U.S. patent application number 11/051469 was filed with the patent office on 2005-08-11 for novel combination of anticholinergic and ss mimetics for the treatment of respiratory diseases.
This patent application is currently assigned to Sofotec GmbH & Co. KG. Invention is credited to Cnota, Peter Jurgen, Goede, Joachim, Maus, Joachim, Szelenyi, Istvan.
Application Number | 20050175549 11/051469 |
Document ID | / |
Family ID | 34837534 |
Filed Date | 2005-08-11 |
United States Patent
Application |
20050175549 |
Kind Code |
A1 |
Goede, Joachim ; et
al. |
August 11, 2005 |
Novel combination of anticholinergic and ss mimetics for the
treatment of respiratory diseases
Abstract
The present invention describes a combination of anticholinergic
and .beta. mimetics for the treatment of respiratory diseases
including airway inflammation or obstruction such as chronic
obstructive pulmonary disease (COPD) and asthma. It further
comprises the preparation of this combination in a locally applied
(inhaled) formulation and application in an inhalation device for
instance in the Novolizer.RTM..
Inventors: |
Goede, Joachim; (Hanau,
DE) ; Maus, Joachim; (Muhlheim, DE) ; Cnota,
Peter Jurgen; (Bad Homburg, DE) ; Szelenyi,
Istvan; (Schwaig, DE) |
Correspondence
Address: |
VENABLE LLP
P.O. BOX 34385
WASHINGTON
DC
20045-9998
US
|
Assignee: |
Sofotec GmbH & Co. KG
Frankfurt am Main
DE
|
Family ID: |
34837534 |
Appl. No.: |
11/051469 |
Filed: |
February 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60541957 |
Feb 6, 2004 |
|
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|
Current U.S.
Class: |
424/46 ; 514/423;
514/651 |
Current CPC
Class: |
A61P 11/08 20180101;
A61K 31/4015 20130101; A61K 45/06 20130101; A61P 11/06 20180101;
A61K 31/401 20130101; A61K 31/167 20130101; A61K 31/138 20130101;
A61K 31/401 20130101; A61K 31/4015 20130101; A61K 31/167 20130101;
A61K 9/0075 20130101; A61K 31/138 20130101; A61P 43/00 20180101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 9/008 20130101; A61P 29/00
20180101; A61P 11/00 20180101 |
Class at
Publication: |
424/046 ;
514/423; 514/651 |
International
Class: |
A61K 031/401; A61K
031/138; A61L 009/04; A61K 009/14 |
Claims
1. A combination of an anticholinergic and a long-acting
.beta.2-mimetic agent for the treatment of respiratory diseases,
especially of inflammatory or obstructive diseases.
2. The combination according to claim 1 wherein the anticholinergic
is selected from the group consiting of racemic glycopyrrolate, an
enantiomer thereof, a diasterioisomer thereof and physiologically
acceptable salts or a mixture and mixtures thereof.
3. The combination according to claim 2 wherein the anticholinergic
is R,R-glycopyrrolate or a physiologically acceptable salt
thereof.
4. The combination according to claim 1 wherein the .beta.2-mimetic
agent is selected from the group consisting of formoterol and
salmeterol and their physiologically acceptable salts.
5. The combination according to claim 4 wherein the .beta.2-mimetic
agent is formoterol or a physiologically acceptable salt
thereof.
6. The combination according to claim 5 wherein the daily dose of
formoterol is from 1 to 72 .mu.g.
7. The combination according to claim 4 wherein the .beta.2-mimetic
agent is salmeterol or its physiologically acceptable salts.
8. The combination according to claim 7 wherein the daily dose of
salmeterol is from 10 to 300 .mu.g.
9. The combination according to claim 1 wherein the daily dose of
R,R-glycopyrrolate is from 5 to 500 .mu.g.
10. The combination according to claim 1 wherein the daily dose of
R,R-glycopyrrolate is from 5 to 100 .mu.g.
