.
[0351] In one type of nebulizer, generally referred to as a jet
nebulizer, compressed gas is forced through an orifice in the
container. The compressed gas forces liquid to be withdrawn through
a nozzle, and the withdrawn liquid mixes with the flowing gas to
form aerosol droplets. A cloud of droplets is then administered to
the patients respiratory tract.
[0352] In another type of nebulizer, generally referred to as a
vibrating mesh nebulizer, energy, such as mechanical energy,
vibrates a mesh. This vibration of the mesh aerosolizes the liquid
pharmaceutical formulation to create an aerosol cloud that is
administered to the patient's lungs. In another type of nebulizer
the nebulizing comprises extrusion through micron or
submicron-sized holes followed by Rayleigh break-up into fine
droplets.
[0353] Alternatively or additionally, the pharmaceutical
formulation may be in a liquid form and may be aerosolized using a
nebulizer as described in WO 2004/071368, which is herein
incorporated by reference in its entirety, as well as U.S.
Published application Nos. 2004/0011358 and 2004/0035413, which are
both herein incorporated by reference in their entireties. Other
examples of nebulizers include, but are not limited to, the
Aeroneb.RTM.Go or Aeroneb.RTM.Pro nebulizers, available from
Aerogen Ltd. of Galway, Ireland; the PARI eFlow and other PARI
nebulizers available from PARI Respiratory Equipment, Inc. of
Midlothian, Va.; the Lumiscope.RTM. Nebulizer 6600 or 6610
available from Lumiscope Company, Inc. of East Brunswick, N.J.; and
the Omron NE-U22 available from Omron Healthcare, Inc. of Kyoto,
Japan. Other examples of nebulizers include devices produced by
Medspray (Enschede, The Netherlands).
[0354] It has been found that a nebulizer of the vibrating mesh
type, such as one that that forms droplets without the use of
compressed gas, such as the Aeroneb.RTM. Pro provides unexpected
improvement in dosing efficiency and consistency. By generating
fine droplets by using a vibrating perforated or unperforated
membrane, rather than by introducing compressed air, the
aerosolized pharmaceutical formulation can be introduced without
substantially affecting the flow characteristics. In addition, the
generated droplets when using a nebulizer of this type are
introduced at a low velocity, thereby decreasing the likelihood of
the droplets being driven to an undesired region. It has been found
that when using a nebulizer of the extrusion/Rayleigh jet breakup
type, the generated droplets are also introduced at a low velocity,
thereby decreasing the likelihood of the droplets being driven to
an undesired region.
[0355] In some cases, the nebulizer can be of the vibrating mesh
type. In some cases, the nebulizer can be of the pressurized jet
type. In some cases, the nebulizer can be of the extrusion/Rayleigh
breakup type. In some cases, the nebulizer is lightweight (at most
60 g, at most 100 g, at most 200 g, at most 250 g) and nearly
silent. In some cases, the nebulizer has a sound level less than 35
A-weighted decibels (dBA) at 1 meter. In some cases, the nebulizer
has a medication cup capacity of 6 mL. In some cases, the nebulizer
has a residual volume of less than 0.3 mL. In some cases, the
nebulizer generates an average flow rate of 0.4 mL/min. In some
cases, the nebulizer generates an average flow rate of 0.5 mL/min.
In some cases, the nebulizer generates an average flow rate of 0.6
mL/min. In some cases, the nebulizer generates an average flow rate
of 0.7 mL/min. In some cases, the nebulizer generates an average
flow rate of 0.8 mL/min. In some cases, the nebulizer generates an
average flow rate of 0.9 mL/min. In some cases, the nebulizer
generates an average flow rate of 1.0 mL/min. In some cases, the
nebulizer generates an average flow rate of 1.1 mL/min. In some
cases, the nebulizer generates an average flow rate of 1.2 mL/min.
In some cases, the nebulizer generates an average particle size of
3.0 .mu.m MMAD. In some cases, the nebulizer generates an average
particle size between 3.0 .mu.m MMAD and 4.0 .mu.m MMAD. In some
cases, the nebulizer generates an average particle size of 3.0
.mu.m MMAD. In some cases, the nebulizer generates an average
particle size between 3.0 .mu.m MMAD and 5.0 .mu.m MMAD. In some
cases, the nebulizer generates an average particle size of 3.0
.mu.m MMAD. In some cases, the nebulizer generates an average
particle size between 3.0 .mu.m MMAD and 6.0 .mu.m MMAD.
[0356] In still another type of nebulizer, ultrasonic waves are
generated to directly vibrate and aerosolize the pharmaceutical
formulation.
[0357] As noted above, the present invention may also involve a dry
powder inhaler. A specific version of a dry powder aerosolization
apparatus is described in U.S. Pat. Nos. 4,069,819 and 4,995,385,
which are incorporated herein by reference in their entireties.
Another useful device, which has a chamber that is sized and shaped
to receive a capsule so that the capsule is orthogonal to the
inhalation direction, is described in U.S. Pat. No. 3,991,761,
which is incorporated herein by reference in its entirety. As also
described in U.S. Pat. No. 3,991,761, a puncturing mechanism may
puncture both ends of the capsule. In another version, a chamber
may receive a capsule in a manner where air flows through the
capsule as described for example in U.S. Pat. Nos. 4,338,931 and
5,619,985, which are incorporated herein by reference in their
entireties. In another version, the aerosolization of the
pharmaceutical composition may be accomplished by pressurized gas
flowing through the inlets, as described for example in U.S. Pat.
Nos. 5,458,135; 5,785,049; and 6,257,233, or propellant, as
described in WO 00/72904 and U.S. Pat. No. 4,114,615, which are
incorporated herein by reference. These types of dry powder
inhalers are generally referred to as active dry powder
inhalers.
[0358] Other dry powder inhalers include those available from
Boehringer Ingelheim (e.g., Respimat inhaler), Hovione (e.g.,
FlowCaps inhaler), Plastiape (e.g., Osmohaler inhaler), and
MicroDose. The present invention may also utilize condensation
aerosol devices, available from Alexza, Mountain View, Calif. Yet
another useful inhaler is disclosed in WO 2008/051621, which is
incorporated herein by reference in its entirety.
[0359] The pharmaceutical formulations disclosed herein may also be
administered to the lungs of a patient via aerosolization, such as
with a metered dose inhaler. The use of such formulations provides
for superior dose reproducibility and improved lung deposition as
disclosed in WO 99/16422, hereby incorporated in its entirety by
reference. MDIs are known in the art and could easily be employed
for administration of the claimed dispersions without undue
experimentation. Breath-activated or breath-actuated MDIs and
pressurized MDIs (pMDIs), as well as those comprising other types
of improvements which have been, or will be, developed are also
compatible with the formulations of the present invention and, as
such, are contemplated as being within the scope thereof.
[0360] Along with DPIs, MDIs and nebulizers, it will be appreciated
that the formulations of one or more embodiments of the present
invention may be used in conjunction with liquid dose instillation
or LDI techniques as disclosed in, for example, WO 99/16421, which
is incorporated herein by reference in its entirety. Liquid dose
instillation involves the direct administration of a formulation to
the lung. With respect to LDI the formulations are preferably used
in conjunction with partial liquid ventilation or total liquid
ventilation. Moreover, one or more embodiments of the present
invention may further comprise introducing a therapeutically
beneficial amount of a physiologically acceptable gas (such as
nitric oxide or oxygen) into the pharmaceutical microdispersion
prior to, during or following administration.
[0361] The pharmaceutical composition of one or more embodiments of
the present invention typically has improved emitted dose
efficiency. Accordingly, high doses of the pharmaceutical
composition may be delivered using a variety of aerosolization
devices and techniques.
[0362] The emitted dose (ED) of the particles of the present
invention may be greater than about 30%, such as greater than about
40%, greater than about 50%, greater than about 60%, or greater
than about 70%.
[0363] One or more embodiments are directed to kits. For instance,
the kit may include an aerosolization device and a container, e.g.,
unit dose receptacle, containing aerosolizable antiarrhythmic
pharmaceutical agent, e.g., liquid or dry powder.
[0364] The kit may further comprise a package, such as a bag, that
contains the aerosolization device and the container.
[0365] In view of the above, the present invention involves methods
to treat acute episodes of and/or chronic arrhythmias. In certain
embodiments, the treating comprises acute treatment after detection
of atrial arrhythmia.
[0366] This method of treatment results in a pulsatile
pharmacokinetic profile and transient pharmacodynamic effect
mimicking the effect of an IV. This method delivers high drug
concentrations that are safe and effective to the heart, while the
distribution to the rest of the body results in the drug being
diluted to sub-therapeutic levels. This method is the shortest
route of delivery to the heart next to intra-cardial injection.
This provides the convenience of self-administration like the
"pill-in-the-pocket" approach, but the effectiveness and fast onset
of action of an IV. Although the delivery of medications through
the lung for systemic effect is not new, it was thought it wouldn't
be effective to the heart, because of the fast passage of drug
through it. The animal and human PK/PD data in this study show that
the drug exposure is sufficient for therapeutic effect at a much
lower dose compared to other routes of administration. This method
ensures dug concentrations in overall plasma are much lower than
what is achieved by oral/IV hence minimizing drug-drug interactions
and side effects.
[0367] In some cases, the T.sub.max of the antiarrhythmic
pharmaceutical agent administered via inhalation can be from about
0.1 minute to about 30 minutes, such as 0.1-0.5, 0.1-1, 0.1-1.5,
0.1-2, 0.1-2.5, 0.1-3, 0.1-3.5, 0.1-4, 0.1-4.5, 0.1-5, 0.1-6,
0.1-8, 0.1-10, 0.1-15, 0.1-20, 0.1-25, 0.1-30, 0.2-0.5, 0.2-1,
0.2-1.5, 0.2-2, 0.2-2.5, 0.2-3, 0.2-3.5, 0.2-4, 0.2-4.5, 0.2-5,
0.2-6, 0.2-8, 0.2-10, 0.2-15, 0.2-20, 0.2-25, 0.2-30, 0.3-0.5,
0.3-1, 0.3-1.5, 0.3-2, 0.3-2.5, 0.3-3, 0.3-3.5, 0.3-4, 0.3-4.5,
0.3-5, 0.3-6, 0.3-8, 0.3-10, 0.3-15, 0.3-20, 0.3-25, 0.3-30, 0.5-1,
0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5, 0.5-4, 0.5-4.5, 0.5-5,
0.5-6, 0.5-8, 0.5-10, 0.5-15, 0.5-20, 0.5-25, 0.5-30, 1-1.5, 1-2,
1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1-6, 1-8, 1-10, 1-15, 1-20,
1-25, 1-30, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5,
1.5-6, 1.5-8, 1.5-10, 1.5-15, 1.5-20, 1.5-25, 1.5-30, 2-2.5, 2-3,
2-3.5, 2-4, 2-4.5, 2-5, 2-6, 2-8, 2-10, 2-15, 2-20, 2-25, 2-30,
2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 2.5-6, 2.5-8, 2.5-10,
2.5-15, 2.5-20, 2.5-25, 2.5-30, 3-3.5, 3-4, 3-4.5, 3-5, 3-6, 3-8,
3-10, 3-15, 3-20, 3-25, 3-30, 3.5-4, 3.5-4.5, 3.5-5, 3.5-6, 3.5-8,
3.5-10, 3.5-15, 3.5-20, 3.5-25, 3.5-30, 4-4.5, 4-5, 4-6, 4-8, 4-10,
4-15, 4-20, 4-25, 4-30, 4.5-5, 4.5-6, 4.5-8, 4.5-10, 4.5-15,
4.5-20, 4.5-25, 4.5-30, 5-6, 5-8, 5-10, 5-15, 5-20, 5-25, 5-30,
5.5-6, 5.5-8, 5.5-10, 5.5-15, 5.5-20, 5.5-25, 5.5-30, 6-8, 6-10,
6-15, 6-20, 6-25, 6-30, 8-10, 8-15, 8-20, 8-25, 8-30, 10-15, 10-20,
10-25, 10-30, 15-20, 15-25, 15-30, 20-25, 20-30, or 25-30 min. A
range given out in the present disclosure can be a range between
two accurate numerical values, in some cases, a range in the
present disclosure can also refer to a range between two
approximate numerical values. For instance, "1-10" can refer to
"from 1 to 10" in some cases, while in other case, "1-10" can refer
to "from about 1 to about 10". In some cases, the T.sub.max of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be 0.01-5, 0.02-5, 0.03-5, 0.04-5, 0.05-5, 0.06-5, 0.07-5, 0.08-5,
0.09-5, 0.12-5, 0.14-5, 0.15-5, 0.16-5, 0.18-5, 0.2-5, 0.24-5,
0.26-5, 0.28-5, 0.3-5, 0.35-5, 0.4-5, 0.5-5, 0.6-5, 0.7-5, 0.8-5,
0.9-5, or 1-5 min. In some cases, the T.sub.max of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be from about 0.1 to about 3 min. In some cases, the T.sub.max of
the antiarrhythmic pharmaceutical agent administered via inhalation
can be from about 0.1 to about 5 min. In some cases, the T.sub.max
of the antiarrhythmic pharmaceutical agent (e.g., flecainide)
administered via inhalation can be from about 0.2 to about 5 min.
In one or more embodiments, the antiarrhythmic pharmaceutical agent
is a class I, class II, class III, or class IV antiarrhythmic. In
some embodiments, the antiarrhythmic pharmaceutical agent is a
class Ic, antiarrhythmic. In other embodiments, the antiarrhythmic
pharmaceutical agent is flecainide or a pharmaceutically acceptable
salt thereof.
[0368] In some cases, the T.sub.max can be calculated as the amount
of time at which the maximum plasma concentration of the
antiarrhythmic pharmaceutical agent is observed. In some cases, the
T.sub.max can be calculated as the amount of time after
administration of the antiarrhythmic pharmaceutical agent when the
maximum plasma concentration is reached. In some cases, the
T.sub.max can be calculated as the amount of time after the
initiation of the administration of the antiarrhythmic
pharmaceutical agent when the maximum plasma concentration is
reached. In some cases, the T.sub.max can be calculated as the
amount of time after the completion of the administration of the
antiarrhythmic pharmaceutical agent when the maximum plasma
concentration is reached. In some cases, the T.sub.max can be
calculated from plasma concentration of the antiarrhythmic
pharmaceutical agent measured in the left ventricular chamber. In
some cases, the T.sub.max can be calculated from plasma
concentration of the antiarrhythmic pharmaceutical agent measured
in the pulmonary artery. In some cases, the T.sub.max can be
calculated from plasma concentration of the antiarrhythmic
pharmaceutical agent measured in the vein (e.g., femoral vein). In
some cases, the T.sub.max can be measured in a human PK/PD study.
The term "human PK/PD study" as used herein can refer to any
settings where a human subject receives administration of a single
dose of the antiarrhythmic agent as provided herein and a
pharmacokinetic (PK) or pharmacodynamic (PD) parameter is measured
from the human subject after the administration of the
antiarrhythmic agent. In some cases, a human PK/PD study as
provided herein can refer to a clinical study performed in a clinic
or hospital settings. In some cases, the human PK/PD study can be a
single center or multi-center study. A human PK/PD study can be
performed on healthy human subjects or human cardiovascular
patients. In some cases, the patients with cardiovascular disease
experience arrhythmia as described herein. In some cases, a human
PK/PD study can be a single-dose study, in other cases, a human
PK/PD study can be a multi-dose (e.g. escalating doses) study.
[0369] In some cases, the C.sub.max of the antiarrhythmic
pharmaceutical agent administered via inhalation can be from about
10 ng/mL to about 5000 ng/mL, such as from about 10-30, 10-50,
10-70, 10-80, 10-90, 10-100, 10-110, 10-120, 10-130, 10-140,
10-150, 10-160, 10-170, 10-180, 10-190, 10-200, 10-250, 10-300,
10-350, 10-400, 10-450, 10-500, 10-550, 10-600, 10-650, 10-700,
10-800, 10-900, 10-1000, 10-1500, 10-2000, 10-3000, 10-4000,
10-5000, 20-30, 20-50, 20-70, 20-80, 20-90, 20-100, 20-110, 20-120,
20-130, 20-140, 20-150, 20-160, 20-170, 20-180, 20-190, 20-200,
20-250, 20-300, 20-350, 20-400, 20-450, 20-500, 20-550, 20-600,
20-650, 20-700, 20-800, 20-900, 20-1000, 20-1500, 20-2000, 20-3000,
20-4000, 20-5000, 30-50, 30-70, 30-80, 30-90, 30-100, 30-110,
30-120, 30-130, 30-140, 30-150, 30-160, 30-170, 30-180, 30-190,
30-200, 30-250, 30-300, 30-350, 30-400, 30-450, 30-500, 30-550,
30-600, 30-650, 30-700, 30-800, 30-900, 30-1000, 30-1500, 30-2000,
30-3000, 30-4000, 30-5000, 50-70, 50-80, 50-90, 50-100, 50-110,
50-120, 50-130, 50-140, 50-150, 50-160, 50-170, 50-180, 50-190,
50-200, 50-250, 50-300, 50-350, 50-400, 50-450, 50-500, 50-550,
50-600, 50-650, 50-700, 50-800, 50-900, 50-1000, 50-1500, 50-2000,
50-3000, 50-4000, 50-5000, 70-80, 70-90, 70-100, 70-110, 70-120,
70-130, 70-140, 70-150, 70-160, 70-170, 70-180, 70-190, 70-200,
70-250, 70-300, 70-350, 70-400, 70-450, 70-500, 70-550, 70-600,
70-650, 70-700, 70-800, 70-900, 70-1000, 70-1500, 70-2000, 70-3000,
70-4000, 70-5000, 80-90, 80-100, 80-110, 80-120, 80-130, 80-140,
80-150, 80-160, 80-170, 80-180, 80-190, 80-200, 80-250, 80-300,
80-350, 80-400, 80-450, 80-500, 80-550, 80-600, 80-650, 80-700,
80-800, 80-900, 80-1000, 80-1500, 80-2000, 80-3000, 80-4000,
80-5000, 90-100, 90-110, 90-120, 90-130, 90-140, 90-150, 90-160,
90-170, 90-180, 90-190, 90-200, 90-250, 90-300, 90-350, 90-400,
90-450, 90-500, 90-550, 90-600, 90-650, 90-700, 90-800, 90-900,
90-1000, 90-1500, 90-2000, 90-3000, 90-4000, 90-5000, 100-110,
100-120, 100-130, 100-140, 100-150, 100-160, 100-170, 100-180,
100-190, 100-200, 100-250, 100-300, 100-350, 100-400, 100-450,
100-500, 100-550, 100-600, 100-650, 100-700, 100-800, 100-900,
100-1000, 100-1500, 100-2000, 100-3000, 100-4000, 100-5000,
110-120, 110-130, 110-140, 110-150, 110-160, 110-170, 110-180,
110-190, 110-200, 110-250, 110-300, 110-350, 110-400, 110-450,
110-500, 110-550, 110-600, 110-650, 110-700, 110-800, 110-900,
110-1000, 110-1500, 110-2000, 110-3000, 110-4000, 110-5000,
120-130, 120-140, 120-150, 120-160, 120-170, 120-180, 120-190,
120-200, 120-250, 120-300, 120-350, 120-400, 120-450, 120-500,
120-550, 120-600, 120-650, 120-700, 120-800, 120-900, 120-1000,
120-1500, 120-2000, 120-3000, 120-4000, 120-5000, 130-140, 130-150,
130-160, 130-170, 130-180, 130-190, 130-200, 130-250, 130-300,
130-350, 130-400, 130-450, 130-500, 130-550, 130-600, 130-650,
130-700, 130-800, 130-900, 130-1000, 130-1500, 130-2000, 130-3000,
130-4000, 130-5000, 140-150, 140-160, 140-170, 140-180, 140-190,
140-200, 140-250, 140-300, 140-350, 140-400, 140-450, 140-500,
140-550, 140-600, 140-650, 140-700, 140-800, 140-900, 140-1000,
140-1500, 140-2000, 140-3000, 140-4000, 140-5000, 150-160, 150-170,
150-180, 150-190, 150-200, 150-250, 150-300, 150-350, 150-400,
150-450, 150-500, 150-550, 150-600, 150-650, 150-700, 150-800,
150-900, 150-1000, 150-1500, 150-2000, 150-3000, 150-4000,
150-5000, 160-170, 160-180, 160-190, 160-200, 160-250, 160-300,
160-350, 160-400, 160-450, 160-500, 160-550, 160-600, 160-650,
160-700, 160-800, 160-900, 160-1000, 160-1500, 160-2000, 160-3000,
160-4000, 160-5000, 170-180, 170-190, 170-200, 170-250, 170-300,
170-350, 170-400, 170-450, 170-500, 170-550, 170-600, 170-650,
170-700, 170-800, 170-900, 170-1000, 170-1500, 170-2000, 170-3000,
170-4000, 170-5000, 180-190, 180-200, 180-250, 180-300, 180-350,
180-400, 180-450, 180-500, 180-550, 180-600, 180-650, 180-700,
180-800, 180-900, 180-1000, 180-1500, 180-2000, 180-3000, 180-4000,
180-5000, 190-200, 190-250, 190-300, 190-350, 190-400, 190-450,
190-500, 190-550, 190-600, 190-650, 190-700, 190-800, 190-900,
190-1000, 190-1500, 190-2000, 190-3000, 190-4000, 190-5000,
200-250, 200-300, 200-350, 200-400, 200-450, 200-500, 200-550,
200-600, 200-650, 200-700, 200-800, 200-900, 200-1000, 200-1500,
200-2000, 200-3000, 200-4000, 200-5000, 250-300, 250-350, 250-400,
250-450, 250-500, 250-550, 250-600, 250-650, 250-700, 250-800,
250-900, 250-1000, 250-1500, 250-2000, 250-3000, 250-4000,
250-5000, 300-350, 300-400, 300-450, 300-500, 300-550, 300-600,
300-650, 300-700, 300-800, 300-900, 300-1000, 300-1500, 300-2000,
300-3000, 300-4000, 300-5000, 350-400, 350-450, 350-500, 350-550,
350-600, 350-650, 350-700, 350-800, 350-900, 350-1000, 350-1500,
350-2000, 350-3000, 350-4000, 350-5000, 400-450, 400-500, 400-550,
400-600, 400-650, 400-700, 400-800, 400-900, 400-1000, 400-1500,
400-2000, 400-3000, 400-4000, 400-5000, 450-500, 450-550, 450-600,
450-650, 450-700, 450-800, 450-900, 450-1000, 450-1500, 450-2000,
450-3000, 450-4000, 450-5000, 500-550, 500-600, 500-650, 500-700,
500-800, 500-900, 500-1000, 500-1500, 500-2000, 500-3000, 500-4000,
500-5000, 550-600, 550-650, 550-700, 550-800, 550-900, 550-1000,
550-1500, 550-2000, 550-3000, 550-4000, 550-5000, 600-650, 600-700,
600-800, 600-900, 600-1000, 600-1500, 600-2000, 600-3000, 600-4000,
600-5000, 650-700, 650-800, 650-900, 650-1000, 650-1500, 650-2000,
650-3000, 650-4000, 650-5000, 700-800, 700-900, 700-1000, 700-1500,
700-2000, 700-3000, 700-4000, 700-5000, 800-900, 800-1000,
800-1500, 800-2000, 800-3000, 800-4000, 800-5000, 900-1000,
900-1500, 900-2000, 900-3000, 900-4000, 900-5000, 1000-1500,
1000-2000, 1000-3000, 1000-4000, 1000-5000, 1500-2000, 1500-3000,
1500-4000, 1500-5000, 2000-3000, 2000-4000, 2000-5000, 3000-4000,
3000-5000, or 4000-5000 ng/mL. In some cases, the C.sub.max of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be from about 20 ng/mL to about 500 ng/mL, such as 20-500, 30-500,
40-500, 50-500, 60-500, 70-500, 80-500, 90-500, 100-500, 150-500,
200-500, or 250-500 ng/mL. In some cases, the C.sub.max of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be from about 50 to about 500 ng/mL. In some cases, the C.sub.max
of the antiarrhythmic pharmaceutical agent administered via
inhalation can be from about 100 to about 250 ng/mL. In one or more
embodiments antiarrhythmic pharmaceutical agent is a class I, class
II, class III, or class IV antiarrhythmic. In some embodiments, the
antiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic.
