Pharmaceutical Composition
Field of Invention
The present invention relates to pharmaceutical compositions for inhalation which
comprise one or more bronchodilators and optionally an inhaled corticosteroid. There is
also provided a process for preparing such compositions and the use thereof in the
treatment and/or prevention of respiratory, inflammatory or obstructive airway disease,
particularly chronic obstructive pulmonary disease.
Background of Invention
Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that is
increasing its prevalence worldwide. In India, the estimated prevalence is about 12.36
million. It is currently the fourth leading cause of death in the UK & US, and predicted to
rank third in the global impact of disease by the year 2020.
COPD is a preventable and treatable disease state characterized by air flow limitation that
is not fully reversible. The airflow obstruction is usually progressive and associated with
an abnormal inflammatory response of the lungs to noxious particles or gases, primarily
caused by cigarette smoking. Although COPD affects the lungs it also produces
significant systemic consequences. COPD is associated with mucus hyper secretion,
emphysema, bronchiolitis.
The major goals of COPD therapy include smoking cessation, relief of symptoms,
improvement in physiological functions and limiting complications, such as abnormal gas
exchange and exacerbation of disease. However, an integrated approach to the treatment
of COPD, involves a combination of healthcare maintenance such as smoking cessation,
avoidance of indoor, outdoor pollutants and allergens, and avoidance of occupational
exposure to allergens, use of drugs and supplemental therapies in a step-wise fashion as
the disease progresses.
Currently, therapy for the treatment or prevention of COPD and asthma includes the use
of one or more long acting bronchodilators and an inhaled corticosteroid (ICS).
Inhaled bronchodilators are the foundation in the therapy of COPD because of their
capacity to alleviate symptoms, decrease exacerbations of disease and improve quality of
life. These drugs also improve airflow limitation and hyperinflation, thereby decreasing
the work of breathing and improving exercise tolerance. In addition, bronchodilators
may reduce respiratory muscle fatigue and improve mucociliary clearance.
More specifically, the choice of bronchodilators includes beta2-agonists and
anticholinergics. Further, beta -agonists can be short acting for immediate relief, or long
acting for long term prevention of asthma symptoms.
Long acting beta2-agonists (LABAs) improve lung function, reduce symptoms and
protect against exercise-induced dyspnea in patients with asthma and COPD. LABAs
induce bronchodilation by causing prolonged relaxation of airway smooth muscle. In
addition to prolonged bronchodilation, LABAs exert other effects such as inhibition of
airway smooth-muscle cell proliferation and inflammatory mediator release, as well as
non smooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection
of the respiratory mucosa and attenuation of neutrophil recruitment and activation.
Also, use of a LABA reduces the frequency of drug administration. Commercially
available LABAs include salmeterol and formoterol.
Anticholinergic agents also act as bronchodilators and are potential alternatives to beta
agonists, particularly LABAs. However, anticholinergics can also be administered along
with LABAs for the management of asthma. Anticholinergics act by competing with
acetylcholine for the receptor sites at vagus nerve or nerve-muscle junctions. This
prevents the transmission of reflexes that are induced by asthma stimuli.
Use of anticholinergics provides an advantage in elderly patients as the responsiveness of
beta2-agonists declines with old age. Further it would be advantageous to use
anticholinergics in patients who are intolerant to the use of beta2-agonists.
Even though it is known that beta2-agonists provide a symptomatic relief in
bronchoconstriction, another component of COPD, which is inflammation, requires a
separate treatment such as with steroids. Most of the inhaled corticosteroids need to be
administered in multiple dosage regimens.
Corticosteroids exhibit inhibitory effects on inflammatory cells and inflammatory
mediators involved in the pathogenesis of respiratory disorders such as COPD.
Treatment with a corticosteroid/glucocorticoid is considered one of the most potent and
effective therapies currently available for COPD.
