U.S. patent application number 17/193014 was filed with the patent office on 2021-12-30 for method and system for the treatment of chronic copd with nebulized anticholinergic administrations.
This patent application is currently assigned to Sunovion Respiratory Development Inc.. The applicant listed for this patent is Sunovion Respiratory Development Inc.. Invention is credited to William GERHART, Ahmet TUTUNCU.
Application Number | 20210401740 17/193014 |
Document ID | / |
Family ID | 1000005828097 |
Filed Date | 2021-12-30 |
United States Patent
Application |
20210401740 |
Kind Code |
A1 |
GERHART; William ; et
al. |
December 30, 2021 |
METHOD AND SYSTEM FOR THE TREATMENT OF CHRONIC COPD WITH NEBULIZED
ANTICHOLINERGIC ADMINISTRATIONS
Abstract
A method is provided for improving lung function in COPD by
administering a muscarinic antagonist with a high efficiency
nebulizer.
Inventors: |
GERHART; William; (La Mesa,
CA) ; TUTUNCU; Ahmet; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Respiratory Development Inc. |
Marlborough |
MA |
US |
|
|
Assignee: |
Sunovion Respiratory Development
Inc.
Marlborough
MA
|
Family ID: |
1000005828097 |
Appl. No.: |
17/193014 |
Filed: |
March 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16217765 |
Dec 12, 2018 |
10940110 |
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17193014 |
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15050280 |
Feb 22, 2016 |
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16217765 |
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12547406 |
Aug 25, 2009 |
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15050280 |
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12393709 |
Feb 26, 2009 |
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12547406 |
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61080184 |
Jul 11, 2008 |
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61031639 |
Feb 26, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0078 20130101;
A61K 31/56 20130101; A61M 11/00 20130101; A61K 31/4015 20130101;
A61K 31/00 20130101; A61K 31/40 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/00 20060101 A61K031/00; A61K 31/4015 20060101
A61K031/4015; A61K 31/56 20060101 A61K031/56; A61K 31/40 20060101
A61K031/40; A61M 11/00 20060101 A61M011/00 |
Claims
1-38. (canceled)
39. A composition for administration with a high efficiency
nebulizer, comprising a concentrated, preservative-free,
pH-adjusted solution formulation of a muscarinic antagonist.
40. The composition of claim 39, wherein the composition is an
aqueous solution of glycopyrrolate having a volume of about 0.5 mL
to about 1.5 mL, a glycopyrrolate concentration of about 25
.mu.g/mL to about 250 .mu.g/mL, and a pH of about 3 to about 5,
wherein the solution is free of other bronchodilating agents.
41. The composition of claim 40, wherein the glycopyrrolate
concentration is about 25 .mu.g/mL and/or the volume is about 1 mL
and/or the pH is about 3 to about 5.
42. A method of treating a respiratory condition in a subject
comprising administering to the subject a composition of claim
39.
43. The method of claim 42, wherein the respiratory condition is
chronic bronchitis, chronic obstructive pulmonary disease (COPD),
or emphysema.
44. A method of treating a respiratory condition in a subject
comprising administering to the subject a composition of claim
40.
45. The method of claim 44, wherein the glycopyrrolate
concentration is about 25 .mu.g/mL and/or the volume is about 1 mL
and/or the pH is about 3 to about 5.
46. The method of claim 44, wherein the composition comprises an
aqueous solution of glycopyrrolate having a volume of about 1.0 mL,
a glycopyrrolate concentration of about 25 .mu.g/mL, and a pH of
about 3 to about 5, wherein the solution is free of other
bronchodilating agents and is substantially free of
preservatives.
47. The method of claim 46, wherein said aqueous solution further
comprises citric acid or a pharmaceutically acceptable salt
thereof.
48. The method of claim 44, wherein the respiratory condition is
chronic bronchitis or emphysema.
49. The method of claim 48, wherein the glycopyrrolate
concentration is about 25 .mu.g/mL and/or the volume is about 1 mL
and/or the pH is about 3 to about 5.
50. The method of claim 48, wherein the composition comprises an
aqueous solution of glycopyrrolate having a volume of about 1.0 mL,
a glycopyrrolate concentration of about 25 .mu.g/mL, and a pH of
about 3 to about 5, wherein the solution is free of other
bronchodilating agents and is substantially free of
preservatives.
51. The method of claim 50, wherein the aqueous solution further
comprises citric acid or a pharmaceutically acceptable salt
thereof.
52. A method of treating a patient having chronic obstructive
pulmonary disease (COPD), comprising administering to the patient,
with a high efficiency nebulizer, a nominal dose of a composition
comprising a muscarinic antagonist that provides the patient with a
therapeutic effect at least about 24 hours after administering the
muscarinic antagonist to the patient.
53. The method of claim 52, wherein the muscarinic antagonist is
glycopyrrolate.
54. The method of claim 53, wherein the glycopyrrolate
concentration is about 25 .mu.g/mL and/or the volume of the
composition is about 1 mL and/or the pH of the composition is about
3 to about 5.
55. The method of claim 52, wherein the composition comprises an
aqueous solution of glycopyrrolate having a volume of about 1.0 mL,
a glycopyrrolate concentration of about 25 .mu.g/mL, and a pH of
about 3 to about 5, wherein the solution is free of other
bronchodilating agents and is substantially free of
preservatives.
56. The method of claim 55, wherein said aqueous solution further
comprises citric acid or a pharmaceutically acceptable salt
thereof.
57. A method for the maintenance treatment of severe chronic
obstructive pulmonary disease (COPD) in a patient, the method
comprising: (a) administering to the patient, with a high
efficiency nebulizer, a first nominal dose of a first aqueous
inhalation solution comprising less than about 80 .mu.g of
glycopyrrolate, and free of other bronchodilating agents; and (b)
administering to the patient, with a high efficiency nebulizer, a
second nominal dose of a second aqueous inhalation solution
comprising less than about 80 .mu.g of glycopyrrolate, and free of
other bronchodilating agents; wherein the combination of the first
and second nominal doses provides the patient with a therapeutic
effect at least 24 hours after administering the first nominal dose
to the patient; and wherein the first and second nominal doses are
administered to the patient in a 24-hour period.
58. The method of claim 57, wherein the glycopyrrolate
concentration is about 25 .mu.g/mL.
Description
[0001] This application claims priority under 35 U.S.C. .sctn. 120
from U.S. nonprovisional patent application Ser. No. 12/393,709,
filed. Feb. 26, 2009, and claims priority under 35 U.S.C. .sctn.
119(e) from U.S. provisional patent application 61/031,639, filed
Feb. 26, 2008, and from U.S. provisional patent application
61/080,184, filed Jul. 11, 2008, each of which applications is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Chronic obstructive airway disease (COPD) is a pulmonary
(lung) disease characterized by chronic obstruction of the airways.
COPD encompasses emphysema and chronic bronchitis. Chronic
bronchitis is diagnosed where a patient suffers from chronic cough,
mucus production, or both, for at least three months in at least
two successive years where other causes of chronic cough have been
excluded. In chronic bronchitis, airway obstruction is caused by
chronic and excessive secretion of abnormal airway mucus,
inflammation, and bronchospasm. Often chronic bronchitis is
exacerbated by frequent or chronic infection.
[0003] Emphysema involves the destruction of elastin in terminal
bronchioles, which leads to remodeling, destruction and ultimate
collapse of the airway walls. Patients with emphysema gradually
lose the ability to exhale, causing a rise in blood waste gasses
(such as carbon dioxide), a drop in blood oxygen, and a general
degradation of patient stamina and overall health. A characteristic
of emphysema is permanent loss of alveoli. Remodeling leads to
permanent enlargement of the air spaces distal to the terminal
bronchioles, and destruction of terminal bronchiole walls, though
without fibrosis. Emphysema is progressive with a poor prognosis.
Since there is no known method for repairing elastin or restoring
the alveoli, therapy is generally palliative and persistent.
[0004] Most patients suffering from COPD have both emphysema and
chronic bronchitis. The standard of treatment for COPD includes
maintenance and/or rescue dosing of bronchodilator and/or
anti-inflammatory aerosol drugs. While most patients respond to
treatment with metered dose inhalers or dry powder inhalers, there
is a subset of patients for whom such options are not well-suited.
Older and sicker CORD patients, for example, often find it
difficult to use, or do not experience therapeutic benefit from the
use of, metered dose inhalers or dry powder inhalers.
[0005] Dry powder inhalers are generally passive delivery devices,
which patients actuate by forceful, controlled inhalation through
the mouth. Metered dose inhalers, on the other hand, are in general
active delivery devices, which create an atomized mist by forcing a
drug solution or suspension through a nozzle under pressure. A
patient activates the metered dose inhaler by pressing an actuator
and simultaneously breathing in through the mouth in order to
deposit the drug in the patient's lungs. Patients whose motor
skills are impaired or not fully developed will often have trouble
activating the device, coordinating their breathing, and generally
using metered dose inhalers. Patients who also have poor inhalation
capacity and control find dry powder inhalers to be difficult to
operate as well. Newer inhaler devices that are breath-actuated or
produce a soft mist are easier for patients to operate; but these
newer devices still require coordination and a breath-hold; and
achievement of sufficient lung deposition and distribution is
reliant on only one or two inhalations. For sicker and older COPD
patients, nebulizer delivery of their medicines is an important
delivery option, since they can generally receive a full dose
regardless of disease state, because all that is required is normal
(tidal) breathing over multiple minutes.
[0006] There are two general categories of bronchodilators
muscarinic antagonists and beta 2-adrenergic agonists. Muscarinic
antagonists are preferred and are recommended first-line therapy
for maintenance treatment of moderate to severe COPD. Long-acting
muscarinic antagonists (so-called LAMAS) are preferred to
short-acting muscarinic antagonists, due to their superior efficacy
and duration of effect. One LAMA that has been approved for use in
cam in the United States is tiotropium bromide powder for
inhalation (Spiriva.RTM., NDA No. 021395, Boehringer Ingelheim).
Tiotriopium bromide is available commercially only as a dry powder,
which is administered by a breath-activated inhaler. A similar mode
of administration is disclosed by Bannister et al. (U.S. Pat. No.
7,229,607) for administration of glycopyrronium bromide
(glycopyrrolate) as a dry powder. The '607 patent claims a method
for achieving grater than 20 hours of bronchodilation in a COPD
patient by means of coated particles in a dry powder formulation.
The '607 patent distinguishes this methodology from administration
of a solution formulation of glycopyrrolate, which is characterized
as being unable to achieve effective treatment of COPD for longer
than 12 hours. For example, Bannister et al. state:
"Schroeckenstein et al., J. Allergy Clin. Immunol., 1988; 82(1):
115-119, discloses the use of glycopyrrolate in an aerosol
formulation for treating asthma. A single administration of the
metered-dose glycopyrrolate aerosol achieved bronchodilation over a
12 hour period." Additionally, Bannister et al. admit: "Skorodin,
Arch Intern, Med, 1993; 153: 814 828, discloses the use of
glycopyrrolate in an aerosol formulation for the treatment of
asthma and COPD. It is stated that, in general, the quaternary
ammonium anticholinergic compounds have a duration of action of 4
to 12 hours. A dose of between 0.2 to 1.0 mg of glycopyrrolate is
recommended at 6 to 12 hour intervals." And the inventors of the
'607 patent also state: "Walker et al., Chest, 1987; 91(1): 49-51,
also discloses the effect of inhaled glycopyrrolate as an asthma
treatment. Again, the duration of effective treatment is shown to
be up to 12 hours, although up to 8 hours appears to be
maximal."
[0007] Hansel et al. ("Glycopyrrolate causes prolonged
bronchoprotection and bronchodilation in patients with asthma," 128
Chest 1974-1979 (2005)) claim to have demonstrated an improvement
in bronchodilation and bronchoprotection in mild-to-moderate
asthmatic patients for a period of up to 30 h with nebulized
glycopyrronium bromide (glycopyrrolate). Single doses of
glycopyrrolate (0.5, 1.0 and 2.0 mg/dose) were administered to
mild-to-moderate asthmatic volunteers ages 18-60, who were then
challenged with doubling increments of methacholine dose until a
>20% fall in FEV.sub.1 was achieved. A log dose-response curve
was constructed with these data by linear interpolation. No clear
dose-response was observed for either bronchodilation or
bronchoprotection. Although the authors claim to have demonstrated
bronchodilation for a period of up to 30 h, the mean response in
FEV.sub.1 was clinically meaningful (>10% change from pre-dose
levels) only at 2 hours post-dose and dropping to approximately 5%
levels from 12 h through 30 h. This indicates that the
bronchodilator response was short-lived and not sustainable beyond
12 hours. In the same study, the authors demonstrated clinically
meaningful bronchoprotective effect of nebulized glycopyrrolate
that was sustained up to 30 h at all dose levels. Although the
bronchoprotective effect in response to a bronchial challenge test
is considered a useful surrogate test for treatment of lung
diseases with airway hyperresponsiveness, such as asthma, a
positive bronchoprotective test is not considered a predictive tool
and useful test in patients with COPD, because of the different
disease pathology and mechanisms involved in COPD. As outlined in
the literature and international guidelines, the airway
hyperresponsiveness test is not considered a suitable test for use
in COPD, therefore the data in asthma patients presented by Hansel
et al. cannot be extrapolated for COPD. In any case, the authors
seem to favor a breath-activated dry powder inhaler as the optimal
mode of delivery. Id. at 1978. Thus, this study can be seen as
being supportive of the dry powder inhalation methodology taught by
Bannister et al. (U.S. Pat. No. 7,229,607). Hansel et al. list as
conclusions that nebulized glycopyrrolate may have a sustained
duration of action and be superior to ipratropium bromide for
treatment of stable COPD. Id. at 1974. Nevertheless none of the
treated patients in Hansel, et al were identified as suffering from
COPD, and no study has demonstrated a clinically meaningful
bronchodilator response in COPD, asthma, or any other respiratory
disease with nebulized glycopyrrolate for greater than 12 hours at
any dose.
[0008] A sub-segment of the COPD population comprising the sickest
and oldest patients requires nebulizer delivery of their medicines
because they are unable to satisfactorily operate a metered dose or
dry powder inhaler. However, the treatment options for these
patients are limited. Although two long-acting beta 2 agonist
solution formulations are approved for nebulizer delivery twice
daily (BID), and indicated for the maintenance treatment of COPD
symptoms, muscarinic antagonists are preferable for the treatment
of moderate to severe COPD. Also, once-daily dosing (QD) is
preferable to BID. Ipratropium bromide is the only muscarinic
antagonist approved for nebulizer delivery in COPD (monotherapy or
in combination with albuterol), however ipratropium+/-albuterol is
indicated for administration four times per day (QID); and QID
dosing and long nebulization times of this short-acting agent is
inconvenient, leading to poor compliance and thus sub-optimal
clinical outcomes. Longer acting aerosol drugs have been
demonstrated to generally be more efficacious and result in better
compliance compared to shorter acting drugs.
[0009] There is thus a need for additional therapeutic options for
the treatment of COPD. There is a need for therapeutic options that
offer greater convenience and better efficacy, especially for the
sub-population of COPD patients who require nebulizer delivery. In
particular there is a need for a nebulized muscarinic antagonist
that provides more than 12 hours, and preferably at least 24 hours
of therapeutic benefit to COPD patients. Heretofore, no method,
device or system has been suggested that satisfies these needs.
SUMMARY OF THE INVENTION
[0010] The foregoing and further needs are satisfied by embodiments
of the present invention. Some embodiments provide long-acting
treatment of one or more symptoms of COPD. Embodiments described
herein provide methods, devices and systems that permit relief of
one or more symptoms of COPD for a period of at least about 18 hr,
preferably at least about 20 hours, and more preferably at least
about 24 hours, with nebulized administration of an antimuscarinic
agent, such as glycopyrronium bromide (glycopyrrolate). In
particular embodiments set forth herein, there are provided
methods, devices and systems for administration of an
antimuscarinic agent, such as glycopyrrolate, via a high efficiency
nebulizer. High efficiency nebulizers provide shorter treatment
times and superior lung deposition as compared to conventional
nebulizers. High efficiency nebulizers can produce smaller particle
sizes with tighter particle size distributions, which can result in
more drug depositing in the lungs, and less drug depositing in the
oropharyngeal pathway. This is particularly advantageous for
delivering a muscarinic antagonist that has as a close-limiting
side effect dry mouth, which can limit the amount of drug that can
be delivered to, and tolerated by, the patient, and thereby prevent
achievement of maximal duration of therapeutic benefit. Also,
smaller particles tend to penetrate more homogenously and farther
into the lungs, thereby enhancing distribution of the drug
throughout the surface of the lungs and targeting a greater
proportion of muscarinic receptors that are involved in the
pathogenesis of one or more symptoms of COPD. Without wishing to be
bound by theory, the inventors believe that the enhanced
deposition, distribution or both of a long-acting muscarinic
antagonist with a high efficiency nebulizer (as opposed to a
conventional nebulizer) enhances outcomes in the treatment of COPD.
In an exemplary embodiment, a nebulizer capable of delivering
droplets having a median particle diameter of less than about 4.5
.mu.m (especially less than about 4.0 .mu.m) and a geometric
standard deviation (GSD) of less than about 2.0, (especially less
than about 1.8) will provide more efficacious and better-tolerated
treatment of COPD with an antimuscarinic agent as compared to a
conventional nebulizer. Some embodiments provide a unit dosage form
adapted or adaptable for administering a nominal dose of a
muscarinic antagonist, such as glycopyrrolate, with a high
efficiency nebulizer for treatment of COPD. Some embodiments
provide a device comprising (1) a combination of a unit dosage form
adapted or adaptable for administering a nominal dose of a
muscarinic antagonist, such as glycopyrrolate, with a high
efficiency nebulizer for treatment of COPD; and (2) a high
efficiency nebulizer.
[0011] Furthermore, previous published reports of delivery of a
glycopyrrolate solution formulation by, nebulizer were at
concentrations of no more than 0.2 mg/ml and contained a
preservative, benzyl alcohol, that is a known lung irritant.
Without wishing to be bound by theory, it is believed that a higher
concentration of glycopyrrolate at the muscarinic receptor level
and a more selective targeting of the muscarinic receptors (higher
quantity of receptor binding) in the airways will contribute to a
faster onset and/or greater magnitude of therapeutic effect and/or
a greater duration of therapeutic effect. Additionally, eliminating
the preservative enables higher or more concentrated doses of
glycopyrrolate to be delivered in a better-tolerated manner.
[0012] Some embodiments described herein provide a method of
treating a patient having chronic obstructive pulmonary disease
(COPD), comprising administering to the patient, with a high
efficiency nebulizer, a nominal dose of a composition comprising a
muscarinic antagonist that provides the patient with a therapeutic
effect for at least about 24 hours. Also provided are systems for
carrying out the aforementioned method, comprising a formulation to
be nebulized and a high efficiency nebulizer. Some embodiments
described herein provide a method of treating a patient having
chronic obstructive pulmonary disease (COPD), comprising
administering to the patient, with a high efficiency nebulizer, a
nominal dose of a composition comprising a muscarinic antagonist,
wherein administering said nominal dose with said high efficiency
nebulizer provides to the patient: (1) an increased magnitude
and/or duration of therapeutic effect; and (2) reduced or
acceptable side effects, compared to administering the same nominal
dose of the muscarinic antagonist with a conventional nebulizer.
