U.S. patent application number 14/002466 was filed with the patent office on 2014-03-20 for use of glycopyrrolate for treating tachycardia.
This patent application is currently assigned to SOSEI R&D LTD. The applicant listed for this patent is Susan Snape, Robert Tansley. Invention is credited to Susan Snape, Robert Tansley.
Application Number | 20140080890 14/002466 |
Document ID | / |
Family ID | 45841526 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140080890 |
Kind Code |
A1 |
Snape; Susan ; et
al. |
March 20, 2014 |
USE OF GLYCOPYRROLATE FOR TREATING TACHYCARDIA
Abstract
The invention relates to a novel use of the antimuscarinic agent
glycopyrrolate, for example the salt glycopyrronium bromide. In
particular, the invention relates to glycopyrrolate for use as a
heart rate lowering agent and more particularly, but not
exclusively, for use in patients suffering from respiratory
conditions such as chronic obstructive pulmonary disease.
Inventors: |
Snape; Susan;
(Cambridgeshire, GB) ; Tansley; Robert;
(Cambridgeshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Snape; Susan
Tansley; Robert |
Cambridgeshire
Cambridgeshire |
|
GB
GB |
|
|
Assignee: |
SOSEI R&D LTD
LONDON
UK
|
Family ID: |
45841526 |
Appl. No.: |
14/002466 |
Filed: |
March 5, 2012 |
PCT Filed: |
March 5, 2012 |
PCT NO: |
PCT/GB2012/050478 |
371 Date: |
November 6, 2013 |
Current U.S.
Class: |
514/424 ;
128/203.12; 128/203.15; 548/556 |
Current CPC
Class: |
A61P 11/00 20180101;
A61K 45/06 20130101; A61P 9/06 20180101; A61K 31/4704 20130101;
A61M 15/0028 20130101; A61P 9/00 20180101; A61M 15/009 20130101;
A61M 15/0045 20130101; A61P 43/00 20180101; A61K 9/0075 20130101;
A61K 31/40 20130101; A61K 9/0078 20130101; A61M 2202/064 20130101;
A61K 31/167 20130101; A61K 31/40 20130101; A61K 2300/00 20130101;
A61K 31/167 20130101; A61K 2300/00 20130101; A61K 31/4704 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/424 ;
128/203.15; 128/203.12; 548/556 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 45/06 20060101 A61K045/06; A61M 15/00 20060101
A61M015/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 4, 2011 |
GB |
1103770.2 |
Feb 9, 2012 |
GB |
1202256.2 |
Claims
1-50. (canceled)
51. An inhalable pharmaceutical composition comprising
glycopyrrolate or a pharmaceutically acceptable salt thereof for
use as a heart rate lowering agent, or for use as a heart rate
suppression agent under resting conditions.
52. An inhalable unit dose comprising the pharmaceutical
composition as defined in claim 51 for use in the treatment or
prophylaxis of tachycardia.
53. The unit dose as defined in claim 52, which comprises a
capsule.
54. The unit dose as defined in claim 52, wherein the unit dose
comprises a capsule made with hypromellose (HPMC) or another
cellulose or cellulose derivative.
55. An inhalation delivery device comprising one or more unit doses
as defined in claim 52 for use in the treatment or prophylaxis of
tachycardia.
56. The delivery device as defined in claim 55, wherein the
delivery device is an inhaler.
57. The delivery device as defined in claim 56, wherein the
delivery device is a dry powder inhaler, a pressurized metered dose
inhaler, or a nebulizer.
58. The delivery device as defined in claim 57, wherein the device
comprises means for protecting the composition from moisture.
59. A pharmaceutical composition as defined in claim 51, contained
in a package which further comprises instructions for administering
said composition to a patient in need of a heart rate lowering
agent, or in anticipation of the need of a heart rate lowering
agent.
60. The pharmaceutical composition according to claim 59, wherein
the instructions are for administering said composition to a
patient suffering from tachycardia or in need of prophylaxis of
tachycardia.
61. A method of treatment or prophylaxis of a condition or disorder
characterised by an increased heart rate, said method comprising
administering to a patient in need of such treatment or
prophylaxis, an effective amount of an inhalable pharmaceutical
composition comprising glycopyrrolate or a pharmaceutically
acceptable salt thereof.
62. The method according to claim 61, wherein the composition is
administered to a patient suffering from a respiratory condition
selected from chronic obstructive pulmonary disease (COPD), asthma,
cystic fibrosis (CF) and related airway diseases.
63. The method, according to claim 62, wherein the patient has
COPD.
64. The method, according to claim 61, wherein the patient has
tachycardia that has been pharmaceutically induced.
65. The method, according to claim 64, wherein the tachycardia has
been induced by administration of salbutamol.
66. The method, according to claim 61, wherein the patient has
tachycardia that is induced by an endocrine disorder.
67. The method, according to claim 61, wherein the patient has a
form of tachycardia selected from the group consisting of
ventricular tachycardia, supraventricular tachycardia, atrial
fibrillation, AV nodal reentrant tachycardia (AVNRT), AV reentrant
tachycardia (AVRT) and junctional tachycardia.
68. The method, according to claim 61, wherein the patient has a
resting heart rate of greater than 90 beats per minute.
69. The method, according to claim 61, wherein the glycopyrrolate
or a pharmaceutically acceptable salt thereof comprises
glycopyrronium bromide.
70. The method, according to claim 61, wherein glycopyrrolate is
present within the composition in an amount of between 10 and 500
pg.
71. The method, according to claim 70, wherein glycopyrrolate is
present within the composition in an amount of 20 pg.
72. The method, according to claim 70, wherein glycopyrrolate is
present within the composition in an amount of 400 pg.
73. The method according to claim 61, wherein the glycopyrrolate is
administered once daily.
74. The method, according to claim 61, wherein the pharmaceutical
composition is formulated as a dry powder formulation.
75. The method, according to claim 61, wherein the composition
additionally comprises a force control agent.
76. The method, according to claim 75, wherein the force control
agent comprises a metal stearate, or a derivative thereof.
77. The method, according to claim 76, wherein the force control
agent comprises zinc stearate, magnesium stearate, calcium
stearate, sodium stearate or lithium stearate.
78. The method, according to claim 77, wherein the force control
agent comprises magnesium stearate.
79. The method, according to claim 61, wherein the composition
further comprises lactose.
80. The method, according to claim 79, wherein the composition
comprises 1% (w/w) glycopyrronium bromide and 99% (w/w)
lactose.
81. The method, according to claim 79, wherein the composition
comprises 1.05% (w/w) glycopyrronium bromide, 98.8% (w/w) lactose
and 0.15% (w/w) magnesium stearate, or 1% (w/w) glycopyrronium
bromide, 98.8% (w/w) lactose and 0.2% (w/w) magnesium stearate.
82. The method, according to claim 61, wherein the composition
further comprises indacateral.
83. The method, according to claim 61, wherein the composition
further comprises a beta agonist.
84. The method, according to claim 61, wherein the patient is
receiving concomitant treatment with a beta agonist.
Description
FIELD OF THE INVENTION
[0001] The invention relates to a novel use of the antimuscarinic
agent glycopyrrolate, for example the salt glycopyrronium bromide.
In particular, the invention relates to glycopyrrolate for use as a
heart rate lowering agent and more particularly, but not
exclusively, for use in patients suffering from respiratory
conditions such as chronic obstructive pulmonary disease.
BACKGROUND OF THE INVENTION
[0002] Tachycardia is a type of arrhythmia which presents with a
high heart rate, typically above 100 for an adult. The disorder
results in a speeding of normal heart rhythm which is known as
sinus tachycardia and which may be brought about by a number of
factors, such as exercise, anemia, fever, anxiety, pregnancy or
drugs. Alternatively, sinus tachycardia may be caused by an
underlying pathological condition as a result of an arrhythmia.
[0003] An electrocardiogram (ECG) is typically used to classify the
type of arrhythmia. Tachycardias may be classified as either narrow
complex tachycardias (supraventricular tachycardias) or wide
complex tachycardias. Narrow and wide refer to the width of the QRS
complex on the electrocardiogram (ECG). Narrow complex tachycardias
tend to originate in the atria, while wide complex tachycardias
tend to originate in the ventricles. Tachycardias can be further
classified as either regular or irregular.
[0004] Ventricular tachycardia (VT or V-tach) is a potentially
life-threatening cardiac arrhythmia that originates in the
ventricles. It is usually a regular, wide complex tachycardia with
a rate between 120 and 250 beats per minute. Ventricular
tachycardia has the potential of degrading to the more serious
ventricular fibrillation. Ventricular tachycardia is a common, and
lethal, complication of a myocardial infarction (heart attack).
[0005] Supraventricular tachycardia is a type of tachycardia that
originates from above the ventricles.
[0006] Examples of narrow complex tachyarrhythmias include: atrial
fibrillation, atrial flutter, AV nodal reentrant tachycardia,
accessory pathway mediated tachycardia, atrial tachycardia,
multifocal atrial tachycardia and junctional tachycardia.
[0007] Atrial fibrillation is one of the most common cardiac
arrhythmias. It is generally an irregular, narrow complex rhythm.
However, it may show wide QRS complexes on the ECG if bundle branch
block is present. It may be difficult to determine the rhythm's
regularity when the rate exceeds 150 beats per minute. Depending on
the patient's health and other variables such as medications taken
for rate control, atrial fibrillation may cause heart rates that
span from 50 to 200 beats per minute (or even higher if an
accessory pathway is present). However, new onset atrial
fibrillation tends to present with rates between 100 and 150 beats
per minute.
[0008] AV nodal reentrant tachycardia (AVNRT) is the most common
reentrant tachycardia. It is a regular narrow complex tachycardia
that usually responds well to the Valsalva manoeuvre or the drug
adenosine.
