U.S. patent application number 16/013165 was filed with the patent office on 2018-10-18 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 Rangachari NARASIMHAN, Carlos A. SCHULER.
Application Number | 20180296480 16/013165 |
Document ID | / |
Family ID | 42739985 |
Filed Date | 2018-10-18 |
United States Patent
Application |
20180296480 |
Kind Code |
A1 |
SCHULER; Carlos A. ; et
al. |
October 18, 2018 |
UNIT DOSES, AEROSOLS, KITS, AND METHODS FOR TREATING HEART
CONDITIONS BY PULMONARY ADMINISTRATION
Abstract
Methods of treating atrial arrhythmia include 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. Other methods of treating
atrial arrhythmia include administering by inhalation an effective
amount of at least one antiarrhythmic pharmaceutical agent to a
patient in need thereof. An amount of the at least one
antiarrhythmic pharmaceutical agent may peak in the coronary sinus
of the heart at a time ranging from 10 seconds to 30 minutes from
initiation of the administering. Unit doses, aerosols, and kits are
also contemplated.
Inventors: |
SCHULER; Carlos A.;
(Kensington, CA) ; NARASIMHAN; Rangachari;
(Saratoga, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
InCarda Therapeutics, Inc. |
Newark |
CA |
US |
|
|
Family ID: |
42739985 |
Appl. No.: |
16/013165 |
Filed: |
June 20, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14632252 |
Feb 26, 2015 |
10045939 |
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16013165 |
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13257249 |
Sep 16, 2011 |
8974828 |
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PCT/US2010/027740 |
Mar 18, 2010 |
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14632252 |
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61210382 |
Mar 18, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4458 20130101;
A61K 31/216 20130101; A61K 31/554 20130101; A61P 9/00 20180101;
A61K 31/18 20130101; A61P 9/06 20180101; A61K 9/0078 20130101; A61M
11/00 20130101; A61K 31/445 20130101; A61K 31/7076 20130101; A61K
31/55 20130101; Y10S 514/821 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/55 20060101 A61K031/55; A61K 31/445 20060101
A61K031/445; A61K 31/4458 20060101 A61K031/4458; A61K 31/7076
20060101 A61K031/7076; A61K 31/216 20060101 A61K031/216; A61K 31/18
20060101 A61K031/18; A61K 31/554 20060101 A61K031/554; A61M 11/00
20060101 A61M011/00 |
Claims
1. A liquid aerosolizable pharmaceutical composition, comprising an
amount of flecainide, a salt, a solvate, or an enantiomer thereof,
wherein the amount of flecainide is effective when the
pharmaceutical composition is administered to a subject
experiencing atrial arrhythmia via aerosolization for cardioversion
of the atrial arrhythmia in the subject.
2. The pharmaceutical composition of claim 1, wherein the
cardioversion converts the atrial arrhythmia in the subject to
normal sinus rhythm.
3. The pharmaceutical composition of claim 1, wherein the atrial
arrhythmia comprises paroxysmal atrial fibrillation.
4. The pharmaceutical composition of claim 1, wherein the amount of
flecainide is less than a second amount of flecainide that is
effective when administered intravenously for cardioversion of the
atrial arrhythmia in the subject.
5. The pharmaceutical composition of claim 1, wherein the amount of
flecainide, when inhaled, is equivalent to a second amount of
flecainide for intravenous administration.
6. The pharmaceutical composition of claim 1, wherein the amount of
flecainide is between 0.5 mg and 150 mg.
7. The pharmaceutical composition of claim 1, wherein the amount of
flecainide is between 1 mg and 100 mg.
8. The pharmaceutical composition of claim 1, wherein a
concentration of flecainide is higher than a second concentration
of flecainide that is effective when administered intravenously for
cardioversion of the atrial arrhythmia in the subject.
9. The pharmaceutical composition of claim 1, wherein a
concentration of flecainide is at least about 30 mg/mL.