11. A pharmaceutical for the treatment of allergies and respiratory
diseases containing as active substances an anticholinergic and at
least a long-acting .beta.2 sympathomimetic.
12. The pharmaceutical according to claim 11, wherein the
anticholinergic is selected from the group consisting of racemic
glycopyrrolate, an enantiomer thereor, a diastereoisomer thereof
and physiologically acceptable salts and mixtures thereof.
13. The pharmaceutical according to claim 12, that comprises R,R
glycopyrrolate or a physiologically acceptable salt thereof.
14. The pharmaceutical according to claim 11, that comprises R,R
glycopyrrolate and formoterol or their physiologically acceptable
salts.
15. The pharmaceutical according to claim 11, wherein the active
substances are available readily mixed in a fixed combination, if
appropriate together with the usual excipients, adjuncts, and
additives in a pharmaceutical form suitable for inhalative
application.
16. The pharmaceutical according to claim 11, where the active
substances are available in separate packing units whereby both
substances can be taken from the separate packing units in such a
way that they are available for simultaneous inhalative
application.
17. The pharmaceutical according to claim 16, where the active
substances can be administered independently from each other.
18. The pharmaceutical according to claim 11, that is an inhalable
aerosol with or without propellant.
19. The pharmaceutical according to claim 11 that is an inhalable
dry powder.
20. The pharmaceutical according to claim 11, that is an inhalable
suspension or solution.
21. The pharmaceutical according to claim 11 presented in an
inhaler.
22. The pharmaceutical according to claim 21, comprising formoterol
as .beta.2 sympathomimetic.
23. The pharmaceutical according to claim 21, comprising salmeterol
as .beta.2 sympathomimetic.
24. The combination of claim 6 wherein the daily dose is from 3 to
50 .mu.g,
25. The combination of claim 24 wherein the daily dose is from 6 to
48 .mu.g.
26. The combination of claim 8 wherein the daily dose is from 25 to
200 .mu.g.
27. The combination of claim 26 wherein the daily dose is from 50
to 200 .mu.g.
28. The combination of claim 9 wherein the daily dose is from 15 to
300 .mu.g.
Description
[0001] The present invention describes a combination of
anticholinergic and .beta. mimetics for the treatment of
respiratory diseases including airway inflammation or obstruction
such as chronic obstructive pulmonary disease (COPD) and asthma. It
further comprises the preparation of this combination in a locally
applied (inhaled) formulation and application in an inhalation
device for instance in the Novolizer.RTM..
[0002] It is state of the art that various .beta.-mimetics and
anticholinergics can successfully be used as bronchospasmolytics
for the treatment of obstructive respiratory ailments, such as COPD
and asthma. Substances with .beta.-sympathomimetic effectiveness,
such as formoterol or salmeterol are known to be associated with
undesirable side-effects in human treatment.
[0003] In general, the central effects manifest as unease,
excitation, sleeplessness, fear, shaking fingers, outbreak of
sweating and headache. Here, inhalative application does not
exclude these side-effects although they are generally less severe
than with peroral or parenteral application.
.beta.-sympathomimetics are primarily associated with a more or
less pronounced .beta.-stimulating effect on the heart. It
generates tachycardia, palpitation, angina pectoris-like complaints
and arrhythmia.
[0004] Anticholinergic agents such as glycopyrrolate prevent the
effects resulting from passage of impulses through the
parasympathetic nerves. This action results from their ability to
inhibit the action of the neurotransmitter acetylcholine by
blocking its binding to muscarinic cholinergic receptors. There are
at least three types of muscarinic receptor subtypes. M1 receptors
are found primarily in brain and other tissue of the central
nervous system, M2 receptors are found in heart and other
cardiovascular tissue, and M3 receptors are found in smooth muscle
and glandular tissues. The muscarinic receptors are located at
neuroeffector on, e.g. smooth muscle and, in particular, M3
muscarinic receptors are located in airway smooth muscle.
Consequently, anticholinergic agents may also be referred to as
muscarinic receptor antagonists.