Some embodiments comprise administering said nominal dose with the
high efficiency nebulizer to the patient that results in
therapeutically acceptable side effects. In some embodiments, the
method comprises administering said nominal dose of the composition
with the high efficiency nebulizer to the patient that results in
reduced side effects compared to administering the same nominal
dose with a conventional nebulizer. In some embodiments, the method
comprises administering said nominal dose of the composition with
the high efficiency nebulizer produces a calculated respirable dose
of the muscarinic antagonist, whereby the patient experiences
reduced side effects compared to administering a nominal dose that
is calculated to achieve the same respirable dose with a
conventional nebulizer. In some embodiments, the method comprises
administering said nominal dose of the composition with the high
efficiency nebulizer achieves a deposited lung dose of the
muscarinic antagonist, whereby the patient experiences reduced side
effects compared to administering a nominal dose that achieves
substantially the same deposited lung dose with a conventional
nebulizer. In some embodiments, the composition comprising the
muscarinic antagonist is a concentrated, preservative-free,
pH-adjusted solution formulation of the muscarinic antagonist. In
some embodiments, e.g. when the muscarinic antagonist is
glycopyrrolate, the concentration of the muscarinic antagonist is
about 25 to about 400 .mu.g/mL. In some embodiments, the
composition has a pH of 3 to 5. In some embodiments, the
formulation is room temperature stable for at least 2 years. In
some embodiments, the composition comprising the muscarinic
antagonist contains about 50 .mu.g to about 1000 .mu.g of
glycopyrrolate as the muscarinic antagonist. In some embodiments,
the composition has a volume of about 1.0 mL or less, e.g. 0.1 to
1.0 mL (especially 0.3 to 0.7 mL) or 0.5 mL. In some embodiments,
the composition is administered in about 3 minutes or less. In some
embodiments, the solution has a stabilizing excipient. In some
embodiments, the stabilizing excipient is
ethylenediaminetetraacetic acid (EDTA) or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
further comprises an excipient to mitigate side effects, for
example dry mouth. In some embodiments, the excipient comprises
citric acid or a pharmaceutically acceptable salt thereof. In some
embodiments, the muscarinic antagonist is a long-acting muscarinic
antagonist. In some embodiments, the nominal dose of the
composition comprising the muscarinic antagonist contains about 25
.mu.g to about 2000 .mu.g, about 25 .mu.g to about 1000 .mu.g, or
about 50 .mu.g to about 1000 .mu.g of glycopyrrolate as the
muscarinic antagonist. In some embodiments, the nominal dose of the
composition comprising the muscarinic antagonist contains about 25
.mu.g to about 2000 .mu.g, about 25 .mu.g to about 1000 .mu.g,
about 25 .mu.g to about 500 .mu.g, about 25 .mu.g to about 350
.mu.g, about 25 .mu.g to about 300 .mu.g, about 25 .mu.g to about
250 .mu.g, about 25 .mu.g to about 200 .mu.g, about 50 .mu.g to
about 2000 .mu.g, about 50 .mu.g to about 1000 .mu.g, about 50
.mu.g to about 500 .mu.g, about 50 .mu.g to about 350 .mu.g, about
50 .mu.g to about 300 .mu.g, about 50 .mu.g to about 250 .mu.g,
about 50 .mu.g to about 200 .mu.g, about 75 .mu.g to about 2000
.mu.g, about 75 .mu.g to about 1000 .mu.g, about 75 .mu.g to about
500 .mu.g, about 75 .mu.g to about 350 .mu.g, about 75 .mu.g to
about 300 .mu.g, about 75 .mu.g to about 250 .mu.g, about 75 .mu.g
to about 200 .mu.g, about 100 .mu.g to about 2000 .mu.g, about 100
.mu.g to about 1000 .mu.g, about 100 .mu.g to about 500 .mu.g,
about 100 .mu.g to about 350 .mu.g, about 100 .mu.g to about 300
.mu.g, about 100 .mu.g to about 250 .mu.g, about 100 .mu.g to about
200 .mu.g, about 50 .mu.g, about 75 .mu.g, about 100 .mu.g, about
125 .mu.g, about 150 .mu.g, about 175 .mu.g, about 200 .mu.g, about
225 .mu.g, about 250 .mu.g, about 275 .mu.g, 300 .mu.g, about 325
.mu.g, about 350 .mu.g, about 400 .mu.g, about 450 .mu.g, about 475
.mu.g, about 500 .mu.g, about 525 .mu.g, about 550 .mu.g, about 575
.mu.g, about 600 .mu.g, about 625 .mu.g, about 650 .mu.g, about 675
.mu.g, about 700 .mu.g, about 725 .mu.g, about 750 .mu.g, about 775
.mu.g, about 800 .mu.g, about 825 .mu.g, about 850 .mu.g, about 875
.mu.g, about 900 .mu.g, about 925 .mu.g, about 950 .mu.g, about 975
.mu.g, about 1000 .mu.g, about 1250 .mu.g, about 1500 .mu.g, about
1750 .mu.g, about 2000 .mu.g of glycopyrrolate as the muscarinic
antagonist. In some embodiments, the high efficiency nebulizer
emits droplets having a Mass Median Aerodynamic Diameter (MMAD) of
less than about 4.5 .mu.m and a geometric standard deviation (GSD)
of less than about 2.0, or optimally an MMAD of less than 4.0 .mu.m
and a GSD less than 1.8. In some embodiments, the therapeutic
effect comprises an improvement of FEV.sub.1 above baseline of at
least about 10% at 24 hours after the composition is administered
with the high efficiency nebulizer. In some embodiments, the
therapeutic effect comprises an improvement of FEV.sub.1 above
baseline of at least about 100 mL at 24 hours after the composition
is administered with the high efficiency nebulizer. In some
embodiments, the composition further comprises a beta
2-adrenoceptor agonist, a corticosteroid, or both 10013 Some
embodiments described herein provide an inhalation system for the
treatment or prophylaxis of a respiratory condition in a patient,
the system comprising: (a) a nominal dose of a muscarinic
antagonist in an aqueous inhalation solution; and (b) a high
efficiency nebulizer, wherein administration of the muscarinic
antagonist with the inhalation device provides muscarinic
antagonist lung deposition (deposited or calculated lung dose) of
at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, at least about 55%, at least
about 60%, about 30% to about 60%, about 30% to about 55%, about
30% to about 50%, about 30% to about 40%, about 30% to about 75%,
about 40% to about 70%, or about 45% to about 60%, of the nominal
dose of the muscarinic antagonist. Some embodiments provide a unit
dosage form, which comprises a container that holds a nominal dose
of a composition comprising a muscarinic antagonist, such as
glycopyrrolate, said container being adapted or adaptable to
operate with a high efficiency nebulizer to carry out the foregoing
method. Some embodiments provide a combination of (1) a high
efficiency nebulizer and (2) the aforementioned unit dosage
form.
[0013] Some embodiments described herein provide a composition for
administration with a high efficiency nebulizer, comprising a
concentrated, preservative-free, pH-adjusted solution formulation
of the muscarinic antagonist. In some embodiments, the muscarinic
antagonist is glycopyrrolate. In some embodiments, the
glycopyrrolate formulation has a concentration of about 50 to about
400 .mu.g/mL. In some embodiments, the glycopyrrolate formulation
has a concentration of at least 0.5 mg/mL. In some embodiments, the
glycopyrrolate has a concentration of at least 1 mg/mL. In some
embodiments, the pH is about 3 to about 5, and the composition
contains a beta 2-adrenoceptor agonist (e.g. albuterol,
levalbuterol, salmeterol, formoterol, or arformoterol), and/or a
corticosteroid (budesonide, fluticasone, ciclesonide). In some
embodiments, the composition further comprises a non-steroidal
anti-inflammatory agent. In some embodiments, the composition is
administered with a high efficiency nebulizer in 2 minutes or
less.
[0014] Some embodiments described herein provide a method of
treating a patient having chronic obstructive pulmonary disease
(COPD), comprising administering to the patient, with a high
efficiency nebulizer, a composition comprising a muscarinic
antagonist that provides to the patient a respirable dose or
deposited dose of a muscarinic antagonist, wherein achievement of
said respirable dose or deposited dose with said high efficiency
nebulizer provides to the patient: (1) a similar or an increased
magnitude and/or duration of therapeutic effect; and (2) reduced or
acceptable side effects, compared to achievement of the same
respirable dose or deposited dose of the muscarinic antagonist with
a conventional nebulizer. In some embodiments, achievement of the
respirable dose or deposited dose with the high efficiency
nebulizer produces in the patient an increased duration of
therapeutic effect of at least 24 hours after administration of the
nominal dose. In some embodiments, the therapeutic effect comprises
an improvement of FEV.sub.1 of at least about 100 mL above baseline
when adjusted for placebo or at least about 10% above baseline,
when adjusted for placebo, 24 hours after the composition is
administered with the high efficiency nebulizer.
[0015] Some embodiments described herein provide a method of
treating a patient having chronic obstructive pulmonary disease
(COPD), comprising administering to the patient, with a nebulizer,
a dose of glycopyrrolate, wherein the administration produces in
the patient an area under the plasma concentration curve of
glycopyrrolate (AUC) of at least about 100 .mu.g/mLhr. In some
embodiments, the administration of the dose of glycopyrrolate
achieves in the patient a ratio of AUC to maximum plasma
concentration of glycopyrrolate (Cmax) of at least about 0.6 hr, at
least about 0.75 hr, at least about 1.0 hr, at least about 1.25 hr,
or at least about 1.5 hr. in some embodiments, the method results
in a therapeutic effect for at least about 24 hours after
administering the glycopyrrolate. In some embodiments, the
glycopyrrolate dose is about 25 .mu.g to about 1000 .mu.g of
glycopyrrolate. In some embodiments, the glycopyrrolate dose is
about 25 .mu.g to about 400 .mu.g of glycopyrrolate. In some
embodiments, the therapeutic effect comprises an improvement of
FEV.sub.1 of at least about 100 mL above baseline when adjusted for
placebo or at least about 10% above baseline when adjusted for
placebo 24 hours after the glycopyrrolate is administered with the
nebulizer. In some embodiments, the nebulizer is a high efficiency
nebulizer.
[0016] Some embodiments described herein provide an inhalation
system for the treatment or prophylaxis of a respiratory condition
in a patient, the system comprising: (a) a nominal dose of a
muscarinic antagonist in an aqueous inhalation solution; and (b) an
inhalation device, wherein the aqueous inhalation solution provides
a duration of therapeutic effect of at least about 12 hr, about 12
hr to about 24 hr, about 18 hr to about 24 hr, about 20 hr to about
24 hr or at least about 24 hr.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Examples of aspects of the current invention are illustrated
in the attached figures, of which:
[0018] FIG. 1 is a graph comparing the placebo-adjusted 24-hour
(trough) FEV.sub.1 (L) obtained by, administering a 200 .mu.g dose
of glycopyrrolate with a high efficiency nebulizer (PART
eFlow.RTM.) and a conventional jet nebulizer,
[0019] FIG. 2 is a graph comparing the placebo-adjusted 24-hour
(trough) FEV.sub.1 (L) obtained by administering 25 .mu.g, 75
.mu.g, 200 .mu.g, 500 .mu.g and 1000 .mu.g of glycopyrrolate with a
high efficiency nebulizer (left 5 bars) and 200 .mu.g with a
conventional jet nebulizer (right bar).
[0020] FIG. 3 is a graph comparing lung function response
(FEV.sub.1 (L) change from baseline) over a time course of 30 hours
for 200 .mu.g of glycopyrrolate administered with a high efficiency
nebulizer, 200 .mu.g of glycopyrrolate administered with a
conventional jet nebulizer, and placebo (saline) administered with
the conventional jet nebulizer. The glycopyrrolate dose
administered with the high efficiency nebulizer provided a mean
improvement in peak lung function (peak FEV.sub.1) of about 45 mL
compared to the same glycopyrrolate dose administered in the
conventional jet nebulizer. Also, the glycopyrrolate dose
administered with the high efficiency nebulizer provided
improvement in lung function of greater than 100 mL FEV.sub.1 above
baseline at the 24 hour time point, whereas the same dose
administered with the conventional jet nebulizer failed to achieve
an increase in FEV.sub.1 above baseline greater than 100 mL at any
time point after 12 hr.
[0021] FIG. 4 is a graph comparing lung function response
(FEV.sub.1 (% change from baseline)) over a time course of 30 hours
for 200 .mu.g of glycopyrrolate administered with a high efficiency
nebulizer (left-most bar at each time point), 200 .mu.g of
glycopyrrolate administered with a conventional jet nebulizer
(right-most bar at each time point), and placebo (saline)
administered with the conventional jet nebulizer (middle bar at
each time point). The glycopyrrolate dose administered with the
high efficiency nebulizer provided improvement in lung function of
greater than 10% improvement in FEV.sub.1 above baseline at the 24
hour time point, whereas the same dose administered with the
conventional jet nebulizer failed to achieve an increase in
FEV.sub.1 above baseline greater than 10% at any time point after
12 hr.
[0022] FIG. 5 is a graph comparing the area under the FEV.sub.1 (L,
above baseline) curve from 0-24 hours (AUC.sub.0-24) obtained by
administering 25 .mu.g, 75 .mu.g, 200 .mu.g, 500 .mu.g and 1000
.mu.g of glycopyrrolate with a high efficiency nebulizer (left 5
bars); and placebo and 200 .mu.g of glycopyrrolate with a
conventional jet nebulizer (right 2 bars). The AUC.sub.0-24 results
are shown in Lhr.
[0023] FIG. 6 is a graph comparing the area under the FEV.sub.1 (L,
above baseline) curve from 0-12 hours (AUC.sub.0-12 hrs) obtained
by administering 25 .mu.g, 75 .mu.g, 200 .mu.g, 500 .mu.g and 1000
.mu.g of glycopyrrolate with a high efficiency nebulizer (left 5
bars); and placebo and 200 of glycopyrrolate with a conventional
jet nebulizer (right 2 bars). The AUC.sub.0-12 results are shown in
Lhr. The AUC values for the doses delivered by the high efficiency
nebulizer achieved a similar robust magnitude of FEV.sub.1
improvement as the dose delivered by the conventional jet nebulizer
over the first 12 hours post-administration.
[0024] FIG. 7 is a graph comparing the area under the FEV.sub.1 (L,
above baseline) curve from 12-24 hours (AUC.sub.12-24) obtained by
administering 25 .mu.g, 75 .mu.g, 200 .mu.g, 500 .mu.g and 1000
.mu.g of glycopyrrolate with a high efficiency nebulizer (left 5
bars); and placebo and 200 .mu.g of glycopyrrolate with a
conventional jet nebulizer (right 2 bars). The AUC.sub.12-24
results are shown in Lhr. Although the subjects that received the
200 .mu.g dose via a conventional nebulizer achieved similar AUC
FEV.sub.1 values from 0-24 hours, and 12-24 hours, as the AUC
FEV.sub.1 values achieved by those subjects who received the 25
.mu.g dose administered by the high efficiency nebulizer, the mean
AUC FEV.sub.1 value for the FEV.sub.1 response to the 200 .mu.g
dose via the conventional nebulizer was inferior and not clinically
meaningful during 12-24 hours post-dosing, whereas all doses
greater than 25 .mu.g administered by the high efficiency nebulizer
achieved robust prolonged duration of bronchodilation over the
entire 24 hours.
[0025] FIG. 8 is a line graph comparing glycopyrrolate blood plasma
concentrations during the first two hours after administration of
200 .mu.g glycopyrrolate with a high efficiency nebulizer (upper
line) and 200 .mu.g glycopyrrolate with a conventional jet
nebulizer (lower line).
DETAILED DESCRIPTION OF THE INVENTION
[0026] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
skill in the art to which the inventions described herein belong.
All publications, patents, and patent applications mentioned in
this specification are herein incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
DEFINITION OF TERMS
[0027] As used herein, the term "about" is used synonymously with
the term "approximately." Illustratively, the use of the term
"about" with regard to a certain therapeutically effective
pharmaceutical dose indicates that values slightly outside the
cited values, e.g. plus or minus 0.1% to 10%, which are also
effective and safe.
[0028] As used herein, the terms "comprising," "including," "such
as," and "for example" (or "e.g.") are used in their open,
non-limiting sense.
[0029] As used herein "mcg" means micrograms, and is synonymous
with ".mu.g" "ug". One microgram is 0.001 mg, or 0.000001 g.
[0030] As used herein, the phrase "consisting essentially of" is a
transitional phrase used in a claim to indicate that the following
list of ingredients, parts or process steps must be present in the
claimed composition, machine or process, but that the claim is open
to unlisted ingredients, parts or process steps that do not
materially affect the basic and novel properties of the
invention.
[0031] "Nominal dose," as used herein, refers to the loaded dose,
which is the amount of active pharmaceutical ingredient ("API") in
an inhalation device prior to administration to the patient. The
volume of solution containing the nominal dose is referred to as
the "fill volume."
[0032] "AUC.sub.(0-t).sup.HEN" as used herein, refers to the area
under a blood plasma concentration curve up to the last time point
for the nominal dose of active pharmaceutical ingredient (API)
administered with a high efficiency nebulizer.
[0033] "AUC.sub.(0-t).sup.Conv" as used herein, refers to the area
under a blood plasma concentration curve up to the last time point
for a nominal dose of active pharmaceutical ingredient (API)
administered with a conventional nebulizer.
[0034] "AUC.sub.(0-.infin.).sup.HEN" as used herein, refers to the
area under a blood plasma concentration curve for a nominal dose of
active pharmaceutical ingredient (API) administered with a high
efficiency nebulizer.
[0035] "AUC.sub.(0-.infin.).sup.CONV" as used herein, refers to the
area under a blood plasma concentration curve for a nominal dose of
active pharmaceutical ingredient (API) administered with a
conventional nebulizer [AUC.sub.(0-.infin.).sup.Conv].
[0036] "Substantially the same nominal dose" as used herein, means
that a first nominal dose of an active pharmaceutical ingredient
(API) contains approximately the same number of millimoles of the
muscarinic antagonist as a second nominal dose of the muscarinic
antagonist.
[0037] "Bioavailability" as used herein, refers to the amount of
unchanged drug that reaches the systemic circulation. By
definition, the bioavailability of an intravenous solution
containing the active pharmaceutical ingredient (API) is 100%.
[0038] "Enhanced lung deposition," as used herein, refers to an
increase in drug deposition (deposited lung dose) arising out of,
for example, the improved efficiency of drug delivery with a high
efficiency nebulizer. In general, a high efficiency nebulizer will
produce a drug cloud having a greater respirable fraction than a
conventional nebulizer. While not wishing to be bound by theory, it
is considered that a greater respirable fraction will permit
greater lung deposition and concomitantly lower oropharyngeal
deposition of the drug. In some embodiments, it is considered that
reduced oropharyngeal deposition of drug will reduce local side
effects, for example dry mouth.