However, the use of corticosteroids has been limited due to potential side effects
associated with their use, including suppression of the Hypothalamic-Pituitary-Adrenal
(HPA) axis, adverse effects on bone growth in children and on bone density in the
elderly, ocular complications (cataract formation and glaucoma) and skin atrophy.
Commercially available corticosteroids include beclomethasone, budesonide, fluticasone,
mometasone, ciclesonide and triamcinolone.
Currently, there are several commercially available pharmaceutical compositions for
inhalation comprising combinations of LABA and inhaled corticosteroid (ICS).
Examples of such combinations for the treatment of asthma and chronic obstructive
pulmonary disease (COPD) are salmeterol/fluticasone propionate (Advair® diskus®,
Advair® HFA), and formoterol fumarate dehydrate/budesonide (Symbicort®).
Thus combination therapy of a bronchodilator with an ICS improves pulmonary
efficiency, reduces inflammatory response and provides symptomatic relief as compared
to higher doses of ICS alone in patients affected by respiratory disorders such as COPD.
The selection of a specific bronchodilator and ICS plays a very important role in
formulation of fixed dose combination therapies.
Further, combination therapy reduces the cost and also provides control of respiratory
disorders. Reducing the dose frequency to the minimum is a main step in simplifying
COPD management for improving patient adherence to the therapy.
US2009088408 discloses pharmaceutical compositions of anticholinergics,
corticosteroids and betamimetics and their use in the treatment of respiratory diseases.
The examples of this application are inhalable powders or suspension aerosol
compositions which contain tiotropium or ipratropium bromide.
US2005042174 discloses a combination of doses of a beta2-agonist, an anticholinergic
agent and an anti-inflammatory steroid.
WO2006 105401 discloses anticholinergic in combination with a corticosteroid, and a
long acting beta agonist, for simultaneous or sequential administration in the prevention
or treatment of a respiratory, inflammatory or obstructive airway disease.
US2008279948 discloses a medicament comprising a beta2-agonist, a glycopyrronium
salt and mometasone furoate. The examples of this application contain the beta2-agonist
indacaterol maleate.
US2008286363 discloses a medicament comprising a beta2-agonist (such as indacaterol
maleate), a glycopyrronium salt and a corticosteroid. The examples of this application
contain the corticosteroid 3-methyl-thiophene-2-carboxylic acid
(6S,9R, 1OS, 11S,13S,16R, 17R)-9-chloro-6-fluoro- 11-hydroxy- 17-methoxycarbonyl-
10,13,1 6-trimethyl-3-oxo-6,7, 8,9, 0, 1,12,13,14,1 ,16,17-dodecahydro-3H-cyclopenta-
[a]phenanthren-17-yl ester.
US20 101 66671 discloses a medicament comprising an antimuscarinic agent, a beta2-
agonist and a corticosteroid. The examples of this application contain glycopyrronioum,
formoterol fumarate and mometasone furoate.
US7439393 discloses certain phenethanolamine derivatives for the treatment of
respiratory diseases. The use of such compounds in combination therapy with other
therapeutic agents is also disclosed.
US20080041369 discloses propellant-free aerosol formulations comprising inter alia
olodaterol, a corticosteroid such as budesonide, beclomethasone or fluticasone and an
anticholinergic such as tiotropium, oxitropium or ipratropium.
US20050239778 discloses medicament combinations comprising inter alia olodaterol
and at least one other active substance, such as a steroid.
US200803 17862 discloses medicaments comprising an antimuscarinic agent and a
corticosteroid for the treatment of inflammatory or obstructive airways diseases. In
particular, this application discloses aerosol compositions comprising glycopyrronium
and mometasone furoate.
US20060069073 discloses a combination of glycopyrronium and one or more steroids as
a second active substance.
WO20051 10402 discloses medicaments comprising glycopyrrolate in combination with a
beta2-agonist such as indacaterol maleate.