[0005] The parasympathetic nervous system plays a major role in
regulation bronchomotor tone, and bronchoconstriction is largely
the result of reflex increases in parasympathetic activity caused
in turn by a diverse set of stimuli.
[0006] There are muscarinic receptors on peripheral systems such as
salivary glands and gut and therefore the use of systemically
active muscarinic receptor antagonists is limited by side-effects
such as dry mouth and constipation. Thus the bronchodilatory and
other beneficial actions of muscarinic receptor antagonists are
ideally produced by an inhaled agent which has a high therapeutic
index for activity in the lung compared with the peripheral
compartment.
[0007] Anticholinergic agents also partially antagonize
bronchoconstriction induced by histamine, bradykinin, or
prostaglandin F2alpha, which is deemed to reflect the participation
of parasympathetic efferents in the bronchial reflexes elicited by
these agents.
[0008] It is well accepted that the stimulation of
.beta.2-adrenergic receptors stimulates adenylate cyclase resulting
in an increased level of the second messenger cAMP that in turn
leads decreased intracellular calcium concentration and
consequently smooth muscle relaxation. Stimulation of M3 receptors
causes hydrolysis of polyphosphoinositides and mobilization of
intracellular calcium which results in a variety of
Ca.sup.2+-mediated responses such as smooth muscle contraction.
Consequently, inhibition of this receptor activation prevents the
intracellular calcium increase and leads to smooth muscle
relaxation.
[0009] As the current treatment of asthma and COPD is not
satisfactory improved, the problem underlying the present invention
was to provide effective and more convenient therapeutic
interventions.
[0010] A solution is given by the combination of a
.beta.-sympathomimetic, which has a long-lasting effect, with an
anticholinergic, which has a long-lasting effect.
[0011] Due to their different mode of action, the combination of
anticholinergic and .beta.-sympathomimetic agents is reasonable,
but surprisingly, it has now been found that the above mentioned
side-effects can be substantially reduced. In addition, it was also
very surprisingly discovered that the bronchospasmolytic effects of
the anticholinergic, which has a long-lasting effect, and the
.beta.-mimetic, which has a long-lasting effect, increase in a
superadditive manner with the combination of active ingredients.
According to the invention, a substantial increase in effectiveness
can be expected--in comparison to the individual substances and
combinations known from prior art--in the case of both COPD and
asthma. In a further aspect, this combination therapy exhibits both
a fast onset of action and a prolonged duration of action, so that
patients feel a rapid improvement in their condition and, in view
of the duration of action, a reduced need for short-acting rescue
medicaments, such as salbutamol or terbutaline. Surprisingly this
effect is exhibited when the two drugs are administered at the same
time, i.e. in a composition containing both drugs or sequentially.
Therefore, medicaments of the invention facilitate the treatment of
inflammatory or obstructive airway diseases because a once daily
therapy may be sufficient. Where necessary, medicaments of the
invention can be used on demand in rescue treatment of obstructive
or inflammatory airway diseases, so that they facilitate treatment
of such diseases with a single medicament.
EXPERIMENTAL PART
[0012] The interaction between formoterol and R,R-glycopyrrolate
was investigated in anesthetized (urethane 2 mg/kg,
intraperitoneally) male guinea pigs weighing 400-600 g. After
cannulating the trachea, animals were respired using a small animal
respiratory pump with a constant tidal volume and a rate of 60
breaths/min. The lung resistance was measured by using a rodent
lung function recording system (MUMED, London, UK). Compounds were
given intravenously (i.v.) via a catheter placed in the right
jugular vein. After surgery, the animals were allowed to stabilize.
10 min before acetylcholine (10 .mu.g/kg, i.v.) administration, the
guinea pigs were disconnected from the respirator and either
vehicle (10 mg/lactose) or different amounts of drugs (blended with
lactose) were administered intratracheally (i.th.) using a syringe.