10. The pharmaceutical composition of claim 1, comprising the
solvate of flecainide, wherein the solvate comprises a solvent
selected from the group consisting of: water, isopropanol, ethanol,
methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, and
combinations thereof.
11. The pharmaceutical composition of claim 1, further comprising a
pharmaceutically acceptable excipient.
12. The pharmaceutical composition of claim 11, wherein the
pharmaceutically acceptable excipient comprises acetic acid, sodium
hydroxide, or both.
13. The pharmaceutical composition of claim 1, wherein a pH of the
pharmaceutical composition is between 4.5 to 7.0.
14. The pharmaceutical composition of claim 1, wherein a volume of
the pharmaceutical composition is between 1 to 3 mL.
15. The pharmaceutical composition of claim 1, comprising
flecainide acetate.
16. The pharmaceutical composition of claim 1, wherein the subject
is human.
17. A kit, comprising: the pharmaceutical composition of claim 1
and a unit dose receptacle.
18. The kit of claim 17, further comprising an aerosolization
device.
19. A method of treating atrial arrhythmia, comprising:
administering the pharmaceutical composition of claim 1 to the
subject experiencing atrial arrhythmia via aerosolization for
cardioversion of the atrial arrhythmia in the subject.
20. The method of claim 19, wherein a dosing time of the
administering is less than 10 minutes.
Description
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0001] The present invention relates to compositions, unit doses,
aerosols, and kits for treating certain heart conditions by
pulmonary administration and methods thereof.
BACKGROUND ART
[0002] 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.
[0003] Atrial arrhythmia 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 primarily cardiac
related, that necessitates extensive monitoring of the patient.
[0004] What is needed for fast and safe cardioversion (resolution
of arrhythmia) is therapy that:
[0005] 1. Has little to no risk of acceleration of ventricular rate
before cardioversion;
[0006] 2. Slows atrio-ventribular (AV) conduction so that there is
rate control and cardioversion at the same time;
[0007] 3. Has little to no effect in prolonging the QRS interval
and should have a low risk of torsade de pointes; and
[0008] 4. Has little 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.
[0009] 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 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).
[0010] 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.
[0011] Paroxysmal supraventricular tachycardia (PSVT) is an
arrhythmia that affects younger and healthy populations who are
active (e.g., athletes). About 500,000 to 600,000 patients have
PSVT in the United States.
[0012] 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 result.
[0013] Oral medications, e.g., pills, tend to require high doses
and 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 with treatment being given intravenously.
[0014] Intravenous injection usually requires a hospital
environment 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.
[0015] Injecting 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.
[0016] 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.
[0017] Cardiac arrhythmias are associated with disabling symptoms
like tightness around the chest, palpitations, feeling tired, and
sometimes chest pain.
[0018] 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
(06/2006); and TWISS et al., "Efficacy of Calcium Channel Blockers
as Maintenance Therapy for Asthma," British J of Clinical
Pharmacology (November 2001).
[0019] 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 OF THE INVENTION
[0020] 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.
[0021] 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.
[0022] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, e.g., tachycardia. The method
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 sinus of the heart at a
time ranging from 10 seconds to 30 minutes from initiation of the
administering.
[0023] 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 of the self-diagnosing.
[0024] In another aspect, the present invention is directed to a
method of treating atrial arrhythmia, comprising 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 initiation of the
administering.
[0025] In still another aspect, the present invention is directed
to a method of treating atrial arrhythmia, comprising 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 initiation of the administering.
[0026] In yet another aspect, the present invention is directed to
a method of treating atrial arrhythmia, comprising 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 initiation of the
administering.
[0027] 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 sinus, and a
pharmaceutically acceptable excipient.
[0028] 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 sinus, and a pharmaceutically
acceptable excipient.
[0029] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] The present invention is further described in the
description of invention that follows, in reference to the noted
plurality of non-limiting drawings, wherein:
[0031] FIG. 1 shows how prior art intravenous drug passes through
the heart and lungs before reaching coronary arteries.