WO2005074900 discloses a combination of an anticholinergic such as glycopyrronium
and a long-acting beta-mimetic agent such as formoterol or salmeterol.
Thus, there is still a need to develop suitable combinations comprising a beta agonist, an
anticholinergic agent and/or an inhaled corticosteroid that alleviate COPD.
Hence, there still exits a need to formulate pharmaceutical compositions comprising a
beta agonist, an anticholinergic agent and an inhaled corticosteroid exhibiting reduced
side effects and which can be administered once a day.
Objects of the Invention
The object of the present invention is to provide pharmaceutical compositions for
inhalation comprising one or more bronchodilators and an inhaled corticosteroid for
administration in the prevention or treatment of respiratory, inflammatory or obstructive
airway disease.
Another object of the present invention is to provide pharmaceutical compositions for
inhalation comprising one or more bronchodilators and an inhaled corticosteroid for once
daily administration for the prevention or treatment of respiratory, inflammatory or
obstructive airway disease.
Yet another object of the present invention is to provide a process for preparing the
pharmaceutical compositions comprising one or more bronchodilators and an inhaled
corticosteroid for administration in the prevention or treatment of respiratory,
inflammatory or obstructive airway disease.
A further object of the present invention is to provide a method for prophylaxis or
treatment of COPD which comprises administering pharmaceutical compositions
comprising one or more bronchodilators and an inhaled corticosteroid.
Summary of the Invention
According to a first aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate and a beta2-agonist.
Preferably the composition further comprises one or more inhaled corticosteroids.
According to a second aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate and vilanterol.
According to a third aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate and olodaterol.
According to a fourth aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate and carmoterol.
According to a fifth aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate, olodaterol and fluticasone, especially an ester of
fluticasone, in particular fluticasone furoate.
According to a sixth aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate, olodaterol and mometasone, especially an ester
of mometasone, in particular mometasone furoate.
According to a seventh aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate, vilanterol and fluticasone, especially an ester of
fluticasone, in particular fluticasone furoate.
According to a eighth aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate, fomoterol and fluticasone, especially an ester of
fluticasone, in particular fluticasone furoate.
According to a ninth aspect of the present invention, there is provided a pharmaceutical
composition comprising glycopyrrolate, indacetrol and fluticasone, especially an ester of
fluticasone, in particular fluticasone furoate.
According to a tenth aspect of the present invention, there is provided a process for
preparing the pharmaceutical compositions described above.
According to a eleventh aspect of the present invention, there is provided a method for
prophylaxis or treatment of asthma, COPD or a related respiratory disorder which
comprises administering a pharmaceutical compositions described above.
According to a twelfth aspect of the present invention there is provided a use in treating
disorders or conditions that respond to, or are prevented, ameliorated or eliminated by,
the administration of pharmaceutical compositions described above.
Detailed Description of the Invention
As discussed above, the selection of a specific beta -agonist, anticholinergic agent and
inhaled corticosteroid (ICS) plays a very important role in formulation of fixed dose
combinations.
The present invention thus provides pharmaceutical compositions for inhalation
comprising or consisting of glycopyrrolate, a beta2-agonist, and an inhaled corticosteroid.
In one embodiment, there is provided a pharmaceutical composition for inhalation
comprising or consisting of:
(a) glycopyrrolate;
(b) a beta2-agonist selected from the group consisting of carmoterol, formoterol,
indacaterol, olodaterol, vilanterol; and, optionally, when the LABA is selected
from formoterol, indacaterol, olodaterol, vilanterol;
(c) an inhaled corticosteroid (ICS) selected from the group consisting of fluticasone,
mometasone;
preferably wherein (a), (b) and (c) are formulated for simultaneous, separate or sequential
administration; and provided that the composition does not comprise glycopyrrolate,
mometasone furoate and indacaterol maleate or formoterol fumarate.