[0009] AV reentrant tachycardia (AVRT) requires an accessory
pathway for its maintenance. AVRT may involve orthodromic
conduction (where the impulse travels down the AV node to the
ventricles and back up to the atria through the accessory pathway)
or antidromic conduction (which the impulse travels down the
accessory pathway and back up to the atria through the AV node).
Orthodromic conduction usually results in a narrow complex
tachycardia, and antidromic conduction usually results in a wide
complex tachycardia that often mimics ventricular tachycardia.
[0010] Junctional tachycardia is an automatic tachycardia
originating in the AV junction. It tends to be a regular, narrow
complex tachycardia and may be a sign of digitalis toxicity.
[0011] Tachycardias resulting from a fast heart rate tend either to
be sinus tachycardia or an abnormal tachyarrhythmia, such as one
which is supraventricular or ventriculuar in origin. The primary
symptoms of sinus tachycardia may be perceived as palpitation. In
susceptible individuals, this sensation can even induce anxiety.
Typically, the symptoms of sinus tachycardia tend to be benign
unless the patient has coexistent pathology which is worsened by a
high heart rate, e.g. coronary ischaemia (angina), heart failure or
heart valve disease. This can then lead to breathlessness or chest
pain or in rare circumstances myocardial infarction, or acute on
chronic heart failure. Tachyarrythmias may cause dizziness,
fainting and black outs etc.
[0012] There is therefore a need for effective heart rate lowering
agents for use in the treatment of tachycardia disorders.
SUMMARY OF THE INVENTION
[0013] According to one aspect of the invention, there is provided
a pharmaceutical composition comprising glycopyrrolate or a
pharmaceutically acceptable salt thereof for use as a heart rate
lowering agent.
[0014] According to a further aspect of the invention, there is
provided an inhalable pharmaceutical composition comprising
glycopyrrolate or a pharmaceutically acceptable salt thereof for
use as a heart rate lowering agent.
[0015] According to a further aspect of the invention, there is
provided an inhalable unit dose comprising the pharmaceutical
composition as defined herein for use in the treatment or
prophylaxis of tachycardia.
[0016] According to a further aspect of the invention, there is
provided an inhalation delivery device comprising one or more unit
doses as defined herein for use in the treatment or prophylaxis of
tachycardia.
DETAILED DESCRIPTION OF THE INVENTION
[0017] According to one aspect of the invention, there is provided
a pharmaceutical composition comprising glycopyrrolate or a
pharmaceutically acceptable salt thereof for use as a heart rate
lowering agent.
[0018] Glycopyrrolate is an antimuscarinic agent which is useful in
the treatment of conditions such as chronic obstructive pulmonary
disease (COPD), asthma, cystic fibrosis (CF) and related airway
diseases. It is known to provide glycopyrrolate formulations in the
form of dry powder formulations, for administration using dry
powder inhalers. Frequently salts of glycopyrrolate are used, such
as glycopyrronium bromide.
[0019] The term "glycopyrrolate" as used in connection with the
invention is intended to encompass salt forms or counterion
formulations of glycopyrrolate, such as glycopyrrolate bromide, as
well as isolated stereoisomers and mixtures of stereoisomers.
Derivatives of glycopyrrolate are also encompassed.
[0020] It is well known that muscarinic antagonists such as
glycopyrronium bromide increase the heart rate within the normal
range and cause tachycardia (for example, see Markos and Snow
(2006) Acta Physiol (Oxf). 186(3), 179-84 inter alia). In addition,
the British National Formulary (BNF) indicates that transient
bradycardia (followed by tachycardia, palpitation and arrhythmias)
are one of the side-effects of antimuscarinics (BNF 62, September
2011, section 1.2). Muscarinic antagonists can also induce
pathological tachyarrythmias either de novo or, more commonly, in
patients with a propensity for tachyarrythmias.
[0021] Furthermore, such is the pronounced role of muscarinic
antagonists in causing tachycardic conditions, that one of the key
indications for glycopyrronium bromide is for intra-operative
bradycardia (i.e. treatment of a slow heart rate) (see BNF 62,
September 2011, section 15.1.3). Therefore, surprisingly, and in
contradistinction with the teaching of the prior art and accepted
medical literature, the inventors have identified that
glycopyrronium bromide is capable of lowering the heart rate as is
demonstrated in the data provided herein.
[0022] According to a further aspect of the invention, there is
provided an inhalable pharmaceutical composition comprising
glycopyrrolate or a pharmaceutically acceptable salt thereof for
use as a heart rate lowering agent.
[0023] Data are provided herein which surprisingly demonstrates
that glycopyrronium bromide administered by inhalation caused a
reduction in heart rate unlike other muscarinic antagonists which
are known to increase heart rate and cause conditions such as
tachycardia. Furthermore, although glycopyrronium bromide has
already been disclosed for the prevention of intra-operative
bradycardia (i.e. increase of a slow heart-rate) the medicament is
typically delivered by the intravenous route (see BNF 62, September
2011, section 15.1.3). Therefore, not only is the medicament of the
invention being applied for a different use to that described in
the literature, but the medicament is also being delivered by an
alternative route. Without being bound by theory, it is believed
that inhalation of the glycopyrronium bromide has the potential to
result in the heart rate lowering properties observed in the data
shown herein.
[0024] In one embodiment, the composition is used in the treatment
of a condition or disorder characterised by an increased heart rate
and where it would be preferable to reduce the heart rate, such as
tachycardia and preferably by inhalation.
[0025] It will be appreciated that the invention finds particular
utility in the treatment of a condition or disorder where it would
be preferable to reduce the heart rate. In addition, the invention
also finds particular utility in the prevention of an increase in
heart rate. Thus, in one embodiment, the composition is used as an
agent for preventing an increase in heart rate. Thus, according to
a further aspect of the invention, there is provided an inhalable
pharmaceutical composition comprising glycopyrrolate or a
pharmaceutically acceptable salt thereof for use as a heart rate
suppression agent (for example, under resting conditions) as
compared with intravenous glycopyrrolate administration or as
compared with placebo. In one embodiment, the use is in a patient
suffering from a respiratory condition, such as a condition
selected from: chronic obstructive pulmonary disease (COPD),
asthma, cystic fibrosis (CF) and related airway diseases. In one
embodiment, the heart rate remains suppressed over a period of at
least 0.75 hours, at least 1.5 hours, at least 5 hours, at least 10
hours, at least 20 hours or at least 30 hours. In one embodiment,
the heart rate remains suppressed over a period of from 0.75 hours
to 30 hours, from 1.5 hours to 30 hours, from 5 hours to 30 hours,
from 10 hours to 30 hours, from 20 hours to 30 hours.
[0026] The glycopyrrolate may be a salt, isomer or derivative of
glycopyrrolate, or mixtures thereof. In one embodiment, the
glycopyrrolate is not R,R-glycopyrrolate.
[0027] In one embodiment, the glycopyrrolate or a pharmaceutically
acceptable salt thereof comprises glycopyrronium bromide.
[0028] Glycopyrronium bromide (known as NVA-237) is a long-acting
muscarinic antagonist is due to be launched in 2012.
[0029] It will be appreciated that the invention finds particular
utility for the treatment of patients suffering from respiratory
conditions such as chronic obstructive pulmonary disease (COPD),
asthma, cystic fibrosis (CF) and related airway diseases who have
been identified as having a risk of, or being diagnosed with,
cardiac disorders which are likely to be worsened by an arrhythmia
characterised by a high heart rate, i.e. tachycardia.
[0030] Tachycardia refers to a faster than normal resting heart
rate where the heart rate of a resting or sleeping individual is
faster than it should be. In humans, the threshold of a normal
heart rate (pulse) is generally based on the person's age.
Tachycardia can be dangerous depending on how hard the heart has to
work. In general, the adult resting heart beats between 60 and 100
times per minute (some doctors place the healthy limit at 90). When
an individual has tachyarrythmia the upper or lower chambers of the
heart beat significantly faster--sometimes this happens to both
chambers. When the heart beats too rapidly, it pumps less
efficiently and blood flow to the rest of the body, including the
heart itself is reduced. The higher-than-normal heartbeat means
there is an increase in demand for oxygen by the myocardium (heart
muscle)--if this persists it can lead to myocardial infarction
(heart attack), caused by the dying off of oxygen-starved
myocardial cells. Some patients with tachycardia may have no
symptoms or complications. Tachyarrythmias in general can be
associated with an increased risk of stroke, sudden cardiac arrest
or death.
[0031] Mortality in COPD is more often due to cardiac rather than
respiratory causes (Chhabra and Gupta (2010) Indian Chest Dis
Allied Sci 52, 225-238). The coexistence of coronary artery disease
and COPD is frequent (33.6%; Falk et al (2008) Proc Am Thorac Soc
5(4), 543-548) but remains under-diagnosed. Both conditions share
several similarities including the age of the population affected,
a common risk factor in smoking and symptoms of exertional
dyspnoea. Both the conditions are punctuated by episodes of acute
exacerbations of symptoms from time to time where differentiation
between these two can be especially challenging. Although
coexistence of the two is common, more often, only one of the two
is diagnosed resulting in under-treatment and unsatisfactory
response. More specifically, tachycardia is a common symptom with
patients suffering from COPD and palpitation is a characteristic
symptom of tachycardia in COPD patients.
[0032] It is believed that patients with COPD tend to be prone to
arrhythmia because of hypoxia, associated infections, pulmonary
hypertension and structural changes to the heart, right ventricular
dilatation and/or atrial dilatation.
[0033] The incidence of different arrhythmias and associated
mortality varies widely in reported studies of patients with COPD,
as shown in the following studies of patients with stable disease
and acute exacerbations.