In other embodiments, the antiarrhythmic pharmaceutical agent is
flecainide or a pharmaceutically acceptable salt thereof.
[0370] In some cases, the C.sub.max can be calculated as the
maximum plasma concentration of the antiarrhythmic pharmaceutical
agent observed. In some cases, the C.sub.max can be calculated as
the peak plasma concentration that the antiarrhythmic
pharmaceutical agent achieves after the drug has been
administrated. In some cases, the C.sub.max can be calculated from
plasma concentration of the antiarrhythmic pharmaceutical agent
measured in the left ventricular chamber. In some cases, the
C.sub.max can be calculated from plasma concentration of the
antiarrhythmic pharmaceutical agent measured in the pulmonary
artery. In some cases, the C.sub.max can be calculated from plasma
concentration of the antiarrhythmic pharmaceutical agent measured
in the vein (e.g., femoral vein). In some cases, the C.sub.max can
be measured in a human PK/PD study.
[0371] In some cases, the AUC.sub.Last of the antiarrhythmic
pharmaceutical agent administered via inhalation can be from about
100 hr*ng/mL to about 10000 hr*ng/mL, such as from 100-200,
100-300, 100-400, 100-420, 100-440, 100-460, 100-480, 100-500,
100-520, 100-540, 100-560, 100-580, 100-600, 100-620, 100-640,
100-660, 100-680, 100-700, 100-800, 100-900, 100-1000, 100-1500,
100-2000, 100-3000, 100-3500, 100-4000, 100-4500, 100-5000,
100-5500, 100-6000, 100-6500, 100-7000, 100-8000, 100-9000,
100-10000, 200-300, 200-400, 200-420, 200-440, 200-460, 200-480,
200-500, 200-520, 200-540, 200-560, 200-580, 200-600, 200-620,
200-640, 200-660, 200-680, 200-700, 200-800, 200-900, 200-1000,
200-1500, 200-2000, 200-3000, 200-3500, 200-4000, 200-4500,
200-5000, 200-5500, 200-6000, 200-6500, 200-7000, 200-8000,
200-9000, 200-10000, 300-400, 300-420, 300-440, 300-460, 300-480,
300-500, 300-520, 300-540, 300-560, 300-580, 300-600, 300-620,
300-640, 300-660, 300-680, 300-700, 300-800, 300-900, 300-1000,
300-1500, 300-2000, 300-3000, 300-3500, 300-4000, 300-4500,
300-5000, 300-5500, 300-6000, 300-6500, 300-7000, 300-8000,
300-9000, 300-10000, 400-420, 400-440, 400-460, 400-480, 400-500,
400-520, 400-540, 400-560, 400-580, 400-600, 400-620, 400-640,
400-660, 400-680, 400-700, 400-800, 400-900, 400-1000, 400-1500,
400-2000, 400-3000, 400-3500, 400-4000, 400-4500, 400-5000,
400-5500, 400-6000, 400-6500, 400-7000, 400-8000, 400-9000,
400-10000, 420-440, 420-460, 420-480, 420-500, 420-520, 420-540,
420-560, 420-580, 420-600, 420-620, 420-640, 420-660, 420-680,
420-700, 420-800, 420-900, 420-1000, 420-1500, 420-2000, 420-3000,
420-3500, 420-4000, 420-4500, 420-5000, 420-5500, 420-6000,
420-6500, 420-7000, 420-8000, 420-9000, 420-10000, 440-460,
440-480, 440-500, 440-520, 440-540, 440-560, 440-580, 440-600,
440-620, 440-640, 440-660, 440-680, 440-700, 440-800, 440-900,
440-1000, 440-1500, 440-2000, 440-3000, 440-3500, 440-4000,
440-4500, 440-5000, 440-5500, 440-6000, 440-6500, 440-7000,
440-8000, 440-9000, 440-10000, 460-480, 460-500, 460-520, 460-540,
460-560, 460-580, 460-600, 460-620, 460-640, 460-660, 460-680,
460-700, 460-800, 460-900, 460-1000, 460-1500, 460-2000, 460-3000,
460-3500, 460-4000, 460-4500, 460-5000, 460-5500, 460-6000,
460-6500, 460-7000, 460-8000, 460-9000, 460-10000, 480-500,
480-520, 480-540, 480-560, 480-580, 480-600, 480-620, 480-640,
480-660, 480-680, 480-700, 480-800, 480-900, 480-1000, 480-1500,
480-2000, 480-3000, 480-3500, 480-4000, 480-4500, 480-5000,
480-5500, 480-6000, 480-6500, 480-7000, 480-8000, 480-9000,
480-10000, 500-520, 500-540, 500-560, 500-580, 500-600, 500-620,
500-640, 500-660, 500-680, 500-700, 500-800, 500-900, 500-1000,
500-1500, 500-2000, 500-3000, 500-3500, 500-4000, 500-4500,
500-5000, 500-5500, 500-6000, 500-6500, 500-7000, 500-8000,
500-9000, 500-10000, 520-540, 520-560, 520-580, 520-600, 520-620,
520-640, 520-660, 520-680, 520-700, 520-800, 520-900, 520-1000,
520-1500, 520-2000, 520-3000, 520-3500, 520-4000, 520-4500,
520-5000, 520-5500, 520-6000, 520-6500, 520-7000, 520-8000,
520-9000, 520-10000, 540-560, 540-580, 540-600, 540-620, 540-640,
540-660, 540-680, 540-700, 540-800, 540-900, 540-1000, 540-1500,
540-2000, 540-3000, 540-3500, 540-4000, 540-4500, 540-5000,
540-5500, 540-6000, 540-6500, 540-7000, 540-8000, 540-9000,
540-10000, 560-580, 560-600, 560-620, 560-640, 560-660, 560-680,
560-700, 560-800, 560-900, 560-1000, 560-1500, 560-2000, 560-3000,
560-3500, 560-4000, 560-4500, 560-5000, 560-5500, 560-6000,
560-6500, 560-7000, 560-8000, 560-9000, 560-10000, 580-600,
580-620, 580-640, 580-660, 580-680, 580-700, 580-800, 580-900,
580-1000, 580-1500, 580-2000, 580-3000, 580-3500, 580-4000,
580-4500, 580-5000, 580-5500, 580-6000, 580-6500, 580-7000,
580-8000, 580-9000, 580-10000, 600-620, 600-640, 600-660, 600-680,
600-700, 600-800, 600-900, 600-1000, 600-1500, 600-2000, 600-3000,
600-3500, 600-4000, 600-4500, 600-5000, 600-5500, 600-6000,
600-6500, 600-7000, 600-8000, 600-9000, 600-10000, 620-640,
620-660, 620-680, 620-700, 620-800, 620-900, 620-1000, 620-1500,
620-2000, 620-3000, 620-3500, 620-4000, 620-4500, 620-5000,
620-5500, 620-6000, 620-6500, 620-7000, 620-8000, 620-9000,
620-10000, 640-660, 640-680, 640-700, 640-800, 640-900, 640-1000,
640-1500, 640-2000, 640-3000, 640-3500, 640-4000, 640-4500,
640-5000, 640-5500, 640-6000, 640-6500, 640-7000, 640-8000,
640-9000, 640-10000, 660-680, 660-700, 660-800, 660-900, 660-1000,
660-1500, 660-2000, 660-3000, 660-3500, 660-4000, 660-4500,
660-5000, 660-5500, 660-6000, 660-6500, 660-7000, 660-8000,
660-9000, 660-10000, 680-700, 680-800, 680-900, 680-1000, 680-1500,
680-2000, 680-3000, 680-3500, 680-4000, 680-4500, 680-5000,
680-5500, 680-6000, 680-6500, 680-7000, 680-8000, 680-9000,
680-10000, 700-800, 700-900, 700-1000, 700-1500, 700-2000,
700-3000, 700-3500, 700-4000, 700-4500, 700-5000, 700-5500,
700-6000, 700-6500, 700-7000, 700-8000, 700-9000, 700-10000,
800-900, 800-1000, 800-1500, 800-2000, 800-3000, 800-3500,
800-4000, 800-4500, 800-5000, 800-5500, 800-6000, 800-6500,
800-7000, 800-8000, 800-9000, 800-10000, 900-1000, 900-1500,
900-2000, 900-3000, 900-3500, 900-4000, 900-4500, 900-5000,
900-5500, 900-6000, 900-6500, 900-7000, 900-8000, 900-9000,
900-10000, 1000-1500, 1000-2000, 1000-3000, 1000-3500, 1000-4000,
1000-4500, 1000-5000, 1000-5500, 1000-6000, 1000-6500, 1000-7000,
1000-8000, 1000-9000, 1000-10000, 1500-2000, 1500-3000, 1500-3500,
1500-4000, 1500-4500, 1500-5000, 1500-5500, 1500-6000, 1500-6500,
1500-7000, 1500-8000, 1500-9000, 1500-10000, 2000-3000, 2000-3500,
2000-4000, 2000-4500, 2000-5000, 2000-5500, 2000-6000, 2000-6500,
2000-7000, 2000-8000, 2000-9000, 2000-10000, 2500-3000, 2500-3500,
2500-4000, 2500-4500, 2500-5000, 2500-5500, 2500-6000, 2500-6500,
2500-7000, 2500-8000, 2500-9000, 2500-10000, 3000-3500, 3000-4000,
3000-4500, 3000-5000, 3000-5500, 3000-6000, 3000-6500, 3000-7000,
3000-8000, 3000-9000, 3000-10000, 3500-4000, 3500-4500, 3500-5000,
3500-5500, 3500-6000, 3500-6500, 3500-7000, 3500-8000, 3500-9000,
3500-10000, 4000-4500, 4000-5000, 4000-5500, 4000-6000, 4000-6500,
4000-7000, 4000-8000, 4000-9000, 4000-10000, 4500-5000, 4500-5500,
4500-6000, 4500-6500, 4500-7000, 4500-8000, 4500-9000, 4500-10000,
5000-5500, 5000-6000, 5000-6500, 5000-7000, 5000-8000, 5000-9000,
5000-10000, 5500-6000, 5500-6500, 5500-7000, 5500-8000, 5500-9000,
5500-10000, 6000-6500, 6000-7000, 6000-8000, 6000-9000, 6000-10000,
6500-7000, 6500-8000, 6500-9000, 6500-10000, 7000-8000, 7000-9000,
7000-10000, 8000-9000, 8000-10000, or 9000-10000 hr*ng/mL. In some
cases, the AUC.sub.Last of the antiarrhythmic pharmaceutical agent
administered via inhalation can be from about 200 to about 2000
hr*ng/mL. In some cases, the AUC.sub.Last of the antiarrhythmic
pharmaceutical agent administered via inhalation can be from about
500 to about 800 hr*ng/mL. In some cases, the AUC.sub.Last of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be from about 400 to about 600 hr*ng/mL. In one or more embodiments
antiarrhythmic pharmaceutical agent is a class I, class II, class
III, or class IV antiarrhythmic. In some embodiments, the
antiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic.
In other embodiments, the antiarrhythmic pharmaceutical agent is
flecainide or a pharmaceutically acceptable salt thereof.
[0372] In some cases, the AUC.sub.Last can be calculated as the
area under the concentration-time curve up to the last measurable
concentration. In some cases, the AUC.sub.Last can be calculated as
the total drug exposure over time. In some cases, the AUC.sub.Last
can be calculated from plasma concentration of the antiarrhythmic
pharmaceutical agent measured in the left ventricular chamber. In
some cases, the AUC.sub.Last can be calculated from plasma
concentration of the antiarrhythmic pharmaceutical agent measured
in the pulmonary artery. In some cases, the AUC.sub.Last can be
calculated from plasma concentration of the antiarrhythmic
pharmaceutical agent measured in the vein (e.g., femoral vein). In
some cases, the AUC.sub.Last can be measured in a human PK/PD
study.