A particularly preferred pharmaceutical composition of the present invention comprises,
or consists of, (a) glycopyrrolate (b) indacaterol and (c) fluticasone (especially
fluticasone furoate).
A further particularly preferred pharmaceutical composition of the present invention
comprises, or consists of, (a) glycopyrrolate, (b) formoterol and (c) fluticasone
(especially fluticasone furoate).
A further particularly preferred pharmaceutical composition of the present invention
comprises, or consists of, (a) glycopyrrolate (b) vilanterol and (c) fluticasone (especially
fluticasone furoate).
A further particularly preferred pharmaceutical composition of the present invention
comprises, or consists of, (a) glycopyrrolate, (b) olodaterol and (c) fluticasone (especially
fluticasone furoate).
A still further particularly preferred pharmaceutical composition of the present invention
comprises, or consists of, (a) glycopyrrolate, (b) olodaterol and (c) mometasone.
In an alternative preferred embodiment of the invention, there is provided a
pharmaceutical composition comprising or consisting of glycopyrrolate and a beta2-
agonist.
In a still further preferred embodiment of the invention, there is provided a
pharmaceutical composition comprising or consisting of (a) glycopyrrolate; and (b) a
beta2-agonist selected from the group consisting of carmoterol, olodaterol, vilanterol;
preferably wherein (a) and (b) are formulated for simultaneous, separate or sequential
administration.
A particularly preferred pharmaceutical composition of the present invention comprises,
or consists of, (a) glycopyrrolate and (b) vilanterol.
A further particularly preferred pharmaceutical composition of the present invention
comprises, or consists of, (a) glycopyrrolate and (b) olodaterol.
A still further particularly preferred pharmaceutical composition of the present invention
comprises, or consists of, (a) glycopyrrolate and (b) carmoterol.
Our inventors have found that the above-mentioned pharmaceutical compositions are
effective for treating inflammatory and/or obstructive diseases of the respiratory tract,
particularly asthma or chronic obstructive pulmonary disease (COPD).
Furthermore, the pharmaceutical compositions of the present invention advantageously
provide a rapid onset of action, longer duration of action and improved control of
obstructive or inflammatory airway diseases, or reduction in the exacerbations of the
diseases.
Also, the pharmaceutical compositions of the present invention advantageously reduce
the risk of undesirable side effects as compared to the repeated exposure of the steroid
alone involved in the treatment of inflammatory or obstructive airways diseases.
Another advantage of the pharmaceutical compositions of the present invention is that the
invention facilitates the treatment of an obstructive and inflammatory airway disease with
a single medicament.
Further the pharmaceutical compositions of the present invention provide for the
administration of combination therapies by use of a single inhaler for patients who
currently have to make use of multiple inhalers. By way of example, patients may
administer pharmaceutical compositions of the present invention from a single inhaler
instead of administering from three different inhalers, one for corticosteroid, one for
anticholinergic and one for a ong acting beta2-agonist. This is particularly important in
case of elderly patients who may get confused between the inhalers and who also suffer
from several other medical conditions such as heart disease and arthritis, and are
receiving multiple other medications.
In a preferred embodiment, the pharmaceutical compositions of the present invention are
formulated for once daily administration.
The pharmaceutical compositions of the present invention comprise glycopyrrolate. The
word "glycopyrrolate" can be interchangeably used with "glycopyrronium".
Glycopyrrolate belongs to the class of quaternary ammonium anticholinergic drugs and
antagonizes the neurotransmitter acetylcholine at its muscarinic receptors. This effect
leads to a considerable smooth muscle relaxation resulting in a prolonged bronchodilating
effect. More specifically it inhibits acetylcholine binding to M3 muscarinic receptors
thereby inhibiting bronchoconstriction.