[0032] FIG. 2A shows how inhaled drug of the present invention
passes through directly from the lungs to coronary arteries.
[0033] FIG. 2B shows how inhaled drug of the present invention
passes through the pulmonary vein to the left atrium.
[0034] 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.
[0035] FIG. 4 shows a six compartment PK-PD model to compare
intravenous and pulmonary delivery.
[0036] FIG. 5 shows the results of a simulation comparing
intravenous and pulmonary delivery of verapamil.
[0037] FIG. 6 shows the results of a simulation comparing
intravenous and pulmonary delivery of lidocaine.
[0038] 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.
[0039] 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
[0040] FIG. 9 shows an ECG trace showing Dog in Afib prior to
dosing of either vehicle or test article.
[0041] FIG. 10 shows an ECG trace showing Dog continues to be in
Afib after pulmonary administration of vehicle (water, 3 ml).
[0042] 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.
[0043] FIG. 12 shows an ECG trace showing Afib converting as soon
as dosing occurred at 2 mg/kg body weight of flecainide
acetate.
[0044] FIG. 13 shows an ECG trace showing Afib converting after
administration of diltiazem HCl at 0.25 mg/kg body weight.
[0045] 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.
[0046] 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.
[0047] 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).
[0048] 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.
[0049] 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.
[0050] 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).
[0051] 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.
DESCRIPTION OF THE INVENTION
[0052] 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.
[0053] Before further discussion, a definition of the following
terms will aid in the understanding of the present invention.
[0054] 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.
[0055] 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.
[0056] As used herein, the term "solvate" is intended to include,
but not be limited to, pharmaceutically acceptable solvates.
[0057] 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.
[0058] As used herein, the term "salt" is intended to include, but
not be limited to, pharmaceutically acceptable salts.
[0059] 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, dinitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
xylenesulfonates, phenylacetates, phenylpropionates,
phenylbutyrates, citrates, lactates, .gamma.-hydroxybutyrates,
glycolates, tartrates, methanesulfonates, propanesulfonates,
naphthalene-1-sulfonates, naphthalene-2-sulfonates, and
mandelates.
[0060] 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.
[0061] 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.
[0062] As used herein, "atrial arrhythmia" means 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.
[0063] As used herein, "tachycardia" means an arrhythmia in which
the heart beat is too fast. 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.
[0064] As used herein, the phrase "heart rhythm arrhythmia" means
an arrhythmia in which the heart beat is irregular.
[0065] As used herein, the "amount of the at least one
antiarrhythmic pharmaceutical agent in blood in the coronary sinus
of the heart" may be measured by extracting a sample from the
coronary sinus of the heart 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.
[0066] As used herein, the terms "treating" and "treatment" 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.
[0067] As used herein, "nominal amount" refers to the amount
contained within the unit dose receptacle(s) that are
administered.
[0068] As used herein, "effective amount" refers to an amount
covering both therapeutically effective amounts and
prophylactically effective amounts.
[0069] 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.
[0070] Unless otherwise specified, the term "therapeutically
effective amount" includes a "prophylactically effective amount,"
i.e., 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.
[0071] As used herein, the phrase "minimum effective amount" means
the minimum amount necessary to achieve an effective amount.
[0072] As used herein, "mass median diameter" or "MMD" refers to
the median diameter of a plurality of particles, typically in a
polydisperse particle population, i.e., 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.
[0073] As used herein, "geometric diameter" refers to the diameter
of a single particle, as determined by microscopy, unless the
context indicates otherwise.
[0074] As used herein, "mass median aerodynamic diameter" or "MMAD"
refers to the median aerodynamic size of a plurality of particles
or particles, typically in a polydisperse population. The
"aerodynamic diameter" is 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.
[0075] As used herein, the term "emitted dose" or "ED" refers 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 (i.e., 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)).
[0076] As used herein, "passive dry powder inhaler" refers 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.