[0034] One study monitored 24 patients with severe COPD using
continuous electrocardiographic recording (Kleiger, R E, Senior, R
M. Chest 1974; 65:483). Arrhythmias were found in 84 percent of
stable ambulatory patients: 72 percent of patients had arrhythmias
of ventricular origin, while 52 percent had arrhythmias of
supraventricular origin. A separate but related study noted that a
reduced FEV1 (a marker of airway obstruction) is an independent
predictor of new onset atrial fibrillation in patients with stable
COPD (Buch, P, Friberg, 3, Scharling, H, et al. Eur Respir J 2003;
21:1012).
[0035] Similar results were noted in another report of 69 hypoxic
patients with severe but stable COPD (Shih, H T, Webb, C R, Conway,
W A, et al. Chest 1988; 94:44). Supraventricular tachycardia
occurred in 69 percent, while atrial fibrillation was the basic
rhythm in 8 percent. Premature ventricular beats (primarily
multiform) and nonsustained ventricular tachycardia were present in
83 percent and 22 percent of patients, respectively. Both leg edema
and hypercapnia, which are frequently present with cor pulmonale
complicating severe COPD, were associated with an increased risk of
ventricular arrhythmia. However, the presence of an arrhythmia was
not associated with increased mortality.
[0036] The third study evaluated 590 patients with an acute COPD
exacerbation (Fuso, L, Incalzi, R A, Pistelli, R, et al. Am J Med
1995; 98:272). Atrial fibrillation and ventricular arrhythmia were
independent predictors of death (in addition to age and a wide
alveolar-arterial oxygen gradient).
[0037] A further study evaluated 70 patients with severe COPD
admitted for acute respiratory failure (Hudson, L D, Kurt, T L,
Petty, T L, Genton, E. Chest 1973; 63:661). Forty-seven percent of
patients had both major supraventricular and ventricular
arrhythmias. In patients with acute respiratory failure, the
presence of arrhythmia may be associated with increased mortality
since no patient with ventricular arrhythmia survived beyond the
study period.
[0038] In a large cohort of 1429 patients with COPD who underwent
5226 Holter recordings, up to 40 percent of patients had atrial
tachycardias without ongoing treatment with long-acting beta
agonists (Hanrahan, J P, Grogan, D R, Baumgartner, R A, et al.
Medicine (Baltimore) 2008; 87:319).
[0039] More critically, studies have shown that resting tachycardia
is a key factor found to decrease survival (Burrows B, Earle R H.
Prediction of survival in patients with chronic airway obstruction.
Am Rev Respir Dis. 1969; 99:865-71).
[0040] Therefore, in one embodiment glycopyrrolate is used as a
heart rate lowering agent in a patient suffering from a respiratory
condition. In a further embodiment, glycopyrrolate is used as a
heart rate lowering agent in a patient suffering from a condition
selected from: chronic obstructive pulmonary disease (COPD),
asthma, cystic fibrosis (CF) and related airway diseases. In a yet
further embodiment, the glycopyrrolate is used as a heart rate
lowering agent in a patient suffering from chronic obstructive
pulmonary disease (COPD). Thus, according to a further aspect of
the invention there is provided an inhalable pharmaceutical
composition comprising glycopyrrolate for use as a heart rate
lowering agent in a patient suffering from a respiratory condition,
such as a condition selected from: chronic obstructive pulmonary
disease (COPD), asthma, cystic fibrosis (CF) and related airway
diseases, in particular chronic obstructive pulmonary disease.
[0041] It can be observed from the data presented herein that the
heart rate lowering effects were demonstrated in COPD patients
having resting heart rates averaging approximately 70 bpm.
Therefore, the invention finds particular utility in reducing the
likelihood of COPD patients developing any of the cardiac disorders
mentioned hereinbefore which may increase mortality rates, such as
coronary ischaemia (angina), heart failure or heart valve disease.
Thus, in one embodiment, the pharmaceutical composition is used in
the treatment or prophylaxis of tachycardia.
[0042] It will also be appreciated that the heart rate lowering
compositions of the invention may be administered to a COPD patient
already experiencing the cardiac effects mentioned hereinbefore.
Thus, in an alternative embodiment, the patient has a resting heart
rate of greater than 90 bpm, such as a resting heart rate of
greater than 100 bpm, in particular greater than 110 bpm, e.g.
greater than 120 bpm.
[0043] In one embodiment, glycopyrrolate is present within the
composition in an amount of greater than 1 .mu.g, such as between
10 and 500 .mu.g. When the composition is delivered by the inhaled
route, it will be appreciated that the amounts referred to herein
refer to the amount of medicament within the composition as opposed
to the amount actually delivered to the lungs of a patient. In a
further embodiment, glycopyrrolate is present within the
composition in an amount of between 20 and 400 .mu.g. In a yet
further embodiment, glycopyrrolate is present within the
composition in an amount of between 50 and 150 .mu.g, such as 50
.mu.g or 100 .mu.g. Data are presented herein (in Table 3
particularly) which shows that the most significant difference in
lowering of heart rate was observed at the dosage amount of 400
.mu.g, an effect which was reduced at the 30 hour time point.
Therefore, in a further embodiment, glycopyrrolate is present
within the composition in an amount of 400 .mu.g. By contrast, the
data presented herein (in Table 3 particularly) show that the
dosage amount of 20 .mu.g provided a more sustained lowering of
heart rate over the entire course of the study (i.e. 30 hours). For
example, -3.4 bpm at 10 hours, -3.6 bpm at 20 hours and -2.7 bpm at
30 hours. Therefore, in a further embodiment, glycopyrrolate is
present within the composition in an amount of 20 .mu.g.
[0044] In one embodiment, the pharmaceutical composition of the
invention is administered once daily. It can be seen from the data
presented herein (in Table 3 particularly) that the mean change in
heart rate from pre-dose to 20 hours (for all doses) and pre-dose
to 30 hours (for all doses other than 125 .mu.g and 250 .mu.g) was
significantly higher than placebo. These observations confirmed
that the inhaled glycopyrrolate provides a bradycardic effect which
is sustained over approximately 1 to 1.5 days. Certain observations
have been published which link glycopyrrolate with a slowing of the
heart rate (for example, see
http://www.Id99.com/reference/notes/text/Anticholinergic
drugs.html) which indicates that when administered intravenously,
glycopyrrolate can cause a paradoxical transient slowing of heart
rate before producing tachycardic effects by countering the
bradycardic effects of other agents. However, the data provided
herein confirm more than a mere "transient" bradycardic effect
(because the bradycardic effect was observed for as much as 30
hours) and, unlike intravenous administration, the subsequent
tachycardic effect is not evident in any of the inhaled doses.
[0045] In one embodiment, the pharmaceutical composition comprises
one or more pharmaceutically acceptable excipients.
[0046] It will be appreciated that glycopyrrolate is typically
administered for the treatment of chronic obstructive pulmonary
disease in the form of a dry powder formulation.
[0047] When the composition of the invention is formulated as a dry
powder formulation, in one embodiment the composition additionally
comprises a force control agent.
[0048] A force control agent is an agent which reduces the cohesion
between the fine particles within the powder formulation, thereby
promoting deagglomeration upon dispensing of the powder from the
dry powder inhaler.
[0049] Suitable force control agents are disclosed in WO 96/23485
and WO 2005/105043 and they typically consist of physiologically
acceptable material, despite the fact that the material may not
always reach the lung.
[0050] The force control agent may comprise or consist of one or
more compounds selected from amino acids and derivatives thereof,
and peptides and derivatives thereof, the peptides suitably having
a molecular weight from 0.25 to 1000 kDa.
[0051] Amino acids, peptides and derivatives of peptides are
physiologically acceptable and give acceptable release or
deagglomeration of the particles of active material on inhalation.
Where the force control agent comprises an amino acid, it may be
one or more of any of the following amino acids: leucine,
isoleucine, lysine, valine, methionine, and phenylalanine. The
force control agent may be a salt or a derivative of an amino acid,
for example aspartame or acesulfame K. The D- and DL-forms of amino
acids may also be used.
[0052] The force control agents may include one or more water
soluble substances. This helps absorption of the force control
agent by the body if it reaches the lower lung.
[0053] The force control agent may include dipolar ions, which may
be zwitterions. It is also advantageous to include a spreading
agent as a force control agent, to assist with the dispersal of the
composition in the lungs. Suitable spreading agents include
surfactants such as known lung surfactants (e.g. ALEC, Registered
Trade Mark) which comprise phospholipids, for example, mixtures of
DPPC (dipalmitoyl phosphatidylcholine) and PG
(phosphatidylglycerol). Other suitable surfactants include, for
example, dipalmitoyl phosphatidylethanolamine (DPPE), dipalmitoyl
phosphatidylinositol (DPPI).
[0054] The force control agent may comprise a metal stearate, or a
derivative thereof, for example, sodium stearyl fumarate or sodium
stearyl lactylate. Advantageously, it comprises a metal stearate.
For example, zinc stearate, magnesium stearate, calcium stearate,
sodium stearate or lithium stearate. In one particular embodiment
which may be mentioned, the additive material comprises or consists
of magnesium stearate.
[0055] The force control agent may include or consist of one or
more surface active materials, in particular materials that are
surface active in the solid state, which may be water soluble or
water dispersible, for example lecithin, in particular soya
lecithin, or substantially water insoluble, for example solid state
fatty acids such as oleic acid, lauric acid, palmitic acid, stearic
acid, erucic acid, behenic acid, or derivatives (such as esters and
salts) thereof such as glyceryl behenate. Specific examples of such
materials are phosphatidylcholines, phosphatidylethanolamines,
phosphatidylglycerols and other examples of natural and synthetic
lung surfactants; lauric acid and its salts, for example, sodium
lauryl sulphate, magnesium lauryl sulphate; triglycerides such as
Dynsan 118 and Cutina H R; and sugar esters in general.
Alternatively, the force control agent may be cholesterol.