[0039] "Deposited dose" or "deposited lung dose" is the amount of
muscarinic antagonist deposited in the lung. The deposited dose or
deposited lung dose may be expressed in absolute terms, for example
the number of .mu.g of API deposited in the lungs. The deposited
lung dose may be expressed as a percentage of the nominal dose
deposited in the lungs. The deposited lung dose may also be
expressed in relative terms, for example comparing the mass of API
deposited in the lungs with a high efficiency nebulizer to the mass
of API deposited in the lungs with a conventional nebulizer.
[0040] "C.sub.max.sup.HEN" as used herein, refers to the maximum
blood plasma concentration for a nominal dose of the active
pharmaceutical ingredient (API) administered with a high efficiency
nebulizer.
[0041] "C.sub.max.sup.Conv" as used herein, refers to the maximum
blood plasma concentration for a nominal dose of the active
pharmaceutical ingredient (API) administered with a conventional
nebulizer.
[0042] "Enhanced pharmacokinetic profile" means an improvement in
some pharmacokinetic parameter. Pharmacokinetic parameters that may
be improved include, AUC.sub.last, AUC.sub.(0-.infin.) T.sub.max,
and optionally a C.sub.max. In some embodiments, the enhanced
pharmacokinetic profile may be measured quantitatively by comparing
a pharmacokinetic parameter obtained for a nominal dose of an
active pharmaceutical ingredient (API) administered with one type
of inhalation device (e.g. a high efficiency nebulizer) with the
same pharmacokinetic parameter obtained with the same nominal dose
of active pharmaceutical ingredient (API) administered with a
different type of inhalation device.
[0043] "Blood plasma concentration" refers to the concentration of
an active pharmaceutical ingredient (API) in the plasma component
of blood of a subject or patient population.
[0044] "Respiratory condition," as used herein, refers to a disease
or condition that is physically manifested in the respiratory
tract, including, but not limited to, chronic obstructive pulmonary
disease (COPD), bronchitis, chronic bronchitis, emphysema, asthma,
or reactive airway disorder (RAD).
[0045] "Patient" refers to the animal (especially mammal) or human
being treated.
[0046] "Muscarinic antagonist" refers to antimuscarinic agents,
which are compounds that have the ability to inhibit the action of
the neurotransmitter acetylcholine by blocking its binding to
muscarinic cholinergic receptors. These agents can be long-acting
or short-acting. Long-acting muscarinic antagonists have a
therapeutic effect lasting greater than about 6 hours. Some
long-acting muscarinic antagonists include, but are not limited to,
glycopyrrolate, tiotropium, aclidinium, trospium, darotropium, QAT
370, GSK 233705, GSK 573719, GSK 656398, TD4208, BEA 218 or a
pharmaceutical acceptable derivative, salt, enantiomer,
diastereomer, or racemic mixture thereof. Short-acting muscarinic
antagonists have a therapeutic effect for less than about 6 hours.
Some short-acting muscarinic antagonists include, but are not
limited to, ipratropium, oxitropium, or a pharmaceutical acceptable
derivative, salt, enantiomer, diastereomer, or racemic mixture
thereof. In some embodiments, the "muscarinic antagonist" is
glycopyrrolate, tiotropium, aclidinium, trospium, QAT370,
GSK233705, GSK 656398, BEA2180, ipratropium, oxitropium, oxybutynin
or a pharmaceutical acceptable derivative, salt, enantiomer,
diastereomer, or a pharmaceutical acceptable derivative, salt,
enantiomer, diastereomer, or racemic mixture thereof.
[0047] "Nebulizer," as used herein, refers to a device that turns
medications, compositions, formulations, suspensions, and mixtures,
etc. into a fine mist for delivery to the lungs. Nebulizers may
also be referred to as atomizers.
[0048] "Drug absorption" or simply "absorption" typically refers to
the process of movement of drug from site of delivery of a drug
across a barrier into a blood vessel or the site of action, e.g., a
drug being absorbed in the pulmonary capillary beds of the
alveoli.
[0049] [T.sub.max.sup.HEN] as used herein, refers to the amount of
time necessary for a nominal dose of an active pharmaceutical
ingredient (API) to attain maximum blood plasma concentration after
administration with a high efficiency nebulizer.
[0050] [T1/2] Half-life: T1/2 in reference to the elimination rate
of a drug, such as a muscarinic antagonist (e.g. glycopyrrolate) is
the amount of time necessary for the drug's plasma concentration to
drop to one-half of its initial plasma concentration.
[0051] [T.sub.max.sup.Conv] as used herein, refers to the amount of
time necessary for a nominal dose of an active pharmaceutical
ingredient (API) to attain maximum blood plasma concentration after
administration with a conventional nebulizer.
[0052] The term "treat" and its grammatical variants (e.g. "to
treat," "treating," and "treatment") refer to administration of an
active pharmaceutical ingredient to a patient with the purpose of
ameliorating or reducing the incidence of one or more symptoms of a
condition or disease state in the patient. Such symptoms may be
chronic or acute; and such amelioration may be partial or complete.
In the present context, treatment entails administering a
muscarinic antagonist (optionally in combination with a beta
2-adrenoceptor agonist) to a patient via a pulmonary inhalation
route.
[0053] The term "prophylaxis" refers to administration of an active
pharmaceutical ingredient to a patient with the purpose of reducing
the occurrence or recurrence of one or more acute symptoms
associated with a disease state in the patient. In the present
context, prophylaxis entails administering a muscarinic antagonist
(optionally in combination with a beta 2-adrenoceptor agonist) to a
patient via a pulmonary inhalation route. Thus, prophylaxis
includes reduction in the occurrence or recurrence rate of acute
exacerbations in chronic obstructive pulmonary disease (COPD).
However, prophylaxis is not intended to include complete prevention
of onset of a disease state in a patient who has not previously
been identified as suffering from a pulmonary condition or disease;
nor does prophylaxis include prevention of pulmonary cancer.
[0054] As used herein, a difference is "significant" if a person
skilled in the art would recognize that the difference is probably
real. In some embodiments, significance may be determined
statistically--in which case two measured parameters may be
referred to as statistically significant. In some embodiments,
statistical significance may be quantified in terms of a stated
confidence interval (CI), e.g. greater than 90%, greater than 95%,
greater than 98%, etc. In some embodiments, statistical
significance may be quantified in terms of a p value, e.g. less
than 0.5, less than 0.1, less than 0.05, etc. The person skilled in
the art will recognize these expressions of significance and will
know how to apply them appropriately to the specific parameters
that are being compared.
[0055] In some embodiments described herein an active
pharmaceutical ingredient (API) is a muscarinic antagonist. In some
embodiments, the API is substantially free of other bronchodilating
agents, such as beta 2-adrenoceptor agonists, like formoterol,
salmeterol and salbutamol (albuterol). In this context,
"substantially free of other bronchodilating agents" indicates that
the solution contains no other bronchodilating agent or contains
less than a quantity of another bronchodilating agent that would be
sufficient to materially affect the properties of the muscarinic
antagonist solution. In some embodiments, the API is a muscarinic
antagonist (optionally in combination with a beta 2-adrenoceptor
agonist and/or in combination with an anti-inflammatory agent which
could include a corticosteroid or a non-steroidal anti-inflammatory
drug (NSAID)). In some embodiments, the API is free of other
bronchodilating agents, such as beta 2-adrenoceptor agonists, like
formoterol, salmeterol and salbutamol (albuterol). In this context,
"free of other bronchodilating agents" means that the solution
contains no other bronchodilating agent than the recited muscarinic
antagonist, or contains less than a detectable amount of the other
bronchodilating agents.
[0056] Methods and Systems for the Treatment of Respiratory
Conditions with HENs
[0057] The present invention provides methods and inhalation
systems for treatment or prophylaxis of a respiratory condition in
a patient, such as chronic obstructive pulmonary disease (CORD),
and optionally chronic bronchitis and/or emphysema. In some
embodiments, the methods and inhalation systems comprise
administering to a patient a nominal dose of an active
pharmaceutical ingredient (API), muscarinic antagonist (optionally
in combination with a beta 2-adrenoceptor agonist and/or in
combination with an anti-inflammatory agent which could include a
corticosteroid or a non-steroidal anti-inflammatory drug (NSAID))
in an aqueous inhalation solution with a high efficiency nebulizer
(HEN), wherein delivering the nominal dose of the muscarinic
antagonist to the patient provides one or more of the following
advantages: (1) an enhanced pharmacokinetic profile as compared to
administration with a conventional nebulizer; (2) an enhanced
therapeutic effect as compared to administration with a
conventional nebulizer; (4) an enhanced lung deposition (deposited
lung dose) evidenced by scintigraphy or deconvolution, or derived
from suitable in vitro indicators such as RDDR, RF, GSD, and/or a
MMAD values as compared to administration with a conventional
nebulizer; (5) reduced administration times, periods, and/or
volumes as compared to administration with a conventional
nebulizer; (6) a reduction in adverse side effects associated with
API treatment and optionally a longer duration of therapeutic
effect as compared to administration with a conventional nebulizer;
(7) optional administration with a beta 2-adrenoceptor agonist and
optionally a corticosteroid; and (8) an enhanced method of
treatment of acute exacerbations of a respiratory condition in a
patient, e.g. COPD. In some embodiments, the methods and inhalation
systems comprise administering to a patient a nominal dose of an
increased concentration of API in an aqueous inhalation device,
metered dose inhaler (MDI), conventional nebulizer, or high
efficiency nebulizer.
[0058] Inhalation Therapy
[0059] An inhalation device, as used herein, refers to any device
that is capable of administering a solution to the respiratory
airways of a patient. Inhalation devices include conventional
inhalation devices, such as metered dose inhalers (MDIs),
conventional nebulizers, such as jet nebulizers, and high
efficiency nebulizers, such as vibrating membrane nebulizers.
[0060] Inhalation nebulizers, or atomizers, are also commonly used
for the treatment of respiratory diseases. Inhalation nebulizers
deliver therapeutically effective amounts of pharmaceuticals by
forming an aerosol which includes droplet sizes that can easily be
inhaled. The aerosol can be used, for example, by a patient within
the bounds of an inhalation therapy, whereby the therapeutically
effective pharmaceutical or drug reaches the patient's respiratory
tract upon inhalation.
[0061] High Efficiency Nebulizers
[0062] High efficiency nebulizers are inhalation devices that
comprise a microperforated membrane through which a liquid solution
is converted through electrical or mechanical means into aerosol
droplets suitable for inhalation. High efficiency nebulizers can
deliver a large fraction of a loaded dose to a patient. In some
embodiments, the high efficiency nebulizer also utilizes one or
more actively or passively vibrating microperforated membranes. In
some embodiments, the high efficiency nebulizer contains one or
more oscillating membranes. In some embodiments, the high
efficiency nebulizer contains a vibrating mesh or plate with
multiple apertures and optionally a vibration generator with an
aerosol mixing chamber. In some such embodiments, the mixing
chamber functions to collect (or stage) the aerosol from the
aerosol generator. In some embodiments, an inhalation valve is also
used to allow an inflow of ambient air into the mixing chamber
during an inhalation phase and is closed to prevent escape of the
aerosol from the mixing chamber during an exhalation phase. In some
such embodiments, the exhalation valve is arranged at a mouthpiece
which is removably mounted at the mixing chamber and through which
the patient inhales the aerosol from the mixing chamber. Still yet,
in some embodiments, the high efficiency nebulizer contains a
pulsating membrane. In some embodiments, the high efficiency
nebulizer is continuously operating.
[0063] In some embodiments, the high efficiency nebulizer contains
a vibrating microperforated membrane of tapered nozzles that
generates a plume of droplets without the need for compressed air.
In these embodiments, a solution in the microperforated membrane
nebulizer is in contact with a membrane, the opposite side of which
is open to the air. The membrane is perforated by a large number of
nozzle orifices of an atomizing head. An aerosol is created when
alternating acoustic pressure in the solution is built up in the
vicinity of the membrane causing the fluid on the liquid side of
the membrane to be emitted through the nozzles as uniformly sized
droplets.
[0064] Some embodiments of high efficiency nebulizers use passive
nozzle membranes and a separate piezoelectric transducer that
stimulates the membrane. In contrast, some high efficiency
nebulizers employ an active nozzle membrane, which use the acoustic
pressure in the nebulizer to generate very fine droplets of
solution via the high frequency vibration of the nozzle
membrane.
[0065] Some high efficiency nebulizers contain a resonant system.
In some such high efficiency nebulizers, the membrane is driven by
a frequency for which the amplitude of the vibrational movement at
the center of the membrane is particularly large, resulting in a
focused acoustic pressure in the vicinity of the nozzle; the
resonant frequency may be about 100 kHz. A flexible mounting is
used to keep unwanted loss of vibrational energy to the mechanical
surroundings of the atomizing head to a minimum. In some
embodiments, the vibrating membrane of the high efficiency
nebulizer may be made of a nickel-palladium alloy by
electroforming.
[0066] In some embodiments, the high efficiency nebulizer achieves
lung deposition (deposited or calculated lung dose) of at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%,
about 30% to about 60%, about 30% to about 55%, about 30% to about
50%, about 30% to about 40%, about 30% to about 90%, about 40% to
about 80%, about 50% to about 60%, or about 60% to about 70% based
on the nominal dose of the muscarinic antagonist (optionally in
combination with a beta 2-adrenoceptor agonist) administered to the
patient. In some embodiments, the high efficiency nebulizer
achieves a respirable dose delivery rate (RDDR) of at least about 2
times, at least about 3 times or at least about 4 times the RDDR
achievable with a conventional nebulizer. In some embodiments where
the muscarinic antagonist is glycopyrrolate the RDDR is at least
about 100 .mu.g/min, at least about 150 .mu.g/min, at least about
200 .mu.g/min, about 100 .mu.g/min to at least about 5,000
.mu.g/min, about 150 .mu.g/min to about 4,000 .mu.g/min or about
200 .mu.g/min to about 3,500 .mu.g/min. In some embodiments,
Wherein the muscarinic antagonist is glycopyrrolate, the high
efficiency nebulizer achieves an output rate of at least about 120
.mu.g/min, at least about 150 .mu.g/min, at least about 200
.mu.g/min or at least about 200 .mu.g/min to at least about 5,000
.mu.g/min, in some embodiments, the high efficiency nebulizer
provides a respirable fraction (RF) of muscarinic antagonist of at
least about 60%, at least about 65%, at least about 70%, at least
about 75%, at least about 80%, at least about 85%, at least about
90%, about 60% to about 95%, about 65% to about 95%, about 65% to
about 90% or about 70% to about 90%. In some embodiments, the high
efficiency nebulizer provides a Geometric Standard Deviation (GSD)
of emitted droplet size distribution of the solution administered
with a high efficiency nebulizer of about 1.1 to about 2.1; about
1.2 to about 2.0, about 1.3 to about 1.9, at least about 1.4 to
about 1.8, at least about 1.5 to about 1.7, about 1.4, about 1.5,
or about 1.6. In some embodiments, administration of the muscarinic
antagonist with the high efficiency nebulizer provides a Mass
Median Aerodynamic Diameter (MMAD) of droplet size of the solution
emitted with the high efficiency nebulizer of about 1 .mu.m to
about 5 .mu.m, about 2 to about 4 .mu.m, about 3 .mu.m to about 4
.mu.m, about 3 to about 4 .mu.m; or about 3.5 to about 4.0 .mu.m.
In some particular embodiments, the high efficiency nebulizer
provides droplets having a particular combination of MMAD and GSD,
for example: an MMAD of less than about 5 .mu.m and a GSD of about
1.1 to about 2.1; an MMAD of less than about 4.5 .mu.m and a GSD of
about 1.1 to about 2.1; an MMAD of about 1 .mu.m to about 5 .mu.m
and a GSD of about 1.1 to about 2.1; an MMAD of about 1.5 to about
4.5 .mu.m and a GSD of about 1.1 to about 2.1; an MMAD of less than
about 5 .mu.m and a GSD of about 1.1 to about 2.0; an MMAD of less
than about 4.5 .mu.m and a GSD of about 1.1 to about 2.0; an MMAD
of about 1 .mu.m to about 5 .mu.m and a GSD of about 1.1 to about
2.0; an MMAD of about 1.5 to about 4.5 .mu.m and a GSD of about 1.1
to about 2.0; an MMAD of less than about 5 .mu.m and a GSD of about
1.1 to about 1.9; an MMAD of less than about 4.5 .mu.m and a GSD of
about 1.1 to about 1.9; an MMAD of about 1 .mu.m to about 5 .mu.m
and a GSD of about 1.1 to about 1.9; an MMAD of about 1.5 to about
4.5 and a GSD of about 1.1 to about 1.9; an MMAD of less than about
5 .mu.m and a GSD of about 1.1 to about 1.8; an MMAD of less than
about 4.5 .mu.m and a GSD of about 1.1 to about 1.8; an MMAD of
about 1 .mu.m to about 5 .mu.m and a GSD of about 1.1 to about 1.8;
or an MMAD of about 1.5 to about 4.5 .mu.m and a GSD of about 1.1
to about 1.8.
[0067] In some embodiments; the high efficiency nebulizer provides
muscarinic antagonist lung deposition (deposited or calculated lung
dose) of at least about 15%, at least about 20%, at least about
25%, at least about 30%; at least about 35%, at least about 40%; at
least about 45%; at least about 50%, at least about 55%, at least
about 60%, about 20% to about 40%, about 25% to about 35%, about 25
to about 30%, about 35% to about 90%, about 40% to about 80%, about
50% to about 60%, or about 60% to about 70% based on the nominal
dose of the muscarinic antagonist. In some embodiments; the high
efficiency nebulizer provides for one or more of (a) or (b); and
one or more of (i), (ii), (iii) or (iv): (a) a respirable dose
delivery rate (RDDR) of at least about 2 times; 3 times or 4 times
the RDDR achievable with a conventional nebulizer (for example,
where the muscarinic antagonist is glycopyrrolate, in some
embodiments, RDDR is at least about 100 .mu.g/min, at least about
150 .mu.g/min, at least about 200 .mu.g/min, about 100 .mu.g/min to
about 5,000 .mu.g/min, about 150 .mu.g/min to about 4,000 .mu.g/min
or about 200 .mu.g/min to about 3,500 .mu.g/min); (b) an output
rate of muscarinic antagonist of at least about 2 times, 3 times or
4 times the output rate achievable with a conventional nebulizer
(for example, where the muscarinic antagonist is glycopyrrolate,
the output rate is at least about 120 .mu.g/min, at least about 150
.mu.g/min, at least about 200 .mu.g/min or at least about 200
.mu.g/min to about 5,000 .mu.g/min); (i) a respirable fraction (RE)
of muscarinic antagonist of at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 65% to at least about 75% or at
least about 75% to at least about 85% respirable fraction upon
administration; (ii) a Geometric Standard. Deviation (GSD) of
emitted droplet size distribution of the solution administered with
a inhalation device of about (iii) about 1.1 to about 2.1, about
1.2 to about 2.0, about 1.3 to about 1.9, about 1.4 to about 1.8,
about 1.5 to about 1.7, about 1.4, about 1.5, or about 1.6; (iv) or
a Mass Median Aerodynamic Diameter (MMAD) of droplet size of the
solution emitted with the inhalation device of about 1 .mu.m to
about 5 .mu.m, about 2 to about 4 .mu.m, about 3 to about 4 .mu.m,
or about 3.5 to about 4.0 .mu.m.