[0077] As used herein, "active dry powder inhaler" refers 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.
[0078] By a "pharmaceutically acceptable" component is meant a
component that is not biologically or otherwise undesirable, i.e.,
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.
[0079] As used herein, "P wave" represents the wave of
depolarization that spreads from the SA node throughout the atria,
and is usually 0.08 to 0.1 seconds (80-100 ms) in duration.
[0080] As used herein, "short form-36 quality of life" means 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.
[0081] As used herein, "preservative" means cresols and benzoates.
Thus, "substantially preservative-free" means that a composition
does not include a substantial amount of any cresols and/or
benzoates. For instance, "substantially preservative-free"
compositions 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"
means that no preservative is present.
[0082] As used herein, "substantially tasteless" means a
composition that has substantially little to no taste upon initial
ingestion.
[0083] 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 vein to the left atrium.
[0084] 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 sinus of the heart at a
time ranging from 10 seconds to 30 minutes from initiation of the
administering.
[0085] 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 of the self-diagnosing.
[0086] 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 initiation of the administering.
[0087] 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 initiation of the
administering.
[0088] 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 initiation of the administering.
[0089] 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 sinus, and a pharmaceutically acceptable
excipient.
[0090] 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
sinus, and a pharmaceutically acceptable excipient.
[0091] In yet another aspect, a kit comprises a container
containing at least one antiarrhythmic pharmaceutical agent and an
aerosolization device.
[0092] 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.
[0093] Inhalation is the shortest route for a drug to reach the
heart, next only to intracardial 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. This characteristic is
expected to reduce much of the dose dependent pro-arrhythmia and QT
prolongation seen with both oral and IV therapies. See 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).
[0094] 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
sinus 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 initiation of the
administering. 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 initiation of the administering. In some embodiments, 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, 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
initiation of the administering. 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 initiation of the administering. In
certain embodiments, the patient has normal sinus rhythm within 30
minutes, such as within 10 minutes, of initiating the
administering.
[0095] 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.
[0096] 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-cardial injection. Drugs delivered
via the lung have a fast onset action compared to those delivered
via the oral route. Pipeline Insights: Antiarrhythmics, Datamonitor
(06/2006). 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.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] Class Ia antiarrhythmics include, but are not limited to,
quinidine, procainamide, and disopyramide. Class Ib antiarrhythmics
include, but are not limited to, lidocaine, tocainide, phenytoin,
moricizine, and mexiletine. Class Ic antiarrhythmics include, but
are not limited to, flecainide, propafenone, and moricizine. Class
II antiarrhythmics include, but are not limited to, propranolol,
acebutolol, soltalol, esmolol, timolol, metoprolol, and atenolol.
Class III antiarrhythmics include, but are not limited to,
amiodarone, sotalol, bretylium, ibutilide, E-4031
(methanesulfonamide), vernakalant, and dofetilide. Class IV
antiarrhythmics include, but are not limited to, bepridil,
nitrendipine, amlodipine, isradipine, nifedipine, nicardipine,
verapamil, and diltiazem. Class V antiarrhythmics include, but are
not limited to, digoxin and adenosine.
[0104] 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. 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.
[0105] 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.
[0106] The antiarrhythmic pharmaceutical agents of the present
invention may be prepared in a racemic mixture (i.e., mixture of
isomers) that contains more than 50%, preferably at least 75%, and
more preferably at least 90% of the desired isomer (i.e., 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.
[0107] 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, 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] Additional active agents for use in the invention 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, i.e., 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.
[0113] 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.
[0114] 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
%.
[0115] 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.
[0116] 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.
[0117] 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 (i.e., palmitoyl and
stearoyl). The phospholipid content may be determined by the active
agent activity, the mode of delivery, and other factors.
[0118] 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 %.
[0119] Generally, compatible phospholipids 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] Examples of ionic surfactants include, but are not limited
to, sodium sulfosuccinate, and fatty acid soaps.
[0125] 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.