[0056] Other possible force control agents include sodium benzoate,
hydrogenated oils which are solid at room temperature, talc,
titanium dioxide, aluminium dioxide, silicon dioxide and starch.
Also useful as force control agents are film-forming agents, fatty
acids and their derivatives, as well as lipids and lipid-like
materials.
[0057] Force control agents which are particularly suitable for use
in the present invention include magnesium stearate, amino acids
including leucine, lysine, arginine, histidine, cysteine and their
derivatives, lecithin and phospholipids. The inclusion of these
force control agents is expected to improve the efficacy of the
glycopyrrolate for treating respiratory disorders such as COPD,
asthma or cystic fibrosis.
[0058] When the composition of the invention is formulated as a dry
powder formulation, in one embodiment the composition additionally
comprises a carrier. In a further embodiment, the carrier comprises
lactose, such as lactose monohydrate.
[0059] In certain embodiments of the invention, the composition
will comprise lactose in the absence of magnesium stearate as a
force control agent. For example, in one embodiment, a suitable
composition of the invention comprises glycopyrronium bromide and
lactose, such as 1% (w/w) glycopyrronium bromide and 99% (w/w)
lactose. In certain alternative embodiments of the invention, the
composition comprises glycopyrrolate, lactose and magnesium
stearate. For example, in one embodiment, a suitable composition of
the invention comprises glycopyrronium bromide, lactose and
magnesium stearate, such as 1.05% (w/w) glycopyrronium bromide,
98.8% (w/w) lactose and 0.15% (w/w) magnesium stearate, or 1% (w/w)
glycopyrronium bromide, 98.8% (w/w) lactose and 0.2% (w/w)
magnesium stearate.
[0060] When present, it is believed to be important for any force
control agent to be predominantly present on the surface of
glycopyrrolate particles, as well as or rather than being on the
surface of the carrier particles. It has been found that a high
shear blending method is advantageous to achieve this.
[0061] In addition to reducing the cohesion between the fine
particles of the glycopyrrolate formulation, additive materials,
including the force control agents mentioned above, may have
further benefits when used in the invention. It has been suggested
that some force control agents, such as magnesium stearate, are
able to themselves reduce the ingress of moisture into the dry
powder formulation.
[0062] Furthermore, many force control agents act as surfactants.
When these agents are administered to the lung, they tend to
rapidly spread over the surface of the lung. It is postulated that
this rapid dispersion of the surfactants may well assist in the
dispersion of the glycopyrrolate in the formulation, thereby
assisting and enhancing its therapeutic effect.
[0063] From the foregoing it can be seen that the desired
improvements in the fine particle fraction of dry powder
formulations containing glycopyrrolate for a period suitable for an
inhalation product (e.g. 1, 2, 3 years) can be achieved by suitable
conditioning, and/or by protection of the formulation from
moisture, and/or by the suitable incorporation of an additive, such
as a force control agent.
[0064] A very important advantage of the process for preparing
stable formulations containing glycopyrrolate is that it allows the
administration of smaller doses than previously used. The reduction
of the dose is made possible by the more consistent and predictable
administration of the glycopyrrolate, for example, through a
consistently improved fine particle fraction and fine particle dose
compared to that observed in connection with the conventional
formulations. Consequently, while the dose dispensed is smaller,
the amount of active agent being administered is the same, with the
same therapeutic effect being achieved.
[0065] The formulations of the present invention may include
glycopyrrolate as the only pharmaceutically active agent.
Alternatively, the formulations may include one or more further
active agents, in addition to the glycopyrrolate. The additional
active agents may include, for example:
[0066] 1) steroid drugs such as, for example, alcometasone,
beclomethasone, beclomethasone dipropionate, betamethasone,
budesonide, clobetasol, deflazacort, diflucortolone,
desoxymethasone, dexamethasone, fludrocortisone, flunisolide,
fluocinolone, fluometholone, fluticasone, fluticasone proprionate,
fluticasone furoate, mometasone furoate, hydrocortisone,
triamcinolone, nandrolone decanoate, neomycin sulphate, rimexolone,
methylprednisolone and prednisolone;
[0067] 2) antibiotic and antibacterial agents such as, for example,
metronidazole, sulphadiazine, triclosan, neomycin, amoxicillin,
amphotericin, clindamycin, aclarubicin, dactinomycin, nystatin,
mupirocin and chlorhexidine;
[0068] 3) systemically active drugs such as, for example,
isosorbide dinitrate, isosorbide mononitrate, apomorphine and
nicotine;
[0069] 4) antihistamines such as, for example, azelastine,
chlorpheniramine, astemizole, cetitizine, cinnarizine,
desloratadine, loratadine, hydroxyzine, diphenhydramine,
fexofenadine, ketotifen, promethazine, trimeprazine and
terfenadine;
[0070] 5) anti-inflammatory agents such as, for example, piroxicam,
benzydamine, diclofenac sodium, ketoprofen, ibuprofen, heparinoid,
nedocromil, sodium cromoglycate, fasafungine and iodoxamide;
[0071] 6) antimuscarinic/anticholinergic agents such as, for
example, atropine, benzatropine, biperiden, cyclopentolate,
oxybutinin, orphenadine hydrochloride, procyclidine, propantheline,
propiverine, tiotropium, tropicamide, trospium, ipratropium
bromide, GSK573719 and oxitroprium bromide;
[0072] 7) anti-emetics such as, for example, bestahistine,
dolasetron, nabilone, prochlorperazine, ondansetron,
trifluoperazine, tropisetron, domperidone, hyoscine, cinnarizine,
metoclopramide, cyclizine, dimenhydrinate and promethazine;
[0073] 8) hormonal drugs such as, for example, protirelin,
thyroxine, salcotonin, somatropin, tetracosactide, vasopressin or
desmopressin;
[0074] 9) bronchodilators, such as salbutamol, fenoterol,
formoterol, indacaterol, vilanterol and salmeterol;
[0075] 10) sympathomimetic drugs, such as adrenaline,
noradrenaline, dexamfetamine, dipirefin, dobutamine, dopexamine,
phenylephrine, isoprenaline, dopamine, pseudoephedrine, tramazoline
and xylometazoline;
[0076] 11) anti-fungal drugs such as, for example, amphotericin,
caspofungin, clotrimazole, econazole nitrate, fluconazole,
ketoconazole, nystatin, itraconazole, terbinafine, voriconazole and
miconazole;
[0077] 12) local anaesthetics such as, for example, amethocaine,
bupivacaine, hydrocortisone, methylprednisolone, prilocalne,
proxymetacaine, ropivacaine, tyrothricin, benzocaine and
lignocaine;
[0078] 13) opiates, such as for pain management, such as, for
example, buprenorphine, dextromoramide, diamorphine, codeine
phosphate, dextropropoxyphene, dihydrocodeine, papavereturn,
pholcodeine, loperamide, fentanyl, methadone, morphine, oxycodone,
phenazocine, pethidine and combinations thereof with an
anti-emetic;
[0079] 14) analgesics and drugs for treating migraine such as
clonidine, codine, coproxamol, dextropropoxypene, ergotamine,
sumatriptan, tramadol and non-steroidal anti-inflammatory
drugs;
[0080] 15) narcotic agonists and opiate antidotes such as naloxone,
and pentazocine;
[0081] 16) phosphodiesterase type 5 inhibitors, such as sildenafil;
and
[0082] 17) pharmaceutically acceptable salts of any of the
foregoing.
[0083] In one embodiment, the additional active agents are
pharmaceutically active agents which are known to be useful in the
treatment of respiratory disorders, such as .beta..sub.2-agonists,
steroids, antimuscarinics/anticholinergics, phosphodiesterase 4
inhibitors, and the like. In one embodiment, the formulation of the
invention does not include formoterol.
[0084] In one particular embodiment which may be mentioned, the
additional active agent includes indacaterol. Indacaterol is an
ultra-long-acting beta-adrenoceptor agonist currently approved in
Europe as Onbrez.TM., marketed by Novartis. It is licensed for the
treatment of chronic obstructive pulmonary disease (COPD) and is
delivered as an aerosol formulation in the Breezhaler.TM. dry
powder inhaler. A combination product of indacaterol and
glycopyrronium bromide (known as QVA-149) is currently in Phase III
clinical trials for COPD and is due to be launched in 2013.
[0085] In an alternative embodiment, the additional agent includes
formoterol fumarate. A dual combination product of formoterol
fumarate and glycopyrrolate (known as PT003) is scheduled to enter
Phase III clinical trials for COPD in 2012 and is currently being
developed by Pearl Therapeutics, Inc. A triple combination product
of formoterol fumarate, glycopyrrolate and an inhaled
corticosteroid (known as PT010) is currently being developed by
Pearl Therapeutics, Inc.
[0086] In an alternative embodiment, the additional agent includes
a beta agonist, such as a .beta..sub.2-agonist. It is well known
that such beta agonists cause tachycardia (see The Merck Manuals
Online Medical Dictionary--Chronic Obstructive Pulmonary Disease).
Thus, in one embodiment, the composition of the invention is used
in the concomitant treatment of a patient suffering from a
respiratory condition and being treated with a beta agonist.
[0087] In a further embodiment, the pharmaceutical composition
comprising glycopyrrolate or a pharmaceutically acceptable salt
thereof is administered to a patient population which suffers from
tachycardia which has been pharmaceutically induced.
[0088] The pharmaceutical composition comprising glycopyrrolate or
a pharmaceutically acceptable salt thereof is administered to a
patient in which tachycardia has been induced or exacerbated by an
inhalable drug, more preferably an inhalable drug used for treating
a pulmonary disorder, more preferably salbutamol. The drug may
alternatively be ephedrine, amphetamines or cocaine. Preferably,
the administration of the pharmaceutical composition comprising
glycopyrrolate or a pharmaceutically acceptable salt thereof is
separate or sequential to that of the tachycardia inducing drug.