[0068] In accordance with the invention, in some embodiments, a
high efficiency nebulizer may be adapted or adaptable to operate in
conjunction with a unit dosage form, such as an ampule or vial,
which contains a single dose of a muscarinic antagonist composition
for the treatment of COPD. The unit dosage form comprises a
container that contains an inhalation solution comprising the
muscarinic antagonist, such as glycopyrrolate. The container is
adapted to cooperate with the high efficiency nebulizer device in
such a way as to permit administration of the nominal dose of the
inhalation solution to a patient. In some embodiments, the high
efficiency nebulizer and the unit dosage form are configured so
that they are useable together, but not with other devices or
dosage forms. In some particular embodiments, the unit dosage form
is configured such that it fits into a keyhole-like structure in
the high efficiency nebulizer, but will not operate with other
nebulizer devices. In such embodiments, the high efficiency
nebulizer is configured such that it will accept and properly
operate with the unit dosage form containing the muscarinic
antagonist, but not with other dosage forms.
[0069] Additional features of a high efficiency nebulizer with
perforated membranes are disclosed in U.S. Pat. Nos. 6,962,151,
5,152,456, 5,261,601, and 5,518,179, each of which is hereby
incorporated by reference in its entirety. Other embodiments of the
high efficiency nebulizer contain oscillatable membranes. Features
of these high efficiency nebulizers are disclosed in U.S. Pat. Nos.
7,252,085; 7,059,320; 6,983,747, each of which is hereby
incorporated by reference in its entirety.
[0070] Commercial high efficiency nebulizers are available from:
PARI (Germany) under the trade name eFlow.RTM.; Aerogen, Ltd.
(Ireland) under the trade names AeroNeb.RTM. Go and AeroNeb.RTM.
Pro, AeroNeb.RTM. Solo, and other nebulizers utilizing the OnQ.RTM.
nebulizer technology; Respironics (Murrysville, Calif.) under the
trade names I-Neb.RTM.; Omron (Bannockburn, Ill.) under the trade
name Micro-Air.RTM.; Activaero (Germany) under the trade name
Akita.RTM., and AerovectRx (Atlanta, Ga.) under the trade name
AerovectRx.RTM.. Other high efficiency nebulizers are contemplated
within the scope of this disclosure; and the recitation of
particular high efficiency nebulizers is not intended to exclude
other high efficiency nebulizers from the scope of the
invention.
[0071] Conventional Nebulizers
[0072] Conventional nebulizers include, for example jet nebulizers
or ultrasonic nebulizers. Jet nebulizers generally utilize
compressors to generate compressed air, which breaks the liquid
medication into small breathable droplets, which form an
aerosolized (atomized) mist. In some of these embodiments, when the
patient breathes in, a valve at the top opens, which then allows
air into the apparatus, thereby speeding up the mist generation;
when the patient breathes out, the top valve closes, thereby
slowing down the mist generation while simultaneously permitting
the patient to breathe out through the opening of a mouthpiece
flap.
[0073] In general, conventional nebulizers are characterized by
relatively low efficiency in delivery of a muscarinic antagonist to
the lung. Thus, a conventional nebulizer, such as a jet nebulizer,
is characterized by one or more of the following: (1) about 20% or
less calculated respirable dose or measured deposited lung dose as
a percentage of the nominal dose of API administered to the
patient; (2) a respirable dose delivery rate (RDDR) of less than
about 100 .mu.g/min of the muscarinic antagonist, when
glycopyrrolate, administered to the patient; (3) an output rate of
less than about 100 .mu.g/min of glycopyrrolate administered to the
patient; (4) a residual volume of greater than about 10% of the
nominal dose of the muscarinic antagonist.
[0074] Some conventional nebulizers are disclosed in U.S. Pat. Nos.
6,513,727, 6,513,519, 6,176,237, 6,085,741, 6,000,394, 5,957,389,
5,740,966, 5,549,102, 5,461,695, 5,458,136, 5,312,046, 5,309,900,
5,280,784, and 4,496,086, each of which is hereby incorporated by
reference in its entirety.
[0075] Commercial conventional nebulizers are available from: PARI
(Germany) under the trade names PART LC Plus.RTM., LC Star.RTM.,
and PARI-Jet.RTM., A & H Products, Inc. (Tulsa, Okla.) under
the trade name AquaTower.RTM.; Hudson RCI (Temecula, Calif.) under
the trade name AVA-NEB.RTM.; Intersurgical, Inc. (Liverpool, N.Y.)
under the trade name Cirrus.RTM.; Salter Labs (Arvin, Calif.) under
the trade name Salter 8900.RTM.; Respironics (Murrysville, Pa.)
under the trade name Sidestream.RTM., Bunnell (Salt Lake City,
Utah) under the trade name Whisper Jet.RTM.; Smiths-Medical Myth
Kent, UK) under the trade name Downdraft.RTM., and DeVilbiss
(Somerset, Pa.) under the trade name DeVilbiss.RTM..
Active Ingredient(s)
[0076] Muscarinic Antagonists
[0077] Acetylcholine released from cholinergic neurons in the
peripheral and central nervous systems affects many different
biological processes through interaction with two major classes of
acetylcholine receptors: the nicotinic and the muscarinic
receptors.
[0078] Muscarinic acetylcholine receptors are widely distributed in
vertebrate organs where they mediate many vital functions. Three
subtypes of muscarinic acetylcholine receptors have been identified
as important in the lung, M1, M2, and M3, each with its unique
pharmacological properties and a product of a distinct gene. These
three subtypes are also located in organs other than the lung.
[0079] In the lung, M3 muscarinic receptors mediate smooth muscle
contraction. Stimulation of M3 muscarinic receptors activate the
enzyme phospholipase C via binding of the stimulatory G protein
Gq/11 (Gs), leading to liberation of phosphatidyl inositol-4,
5-bisphosphate, resulting in phosphorylation of contractile
proteins and bronchial constriction. M3 muscarinic receptors are
also found on pulmonary submucosal glands. Stimulation of this
population of M3 muscarinic receptors results in mucus secretion.
M2 muscarinic receptors make up approximately 50-80% of the
cholinergic receptor population on airway smooth muscles. Under
normal physiological conditions; M2 muscarinic receptors provide
tight control of acetylcholine release from parasympathetic nerves.
M1 muscarinic receptors are found in the pulmonary parasympathetic
ganglia where they function to enhance neurotransmission.
[0080] Muscarinic acetylcholine receptor dysfunction in the lungs
has been noted in a variety of different pathophysiological states.
In COPD patients, inflammatory conditions lead to loss of
inhibitory M2 and M3 muscarinic acetylcholine autoreceptor function
on parasympathetic nerves supplying the pulmonary smooth muscle,
causing an increased release of acetylcholine. This dysfunction in
muscarinic receptors results in airway hyperreactivity and
hyperresponsiveness.
[0081] Muscarinic acetylcholine receptor antagonist agents, or
muscarinic antagonists, have the ability to inhibit the action of
the neurotransmitter acetylcholine by blocking its interaction with
muscarinic cholinergic receptors in general, and its interaction
with specific muscarinic receptor subtypes in particular.
Muscarinic antagonists thereby prevent the effects resulting from
the passage of unnecessary impulses through the parasympathetic
nerves mediated by increased stimulation in patients with
dysfunctional receptors, resulting in, among other physiological
effects, relaxation of smooth muscles in the lung.
[0082] Aclidinium,
((3R-3-{[hydroxydi(thiophen-2-yl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azonia-
bicyclo[2.2.2]octane bromide), is a specific long-acting muscarinic
receptor antagonist. Aclidinium is in development for use as an
anticholinergic agent. Clinically, aclidinium has been tested in a
dry powder inhaled format.
[0083] In some embodiments of the present invention, the muscarinic
antagonist is aclidinium and is administered at a nominal dosage of
100 .mu.g/dose to about 5 mg/dose, about 50 .mu.g/dose to about 2
mg/dose or about 50 .mu.g/dose to about 1 mg per dose. In other
embodiments, aclidinium is given in 100 .mu.g, 200 .mu.g, 300
.mu.g, 400 .mu.g, 500 .mu.g, 600 .mu.g, 700 .mu.g, 800 .mu.g, 900
.mu.g, or 1,000 .mu.g doses.
[0084] The process of making aclidinium is known by a person of
ordinary skill in the art. Aclidinium can be made by a number of
known methods including those described in U.S. Pat. No. 6,750,226,
which is incorporated herein by reference in its entirety, and
which sets forth several structurally related muscarinic
antagonists. Additional examples of muscarinic antagonists are set
forth in U.S. Pat. Nos. 7,312,231 and 7,208,501, each of which is
incorporated herein by reference in its entirety.
[0085] Trospium
(endo-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]ocatane-8-
,1'-pyrrolidinium] chloride benzilate), is a specific long-acting
muscarinic; receptor antagonist. Trospium has been known for many
years to be an effective anticholinergic agent. Clinically,
trospium has been used in several indications and been delivered by
a number of different routes. Currently, trospium is used as a
urinary antispasmotic and is sold under the brand name
Sanctura.RTM..
[0086] In some embodiments of the present invention, the muscarinic
antagonist is trospium and is administered at a nominal dosage of
10 .mu.g/dose to about 5 mg/dose, about 10 .mu.g/dose to about 2
mg/dose or about 50 .mu.g/dose to about 1 mg per dose. In other
embodiments, trospium is given in 10 .mu.g, 50 .mu.g, 100 .mu.g,
200 .mu.g, 300 .mu.g, 400 .mu.g, 500 .mu.g, 600 .mu.g, 700 .mu.g,
800 .mu.g, 900 .mu.g, or 1,000 .mu.g doses.
[0087] The process of making trospium is known by a person of
ordinary skill in the art. Trospium can be made by a number of
known methods including those described in U.S. Pat. No. 3,480,626,
which is incorporated herein by reference in its entirety.
[0088] Glycopyrrolate,
3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium,
is a specific long-acting muscarinic receptor antagonist.
Glycopyrrolate has been known for many years to be an effective
anticholinergic agent. Clinically, glycopyrrolate has been used in
several indications and been delivered by a number of different
routes. Currently, glycopyrrolate is approved for use as an
injectable compound to reduce secretions during anesthesia and also
as an oral product for treating gastric ulcers.
[0089] In some embodiments of the present invention, the muscarinic
antagonist is glycopyrrolate and is administered with a high
efficiency nebulizer at a nominal dosage of about 25 .mu.g/dose to
about 1 mg/dose, about 25 pig/dose to about 0.5 mg/dose, about 25
.mu.g/dose to about 400 .mu.g/dose, about 25 .mu.g/dose to about
300 .mu.g/dose, about 25 .mu.g/dose to about 200 .mu.g/dose, about
25 .mu.g/dose to about 150 .mu.g/dose, about 25 .mu.g/dose to about
125 .mu.g/dose, about 25 .mu.g/dose to about 100 .mu.g/dose 50
.mu.g/dose to about 1 mg/dose, about 50 .mu.g/dose to about 0.5
mg/dose, about 50 .mu.g/dose to about 300 .mu.g/dose, about 50
.mu.g/dose to about 250 .mu.g/dose, about 50 .mu.g/dose to about
200 .mu.g/dose, about 50 .mu.g/dose to about 150 .mu.g/dose, about
50 .mu.g/dose to about 125 .mu.g/dose, about 50 .mu.g/dose to about
100 .mu.g/dose, less than about 150 .mu.g/dose, less than about 100
.mu.g/dose, equal to or less than about 80 .mu.g/dose, 100
.mu.g/dose to about 5 mg/dose, about 200 .mu.g/dose to about 2
mg/dose or about 250 .mu.g/dose to about 1 mg per dose. In some
preferred embodiments, the muscarinic antagonist is glycopyrrolate
and is administered with a high efficiency nebulizer at a nominal
dosage of about 25 .mu.g, about 30 .mu.g, about 35 .mu.g, about 40
.mu.g, about 45 .mu.g, about 50 .mu.g, about 55 .mu.g, about 60
.mu.g, about 65 .mu.g, about 70 .mu.g, about 75 .mu.g, about 80
.mu.g, about 85 .mu.g, about 90 .mu.g, about 95 .mu.g, about 100
.mu.g, about 110 .mu.g, about 120 .mu.g, about 125 .mu.g, about 130
.mu.g, about 135 .mu.g, about 140 .mu.g, about 150 .mu.g, about 160
.mu.g, about 170 .mu.g, about 175 .mu.g, about 180 .mu.g, about 190
.mu.g, about 200 .mu.g, about 25 .mu.g to about 500 .mu.g, about 50
.mu.g to about 500 .mu.g, about 50 .mu.g to about 300 .mu.g, about
50 .mu.g to about 250 .mu.g, about 50 .mu.g to about 200 .mu.g,
about 50 .mu.g, about 75 .mu.g, about 100 .mu.g, about 125 .mu.g,
about 150 .mu.g, about 175 .mu.g, about 200 .mu.g, about 225 .mu.g,
about 250 .mu.g, about 275 .mu.g or about 300 .mu.g of
glycopyrrolate per dose, in some preferred embodiments,
administration of the nominal dose of glycopyrrolate with a high
efficiency nebulizer produces clinically meaningful improvement in
lung function in a COPD patient at least 24 hours after
administration of a single dose.
[0090] The process of making glycopyrrolate is known by a person of
ordinary skill in the art. Glycopyrrolate can be made as follows.
First, alpha-phenylcyciopentaneglycolic acid is esterified by
refluxing with methanol in the presence of hydrochloric acid and
the resulting ester is transesterified with 1-methyl-3-pyrrolidinol
using sodium as a catalyst; the transester is then reacted with
methyl bromide to give glycopyrrolate. U.S. Pat. No. 6,433,003,
which describes this process in more detail, is hereby incorporated
by reference in its entirety.
[0091] Glycopyrrolate for injectable and oral administration is
readily commercially available. Injectable glycopyrrolate in
commercial administrations are sold by: Baxter Healthcare, Inc.
(Deerfield, Ill.) under the trade name Robinul and by Luitpold
Pharmaceuticals, Inc. (Shirley, N.Y.) under the generic name
glycopyrrolate. Oral glycopyrrolate is commercially available under
the generic name glycopyrrolate from Corepharma, LLC (Middlesex,
N.J.) and Kali Laboratories, Inc. (Somerset, N.J.), and is
available from Sciele Pharma, Inc. (Atlanta, Ga.) under the trade
names Robinul and Robinul Forte.
[0092] Tiotropium is another long-acting muscarinic antagonist that
may be mentioned. In some embodiments, the dose of tiotropium
administered with a high efficiency nebulizer will be less than
about 15 .mu.g, less than about 12 .mu.g, less than about 10 .mu.g
or less than about 8 .mu.g. In some embodiments, the dose will be
in a range of about 1-10 .mu.g, about 1-9 .mu.g, about 1-8 .mu.g or
about 1-5 .mu.g about 1 .mu.g, about 2 .mu.g, about 3 .mu.g, about
4 .mu.g, about 5 .mu.g, about 6 .mu.g, about 7 .mu.g, about 8
.mu.g, about 9 .mu.g or about 10 .mu.g per dose.
[0093] Muscarinic antagonists can be long-acting or short-acting.
Long-acting muscarinic antagonists have a therapeutic effect
lasting greater than about 6 hours. Short-acting muscarinic
antagonists have a duration of therapeutic effect of less than
about 6 hours. Long-acting muscarinic antagonists include, but are
not limited to, glycopyrrolate, tiotropium, aclidinium, trospium,
QAT370, GSK233705, GS K656398, BEA 2180, or a pharmaceutical
acceptable derivative, salt, enantiomer, diastereomer, or racemic
mixtures thereof.
[0094] Short-acting muscarinic antagonists include, but are not
limited to ipratropium, oxitropium or a pharmaceutical acceptable
derivative, salt, enantiomer, diastereomer, or racemic mixtures
thereof.
[0095] In some embodiments, the muscarinic antagonist is
glycopyrrolate, tiotropium, aclidinium, trospium, QAT370,
GSK233705, GSK 656398, BEA2180, ipratropium, oxitropium, oxybutynin
or a pharmaceutical acceptable derivative, salt, enantiomer,
diastereomer, or a pharmaceutical acceptable derivative, salt,
enantiomer, diastereomer, or racemic mixture thereof.
[0096] In some embodiments, the inhalation solution comprising the
muscarinic antagonist(s) further comprises a corticosteroid, such
as fluticasone, mometasone, beclomethasone, triamcinolone,
fluniolide, ciclesonide, or budesonide. In some embodiments, the
inhalation solution further comprises an excipient, including an
organic acid, such as citric acid, ascorbic acid or optionally a
combination of both, pilocarpine, cevimeline or
carboxymethylcellulose, or a mucolytic compound. In some
embodiments, the inhalation solution contains muscarinic antagonist
(such as glycopyrrolate) a beta 2-adrenoceptor agonist and/or a
corticosteroid or non-steroidal anti-inflammatory.
Beta 2-Adrenoceptor Agonists
[0097] The stimulation of beta 2-adrenergic receptors stimulate
adenylate cyclase, resulting in an increased level of the second
messenger cAMP that in turn leads to decreased intracellular
calcium concentration and consequently smooth muscle relaxation.
Stimulation of certain beta 2-adrenoceptor receptors in particular
causes hydrolysis of polyphosphoinositides and mobilization of
intracellular calcium which results in a variety of calcium
mediated responses such as smooth muscle contraction. Consequently,
inhibition of this receptor activation prevents the intracellular
calcium increase and leads to smooth muscle relaxation.
[0098] Beta 2-adrenoceptor agonists can be long-acting or
short-acting. Long-acting beta 2-adrenoceptor agonists (LABAs) have
a therapeutic effect lasting greater than about 6 hours.
Short-acting beta 2-adrenoceptor agonists (SABA s) have a duration
of therapeutic effect of less than about 6 hours.
[0099] Compounds having beta 2-adrenoceptor agonist activity with a
long-acting or short-acting effect have been developed to treat
respiratory conditions. Such compounds include, but are not limited
to, albuterol; bambuterol; bitoiterol; broxaterol; carbuterol;
clenbuterol; ibuterol; sulfonterol; isoproterenol; trimetoquinol;
formoterol; desformoterol; hexoprenaline; ibuterol; indaeaterol;
isoetharine; isoprenaline; isoproterenol; levalbuterol;
metaproterenol; picumeterol; pirbuterol; procaterol; reproterol;
rimiterol; salbutamol, salmeterol; suifonteroi; terbutaline;
trimetoquinol; tulobuterol; and TA-2005
(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl-
) amino)ethyl)-carbostyril hydrochloride); or a or a pharmaceutical
acceptable derivative, salt, enantiomer, diasteriomer, or racemic
mixtures thereof.
[0100] Formoterol is a long-acting beta 2-adrenoceptor compound.
The process of making formoterol is known by one of skill in the
art. Formoterol is derived from adrenaline and is used as a beta
2-adrenoceptor agonist in inhalation therapy of respiratory
diseases. Formoterol has been formulated as a dry powder and
administered via devices such as the Turbuhaler.RTM. and the
Aerolizer.RTM..