The trachea was then reconnected to the respirator and changes in
pulmonary mechanics were recorded. Acetylcholine (10 .mu.g/kg) was
injected intravenously, in every 10 minutes for 60 min.
[0013] Acetylcholine administered i.v. caused a sustainable, three
to four-fold increase in the pulmonary resistance. Both
R,R-glycopyrrolate and formoterol dose-dependently inhibited the
acetylcholine-induced bronchoconstriction. R,R-glycopyrrolate was
not effective at the dose of 1 .mu.g/kg, i.th., but it inhibited
the bronchospasm by ca. 40% at 3 .mu.g/kg, i.th. and by about 80%
at 10 .mu.g/kg, i.th., respectively. Similarly, formoterol did not
show any bronchodilatory effects at the lowest dose of 1 .mu.g/kg,
i.th., but it slightly dilated the airways at the medium dose of 3
mg/kg, i.th. (about 20%). At the highest dose of 10 .mu.g/kg, i.th.
formoterol almost completely attenuated bronchoconstriction induced
by i.v. acetylcholine. When applying R,R-glycopyrrolate and
formoterol each at the dose of 1 .mu.g/kg, i.th., together, the
simultaneous administration resulted in an almost complete
attenuation of acetylcholine-induced bronchoconstriction.
Surprisingly, the two compounds given in doses which alone were not
effective at all, led, when administered simultaneously, to a very
strong bronchodilatory effect in guinea pigs clearly indicating the
overadditive nature of this interaction.
[0014] The types of diseases that may be treated using the
combinations of the present invention include, but are not limited
to, asthma, chronic or acute bronchoconstriction, chronic
bronchitis, airway obstruction, emphysema, chronic obstructive
pulmonary disease (COPD), COPD that has chronic bronchitis,
pulmonary emphysema or dyspnea associated therewith and COPD that
is characterized by irreversible, progressive airway obstruction,
and exacerbation of airway reactivity consequent to other drug
therapy, e.g., aspirin therapy. In one aspect, the present
invention provides a medicament containing, separately or together,
(A) formoterol or salmeterol, or a pharmaceutically acceptable
salts thereof or a solvate of form oterol/salmeterol or said salts
and (B) racemic glycopyrrolate, one of its enantiomers, especially
of (R,R)-glycopyrrolate, one of its diastereoisomers, or its
pharmaceutically acceptable salts, for simultaneous, sequential or
separate administration in the treatment of respiratory diseases,
especially inflammatory or obstructive diseases.
[0015] In another aspect, the present invention provides a method
of treating a respiratory, especially inflammatory or obstructive
disease which comprises administering to a subject in need of such
treatment effective amounts of (A) as herein before defined and (B)
as herein before defined.
[0016] In a further aspect, the present invention provides a
pharmaceutical composition comprising a mixture of effective
amounts of (A) as herein before defined and (B) as herein before
defined, optionally together with a pharmaceutically acceptable
carrier.
[0017] The present invention also provides (A) and (B) as herein
before defined in combination therapy by simultaneous, sequential,
or separate administration in the treatment of respiratory
diseases.
[0018] The invention further provides the use of (A) as herein
before defined or (B) as herein before defined in the preparation
of a medicament for combination therapy by simultaneous,
sequential, or separate administration of (A) and (B) in the
treatment of respiratory diseases.
[0019] The present invention still further provides the use of (A)
and (B) as herein before defined for the preparation of a
medicament for combination therapy by simultaneous, sequential, or
separate administration in the treatment of respiratory
diseases.
[0020] Pharmaceutically acceptable salts of formoterol or
salmeterol include, for example, salts of inorganic acids such as
hydrochloric, hydrobromic, sulfuric and phosphoric acids, and
organic acids such as fumaric, maleic, acetic, lactic, citric,
tartaric, ascorbic, succinic, glutaric, gluconic, tricarballylic,
oleic, benzoic, p-methoxybenzoic, salicylic, o-and
p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic,
p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids.