[0373] In some cases, the distribution t.sub.1/2 of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be from about 0.1 minute to about 15 minutes, such as from about
0.1-0.5, 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5, 0.1-2.6, 0.1-2.7, 0.1-2.8,
0.1-2.9, 0.1-3, 0.1-3.1, 0.1-3.2, 0.1-3.3, 0.1-3.4, 0.1-3.5,
0.1-3.6, 0.1-3.7, 0.1-3.8, 0.1-3.9, 0.1-4, 0.1-4.1, 0.1-4.2,
0.1-4.3, 0.1-4.4, 0.1-4.5, 0.1-5, 0.1-5.5, 0.1-6, 0.1-7, 0.1-8,
0.1-9, 0.1-10, 0.1-11, 0.1-12, 0.1-13, 0.1-14, 0.1-15, 0.5-1,
0.5-1.5, 0.5-2, 0.5-2.5, 0.5-2.6, 0.5-2.7, 0.5-2.8, 0.5-2.9, 0.5-3,
0.5-3.1, 0.5-3.2, 0.5-3.3, 0.5-3.4, 0.5-3.5, 0.5-3.6, 0.5-3.7,
0.5-3.8, 0.5-3.9, 0.5-4, 0.5-4.1, 0.5-4.2, 0.5-4.3, 0.5-4.4,
0.5-4.5, 0.5-5, 0.5-5.5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10,
0.5-11, 0.5-12, 0.5-13, 0.5-14, 0.5-15, 1-1.5, 1-2, 1-2.5, 1-2.6,
1-2.7, 1-2.8, 1-2.9, 1-3, 1-3.1, 1-3.2, 1-3.3, 1-3.4, 1-3.5, 1-3.6,
1-3.7, 1-3.8, 1-3.9, 1-4, 1-4.1, 1-4.2, 1-4.3, 1-4.4, 1-4.5, 1-5,
1-5.5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15,
1.5-2, 1.5-2.5, 1.5-2.6, 1.5-2.7, 1.5-2.8, 1.5-2.9, 1.5-3, 1.5-3.1,
1.5-3.2, 1.5-3.3, 1.5-3.4, 1.5-3.5, 1.5-3.6, 1.5-3.7, 1.5-3.8,
1.5-3.9, 1.5-4, 1.5-4.1, 1.5-4.2, 1.5-4.3, 1.5-4.4, 1.5-4.5, 1.5-5,
1.5-5.5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12,
1.5-13, 1.5-14, 1.5-15, 2-2.5, 2-2.6, 2-2.7, 2-2.8, 2-2.9, 2-3,
2-3.1, 2-3.2, 2-3.3, 2-3.4, 2-3.5, 2-3.6, 2-3.7, 2-3.8, 2-3.9, 2-4,
2-4.1, 2-4.2, 2-4.3, 2-4.4, 2-4.5, 2-5, 2-5.5, 2-6, 2-7, 2-8, 2-9,
2-10, 2-11, 2-12, 2-13, 2-14, 2-15, 2.5-2.6, 2.5-2.7, 2.5-2.8,
2.5-2.9, 2.5-3, 2.5-3.1, 2.5-3.2, 2.5-3.3, 2.5-3.4, 2.5-3.5,
2.5-3.6, 2.5-3.7, 2.5-3.8, 2.5-3.9, 2.5-4, 2.5-4.1, 2.5-4.2,
2.5-4.3, 2.5-4.4, 2.5-4.5, 2.5-5, 2.5-5.5, 2.5-6, 2.5-7, 2.5-8,
2.5-9, 2.5-10, 2.5-11, 2.5-12, 2.5-13, 2.5-14, 2.5-15, 2.6-2.7,
2.6-2.8, 2.6-2.9, 2.6-3, 2.6-3.1, 2.6-3.2, 2.6-3.3, 2.6-3.4,
2.6-3.5, 2.6-3.6, 2.6-3.7, 2.6-3.8, 2.6-3.9, 2.6-4, 2.6-4.1,
2.6-4.2, 2.6-4.3, 2.6-4.4, 2.6-4.5, 2.6-5, 2.6-5.5, 2.6-6, 2.6-7,
2.6-8, 2.6-9, 2.6-10, 2.6-11, 2.6-12, 2.6-13, 2.6-14, 2.6-15,
2.7-2.8, 2.7-2.9, 2.7-3, 2.7-3.1, 2.7-3.2, 2.7-3.3, 2.7-3.4,
2.7-3.5, 2.7-3.6, 2.7-3.7, 2.7-3.8, 2.7-3.9, 2.7-4, 2.7-4.1,
2.7-4.2, 2.7-4.3, 2.7-4.4, 2.7-4.5, 2.7-5, 2.7-5.5, 2.7-6, 2.7-7,
2.7-8, 2.7-9, 2.7-10, 2.7-11, 2.7-12, 2.7-13, 2.7-14, 2.7-15,
2.8-2.9, 2.8-3, 2.8-3.1, 2.8-3.2, 2.8-3.3, 2.8-3.4, 2.8-3.5,
2.8-3.6, 2.8-3.7, 2.8-3.8, 2.8-3.9, 2.8-4, 2.8-4.1, 2.8-4.2,
2.8-4.3, 2.8-4.4, 2.8-4.5, 2.8-5, 2.8-5.5, 2.8-6, 2.8-7, 2.8-8,
2.8-9, 2.8-10, 2.8-11, 2.8-12, 2.8-13, 2.8-14, 2.8-15, 2.9-3,
2.9-3.1, 2.9-3.2, 2.9-3.3, 2.9-3.4, 2.9-3.5, 2.9-3.6, 2.9-3.7,
2.9-3.8, 2.9-3.9, 2.9-4, 2.9-4.1, 2.9-4.2, 2.9-4.3, 2.9-4.4,
2.9-4.5, 2.9-5, 2.9-5.5, 2.9-6, 2.9-7, 2.9-8, 2.9-9, 2.9-10,
2.9-11, 2.9-12, 2.9-13, 2.9-14, 2.9-15, 3-3.1, 3-3.2, 3-3.3, 3-3.4,
3-3.5, 3-3.6, 3-3.7, 3-3.8, 3-3.9, 3-4, 3-4.1, 3-4.2, 3-4.3, 3-4.4,
3-4.5, 3-5, 3-5.5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13,
3-14, 3-15, 3.1-3.2, 3.1-3.3, 3.1-3.4, 3.1-3.5, 3.1-3.6, 3.1-3.7,
3.1-3.8, 3.1-3.9, 3.1-4, 3.1-4.1, 3.1-4.2, 3.1-4.3, 3.1-4.4,
3.1-4.5, 3.1-5, 3.1-5.5, 3.1-6, 3.1-7, 3.1-8, 3.1-9, 3.1-10,
3.1-11, 3.1-12, 3.1-13, 3.1-14, 3.1-15, 3.2-3.3, 3.2-3.4, 3.2-3.5,
3.2-3.6, 3.2-3.7, 3.2-3.8, 3.2-3.9, 3.2-4, 3.2-4.1, 3.2-4.2,
3.2-4.3, 3.2-4.4, 3.2-4.5, 3.2-5, 3.2-5.5, 3.2-6, 3.2-7, 3.2-8,
3.2-9, 3.2-10, 3.2-11, 3.2-12, 3.2-13, 3.2-14, 3.2-15, 3.3-3.4,
3.3-3.5, 3.3-3.6, 3.3-3.7, 3.3-3.8, 3.3-3.9, 3.3-4, 3.3-4.1,
3.3-4.2, 3.3-4.3, 3.3-4.4, 3.3-4.5, 3.3-5, 3.3-5.5, 3.3-6, 3.3-7,
3.3-8, 3.3-9, 3.3-10, 3.3-11, 3.3-12, 3.3-13, 3.3-14, 3.3-15,
3.4-3.5, 3.4-3.6, 3.4-3.7, 3.4-3.8, 3.4-3.9, 3.4-4, 3.4-4.1,
3.4-4.2, 3.4-4.3, 3.4-4.4, 3.4-4.5, 3.4-5, 3.4-5.5, 3.4-6, 3.4-7,
3.4-8, 3.4-9, 3.4-10, 3.4-11, 3.4-12, 3.4-13, 3.4-14, 3.4-15,
3.5-3.6, 3.5-3.7, 3.5-3.8, 3.5-3.9, 3.5-4, 3.5-4.1, 3.5-4.2,
3.5-4.3, 3.5-4.4, 3.5-4.5, 3.5-5, 3.5-5.5, 3.5-6, 3.5-7, 3.5-8,
3.5-9, 3.5-10, 3.5-11, 3.5-12, 3.5-13, 3.5-14, 3.5-15, 3.6-3.7,
3.6-3.8, 3.6-3.9, 3.6-4, 3.6-4.1, 3.6-4.2, 3.6-4.3, 3.6-4.4,
3.6-4.5, 3.6-5, 3.6-5.5, 3.6-6, 3.6-7, 3.6-8, 3.6-9, 3.6-10,
3.6-11, 3.6-12, 3.6-13, 3.6-14, 3.6-15, 3.7-3.8, 3.8-3.9, 3.8-4,
3.8-4.1, 3.8-4.2, 3.8-4.3, 3.8-4.4, 3.8-4.5, 3.8-5, 3.8-5.5, 3.8-6,
3.8-7, 3.8-8, 3.8-9, 3.8-10, 3.8-11, 3.8-12, 3.8-13, 3.8-14,
3.8-15, 3.9-4, 3.9-4.1, 3.9-4.2, 3.9-4.3, 3.9-4.4, 3.9-4.5, 3.9-5,
3.9-5.5, 3.9-6, 3.9-7, 3.9-8, 3.9-9, 3.9-10, 3.9-11, 3.9-12,
3.9-13, 3.9-14, 3.9-15, 4-4.1, 4-4.2, 4-4.3, 4-4.4, 4-4.5, 4-5,
4-5.5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14, 4-15,
4.1-4.2, 4.1-4.3, 4.1-4.4, 4.1-4.5, 4.1-5, 4.1-5.5, 4.1-6, 4.1-7,
4.1-8, 4.1-9, 4.1-10, 4.1-11, 4.1-12, 4.1-13, 4.1-14, 4.1-15,
4.2-4.3, 4.2-4.4, 4.2-4.5, 4.2-5, 4.2-5.5, 4.2-6, 4.2-7, 4.2-8,
4.2-9, 4.2-10, 4.2-11, 4.2-12, 4.2-13, 4.2-14, 4.2-15, 4.3-4.4,
4.3-4.5, 4.3-5, 4.3-5.5, 4.3-6, 4.3-7, 4.3-8, 4.3-9, 4.3-10,
4.3-11, 4.3-12, 4.3-13, 4.3-14, 4.3-15, 4.4-4.5, 4.4-5, 4.4-5.5,
4.4-6, 4.4-7, 4.4-8, 4.4-9, 4.4-10, 4.4-11, 4.4-12, 4.4-13, 4.4-14,
4.4-15, 4.5-5, 4.5-5.5, 4.5-6, 4.5-7, 4.5-8, 4.5-9, 4.5-10, 4.5-11,
4.5-12, 4.5-13, 4.5-14, 4.5-15, 5-5.5, 5-6, 5-7, 5-8, 5-9, 5-10,
5-11, 5-12, 5-13, 5-14, 5-15, 5.5-6, 5.5-7, 5.5-8, 5.5-9, 5.5-10,
5.5-11, 5.5-12, 5.5-13, 5.5-14, 5.5-15, 6-7, 6-8, 6-9, 6-10, 6-11,
6-12, 6-13, 6-14, 6-15, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14,
7-15, 8-9, 8-10, 8-11, 8-12, 8-13, 8-14, 8-15, 9-10, 9-11, 9-12,
9-13, 9-14, 9-15, 10-11, 10-12, 10-13, 10-14, 10-15, 11-12, 11-13,
11-14, 11-15, 12-13, 12-14, 12-15, 13-14, 13-15, or 14-15 min. In
some cases, the distribution t.sub.1/2 of the antiarrhythmic
pharmaceutical agent administered via inhalation can be from about
3 to about 5 minutes. In one or more embodiments antiarrhythmic
pharmaceutical agent is a class I, class II, class III, or class IV
antiarrhythmic. In some embodiments, the antiarrhythmic
pharmaceutical agent is a class Ic, antiarrhythmic. In other
embodiments, the antiarrhythmic pharmaceutical agent is flecainide
or a pharmaceutically acceptable salt thereof.
[0374] In some cases, the distribution t.sub.1/2 can be calculated
as the time at which the antiarrhythmic pharmaceutical agent plasma
levels decreased to half of what they were at equilibrium due to
distribution to tissues throughout the body. In some cases, the
distribution t.sub.1/2 can be calculated as the time it takes for
an antiarrhythmic pharmaceutical agent to lose half of its
pharmacologic activity. In some cases, the distribution t.sub.1/2
can be calculated from plasma concentration of the antiarrhythmic
pharmaceutical agent measured in the left ventricular chamber. In
some cases, the distribution t.sub.1/2 can be calculated from
plasma concentration of the antiarrhythmic pharmaceutical agent
measured in the pulmonary artery. In some cases, the distribution
t.sub.1/2 can be calculated from plasma concentration of the
antiarrhythmic pharmaceutical agent measured in the vein (e.g.,
femoral vein). In some cases, the distribution t.sub.1/2 can be
measured in a human PK/PD study.
[0375] In some cases, the elimination t.sub.1/2 of the
antiarrhythmic pharmaceutical agent administered via inhalation can
be from about 1 hour to about 25 hours, such as from about 1-3,
1-5, 1-7, 1-7.5, 1-8, 1-8.5, 1-8.7, 1-8.9, 1-9.1, 1-9.3, 1-9.5,
1-9.7, 1-9.9, 1-10.1, 1-10.3, 1-10.5, 1-10.7, 1-10.9, 1-11.1,
1-11.3, 1-11.5, 1-11.7, 1-11.9, 1-12.1, 1-12.5, 1-13, 1-13.5, 1-14,
1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-25, 3-5, 3-7, 3-7.5, 3-8,
3-8.5, 3-8.7, 3-8.9, 3-9.1, 3-9.3, 3-9.5, 3-9.7, 3-9.9, 3-10.1,
3-10.3, 3-10.5, 3-10.7, 3-10.9, 3-11.1, 3-11.3, 3-11.5, 3-11.7,
3-11.9, 3-12.1, 3-12.5, 3-13, 3-13.5, 3-14, 3-15, 3-16, 3-17, 3-18,
3-19, 3-20, 3-25, 5-7, 5-7.5, 5-8, 5-8.5, 5-8.7, 5-8.9, 5-9.1,
5-9.3, 5-9.5, 5-9.7, 5-9.9, 5-10.1, 5-10.3, 5-10.5, 5-10.7, 5-10.9,
5-11.1, 5-11.3, 5-11.5, 5-11.7, 5-11.9, 5-12.1, 5-12.5, 5-13,
5-13.5, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-25, 7-7.5, 7-8,
7-8.5, 7-8.7, 7-8.9, 7-9.1, 7-9.3, 7-9.5, 7-9.7, 7-9.9, 7-10.1,
7-10.3, 7-10.5, 7-10.7, 7-10.9, 7-11.1, 7-11.3, 7-11.5, 7-11.7,
7-11.9, 7-12.1, 7-12.5, 7-13, 7-13.5, 7-14, 7-15, 7-16, 7-17, 7-18,
7-19, 7-20, 7-25, 7.5-8, 7.5-8.5, 7.5-8.7, 7.5-8.9, 7.5-9.1,
7.5-9.3, 7.5-9.5, 7.5-9.7, 7.5-9.9, 7.5-10.1, 7.5-10.3, 7.5-10.5,
7.5-10.7, 7.5-10.9, 7.5-11.1, 7.5-11.3, 7.5-11.5, 7.5-11.7,
7.5-11.9, 7.5-12.1, 7.5-12.5, 7.5-13, 7.5-13.5, 7.5-14, 7.5-15,
7.5-16, 7.5-17, 7.5-18, 7.5-19, 7.5-20, 7.5-25, 8-8.5, 8-8.7,
8-8.9, 8-9.1, 8-9.3, 8-9.5, 8-9.7, 8-9.9, 8-10.1, 8-10.3, 8-10.5,
8-10.7, 8-10.9, 8-11.1, 8-11.3, 8-11.5, 8-11.7, 8-11.9, 8-12.1,
8-12.5, 8-13, 8-13.5, 8-14, 8-15, 8-16, 8-17, 8-18, 8-19, 8-20,
8-25, 8.5-8.7, 8.5-8.9, 8.5-9.1, 8.5-9.3, 8.5-9.5, 8.5-9.7,
8.5-9.9, 8.5-10.1, 8.5-10.3, 8.5-10.5, 8.5-10.7, 8.5-10.9,
8.5-11.1, 8.5-11.3, 8.5-11.5, 8.5-11.7, 8.5-11.9, 8.5-12.1,
8.5-12.5, 8.5-13, 8.5-13.5, 8.5-14, 8.5-15, 8.5-16, 8.5-17, 8.5-18,
8.5-19, 8.5-20, 8.5-25, 8.7-8.9, 8.7-9.1, 8.7-9.3, 8.7-9.5,
8.7-9.7, 8.7-9.9, 8.7-10.1, 8.7-10.3, 8.7-10.5, 8.7-10.7, 8.7-10.9,
8.7-11.1, 8.7-11.3, 8.7-11.5, 8.7-11.7, 8.7-11.9, 8.7-12.1,
8.7-12.5, 8.7-13, 8.7-13.5, 8.7-14, 8.7-15, 8.7-16, 8.7-17, 8.7-18,
8.7-19, 8.7-20, 8.7-25, 8.9-9.1, 8.9-9.3, 8.9-9.5, 8.9-9.7,
8.9-9.9, 8.9-10.1, 8.9-10.3, 8.9-10.5, 8.9-10.7, 8.9-10.9,
8.9-11.1, 8.9-11.3, 8.9-11.5, 8.9-11.7, 8.9-11.9, 8.9-12.1,
8.9-12.5, 8.9-13, 8.9-13.5, 8.9-14, 8.9-15, 8.9-16, 8.9-17, 8.9-18,
8.9-19, 8.9-20, 8.9-25, 9.1-9.3, 9.1-9.5, 9.1-9.7, 9.1-9.9,
9.1-10.1, 9.1-10.3, 9.1-10.5, 9.1-10.7, 9.1-10.9, 9.1-11.1,
9.1-11.3, 9.1-11.5, 9.1-11.7, 9.1-11.9, 9.1-12.1, 9.1-12.5, 9.1-13,
9.1-13.5, 9.1-14, 9.1-15, 9.1-16, 9.1-17, 9.1-18, 9.1-19, 9.1-20,
9.1-25, 9.3-9.5, 9.3-9.7, 9.3-9.9, 9.3-10.1, 9.3-10.3, 9.3-10.5,
9.3-10.7, 9.3-10.9, 9.3-11.1, 9.3-11.3, 9.3-11.5, 9.3-11.7,
9.3-11.9, 9.3-12.1, 9.3-12.5, 9.3-13, 9.3-13.5, 9.3-14, 9.3-15,
9.3-16, 9.3-17, 9.3-18, 9.3-19, 9.3-20, 9.3-25, 9.5-9.7, 9.5-9.9,
9.5-10.1, 9.5-10.3, 9.5-10.5, 9.5-10.7, 9.5-10.9, 9.5-11.1,
9.5-11.3, 9.5-11.5, 9.5-11.7, 9.5-11.9, 9.5-12.1, 9.5-12.5, 9.5-13,
9.5-13.5, 9.5-14, 9.5-15, 9.5-16, 9.5-17, 9.5-18, 9.5-19, 9.5-20,
9.5-25, 9.7-9.9, 9.7-10.1, 9.7-10.3, 9.7-10.5, 9.7-10.7, 9.7-10.9,
9.7-11.1, 9.7-11.3, 9.7-11.5, 9.7-11.7, 9.7-11.9, 9.7-12.1,
9.7-12.5, 9.7-13, 9.7-13.5, 9.7-14, 9.7-15, 9.7-16, 9.7-17, 9.7-18,
9.7-19, 9.7-20, 9.7-25, 9.9-10.1, 9.9-10.3, 9.9-10.5, 9.9-10.7,
9.9-10.9, 9.9-11.1, 9.9-11.3, 9.9-11.5, 9.9-11.7, 9.9-11.9,
9.9-12.1, 9.9-12.5, 9.9-13, 9.9-13.5, 9.9-14, 9.9-15, 9.9-16,
9.9-17, 9.9-18, 9.9-19, 9.9-20, 9.9-25, 10.1-10.3, 10.1-10.5,
10.1-10.7, 10.1-10.9, 10.1-11.1, 10.1-11.3, 10.1-11.5, 10.1-11.7,
10.1-11.9, 10.1-12.1, 10.1-12.5, 10.1-13, 10.1-13.5, 10.1-14,
10.1-15, 10.1-16, 10.1-17, 10.1-18, 10.1-19, 10.1-20, 10.1-25,
10.3-10.5, 10.3-10.7, 10.3-10.9, 10.3-11.1, 10.3-11.3, 10.3-11.5,
10.3-11.7, 10.3-11.9, 10.3-12.1, 10.3-12.5, 10.3-13, 10.3-13.5,
10.3-14, 10.3-15, 10.3-16, 10.3-17, 10.3-18, 10.3-19, 10.3-20,
10.3-25, 10.5-10.7, 10.5-10.9, 10.5-11.1, 10.5-11.3, 10.5-11.5,
10.5-11.7, 10.5-11.9, 10.5-12.1, 10.5-12.5, 10.5-13, 10.5-13.5,
10.5-14, 10.5-15, 10.5-16, 10.5-17, 10.5-18, 10.5-19, 10.5-20,
10.5-25, 10.7-10.9, 10.7-11.1, 10.7-11.3, 10.7-11.5, 10.7-11.7,
10.7-11.9, 10.7-12.1, 10.7-12.5, 10.7-13, 10.7-13.5, 10.7-14,
10.7-15, 10.7-16, 10.7-17, 10.7-18, 10.7-19, 10.7-20, 10.7-25,
10.9-11.1, 10.9-11.3, 10.9-11.5, 10.9-11.7, 10.9-11.9, 10.9-12.1,
10.9-12.5, 10.9-13, 10.9-13.5, 10.9-14, 10.9-15, 10.9-16, 10.9-17,
10.9-18, 10.9-19, 10.9-20, 10.9-25, 11.1-11.3, 11.1-11.5,
11.1-11.7, 11.1-11.9, 11.1-12.1, 11.1-12.5, 11.1-13, 11.1-13.5,
11.1-14, 11.1-15, 11.1-16, 11.1-17, 11.1-18, 11.1-19, 11.1-20,
11.1-25, 11.3-11.5, 11.3-11.7, 11.3-11.9, 11.3-12.1, 11.3-12.5,
11.3-13, 11.3-13.5, 11.3-14, 11.3-15, 11.3-16, 11.3-17, 11.3-18,
11.3-19, 11.3-20, 11.3-25, 11.5-11.7, 11.5-11.9, 11.5-12.1,
11.5-12.5, 11.5-13, 11.5-13.5, 11.5-14, 11.5-15, 11.5-16, 11.5-17,
11.5-18, 11.5-19, 11.5-20, 11.5-25, 11.7-11.9, 11.7-12.1,
11.7-12.5, 11.7-13, 11.7-13.5, 11.7-14, 11.7-15, 11.7-16, 11.7-17,
11.7-18, 11.7-19, 11.7-20, 11.7-25, 11.9-12.1, 11.9-12.5, 11.9-13,
11.9-13.5, 11.9-14, 11.9-15, 11.9-16, 11.9-17, 11.9-18, 11.9-19,
11.9-20, 11.9-25, 12.1-12.5, 12.1-13, 12.1-13.5, 12.1-14, 12.1-15,
12.1-16, 12.1-17, 12.1-18, 12.1-19, 12.1-20, 12.1-25, 12.5-13,
12.5-13.5, 12.5-14, 12.5-15, 12.5-16, 12.5-17, 12.5-18, 12.5-19,
12.5-20, 12.5-25, 13-13.5, 13-14, 13-15, 13-16, 13-17, 13-18,
13-19, 13-20, 13-25, 13.5-14, 13.5-15, 13.5-16, 13.5-17, 13.5-18,
13.5-19, 13.5-20, 13.5-25, 14-15, 14-16, 14-17, 14-18, 14-19,
14-20, 14-25, 15-16, 15-17, 15-18, 15-19, 15-20, 15-25, 16-17,
16-18, 16-19, 16-20, 16-25, 17-18, 17-19, 17-20, 17-25, 18-19,
18-20, 18-25, 19-20, 19-25, or 20-25 hours. In some cases, the
elimination t.sub.1/2 of the antiarrhythmic pharmaceutical agent
administered via inhalation can be from about 8.5 to about 10.5
hours. In one or more embodiments antiarrhythmic pharmaceutical
agent is a class I, class II, class III, or class IV
antiarrhythmic. In some embodiments, the antiarrhythmic
pharmaceutical agent is a class Ic, antiarrhythmic. In other
embodiments, the antiarrhythmic pharmaceutical agent is flecainide
or a pharmaceutically acceptable salt thereof.
[0376] In some cases, the elimination t.sub.1/2 can be calculated
as the time at which the antiarrhythmic pharmaceutical agent plasma
levels decreased to half of what they were at equilibrium due to
metabolism and elimination. In some cases, the elimination
t.sub.1/2 can be calculated from plasma concentration of the
antiarrhythmic pharmaceutical agent measured in the left
ventricular chamber. In some cases, the elimination t.sub.1/2 can
be calculated from plasma concentration of the antiarrhythmic
pharmaceutical agent measured in the pulmonary artery. In some
cases, the elimination t.sub.1/2 can be calculated from plasma
concentration of the antiarrhythmic pharmaceutical agent measured
in the vein (e.g., femoral vein). In some cases, the elimination
t.sub.1/2 can be measured in a human PK/PD study.