Glycopyrrolate is a quaternary ammonium salt. Suitable counter ions are
pharmaceutically acceptable counter ions including, for example, fluoride, chloride,
bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate,
butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate,
diphenyl-acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-
hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate,
methanesulfonate and benzenesulfonate. A particularly preferred salt of glycopyrrolate is
the bromide salt thereof. The bromide salt of glycopyrrolate is chemically known as {3-
[(Cyclopentyl-hydroxyphenylacetyl) oxy]-l, 1-dimethylpynrolidinium bromide}.
Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four
stereoisometric forms namely (3R, 2'R)-, (3S, 2'R)-, (3R, 2'S)- and (3S, 2'S), i. e. , two
enantiomeric pairs of diastereomers. The two di- astereomer pairs have been separated
from one another. Commercially available formulations of glycopyrrolate contain both
the (R, S)-glycopyrrolate and (S, R)-glycopyrrolate enantiomers.
Glycopyrrolate is currently available marketed in the form of oral tablets for adjunctive
therapy in the treatment of peptic ulcer, as an injectable for therapy in the treatment of
peptic ulcer and as a preoperative antimuscarinic to reduce secretions and as a capsule for
reducing chronic severe drooling in patients aged between 3 to 16 years with neurologic
conditions associated with problem drooling.
Glycopyrrolate also 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. Further, inhaled glycopyrrolate exhibits low systemic absorption, and
therefore is not associated with typical systemic antimuscarinic adverse effects.
According to the present invention, glycopyrrolate may be present in an amount of from
about 50mcg to about 200mcg.
Bronchodilators used according to the present invention may be beta-agonists and/or
anticholinergics. According to the present invention, beta agonists may comprise, one or
more, short acting beta agonist(s), long acting beta agonist(s) and/or ultra long acting beta
agonist(s).
In addition to glycopyrrolate, the pharmaceutical compositions of the present invention
further comprise a beta2-agonist, preferably selected from the group comprising
carmoterol, formoterol, indacaterol, olodaterol, vilanterol.
Carmoterol is chemically known as 8-hydroxy-5 - (l-hydroxy-2-(N-(2-(4-
methoxy:phenyi) - 1-methyl :ethyl) amino)ethyI)-2 (lH)-quinolinone. Carmoterol is a
long acting beta2-agonist characterized by having a rapid onset of action, prolonged
duration of action and also having a high selectivity towards the beta2 adrenoreceptor.
Furthermore, carmoterol is more potent than other LABAs such as formoterol and
salmeterol. A particularly preferred pharmaceutically acceptable salt of carmoterol is
carmoterol hydrochloride. According to the present invention, carmoterol may be present
in an amount of from about lmcg to about 4mcg.
Formoterol is chemically known as (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-
methoxyphenyl)- methylethyI]-amino] ethyl] formanilide. Formoterol is a selective
LABA. Formoterol exhibits a quick onset of action (1-3 minutes) which helps to achieve
an immediate therapeutic response. Furthermore formoterol exhibits a long duration of
action of more than 12 hours. A particularly preferred pharmaceutically acceptable ester
of formoterol is formoterol fumarate. A particularly preferred pharmaceutically
acceptable ester of formoterol is formoterol fumarate dihydrate. According to the present
invention, formoterol may be present in an amount of from about 12 to about 24mcg,
preferably about 24mcg.
Indacaterol is chemically known as (i?)-5-[2-[(5,6-Diethyl-2,3-dihydro-l H-inden-2-
yl)amino]-l-hydroxyethyl]-8-hydroxyquinolin-2(l H)-one is a ultra-long acting beta2-
agonist. Indacaterol has a fast onset of action which is similar to that of formoterol and
faster than that of salmeterol. Furthermore, indacaterol exhibits a longer duration of
action than salmeterol as well as has greater cardiovascular safety margin as compared to
salmeterol and formoterol. A particularly preferred pharmaceutically acceptable salt of
indacaterol is indacterol maleate. According to the present invention, indacaterol may be
present in an amount of from about 25meg to about 800mcg.