[0126] 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.
[0127] Examples of buffers include, but are not limited to, tris or
citrate.
[0128] Examples of acids include, but are not limited to,
carboxylic acids.
[0129] 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.
[0130] Examples of organic solids include, but are not limited to,
camphor, and the like.
[0131] 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).
[0132] 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.
[0133] 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.
[0134] 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.
[0135] The pharmaceutical compositions of one or more embodiments
of the present invention often 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.
[0136] 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.
[0137] 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).
[0138] 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.
[0139] In some embodiments, the isotonicity of the solution ranges
from isotonic to physiologic isotonicity. Physiologic isotonicity
is the isotonicity of physiological fluids.
[0140] 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.
[0141] 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.
[0142] 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.
[0143] 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.
[0144] 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.
[0145] 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] Unit doses of the pharmaceutical compositions may be
contained 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.
[0163] 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.
[0164] For solutions, the amount of the composition in the unit
dose typically ranges from about 2 ml to about 15 ml, such as from
about 3 ml to about 10 ml, about 4 ml to about 8 ml, or about 5 ml
to about 6 ml.
[0165] 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.
[0166] 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 .mu.m filter into a sterilized receiving vessel.
Filling components may be sterilized before use in filling the
batch into vials, e.g., 10 ml vials.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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.
[0175] 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.
[0176] The lyophilizing is generally conducted within about 72
hours, such as within about 8 hours, or within about 4 hours, of
the dissolving.
[0177] 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.
[0178] 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.
[0179] 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.
[0180] 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.
[0181] 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.
[0182] 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 %.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] For dry powders, the composition may be formed by spray
drying, lyophilization, milling (e.g., wet milling, dry milling),
and the like.
[0187] 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.
[0188] 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.
[0189] 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)).
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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 non-fluorinated oils,
chloroform, Freon.RTM. fluorocarbons, ethyl acetate, alcohols,
hydrocarbons, nitrogen, and carbon dioxide gases. The blowing agent
may be emulsified with a phospholipid.
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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.
[0198] 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.
[0199] 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.
[0200] The compositions of one or more embodiments of the present
invention may be administered by inhalation.
[0201] 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.
[0202] 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), permanent atrial
fibrillation, persistent atrial fibrillation, atrial flutter,
paroxysmal atrial flutter, and lone atrial fibrillation.
[0203] 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 is not taken as a
preventative, i.e., when the patient is well, there is no need for
drug--this makes the therapy more effective and safe due to
sporadic or intermittent dosing, and focused on reducing disabling
symptoms.
[0204] 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 its normal
intravenous dose. The pulmonary dose is similar to intracardial
doses. Inhalation avoids dilution of drug in the body as compared
to intravenous or oral dosing.
[0205] 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 is 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).
[0206] 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.
[0207] 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.
[0208] 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 overall 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.
[0209] 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.
[0210] 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.
[0211] 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.
[0212] 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.
[0213] The dosing may be guided by how the patient feels. Also or
alternatively, dosing may be guided by a portable ECG. For
instance, the dosing may be guided by a Holter monitor.
[0214] 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.
[0215] 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.
[0216] 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.
[0217] 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.
[0218] 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.
[0219] 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, and sometimes greater than about 15 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.
[0220] 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.
[0221] In certain embodiments, 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, such as within one hour, 30
minutes, or within 15 minutes, of the self-diagnosing.
[0222] 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.
[0223] 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.
[0224] 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.
[0225] 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 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.
[0226] 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
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
with in the scope thereof.
[0227] 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.
[0228] 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.
[0229] 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.
[0230] 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.
[0231] 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.
[0232] In still another type of nebulizer, ultrasonic waves are
generated to directly vibrate and aerosolize the pharmaceutical
formulation.
[0233] 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.
[0234] 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.
[0235] 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 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.
[0236] 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.
[0237] 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.
[0238] 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%.
[0239] 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.