[0377] In some cases, the maximum change in QRS interval duration
(.DELTA.QRS) following the antiarrhythmic pharmaceutical agent
administered via inhalation can be from about 0.01 msec to about
100 msec, such as from about 0.01-0.1, 0.01-0.5, 0.01-1, 0.01-1.5,
0.01-2, 0.01-2.5, 0.01-3, 0.01-3.5, 0.01-4, 0.01-4.5, 0.01-5,
0.01-5.5, 0.01-6, 0.01-8, 0.01-10, 0.01-15, 0.01-20, 0.01-25,
0.01-30, 0.01-40, 0.01-50, 0.01-60, 0.01-70, 0.01-80, 0.01-90,
0.01-100, 0.1-0.5, 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5, 0.1-3, 0.1-3.5,
0.1-4, 0.1-4.5, 0.1-5, 0.1-5.5, 0.1-6, 0.1-8, 0.1-10, 0.1-15,
0.1-20, 0.1-25, 0.1-30, 0.1-40, 0.1-50, 0.1-60, 0.1-70, 0.1-80,
0.1-90, 0.1-100, 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5,
0.5-4, 0.5-4.5, 0.5-5, 0.5-5.5, 0.5-6, 0.5-8, 0.5-10, 0.5-15,
0.5-20, 0.5-25, 0.5-30, 0.5-40, 0.5-50, 0.5-60, 0.5-70, 0.5-80,
0.5-90, 0.5-100, 1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5,
1-5.5, 1-6, 1-8, 1-10, 1-15, 1-20, 1-25, 1-30, 1-40, 1-50, 1-60,
1-70, 1-80, 1-90, 1-100, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4,
1.5-4.5, 1.5-5, 1.5-5.5, 1.5-6, 1.5-8, 1.5-10, 1.5-15, 1.5-20,
1.5-25, 1.5-30, 1.5-40, 1.5-50, 1.5-60, 1.5-70, 1.5-80, 1.5-90,
1.5-100, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5, 2-5, 2-5.5, 2-6, 2-8, 2-10,
2-15, 2-20, 2-25, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100,
2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 2.5-5.5, 2.5-6, 2.5-8,
2.5-10, 2.5-15, 2.5-20, 2.5-25, 2.5-30, 2.5-40, 2.5-50, 2.5-60,
2.5-70, 2.5-80, 2.5-90, 2.5-100, 3-3.5, 3-4, 3-4.5, 3-5, 3-5.5,
3-6, 3-8, 3-10, 3-15, 3-20, 3-25, 3-30, 3-40, 3-50, 3-60, 3-70,
3-80, 3-90, 3-100, 3.5-4, 3.5-4.5, 3.5-5, 3.5-5.5, 3.5-6, 3.5-8,
3.5-10, 3.5-15, 3.5-3.20, 3.5-3.25, 3.5-3.30, 3.5-40, 3.5-50,
3.5-60, 3.5-70, 3.5-80, 3.5-90, 3.5-100, 4-4.5, 4-5, 4-5.5, 4-6,
4-8, 4-10, 4-15, 4-20, 4-25, 4-30, 4-40, 4-50, 4-60, 4-70, 4-80,
4-90, 4-100, 4.5-5, 4.5-5.5, 4.5-6, 4.5-8, 4.5-10, 4.5-15, 4.5-20,
4.5-25, 4.5-30, 4.5-4.50, 4.5-50, 4.5-60, 4.5-70, 4.5-80, 4.5-90,
4.5-100, 5-5.5, 5-6, 5-8, 5-10, 5-15, 5-20, 5-25, 5-30, 5-40, 5-50,
5-60, 5-70, 5-80, 5-90, 5-100, 5.5-6, 5.5-8, 5.5-10, 5.5-15,
5.5-20, 5.5-25, 5.5-30, 5.5-40, 5.5-50, 5.5-60, 5.5-70, 5.5-80,
5.5-90, 5.5-100, 6-8, 6-10, 6-15, 6-20, 6-25, 6-30, 6-40, 6-50,
6-60, 6-70, 6-80, 6-90, 6-100, 8-10, 8-15, 8-20, 8-25, 8-30, 8-40,
8-50, 8-60, 8-70, 8-80, 8-90, 8-100, 10-15, 10-20, 10-25, 10-30,
10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 15-20, 15-25,
15-30, 15-40, 15-50, 15-60, 15-70, 15-80, 15-90, 15-100, 20-25,
20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 25-30,
25-40, 25-50, 25-60, 25-70, 25-80, 25-90, 25-100, 30-40, 30-50,
30-60, 30-70, 30-80, 30-90, 30-100, 40-50, 40-60, 40-70, 40-80,
40-90, 40-100, 50-60, 50-70, 50-80, 50-90, 50-100, 60-70, 60-80,
60-90, 60-100, 70-80, 70-90, 70-100, 80-90, 80-100, or 90-100 msec.
In some cases, the maximum change in QRS interval duration
(.DELTA.QRS) following the antiarrhythmic pharmaceutical agent
administered via inhalation can be from about 1 to about 10 msec.
In some cases, the maximum change in QRS interval duration
(.DELTA.QRS) following the antiarrhythmic pharmaceutical agent
administered via inhalation can be from about 5 to about 20 msec.
In some cases, the .DELTA.QRS can be measured in a human PK/PD
study. In the present disclosure, the term ".DELTA.QRS", if not
referred to with reference to time post-administration of the
antiarrhythmic agent, can be used interchangeably with the term
"maximum .DELTA.QRS", e.g. meaning the maximum change in QRS
following administration of the antiarrhythmic agent as provided
herein. In one or more embodiments antiarrhythmic pharmaceutical
agent is a class I, class II, class III, or class IV
antiarrhythmic. In some embodiments, the antiarrhythmic
pharmaceutical agent is a class Ic, antiarrhythmic. In other
embodiments, the antiarrhythmic pharmaceutical agent is flecainide
or a pharmaceutically acceptable salt thereof.
[0378] In some cases, the time point at which the QRS interval is
measured following the antiarrhythmic pharmaceutical agent
administration via inhalation to determine the .DELTA.QRS relative
to pre-dose can be from about 0.1 minute to about 450 minutes, such
as from about 0.1-1, 0.1-3, 0.1-5, 0.1-10, 0.1-15, 0.1-30, 0.1-45,
0.1-60, 0.1-90, 0.1-120, 0.1-150, 0.1-180, 0.1-210, 0.1-240,
0.1-270, 0.1-300, 0.1-330, 0.1-360, 0.1-390, 0.1-410, 0.1-450, 1-3,
1-5, 1-10, 1-15, 1-30, 1-45, 1-60, 1-90, 1-120, 1-150, 1-180,
1-210, 1-240, 1-270, 1-300, 1-330, 1-360, 1-390, 1-410, 1-450, 3-5,
3-10, 3-15, 3-30, 3-45, 3-60, 3-90, 3-120, 3-150, 3-180, 3-210,
3-240, 3-270, 3-300, 3-330, 3-360, 3-390, 3-410, 3-450, 5-10, 5-15,
5-30, 5-45, 5-60, 5-90, 5-120, 5-150, 5-180, 5-210, 5-240, 5-270,
5-300, 5-330, 5-360, 5-390, 5-410, 5-450, 10-15, 10-30, 10-45,
10-60, 10-90, 10-120, 10-150, 10-180, 10-210, 10-240, 10-270,
10-300, 10-330, 10-360, 10-390, 10-410, 10-450, 15-30, 15-45,
15-60, 15-90, 15-120, 15-150, 15-180, 15-210, 15-240, 15-270,
15-300, 15-330, 15-360, 15-390, 15-410, 15-450, 30-45, 30-60,
30-90, 30-120, 30-150, 30-180, 30-210, 30-240, 30-270, 30-300,
30-330, 30-360, 30-390, 30-410, 30-450, 45-60, 45-90, 45-120,
45-150, 45-180, 45-210, 45-240, 45-270, 45-300, 45-330, 45-360,
45-390, 45-410, 45-450, 60-90, 60-120, 60-150, 60-180, 60-210,
60-240, 60-270, 60-300, 60-330, 60-360, 60-390, 60-410, 60-450,
90-120, 90-150, 90-180, 90-210, 90-240, 90-270, 90-300, 90-330,
90-360, 90-390, 90-410, 90-450, 120-150, 120-180, 120-210, 120-240,
120-270, 120-300, 120-330, 120-360, 120-390, 120-410, 120-450,
150-180, 150-210, 150-240, 150-270, 150-300, 150-330, 150-360,
150-390, 150-410, 150-450, 180-210, 180-240, 180-270, 180-300,
180-330, 180-360, 180-390, 180-410, 180-450, 210-240, 210-270,
210-300, 210-330, 210-360, 210-390, 210-410, 210-450, 240-270,
240-300, 240-330, 240-360, 240-390, 240-410, 240-450, 270-300,
270-330, 270-360, 270-390, 270-410, 270-450, 300-330, 300-360,
300-390, 300-410, 300-450, 330-360, 330-390, 330-410, 330-450,
360-390, 360-410, 360-450, 390-410, 390-450, or 410-450 min.
[0379] The antiarrhythmic activity of pharmaceutical agent can be
correlated with QRS interval duration. In some examples, the
antiarrhythmic pharmaceutical agent administered via inhalation can
have higher antiarrhythmic activity as compared to the
antiarrhythmic pharmaceutical agent administered by intravenous
delivery (e.g., intravenous infusion). In some cases, such a higher
antiarrhythmic activity is reflected by a higher ratio of maximum
.DELTA.QRS to C.sub.max. For example, given the same C.sub.max,
e.g., peak plasma concentration of the antiarrhythmic pharmaceutic
agent, inhalation delivery of the antiarrhythmic agent as provided
herein can have a higher maximum .DELTA.QRS as compared to
intravenous delivery of the same agent. In some cases, the
comparison may not be made between corresponding doses via the two
different administration routes, for example, inhalation of a first
dose of the agent can have a first C.sub.max (C.sub.max1) and a
first maximum .DELTA.QRS (.DELTA.QRS.sub.max1), and intravenous
administration of a second dose of the agent can have a second
C.sub.max (C.sub.max2) and a second maximum .DELTA.QRS
(.DELTA.QRS.sub.max2). In some cases, C.sub.max1 and C.sub.max2 can
be similar. In other case, C.sub.max1 and C.sub.max2 can be
dissimilar. In some examples of the present disclosure, the ratio
of .DELTA.QRS.sub.max1 versus C.sub.max1 can be higher than
.DELTA.QRS.sub.max2 versus C.sub.max2, i.e.,
.DELTA.QRS.sub.max1/C.sub.max1>.DELTA.QRS.sub.max2/C.sub.max2.
In some cases, .DELTA.QRS.sub.max1/C.sub.max1 is at least 1.1
folds, at least 1.2 folds, at least 1.3 folds, at least 1.4 folds,
at least 1.5 folds, at least 1.6 folds, at least 1.7 folds, at
least 1.8 folds, at least 1.9 folds, at least 2.0 folds, at least
2.1 folds, at least 2.2 folds, at least 2.3 folds, at least 2.4
folds, at least 2.5 folds, at least 2.6 folds, at least 2.7 folds,
at least 2.8 folds, at least 2.9 folds, at least 3.0 folds, at
least 3.1 folds, at least 3.2 folds, at least 3.3 folds, at least
3.4 folds, at least 3.5 folds, at least 3.6 folds, at least 3.7
folds, at least 3.8 folds, at least 3.9 folds, at least 4.0 folds,
at least 4.2 folds, at least 4.4 folds, at least 4.6 folds, at
least 4.8 folds, at least 5.0 folds, at least 5.5 folds, at least 6
folds, at least 7 folds, at least 8 folds, at least 9 folds, at
least 10 folds, at least 12 folds, at least 15 folds, at least 20
folds, at least 25 folds, or at least 50 folds greater than
.DELTA.QRS.sub.max2/C.sub.max2. In some cases,
.DELTA.QRS.sub.max1/C.sub.max1 is at least 2 folds greater than
.DELTA.QRS.sub.max2/C.sub.max2. In one or more embodiments
antiarrhythmic pharmaceutical agent is a class I, class II, class
III, or class IV antiarrhythmic. In some embodiments, the
antiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic.
In other embodiments, the antiarrhythmic pharmaceutical agent is
flecainide or a pharmaceutically acceptable salt thereof.
[0380] The present invention will be further illustrated by way of
the following Examples. These examples are non-limiting and do not
restrict the scope of the invention. Unless stated otherwise, all
percentages, parts, etc. presented in the examples are by
weight.
EXAMPLES
Example 1
Prophetic Analytical Model Involving Verapamil and Lidocaine
[0381] Published pharmacokinetic and pharmacodynamic models (FIG.
4) show relationships between drug concentration in coronary blood
and desired coronary effect. IV drug information was used from
published literature. HARRISON et al., "Effect of Single Doses of
Inhaled Lignocaine on FEV1 and Bronchial Reactivity in Asthma,"
Respir Med., 12:1359-635 (December 1992). Inhaled drug information
was simulated based on known properties of pulmonary small molecule
absorption.
[0382] FIG. 5 shows the different time concentration profiles of
drug administered via the IV and inhalation routes. Verapamil was
selected as an example heart drug as it possesses both cardiac rate
and rhythm control properties and is often used to rescue acute
arrhythmia episodes (e.g., PSVT, paroxysmal supraventricular
tachycardia).
[0383] FIG. 6 also shows different time concentration profiles of
drug administered via the IV and inhalation routes. Lidocaine was
selected as an example heart drug. This PK/PD modeling with
lidocaine shows same high feasibility.
Example 2
Effects of Intratracheal (IT) Administration of Anti-Arrhythmic
Compounds on the Ventricular Response of Dogs with Induced Atrial
Fibrillation and Supraventricular Tachycardia (SVT)
[0384] Objective:
[0385] To evaluate the effects/efficacy of common antiarrhythmic
drugs when given via the pulmonary route, on the
electrophysiological response of anesthetized dogs with induced
atrial fibrillation and supraventricular tachycardia.
[0386] Animal Models Used
[0387] Atrial Fibrillation Model:
[0388] Anesthesia/Surgical Preparation:
[0389] A venous catheter was placed in a peripheral vessel (i.e.,
cephalic) for administration of anesthetic. For anesthesia
induction, all animals were given morphine sulfate (.about.2 mg/kg)
and a bolus of alpha chloralose (.about.100 mg/kg) intravenously
through the venous catheter. Anesthesia was sustained with alpha
chloralose (35-75 mg/kg/hour IV), until completion of the study
(<2 hours). Following induction, animals were endotracheally
intubated and mechanically ventilated (.about.12 breaths/minute
with a tidal volume of 200-300 mL). Subsequently, a cut-down on a
jugular vein permitted introduction of a pacing lead into the right
atrium. Transthoracic electrodes forming ECG lead II were placed.
For test/vehicle article delivery, a 4F catheter was introduced
through the trachea and wedged into a small airway, and a venous
catheter was placed in a peripheral vessel (i.e., cephalic).
[0390] Experiments:
[0391] Following instrumentation and hemodynamic stabilization (for
at least 15 minutes), phenylephrine was continuously infused (2
ug/kg/min IV) to elevate the systemic arterial pressure and
increase vagal (parasympathetic) efferent activity for the duration
of the study. Approximately 5 min after administration of this
parasympathomimetic was started; the following experiments were
performed:
[0392] First, the right atrium was paced (20 V, 40 Hz, 4 ms pulse)
for 15 minutes, and following pacing discontinuation, atrial
fibrillation ensued. Approximately 3 minutes after pacing was
stopped and atrial fibrillation was observed, the animals were
given vehicle (.about.3 mL) intra-tracheally (IT); the duration
between dosing and, (if observed) the return to sinus rhythm and/or
the ventricular rate was noted. Observations were made for up to 10
minutes.
[0393] Subsequently, atrial fibrillation was re-established via
15-minute pacing cycle(s), as described above. Once pacing was
discontinued and atrial fibrillation was observed/stable for 3
minutes, the animals were administered the vehicle or one of the
test articles, delivered as a bolus (.about.3 mL) directly into a
small airway through the intratracheal catheter. Vehicle was only
water. In the case of flecainide as the test article, the
concentration was 15 mg of flecainide/3 ml of water. Following
dosing, the duration between cessation of administration and, if
observed, return to sinus rhythm and/or ventricular rate were
noted; observations were made for up to 10 minutes. Overall, three
groups/test-articles were studied, and up to two animals were
assigned to each group (n=2/group): one group received flecainide
acetate (2-4 mg/kg, FLE), while the others received diltiazem
(0.25-0.50 mg/kg, DIL) or dofetilide (20-60 ug/kg, DOF); only one
test article was administered per animal. The experimental
protocol(s) are summarized in FIG. 7.
[0394] Supraventricular Tachycardia Model:
[0395] Anesthesia/Surgical Preparation:
[0396] A venous catheter was placed in a peripheral vessel (i.e.,
cephalic) for administration of anesthetic(s). For anesthesia
induction, all animals were given a combination of diazepam
(.about.0.5 mg/kg) and ketamine (.about.10 mg/kg) intravenously
through this venous catheter. Anesthesia was sustained until
completion of the study with an intravenous infusion of
pentobarbital (5-15 mg/kg/hr). Following induction, animals were
endotracheally intubated and mechanically ventilated (.about.12
breaths/min with a tidal volume of 200-300 mL).
[0397] Subsequently, a cut-down on a jugular vein permitted the
introduction of a pacing lead into the right atrium. Similarly, for
arterial pressure monitoring, a solid-state micromanometer catheter
(Millar Instruments) was advanced into the aortic root via a
cut-down over an artery (e.g., femoral, carotid). Transthoracic
electrodes forming ECG lead II was placed. For vehicle/test article
delivery, a 4F catheter was introduced through the trachea and
wedged into a small airway, and a venous catheter was placed in a
peripheral vessel (i.e., cephalic).
[0398] Experiments:
[0399] Following instrumentation/hemodynamic stabilization (for at
least 15 minutes), right atrial pacing (5-10 V, 40 Hz, 2 ms pulses)
was established in order to induce supraventricular tachycardia
(SVT); pacing and SVT was sustained throughout the duration of the
experiments. Approximately 5 minutes after onset of SVT and while
monitoring ECG/arterial pressure continuously, the animals were
administered three escalating doses (one at a time) of a test
article; each dose was delivered as a bolus (.about.3 mL) directly
into a small airway through the intratracheal catheter (IT).
Following dosing, the heart-rate (HR) and arterial pressure
response were monitored for 15 minutes.
[0400] Subsequently (once the response to three IT doses had been
recorded), hemodynamic recovery was allowed for approximately 30
minutes, and the electrocardiographic/hemodynamic response to the
highest test-article dose was re-evaluated; however, for comparison
purposes, this dose was delivered intravenously (IV).
[0401] Overall, two groups/test-articles were studied, and up to
two animals were assigned to each group (n=2/group): one group
received esmolol HCL (0.5-1.0 mg/kg, ESM), while the other received
adenosine (0.25-1.0 mg/kg, ADN); only one test article was
administered to per animal. The experimental protocol(s) are
summarized in FIG. 8.
[0402] Observations:
[0403] Atrial Fibrillation:
[0404] Among the three test articles (flecainide, diltiazem and
dofetilide) studied, both flecainide and diltiazem rapidly
converted the Atrial Fibrillation to normal sinus rhythm, while
dofetilide marginally slowed the ventricular rate.
[0405] Vehicle:
[0406] FIG. 9 shows a representative example of a dog in atrial
fibrillation prior to administration of either vehicle or test
article. FIG. 10 shows an example of the vehicle having no effect
on the arrhythmia. Vehicle administered in same volumes as the test
articles had no effect on the arrhythmia.
[0407] Flecainide:
[0408] At pulmonary dose between 2-4 mg/kg body weight, flecainide
converted the induced atrial fibrillation to normal sinus rhythm.
Large doses of the drug also resulted in slower ventricular rates.
None to minimal drop in mean arterial pressure was noted. Neither
dogs exhibited any known adverse events such as proarrhythmia. See
FIGS. 11 and 12.
[0409] Diltiazem:
[0410] At pulmonary doses of 0.25 mg/kg body weight, diltiazem
converted the induced atrial fibrillation to normal sinus rhythm
and also prolonged the PQ interval. Heart rate also slowed down but
marginally. There was however a notable drop in mean arterial blood
pressure (MAP). See FIG. 13.
[0411] Dofetilide:
[0412] At escalating pulmonary doses of 10-40 mcg/kg body weight,
dofetilide caused minor reduction in heart rate.
[0413] Supraventricular Tachycardia (SVT):
[0414] Diltiazem:
[0415] The diltiazem delivered via the pulmonary and IV routes were
comparable in all aspects. The Mean Arterial Pressure (MAP) dropped
significantly in both cases, attributed directly to the dose of the
drug. Diltiazem also prolonged the PR interval indicating that the
drug delivered by either IV or pulmonary routes has the potential
to convert the SVT to normal sinus rhythm. The timing of the
electrophysiological change was comparable between IV and
pulmonary. See FIGS. 14 and 15.
[0416] Esmolol:
[0417] Elevating doses of esmolol were shown to produce 2.sup.nd
degree AV block at lower doses and also prolonging the PR intervals
in the ECG traces. See FIGS. 16-20.