[0021] Component (A) may be in any isomeric form or mixture of
isomeric forms, for example a pure enantiomer, a mixture of
enantiomers, a racemate or a mixture thereof. It may be in the form
of a solvate, for example a hydrate, thereof, for example a pure
enantiomer, a mixture of enatiomers, a racemate or a mixture
thereof. It may be in the form of a solvate, for example a hydrate,
thereof, and may be present in a particular crystalline form.
Preferably, component (A) is formoterol fumarate, especially in the
form of the dihydrate or is salmeterol xinafoate, especially in the
form of the pure salt but also in the form of a solvate, for
example a monohydrate or a dihydrate.
[0022] Administration of the medicament or pharmaceutical
composition as herein before described, with (A) and (B) in
admixture or separate, is preferably by inhalation, i.e. (A) and
(B) or the mixture thereof are in inhalable form. The inhalable
form of the medicament of (A) (B) may be, for example, an
atomizable composition such as an aerosol comprising the active
ingredient, (A) and (B) separately or in admixture, in solution or
dispersion in a propellant, or a nebulizable composition comprising
a dispersion of the active ingredient in an aqueous/organic or
medium. For example, the inhalable form of the medicament may be an
aerosol comprising a mixture of (A) and (B) in solution or
dispersion in a propellant, or a combination of an aerosol
containing (A) in solution or dispersion in a propellant with an
aerosol containing (B) in solution or dispersion in a propellant.
In another example, the inhalable form is a nebulized composition
comprising a dispersion of (A) and (B) in an aqueous or organic
medium, or a combination of a dispersion of (A) in such a medium
with a dispersion of (B) in such a medium.
[0023] In another embodiment of the invention, the inhalable form
is a dry powder, i.e. (A) and/or (B) are present in a dry powder
comprising finely divided (A) and/or (B) optionally together with a
finely divided pharmaceutically acceptable carrier, which is
preferably present and may be chosen from materials known as
carriers in dry powder inhalation compositions, for example
saccharides, including monosaccharides, disaccharides,
polysaccharides and sugar alcohols such as arabinose, fructose,
ribose, mannose, sucrose, trehalose, lactose, starches, dextran or
mannitol. An especially preferred carrier is lactose. The dry
powder may be in capsules of gelatin or plastic, or in blisters,
for in a dry powder inhalation device. Alternatively, the dry
powder may be contained as a reservoir in a dose dry powder
inhalation device.
[0024] In the finely divided particulate form of the medicament,
and in the aerosol composition where the active ingredient is
present in particulate form, the active ingredient may have an
average particle diameter of up to 4 .mu.m. The finely divided
carrier, where present, generally has a maximum diameter up to
approximately 500 .mu.m and conveniently has a mean particle
diameter of 10 to 350 .mu.m, preferably approx. 110 to 290 .mu.m.
The particle size of the active ingredient, and that of the carrier
where present in dry powder compositions, can be reduced to the
desired level by conventional methods, for example by grinding in
an air-jet mill, ball mill or vibrator mill, microprecipitation,
spray-drying, lyophilisation or recrystallisation from
supercritical media.
[0025] The inhalable medicament may be administered using an
inhalation device for the inhalable form, such devices being well
known in the art. Accordingly, the invention also provides a
pharmaceutical product comprising a medicament or pharmaceutical
composition as herein before described in inhalable form as herein
before described in association with one or more inhalation
devices. In a further aspect, the invention provides an inhalation
device, or a pack of two or more inhalation devices, containing a
medicament or pharmaceutical composition as herein before described
in inhalable form as herein before described. A suitable daily dose
of formoterol, or salt or thereof, particularly as formoterol
fumarate dihydrate, for inhalation may be from 1 to 72 .mu.g,
generally from 3 to 50 .mu.g, preferably from 6 to 48 .mu.g, for
instance from 6 to 24 .mu.g.
[0026] A suitable daily dose of salmeterol, or salt or thereof,
particularly as salmeterol xinafoate, for inhalation may be from 10
to 300 .mu.g, generally from 25 to 200 .mu.g, preferably from 50 to
200 .mu.g, for instance from 50 to 100 .mu.g.