Where administration is separate or sequential, preferably
administration of the glycopyrrolate or a pharmaceutically
acceptable salt thereof takes place within 4 hours of the
tachycardia inducing drug, preferably within 2 hours of the
tachycardia inducing drug, preferably within 1 hour of the
tachycardia inducing drug, preferably within 10 minutes of the
tachycardia inducing drug.
[0089] In a further embodiment, the pharmaceutical composition
comprising glycopyrrolate or a pharmaceutically acceptable salt
thereof is administered to a patient population which suffers from
tachycardia which has not been pharmaceutically induced, such as an
endocrine disorders, for example pheochromocytoma or
hyperthyroidism.
[0090] Preferably, the pharmaceutical composition comprising
glycopyrrolate or a pharmaceutically acceptable salt thereof is
administered to a patient population which suffers from a form of
tachycardia selected from the group consisting of ventricular
tachycardia, supraventricular tachycardia, atrial fibrillation, AV
nodal reentrant tachycardia (AVNRT), AV reentrant tachycardia
(AVRT) and junctional tachycardia.
[0091] It will be appreciated that the compositions of the
invention may be formulated in accordance with known procedures. In
particular, the skilled person is directed to the contents of WO
2005/105043 which provide a detailed description of how stable
formulations containing glycopyrrolate may be prepared. In
particular, formulations may be prepared which are stable for a
period of at least 1 year, such as a period of at least 2 years and
in particular a period of at least 3 years.
[0092] The stability of a composition should be indicated by
consistent dispersability of the powder over these periods, which
may, for example, be measured in terms of a consistently good fine
particle fraction or fine particle dose over time. In one
embodiment of the stable composition, the fine particle fraction
(<5 .mu.m) is consistently greater than about 30% over a period
of at least 1 year, at least 2 years or at least 3 years when
stored at normal temperatures and humidities for pharmaceutical
products. In another embodiment of the invention, the fine particle
fraction (<5 .mu.m) is consistently greater than about 40% over
a period of at least 1 year, at least 2 years or at least 3 years.
In one embodiment, the fine particle fraction (<5 .mu.m) is
consistently greater than 30% or greater than 40% when the
formulations are stored under standard testing condition's, such as
25.degree. C./60% RH, 30.degree. C./60% RH, 40.degree. C./70% RH or
40.degree. C./75% RH.
[0093] In one embodiment of the stable composition, the fine
particle fraction of the dry powder formulations is consistently at
least about 30%, at least about 40%, at least about 50%, at least
about 60%, at least about 70% or at least about 80%.
[0094] In one embodiment of the stable composition, the fine
particle dose of the dry powder formulations is consistently at
least about 30%, at least about 40%, at least about 50%, at least
about 60%, at least about 70% or at least about 80%.
[0095] In another embodiment of the stable composition, the dry
powder formulations are packaged for storage and/or delivery by a
dry powder inhaler and the packaged formulations are stable for at
least 1, 2 or 3 years when stored at normal temperatures and
humidities, i.e. the packaged formulations or products comprising
the formulations do not have to be stored in a controlled
environment in order to exhibit the desired stability.
[0096] As the instability of the conventional glycopyrrolate
formulations appears to be due to moisture absorption, there are a
number of measures which are proposed to increase stability.
[0097] Firstly, the amorphous content of the glycopyrrolate is to
be reduced by improving the processing of the glycopyrrolate. Where
the glycopyrrolate is micronised, the micronisation process may be
improved, for example, by adjusting the conditions under which the
milling takes place, to prevent the formation of amorphous
material. Additionally or alternatively, the micronised product may
be "conditioned" to remove the amorphous material.
[0098] Alternatively, the particles of glycopyrrolate may be
engineered so that they include little or no amorphous material.
Suitable methods for doing this are known to those skilled in the
art. For example, glycopyrrolate powders with low non-crystalline
content may be made using methods such as supercritical fluid
processing using carbon dioxide, or other controlled forms of
crystallisation or precipitation, such as slow precipitation, by
emulsion methods, sono-crystallisation and the like.
[0099] Secondly, the exposure of the dry powder formulation to
moisture when the powder is stored is suitably reduced. In this
regard, it is particularly desirable to reduce exposure of the
formulation to moisture during storage in capsules or blisters.
[0100] Finally, the inclusion of additive materials in the dry
powder formulation can enhance the powder dispersability and
protect the formulation from the ingress of moisture.
[0101] Batches of micronised glycopyrrolate were obtained and,
following sealed storage for several weeks, the physical changes of
the material from fine cohesive powders to solid agglomerates were
observed.
[0102] The following section summarises the tests conducted on
reported batches of glycopyrrolate received following
micronisation:
[0103] Batch A:
[0104] Micronised at 0.5 kg/hr
[0105] Injection pressure: 10 bar
[0106] Micronisation pressure: 7 bar
[0107] Sympatec sizing: d10 0.7 .mu.m, d50 1.8 .mu.m, d90 3.6
.mu.m
[0108] Loss on drying: 0.7%
[0109] DVS indicated crystalline material. On storage, soft lumps
of material were found in bulk powder, and repeated particle sizing
gave d50 values ranging between 2.6 and 3.5 .mu.m.
[0110] Batch B:
[0111] Micronised at 0.5 kg/hr
[0112] Injection pressure: 10 bar
[0113] Micronisation pressure: 7 bar
[0114] Sympatec sizing: d10 1.0 .mu.m, d50 2.4 .mu.m, d90 4.8
.mu.m
[0115] Loss on drying: 0.6%
[0116] Water activity: 54% RH
[0117] DVS indicated amorphous material was present. On storage,
large hard lumps of material were found, and repeated particle
sizing gave d50 values ranging between 36 and 160 .mu.m.
[0118] Batch C:
[0119] Micronised at 0.4 kg/hr
[0120] Injection pressure: 10 bar
[0121] Micronisation pressure: 9.8 bar
[0122] Sympatec sizing: d10 0.8 .mu.m, d50 2.3 .mu.m, d90 4.8
.mu.m
[0123] Loss on drying: 0.4%
[0124] DVS indicated amorphous material was present. On storage,
large hard lumps of material were found in bulk powder, and
repeated particle sizing gave d50 value of 51 .mu.m.
[0125] Remicronised Batch C:
[0126] Micronised at 0.5 kg/hr
[0127] Injection pressure: 10 bar
[0128] Micronisation pressure: 9 bar
[0129] Sympatec sizing: d10 1.0 .mu.m, d50 2.4 .mu.m, d90 4.5
.mu.m
[0130] Loss on drying: 0.5%
[0131] On storage, only soft lumps of material were found in bulk
powder.
[0132] This summary shows that selected batches of micronised
glycopyrrolate had formed hard agglomerates, and this appears to be
associated with the presence of amorphous material, as the first
batch, which contained no detectable amorphous material, exhibited
good powder properties following storage. Consequently, it is
believed that the formation of hard agglomerates occurs within a
micronised powder that contains surface non-crystalline material,
whether formulated with excipient, any moisture protection agent, a
force control agent, or on its own.
[0133] The amorphous material will be located on the surface to
have the greatest effect of this kind. The quantity of amorphous
material relative to the bulk mass may be very small, as long as it
is sufficient to produce this effect. The non-crystalline material
will draw moisture from its surroundings. Sources of moisture may
include the surrounding air or gas, the surrounding excipients or
additives (such as lactose or force control agents), the packaging
or device, such as a gelatin or other capsule material, or a
plastic.
[0134] Tests have shown that all micronised glycopyrronium bromide
prototype formulations made using conventional methods, including
those that comprise additives (including magnesium stearate), have
been found to degrade or deteriorate in aerosolisation performance
over a period of 6 months. This deterioration has even been found
to occur when stored under dry conditions. Deterioration in
performance has been seen to be approximately 30 to 50% of original
performance or more. Such deterioration would make these
formulations unattractive for commercial use.
[0135] It has been suggested that conducting micronisation under
the use of humidified air or other gas may help to reduce the
generation of amorphous materials. Both WO 99/54048 and WO 00/32165
disclose that milling under increased humidity can reduce the
generation of amorphous material. WO 00/32313 discloses the milling
of material at reduced temperature using helium or a mixture of
helium and another gas in order to reduce the formation of
amorphous material. It should be noted that none of these prior art
documents disclose that the milling of glycopyrrolate under these
special conditions is beneficial.
[0136] However, the milling conditions disclosed in the prior art
are not standard in micronisation practice and it may well prove to
be difficult to control these processes. It may also prove
difficult to use such processes on a commercial scale.
[0137] Finally, the extent to which such processes may help to
control the generation of amorphous material for the specific
problem of glycopyrrolate is also not known.
[0138] As mentioned above, glycopyrrolate presents particular
problems because of its inherent instability.
[0139] In accordance with one embodiment of the stable composition,
the dry powder formulation comprising glycopyrrolate is prepared
using a process, suitably a micronisation process, which is carried
out under conditions which reduce the formation of amorphous
material. Examples of suitable micronisation conditions include
increased relative humidity (for example 30-70%) or micronisation
using helium at reduced temperatures.
[0140] In another embodiment, the dry powder formulation comprising
glycopyrrolate is micronised and then undergoes a "conditioning"
step to remove or reduce the amorphous material content. Such
conditioning steps include exposure to moisture to encourage
re-crystallisation of the amorphous material without the formation
of hard agglomerates. Examples of such conditioning are discussed
in more detail below.
[0141] Examples of suitable dry powder formulations which may be
used in accordance with the invention include those described in WO
2008/000482 such as Examples 1 and 2 below:
Example 1
[0142] 37 g of magnesium stearate are mixed with 1 kg of
crystalline glycopyrronium bromide in a Turbula.RTM. blender for 5
hours. The resulting mixture is micronised using a Hosokawa
Alpine.RTM. 100 AFG fluid bed opposed jet mill with the following
parameters: classifier speed, 13000 rpm; milling gas pressure, 3.5
bar. The mill is equipped with 3 nozzles of 1.9 mm diameter.