[0418] However, higher doses of esmolol at 1.0 mg/kg did not
produce the same electrophysiological effects. It is noteworthy
that esmolol delivered via the lung did not cause a drop in MAP in
any of the doses.
[0419] Adenosine:
[0420] Adenosine administered via the lung did not have any effect
on the heart. Adenosine is known to metabolize differently in
different species and it is not clear whether the effect was due to
the ultra-rapid metabolism of adenosine or the model not being
sensitive enough.
[0421] Summary:
[0422] There was a clear cardiovascular effect of diltiazem,
flecainide, and a probable effect of esmolol and dofetilide when
given by intratracheal instillation. These drugs comprise four
divergent classes of chemical and pharmacological agents. Although
a clear response was not observed with adenosine, it is still
considered worthy of evaluation in other animal models. The
responses mimicked qualtitatively those of the IV route and known
physiological effects of all test articles for diltiazem,
flecainide, and esmolol. There may be some physical or
physicochemical property of adenosine that precludes absorption
from the tracheal route in this animal model. Additionally,
administration into a single small airway would not be expected to
produce the same exposure as administration by inhalation where the
surface for diffusion would be many orders of magnitude
greater.
[0423] These studies confirm the physiological effects of divergent
chemicals on cardiovascular function. The intratracheal route of
administration possesses 3 potential advantages. (1) It is the
shortest route from point of administration to the target
organ--the heart. (2) There is less dilution therefore a higher
concentration to the target organ would be expected. (3) There
would be a reduction in metabolism (i.e., first pass effect) since
there is no organ (e.g., liver) for metabolizing between site of
administration and target organ.
Example 3
Preliminary Evaluation of Solubility and Taste of Antiarrhythmic
Pharmaceutical Agents when Administered as an Aerosol
[0424] Objective:
[0425] To evaluate the solubilities of flecainide acetate and
diltiazem hydrochloride in water and to evaluate the acceptability
of taste and aftertaste of these two drugs for administration as
liquid aerosols.
Experiment and Observations
Preformulation Studies
[0426] Diltiazem's solubility was >90 mg/mL at room temperature.
The pH of a 3.5 mg/mL solution of diltiazem in water was 6.7. At 50
mg/mL, a diltiazem in water solution was about 80% to isotonic.
[0427] Flecainide's solubility was about 30 mg/mL at room
temperature. The pH of a 2.6 mg/mL solution of flecainide in water
was 5.0. At 30 mg/mL, a flecainide in water solution was about 50%
to isotonic.
[0428] The following solution strengths were prepared for taste
evaluation: (1) diltiazem hydrochloride--50 mg/ml solution in
distilled water; and (2) flecainide acetate--30 mg/ml solution in
distilled water. The solutions were clear with no visible
particulate matter.
[0429] Inhalation Device:
[0430] The Aeroneb.RTM.GO device was used because it is a
simple-to-use device developed specifically for patients who
require respiratory therapy in and away from the home. The device
can be used by patients of all ages (infant through adult) and
aerosolizes solutions intended for inhalation. Aeroneb.RTM. Go
works with either an AC wall controller or a battery pack, and can
be cleaned with soap and water.
[0431] Inhalation Procedure:
[0432] Volunteers:
[0433] Number of subjects: 2 healthy male volunteers
[0434] Volunteer-1: age--48
[0435] Volunteer-2: age--63
[0436] Nebulizer Testing:
[0437] Water was poured into the nebulizer cup, and the nebulizer
was turned on. The visible cloud of aerosol generated when the
nebulizer was turned on was treated as a qualitative aerosol
standard.
[0438] Flecainide Acetate:
[0439] About 1 ml of the 30 mg/ml solution was poured into the cup
of the nebulizer. The nebulizer was turned on and the resulting
aerosol was similar to but not as dense as the aerosol formed with
the water alone.
[0440] The nebulizer was then placed in the mouth and switched on.
Deep lung inhalation was performed through the nebulizer. About 40
.mu.l (.about.1.2 mg of flecainide acetate) of the test solution
was inhaled. The inhaled dose was sub-therapeutic in nature as it
was much less than the regular 100 mg administered as tablets.
Flecainide acetate is also available as an IV injection in Europe
as 10 mg/ml strength in 15 ml ampoules.
[0441] Diltiazem Hydrochloride:
[0442] About 1 ml of the 50 mg/ml solution was poured into the cup
of the nebulizer. The nebulizer was turned on and the resulting
aerosol was similar to but not as dense as the aerosol formed with
the water alone.
[0443] The nebulizer was then placed in the mouth and a switched
on. Deep lung inhalation was performed through the nebulizer. About
40 .mu.l (.about.2 mg of diltiazem hydrochloride) of the test
solution was inhaled. The inhaled dose was sub-therapeutic in
nature as it was much less than the IV injection marketed in the
U.S. as 5 mg/ml in 5 ml vials.
Conclusions and Observations
[0444] 1. The visible aerosol characteristics test solutions were
similar to each other but not as dense as the water.
[0445] 2. Flecainide acetate: The taste feedback from both
volunteers was very similar.
[0446] a. Taste: Mildly bitter taste felt in the back of the
tongue
[0447] b. Aftertaste: There was none to little aftertaste 5 minutes
after the inhalation maneuver.
[0448] 3. Diltiazem hydrochloride: Water was inhaled to wash out
any of the flecainide residues. The taste feedback from both
volunteers was very similar.
[0449] a. Taste: Mildly bitter taste felt in the back of the
tongue
[0450] b. Aftertaste: There was none to little aftertaste 5 minutes
after the inhalation maneuver.
[0451] 4. Other observations:
[0452] a. No burning sensations was felt in the mouth, throat, or
lungs
[0453] b. No visible adverse events were observed. Both volunteers
rested for 60 minutes after dosing.
Example 4
A Single Ascending Dose Study of Flecainide Acetate Inhalation
Solution to Assess the Safety, Tolerability, Pharmacokinetics and
Pharmacodynamics of the Drug
[0454] A Phase 1 study was performed in normal healthy volunteers
to assess the safety, tolerability, pharmacokinetics (PK) and
pharmacodynamics (PD) of oral inhaled flecainide and to compare the
PK/PD relationship of inhaled flecainide acetate solution to
intravenous (IV) flecainide acetate. The Phase 1 clinical study
(FLE-001) was a single center study conducted at CMAX in Adelaide,
Australia, comprised of two parts (sub-studies), Part A and Part B.
The 1) pharmacokinetics (PK), 2) pharmacodynamics (PD), and 3)
safety and tolerability of single ascending doses (SADs) of inhaled
flecainide acetate compared to placebo in healthy volunteers were
evaluated.
[0455] Study Design:
[0456] This was a single-center study comprising two parts, A and
B. The study design schematic is shown in FIG. 21.
[0457] Part A was a double-blind, randomized, placebo-controlled
design consisting of SADs of flecainide acetate inhalation solution
(estimated total lung doses [eTLD] of 20 mg, 40 mg, or 60 mg) or
matching placebo inhalation solution administered using a hand-held
inhaler device (AeroEclipse.RTM. II Breath Actuated Nebulizer
(BAN)) to healthy adult males and females. Subjects were randomized
to receive a single inhalation of either flecainide acetate
inhalation solution or placebo inhalation solution in double-blind
fashion. 3 cohorts of subjects, in total 34 healthy adult
volunteers, were recruited for Part A study.
[0458] Part B was an open label non-randomized crossover in a
cohort of 6 evaluable healthy adult volunteers. This part of the
study consisted of two periods with each subject receiving a total
of 2 doses of flecainide, one dose in each period. In Period 1, 3
subjects received flecainide acetate solution by inhalation at the
dose level of 30 mg eTLD, and 3 subjects received a single dose of
2 mg/kg (or 150 mg, whichever is less) via a 10 min intravenous
(IV) infusion of flecainide (Tambocor.TM. Injection; approved and
used in clinical practice in Australia). In Period 2, the subjects
who received flecainide inhalation solution in Period 1 now
received a single dose of IV flecainide (2 mg/kg or 150 mg,
whichever is less, via a 10 min infusion), while the subjects who
received IV flecainide in Period 1 now received flecainide
inhalation solution (30 mg eTLD). Shown in FIGS. 87A and 87B are
the baseline (pre-dose) values of HR, Systolic BP and Diastolic BP
(FIG. 87A) and, PR and QRS interval durations (FIG. 87B) for Period
1 and Period 2 in the 6 subjects studied (prior to administration
of flecainide, either via IV infusion or oral inhalation. The
finding that the baseline values for Period 1 and Period 2 prior to
dosing are near identical is consistent with the expectation from a
cross-over design study. The interpretation that there was no carry
over effect of treatment or other changes in the subjects' vital
signs and ECG intervals between the two periods.
[0459] Chronologically, experiments involving Cohorts 1, 2, and 5
started in early stage of this clinical study, while experiments
involving subjects in Cohort 3 started later. As a result, some of
the data analyses presented below are based on data from Cohorts 1,
2, and/or 5 without data from Cohorts 3.
[0460] Study Population:
[0461] In Cohorts 1 and 2, all 22 volunteer subjects were healthy
male Caucasians, except for one Asian.
[0462] In Cohort 3, all 12 volunteer subjects were male
Caucasians.
[0463] In Cohort 5, 7 volunteer subjects were enrolled, among which
6 completed the study. All subjects were male. Of the 6 volunteer
subjects who completed the study, 5 were Caucasians and one
Asian.
[0464] Doses:
[0465] Subjects in Cohort 1 (n=8) inhaled placebo (n=2) or 20 mg
eTLD of a flecainide acetate solution (n=6). Subjects in Cohort 2
(n=14) inhaled placebo (n=4) or 40 mg eTLD of a flecainide acetate
solution (n=10). Subjects in Cohort 3 (n=12) inhaled placebo (n=3)
or 60 mg eTLD of a flecainide acetate solution (n=9). Subjects in
Cohort 5 first inhaled 30 mg eTLD of a flecainide acetate solution
and later received 2 mg/kg of flecainide by IV infusion (n=3), or
subjects in Cohort 5 initially received 2 mg/kg of flecainide by IV
infusion and subsequently inhaled 30 mg eTLD of a flecainide
acetate solution (n=3).
[0466] In this study, for inhalation delivery of flecainide, the
estimated total lung doses (eTLDs) were calculated to account for
losses of flecainide in the inhalation device and losses of
flecainide in subjects' mouth and throat. eTLD was thereby used to
denote the dose that actually reached the lungs of the subjects. By
design, in all nebulizers there can be a residual volume or mass of
drug solution that stays in the nebulizer, and there can also be a
percentage of the aerosol caught by subject's throat and mouth. For
instance, in this study, it was estimated that 30% of the aerosol
was lost in subject's throat and mouth. Therefore the eTLD would
be:
eTLD=(100-30)%*amount of aerosolized drug that left
nebulizer=70%*(amount of drug placed in nebulizer-amount of drug
staying in nebulizer).
[0467] The percentage of aerosol that is caught by subject's throat
and mouth can depend on the aerosol particle size, for example, the
fraction of the aerosol that is above approximately 5 microns. The
amount that passes the throat and gets to the lungs can be termed
"Fine Particle Fraction (FPF)."
[0468] The amount of drug that stays in the nebulizer can depend on
the design of the nebulizer and how it is operated. For example,
for some jet nebulizers, this can be about 0.5 to 2 mL of solution.
For some vibrating mesh nebulizers, it can be 0.05 to 0.3 mL. For
Dry Powder Inhalers, it can be 10% to 50% of the dose, etc.
[0469] Safety:
[0470] Heart rate and systolic and diastolic blood pressure were
measured pre-dose, immediately following oral inhalation or IV
infusion of placebo or flecainide, and up to 360 minutes after oral
inhalation or IV infusion of placebo or flecainide to evaluate
cardiovascular safety.
[0471] Pulmonary safety was assessed by performing lung spirometry
tests and measuring peripheral oxygen saturation (SpO.sub.2%) prior
to dosing and at various times after completion of the inhalation.
Lung spirometry tests evaluated all lung function parameters,
including forced vital capacity (FVC), forced expiratory volume in
1 second (FEV1), peak expiratory flow (PEF), and forced expiratory
flow at 25% and 75% intervals (FEF25-75). Auscultation and
respiration rate were also measured prior to dosing and at various
times after inhalation. Chest x-rays were performed on subjects
before and after flecainide inhalation.
[0472] Adverse events were monitored and recorded.
[0473] PK:
[0474] Venous plasma concentration of flecainide was measured
following oral inhalation or IV infusion (10 min) of
flecainide.
[0475] The following PK parameters were calculated: the maximum
venous plasma concentration of flecainide observed (C.sub.max), the
time at which the C.sub.max was observed (T.sub.max), the area
under the concentration-time curve up to the last measurable
concentration (AUC.sub.Last), the time at which flecainide plasma
levels decreased to half of what they were at equilibrium due to
distribution to tissues throughout the body (distribution
t.sub.1/2), and the time at which flecainide plasma levels
decreased to half of what they were at equilibrium due to
metabolism and elimination (elimination t.sub.1/2).
[0476] PD:
[0477] Intensive electrocardiographic (ECG) monitoring was
performed in all subjects during the study to assess the
pharmacodynamic activity (e.g., QRS intervals) of inhaled or IV
administered flecainide. The ECG recordings included: 1) Continuous
real-time ECG telemetry for observation of patient safety starting
at 12 hours pre-dose and continuing for 12 hours post-dose, 2)
12-lead ECGs for immediate review by medical staff to ascertain the
safety of the procedures and drug administration were recorded at
pre-specified (or any time as needed) before dosing (pre-dose) and
after dosing (post-dose), and 3) continuous 12-lead ECG (cECG,
iCardiac Holter monitoring) was recorded for 24 hours, starting 1
hour prior to dosing and up to 24 hours post dosing.
[0478] Results:
[0479] Safety Evaluations:
[0480] The changes in heart rate (HR), arterial systemic blood
pressure (BP), and pulmonary function test parameters associated
with administration of flecainide or placebo were assessed. In
addition, the effects of changing posture from semi-recumbent to
seated upright, vice-versa and during inhalation on HR and BP were
assessed (Cohort 5).
[0481] Transient increases (between 1 and 3 minutes) in both HR and
systolic and diastolic BPs were observed in subjects administered
inhaled flecainide and placebo. These changes can be attributed to
the sympathetic reflex (unloading of baroreceptors) responses to
postural changes (from semi-recumbent to seated) and likely to the
oral inhalation procedure, e.g., the relatively prolonged and deep
respiratory breath, akin to .about.2 seconds of breath-holding at
the end of inspiratory phase of the inhalation.
[0482] Heart Rate Measurements:
[0483] The magnitude of the increases in HR was variable, not
dose-dependent (e.g., greater increases in the 20 mg eTLD than in
the 30, 40 and 60 mg eTLD groups). The baseline HR in beats per
minute (bpm) was within the expected range for the population of
healthy subjects in Cohort 1. Immediately, at the end of inhalation
of 20 mg eTLD of flecainide acetate, there was an initial increase
in HR from baseline with mean change-from-baseline heart rate
(.DELTA.HR) of .about.12 bpm at 1 and 3 minutes, with subsequently
smaller increases at later time points. Fifteen and 30 minutes
after the end of inhalation, mean .DELTA.HR was .about.4 bpm (FIG.
22).
[0484] In subjects of Cohort 2, there was an initial transient
increase in the HR of 12 to 8 bpm at 1 to 3 minutes, respectively,
after completion of inhalation of 40 mg eTLD of flecainide.
Thereafter, the HR quickly decreased toward the pre-dose; at 10
minutes, post-dosing .DELTA.HR was +5 bpm (FIG. 23).
[0485] The time course of the changes in HR in subjects of Cohort 3
that were given either flecainide (eTLD of 60 mg) or placebo
inhalation solutions are shown in FIG. 72. For 60 mg eTLD (FIG. 72)
the changes in heart rate (HR) were comparable to those observed in
the placebo group.
[0486] An increase in HR was observed in subjects of Cohort 5
following single dose administration of inhaled flecainide (30 mg
eTLD) and IV flecainide (2 mg/kg) (FIG. 24).
[0487] There was no change in HR following the inhalation of the
placebo solution.
[0488] Systolic and Diastolic Blood Pressure Measurements:
[0489] During inhalation of either flecainide acetate or placebo
solutions, both systolic and diastolic blood pressure (BP) of
subjects in Cohort 1 increased during the first 15 minutes
(placebo) to 30 minutes (flecainide) after completion of the
inhalation. Thereafter, they declined toward the pre-dose pressures
(FIGS. 25A and B).
[0490] During inhalation of either flecainide (40 mg eTLD) or
placebo, both systolic and diastolic pressures in subjects of
Cohort 2 rose transiently during the initial 1 to 3 minutes and
declined toward pre-dose values within the following 10 to 15
minutes after completion of the inhalation (FIGS. 26A and B).
[0491] In the subjects of cohort 3, those that inhaled the highest
eTLD of 60 mg, the increases in systolic and diastolic BP at or
near the time (T.sub.max) of maximal (peak) concentration
(C.sub.max) of flecainide achieved, were 5 and 4 mmHg,
respectively; whereas for subjects that inhaled the placebo
solution, the increases were 3 and 2 mmHg, respectively.
[0492] Considering the overlapping standard deviations of the mean
values, the magnitude of the changes in blood pressure (systolic
and diastolic), for subjects receiving either inhaled flecainide or
placebo, were similar for all doses tested.
[0493] Increases in systolic and diastolic BP were observed in
subjects of Cohort 5 following single dose administration of
inhaled flecainide (30 mg eTLD; FIGS. 27A and B). Decreases in
systolic and diastolic BP were observed following IV flecainide
administration (2 mg/kg; FIGS. 27A and B).
[0494] Further analyses are shown in FIG. 73 with regards to
changes in HR and blood pressures after IV flecainide or inhaled
flecainide. The maximal increase in HR with administration of IV
infusion of flecainide was 7 bpm, at the end of infusion (FIG. 73).
The increases in HR during and following the IV infusion of
flecainide were accompanied by a transient decrease in systolic
pressure of 9 mmHg at the end of infusion (FIG. 73) and as much as
18 mmHg at 3 minutes post-dosing (FIG. 75A). Diastolic pressure
decreased by .about.2 mmHg at the end of infusion (not shown) and
by as much as 7 mmHg at 3 minutes post-dosing (FIG. 75B). The
maximal increase in HR with administration of inhaled flecainide
was 5 bpm, at the end of inhalation (FIG. 74). During oral
inhalation of flecainide, the HR at 1 minute after completion of
inhalation (duration of inhalation .about.4.5 minutes) increased by
2 bpm (FIG. 74). Not shown at mid-point (1.5 minutes) into the
inhalation, the HR, which was highly variable among subjects,
increased from 68.+-.12 to 77.+-.17 bpm (data not available for 4
of 6 subjects). The changes in systolic (FIGS. 74 and 75A) and
diastolic (FIG. 75B) pressures were rather small, in the range of
-3 to +1 mmHg. For the administration via inhalation, the changes,
increases or decreases, in HR and BP can be attributed, in part, to
the change in posture and/or inhalation procedure (FIGS. 72, 75A
and 75B). For the IV infusion, the transient decrease in BP can be
attributed to the negative ionotropic effects of flecainide,
whereas the increase in HR is due to the baroreceptor reflex
triggered by the fall in BP. FIGS. 75A and 75B summarize the
changes in systolic (FIG. 75A) and diastolic blood (FIG. 75B)
pressures following administration of IV infusion or oral
inhalation of flecainide, and it shows a lack of negative
hemodynamic effects of inhaled flecainide at an eTLD of 30 mg
compared to the .about.5-fold higher dose (.about.150 mg) of
flecainide given via IV infusion.
[0495] Lung Spirometry Measurements:
[0496] For all the subjects in Cohorts 1, 2, 3, and 5, all standard
lung spirometry measurements (e.g., FEV1, PEF, FVC and FEF 25-75)
and peripheral 02 saturation values were normal before and after
flecainide or placebo. Likewise, there were minimal or no changes
in respiratory rate. There were no differences among cohorts or
between randomized treatment assignment.
[0497] The results of the lung spirometry tests performed in
subjects of Cohort 1 are summarized in Table 1 below.