Olodaterol is chemically known as 6-hydroxy-8-[(lR)-l-hydroxy-2-[[2-(4-
methoxyphenyl)-l ,1-dimethylethyl]amino]ethyl]-2H- 1,4-benzoxazin-3(4H)- one. A
particularly preferred pharmaceutically acceptable salt of olodaterol is olodaterol
hydrochloride monohydrate. According to the present invention, olodaterol may be
present in an amount of from about 3mcg to about 50mcg.
Vilanterol is chemically known as 4-{(lR)-2-[(6-{2-[(2,6-
dichlorobenzyl)oxy]ethoxy}hexyl)amino]-l-hydroxyethyl}-2-(hydroxymethyl)phenol is
a long acting beta2-agonist. A particularly preferred pharmaceutically acceptable salt of
vilanterol is vilanterol trifenatate. According to the present invention, vilanterol may be
present in an amount of from about 3mcg to about 50mcg.
In addition to glycopyrrolate and a beta2-agonist, the pharmaceutical compositions of the
present invention may also comprise a corticosteroid; preferably selected from the group
consisting of mometasone, fluticasone.
Fluticasone is currently commercially available as a furoate salt and a propionate salt.
Fluticasone furoate is a novel corticosteroid which substantially overcomes the potential
side effects that are generally produced by the use of conventional corticosteroids.
Moreover fluticasone furoate exhibits a 1.7 times higher binding affinity for the human
glucocorticoid receptor as compared to that of fluticasone propionate and also provides
prolonged protection up to 26 hours against airway hyperresponsiveness as compared to
fluticasone propionate. Fluticasone furuoate has a longer duration of action with an
elimination half life of 15.1 hrs.
Fluticasone furoate is a synthetic fluorinated corticosteroid that has been developed as an
intranasal treatment for patients with symptoms of rhinitis and has an enhanced affinity
towards the glucocorticoid receptor. Further, fluticasone furoate has greater potency than
other clinically used corticosteroids such as mometasone furoate, budesonide, fluticasone
propionate, ciclesonide for the glucocorticoid receptor and against the proinflammatory
transcription factors nuclear factor (NF-), activation protein- 1, and tumor necrosis
factor- induced interleukin-8 cytokine production. Chronic inflammation which is
commonly associated with asthma is managed by fluticasone furoate.
Particularly preferred pharmaceutically acceptable esters of fluticasone are fluticasone
furoate and fluticasone propionate, most preferably fluticasone furoate. According to the
present invention, fluticasone furoate may be present in an amount of from about 25mcg
to about 800mcg.
Mometasone furoate is chemically known as ( 1 1[], 16[])-9, 21-dichloro-17-[(2-
furanylcarbonyl) oxy]-l l-hydroxy-16-methylpregna-l,4-diene-3,20-dione. Mometasone
furoate is a synthetic 17-heterocyclic corticosteroid and exhibits a long duration of action
A particularly preferred pharmaceutically acceptable ester of mometasone is mometasone
furoate. According to the present invention, mometasone furoate may be present in an
amount of from about 400mcg to about 800mcg.
As used herein the terms "glycopyrronium", "glycopyrrolate", "fluticasone furoate",
"mometasone furoare", "carmoterol", "olodaterol, "vilanteroP, "formoterol" and
"indacaterol" are used in broad sense to include not only "glycopyrronium",
"glycopyrrolate" "fluticasone furoate" "mometasone furoare", "carmoterol", "olodaterol,
"vilanteroP, "formoterol" and "indacaterol" per se but also their pharmaceutically
acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable
hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable
derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable
prodrugs, etc.
In addition to active pharmaceutical ingredients, the pharmaceutical compositions of the
present invention typically comprise one or more pharmaceutically acceptable excipients.
The active ingredients may be used as separate formulations or as a single combined
formulation. When combined in the same formulation, it will be appreciated that the
active ingredients must be stable and compatible with each other and the other
components of the formulation.