[0143] The resulting mixture has a median particle size of about 3
micron (x90=7 micron, x50=3 micron, x10=1 micron). The magnesium
stearate is well distributed over the drug substance surface.
[0144] Lactose carrier particles (99.7% w/w of final composition)
are admixed to give an inhalable dry powder.
Example 2
[0145] Drug substance 1: 50 g of magnesium stearate are mixed with
1 kg of crystalline glycopyrronium bromide in a Turbula.RTM.
blender for 5 hours. The resulting mixture is micronised using a
Hosokawa Alpine.RTM. 100 AFG fluid bed opposed jet mill (equipped
with 3 nozzles of 1.9 mm diameter) with the following parameters:
classifier speed, 13000 rpm; milling gas pressure, 3.5 bar, to give
particles that have an average particle size of less than 5
microns.
[0146] Drug substance 2: 1 kg of crystalline glycopyrronium bromide
is micronised using a Hosokawa Alpine.RTM. 100 AFG fluid bed
opposed jet mill (equipped with 3 nozzles of 1.9 mm diameter) with
the following parameters: classifier speed, 13000 rpm; milling gas
pressure, 3.5 bar, to give particles that have an average particle
size of less than 5 microns.
[0147] These drug substances are used to prepare the following
formulations:
[0148] Formulation 1: Lactose carrier particles (99% w/w of final
composition) are admixed with drug substance 2 to give an inhalable
dry powder.
[0149] Formulation 2: Lactose carrier particles (98.8% vv/w of
final composition) and magnesium stearate (0.15%) are admixed with
drug substance 2 to give an inhalable dry powder.
[0150] Formulation 3: Lactose carrier particles (98.8% w/w of final
composition) and magnesium stearate (0.15%) are admixed with drug
substance 1 to give an inhalable dry powder.
[0151] The resulting powders are filled in aliquots of 25 mg into
size 3 hydroxypropylmethyl-cellulose (HPMC) capsules. The resulting
capsules are tested for aerodynamic particle size distribution
(fine particle fraction) either immediately after manufacture or
after storage under different conditions.
[0152] The fine particle fraction (FPF) and emitted dose (ED) of
the powder in each capsule is measured using the Next Generation
Impactor (NGI) particle-classifying cascade impactor at a flow rate
of 85 L/min.
[0153] According to a further aspect of the invention there is
provided an inhalable unit dose comprising the pharmaceutical
composition as hereinbefore defined for use in the treatment or
prophylaxis of tachycardia. In one embodiment, the unit dose
comprises a capsule. In a further embodiment, the capsule is opaque
or transparent. In a further embodiment, the capsule is
transparent. Such an embodiment provides the advantage of informing
a user that successful inhalation of the dosage has been
achieved.
[0154] In one embodiment, the capsule comprises a gelatin capsule.
It is known for gelatin capsules to contain in the order of 10 to
15% w/w water, and for this to provide a sufficient source of water
to create a moisture instability problem.
[0155] The moisture content of the gelatin capsules has been shown
to drop as the water is extracted by the capsule contents. The
water content in the gelatin capsules acts as a plasticizer so that
when the water is extracted and the water content drops, the
capsules become more brittle, which will affect piercing and the
like.
[0156] An article on improvements in hypromellose capsules (B. E.
Jones, Drug Delivery Technology, Vol 3 No. 6, page 2, 2003),
describes the problems associated with gelatin capsules for use in
dry powder inhalers. These problems include changes in brittleness
and hence piercing consistency, and related dispersion performance
as a function of the changes in gelatin moisture content. The
potential of the gelatin to act as a moisture source, which can be
released to the powdered contents of the capsule, is also
discussed, as are the variations in electrostatic charge
properties.
[0157] In one embodiment, the capsule is made with hypromellose
(HPMC) or other celluloses or cellulose derivatives which do not
rely on moisture as a plasticizer. The moisture content of such
capsules can be less than 10%, or even below 5% or 3% w/w, and this
makes such capsules more suitable for use with glycopyrrolate.
[0158] Capsules can also be made from gelatin containing one or
more plasticizers other than water, such as PEG, glycerol,
sorbitol, propyleneglycol or other similar polymers and
co-polymers, hence allowing the moisture content to be reduced to
below 10%, or even below 5% or 3% w/w.
[0159] Alternatively, capsules can be made from synthetic plastics
or thermoplastics (polyethylene or polycarbonate or related
plastics) containing reduced moisture content below 10%, or even
below 5% or 3% w/w. Further alternative capsules with reduced
moisture content are made from starch or starch derivatives or
chitosan.
[0160] In the foregoing capsules, the problem of brittleness is
reduced. Furthermore, capsules such as those made from celluloses
have been found to pierce more consistently and reliably, and the
pierce hole made appears to be more cleanly formed and spherical,
with less shedding of particles. The aerosolisation of the powder
contents has also been found to be improved, as well as being more
consistent.
[0161] According to a further aspect of the invention there is
provided an inhalation delivery device comprising one or more doses
of the pharmaceutical composition as hereinbefore defined for use
in the treatment or prophylaxis of tachycardia. In one embodiment,
the delivery device is an inhaler. In a further embodiment, the
delivery device is a pressurised metered dose inhaler. It will be
appreciated that the metered dose inhaler may suitably comprise a
reservoir containing device or a multi-unit dose containing device
or a unit dose containing device. It will also be appreciated that
the pressurised metered dose inhaler may be suitable for when the
composition of the invention additionally comprises propellants
such as hydrofluoroalkanes (HFAs) and the like or any such
propellant suitable for use with compositions of the invention.
Examples of formulations according to the invention which are
suitable for administration by pressurised metered dose inhalers
(pMDIs) include those developed by Pearl Therapeutics, Inc. such as
PT001 (glycopyrrolate HFA-MDI monotherapy for COPD), PT003
(combination of glycopyrrolate and formoterol fumarate HFA-MDI
formulation for COPD) and PT010 (triple combination of
glycopyrrolate, formoterol fumarate and an inhaled corticosteroid
as an HFA-MDI formulation for COPD). A further example includes a
pMDI formulation containing 100 .mu.g glycopyrrolate which has been
used in clinical trials by Chiesi Farmaceutici S.p.A.
[0162] In one embodiment, the delivery device is a nebulizer.
[0163] In a further embodiment, the delivery device is a dry powder
inhaler. Examples of suitable devices include, but are not limited
to, the TURBUHALER (Astra Zeneca), CLICKHALER, DUOHALER (Innovata
Biomed), EASYHALER (Orion), ACCUHALER, DISKUS, DISKHALER,
ROTAHALER, GEMINI (GlaxoSmithKline), HANDIHALER, INHALATOR,
AEROHALER (Boehringer Ingelheim), TWISTHALER (Schering Plough),
AEROLIZER, BREEZHALER, SOLIS (Novartis), MONOHALER (Miat), AIRMAX,
CYCLOHALER (Teva), GENUAIR (Almirall), NEXTDPI (Chiesi) and
NOVOLIZER (ASTA Medica).
[0164] In one embodiment, the inhaler device includes a means for
protecting the formulation from moisture, for example within a
sealed blister, such as a foil blister, with suitable sealing to
prevent the ingress of moisture. Such an embodiment seeks to solve
the problem of moisture absorption by dry powder glycopyrrolate
formulations. Such devices are known, for example the GYROHALER
(Vectura) or DISKUS (GlaxoSmithKline) devices.
[0165] It is believed to be particularly advantageous if the
blister is pierced using a simple mechanism, such as with the
GYROHALER. This device and this technology has been developed by
Vectura and relates to an inhalation device for oral or nasal
delivery of a medicament in powdered form. The powdered medicament
is stored in a strip of blisters and each blister has a puncturable
lid. When the inhaler is to be used, the lid of the aligned blister
is punctured, thereby allowing an airflow through the blister to be
generated to entrain the dose contained therein and to carry the
dose out of the blister and into the user's airway via the inhaler
mouthpiece. This arrangement with blisters having puncturable lids
allows the blisters to have the best possible seal. In contrast, in
blister systems such as the Diskus where the lids of the blisters
are peeled open, it is more difficult to maintain an optimum seal
due to the restrictions on the nature of the bond required to allow
peeling to occur.
[0166] In a further embodiment, the dry powder formulation
comprising glycopyrrolate is stored in packaging made from a
material which itself has a moisture content of less than 10%, such
as less than 5% and in particular less than 3%.
[0167] The packaging should also suitably prevent the ingress of
moisture, so that the powder is protected from external sources of
moisture. Foil sealed blisters are an example of a packaging which
prevents ingress of moisture.
[0168] In this latter regard, the prevention of the ingress of
moisture from external sources may be assisted by further
packaging. For example, HPMC capsules may be stored in a sealed
environment, such as an additional layer of foil packaging.
[0169] In an alternative embodiment, the dry powder formulation is
dispensed from a multidose dry powder inhaler device wherein the
powder is stored in a reservoir as opposed to individually packaged
doses. In such an embodiment, the device should offer superior
moisture protection compared to conventional reservoir devices. For
example, the device should include one or more of the following
features: a sealed reservoir chamber (for example including a
sealing gasket to seal the reservoir chamber), plastics materials
exhibiting very low moisture permeability (for forming the walls of
the reservoir chamber), and a desiccant.
[0170] According to a further aspect of the present invention,
there is provided a pharmaceutical composition as defined herein,
contained in a package which further comprises instructions for
administering said composition to a patient in need of a heart rate
lowering agent, or in anticipation of the need of a heart rate
lowering agent. Preferably, the instructions comprise directions
for administering said composition to a patient suffering from
tachycardia or in need of prophylaxis of tachycardia.