[0101] Formoterol is also available as a tablet and a dry syrup in
certain areas of the world (e.g., Atock.RTM., marketed by
Yamanouchi Pharmaceutical Co. Ltd., Japan). Formoterol
administrations are also available in other areas (e.g., Europe and
U.S.) for propellant-based metered dose inhalers and dry powder
inhalers (e.g., Turbuhaler.RTM., Aerolizer..RTM. and Foradil
Aerolizer.RTM.). None of these administrations are water based
solutions.
[0102] Commercial administrations of arformoterol tartrate
(formoterol) are sold by Sepracor, Inc, (Marlborough, Mass.) under
the trade name Brovana.RTM.. Formoterol fumarate is sold by several
companies including AstraZeneca, Inc. (London, England) under the
trade name Symbicort.RTM., Novartis International AG (Basel,
Switzerland) under the trade names Foradil.RTM. and
Certihaler.RTM., and Dey, L. P. (Napa, Calif.) under the trade name
Perforomist.RTM..
[0103] Salmeterol is a long-acting beta 2-adrenoceptor compound.
The process for making salmeterol is known by a person of ordinary
skill in the art and is described in U.S. Pat. No. 4,992,474, which
is hereby incorporated by reference. Commercial administrations of
salmeterol are sold by GlaxoSmithKline, Inc. (Triangle Park, N.C.)
under the trade names Advair.RTM. and Serevent.RTM..
[0104] Inhalation Solutions
[0105] The present invention relates to methods and inhalation
systems for the use of inhalation solutions in an inhalation device
for the treatment or prophylaxis of a respiratory condition in a
patient, such as COPD, chronic bronchitis, or emphysema. In some
embodiments, the methods and inhalation systems comprise
administering to the patient a nominal dose of one or more API, for
example muscarinic antagonist (optionally in combination with a
beta 2-adrenoceptor agonist and/or a corticosteroid) in an aqueous
inhalation solution with an inhalation device, e.g. a high
efficiency nebulizer, conventional nebulizer, and optionally a
conventional inhalation device.
[0106] In some embodiments, an aqueous inhalation solution
containing glycopyrrolate is administered with a high efficiency
nebulizer at a concentration greater than about 0.5 mg/mL. In some
embodiments, an aqueous inhalation solution containing
glycopyrrolate is administered with a high efficiency nebulizer at
a concentration of 0.05 mg/mL to about 2.0 mg/mL, at least about
0.05 mg/mL, at least about 0.5 mg/mL, at least about 1.0 mg/mL to
about 2.0 mg/mL, at least about 0.25 mg/mL, at least about 0.5
mg/mL, at least about 1.0 mg/mL, at least about 1.5 mg/mL, or at
least about 2.0 mg/mL. Without wishing to be bound by theory, it is
believed that the higher concentration of muscarinic antagonist,
for example glycopyrrolate, results in saturation and/or targeting
of a greater number of muscarinic receptors with the muscarinic
antagonist and/or targeting of the muscarinic receptors with the
muscarinic antagonist for a greater period of time. In some
embodiments, it is believed that administration of a muscarinic
antagonist, such as glycopyrrolate, at a concentration of at least
about 100 to about 300 .mu.g/mL will result in greater duration
and/or magnitude of therapeutic effect. Without wishing to be bound
by theory, it is believed that the higher concentration of
muscarinic antagonist, for example glycopyrrolate, coupled with the
improved delivery and/or lung distribution achievable with a high
efficiency nebulizer, results in saturation and/or targeting of a
greater number of muscarinic receptors with the muscarinic
antagonist and/or targeting of the muscarinic receptors with the
muscarinic antagonist for a greater period of time. In some
embodiments, it is believed that administration of a muscarinic
antagonist, such as glycopyrrolate, in a nebulized form having an
MMAD of less than about 4 .mu.m and a USD of less than about 1.8,
wherein the loaded dose has a concentration greater than 0.25
mg/mL, will result in greater duration and/or magnitude of
therapeutic effect. Without wishing to be bound by theory, it is
believed that this combination of characteristics results in
saturation and/or targeting of a greater number of muscarinic
receptors with the muscarinic antagonist and/or targeting of the
muscarinic receptors for a greater period of time.
[0107] In some embodiments, the methods, devices and systems employ
an aqueous inhalation solution containing glycopyrrolate, at an
administration of about 25 .mu.g/dose to about 1 mg/dose, about 25
.mu.g/dose to about 500 .mu.g/dose, about 25 .mu.g/dose to about
400 .mu.g/dose, about 25 .mu.g/dose to about 250 .mu.g/dose, about
50 .mu.g/dose to about 1 mg/dose, about 50 .mu.g/dose to about 500
.mu.g/dose, about 50 .mu.g/dose to about 400 .mu.g/dose, about 50
.mu.g/dose to about 250 .mu.g/dose, about 25 .mu.g/dose to about 5
mg/dose, about 200 .mu.g/dose to about 2 mg/dose, or about 250
.mu.g/dose to about 1 mg per dose. In some embodiments, the
methods, devices and systems comprise a composition containing
glycopyrrolate in an amount of about 50 .mu.g/dose to about 1
mg/dose, about 50 .mu.g/dose to about 0.5 mg/dose, about 50
.mu.g/dose to about 250 .mu.g/dose, about 50 .mu.g/dose to about
150 .mu.g/dose, about 50 .mu.g/dose to about 125 .mu.g/dose, about
50 .mu.g/dose to about 100 .mu.g/dose, less than about 150
.mu.g/dose, less than about 100 .mu.g/dose, equal to or less than
about 80 .mu.g/dose, 100 .mu.g/dose to about 5 mg/dose, about 200
.mu.g/dose to about 2 tug/dose or about 250 .mu.g/dose to about 1
mg per dose.
[0108] In some embodiments, the aqueous inhalation solution is
administered with an inhalation device, e.g. high efficiency
nebulizer, at a fill volume of about 0.1 to about 1.0 mL, e.g.
about 0.3 to about 0.7 mL. In some embodiments, the fill volume is
less than about 0.5 mL, at least about 0.5 mL, to about 1.5 mL, at
least about 0.25 mL or less, at least about 0.5 mL to about 1.5 mL,
at least about 1.5 mL, or at least about 2.0 mL. In some
embodiments, the aqueous inhalation solution is administered with
an inhalation device, e.g. high efficiency nebulizer, at a fill
volume of at least about 0.25 mL to about 2.0 mL, about 0.5 mL to
about 1.5 mL, about 0.5 mL to about 1.0 mL, about 0.5 mL or less,
about 1 mL or less, about 1.5 mL or less, or about 2.0 mL or less.
In some embodiments, the aqueous inhalation solution is
administered with an inhalation device, e.g. high efficiency
nebulizer, which provides for a residual volume of muscarinic
antagonist after administration of the muscarinic antagonist of
less than about 10%, less than about 5%, or less than about 3% of
the nominal dose.
[0109] In some embodiments, the aqueous inhalation solution is
administered in about 0.25 to about 10 minutes, about 0.50 to about
8 minutes, less than about 8, less than about 7, less than about 6,
less than about 5, less than about 4, less than about 3, less than
about 2, less than about 1.75 minutes, or less than about 1.5
minutes. In some embodiments, the aqueous inhalation solution is
administered in about 3 minutes or less.
[0110] In some embodiments, a muscarinic antagonist is
co-administered with a beta 2-adrenoceptor agonist in the aqueous
inhalation solution. In some embodiments, the beta 2-adrenoceptor
agonist is a long-acting beta agonist (LABA). In some embodiments,
the beta 2-adrenoceptor agonist is a short-acting beta agonist
(SABA). In some embodiments, the beta 2-adrenoceptor agonist is
either a SABA or a LAMA.
[0111] In some embodiments, the nominal, dose administered with the
high efficiency nebulizer is a muscarinic antagonist (optionally in
combination with a beta 2-adrenoceptor agonist and/or
corticosteroid or non-steroidal anti-inflammatory) that is
substantially free of preservative, such as benzyl alcohol. In some
embodiments, the nominal dose of muscarinic antagonist (optionally
in combination with a beta 2-adrenoceptor agonist and/or
corticosteroid or non-steroidal anti-inflammatory) is in an
inhalation solution that further comprises at least one excipient
or active pharmaceutical ingredient. In some embodiments, the
excipient or active ingredient is a member of the group consisting
of organic acid (such as a low molecular weight organic acid like
citric acid or ascorbic acid), an antioxidant (such as EDTA), an
osmolarity adjusting agent (such as a salt like sodium chloride) or
a pH buffer.
[0112] In some embodiments, the inhalation solution comprising the
muscarinic antagonist(s) further comprises a corticosteroid, such
as fluticasone, mometasone, beclomethasone, triamcinolone,
fluniolide, ciclesonide, or budesonide. In some embodiments, the
inhalation solution further comprises an excipient or an active
pharmaceutical ingredient. In some embodiments, the excipient or
active pharmaceutical ingredient is an organic acid (such as citric
acid, ascorbic acid, or both), pilocarpine, cevimeline,
carboxymethylcellulose, or a mucolytic compound.
[0113] Characterization of Inhalation Devices
[0114] The efficiency of a particular inhalation device can be
measured in many different ways, including an analysis of
pharmacokinetic properties, measurement of lung deposition
(deposited lung dose), measurement of respirable dose delivery
rates (RDDR), a determination of output rates, respirable fraction
(RF), geometric standard deviation (GSD), mass median aerodynamic
diameter (MMAD), and mass median diameter (MMD) among others.
[0115] A person skilled in the art is knowledgeable of methods and
systems for examining a particular inhalation device. One such
system consists of a computer and a hollow cylinder in a pump with
a connecting piece to which an inhalation device is to be
connected. In the pump there is a piston rod, which extends out of
the hollow cylinder. A linear drive unit can be activated in such a
manner that one or more breathing pattern will be simulated on the
connecting piece of the pump. In order to be able to carry out the
evaluation of the inhalation device, the computer is connected in
an advantageous configuration with a data transmission. With the
aid of the data transmission, the computer can be connected with
another computer with specific data banks, in order to exchange the
data of breathing patterns. In this manner, a breathing pattern
library which is as representative as possible can be very, rapidly
formed. U.S. Pat. No. 6,106,479 discloses this method for examining
an inhalation device in more detail, and is hereby incorporated by
reference in its entirety.
[0116] Pharmacokinetic Profile
[0117] Pharmacokinetics is concerned with the uptake, distribution,
metabolism and excretion of a drug substance. A pharmacokinetic
profile comprises one or more biological measurements designed to
measure the absorption, distribution, metabolism and excretion of a
drug substance. One way of visualizing a pharmacokinetic profile is
by means of a blood plasma concentration curve, which is a graph
depicting mean active ingredient blood plasma concentration on the
Y-axis and time (usually in hours) on the X-axis. Some
pharmacokinetic parameters that may be visualized by means of a
blood plasma concentration curve include:
[0118] AUC.sub.(0-t): The area under the curve from time zero to
time of last measurable concentration.
[0119] AUC.sub.(0-.infin.): The total area under the curve.
[0120] C.sub.max: The maximum plasma concentration in a
patient.
[0121] T.sub.max: The time to reach maximum plasma concentration in
a patient
[0122] T1/2: The elimination half life.
[0123] An enhanced pharmacokinetic profile in a patient can be
indicated by an increased AUC.sub.(0-t), AUC.sub.(0-.infin.),
C.sub.max, T1/2, or T.sub.max, or an increased slope in the plasma
concentration curve within the first hour after treatment. Enhanced
levels of a pharmaceutical agent in the blood plasma of a patient
may result in one or more improved symptoms of an airway
respiratory condition, e.g. COPD.
[0124] In some embodiments, a method or system described herein
provides at least about a two-fold enhancement in pharmacokinetic
profile, meaning that administration of an active pharmaceutical
ingredient ("API"--e.g. a muscarinic antagonist, optionally in
combination with a beta 2-adrenergic agonist) with a high
efficiency nebulizer provides at least about a two-fold increase in
one or more of AUC.sub.last, AUC.sub.(0-.infin.), or C.sub.max as
compared to the same or lower nominal dose of API administered with
a conventional nebulizer.
[0125] In some embodiments, a method or system described herein
provides at least about a two-fold enhancement in pharmacokinetic
profile, meaning that administration of an active pharmaceutical
ingredient ("API"--e.g. a muscarinic antagonist, optionally in
combination with a beta 2-adrenergic agonist) with a high
efficiency nebulizer provides at least about a 1.8-fold increase in
one or more of AUC.sub.last, AUC.sub.(0-.infin.), or C.sub.max as
compared to the same or lower nominal dose of API administered with
a conventional nebulizer.
[0126] In some embodiments, a method or system described herein
provides at least about a two-fold enhancement in pharmacokinetic
profile, meaning that administration of an active pharmaceutical
ingredient ("API"--e.g. a muscarinic antagonist, optionally in
combination with a beta 2-adrenergic agonist) with a high
efficiency nebulizer provides at least about a 1.5-fold increase in
one or more of AUC.sub.last, AUC.sub.(0-.infin.), or C.sub.max as
compared to the same or lower nominal dose of API administered with
a conventional nebulizer.
[0127] In some embodiments, a method or system described herein
provides at least about a two-fold enhancement in pharmacokinetic
profile, meaning that administration of an active pharmaceutical
ingredient ("API"--e.g. a muscarinic antagonist, optionally in
combination with a beta 2-adrenergic agonist) with a high
efficiency nebulizer provides a comparable AUC.sub.last,
AUC.sub.(0-.infin.), or C.sub.max as compared to the same or lower
nominal dose of API administered with a conventional nebulizer.
[0128] Enhanced Therapeutic Effect
[0129] The assessment of therapeutic effect is known to those
skilled in the art, such as pulmonologists trained to recognize the
distinctions between various types of respiratory illnesses,
including chronic obstructive airway disease ("COPD") and asthma.
Assessment of efficacy may be carried out by various methods known
to the person skilled in the art, and may include both objective
and subjective (patient-generated) measures of efficacy. Objective
measures of efficacy can be obtained inter aria by spirometry; and
subjective measures of efficacy can be obtained for example by
employing one or more patient symptom questionnaires or surveys. In
some embodiments, the methods and systems herein are for treatment
of COPD, and thus such embodiments are discussed in further detail
below. It is considered that embodiments of the methods and
symptoms described herein. (including those employing
administration of muscarinic antagonist, optionally in combination
with a beta 2-adrenoceptor agonist and/or a corticosteroid, with a
high efficiency nebulizer or at a high concentration) will provide
superior efficacy in treatment of COPD as compared to treatment
with conventional methods (such as those in which muscarinic
antagonist is administered with a conventional nebulizer and/or at
a lower concentration).
[0130] COPD Efficacy Assessment
[0131] COPD is a progressive, chronic disease of the airways,
characterized by chronic inflammation and destruction of the
airways and lung parenchyma, resulting in airflow obstruction.
Thus, efficacy in the treatment of COPD refers to the ability to
restore airflow to the patient. In some cases, especially in older
and immune-compromised patients, COPD can be further characterized
by exacerbations--acute, often pathogen- or allergen-induced,
degradation of airflow. There are several indicators (endpoints) of
efficacy in the treatment of COPD. Some efficacy endpoints that are
used in COPD studies are set forth below. It is considered that a
muscarinic antagonist will demonstrate efficacy in one or more of
these tests. In particular, it is considered that in some
embodiments a nominal dose of a muscarinic antagonist administered
with a high efficiency nebulizer will out-perform substantially the
same or higher nominal dose of muscarinic antagonist administered
with a conventional nebulizer, as determined by one or more of
these endpoints.
[0132] Pulmonary function tests: Pulmonary function testing by
spirometry is a useful way to assess airflow obstruction and,
therefore, is a useful way to assess the efficacy of COPD treatment
as well as to compare the relative merits of different COPD
treatments--e.g. administration of different dosages of active
pharmaceutical ingredient ("API"), administration of substantially
the same dosages of API with different delivery devices, or
administration of different dosages of API with different delivery
devices. Forced expiratory volume in one second (FEV.sub.1)
obtained from typical spirometry is commonly used as an efficacy
endpoint because FEV.sub.1 is a reflection of the extent of airway
obstruction. Spirometry is also well-standardized, is easy to
perform and provides consistent, reproducible results across
different pulmonary function laboratories. Air-trapping and
hyperinflation are common features in COPD, particularly in
emphysema, and are reflected in parameters of lung function
testing, such as an elevation in the residual volume to total lung
capacity ratio (RV/TLC). Hyperinflation is believed to be
responsible, at least in part, for the sense of dyspnea.
[0133] Outcome Measures can also be used, alone or preferably in
combination with one or more objective tests, to determine efficacy
of COPD therapy.
[0134] Exacerbation: The progressive course of COPD is often
aggravated by periods of exacerbations generally defined as
increased symptoms, particularly increasing cough, dyspnea and
production of sputum over baseline that usually requires change in
treatment. Exacerbations are mostly caused by bronchial infections
and are the most frequent cause of medical visits, hospital
admissions and death in patients with COPD. One of the main
objectives of COPD treatment is to reduce the frequency and
severity of exacerbations and the frequency of hospitalizations and
duration of hospital stay. The characteristics, including the
limitations, of these tests will be known to those skilled in the
art.
[0135] Exercise capacity: Reduced capacity for exercise is a
typical consequence of airflow obstruction in COPD patients,
particularly because of dynamic hyperinflation occurring during
exercise. Exercise testing provides useful assessment of the degree
of lung impairment, prognosis and the effects of treatments.
Assessment of exercise capacity by treadmill or cycle ergometry
combined with lung volume assessment is in some cases a tool to
assess efficacy of a COPD drug. Alternative assessments of exercise
capacity, such as the Six Minute Walk or Shuttle Walk, can also be
used in some cases. The characteristics, including the limitations,
of these tests will be known to those skilled in the art.
[0136] Symptom Scores: Symptom scores determined by asking patients
to evaluate specific symptoms on a categorical, visual or numerical
scale can be a simple way to assess efficacy of a drug based on the
patient's own assessment of health status. Symptom scores can be
valuable for assessing efficacy of a drug specifically aimed at
relieving a symptom. In clinical programs aimed at other aspects of
COPD, patient-reported symptom scores can be useful in assessing
secondary effects of the therapy and may provide important
additional evidence of efficacy. The characteristics, including the
limitations, of these tests will be known to those skilled in the
art.
[0137] Activity Scales: Activity scales provide an assessment of
the patient's severity of breathlessness and how activities of
daily living influence the patient's breathlessness. Activity
scales such as the Medical Research Council dyspnea score, the Borg
Scale, and the Mahler Baseline Dyspnea Index/Transitional Dyspnea
Index, can be used in some cases as supportive evidence of
efficacy. These scales are relatively simple to administer. The
characteristics, including the limitations, of these tests will be
known to those skilled in the art.