[0027] A suitable daily dose of glycopyrrolate salt, particularly
as (R,R)-glycopyrrolate, for inhalation may be from 5 to 500 .mu.g,
preferably from 15 to 300 .mu.g. A dosage range between 5 and 100
.mu.g/day is especially preferred.
[0028] The precise doses used will of depend on the condition to be
treated, the patient and the efficiency of the inhalation device.
The unit doses of (A) and (B) and their frequency of administration
may be chosen accordingly.
[0029] In accordance with the above, the invention also provides a
pharmaceutical kit comprising (A) and (B) as herein before defined
in separate unit dosage forms, said forms being suitable for
administration of (A) and (B) in effective amounts. Such a kit
suitably further comprises one or more inhalation devices for
administration of (A) and (B). For example, the kit may comprise
one or more dry powder inhalation devices adapted to deliver dry
powder from a capsule, together with capsules containing a dry
powder comprising a dosage unit of (A) and capsules containing a
dry powder comprising a dosage unit of (B). In another example, the
kit may comprise a multidose dry powder inhalation device
containing in the reservoir thereof a dry powder comprising (A) and
a multidose dry powder inhalation device containing in the
reservoir thereof a dry powder comprising (B). In a further
example, the kit may comprise a metered dose inhaler containing an
aerosol comprising (A) in a propellant and a metered dose inhaler
containing an aerosol comprising (B) in a propellant.
[0030] Treatment of inflammatory or obstructive airway diseases in
accordance with the invention may be symptomatic or prophylactic
treatment. Inflammatory or obstructive airway diseases to which the
present invention is applicable include asthma of whatever type or
genesis including both intrinsic non-allergic asthma and extrinsic
(allergic) asthma.
[0031] The invention is illustrated by but not restricted to the
following two examples.
Example 1
Powder Inhalation with 12 .mu.g Formoterol Fumarate Dihydrate and
120 .mu.g R,R-glycopyrrolate Per Single Dose
[0032] A quantity of 12 g micronized formoterol fumarate dihydrate
is mixed with 100 g alpha lactose monohydrate, the mixture is given
on a sieve of 0.5 mm mesh size and finally mixed again. 120 .mu.g
micronized R,R-glycopyrrolate is mixed with 1000 g alpha lactose
monohydrate, the mixture is given on a sieve of 0.8 mm mesh size
and finally mixed again. The two mixtures received are blended and
filled up with alpha lactose monohydrate to 12000 g. Subsequently,
it is mixed again and the powder mixture received is filled in
powder inhalers releasing 12 mg of powder per single dose. Per
single dose, 12 .mu.g formoterol fumarate dihydrate and 120 .mu.g
R,R-glycopyrrolate are released from a powder inhaler and supplied
to the patient's airways.
EXAMPLE 2
Dosage Aerosol with 6 .mu.g Formoterol Fumarate Dihydrate and 350
.mu.g R,R-glycopyrrolate Per Single Dose
[0033] A quantity of 1000 g 1,1,1,2,3,3,3 heptafluoropropane (=HFA
227) is cooled down at a temperature of -55.degree. C. and, while
stirring, mixed with a solution of 11.7 g
polyoxethylene-25-glyceryl-trioleate (trade name: Tagat TO) in 11.7
g absolute ethanol. Subsequently, 0.1008 g micronized formoterol
fumarate dihydrate and 5.88 g micronized R,R-glycopyrrolate as well
as 0.9 g micronized saccharin sodium is added, and the suspension
produced is intensively homogenized. While further cooling and
stirring, the suspension is filled up with refrigerated propellant
227 to 1170 g and after mixing again filled in metal cans which are
closed with metering valves releasing 50 .mu.l of the suspension
per actuation. Thus, 6 .mu.g formoterol fumarate dihydrate and 350
.mu.g R,R-glycopyrrolate are released per actuation.
* * * * *