[0171] According to a further aspect of the present invention,
there is provided an inhalable unit dose as defined herein,
contained in a package which further comprises instructions for
administering said composition to a patient in need of a heart rate
lowering agent, or in anticipation of the need of a heart rate
lowering agent. Preferably, the instructions comprise directions
for administering said composition to a patient suffering from
tachycardia or in need of prophylaxis of tachycardia.
[0172] According to a further aspect of the present invention,
there is provided an inhalation delivery device as defined herein,
contained in a package which further comprises instructions for
administering said composition to a patient in need of a heart rate
lowering agent, or in anticipation of the need of a heart rate
lowering agent. Preferably, the instructions comprise directions
for administering said composition to a patient suffering from
tachycardia or in need of prophylaxis of tachycardia.
[0173] According to a further aspect of the present invention,
there is provided a method of treatment or prophylaxis of a
condition or disorder characterised by an increased heart rate,
such as tachycardia, said method comprising administering an
effective amount of an inhalable pharmaceutical composition
comprising glycopyrrolate or a pharmaceutically acceptable salt
thereof to a patient in need thereof. The method preferably
comprises administering the composition to a patient who also
suffers from a respiratory condition, such as a condition selected
from: chronic obstructive pulmonary disease (COPD), asthma, cystic
fibrosis (CF) and related airway diseases.
[0174] The following study illustrates the invention:
[0175] Study Methodology
[0176] (a) Study Design and Plan
[0177] The study was a Phase IIa, multi-centre, randomised,
double-blind, placebo-controlled, crossover, dose-ranging study
using four dose levels of glycopyrronium bromide in subjects with
COPD. A total of 40 subjects were required to complete the
study.
[0178] Subjects were randomised to receive a single inhaled dose of
20, 125, 250 and 400 .mu.g of glycopyrronium bromide in ascending
order, with a placebo dose randomised into the sequence over 5
study visits. Subjects were randomised to receive treatment on
Study Day 1 prior to dosing. All doses, including placebo, were
administered using the Miat Monohaler.
[0179] The study consisted of a Screening period, Treatment period
of five study visits (separated by a 5-14-day wash-out period), and
a Follow-up Visit, 7-14 days after final treatment and prior to
discharge from the study.
[0180] (b) Study Timing
[0181] Subjects underwent an initial pre-screening visit to sign an
Informed Consent Form (ICF), followed by a Screening Visit to
confirm eligibility. The Pre-screening Visit and Screening. Visit
could have been combined if the subject signed the ICF and had not
taken any bronchodilators within the prohibited period before the
pulmonary function tests (PFTs). Following the Screening Visit,
subjects were then randomised on Study Day 1 prior to dosing.
[0182] The Treatment period then consisted of five study visits
(separated by a 5-14-day wash-out period), during which subjects
were dosed with a single inhaled dose of glycopyrronium bromide
using a Miat Monohaler, in ascending order (20, 125, 250 or 400
.mu.g). A placebo was randomly administered (using a Miat
Monohaler) at one of the study visits; subsequent visits continued
with the next highest dose of glycopyrronium bromide to that which
was administered prior to the placebo.
[0183] At the end of the study, subjects were required to attend
the clinic for a Follow-up Visit, 7-14 days after final treatment.
The subjects were then discharged from the study.
[0184] Each subject was expected to be involved in the study for
between 8-10 weeks.
[0185] (c) Study Population
[0186] The population to be studied were to be male or female, aged
40 years and over with a diagnosis of mild-moderate COPD that was
responsive to anti-cholinergic therapy. Responsiveness to
anti-cholinergic therapy is defined as an increase in FEV.sub.1 of
.gtoreq.12% and at least 150 ml following administration of 80
.mu.g ipratropium bromide.
[0187] (i) Number of Subjects
[0188] Up to 140 subjects were to be screened and 40 subjects were
required to complete the study.
[0189] The estimate of number of subjects to be screened was based
on screening data from previous studies where subjects had to
demonstrate reversibility in order to be eligible to participate in
the study. This information indicated that between 2 and 4 subjects
would need to be screened to achieve one eligible subject. The
maximum number of eligible subjects to be enrolled was not
specified as it was not known how many subjects were likely to
prematurely discontinue from the study.
[0190] (ii) Selection Criteria
[0191] Inclusion Criteria
[0192] Subjects were included in the study providing they met the
following criteria: [0193] 1. Male or female, aged 40 years or
over. [0194] 2. Had been diagnosed with COPD (cough, sputum
production, dyspnoea, and/or a history of exposure to risk factors
for the disease). [0195] 3. Were current or ex-smokers with a
smoking history of at least 10 pack years. [0196] 4. Had a
pre-bronchodilator FEV.sub.1 between 40% and 80% of the predicted
normal value. [0197] 5. Had a pre-bronchodilator FEV.sub.1/FVC
ratio of <70%. [0198] 6. Improved their FEV.sub.1 by 12% or more
and by at least 150 ml after administration of 80 .mu.g Atrovent
(ipratropium bromide) delivered via spacer. [0199] 7. Were willing
and able to withhold long-acting anticholinergic therapy during the
study. [0200] 8. Were able to understand the nature of the study
and give written informed consent.
[0201] Exclusion Criteria
[0202] Subjects were excluded from the study for any of the
following reasons: [0203] 1. Were pregnant or breast-feeding. Women
of child bearing potential had to use an adequate method of
contraception during the course of the study and had to have a
negative pregnancy test prior to receiving study drug. [0204] 2.
Had a history of narrow-angle glaucoma, prostatic hyperplasia or
bladder neck obstruction. [0205] 3. Had significant concurrent
cardiac, renal, hepatic or metabolic disease. [0206] 4. Had
evidence of atopy, allergic rhinitis, or, in the investigator's
opinion, had predominant asthma rather than COPD. [0207] 5. Had a
blood eosinophil cell count >600 mm.sup.3. [0208] 6. Had been
treated with oral steroids 8 weeks prior to screening or for 4 or
more weeks in the 12 months prior to Screening Visit. [0209] 7.
Were receiving inhaled corticosteroids or oral theophylline, but
had not maintained a stable dose in the 4 weeks prior to Screening
Visit, and were not able to maintain a stable dose during the
treatment period. [0210] 8. Were sensitive to antimuscarinic
agents. [0211] 9. Required oxygen therapy. [0212] 10. Had
experienced an upper respiratory tract infection or had
exacerbations of their COPD requiring treatment with antibiotics in
the 6 weeks prior to Screening Visit. [0213] 11. Had taken part in
any other clinical trial involving administration of an
investigational drug within the 3 months prior to the start of
dosing.
[0214] (d) Study Treatment
[0215] (i) Treatments Administered
[0216] All subjects were scheduled to be dosed between 08:00 and
10:00 am. For individual subjects, dosing was at the same time of
day (.+-.30 minutes). At each dosing visit, subjects received a
single dose of glycopyrronium bromide or placebo administered via
Miat Monohaler. Each different dose (20, 125, 250 or 400 .mu.g) was
contained in one capsule. An appropriate number of Miat Monohalers
to conduct the study was also supplied to the site. A new Miat
Monohaler was used to administer each dose at each visit.
[0217] On the ward, the study nurse placed each capsule into the
Miat Monohaler for the subject to inhale. This was done immediately
prior to the inhalation. For each capsule the subjects were asked
to inhale twice through the Miat Monohaler.
[0218] (ii) Description of Investigational Product
[0219] Glycopyrronium bromide was presented in size 3, white
opaque, hard, gelatin capsules packaged in aluminium pouches. The
capsules were presented in four dose strengths containing 20, 125,
250, or 400 .mu.g glycopyrronium bromide. In addition to
glycopyrronium bromide, excipient present in the capsule
formulation consisted of the PowderHale.TM. formulation of lactose
and magnesium stearate.
TABLE-US-00001 TABLE 1 Formulation of Investigational Product
Product Description 20 .mu.g 125 .mu.g 250 .mu.g 400 .mu.g
Glycopyrronium 0.08 0.50 1.60 1.60 bromide/ PowderHale .TM. (% w/w)
Capsule fill weight 25.0 25.0 15.6 25.0 (mg)
[0220] A placebo-to-match product was also provided which consisted
of size 3 white, opaque, hard gelatin capsules containing the
non-active PowderHale.TM. formulation alone.
[0221] Glycopyrronium bromide capsules for inhalation were stored
below 25.degree. C. in a dry place.
[0222] (iii) Selection and Timing of Dose for Individual
Subjects
[0223] Each subject received 20, 125, 250 and 400 .mu.g
glycopyrronium bromide in ascending order, with a placebo dose
randomised into the sequence over five study visits (i.e., one dose
per visit).
[0224] All subjects were scheduled to receive study medication
between 08:00 am and 10:00 am. Study medication was administered to
each subject at approximately the same time (within 30 minutes) on
each study day.
[0225] (e) Study Assessments
[0226] All vital signs were measured on each study day, including
heart rate (with the subject semi-supine for 5 minutes prior to
measurement); blood pressure; respiratory rate and temperature were
measured at each visit and before receiving study medication
(pre-treatment), if applicable. Blood pressure and heart rate were
also measured at 45, 90 minutes and 5, 10, 20 and 30 hours
post-treatment on study days.
[0227] (f) Planned Statistical Analysis
[0228] The statistical analyses were to be reported using summary
tables and data listings. Statistical tests for the evaluation were
to be performed at the 0.05 significance level using a two-sided
test.
[0229] All analyses and tabulations were to be performed using
SAS.RTM. Version 6.12 on a PC platform. Continuous variables were
to be summarised with sample size (n), mean, standard deviation
(SD), minimum, median, and maximum. The median, minimum and maximum
was to be displayed to the same number of decimal places the
results were to be recorded to. The mean was to have one extra
decimal place and the standard deviation was to have two extra
decimal places. Categorical variables were to be summarised with
number and percentage of subjects.