[0138] Health-related, quality-of-life instruments: Health-related
quality of life measurement provides a standardized assessment of
the impact of the disease on patients' daily lives, activity and
well-being. Health-related quality-of-life instruments, such as the
St. George's Respiratory Questionnaire and the Chronic Respiratory
Questionnaire, are designed to systematically assess many different
aspects of the effect of COPD on a patient's life. These
instruments can be used to assess efficacy of a drug. These
instruments are multidimensional and assess various effects of the
disease on a patient's life and health status. The characteristics,
including the limitations, of these tests will be known to those
skilled in the art.
[0139] Further information regarding testing drugs for efficacy in
the treatment of COPD can be found in the United States Food and
Drug Administration's guidance document entitled: "Guidance for
Industry: Chronic Obstructive Pulmonary Disease: Developing Drugs
for Treatment," November, 2007, which is available from
www.fda.gov/cder/guidance/index.htm.
[0140] A muscarinic antagonist is said to have a therapeutic effect
in the treatment of COPD (at a relevant time point) when it causes
an increase in one or more measures of pulmonary function to a
predetermined percentage above baseline. In some embodiments, the
predetermined percentage above baseline is about 5%, about 10%,
about 15%, about 20%, or about 25%. In some specific embodiments, a
muscarinic antagonist will be considered to have a therapeutic
effect when it raises one or more of the above-mentioned spirometry
measurements (e.g. FEV.sub.1) at least about 15% above baseline. In
general, an improvement in pulmonary function (e.g. FEV.sub.1) of
100 mL or 10% above baseline is considered clinically relevant; and
an improvement in pulmonary function above baseline of 100 mL or
10% above baseline at 24 hours post dosing is considered clinically
relevant for a QD (1.times. daily dosing) drug.
[0141] Spirometry is the measurement of respiration, which is
generally conducted by a physician with the aid of a spirometer.
Spirometers measure inspired and expired airflow for the purpose of
assessing pulmonary ventilatory function. Spirometry is the most
common pulmonary function test measuring lung function. Typical
spirometers display volume-time curves (showing volume on the
Y-axis and time, usually in seconds, on the X-axis) and optionally
a flow-volume curves (showing rate of flow on the Y-axis and the
total volume inspired/expired on the X-axis). U.S. Pat. No.
7,291,115 discloses a spirometer and method to measure the
ventilatory function by spirometry, and is hereby incorporated by
reference in its entirety. Methods of using a spirometer are
familiar to those skill in the art.
[0142] Relevant parameters measured by spirometers include: [0143]
FEV1 (or FEV.sub.1): Forced Expiratory Volume in 1 Second, which is
the maximum volume of air exhaled during the first second of
maximum effort from a maximum inhalation. It is expressed in units
of volume (e.g. liters (L)), especially as volume change from
baseline or placebo, and/or in percentage change in FEV.sub.1 from
baseline or placebo. It becomes altered in cases of bronchial
obstruction and it is fundamental for diagnosing and monitoring
obstructive diseases, e.g. COPD. [0144] Change in FEV.sub.1: Change
in FEV.sub.1 may be calculated as the difference between the
FEV.sub.1 value measured after dosing and the FEV.sub.1 measured
immediately prior to dosing. Change in FEV.sub.1 may also be
measured in reference to a placebo. These values may be expressed
in absolute terms or in terms of percent change from baseline or
placebo. [0145] FEV.sub.1AUC: This is the area between the FEV1
measurements vs. time curve (relative to baseline and/or placebo)
over a time course. In some embodiments, the time course is a
predetermined period, such as 12 hr., 18 hr., 24 hr., 30 hr., or 36
hr. FEV.sub.1AUC (e.g. relative to baseline and/or placebo) may be
measured from one time point to another. Some clinically relevant
time courses include 0-12 hr, 0-24 hr, 12-24 hr after dose
administration. In the context of 24 hour efficacy for QD dosing,
the FEV.sub.1AUC(12-24 hr) (baseline- and/or placebo-adjusted
FEV.sub.1 area under the curve (AUC) from 12 to 24 hours after
administration of the muscarinic antagonist to the patient) is
particularly, relevant. In some embodiments, an FEV.sub.1AUC(12-24
hr) of at least 0.5 Lhr for inhaled glycopyrrolate is required to
achieve prolonged duration of bronchodilation over 24 hours. In
some embodiments, an FEV.sub.1AUC(12-24 hr) of greater than 40% of
the FEV.sub.1AUC(0-12 hr) for inhaled glycopyrrolate is required to
achieve prolonged duration of bronchodilation over 24 hours. [0146]
Mean FEV.sub.1: This is the mean FEV.sub.1 between two time points,
calculated by dividing the FEV.sub.1AUC.sub.t1-t2 (wherein t.sub.1
is the starting time and t.sub.2 is the ending time for the
relevant time course) by the difference between t.sub.2 and
t.sub.1. Some clinically relevant time courses for Mean FEV.sub.1
include 0-12 hr, 0-24 hr, 12-24 hr, after dose administration. In
the context of 24 hour efficacy for QD dosing, the Mean FEV.sub.1
(12-24) (placebo-adjusted Mean FEV.sub.1 from 12 to 24 hours after
the muscarinic antagonist to the patient) is particularly relevant.
[0147] Trough FEV.sub.1: This is the FEV.sub.1 value measured just
prior to administration of the drug (e.g. just prior to the next
administration of the drug). In some cases, the trough FEV.sub.1 is
obtained in the morning, just prior to administration of the drug.
In some embodiments, the change in trough FEV.sub.1 is the
difference between the trough FEV.sub.1 for the drug and the trough
FEV.sub.1 for a placebo, after a period of time. In general, for a
once daily (QD) bronchodilator drug, trough FEV.sub.1 (at 24 hours
post-dosing and, prior to administration of the next dose) is
considered the clinically relevant endpoint. In some embodiments,
the change in the trough. FEV.sub.1 is measured over a
predetermined time course, such as 1 wk, 2 wk, 4 wk or 12 wk.
[0148] FVC: Forced Vital Capacity, which is the maximal volume of
air exhaled with maximal effort from a position of maximal
inhalation. It is expressed in liters and in percentage of a
patient's reference value from baseline, [0149] FEV.sub.1/FVC: The
quotient of FEV.sub.1 and PVC. [0150] FEF: Peak Expiratory Flow,
which is the highest expiratory flow achieved with maximal effort
from a position of maximal inspiration. This is essentially the
speed of the air moving out of the lungs of a patient at the
beginning of expiration. It is expressed in liters/second or in
liters/minute. [0151] FEF.sub.25-75: Forced Expiratory Flow from
25% to 75% on the flow-volume curve, which is the average flow (or
speed) of air coming out of the lung during the middle portion of
expiration. [0152] FEF.sub.25-50: Forced Expiratory Flow from 25%
to 50% on the flow-volume curve, which is another measure of the
average flow (or speed) of air coming out of the lung during the
initial portion of expiration. [0153] FIF.sub.25-75: Forced
Inspiratory Flow from 25% to 75% on the flow-volume curve, which is
the average flow (or speed) of air entering the lung during the
middle portion of inspiration. [0154] FIF.sub.25-50: Forced
Inspiratory Flow from 25% to 50% on the flow-volume curve, which is
another measure of the average flow (or speed) of air entering the
lung during the initial portion of inspiration.
[0155] An enhanced therapeutic effect can include an increased
magnitude of therapeutic effect, an enhanced duration of
therapeutic effect, an enhanced time to onset of therapeutic
effect, a shorter time to maximum therapeutic effect or a greater
magnitude of therapeutic effect. In some embodiments described
herein, an enhanced therapeutic effect relates to the increased
ability of a pharmaceutical agent to relieve the symptoms of an
airway respiratory disorder, e.g. COPD. Thus, an enhanced
therapeutic effect may be determined by comparing values of change
in FEV.sub.1 (i.e. change in FEV.sub.1 from baseline or compared to
a placebo). % change in FEV.sub.1 (i.e. percent change in FEV.sub.1
from baseline or compared to placebo), FEV.sub.1 AUC, trough
FEV.sub.1, FEV.sub.1/FVC, PEE, FEF.sub.25-75, FEF.sub.25-50,
FIF.sub.25-75, FIF.sub.25-50 obtained from a patient or patient
population in one therapeutic milieu versus another anther
therapeutic milieu. For example, an enhanced therapeutic effect may
be determined by comparing FEV.sub.1 values for a patient or
patient population treated with a muscarinic antagonist
administered with a high efficiency nebulizer against the same drug
administered with a conventional nebulizer. In another example, an
enhanced therapeutic effect may be determined by comparing
FEV.sub.1 values for a patient or patient population treated with a
muscarinic antagonist administered at a high concentration against
the same drug administered at a low concentration. In some cases,
an enhanced therapeutic effect may be determined by comparing
FEV.sub.1 values for a patient or patient population treated with a
muscarinic antagonist administered with a high efficiency nebulizer
against a muscarinic antagonist alone administered with a
conventional nebulizer. In another example, an enhanced therapeutic
effect may be determined by comparing FEV.sub.1 values for a
patient or patient population treated with a muscarinic antagonist
administered at a high concentration against a muscarinic
antagonist alone administered at a low concentration. In some
embodiments, the enhanced therapeutic effect is an increased
magnitude of therapeutic effect. In some embodiments, the increased
magnitude of therapeutic effect is an increase in the peak
FEV.sub.1 obtained with a high efficiency nebulizer versus the peak
FEV.sub.1 obtained with a conventional nebulizer. In some
embodiments, the peak FEV.sub.1 obtained with a high efficiency
nebulizer is at least about 10%, 15%, 20%, or 30% above that
obtained with a conventional nebulizer. In some embodiments, the
peak FEV.sub.1 obtained with a high efficiency nebulizer is at
least about 25 mL, 50 mL, or 100 mL above that obtained with a
conventional nebulizer. In some embodiments, the increased
magnitude of therapeutic effect is an increase in the mean
FEV.sub.1 obtained with a high efficiency nebulizer versus the mean
FEV.sub.1 obtained with a conventional nebulizer. In some
embodiments, the mean FEV.sub.1 obtained with a high efficiency
nebulizer is at least about 5%, 10%, or 15% above that obtained
with a conventional nebulizer. In some embodiments, the mean
FEV.sub.1 obtained with a high efficiency nebulizer is at least
about 50 mL, 100 mL, or 150 mL above that obtained with a
conventional nebulizer. In some embodiments, the increased
magnitude of therapeutic effect is an increase in the AUC for the
FEV.sub.1 versus time curve obtained with a high efficiency
nebulizer versus the AUC for the FEV.sub.1 versus time curve
obtained with a conventional nebulizer. In some embodiments, the
increase in AUC of the FEV.sub.1 versus time curve obtained with a
high efficiency nebulizer is at least about 50%, 75% or 100% above
that obtained with a conventional nebulizer.
[0156] In some embodiments, the method or system (e.g. muscarinic
antagonist, optionally in combination with a beta 2-adrenergic
agonist, administered at a high concentration and/or with a high
efficiency nebulizer) provides an enhanced duration of therapeutic
effect, as determined by the amount of time that a spirometric
parameter (e.g. FEV.sub.1, trough FEV.sub.1) is above a
predetermined threshold after therapy is administered. In some
embodiments, the predetermined threshold is at least about 5% above
baseline, at least about 10% above baseline, at least about 15%
above baseline, at least about 20% above baseline, at least about
25% above baseline. In some specific embodiments, the threshold is
about 15% above baseline. In some specific embodiments, the
threshold is about 10% above baseline. In some embodiments, the
threshold is 50 mL, 100 mL, 150 mL or more than about 150 mL above
baseline. In some specific embodiments, the threshold is about 100
mL above baseline. Baseline can be determined by either a one-time
reference to the spirometric parameter (e.g, FEV.sub.1) immediately
prior to administration of API, or by reference to the spirometric
parameter level at several time periods during the study following
administration of placebo to a predetermined set of patients. In
some embodiments, baseline is determined based on the level of
spirometric parameter (e.g. FEV.sub.1) immediately prior to
administration to the patient of muscarinic antagonist administered
at a high concentration and/or with a high efficiency nebulizer. In
some embodiments, baseline is determined by reference to the level
of spirometric parameter (e.g. FEV.sub.1) at several time periods
(e.g., 12 hours, 24 hours) during evaluation of certain patients
following placebo administration, with the simultaneous evaluation
of other patients administered a muscarinic antagonist administered
at a high concentration and/or with a high efficiency
nebulizer.
[0157] In some embodiments, a duration of therapeutic effect is the
period during which FEV.sub.1 is at least about 5% above baseline,
at least about 10% above baseline, at least about 15% above
baseline, at least about 20% above baseline, at least about 25%
above baseline. In some specific embodiments, the duration of
therapeutic effect is the amount of time that the FEV.sub.1 is at
least 15% above baseline. In some specific embodiments, the
duration of therapeutic effect is the amount of time that the FEN)
is at least 10% above baseline. In some specific embodiments, the
duration of therapeutic effect is the amount of time that the
FEV.sub.1 is at least 50 mL, 100 mL, or 150 mL above baseline. In
some embodiments, a duration of therapeutic effect is the period
during which FEV.sub.1/FVC is at least about 5% above baseline, at
least about 10% above baseline, at least about 15% above baseline,
at least about 20% above baseline, at least about 25% above
baseline. In some embodiments, the duration of therapeutic effect
is the amount of time that the FEV.sub.1/FVC is at least 15% above
baseline. In some embodiments, a duration of therapeutic effect is
the period during which PEF is at least about 5% above baseline, at
least about 10% above baseline, at least about 15% above baseline,
at least about 20% above baseline, at least about 25% above
baseline. In some embodiments, the duration of therapeutic effect
is the amount of time that the PEF is at least 15% above baseline.
In some embodiments, a duration of therapeutic effect is the period
during which FEF.sub.25-75 is at least about 5% above baseline, at
least about 10% above baseline, at least about 15% above baseline,
at least about 20% above baseline, at least about 25% above
baseline. In some embodiments, the duration of therapeutic effect
is the amount of time that the FEF.sub.25-75 is at least 15% above
baseline. In some embodiments, a duration of therapeutic effect is
the period during which FEF.sub.25-50 is at least about 5% above
baseline, at least about 10% above baseline, at least about 15%
above baseline, at least about 20% above baseline, at least about
25% above baseline. In some embodiments, the duration of
therapeutic effect is the amount of time that the FEF.sub.25-50 is
at least 15% above baseline. In some embodiments, a duration of
therapeutic effect is the period during which FIF.sub.25-75 is at
least about 5% above baseline, at least about 10% above baseline,
at least about 15% above baseline, at least about 20% above
baseline, at least about 25% above baseline. In some embodiments,
the duration of therapeutic effect is the amount of time that the
FIF.sub.25-75 is at least 15% above baseline. In some embodiments,
a duration of therapeutic effect is the period during which
FIF.sub.25-50 is at least about 5% above baseline, at least about
10% above baseline, at least about 15% above baseline, at least
about 20% above baseline, at least about 25% above baseline. In
some embodiments, the duration of therapeutic effect is the amount
of time that the FIF.sub.25-50 is at least 15% above baseline.
[0158] A significantly greater, or greater, duration of therapeutic
effect, indicates that the method or system (e.g. a high efficiency
nebulizer-administered muscarinic antagonist) provides an increased
period of time the spirometric parameter is above a predetermined
threshold of about 5% above baseline, about 10% above baseline,
about 15% above baseline, about 20% above baseline, about 25% above
baseline, especially about 15% above baseline, for one or more of
the spirometric parameters compared to the same spirometric
parameter obtained with substantially the same nominal dose of drug
administered with a different inhalation device, e.g. a
conventional nebulizer. In some embodiments, the threshold for the
spirometric parameter (e.g. FEV.sub.1, or trough FEV.sub.1) is 50
mL, 100 mL, 150 mL or more than about 150 mL above baseline. In
some specific embodiments, the threshold is about 100 mL above
baseline.
[0159] "About the same" duration of therapeutic effect means that
the method or system (e.g. a high efficiency nebulizer-administered
muscarinic antagonist, optionally in combination with a beta
2-adrenergic agonist) provides substantially the same period of
time that the spirometric parameter is above a predetermined
threshold of about 5% above baseline, about 10% above baseline,
about 15% above baseline, about 20% above baseline, about 25% above
baseline, or especially about 15% above baseline, for one or more
of the above spirometric parameters compared to the same
spirometric parameter obtained with a substantially greater nominal
dose of the muscarinic antagonist administered with a different
inhalation device, e.g. conventional nebulizer (reference
administration).
[0160] In some embodiments, an inhalation solution described herein
(e.g. a muscarinic antagonist inhalation solution administered with
a high efficiency nebulizer and/or at a high concentration)
provides a duration of therapeutic effect of at least about 12 hr,
about 12 hr to about 24 hr, about 18 hr to about 24 hr, about 20 hr
to about 24 hr, or at least about 24 hr, in some embodiments.
[0161] A time to onset of therapeutic effect is the time for the
spirometric parameter to reach a predetermined threshold of about
5% above baseline, about 10% above baseline, about 15% above
baseline, about 20% above baseline, or about 25% above baseline,
especially about 15% above baseline for one or more of the
spirometric parameters of a muscarinic antagonist administered with
an inhalation device. An enhanced time to onset of therapeutic
effect relates to the increased ability of a pharmaceutical agent
to relieve the symptoms of an airway respiratory disorder, e.g.
COPD. The enhanced time to onset of therapeutic effect may be a
measure of the FEV.sub.1, FEV.sub.1/FVC, PEF, FEF.sub.25-75,
FEF.sub.25-50, FIF.sub.25-75. FIF.sub.25-50 levels.
[0162] A significantly shorter, or shorter, time to onset of
therapeutic effect, in some embodiments, means that the method or
system (a muscarinic antagonist inhalation solution administered
with a high efficiency nebulizer and/or at a high concentration)
provides for a shortened period of time for one or more spirometric
parameters (e.g, FIND to reach a predetermined threshold of about
5% above baseline, about 10% above baseline, about 15% above
baseline, about 20% above baseline, or about 25% above baseline,
especially about 15% above baseline, for one or more of the
spirometric parameters compared to the same spirometric
parameter(s) obtained with substantially the same nominal dose of
the drug solution administered with a different inhalation device,
e.g. a conventional nebulizer and/or at a lower concentration. In
other embodiments, "about the same" time to onset of therapeutic
effect means the method or system (e.g. administration of a
muscarinic antagonist with a high efficiency nebulizer and/or at a
high concentration) provides for substantially the same period of
time for the spirometric parameter to reach a predetermined
threshold of about 5% above baseline, about 10% above baseline,
about 15% above baseline, or about 20% above baseline for one or
more of the spirometric parameters compared to the same spirometric
parameter obtained with a substantially greater nominal of the dose
the drug solution administered with a different inhalation device,
e.g. a conventional nebulizer.
[0163] An inhalation solution that provides an onset of therapeutic
effect of less than about 30 minutes, less than about 25 minutes,
less than about 20 minutes, less than about 15 minutes, or less
than about 10 minutes, in some embodiments, refers to an amount of
time for the spirometric parameter to reach a predetermined
threshold of about 5% above baseline, about 10% above baseline,
about 15% above baseline, or about 20% above baseline.