TABLE-US-00001 TABLE 1 Changes in pulmonary function parameters of
subjects from Cohort 1 prior to and following oral inhalation of
flecainide acetate (20 mg eTLD) and placebo solutions. Flecainide
(n = 6) Placebo (n = 2) Time Std. Std. Point Test Unit Mean Dev SEM
Mean Dev SEM 12 hours FVC L 6.02 0.25 0.11 6.17 1.12 0.80 Pre-dose
FEV1 L 5.26 1.25 0.51 5.19 0.95 0.67 PEF L/s 11.30 1.86 0.76 9.52
0.15 0.11 FEF 25-75 L/s 5.38 2.13 0.87 5.67 1.05 0.75 3 hours FVC L
6.42 0.96 0.39 6.10 1.44 1.02 Post-dose FEV1 L 5.27 1.22 0.50 5.14
1.11 0.78 PEF L/s 10.87 1.88 0.77 10.37 2.34 1.66 FEF 25-75 L/s
5.48 1.99 0.81 5.48 0.99 0.70 24 hours FVC L 6.36 0.98 0.40 6.18
1.31 0.93 Post-dose FEV1 L 5.18 1.27 0.52 5.25 1.03 0.73 PEF L/s
11.09 2.01 0.82 10.70 2.14 1.52 FEF 25-75 L/s 5.40 2.73 1.12 5.69
0.84 0.59 Abbreviations: FVC = forced vital capacity; FEV1 = forced
expiratory volume in 1 second; PEF = peak expiratory flow; FEF25-75
= forced expiratory flow at 25% and 75% intervals
[0498] The results of the lung spirometry tests performed in
subjects of Cohort 2 are summarized in Table 2 below.
TABLE-US-00002 TABLE 2 Changes in pulmonary function parameters of
subjects from Cohort 2 prior to and following oral inhalation of
flecainide acetate (40 mg eTLD) and placebo solutions Flecainide (n
= 10) Placebo (n = 4) Time Std. Std. Point Test Units Mean Dev SEM
Mean Dev SEM 12 hours FVC L 6.18 0.96 0.32 5.56 0.53 0.26 Pre-dose
FEV1 L 5.04 0.74 0.25 4.67 0.56 0.28 PEF L/s 10.83 1.73 0.55 9.71
0.91 0.46 FEF25-75 L/s 5.00 0.91 0.29 4.61 0.95 0.48 3 hours FVC L
6.19 0.72 0.23 5.64 0.56 0.28 Post-dose FEV1 L 4.96 0.57 0.18 4.58
0.36 0.18 PEF L/s 10.66 1.94 0.61 9.59 1.28 0.64 FEF25-75 L/s 4.34
0.77 0.24 4.51 0.54 0.27 24 hours FVC L 6.39 0.68 0.22 5.68 0.80
0.40 Post-dose FEV1 L 5.08 0.51 0.16 4.60 0.66 0.33 PEF L/s 11.14
1.96 0.62 9.60 1.54 0.77 FEF25-75 L/s 4.80 0.73 0.23 4.60 0.82
0.41
[0499] The pre-dose and post-dose for all lung function parameters
(e.g., FVC, FEV1, PEF, and FEF25-75) were within the normal range
for the population studied, and not different from each other.
There were no differences between either cohorts (1 vs 2) or groups
(placebo vs flecainide) within each cohort (Table 1 and Table
2).
[0500] Peripheral oxygen saturation measurements: peripheral oxygen
saturation levels measured in subjects of Cohort 1 are summarized
in Table 3.
[0501] Peripheral oxygen saturation levels measured in subjects of
Cohort 2 are summarized in Table 4.
[0502] The pre-dose and post-dose values for SpO.sub.2 were within
the normal range (97-98%) and not different from each other. There
were minimal or no differences in SpO.sub.2% between groups
(flecainide vs placebo) and Cohorts (1 vs 2).
[0503] Auscultation was normal in all subjects before and after
inhalation of flecainide (20 mg eTLD, 30 mg eTLD, 40 mg eTLD) and
placebo solutions.
[0504] No changes in respiration rate were measured before and
after inhalation of flecainide (20 mg eTLD, 30 mg eTLD, 40 mg eTLD)
and placebo solutions.
[0505] Chest x-rays were normal and showed no changes in subjects
before and after inhalation of flecainide (20 mg eTLD, 30 mg eTLD,
40 mg eTLD) and placebo solutions.
TABLE-US-00003 TABLE 3 Summary of data on peripheral oxygen
saturation (SpO.sub.2%) for subjects of Cohort 1 measured prior to
and at various times following inhalation of flecainide acetate
solution (20 mg eTLD) or placebo. Oxygen Saturation (SpO2%) Time
Point Mean Std. Dev SEM Flecainide Predose 98 0.82 0.33 (n = 6) 15
min Postdose 97 1.21 0.49 30 min Postdose 97 1.60 0.65 45 min
Postdose 97 1.21 0.49 60 min Postdose 97 0.75 0.31 75 min Postdose
98 0.84 0.34 90 min Postdose 98 0.52 0.21 105 min Postdose 97 0.89
0.37 120 min Postdose 98 0.55 0.22 Placebo Predose 98 0.71 0.50 (n
= 2) 15 min Postdose 97 0.00 0.00 30 min Postdose 97 1.41 1.00 45
min Postdose 97 0.71 0.50 60 min Postdose 97 0.00 0.00 75 min
Postdose 98 0.71 0.50 90 min Postdose 98 0.71 0.50 105 min Postdose
98 0.71 0.50 120 min Postdose 98 0.71 0.50
TABLE-US-00004 TABLE 4 Summary of data on peripheral oxygen
saturation (SpO.sub.2%) for subjects of Cohort 2 measured prior to
and at various times following inhalation of flecainide acetate
solution (40 mg eTLD) or placebo. Oxygen Saturation (SpO2%) Time
Mean Std. Dev SEM Flecainide Predose 97 0.79 0.25 (n = 10) 15 min
Postdose 96 1.81 0.57 30 min Postdose 97 0.85 0.27 45 min Postdose
96 0.82 0.26 60 min Postdose 96 0.92 0.29 75 min Postdose 97 1.16
0.37 90 min Postdose 97 0.63 0.20 105 min Postdose 97 0.88 0.28 120
min Postdose 97 0.52 0.16 Placebo Predose 98 0.50 0.25 (n = 4) 15
min Postdose 98 0.82 0.41 30 min Postdose 98 0.50 0.25 45 min
Postdose 98 0.58 0.29 60 min Postdose 98 0.00 0.00 75 min Postdose
98 0.58 0.29 90 min Postdose 98 0.96 0.48 105 min Postdose 98 0.50
0.25 120 min Postdose 98 0.50 0.25
[0506] Adverse Events:
[0507] In part A of the study, out of 34 subjects studied, 25 were
given a flecainide solution via oral inhalation and 9 subjects were
given a placebo solution. There was a total of 66
treatment-emergent adverse events (TEAEs) in 28 out of 34 subjects
(82%). All adverse events were mild and required no treatment.
[0508] In study involving Cohorts 1 and 2, the majority of adverse
events lasted between 15-90 minutes. Flecainide was well tolerated,
and no subject interrupted the inhalation. Table 5 below summarizes
the most common adverse events reported by subjects in Cohorts 1
and 2.
TABLE-US-00005 TABLE 5 Summary of the most common adverse events in
subjects following inhalation of a flecainide acetate solution or
placebo solution Cohort 1 (n = 8) Cohort 2 (n = 14) Placebo
Flecainide Placebo Flecainide Adverse Event (n = 2) (n = 6) (n = 4)
(n = 10) Throat Discomfort/ 0 2 1 5 Irritation Lightheadedness 1 1
0 1 Cough 0 1 1 1
[0509] A summary of the study-drug related AEs and the assessment
of their intensity is summarized in Table 6. From all 34 subjects
studied, 24 (71%) had a total of 47 TEAEs that were considered
study-drug related. Only 2 (6%) subjects had a total of 3 moderate
or severe TEAEs; 1 subject (3%) had 2 TEAEs that were considered
study-drug related. No serious adverse events were reported, and no
subject had to interrupt the inhalation of the flecainide acetate
or placebo solutions.
TABLE-US-00006 TABLE 6 Summary of Treatment-Emergent Adverse Events
by Treatment by Cohort/Inhaled Flecainide Dose Level and Treatment
Type: Part A (Safety Population) IH Flecainide Total 20 mg 40 mg 60
mg Flecainide Placebo (N = 6) (N = 10) (N = 9) (N = 25) (N = 9) n
(%) n (%) n (%) n (%) n (%) Subjects with at least one: TEAE 4 (67)
10 (100) 8 (89) 22 (88) 6 (67) Study Drug 2 (33) 10 (100) 8 (89) 22
(80) 4 (44) Related.sup.1,3 Moderate or Severe.sup.2 1 (17) 1 (10)
2 (8) Study Drug Related, 1 (10) 1 (4) Moderate or Severe.sup.1,2,3
SAEs Number of: TEAEs 12 24 23 59 7 Study Drug 7 19 17 43 4
Related.sup.1,2 Moderate or Severe.sup.3 1 2 3 Study Drug Related,
2 2 Moderate or Severe.sup.1,2,3 SAEs Abbreviations: N = number of
subjects; SAE = serious adverse event; TEAE = treatment-emergent
adverse event; .sup.1Related TEAE = Probable and Possible Related
TEAEs; .sup.2Subjects reporting more than one TEAE were counted
only once using the strongest study drug relationship category;
.sup.3subjects reporting more than one TEAE were counted only once
using the highest severity grade.
[0510] The majority of TEAEs occur in 1 or 2 subjects each; those
occurring in .gtoreq.2 subjects across all cohorts and receiving
either flecainide or placebo inhalation solution are summarized in
Table 7.
[0511] The AEs that occurred more frequently in subjects receiving
flecainide were oropharyngeal discomfort, shortness of breath
(dyspnoea), cough and dry mouth. However, the incidence of AEs
reported by the subjects that received flecainide appears not to be
dose-dependent. These AEs were considered mild in intensity and
required no treatment. Two moderate adverse events (AEs) were
reported by one subject from Cohort #2 (40 mg eTLD);
lightheadedness and oropharyngeal discomfort.
[0512] Of the 43 total TEAEs in the combined flecainide dose
groups, 38 (in 19/25 subjects, 76%) and 5 events in 1 subject (4%)
were considered to be probably and possibly study-drug related,
respectively. The most frequent events in the total flecainide
group were (events, subjects and percentage): Oropharyngeal
discomfort: 10 events in 10/25 subjects (40%); Dyspnoea (shortness
of breath): 4 events in 4/25 subjects (16%); Dizziness: 3 events in
3/25 subjects (12%); Cough: 3 events in 3/25 subjects (12%); Dry
mouth: 3 events in 3/25 subjects (12%); Headache: 3 events in 2/25
subjects (8%); Dysgeusia: 2 events in 2/25 subjects (8%).
TABLE-US-00007 TABLE 7 Summary of Treatment-Emergent Adverse Events
in .gtoreq.2 Subjects in the Total Flecainide or Placebo Groups by
MedDRA System Organ Class, Preferred Term, Cohort/Inhaled
Flecainide Dose Level and Treatment Type: Part A (Safety
Population) IH Flecainide Dose Group Total 20 mg 40 mg 60 mg IH
Flecainide Placebo System Organ Class, (N = 6) (N = 10) (N = 9) (N
= 25) (N = 9) Preferred Term n (%) [events] n (%) [events] n (%)
[events] n (%) [events] n (%) [events] Nervous system 2 (33) [4] 3
(30) [4] 3 (33) [3] 8 (32) [11] 1 (11) [1] disorders Dizziness 1
(17) [1] 1 (10) [1] 1 (11) [1] 3 (12) [3] 1 (11) [1] Dysgeusia 2
(20) [2] 2 (8) [2] Headache 2 (33) [3] 2 (22) [2] 4 (16) [5]
Respiratory, thoracic 3 (50) [5] 8 (80) [11] 6 (67) [9] 17 (68)
[25] 3 (33) [4] and mediastinal disorders Cough 1 (17) [2] 1 (10)
[1] 1 (11) [1] 3 (12) [4] Dyspnoea 1 (17) [1] 3 (30) [3] 2 (22) [2]
6 (24) [6] Oropharyngeal 2 (33) [2] 5 (50) [5] 4 (44) [4] 11 (44)
[11] 1 (11) [1] discomfort Gastrointestinal 3 (30) [3] 5 (56) [8] 8
(32) [11] 2 (22) [2] disorders Diarrhoea 2 (22) [2] 2 (8) [2] Dry
mouth 1 (10) [1] 2 (22) [2] 3 (12) [3] 1 (11) [1] General disorders
and 2 (20) [2] 1 (11) [2] 3 (12) [4] administration site conditions
Catheter site pain 1 (10) [1] 1 (11) [1] 2 (8) [2] Abbreviations: N
= number of subjects; SAE = serious adverse event; TEAE =
treatment-emergent adverse event; Note: If a subject had more than
one AE coded to the same MedDRA term, the subject was counted only
once.
[0513] In the pooled placebo group, there were 4 events in 4/9
subjects (44%) deemed possibly or probably related to study-drug;
they were the following: oropharyngeal discomfort, respiratory
tract irritation, abdominal discomfort, and dry mouth. No TEAEs
related to the study device were reported.
[0514] In Part B of the study, all six subjects had a total of 12
and 49 TEAEs during inhaltion (IH) and 10 min IV infusion of
flecainide, respectively, that is 4-fold fewer TEAEs with IH than
IV (Table 8). All subjects had at least 1 study-drug-related TEAE.
All TEAEs reported by subjects following inhalation were mild in
intensity whereas following IV infusion, 4 of these in 2 subjects
(29%) were considered moderate or severe (Table 8). There were 1
severe and 2 moderate intensity AEs, probably related to the study
drug, reported by the same 6 subjects when they received IV
infusion of flecainide. The serious AE occurred in a subject in
which the IV infusion had to be interrupted for hypotension
(systolic BP<65 mmHg) and reported severe light-headedness
(dizziness). There were no SAEs reported with either IH or IV
flecainide administration (Table 8).
TABLE-US-00008 TABLE 8 Overall Summary of Treatment-Emergent
Adverse Events by Flecainide Dosing Route (IH and IV): Part B
(Safety Population) IH IV (N = 6) (N = 7) n (%) n (%) Number of
Subjects with at least one: TEAE 6 (100) 7 (100) Related TEAEs1 6
(100) 7 (100) Moderate or Severe TEAEs.sup.3 0 2 (29) Related,
Moderate or Severe TEAEs.sup.1,2,3 0 2 (29) SAE 0 0 Number of
Treatment-Emergent Adverse Events 12 49 Related TEAEs.sup.1 9 35
Moderate or Severe TEAEs 0 4 Related, Moderate or Severe
TEAEs.sup.1 0 4 SAEs 0 0 Abbreviations: IH = inhaled (30 mg eTLD
inhaled flecainide); IV = intravenous (2 mg/kg intravenous
flecainide [Tambacor] to a maximum dose of 150 mg); N = number of
subjects; SAE = serious adverse event; TEAE = treatment emergent
adverse event; .sup.1Related TEAE = Probable and Possible Related
TEAEs; .sup.2Subjects reporting more than one TEAE were counted
only once using the strongest study drug relationship category;
.sup.3Subjects reporting more than one TEAE were counted only once
using the highest severity grade.
[0515] The majority of the TEAEs occurred in 1 or 2 subjects each;
those occurring in .gtoreq.2 subjects that received either
flecainide via oral inhalation (IH) or IV infusion are summarized
in Table 9. All subjects experienced at least 1 TEAE in each dosing
condition (IH and IV); however, as already pointed out, there were
4-fold fewer TEAEs associated with IH administration compared with
IV: 12 events in 6 subjects (average of 2 events per subject),
versus 49 events in 7 subjects (average of 7 events per subject),
respectively.
[0516] The most frequent TEAEs associated with IV infusion of
flecainide were the following: dizziness (6 events in 6/7 subjects,
86%) and headache (6 events in 5/7 subjects, 71%). Also, oral
paraesthesia, occurred only in conjunction with IV infusion in 3
subjects (43%). Three events of peripheral coldness and chest
discomfort in 2 and 1 subject each, and 2 events in 2 subjects each
of application site coldness, catheter site pain, chest discomfort,
and fatigue were also associated with IV infusion.
TABLE-US-00009 TABLE 9 Summary of Treatment-Emergent Adverse Events
in .gtoreq.2 Total Subjects by MedDRA System Organ Class, Preferred
Term, and Flecainide Dosing Route (IH and IV) (Part B) Safety
Population IH IV System Organ Class, (N = 6) (N = 7) Preferred Term
n (%) [events] n (%) [events] Nervous system disorders 7 (100) [13]
Dizziness 6 (86) [6] Headache 5 (71) [6] Vascular disorders 3 (43)
[4] Peripheral coldness 2 (29) [3] Respiratory, thoracic and 5 (83)
[7] 2 (29) [3] mediastinal disorders Oropharyngeal discomfort 4
(67) [4] Gastrointestinal disorders 1 (17) [1] 5 (71) [6]
Hypoaesthesia oral 1 (17) [1] 1 (14) [1] Paraesthesia oral 3 (43)
[3] General disorders and 2 (33) [2] 4 (57) [13] administration
site conditions Application site coldness 2 (29) [2] Catheter site
pain 2 (29) [2] Chest discomfort 2 (33) [2] 1 (14) [3] Fatigue 2
(29) [2] Abbreviations: IH = inhaled (30 mg eTLD inhaled
flecainide); IV = intravenous (2 mg/kg intravenous flecainide
[Tambacor] to a maximum dose of 150 mg); N = number of subjects;
TEAE = treatment-emergent adverse event; Note: If a subject had
more than one AE coded to the same MedDRA term, the subject was
counted only once.
[0517] With IH administration of flecainide, oropharyngeal
discomfort was the most frequent TEAE occurring in 4 of 4/6
subjects (67%). The only other TEAE associated with IH
administration that occurred in more than 1 subject was chest
discomfort, in 2 of 2/6 subjects (33%). However, 3 such events also
occurred in 1 subject in conjunction with IV infusion of
flecainide.
[0518] Among the TEAEs associated with both IH and IV infusion, 9
such events from a total of 12, and 35 events from a total of 49,
respectively were considered study-drug related. The type of
study-drug related events associated with IV infusion of flecainide
were the following: dizziness (6 events in 6 subjects), and
headache (5 events in 5 subjects), and paresthesia oral (3 events
in 3 subjects). Other study-drug related events associated with IV
flecainide administration were: peripheral coldness, palpitations,
and chest discomfort, each occurring 2 times 1 subject, and 2
occurrences in 2 subjects of application site coldness.
[0519] There were 4 probably study-drug related events associated
with IH administration of flecainide; oropharyngeal discomfort in 4
subjects, the remaining 5 study-drug related events for the IH
administration route all occurred once in 1 subject each. They were
cough, dysphonia, dyspnoea, oral hypoesthesia and chest discomfort.
No TEAEs were considered to be related to study device.
[0520] PK Results:
[0521] Initial analyses demonstrated that oral inhalation of
flecainide acetate solution (20 mg eTLD, 30 mg eTLD, or 40 mg eTLD)
resulted in venous plasma concentrations of drug that exhibited
near dose proportionality (FIG. 28).
[0522] FIGS. 76A and 76B show plots of the mean plasma flecainide
concentration versus time for the eTLDs of 20, 40 and 60 mg eTLD
oral inhalation doses generated per protocol (FIG. 76A) and from
post-hoc (FIG. 76B) datasets. In the majority of the subjects (21
of 25 subjects, 84%), following completion of oral inhalation (IH)
of flecainide acetate solution, the venous plasma concentration of
drug rose rapidly, within 1 to 3 minutes after completion of
inhalation, and quickly declined. In two subjects, each in the 40
and 60 mg eTLD cohorts, the T.sub.max values (e.g., time to
occurrence of the maximum plasma concentration) were greater than
15 minutes, (e.g., ranged from 20 min to 4 hours) after the end of
inhalation, and, in addition, the C.sub.max (e.g., maximum plasma
concentration) values were 3-fold lower (see below) than the other
21 subjects. Removal of all data from these four subjects from the
main analysis (e.g., per-protocol) dataset had minimal effect on
the range and distribution of all pharmacokinetic parameter values.
However, the C.sub.max of the two subjects (70.9 and 43.5 ng/ml)
from the 40 mg eTLD cohort were 3.0-fold lower and for the two
subjects (82.3 and 51.3 ng/ml) from the 60 mg eTLD cohort were
3.4-fold lower than the mean C.sub.max values of the remaining
subjects of the respective cohorts. Inclusion of C.sub.max data
from these subjects markedly increased the range of C.sub.max
values and consequently, the PD data from these subjects were also
excluded from subsequent analyses. The dataset that excludes these
four subjects is referred to as post-hoc dataset (FIG. 76B). The
data described in the text, presented in the tables and figures,
hereinafter, are from the post-hoc population, which does not
include data from the four subjects mentioned above.
[0523] Table 10 summarizes the estimates of the pharmacokinetic
(PK) parameters of flecainide administered via oral inhalation with
a rapid distribution phase lasting .about.10-15 minutes (estimated
t.sub.1/2.alpha. of 3.5-4.2 minutes) and elimination
t.sub.1/2.beta. of 9-12 hours. The distribution phase and
elimination half-life were independent of the doses of flecainide.