[0230] Results
[0231] The results of this study may be seen in Tables 2-4.
[0232] All subjects had normal heart rate at the time of screening.
Following the study, there was a dose dependent decrease in mean
heart rate from Test Day Baseline up to 5 hours post-dose.
[0233] At 10 hours, the decrease in mean heart rate from Test Day
Baseline was intermittent, with the greatest decrease recorded in
the 400 .mu.g treatment group at -6.4 bpm.
[0234] At 20 hours, the decrease in mean heart rate from Test Day
Baseline was also intermittent, with the greatest decrease recorded
in the 400 .mu.g treatment group at -5.6 bpm.
[0235] Statistical significance was achieved at the 45 minute to 10
hour timepoints, inclusive, relative to placebo (p<0.05) for the
400 .mu.g dose.
TABLE-US-00002 TABLE 2 Vital Signs-Heart Rate (bpm) 20 .mu.g 125
.mu.g 250 .mu.g 400 .mu.g Placebo Time Point (N = 45) (N = 43) (N =
41) (N = 40) (N = 42) Pre-dose n 45 42 41 40 41 Mean 72.8 69.3 70.8
72.7 70.6 SD 11.73 10.58 12.16 11.01 10.62 Min 48 50 50 54 52
Median 72.0 68.0 68.0 72.0 70.0 Max 105 93 115 100 100 45 mins
post-dose n 45 42 40 40 41 Mean 70.3 65.5 65.1 65.4 68.0 SD 11.65
9.94 9.44 9.09 9.82 Min 49 50 48 52 52 Median 68.0 63.5 64.0 65.0
67.0 Max 113 88 90 91 87 90 mins post-dose n 45 42 39 40 41 Mean
72.5 67.6 68.2 67.1 71.6 SD 13.61 10.29 9.65 10.19 10.68 Min 51 47
51 50 50 Median 71.0 69.0 69.0 67.5 70.0 Max 126 87 92 89 98 5 hrs
post-dose n 45 40 40 39 41 Mean 72.8 70.6 68.4 69.7 72.2 SD 11.89
10.89 10.96 9.61 11.46 Min 48 48 53 49 53 Median 74.0 73.0 68.5
69.0 72.0 Max 95 96 97 87 109 10 hrs post-dose n 43 39 39 38 39
Mean 69.1 67.0 66.3 65.7 68.5 SD 10.27 10.47 10.62 8.96 10.03 Min
50 48 49 49 49 Median 68.0 67.0 65.0 65.5 68.0 Max 88 90 97 84 97
20 hrs post-dose n 44 40 39 36 40 Mean 68.8 66.4 66.6 66.7 68.1 SD
9.76 9.36 10.04 8.67 8.71 Min 48 51 50 52 51 Median 69.5 66.0 65.0
66.0 67.5 Max 95 90 100 83 98 30 hrs post-dose n 43 38 38 36 39
Mean 69.8 72.1 70.7 70.9 71.1 SD 10.69 10.46 11.38 10.52 9.22 Min
42 55 47 42 42 Median 70.0 72.0 71.5 70.0 71.0 Max 93 103 95 96
100
TABLE-US-00003 TABLE 3 Vital Signs-Heart Rate (bpm)-Change from
Test day Baseline 20 .mu.g 125 .mu.g 250 .mu.g 400 .mu.g Placebo
Time Point (N = 45) (N = 43) (N = 41) (N = 40) (N = 42) Pre-dose n
45 42 41 40 41 Mean 72.8 69.3 70.8 72.7 70.6 SD 11.73 10.58 12.16
11.01 10.62 Min 48 50 50 54 52 Median 72.0 68.0 68.0 72.0 70.0 Max
105 93 115 100 100 Change from pre-dose to 45 mins post-dose n 45
42 40 40 41 Mean -2.5 -3.8 -4.6 -7.4 -2.7 SD 8.61 5.74 6.05 7.23
5.72 Min -16 -17 -20 -22 -15 Median -2.0 -4.0 -4.5 -6.5 -3.0 Max 37
10 10 4 11 Change from pre-dose to 90 mins post-dose n 45 42 39 40
41 Mean -0.2 -1.8 -1.7 -5.7 0.9 SD 11.82 6.84 8.12 9.29 7.35 Min
-20 -15 -24 -27 -16 Median 0.0 -2.0 -1.0 -4.5 0.0 Max 50 19 20 12
16 Change from pre-dose to 5 hours post-dose n 45 40 40 39 41 Mean
-0.0 1.2 -1.4 -3.1 1.6 SD 9.35 7.97 7.31 9.74 8.39 Min -20 -13 -22
-23 -18 Median 1.0 0.5 0.0 -4.0 2.0 Max 19 22 13 22 19 Change from
pre-dose to 10 hours post-dose n 43 39 39 38 39 Mean -3.4 -2.1 -3.6
-6.4 -2.1 SD 9.27 10.03 8.48 8.46 7.26 Min -26 -21 -26 -26 -18
Median -1.0 -3.0 -4.0 -5.5 -3.0 Max 11 37 17 10 12 Change from
pre-doseto 20 hours post-dose n 44 40 39 36 40 Mean -3.6 -2.5 -3.4
-5.6 -2.4 SD 9.23 8.91 7.87 11.04 9.40 Min -29 -25 -22 -29 -20
Median -3.0 -1.5 -4.0 -4.5 -2.0 Max 17 23 12 18 23 Change from
pre-dose to 30 hours post-dose n 43 38 38 36 39 Mean -2.7 2.8 1.0
-1.4 0.3 SD 8.56 9.31 8.45 10.19 8.27 Min -24 -18 -21 -29 -20
Median -2.0 1.0 2.5 0.0 1.0 Max 13 28 19 16 11
TABLE-US-00004 TABLE 4 Vital Signs-Adjusted Means for Average
Change in Heart Rate (bpm) from Test day Baseline to Scheduled
Time-Point Placebo 20 .mu.g 125 .mu.g 250 .mu.g 400 .mu.g Change
from Test day baseline to 45 mins post-dose n 41 45 42 40 40
Adjusted Mean -2.328 -2.323 -2.854 -3.693 -7.052 95% CI (-4.09422,
-0.56267) (-4.91033, 0.26356) (-5.07662, -0.63184) (-5.90752,
-1.47803) (-9.88041, -4.22321) Dose v Placebo Difference 0.005
-0.526 -1.364 -4.723 95% CI (-3.07363, 3.08375) (-3.33005, 2.27848)
(-4.09076, 1.36209) (-8.02112, -1.42561) p-value 0.997 0.712 0.324
0.005 Change from Test day baseline to 90 mins post-dose n 41 45 42
39 40 Adjusted Mean 1.272 0.033 -0.650 -0.763 -4.315 95% CI
(-0.74950, 3.29304) (-2.92902, 2.99540) (-3.20085, 1.90171)
(-3.32741, 1.80079) (-3.55658, -1.07293) Dose v Placebo Difference
-1.239 -1.921 -2.035 -5.587 95% CI (-4.76442, 2.28726) (-5.13729,
1.29462) (-5.17883, 1.10867) (-9.36612, -1.80692) p-value 0.489
0.240 0.203 0.004 Change from Test day baseline to 5 hours
post-dose n 41 45 40 40 39 Adjusted Mean 2.047 1.933 2.382 -0.586
-3.455 95% CI (0.19190, 3.90181) (-0.79314, 4.65850) (-0.02094,
4.78474) (-2.91632, 1.74388) (-6.43492, -0.47462) Dose v Placebo
Difference -0.114 0.335 -2.633 -5.502 95% CI (-3.35614, 3.12779)
(-2.66650, 3.33659) (-5.49990, 0.23375) (-8.97358, -2.02968)
p-value 0.945 0.826 0.072 0.002 Change from Test day baseline to 10
hours post-dose n 39 43 39 39 38 Adjusted Mean -1.824 -0.126 -0.186
-4.657 -6.919 95% CI (-3.86270, 0.21448) (-3.13166, 2.87986)
(-2.84168, 2.46964) (-7.20022, -2.11286) (-10.1839, -3.65480) Dose
v Placebo Difference 1.698 1.638 -2.832 -5.095 95% CI (-1.87535,
5.27177) (-1.73715, 5.01331) (-5.98176, 0.31690) (-8.84274,
-1.34775) p-value 0.349 0.339 0.078 0.008 Change from Test day
baseline to 20 hours post-dose n 40 44 40 39 36 Adjusted Mean
-1.468 -4.339 -1.590 -1.858 -2.371 95% CI (-3.20697, 0.27186)
(-6.94011, -1.73828) (-3.83515, 0.65493) (-4.05201, 0.33697)
(-5.20811, 0.46674) Dose v Placebo Difference -2.872 -0.123 -0.390
-0.903 95% CI (-5.95884, 0.21556) (-2.96521, 2.72010) (-3.05829,
2.27836) (-4.15040, 2.34414) p-value 0.068 0.932 0.773 0.583 Change
from Test day baseline to 30 hours post-dose n 39 43 38 38 36
Adjusted Mean 0.619 -0.880 2.796 1.436 0.475 95% CI (-1.26084,
2.49824) (-3.74493, 1.98437) (0.29937, 5.29187) (-0.93038, 3.80168)
(-2.55383, 3.50427) Dose v Placebo Difference -1.499 2.177 0.817
-0.143 95% CI (-4.85467, 1.85672) (-0.92921, 5.28305) (-2.09946,
3.73337) (-3.62665, 3.33970) p-value 0.379 0.168 0.581 0.935 Note:
Adjusted Means and CIs calculated using ANCOVA.
* * * * *
References