[0164] In some embodiments, the methods or systems are provided for
the treatment of acute exacerbations of chronic obstructive
pulmonary disease (AECOPD), chronic bronchitis, and/or emphysema in
a patient, comprising administering to the patient a nominal dose
of a muscarinic antagonist, optionally in combination with a
long-acting or short-acting beta 2 agonist, with a high efficiency
nebulizer to provide a rapid onset of therapeutic effect and a long
duration of therapeutic effect. In some embodiments, the rapid
onset of therapeutic effect is less than about 30 minutes, less
than about 25 minutes, less than about 20 minutes, less than about
15 minutes or less than about 10 minutes. In some embodiments, the
long duration of therapeutic effect is at least about 12 hr to
about 24 hr, about 18 hr to about 24 hr, about 20 hr to about 24 hr
or at least about 24 hr.
[0165] A time to maximum therapeutic effect means the amount of
time for a preselected spirometric parameter to reach its peak
level. In some embodiments, an enhanced time to maximum therapeutic
effect means that administration of a muscarinic antagonist with a
high efficiency nebulizer, at a high concentration or both, results
in a faster time to maximum therapeutic effect than would a dose of
the muscarinic antagonist administered with a conventional
nebulizer or at a lower concentration. The parameters used to
determine an enhanced time to maximum therapeutic effect may be one
or more of FEV.sub.1, FEV.sub.1/FVC, PEF, FEF.sub.25-75,
FEF.sub.25-50, FIF.sub.25-75, or FIF.sub.25-50.
[0166] Reduction in Adverse Side Effects
[0167] Conventional CORD therapy employing a muscarinic antagonist
with a conventional nebulizer often results in deposition of
pharmaceutically active ingredient in sections distinct from the
lung, e.g., mouth, throat, stomach, and/or esophagus. This results
in antagonism of muscarinic receptors on peripheral systems other
than the lung, for example in salivary glands, stomach, heart,
and/or CNS and elsewhere. Therefore the tolerated doses of
systemically active muscarinic antagonists, such as glycopyrrolate,
are limited by side-effects such as, but not limited to, xerostomia
(dry mouth), urinary hesitancy and retention, blurred vision,
tachycardia, dizziness, insomnia, impotence, mental confusion,
excitement, headache, anxiety, hypotension and/or palpitations.
[0168] In the present invention, the bronchodilation and other
beneficial actions of a muscarinic antagonist are produced by an
inhaled agent providing for a high therapeutic index for activity
in the lung, i.e. lung deposition, compared with deposition of
muscarinic antagonist in non-pulmonary regions, i.e. periphery
compartments, mouth and pharynx. The present invention further
provides for an inhalable muscarinic antagonist with low
bioavailability in areas within a patient other than the lung (e.g.
systemic bioavailability, local oropharyngeal or gastric regions),
resulting in a decreased incidence and/or severity of systemic
and/or local toxicity and/or side effects. A practitioner of
ordinary skill can quantify a reduction in adverse side effects by
measuring the incidence and/or severity of systemic and/or local
toxicity and/or side effects in a given patient or patient
population.
[0169] A reduced, or decreased, incidence or severity of systemic
and/or local toxicity and/or side effects means that the method or
system (e.g. muscarinic antagonist, optionally in combination with
a beta 2-adrenoceptor agonist, administered with a high efficiency
nebulizer and/or at a high concentration) provides a decreased
incidence and/or severity of systemic and/or local toxicity and/or
side effects (for example dry mouth) in a given patient or patient
population compared to a given reference therapy. In some
embodiments, the reference therapy is administration of a
muscarinic antagonist with a conventional nebulizer. Some
embodiments provide a method for the treatment of COPD in a
patient, comprising administering to the patient a nominal dose of
muscarinic antagonist which, when administered with a high
efficiency nebulizer, provides a calculated respirable dose of a
muscarinic antagonist with a high efficiency nebulizer, wherein the
calculated respirable dose of the muscarinic antagonist
administered with the high efficiency nebulizer demonstrates a
decreased incidence and/or severity of systemic and/or local
toxicity and/or side effects in the patient as compared to a
nominal dose that achieves substantially the same calculated
respirable dose of the muscarinic antagonist administered with a
conventional nebulizer. Some embodiments provide a method for the
treatment of COPD in a patient, comprising administering to the
patient a nominal dose of muscarinic antagonist which, when
administered with a high efficiency nebulizer, provides a deposited
lung dose of a muscarinic antagonist with a high efficiency
nebulizer, wherein the deposited lung dose of the muscarinic
antagonist administered with the high efficiency nebulizer
demonstrates a decreased incidence and/or severity of systemic
and/or local toxicity and/or side effects in the patient as
compared to a nominal dose that achieves substantially the same
deposited lung dose of the muscarinic antagonist administered with
a conventional nebulizer. Some embodiments provide a system for
performing the foregoing methods.
[0170] In some embodiments, the method or system (e.g.
administration of a muscarinic antagonist with a high efficiency
nebulizer and/or at a high concentration) provides a method and/or
inhalation system for administration of a muscarinic antagonist in
a volume of about 0.5 mL or less, 1 mL or less, 1.5 mL or less, or
2.0 mL or less and wherein the muscarinic antagonist demonstrates
less incidence and/or severity of systemic and/or local toxicity
and/or side effects (for example dry mouth) in the patient as
compared to substantially the same nominal dose of the muscarinic
antagonist administered in a substantially higher volume of
solution.
[0171] In some embodiments, the method or system (e.g. muscarinic
antagonist with a high efficiency nebulizer and/or at a high
concentration) provides for methods and inhalation systems for
reducing at least one side effect of the muscarinic antagonist and
providing a duration of therapeutic effect of at least about 12 hr,
about 12 hr to about 24 hr, about 18 hr to about 24 hr, about 20 hr
to about 24 hr, or at least about 24 hours. In some embodiments,
the method or system (e.g. administration of a muscarinic
antagonist with a high efficiency nebulizer and/or at a high
concentration) provides for co-administration of other drugs and
optionally excipients, for example an organic acid, such as
ascorbic acid, citric acid or a mixture of both, pilocarpine,
cevimeline or carboxymethylcellulose, or a mucolytic compound.
[0172] Enhanced. Lung Deposition
[0173] Muscarinic receptors and beta 2-adrenoceptors are widely
distributed throughout the body. The ability to apply these active
pharmaceutical agents (APIs) locally to the respiratory tract with
sufficient lung deposition is particularly advantageous, as it
would allow for administration of lower doses of the drug fostering
increased patient compliance
[0174] The principle advantage of administration of a nebulized API
solution with a high efficiency nebulizer over other methods of
pulmonary delivery of APIs is that the methods and systems
described herein offer more efficient delivery of higher doses of
API compared to conventional inhalation methods and systems,
resulting in greater efficacy and a reduced incidence and
optionally a severity of side effects in the patient. A more
efficient delivery of API is evidenced by direct delivery and
deposition of an API to the site of action, i.e. the lung (as used
herein, "lung" refers to either or both the right and left lung
organs). It can be assumed that substantially all of an API
delivered at the receptor site in the lungs will be absorbed into
the blood plasma of the patient. In embodiments of the invention,
the API is a muscarinic antagonist (optionally in combination with
a beta 2-adrenoceptor agonist), such as glycopyrronium bromide
(glycopyrrolate).
[0175] The deposited dose may be expressed in terms of lung
deposition. A lung deposition of 30% means 30% of the active
ingredient in the inhalation device just prior to administration is
deposited in the lung. Likewise, a lung deposition of 60% means 60%
of the active ingredient in the inhalation device just prior to
administration is deposited in the lung, and so forth. Lung
deposition (deposited lung dose) can be determined using methods of
scintigraphy or deconvolution. In some embodiments, the present
invention provides for methods and inhalation systems for the
treatment or prophylaxis of a respiratory condition in a patient,
comprising administering to the patient a nominal dose of a
muscarinic antagonist solution with a high efficiency nebulizer
wherein administration of the muscarinic antagonist with the
inhalation device provides lung deposition (deposited lung dose) of
the muscarinic antagonist of at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 60%, about 30% to about 60%, about
30% to about 55%, about 30% to about 50%, about 30% to about 40%,
about 30% to about 90%, about 40% to about 80%, about 50% to about
60%, or about 60% to about 70% based on the nominal dose of the
muscarinic antagonist. In some embodiments, the present invention
provides for methods and inhalation systems for the treatment or
prophylaxis of a respiratory condition in a patient, comprising
administering to the patient a nominal dose of a muscarinic
antagonist in an aqueous inhalation solution with an inhalation
device wherein administration of the muscarinic antagonist with the
inhalation device provides lung deposition (deposited lung dose) of
the muscarinic antagonist of at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, about 20% to about 40%, about 25% to
about 35%, about 25% to about 30%, about 35% to about 90%, about
40% to about 80%, about 50% to about 60%, or about 60% to about 70%
based on the nominal dose of the muscarinic antagonist.
[0176] Aerosol particle/droplet size is one of the most important
factors determining the deposition of aerosol drugs in the airways.
The portion of an aerosol that has the highest probability of
bypassing the upper airway and depositing in the lung measure
between 1 and 5 .mu.m. Particles larger than this are generally
deposited in the oropharyngeal region and are swallowed, while
sub-micron particles do not carry much drug and may be exhaled
before deposition takes place or are absorbed systemically. Smaller
particles tend to deposit more peripherally in the lung than
coarser particles, which may lead to a different clinical response.
Consequently, differences in particle size of the aerosol emitted
from inhalation devices may account for some of the variability in
therapeutic efficacy and safety. Measurement of particle size,
therefore, has an important role in guiding product development and
in quality control of the marketed product.
[0177] The distribution of aerosol particle/droplet size can be
expressed in terms of either or both of: The Mass Median
Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation
(GSD), wherein the MMAD is the droplet size at which half of the
mass of the aerosol is contained in smaller droplets and half in
larger droplets and the GSD is the geometric standard deviation of
the particle population. While MMAD is most often determined by a
cascade impactor apparatus, the mass median diameter (MMD) is most
often measured by laser diffraction and can be used as a surrogate
for the MMAD value.
[0178] The Fine Particle Fraction (FPF), which is the fraction of
particles (which may be expressed as a percentage) that are <5
.mu.m in diameter.
[0179] These measures have been used for comparisons of the in
vitro performance of different inhaler device and drug
combinations. In general, the higher the fine particle fraction;
the higher the proportion of the emitted dose that is likely to
reach the lung.
[0180] There are two main methods used to measure aerosol
deposition in the lungs. First, .gamma.-scintigraphy is performed
by radiolabeling the drug with a substance like 99m-technetium, and
scanning the subject after inhalation of the drug. This technique
has the advantage of being able to quantify the proportion of
aerosol inhaled by the patient, as well as regional distribution in
the upper airway and lungs. Second, since most of the drug
deposited in the lower airways will be absorbed into the
bloodstream, pharmacokinetic techniques are used to measure lung
deposition (deposited lung dose). This technique can assess the
total amount of drug that interacts with the airway epithelium and
is absorbed systemically, but will miss the small portion that may
be expectorated or swallowed after mucociliary clearance, and
cannot tell us about regional distribution. Therefore,
.gamma.-scintigraphy and pharmacokinetic studies are in many cases
considered complementary.
[0181] The relationship between pulmonary deposition of inhaled
.beta.2-agonists and therapeutic effect is now well-established,
since the immediate effects of these agents on the airways are
relatively easy to measure. As the pulmonary dose-response curve
for the .beta.2-agonists is sigmoidal (i.e. an initial slope
followed by a plateau), increasing the dose deposited in the lung
will elicit an increased therapeutic effect only if the initial
dose was on the rising slope of the dose-response curve.
[0182] Lung deposition of a particular drug is influenced by the
mass of drug contained in the nebulized droplets administered to a
patient with a particular Mass Median Aerodynamic Diameter (MMAD)
and Geometric Standard Deviation (GSD). In general, there is an
inverse relationship between the average MMAD and GSD of a
particular nebulizer's emitted droplets and deposition of the
droplets in a patient's lung. A smaller MMAD results in an
increased likelihood of lung deposition in a patient. When the MMAD
is in the range of about 3.0-4.5 .mu.m, a narrower GSD results in a
higher degree of lung deposition, since a higher percentage of
particles will be under 5 .mu.m in diameter. It is believed that,
in general, aerosol particles greater than .about.10 .mu.m in
aerodynamic diameter deposit primarily in the oropharynx and are
swallowed rather than reaching the lungs. Because of the plausible
link between MMAD and GSD values and eventual deposition site
within the respiratory tract, smaller MMAD and GSD values may
affect both the safety (by reducing non-pulmonary deposition and
possibly thereby, reducing local and potentially systemic effects)
and the efficacy (by increasing the amount of drug actually
deposited in the lungs) of drug products administered with such
high efficiency inhalation devices. Cascade impaction and
laser-diffraction provides for an in vitro method of determining
MMAD (or MMD) and GSD data, which can then be plotted onto what
usually results in a log-normal shaped curve (depicting mass
distribution % on the Y-axis and droplet diameter on the X-axis).
Laser-diffraction methods are well-known to one of ordinary skill
in the art. In addition to laser-diffraction methods, in vitro data
for MMAD and GSD can also be measured using cascade impaction or
time-of-flight analytical methods, both of which are known to one
of ordinary skill in the art.
[0183] Geometric Standard Deviation (GSD) is a dimensionless
measure of dispersion from a geometric mean, such as the MMAD. In
general, the smaller the GSD for a particular particle size
distribution, the narrower the distribution curve. In some
embodiments, administration of the muscarinic antagonist with the
high efficiency nebulizer provides a GSD of emitted droplet size
distribution of the solution administered with a high efficiency
nebulizer of about 1.1 to about 2.1, about 1.2 to about 2.0, about
1.3 to about 1.9, less than about 2, at least about 1.4 to about
1.8, at least about 1.5 to about 1.7, about 1.4, about 1.5, or
about 1.6. In some embodiments, administration of API with a high
efficiency nebulizer provides a Mass Median Aerodynamic Diameter
(MMAD) of droplet size of the solution emitted with the high
efficiency nebulizer of about 1 .mu.m to about 5 .mu.m, about 2 to
about 4 .mu.m, about 3 to about 4 .mu.m, or about 3.5 to about 4.5
.mu.m.
[0184] Respirable Fraction (RF), Emitted Dose (ED) or Delivered
Dose (DD), Respirable Dose (RD), and the Respirable Dose Delivery
Rate (RDDR) are in vitro-derived (calculated) parameters that
provide technical dimensions for the efficiency of a nebulizer
inhalation device. RF, which is measured with a cascade impactor or
laser diffraction apparatus, is a generally accepted estimate
within the medical community of the fraction, which may be
expressed as a percentage, of drug that is available for lung
deposition. Droplets of less than 5.0 .mu.m in diameter are
considered to penetrate to the lung and can be defined as "RF<5
.mu.m" (i.e. fine particle fraction (FPF)). In some embodiments,
administration of the muscarinic antagonist with a high efficiency
nebulizer provides a respirable fraction (RE) of API of at least
about 60%, at least about 65%, at least about 70%, at least about
75%, at least about 80%, at least about 85%, at least about 90%,
about 60% to about 95%, about 65% to about 95%, or about 70% to
about 90%. In some embodiments, the high efficiency nebulizer is
characterized by an RF of at least about 80% or about 70% to about
90%.
[0185] The Emitted Dose (ED), or Delivered Dose (DD), of drug
administered to a patient is the portion of volume of liquid filled
into the nebulizer, i.e. the fill volume, which is actually emitted
from the mouthpiece of the device. The difference between the
nominal dose and the ED is the amount of volume lost primarily to
residues, i.e. the amount of fill volume remaining in the nebulizer
after administration, or is lost in aerosol form. The ED of the
muscarinic antagonist is to be tested under simulated breathing
conditions using a standardized bench setup, which are known to one
of skill in the art. In some embodiments, the ED of the muscarinic
antagonist of the present invention is at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55%, at least about 60%, about 30% to about
60%, about 30% to about 55%, about 30% to about 50%, about 30% to
about 40%, about 30% to about 75%, about 40% to about 70%, or about
45% to about 60%. The Respirable Dose (RD) is an expression of the
delivered mass of drug contained within emitted droplets from a
nebulizer that are small enough to reach the lung of a patient. The
RD is determined by multiplying the ED by the RF, and can be
readily determined using the respective ED and RE values provided
herein.
[0186] The output rate is the speed at which API is administered
from the inhalation device. In some embodiments, administration of
the muscarinic antagonist with the high efficiency nebulizer
provides an output rate of API of at least about 2 times, 3 times
or 4 times the output rate achievable with a conventional
nebulizer. For example, where the muscarinic antagonist is
glycopyrrolate, in some embodiments the output rate is at least
about 120 .mu.g/min, at least about 150 .mu.g/min, at least about
200 .mu.g/min or at least about 200 .mu.g/min to at least about
5,000 .mu.g/min. In some embodiments, administration of
glycopyrrolate with the high efficiency nebulizer provides an
output rate of API of at least about 120 .mu.L/min, at least about
150 .mu.L/min, at least about 200 .mu.L/min or at least about 200
.mu.L/min to at least about 5,000 .mu.L/min.
[0187] The Respirable Dose Delivery Rate (RDDR) is the speed at
which a respirable dose of the drug is nebulized, administered, and
delivered to a patient's lungs. RDDR, measured as a function of
.mu.g/min, is determined by dividing the RD (in .mu.g) by the
amount of time necessary for inhalation. The amount of time
necessary for inhalation is measured as the amount of time from the
first moment of administration of the emitted droplet from the
nebulizer until the emitted droplet of respirable diameter is
delivered to the lung, as measured using a standardized bench setup
simulating breathing conditions. In some embodiments,
administration of the muscarinic, antagonist to the patient with
the high efficiency nebulizer provides a respirable dose delivery
rate (RDDR) of at least about 2 times, 3 times or 4 times the
delivery rate achievable with a conventional nebulizer. Where the
muscarinic antagonist is glycopyrrolate, in some embodiments the
RDDR is at least about 100 .mu.g/min, at least about 150 .mu.g/min,
at least about 200 .mu.g/min, about 100 .mu.g/min to about 5,000
.mu.g/min, about 150 .mu.g/min to about 4,000 .mu.g/min or about
200 .mu.g/min to about 3,500 .mu.g/min. In some embodiments,
administration of the glycopyrrolate to the patient with an aqueous
inhalation device provides an RDDR of at least about 100 .mu.g/min
or about 100 .mu.g/min to about 5,000 .mu.g/min.
EXAMPLES
[0188] The following ingredients, processes and procedures for
practicing the systems and methods disclosed herein correspond to
that described above. The procedures below describe some
embodiments of methods of delivery of a nebulized long-acting
cholinergic antagonist aqueous solution (as a monotherapeutic
agent), or in combination with a nebulized .beta.2-adrenoceptor
aqueous solution (in combination therapy) as described herein and
pharmacokinetic profiles thereof. Methods, materials, or excipients
which are not specifically described in the following examples are
within the scope of the invention and will be apparent to those
skilled in the art with reference to the disclosure herein.