The C.sub.max and AUC.sub.Last were dose-dependent. It is
noteworthy that the venous plasma concentration-time curves for
flecainide (eTLDs of 20, 40, or 60 mg eTLD) administered via oral
inhalation or via IV infusion are similar (see FIGS. 84A and 84B).
The great similarity in the concentration-time profile curves
between flecainide delivered via oral inhalation and IV infusion
(shown in FIGS. 84A and 84B) indicates comparable pharmacokinetics
by these two routes of administration. This finding is relevant
because the IV route of administration of 2 mg/kg (or maximum 150
mg) of flecainide has been established to be safe and highly
efficacious in converting recent onset symptomatic AF into NSR.
[0524] Part B study provided comparison of PK profiles between IV
flecainide and inhaled flecainide. In subjects of Cohort 5, the
venous plasma concentration-time curves for inhaled flecainide (30
mg eTLD) were similar to those for flecainide administered via IV
infusion (2 mg/kg; FIGS. 29A and B). The peripheral venous plasma
concentration-time curves for flecainide delivered via IV infusion
(2 mg/kg over 10 min; total dose of 149.+-.17 mg) or inhalation
(eTLD of 30 mg) are also replotted on a different time scale in
FIGS. 77A and 77B. Peak plasma concentrations of flecainide
(C.sub.max) following intravenous administration and inhalation
were 749.+-.308 and 120.+-.70 ng/ml, respectively. The time to
C.sub.max (T.sub.max) for intravenous infusion was between 1 and 60
minutes after the end of 10 min infusion, and .ltoreq.1 min
post-inhalation (Table 11). The mean time to complete the
inhalation of 30 mg eTLD of flecainide in the six subjects was 4.5
min. The summary of the pharmacokinetic parameters (C.sub.max,
Distribution (t.sub.1/2.alpha.) and Elimination (t.sub.1/2.beta.)
half-lives) are presented in Table 11. Distribution phase and
elimination half-life were nearly identical for intravenous
infusion and inhalation: 4.7.+-.01.4 min and 10.0.+-.1.8 hrs,
respectively, for intravenous, and 4.3.+-.1.5 min and 10.1.+-.2.0
hrs, respectively, for inhalation. Furthermore, the distribution
and elimination half-lives following intravenous administration in
this Phase 1 study were similar to those published in the
literature for intravenous flecainide.
TABLE-US-00010 TABLE 10 Summary of PK Values of Flecainide
administered via Oral Inhalation or IV Route of Adminis- T.sub.max
C.sub.max AUC.sub.Last Elim. t.sub.1/2.beta. Dist.
t.sub.1/2.alpha..sup.# tration min ng/mL Hr ng/mL hours min Inhaled
1 (1, 3) 95.1 (79) 421 (45) 9.87 (25) 3.86 (34) (20 mg) n = 6
Inhaled 1 (0, 1) 173 (47) 685 (26) 9.0 (24) 4.19 (39) (40 mg) n =
8* Inhaled 1 (0, 3) 232 (78) 946 (22) 12.0 (14) 3.47 (17) (60 mg) n
= 7* All values for inhaled flecainide are arithmetic mean (CV %)
except T.sub.max values (measured from end of inhalation) which are
median (min, max). *Based on PK cut-off criteria of T.sub.max
.gtoreq. 15 min, data from 2 subjects were excluded. .sup.#Data
from 1 subject from 20 and 40 mg eTLD cohorts and 3 subjects from
the 60 mg eTLD cohort could not be estimated.
[0525] To directly compare the PK profiles of flecainide given via
IV infusion and oral inhalation, the mean+/-SD plasma flecainide
concentration vs time for the IV dose was normalized to 30 mg in
order to match the 30 mg eTLD oral inhalation dose. FIG. 29B and
FIG. 78 show the comparison between the normalized plasma
flecainide concentration of IV infusion and plasma flecainide
concentration of inhalation on different time scales, respectively.
The resulting concentration-time profile curves are near-identical,
indicating comparable pharmacokinetics by these two routes of
administration.
TABLE-US-00011 TABLE 11 Summary of PK values of Flecainide
Administered via IH or IV and from Literature (shaded) Route of
T.sub.max C.sub.max AUC.sub.last Dist. t.sub.1/2 Elim. t.sub.1/2
administration (min after EOI) (ng/mL) (hr*ng/mL) (min) (hr) IV (2
mg/Kg) 1 (0, 60) 749 (41) 3051 (11) 4.28.sup.# (36) 10.0 (18)
Cohort 5, n = 6 Inhaled (30 mg) 0.5 (0, 1) 120 (59) 487 (20)
4.67.sup.# (30) 10.1 (20) Cohort 5, n = 6 IV (2 mg/Kg)* 10.0 1644
.+-. 534 4211 .+-. 456 2.6 .+-. 0.7 9.3 .+-. 0.1 n = 3 (Mean .+-.
SEM) EOI = end of inhalation or infusion All values (from Part B of
study, shown in rows 1-2) are arithmetic mean (CV %) except
T.sub.max values which are median (min, max) .sup.#Data front 1
subject in the IH arm and 2 subjects in the IV arm could not be
estimated *Tambacor package insert, 2012, Eisai Co. Ltd.
[0526] PD Results:
[0527] QRS Interval Duration:
[0528] There was a small increase of mean .DELTA.QRS (mean change
from baseline, pre-dose QRS interval duration) between 1 and 3
minutes after the end of flecainide inhalation in subjects of
Cohort 1. FIG. 31 shows the time course of the changes in QRS
interval duration (.DELTA.QRS) in 6 subjects following the
inhalation of 20 mg eTLD of flecainide and in 2 subjects following
the inhalation of placebo.
[0529] There was a transient increase between 1 and 3 minutes
post-dosing in the QRS duration in subjects of Cohort 2 (40 mg eTLD
flecainide); in the majority of subjects, the maximal increase in
the QRS interval duration (.DELTA.QRS) was observed at 1 minute
post-dosing. The changes in QRS interval duration for the 10
subjects of Cohort 2 that were exposed to inhaled flecainide are
depicted in FIG. 32.
[0530] Representative ECG tracings from an individual subject
(R222) in Cohort 2 who was exposed to inhaled flecainide (40 mg
eTLD) acetate solution are shown in FIG. 33A. The ECG tracings show
that the QRS duration (QRSd) increased by 10 msec at 1 minute
post-dosing, whereas the amplitude of the R-wave (QRSa) decreased
by 400 .mu.V at 3 min post-dosing. The bar graphs summarize the
average changes in QRS interval duration (FIG. 33B) and R-wave
amplitude (FIG. 33C) of subject R222 recorded from several tracings
of ECGs for each time point. The maximal increase in duration
(.about.9 msec) and decrease in amplitude (.about.480 .mu.V) of the
QRS interval complexes were transient and statistically significant
(p<0.05).
[0531] The time course of changes in the QRS interval duration in
Cohorts 1, 2, and 3 were all plotted following after completion of
inhalation either inhalation of flecainide acetate or placebo
solutions (FIG. 79; only data for post-hoc population). The
magnitude of QRS prolongation at 1 min post-inhalation dosing was
minimal (3.0 msec) with the eTLD of 20 mg eTLD, intermediate (8.2
msec) with the 40 mg dose and attained a maximum of 16 msec with
the 60 mg eTLD. The magnitude of the maximal QRS widening achieved
following the administration of the three doses were 2.9-fold
between 20 mg eTLD and 40 mg eTLD, and 4.5-fold between 20 mg eTLD
and 60 mg eTLD. Once the maximal QRS interval prolongation was
achieved (1 to 3 minutes, in general), the QRS interval duration
decreased as a function of time; at 30 min after completion of
inhalation, the QRS interval duration returned to near pre-dose
levels. At 2, 4, 6, 8 and 24 hours post-inhalation dosing, the QRS
interval durations, for all subjects of the 3 cohorts, remained
unchanged at near the pre-dose (baseline) values (range 80 to 90
msec). Subjects who received placebo had minimal changes in QRS
interval, at any timepoint.
[0532] In Part B study, the time course of the changes in QRS
interval duration measured from 12-lead ECGs were obtained in the
six subjects prior to, during and following flecainide IV infusion
(2 mg/kg, administered over 10 mins) and inhalation (30 mg eTLD,
mean time 4 min). Subjects in Cohort 5 demonstrated a marked
prolongation of the QRS interval after IV infusion of flecainide (2
mg/kg) and showed a transient increase in the QRS interval duration
between 1 and 3 minutes post-inhalation of 30 mg eTLD of flecainide
acetate solution (FIG. 34). QRS interval duration data from Cohort
5 are also shown in FIGS. 80A and 80B. The mean (.+-.SEM) of the
maximal increase in QRS interval duration following IV infusion was
34.2.+-.2.4 msec and following inhalation was 12.4.+-.2.6 msec. The
widening of the QRS interval duration was transient in both cases
but lasted much longer following intravenous (>60 min) compared
to inhalation (15-30 min). At 2 hours following the IV infusion the
QRs interval duration was still 12.5 msec longer than baseline
(pre-dose value of 78.+-.2 msec), and then steadily shortened at 4,
6 and 8 hours post-dosing. At 24 hours, prior to discharge, the QRS
interval duration was still .about.7 msec longer than the pre-drug
baseline value. In 3 of 6 subjects the IV infusion of flecainide
caused a non-specific intraventricular conduction delay, indicative
of excessive prolongation of the QRS interval duration. In
contrast, these changes were not observed in any of the same
subjects when flecainide (eTLD of 30 mg) was given via oral
inhalation. From 2 to 24 hours, post-inhalation of the eTLD of 30
mg, the QRS interval duration differed by <2 msec from the
pre-dose baseline value of 78.+-.2 msec.
[0533] PR Interval:
[0534] PR interval measurements were also obtained as flecainide is
known to prolong the PR interval in a dose-dependent manner.
[0535] In subjects of Cohort 1, the PR interval (time elapsed from
onset of atrial depolarization and onset of ventricular
depolarization) was shortened at early time points with mean
.DELTA.PR of -6 msec and -4.5 msec at 1 and 3 minutes post-dosing,
and values smaller than -3.0 msec from 10 minutes to 4 hours after
dosing (FIG. 30).
[0536] Data for Cohort 3 subjects inhaling 60 mg eTLD of flecainide
or placebo solution are shown in FIG. 81. There was a .about.5 msec
prolongation in the PR interval duration at the early time points
(1 to 5 min), and up to 12 msec at 10 and 15 minutes following
administration of flecainide. In contrast, following the inhalation
of placebo solution, there was a .about.5 msec shortening in the PR
interval duration for the first 5 min, and thereafter it returned
towards the pre-dose values. Minimal or no changes of the PR
interval duration were seen in subjects that inhaled 20 or 40 mg
eTLD of flecainide. The PR interval durations at 2, 4, 6, 8 and 24
hours post-inhalation dosing, from the subjects of all 3 cohorts,
were near identical to the baseline (pre-dose) values, that is, in
the range of 140 to 150 msec. In all subjects that inhaled the
placebo solution (combined cohorts), the PR interval shortened. The
relatively small or no changes in PR interval observed prior to,
during and after (up to 5-10 minutes post-dosing) can be attributed
to the confounding effects of postural changes and the inhalation
procedure itself. The protocol required a seated posture during
inhalation of flecainide or placebo solution. The postural changes
from semi-recumbent (before inhalation) to seated (during
inhalation) position triggers a sympathetic reflex that leads to a
shortening of the PR interval. The sympathetic reflex-driven PR
interval shortening with seated posture is evident in the placebo
curve of FIG. 81. Therefore, the PR interval shortening associated
with upright posture likely negated most of the expected
lengthening of the PR interval in subjects receiving
flecainide.
[0537] The results of Part B of the Phase 1 study, in which
interval measurements were obtained before, during, and after
seated position, clearly shows the re-lengthening of the PR
interval following inhalation of flecainide after being shortened
during the change in subject's position from semi-recumbent to
seated upright posture of the subjects. FIGS. 82A and 82B show the
changes in PR interval duration measured from 12-lead ECGs in the
six subjects prior to, during and following IV infusion. Forty-five
min prior to administration of flecainide the PR interval durations
were similar being 164.+-.1 msec with IV infusion and 165.+-.2.0
msec with inhalation. At the end of the IV infusion of flecainide
(FIG. 82A), the PR interval prolonged to 187.+-.6 and remained
prolonged at 60 min post-IV infusion. At 2 hours post-IV infusion,
the PR interval was still .about.12 msec longer than the pre-drug
baseline value of 161.+-.3 msec, and thereafter returned toward
baseline; at 8 and 24 hours the PR interval had fully returned to
pre-drug baseline. The ECG changes in PR interval duration with
inhalation were more complex because of the effects of postural
changes. As shown in FIG. 82B, when the subjects changed position
from semi-recumbent to seated, the PR interval duration shortened
by 13 msec from the pre-dose value measured at -45 min.
Subsequently, from the start to the end of the inhalation, the PR
interval duration prolonged by 12 msec at 5 min after completion of
inhalation and then decreased toward the pre-dose values. The
shortening of the PR interval duration following the postural
change (from semi-recumbent to seated) can be attributed to an
increase in sympathetic tone and was consistent with the observed
increases in heart rate (FIG. 72) and systolic blood pressure. The
PR interval at 2 hours and beyond (4, 6, 8 and 24 hours) post-oral
IH flecainide was (160 msec), approximately 2 msec longer than the
158.5 msec of the pre-drug baseline value. In summary, IV infusion
and oral inhalation of flecainide were associated with maximal PR
interval prolongations of 25 msec and 12 msec, respectively.
[0538] Fridericia HR Corrected QT (QTcF) Interval:
[0539] The QTcF interval changed little in subjects of Cohort 1
following inhalation of 20 mg eTLD of flecainide, with small mean
changes across post-inhalation time points that varied between +4.0
msec and -2.7 msec during the first 6 hours (FIG. 35).
[0540] In subjects of Cohorts 2 and 5, .DELTA.QTcF post-inhalation
time points varied .+-.4 msec for 40 mg eTLD and 30 mg eTLD inhaled
flecainide, respectively.
[0541] T-Wave Morphology:
[0542] No changes in T-wave morphology were observed following
inhalation of flecainide acetate solution (20 mg eTLD, 30 mg eTLD,
and 40 mg eTLD).
[0543] T-wave notching, which is an abnormality in T-wave
morphology, has been observed following IV infusion of flecainide
(2 mg/kg; FIG. 36).
[0544] PK-PD Relationship:
[0545] The antiarrhythmic efficacy of flecainide can be strongly
correlated with the widening of the QRS interval. FIG. 83 shows the
dose-concentration response relationship, for the post-hoc
population in Cohorts 1, 2, and 3, of the effects of inhalation of
flecainide on the prolongation of the QRS interval duration. The
PK-PD relationship shown below is based on the non-steady state,
peak plasma levels of flecainide and maximal changes in QRS
interval durations post-inhalation. The maximal QRS interval
prolongations were 3.5.+-.1.0, 10.+-.1.5, 16.+-.1.4 for the eTLDs
of 20, 40 and 60 mg eTLD, respectively.
[0546] In Part B of the present study (FLE-001), flecainide was
administered in single doses via either IV infusion (over 10
minutes) and via oral inhalation (.about.4.5 min) in the same
subjects. Thus, steady-state plasma levels of flecainide given
either via IV or oral inhalation were not achieved. Consequently,
the PK-PD relationship described below are based on the non-steady
state, rapidly changing plasma levels of flecainide
([Flec].sub.plasma) and changes in QRS interval durations
(.DELTA.QRS) measured at specific times. As expected from
non-steady state conditions, and shown in FIGS. 84A and 84B, a
temporal dissociation is observed between ([Flec].sub.plasma) and
.DELTA.QRS. During both the rapid rise and decline (distribution
phase) of the plasma concentration of flecainide, the changes in
QRS interval duration lag those of the peripheral venous
concentrations of flecainide. The hysteresis between concentrations
and responses (QRS) applies for both routes of administration, IV
and inhalation.
[0547] According to results of the early PK studies of flecainide
by Conard et al (1984), peripheral venous plasma levels of
flecainide "reflect cardiac tissue concentrations of unchanged
flecainide". Hence, as a corollary, the prolongation of the QRS
interval duration caused by flecainide can reflect the ventricular
myocardium (primarily left) concentrations of flecainide.
[0548] Based on the findings shown in FIGS. 84A and 84B, it was
sought to determine the relationship between peak plasma levels of
flecainide (C.sub.max) and the maximal .DELTA.QRS instead of using
the time-matched values of both variables. The results of this
analysis are shown in FIG. 85.
[0549] The lower dose of flecainide delivered via oral inhalation
(eTLD of 30 mg) resulted in lower (6.2-fold) maximal plasma levels
of flecainide when compared to the higher dose delivered via IV
infusion (.about.150 mg). Likewise, the pharmacodynamic activity of
flecainide, reflected by changes in the QRS interval duration, were
accordingly smaller (2.7-fold) following inhalation than IV
infusion. Thus, it appears that a 2.3-fold (6.2/2.7) lower plasma
concentration of flecainide given by inhalation can cause
prolongation of QRS interval duration of magnitudes achieved
following a 10 min IV infusion. In keeping with this
interpretation, as depicted in FIG. 86, a direct comparison of data
from the subjects with near-equal .DELTA.QRS (12.0 to 16 msec)
following either IV infusion or oral inhalation, yielded plasma
concentrations of 222.+-.23 and 85.+-.40.3 ng/ml, respectively.
Thus, a 2.6-fold lower plasma level of flecainide achieved
following inhalation results in a .DELTA.QRS of 14 msec, a QRS
interval widening similar to that achieved at 5 min into the IV
infusion of flecainide; equivalent to 1 mg/kg, that is, half of the
dose administered (FIGS. 84A and 84B).
[0550] Summary:
[0551] The results of this Phase 1 study demonstrated that
inhalation doses of flecainide, in the range of 30 to 60 mg eTLD,
are safe, well-tolerated and deliver flecainide into the systemic
circulation, within 1 to 3 minutes after the completion of
inhalation, in sufficient amounts to elicit the expected
electrophysiological effects of flecainide, such as prolongation of
QRS interval. In Part B of the study, head-to-head comparisons were
made between the PK, PD, safety and tolerability of an eTLD of 30
mg of flecainide given via oral inhalation and that of a 10-minute
IV infusion dose of 2 mg/kg of flecainide (.about.150 mg). Inhaled
flecainide was compared with IV flecainide because flecainide given
via IV at the approved dose of 2 mg/kg is an established agent for
acute pharmacological cardioversion of recent onset atrial
fibrillation. Relevant to the potential effectiveness of inhaled
flecainide to cardiovert AF is the observation that at the time of
conversion of atrial fibrillation to sinus rhythm by flecainide IV,
the venous plasma flecainide concentrations are in the range of 114
to 742 ng/ml and the increases in QRS interval duration are in the
range of 12 to 30 msec (Crijns H et al, 1988; Suttorp M J et al,
1990; Donovan K D et al, 1995). Inhaled flecainide at eTLD
.gtoreq.30 mg was found to yield venous plasma flecainide
concentrations and cause QRS interval prolongation within the same
range reported above for IV, albeit in the lower end of the range
reported to convert atrial fibrillation to sinus rhythm by IV
flecainide. Therefore, based on the pharmacokinetics and
pharmacodynamics of flecainide reported in the literature, inhaled
flecainide at eTLDs .gtoreq.30 mg could be effective in converting
recent-onset atrial fibrillation to sinus rhythm within minutes of
administration. Compared to the approved IV flecainide dose, the
lower doses of inhaled flecainide are likely to be better tolerated
and safer.
Example 5
Pharmacokinetic and Pharmacodynamic Effects of Intratracheal
Instillation of Flecainide Acetate with Comparison to Intravenous
Administration in Anesthetized Pigs
[0552] The PK and PD responses to intratracheal (IT) instillation
were compared with IV delivery of flecainide in an intact porcine
model that has been previously shown to be clinically relevant
(Kumar et al 2009).
[0553] Experimental Design:
[0554] The studies were carried out in male Yorkshire pigs (n=9)
weighing 36.+-.1.0 kg (mean.+-.SEM). The pigs were pre-anesthetized
with telazol (4.7 mg/kg, intramuscular) and subsequently further
anesthetized using alpha-chloralose (80 mg/kg, IV bolus, followed
by 24 mg/kg/h continuous IV infusion). The animals were intubated
and ventilated at a constant rate of 12 breaths/min and tidal
volume of 400 ml per stroke.
[0555] All catheters were positioned under fluoroscopic guidance.