[0240] The kit may further comprise a package, such as a bag, that
contains the aerosolization device and the container.
[0241] 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.
[0242] 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 PK/PD modeling originating this invention shows
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.
[0243] 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
[0244] 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.
[0245] 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.: paroxysmal ventricular tachycardia and
paroxysmal atrial fibrillation).
[0246] 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)
[0247] Objective:
[0248] 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.
[0249] Animal Models Used
[0250] Atrial Fibrillation Model:
[0251] Anesthesia/Surgical Preparation: 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).
[0252] Experiments: 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:
[0253] 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.
[0254] 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, OIL) or dofetilide (20-60 ug/kg, DOF); only one
test article was administered per animal. The experimental
protocol(s) are summarized in FIG. 7.
[0255] Supraventricular Tachycardia Model:
[0256] Anesthesia/Surgical Preparation: 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).
[0257] 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).
[0258] Experiments: 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.
[0259] 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).
[0260] 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.
[0261] Observations:
[0262] Atrial Fibrillation:
[0263] 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.
[0264] Vehicle: FIG. 9 shows the dog in atrial fibrillation prior
to administration of either vehilcle 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.
[0265] Flecainide: 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.
[0266] Diltiazem: 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. Heart rate also slowed down
marginally. There was however a notable drop in mean arterial blood
pressure (MAP). See FIG. 13.
[0267] Dofetilide: At escalating pulmonary doses of 10-40 mcg/kg
body weight, dofetilide caused minor reduction in heart rate.
[0268] Supraventricular Tachycardia (SVT):
[0269] Diltiazem: 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 ability to correct the SVT to normal sinus rhythm. The
timing of the electrophysiological change was comparable between IV
and pulmonary. See FIGS. 14 and 15.
[0270] Esmolol: Elevating doses of esmolol were shown to produce
2.sup.nd degree AV block at lower doses and also affecting the PR
intervals in the ECG traces. See FIGS. 16-20.
[0271] 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.
[0272] Adenosine: 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 localized adenosine administration or the model
not being sensitive enough.
SUMMARY:
[0273] There was a clear cardiovascular effect of diltiazem,
flecainide, and a probable effect of esmolol and dofetilide when
given intratracheally. 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 more specific 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.
[0274] 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
[0275] Objective:
[0276] 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.
[0277] Experiment and Observations:
[0278] Preformulation Studies:
[0279] 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.
[0280] 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.
[0281] 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.
[0282] Inhalation Device:
[0283] 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. More details about this device can
be obtained at www.aerogen.com.
[0284] Inhalation Procedure:
[0285] Volunteers:
[0286] Number of subjects: 2 healthy male volunteers
[0287] Volunteer-1: age--48
[0288] Volunteer-2: age--63
[0289] Nebulizer Testing:
[0290] 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.
[0291] Flecainide Acetate:
[0292] 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.
[0293] 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.
[0294] Diltiazem Hydrochloride:
[0295] 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.
[0296] 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.
[0297] Conclusions and Observations: [0298] 1. The visible aerosol
characteristics test solutions were similar to each other but not
as dense as the water. [0299] 2. Flecainide acetate: The taste
feedback from both volunteers was very similar. [0300] a. Taste:
Mildly bitter taste felt in the back of the tongue [0301] b.
Aftertaste: There was none to little aftertaste 5 minutes after the
inhalation maneuver. [0302] 3. Diltiazem hydrochloride: Water was
inhaled to wash out any of the flecainide residues. The taste
feedback from both volunteers was very similar. [0303] a. Taste:
Mildly bitter taste felt in the back of the tongue [0304] b.
Aftertaste: There was none to little aftertaste 5 minutes after the
inhalation maneuver. [0305] 4. Other observations: [0306] a. No
burning sensations was felt in the mouth, throat, or lungs [0307]
b. No visible adverse events were observed. Both volunteers rested
for 60 minutes after dosing.
[0308] 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.
[0309] 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.
[0310] 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.
* * * * *
References