Example 1: Single-Dose, Dose Escalation Study to Assess
Glycopyrrolate Inhalation Solution (GIS) Using a High Efficiency
Nebulizer in Patients with COPD
[0189] Objectives:
[0190] The objectives of the study were as follows: Primary: To
assess the safety and tolerability of single ascending doses of
glycopyrrolate inhalation solution when administered using a high
efficiency nebulizer in patients with COPD. Secondary: (1) To
assess and to compare the magnitude and duration of bronchodilator
response in patients with COPD following single doses of
glycopyrrolate inhalation solution when administered using a high
efficiency nebulizer and a conventional jet nebulizer; and (2) To
assess the pharmacokinetic (PK) profile of an inhaled
glycopyrrolate solution formulation.
[0191] Methodology:
[0192] This two part study was a two-center, single dose,
dose-escalation study in patients with COPD of 40-75 years of age.
There were 12 subjects included in the study.
[0193] Part 1 was an open label study to assess the safety,
tolerability, PK profile and bronchodilator response following
single doses of glycopyrrolate inhalation solution when
administered via a high efficiency nebulizer. Subjects were studied
in two cohorts in parallel. Prior to treatment, subjects received a
thorough medical examination (Screening Visit). A Treatment Period
consisted of two doses of glycopyrrolate inhalation solution being
administered in the first cohort in a dose-escalation manner at two
separate visits (Treatment Visits), and three doses being
administered in the second cohort in three separate visits
(Treatment Visits), with a washout period of 5 to 12 days between
doses for both cohorts. After identifying an effective dose of
glycopyrrolate inhalation solution that provided 24 hours of
bronchodilation when using a high efficiency nebulizer in Part 1,
all subjects entered Part 2 of the study and received, in a
randomized, double-blind manner, a single dose of either
glycopyrrolate inhalation solution (as determined in Part 1) or
placebo via a conventional jet nebulizer. The high efficiency
nebulizer tested was the eFlow.RTM. (PARI, Germany). The
conventional jet nebulizer tested was a DeVilbiss 800D.
[0194] Study procedures during each Treatment Period included
serial spirometry (including FEV.sub.1, FVC and PEFR) pre-dose and
immediately following dosing (within 5 minutes) and 15, 30 60, 90
minutes and 2, 4, 6, 8, 10, 12, 15, 23, 24, 27, and 30 hours
post-dose. Blood samples were obtained to determine plasma GP
concentrations at pre-dose and 5, 15, 30, 45 minutes and 1, 2, 4,
6, 8 and 12 hours post-dose. Vital signs and 12-lead
electrocardiogram were obtained at pre-dose and 30 and 60 minutes
and 2, 4, 8, 12, 24 and 30 hours post-dose. Clinical labs were done
at the Screening Visit and within 7 days following the last study
treatment (Safety Follow-up Visit).
[0195] Study Treatments, Dose and Mode of Administration:
[0196] Part 1 (n=12): Subjects were randomly allocated to one of 2
cohorts running in parallel.
[0197] Cohort 1 (n=6): 1. Glycopyrrolate inhalation solution (GIS)
25 .mu.g/0.5 mL oral inhalation via eFlow; 2. GIS 200 .mu.g/0.5 mL
oral inhalation via eFlow.
[0198] Cohort 2 (n:=6): 1. GIS 75 .mu.g/0.5 mL oral inhalation via
eFlow; 2. GIS 500 .mu.g/0.5 mL oral; 3. GIS 1000 .mu.g/0.5 mL oral
inhalation via eFlow.
[0199] Part 2 (n=12): All subjects who participated in Part 1 were
included. Glycopyrrolate inhalation solution (200 mcg (.mu.g) dose
(selected from Part 1) or placebo in 2 mL solution formulation via
the conventional jet nebulizer.
[0200] Assessments
[0201] The primary efficacy variable was serial spirometry
throughout the 36 hour period after dosing. The spirometry
assessments include forced expiratory volume in one second
(FEV.sub.1), forced vital capacity (FVC), peak expiratory flow rate
(PEFR), FEV.sub.1% of predicted normal.
[0202] The PK parameters to be evaluated for plasma glycopyrrolate
are maximum concentration (C.sub.max), time to maximum
concentration (T.sub.max), terminal elimination half-life
(T.sub.1/2), area under the plasma concentration-time curve from
time=0 to time of last measurable drug concentration (AUC.sub.0-t),
and area under the plasma concentration-time curve from time=0 to
infinity (AUC.sub.0-inf).
[0203] Safety parameters include adverse events (AEs) including
assessment of dry mouth, and changes in vital signs, 12-lead ECG
(including QTc interval), and clinical laboratory tests.
[0204] The results are summarized in Table 1-1 and in FIG. 1
through FIG. 8.
[0205] In part 1, subjects in Cohort 1 received 25 .mu.g and, after
the washout period, 200 .mu.g of glycopyrrolate with the high
efficiency nebulizer, while Cohort 2 received 75 .mu.g, 500 .mu.g
and 1000 .mu.g doses of glycopyrrolate separated by washout
periods. Based on the results of part 1, 200 .mu.g of
glycopyrrolate was chosen as the comparator for carrying into part
2 of the study.
[0206] In part 2, the two cohorts were randomized to a placebo
group and an "active" group. The placebo group received normal
saline and the "active" group received 200 .mu.g of glycopyrrolate,
both via the conventional jet nebulizer. The results of this study
are depicted in the line graph in FIG. 3, where the 200 .mu.g
eFlow.RTM. high efficiency nebulizer results are also depicted for
comparison. As can be seen in FIG. 3, the 200 .mu.g dose of
glycopyrrolate administered with the conventional jet nebulizer did
not provide clinically meaningful improvement in FEV.sub.1 at 12
hours and beyond, whereas the same dose administered with the high
efficiency nebulizer provided clinically relevant improvements in
FEV.sub.1 up to and beyond the 24 hour time point. Also, the
glycopyrrolate dose administered with the high efficiency nebulizer
provided a mean improvement in peak lung function (peak FEV.sub.1)
of about 45 mL compared to the same glycopyrrolate dose
administered in the conventional jet nebulizer,
[0207] FIG. 4 is a graph comparing lung function response (FEV1%
change from baseline) over a time course of 30 hours for 200 .mu.g
of glycopyrrolate administered with a high efficiency nebulizer
(left-most bar at each time point), 200 .mu.g of glycopyrrolate
administered with the conventional jet nebulizer (right-most bar at
each time point), and placebo (saline) administered with the
conventional jet nebulizer (middle bar at each time point). The
glycopyrrolate dose administered with the high efficiency nebulizer
provided improvement in lung function of greater than 10% in FEV1
above baseline at the 24 hour time point, whereas the same dose
administered with the conventional jet nebulizer failed to achieve
an increase in FEV1 above baseline greater than 10% at the 12 hr
time point and beyond.
[0208] As shown in FIG. 1, which is a bar graph comparing the mean
placebo-adjusted 24-hour (trough) change in FEV1 (L) for the 200
.mu.g dose of glycopyrrolate delivered via the high efficiency
nebulizer to the 200 .mu.g dose delivered via the conventional jet
nebulizer, the high efficiency nebulizer provided significantly
improved improvement in lung function at 24 hours
post-administration of glycopyrrolate. This is the first known
disclosure of a clinically meaningful improvement in lung function
greater than 12 hours for any solution formulation of
glycopyrrolate at any dose.
[0209] Administration of glycopyrrolate with a high efficiency
nebulizer provides prolonged efficacy across a broad dosage range.
As can be seen in FIG. 2, which is a graph comparing the mean
placebo-adjusted 24-hour (trough) FEV1 (L) obtained by
administering 25 .mu.g, 75 .mu.g, 200 .mu.g, 500 .mu.g and 1000
.mu.g of glycopyrrolate with a high efficiency nebulizer (left 5
bars) and 200 .mu.g with the conventional jet nebulizer (right
bar), the high efficiency nebulizer provided significant
improvement in lung function compared to baseline at 24 hours
post-administration of glycopyrrolate for each of 75 .mu.g, 200
.mu.g, 500 .mu.g and 1000 .mu.g glycopyrrolate doses. There is no
known teaching in the art that administration of a drug with a high
efficiency nebulizer will result in greater duration of
efficacy.
[0210] Another measure of improved lung function is the baseline-
and placebo-adjusted area under the FEV.sub.1 change curve from
0-24 hours (FEV.sub.1AUC.sub.0-24). FIG. 5 compares the area under
the FEV.sub.1 change (L, above baseline) curve from 0-24 hours
(FEV.sub.1 AUC.sub.0-24) obtained by administering 25 .mu.g, 75
.mu.g, 200 .mu.g, 50 .mu.g and 1000 .mu.g of glycopyrrolate with a
high efficiency nebulizer (left 5 bars); and placebo and 200 .mu.g
of glycopyrrolate with the conventional jet nebulizer (right 2
bars). The FEV.sub.1 AUC.sub.0-24 results are shown in units of
Lhr. As can be seen in FIG. 5, glycopyrrolate delivered with a high
efficiency nebulizer produced significantly improved lung function
over the period from 0-24 hours.
[0211] FIG. 6 is a graph comparing the area under the FEV.sub.1
change (L, above baseline) curve from 0-12 hours (AUC.sub.0-12 hrs)
obtained by administering 25 .mu.g, 75 .mu.g, 200 .mu.g, 500 .mu.g
and 1000 .mu.g of glycopyrrolate with a high efficiency nebulizer
(left 5 bars); and placebo and 200 .mu.g of glycopyrrolate with a
conventional jet nebulizer (right 2 bars). The AUC.sub.0-12 results
are shown in Lhr. The FEV.sub.1 AUC values for the 25 .mu.g dose
delivered by the high efficiency nebulizer achieved a similar
robust magnitude of FEV.sub.1 improvement as the dose delivered by
the conventional jet nebulizer over the first 12 hours
post-administration. The FEV.sub.1 AUC values for the 75 .mu.g, 200
.mu.g, 500 .mu.g and 1000 .mu.g of glycopyrrolate delivered with a
high efficiency nebulizer were significantly higher compared to the
FEV.sub.1 AUC value for the 200 .mu.g dose delivered with the
conventional jet nebulizer.
[0212] The improved duration of therapeutic activity of
glycopyrrolate administered with a high efficiency nebulizer, as
compared to the conventional jet nebulizer, can best be observed in
FIG. 7, which compares the area under the FEV.sub.1 change (L,
above baseline) curve from 12-24 hours (AUC.sub.12-24) obtained by
administering 25 .mu.g, 75 .mu.g, 200 .mu.g, 500 .mu.g and 1000
.mu.g of glycopyrrolate with a high efficiency nebulizer (left 5
bars); and placebo and 200 .mu.g of glycopyrrolate with a
conventional jet nebulizer (right 2 bars). The FEV.sub.1
AUC.sub.12-24 results are shown in units of Lhr. As can be seen in
FIG. 7, at every glycopyrrolate dose tested, the improvement in
lung function with glycopyrrolate administered with a high
efficiency nebulizer was significantly greater between 12 and 24
hours than with the dose of glycopyrrolate administered with the
conventional jet nebulizer.
[0213] In order to better understand the mechanism by which
administration of glycopyrrolate with a high efficiency nebulizer
improves lung function, blood plasma concentration levels of
glycopyrrolate were obtained for the 200 .mu.g high efficiency
nebulizer and 200 .mu.g conventional nebulizer study arms. Table
1-3 summarizes the pharmacokinetic (PK) measurements obtained. FIG.
8 is a line graph comparing glycopyrrolate blood plasma
concentrations during the first two hours after administration of
200 .mu.g glycopyrrolate with a high efficiency nebulizer (upper
line) and 200 .mu.g glycopyrrolate with the conventional jet
nebulizer (lower line). As can be seen in FIG. 8, in addition to
exhibiting a later Tmax and a considerably higher Cmax, the high
efficiency nebulizer (HEN) arm also exhibited significantly longer
elimination. Without wishing to be bound by theory, it appears that
this may be evidence of a depot effect, whereby the enhanced
deposition of glycopyrrolate in the lungs, and particularly in the
periphery of a diseased COPD lung which is characterized by poor
mucociliary clearance, may result in prolonged duration of
bronchodilation.
[0214] One property of administration of glycopyrrolate with a high
efficiency nebulizer is an enhancement in glycopyrrolate blood
plasma AUC relative to Cmax. As can be seen in Table 1-1, the ratio
of AUC/Cmax for glycopyrrolate administered with a high efficiency
nebulizer is much greater than the AUC/Cmax for glycopyrrolate
administered with the conventional jet nebulizer. Achievement of a
AUC/Cmax ratio greater than 0.5 hrs, or 1 hr, or 1.5 hrs, or 2 hrs
in combination with a total AUC.sub.0-4 greater than 100 .mu.g/mLh,
or 200 .mu.g/mLh is believed to be important for achievement of a
24 hour duration of activity for a solution formulation of
glycopyrrolate.
TABLE-US-00001 TABLE 1-1 PK Values for Administration of
Glycopyrrolate with High Efficiency and Conventional Jet Nebulizers
Pharmacokinetic High Efficiency Conventional Value Nebulizer 200
.mu.g Nebulizer 200 .mu.g Cmax 177 pg/mL 76 pg/mL Tmax 11.6 min 8.2
min AUC.sub.(0-t) 429 pg/mL h 26 pg/mL h AUC.sub.(0-inf) 615 pg/mL
h 70 pg/mL h Cmax/AUC.sub.(0-t) 0.41/h 2.92/h AUC.sub.(0-t)/Cmax
2.42 h 0.35 h t 1/2 4.1 h 0.9 h t 1/2.sub.(0-60 min) 72 min 46
min
[0215] As can be seen in Table 1.1, the Tmax is longer (about 12
min. vs about 8 min.) for glycopyrrolate when administered with the
high efficiency nebulizer than with the conventional jet nebulizer,
demonstrating a slower elimination of glycopyrrolate from the
lung/airway compartment into the systemic blood when using the high
efficiency nebulizer. Additional evidence of a slower elimination
of glycopyrrolate from the lung/airway compartment when delivered
by a high efficiency nebulizer is that, for the first 60 minutes
post-dosing, the plasma elimination half-life of glycopyrrolate was
much greater (prolonged) as compared to administration of the same
dose with a conventional jet nebulizer (72 min. vs 46 min.).
Example 2: Randomized, Double-Blind, Placebo-Controlled Cross-Over,
Single Dose Study
[0216] At least about thirty (30) adult human COPD patients of ages
>45 years are randomized to one of six treatment groups: (1) 2.5
.mu.g glycopyrrolate administered with a high efficiency nebulizer;
(2) 50 .mu.g of glycopyrrolate administered with a high efficiency
nebulizer; (3) 100 .mu.g of glycopyrrolate administered with a high
efficiency nebulizer; (4) 200 .mu.g of glycopyrrolate administered
with a high efficiency nebulizer; (5) 500 .mu.g of glycopyrrolate
administered with a high efficiency nebulizer; (6) placebo
administered with a high efficiency nebulizer.
[0217] Lung function is determined by spirometry, which measures
e.g. FEV.sub.1 and other suitable spirometry parameters. Spirometry
is conducted immediately before and at predetermined intervals
following administration of the glycopyrrolate to the patients.
Additionally, the patients will be monitored for any adverse
events, as well as for vital signs and electrocardiogram.
[0218] A goal of this study is to verify that glycopyrrolate
administered to human patients with a high efficiency nebulizer at
the tested doses produces in a patient or population of patients a
therapeutic effect (i.e. at least one spirometry measurement, e.g.
trough FEV.sub.1, is at least 10% above baseline for a significant
period of time, e.g. at least 24 hours.)
[0219] Another goal of this study is to verify that glycopyrrolate
administered to human patients with a high efficiency nebulizer
produces in a patient or population of patients a suitable adverse
event profile.
Example 3: Aerosol Characterization of Glycopyrrolate Inhalation
Solution in a High Efficiency Nebulizer and a Conventional Jet
Nebulizer
Objective
[0220] The object of the study was to determine and compare the
drug delivery efficiency of two different nebulizer systems, a high
efficiency nebulizer and a conventional jet nebulizer, using a
glycopyrrolate inhalation solution (GIS). Droplet size and
respirable fraction of the aerosol were measured by laser
diffraction, while delivered dose, nebulization time and nebulizer
residue were assessed by breath simulation using a standard adult
breathing pattern.
Summary
[0221] Two different nebulizers were characterized by laser
diffraction and breath simulation. An innovative new vibrating
membrane, high efficiency nebulizer (PARI eFlow.RTM. 30 L), and a
commonly used conventional jet nebulizer (DeVilbiss 800D). 12 laser
diffraction and 12 breath simulation experiments in total were
carried out. The parameters of DD, nebulization time, MMD, GSD,
RD<5 .mu.m and RDDR were determined upon these measurements.
[0222] The high efficiency nebulizer generated droplets of a mass
median diameter (MMD) of around 3.5 .mu.m and a geometric standard
deviation (GSD) of 1.55 compared to the MMD and GSD obtained from
the conventional jet nebulizer (3.6 .mu.m, 2.94).
[0223] To determine the delivered dose (DD), breath simulator
experiments were performed with an adult breathing pattern.
[0224] The respirable dose (RD) is calculated by multiplying the
DI), obtained in breath simulation experiments, by the percentage
of aerosol particles less than 5 .mu.m (RD<5 .mu.m) determined
by laser diffraction.
[0225] Materials and Methods
[0226] The drug formulation was a 2 mg/mL, glycopyrrolate solution
(GIS). This solution was tested at the following quantities (mg)
and volumes (mL): High efficiency nebulizer @ 1 mg/0.5 mL, and
conventional jet nebulizer @ 4 mg/2 mL.
[0227] Breath simulation tests were conducted and a breath
simulator with adult breathing pattern was conducted (500 mL tidal
volumes, 15 breaths/min, inhalation/exhalation ratio 50:50).
[0228] The nebulizers were equipped with expiratory filters and
connected via an inspiratory filter to the breathing simulator. The
inspiratory filter was changed after the first minute, the second
filter remained until the end of nebulization. The end of the
nebulization was reached for the high efficiency nebulizer when the
nebulizer switched off automatically; for the jet nebulizer, the
end of nebulization was achieved one minute after sputtering
began.
[0229] Laser diffraction was used to assess the geometric droplet
size distribution with a Malvern MasterSizerX.RTM. laser
diffraction measurement device. Airflow was 15 L/min.+-.0.1 L/min;
temperature was 23.degree. C..+-.2.degree. C.; relative humidity
was 50%.+-.5%. The parameters obtained with laser diffraction were:
mass median diameter of the droplets (MMD), respirable fraction
(RF), geometric standard deviation (GSD), and total output rate
(TOR).
[0230] The calculated parameters were respirable dose (RD) and
respirable drug delivery rate (RDDR).
[0231] The results of this in vitro aerosol characterization are
presented in Table 5-1.
TABLE-US-00002 TABLE 5-1 In vitro aerosol characterization of a
high efficiency nebulizer and a conventional jet nebulizer. High
Efficiency Conventional Jet Nebulizer Nebulizer MMD/MMAD 3.5 .mu.m
3.6 .mu.m GSD 1.6 .mu.m 2.9 .mu.m DD 66% 11% RF < 5 .mu.m 80%
67% RD < 5 .mu.m 52.6% 7.5% RDDR < 5 .mu.m 39% 2%
CONCLUSION
[0232] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended, that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *
References