An Orbiter electrode catheter was placed in the right atrium for
recording local atrial electrograms. Ventricular electrograms were
obtained using a decapolar electrode catheter positioned in the
left ventricle (LV). Arterial blood pressure was continuously
monitored from a femoral arterial sheath. Simultaneous blood
samples were drawn from the pigtail catheter positioned in the LV
and from a catheter in the jugular vein. Electrograms were
monitored using a Prucka CardioLab workstation (GE Medical Systems,
Milwaukee, Wis.) from atrial and ventricular sites. For IT
instillation of flecainide acetate solution, a 5Fr angioplasty
catheter that was 1 cm longer than the endotracheal tube was
introduced into the trachea via the endotracheal tube and its tip
was positioned under fluoroscopy at the tracheal carina level.
[0556] In the IV infusion experiments, flecainide (2 mg/kg, IV
bolus over 2 min) was infused via a 7Fr sheath inserted into the
right femoral vein. The RR, PR, QTc, and JTc intervals and QRS
duration were measured in six sequential beats, recorded seconds
before each time point.
[0557] In the IT instillation experiments, flecainide (2 mL of 0.75
mg/kg or 1.5 mg/kg concentrations, IT) was administered in a single
"push" of 2 to 3 sec via the angioplasty catheter positioned in the
endotracheal tube. For example, for a 36 kg pig, a dose of 27 mg/2
mL (0.75 mg/kg) or 54 mg/2 mL (1.5 mg/kg) of flecainide solution
can be used. The QT interval was corrected using Bazett's formula
(QTc=QT/ RR) and is presented in this report as the QTc
interval.
[0558] When more than one dose was tested in a single experiment, a
washout period of 30 to 60 min was allowed in order to keep
residual levels of flecainide to a minimum before testing the new
dose.
[0559] For the experiments on the effects of IT instillation of
flecainide on duration of AF, the arrhythmia was induced using
intrapericardial administration of acetylcholine (ACh) (1 mL at a
concentration of 15 mg/mL) followed by burst pacing for 1 min.
Flecainide (1.5 mg/kg, IT) was given after 2 min of successful AF
induction.
[0560] Blood samples were collected from venous circulation and
through the LV pigtail catheter in sodium heparin tubes at 0, 2, 5,
10, 15 and 30 min after the start of IV or IT flecainide. The
samples were centrifuged and frozen at -80.degree. C. until drug
level determination was performed using a bioanalytical assay
method developed by Climax Laboratories, Inc.
[0561] Data are reported as means.+-.SEM. Statistical analyses were
performed using the SAS system (9.4) to apply ANOVA with a post-hoc
Dunnett's test. Statistical significance was assumed at
p<0.05.
[0562] Results:
[0563] PK Responses:
[0564] IV Infusion:
[0565] Following IV infusion of flecainide (2 mg/kg over 2 min),
both LV and venous plasma levels peaked at 2 min (LV: 5127.+-.849.4
ng/mL, p<0.05; Venous: 4151.+-.1030.0 ng/mL, p<0.05) and
progressively declined throughout the experiment to lower levels at
30 min (LV: 497.+-.189.5 ng/mL; Venous: 519.+-.195.6 ng/mL) (FIG.
39).
[0566] IT Instillation of 0.75 mg/kg:
[0567] Following IT instillation of the lower dose of flecainide
(0.75 mg/kg), both LV and venous plasma levels peaked at 2 min (LV:
1916.+-.122.2 ng/mL, p<0.05; Venous: 1688.+-.176.7 ng/mL,
p<0.05) and remained significantly elevated compared to baseline
at 5, 10, and 15 min before progressively declining throughout the
experiment to lower levels at 30 min (LV: 299.+-.28.6 ng/mL;
Venous: 341.+-.54.6 ng/mL) (FIG. 40).
[0568] IT Instillation of 1.5 mg/kg:
[0569] Following IT instillation of the higher dose of flecainide
(1.5 mg/kg) both LV and venous plasma levels peaked at 2 min (LV:
3308.+-.247.5 ng/mL, p<0.05; Venous: 2808.+-.216.5 ng/mL,
p<0.05) and remained significantly elevated compared to baseline
at 5, 10, and 15 min. Venous plasma remained significantly elevated
compared to baseline at 30 min (Venous: 676.+-.79.7 ng/mL,
p<0.05) while left ventricular chamber plasma did not (LV:
637.+-.69.5 ng/mL) (FIG. 41).
[0570] PD Responses:
[0571] IV Infusion:
[0572] Heart Rate:
[0573] Prior to IV infusion of flecainide (2 mg/kg, IV bolus over 2
min), heart rate was 103.+-.1.9 bpm. After IV flecainide infusion,
ANOVA revealed that heart rate was not significantly altered across
30 min (p=0.9936) (FIG. 42).
[0574] Arterial Blood Pressure:
[0575] Prior to IV infusion of flecainide (2 mg/kg, IV bolus over 2
min), mean arterial blood pressure was 105.+-.6.7 mmHg. After IV
flecainide infusion, ANOVA analysis revealed that mean arterial
pressure was not significantly altered across 30 min (p=0.8852)
(FIG. 43).
[0576] PR Interval:
[0577] Prior to IV infusion of flecainide (2 mg/kg, IV bolus over 2
min), the PR interval was 127.+-.7.8 ms. After IV flecainide
administration, ANOVA revealed that the PR interval was not
significantly changed across 30 min (p=0.5161; FIG. 44).
[0578] QRS Duration:
[0579] Prior to IV infusion of flecainide (2 mg/kg bolus over 2
min), QRS duration was 58.+-.1.9 ms. After IV flecainide
administration, QRS duration significantly increased to 77.+-.6.2
ms and 76.+-.4.8 ms coincident with peak plasma levels of the drug
at 2 min and 5 min, respectively (p<0.05). Thereafter, QRS
duration progressively decreased toward the baseline levels
(59.+-.3.0 ms) at 30 min (FIG. 45).
[0580] QTc Interval:
[0581] Prior to IV infusion of flecainide (2 mg/kg bolus over 2
min), the QTc interval was 442.+-.7.9 ms. After IV flecainide
administration, ANOVA revealed that the QTc interval was not
significantly changed across 30 min (p=0.35; FIG. 46).
[0582] JTc Interval:
[0583] Prior to IV infusion of flecainide (2 mg/kg bolus over 2
min), the duration of the JTc interval was 367.+-.7.4 ms. After IV
flecainide administration, ANOVA revealed that the JTc interval was
not significantly changed across 30 min (p=0.9686; FIG. 47).
[0584] IT Instillation of 0.75 mg/kg:
[0585] Heart Rate:
[0586] Prior to IT instillation of the lower dose of flecainide
(0.75 mg/kg), heart rate was 111.+-.6.4 bpm. After IT infusion,
ANOVA revealed that heart rate was not significantly altered across
30 min (p=0.9970; FIG. 48).
[0587] Arterial Blood Pressure:
[0588] Prior to the IT instillation of the lower dose of flecainide
(2 mL of 0.75 mg/kg), mean arterial blood pressure was 111.+-.3.6
mmHg. After IV flecainide infusion, ANOVA analysis revealed that
mean arterial pressure was not significantly altered across 30 min
(p=0.9112; FIG. 49).
[0589] PR Interval:
[0590] Prior to the IT instillation of the lower dose of flecainide
(2 mL of 0.75 mg/kg), the PR interval was 130.+-.5.3 ms. After IT
flecainide instillation, ANOVA revealed that the PR interval was
not significantly changed across 30 min (p=0.9351; FIG. 50).
[0591] QRS Duration:
[0592] Prior to the IT instillation of the lower dose of flecainide
(2 mL of 0.75 mg/kg), QRS duration was 58.+-.1.8 ms. After
instillation, QRS duration significantly increased to 64.+-.1.6 ms
and 65.+-.1.7 ms (p<0.05) coincident with peak plasma levels of
the drug at 2 and 5 min, respectively. Thereafter, QRS duration
progressively decreased toward the baseline levels (58.+-.0.9 ms)
at 30 min (FIG. 51).
[0593] QTc Interval:
[0594] Prior to the IT instillation of the lower dose of flecainide
(2 mL of 0.75 mg/kg), the QTc interval was 435.+-.12.9 ms. After
instillation, ANOVA revealed that QTc was not significantly changed
across 30 min (p=0.5505; FIG. 52).
[0595] JTc Interval:
[0596] Prior to the IT instillation of the lower dose of flecainide
(2 mL of 0.75 mg/kg), the JTc interval was 354.+-.12.0 ms. After IT
flecainide administration, ANOVA revealed that the JTc interval was
not significantly changed across 30 min (p=0.7605; FIG. 53).
[0597] IT Instillation of 1.5 mg/kg:
[0598] Heart Rate:
[0599] Prior to IT instillation of the higher dose of flecainide
(1.5 mg/kg), heart rate was 118.+-.13.2 bpm. After IT infusion,
ANOVA revealed that heart rate was not significantly altered across
30 min (p=0.9999; FIG. 54).
[0600] Arterial Blood Pressure:
[0601] Prior to IT instillation of the higher dose of flecainide
(1.5 mg/kg), mean arterial blood pressure was 108.+-.9.4 mmHg.
After IT infusion, ANOVA analysis revealed that mean arterial
pressure was not significantly altered across 30 min (p=0.9894;
FIG. 55).
[0602] PR Interval:
[0603] Prior to the IT instillation of the higher dose of
flecainide (2 mL of 1.5 mg/kg), the PR interval was 127.+-.2.3 ms.
After instillation, ANOVA revealed that the PR interval was not
significantly changed across 30 min (p=0.0819; FIG. 56).
[0604] QRS Duration:
[0605] Prior to the intratracheal instillation of the higher dose
of flecainide (2 mL of 1.5 mg/kg), QRS duration was 57.+-.0.4 ms.
Following IT instillation of the higher dose of flecainide (1.5
mg/kg), QRS duration significantly increased to 68.+-.1.9 ms,
69.+-.2.2 ms, 67.+-.1.7 ms, and 64.+-.1.3 ms (p<0.05),
coincident with the increase in the plasma level of the drug at 2
(peak plasma level), 5, 10, and 15 min, respectively. Thereafter,
QRS duration progressively decreased toward the baseline levels
(60.+-.0.9 ms) at 30 min (FIG. 57).
[0606] QTc Interval:
[0607] Prior to the IT instillation of the higher dose of
flecainide (2 mL of 1.5 mg/kg), the QTc interval was 436.+-.7.1 ms.
After instillation, ANOVA revealed that the QTc interval was not
significantly changed across 30 min (p=0.1510; FIG. 58).
[0608] JTc Interval:
[0609] Prior to the IT instillation of the higher dose of
flecainide (2 mL of 1.5 mg/kg), the JTc interval was 364.+-.11.5
ms. After instillation, ANOVA revealed that the JTc interval was
not significantly changed across 30 min (p=0.9968; FIG. 59).
[0610] Duration of Atrial Fibrillation:
[0611] At one min after intrapericardial administration of ACh (1
ml of 100 mM), burst pacing was performed to initiate AF in the
control cohort (FIG. 60).
[0612] In the absence of flecainide, AF persisted for 11.+-.0.6 min
before spontaneous conversion to sinus rhythm. The data are shown
in Table 12 below.
TABLE-US-00012 TABLE 12 Effects of intratracheal instillation of
flecainide (1.5 mg/kg) on AF duration. AF duration Pig #s No drug
Flecainide 239 12 3 236 10 4 238 12 3 Mean 11 3 SEM 0.6 0.2 p value
0.008992
[0613] In the experimental cohort, after ACh and
burst-pacing-induced AF, a stable period of 2 min of AF was allowed
(FIG. 60). Then, IT instillation of the higher dose of flecainide
(2 mL of 1.5 mg/kg) was performed. AF was converted to sinus rhythm
at 3.+-.0.2 min, a reduction of 73% in AF duration from the
untreated condition (p<0.009; Table 12; FIG. 61). Importantly,
once sinus rhythm was restored by flecainide, no recurrence of AF
occurred within the 30-min window of observation.
[0614] In a separate study using a porcine model, the effect of the
delivery rate (i.e., slow versus rapid infusion) of IV administered
flecainide on the PK and PD was evaluated. Venous plasma
concentrations (FIG. 62A) and the QRS interval duration (FIG. 62B)
varied in response to slow infusion (10 min) compared with rapid
infusion (2 min) of IV flecainide.
[0615] As shown in FIG. 62C, venous plasma levels of flecainide
were positively correlated with QRS duration.
[0616] Summary:
[0617] IT instillation of the antiarrhythmic agent flecainide
generated a pharmacokinetic profile that was similar to IV infusion
of flecainide.
[0618] In addition, IT instillation of flecainide altered
electrocardiographic parameters in a manner consistent with its
pharmacological activity and conducive to conversion of
recent-onset AF to sinus rhythm.
Example 6
Accelerated Cardioversion of Atrial Fibrillation to Normal Sinus
Rhythm by Intratracheal Delivery of Flecainide Acetate in an Intact
Porcine Model
[0619] The study tested the efficacy of intratracheal (IT)
flecainide to convert atrial fibrillation (AF) to normal sinus
rhythm in a large animal model that reproducibly induces AF.
[0620] Experimental Design:
[0621] In closed-chest anesthetized Yorkshire pigs,
intrapericardial (IPC) acetylcholine (ACh) (1 mL of 102.5 mM
solution) followed by burst pacing reproducibly induced AF (n=6).
Catheter placement is shown in FIG. 63.
[0622] At 2 min after AF induction in all 6 animals, IT flecainide
(1.5 or 0.75 mg/kg) or no drug was randomly administered. After
30-min recovery, the alternate intervention was tested. Times for
conversion to normal sinus rhythm were compared.
[0623] Results:
[0624] Both IT flecainide doses used accelerated conversion of AF
to normal sinus rhythm. As shown in FIG. 64, AF duration correlated
with flecainide dose. IT instillation of flecainide (1.5 mg/kg;
n=5) accelerated conversion of AF to normal sinus rhythm in
3.4.+-.0.3 min (mean.+-.SEM) compared to 12.3.+-.1.9 min following
no drug (p=0.008), a shortening in AF duration of 72%. The lower IT
dose of flecainide (0.75 mg/kg; n=3) converted AF to normal sinus
rhythm in 8.1.+-.1.0 min, reducing AF duration by 50% vs. no-drug
(16.2.+-.0.9; p=0.003).
[0625] FIG. 65 shows representative electrograms demonstrating AF
conversion at 5 min after IT flecainide (1.5 mg/kg) compared to no
conversion by 10 min after no drug.
[0626] FIG. 66A illustrates that the plasma concentration of
flecainide reached levels required for conversion within 10 min
after IT flecainide (0.75 mg/kg and 1.5 mg/kg).
[0627] FIG. 66B depicts the plasma concentrations of flecainide at
the time of conversion of AF to NSR following IT instillation of
flecainide (0.75 mg/kg and 1.5 mg/kg).
[0628] FIG. 67 demonstrates that IT flecainide reduced the dominant
frequency of AF.
[0629] Summary:
[0630] IT flecainide instillation (1.5 mg/kg or 0.75 mg/kg) was
100% effective in rapidly converting AF to normal sinus rhythm and
restored MAP and ventricular rate to baseline values.
[0631] The basis for this efficacy is likely rapid absorption of
the drug through the lungs and delivery as a first-pass bolus to
the left atrium via pulmonary veins.
[0632] If the present findings can be confirmed in human subjects,
flecainide delivered via inhalation could provide a potential
option for therapy of new-onset paroxysmal AF.
Example 7
Rapid Cardioversion of Recent-Onset Atrial Fibrillation with
Pulmonary Delivery of Flecainide in Anesthetized Dogs
[0633] The study tested the hypothesis that pulmonary delivery of
flecainide via IT instillation can, within seconds/few minutes of
administration, convert AF into normal sinus rhythm in a dog model
of stable AF.
[0634] Experimental Design:
[0635] The study was carried out in anesthetized healthy adult
beagle dogs with induced AF. Acute AF was induced using the
combination of phenylephrine (2-10 mg/kg), to increase
heterogeneity of atrial refractory periods via increased loading
and through a baroreceptor-mediated increase in parasympathetic
efferent activity, and right atrial burst pacing (40-50 Hz for
.about.15 min). The AF induced using this method was, in general,
stable for more than 30 mins.
[0636] After induction of AF, animals were first given vehicle
(0.9% NaCl, volume-matched) via IT installation. Later flecainide,
at 2 mg/mL bolus was given (<20 sec) via IT at single or
cumulative doses of 0.25 to 0.75 mg/kg. For comparison purposes,
two dogs were given flecainide via intravenous bolus injection
(<20 sec) at single or cumulative doses of 0.25 to 0.75
mg/kg.
[0637] The cardiac rhythm was monitored prior to, during AF, and up
to 10 min post-dosing and/or until conversion to NSR.
[0638] Plasma concentrations of flecainide were measured in the LV
and femoral vein at the time of conversion. In some dogs, plasma
levels of flecainide were also measured in the pulmonary artery
(PA).
[0639] Results:
[0640] No conversion of AF to NSR was observed in vehicle treated
dogs (0/6).
[0641] As shown in Table 13 below, IT-delivered flecainide
converted AF to NSR in 63.+-.18 sec at a mean dose of 0.79.+-.0.04
mg/kg in 6/6 dogs. At the time of conversion of AF to NSR, plasma
levels of flecainide were .about.2-fold higher in the LV than in
the systemic venous circulation. In 2/2 dogs, IV bolus of
flecainide converted AF to NSR in 29 seconds.
TABLE-US-00013 TABLE 13 Effects of IT flecainide in the setting of
AF on conversion times to NSR, and systemic and LV plasma
concentration at the time of conversion. Plasma Time to
Concentration.sup.2 Animal Dose.sup.1 NSR (ng/mL) Route # (mg/kg)
(sec) LV Venous IT 001 0.75 (0.25 + 0.5) 147 538 421 002 0.75 (0.25
+ 0.5) 52 1140 533 003* 0.75 12 3105 1670 004 0.75 23 700 219 005
0.75 62 351 109 006 1.0 (0.75 + 0.25) 83 1000 717 Mean .+-. 0.79
.+-. 0.04 63 .+-. 18 1139 .+-. 380 611 .+-. 213 SEM
.sup.1Cumulative dose of flecainide with individual doses shown in
parenthesis. .sup.2Measured at the time of conversion (.+-.1 min).
*This animal had a time to NSR (12 seconds) that was 2- to 10-fold
faster than in the other dogs. Likewise, in this dog, the LV and
venous plasma levels (ng/mL) were 10- to 2.7-fold and 15- and
2-fold higher, respectively than that observed in other dogs.
[0642] FIGS. 68A-D show a representative ECG demonstrating
conversion of AF to NSR by IT flecainide, but not by vehicle.
[0643] FIG. 69 summarizes the changes in blood pressure (BP),
ventricular rate (VR), and LV dP/dtmax (the maximal rate of rise of
LV pressure) upon conversion of AF to NSR following administration
of flecainide via IV or IT. Flecainide given IV caused greater
effects in BP, VR and LV dP/dtmax upon conversion of AF to NSR
compared with IT administration.
[0644] The plasma concentrations of flecainide in the pulmonary
artery (PA) and left ventricular chamber (LV) were dependent on the
route of delivery (IT and IV) of flecainide (FIG. 70). Following IV
infusion, the concentrations of flecainide in the PA were
transiently higher (2.1- to 3.5-fold) than those in the LV chamber.
Conversely, after IT instillation of flecainide, its concentrations
were transiently higher (1.4- to 3.2-fold) in the LV chamber than
in the PA.
[0645] The ratios of the plasma concentrations of flecainide
between LV and PA (and vice versa PA and LV) for IT were reversed
to those for IV delivery (FIG. 71).
[0646] Summary:
[0647] LV (left atrium) levels of flecainide achieved following
pulmonary delivery of flecainide were sufficient to rapidly
terminate AF.
[0648] The plasma concentrations of flecainide when delivered via
IT were transiently higher (.about.2.5 fold) in the LV than in the
PA. Conversely, following IV infusion, flecainide plasma
concentrations were transiently higher (.about.3.5 fold) in the PA
than in the LV. At about 4-10 mins after the administration of
flecainide (IV or IT), the LV and PA concentrations were nearly
equal.
[0649] Direct delivery of flecainide to the left atrium using oral
inhalation may prove to be more efficacious, faster, and safer than
either the IV or oral delivery alternatives.
[0650] The foregoing embodiments and advantages are merely
exemplary and are not to be construed as limiting the present
invention. The description of the present invention is intended to
be illustrative, and not to limit the scope of the claims. Many
alternatives, modifications, and variations will be apparent to
those skilled in the art.
[0651] Having now fully described this invention, it will be
understood to those of ordinary skill in the art that the methods
of the present invention can be carried out with a wide and
equivalent range of conditions, formulations, and other parameters
without departing from the scope of the invention or any
embodiments thereof.
[0652] All patents and publications cited herein are hereby fully
incorporated by reference in their entirety. The citation of any
publication is for its disclosure prior to the filing date and
should not be construed as an admission that such publication is
prior art or that the present invention is not entitled to antedate
such publication by virtue of prior invention.
* * * * *