The pharmaceutical compositions of the present invention are formulated for inhalation
and may therefore be administered by any suitable methods used for delivery of the drugs
to the respiratory tract. For example, the composition of the present invention may be in
the form of an aerosol composition, a nasal spray, nasal drops or an insufflation powder.
Such aerosol compositions may be administered by any conventional means, for example
using a metered dose inhaler (MDI), dry powder inhaler (DPI) or nebulizer.
The various dosage forms according to the present invention may comprise
carriers/excipients suitable for formulating the same.
In one embodiment, the pharmaceutical compositions of the present invention are in a
form suitable for administration by a MDI, for example, in the form of an aerosol
composition. Such compositions may comprise one or more pharmaceutically acceptable
excipients, in particular selected from the group of HFC/HFA propellants, co-solvents,
bulking agents, non-volatile components, buffers/pH adjusting agents, surface active
agents, preservatives, complexing agents, or combinations thereof.
Suitable propellants are those which, when mixed with the cosolvent(s), form a
homogeneous propellant system in which a therapeutically effective amount of the
medicament can be dissolved. The HFC/HFA propellant must be toxicologically safe
and must have a vapor pressure which is suitable to enable the medicament to be
administered via a pressurized MDI.
According to the present invention, the HFC/HFA propellants may comprise, one or more
of 1,1,1,2-tetrafluoroethane (HFA-134(a)) and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-
227), HFC-32 (difiuoromethane), HFC- 143(a) (1,1,1-trifluoroethane), HFC- 134 (1,1,2,2-
tetrafluoroethane), and HFC- 152a (1,1-difluoroethane) or combinations thereof and such
other propellants which may be known to the person having a skill in the art.
In the context of the present invention, the term "co-solvent" means any solvent which is
miscible in the formulation in the amount desired and which, when added provides a
formulation in which the medicament can be dissolved. The function of the co-solvent is
to increase the solubility of the medicament and the excipients in the formulation.
According to the present invention, the co-solvent may comprise one or more of, C2- C
aliphatic alcohols, such as, but not limited to, ethyl alcohol and isopropyl alcohol; glycols
such as but not limited to propylene glycol, polyethylene glycols, polypropylene glycols,
glycol ethers, and block copolymers of oxyethylene and oxypropylene; and other
substances, such as, but not limited to, glycerol, polyoxyethylene alcohols, and
polyoxyethylene fatty acid esters; hydrocarbons such as but not limited to n-propane, nbutane,
isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and ethers such as
but not limited to diethyl ether and combinations thereof.
Suitable surfactants which may be employed in an aerosol composition of the present
invention include those which may serve to stabilize the solution formulation and
improve the performance of valve systems of the metered dose inhaler. Preferred
surfactants include one or more ionic and/or non- ionic surfactants. Examples of suitbale
surfactants include, but are not limited to, oleic acid, sorbitan trioleate, lecithin,
isopropylmyristate, tyloxapol, polyvinylpyrrolidone, polysorbates such as polysorbate 80,
vitamin E-TPGS, and macrogol hydroxystearates such as macrogol- 15-hydroxystearate
and combinations thereof.
In the context of the present invention, the term "non-volatile component" refers to the
suspended or dissolved constituents of the pharmaceutical composition that would remain
after evaporation of the solvent(s) present.
According to the present invention, the non-volatile component may comprise one or
more of monosaccharides such as, but not limited to, glucose, arabinose; disaccharides
such as lactose, maltose; oligosaccharides and polysaccharides such as, but not limited to,
dextrans; polyalcohol such as, but not limited to, glycerol, sorbitol, mannitol, xylitol;
salts such as, but not limited to, potassium chloride, magnesium chloride, magnesium
sulphate, sodium chloride, sodium citrate, sodium phosphate, sodium hydrogen
phosphate, sodium hydrogen carbonate, potassium citrate, potassium phosphate,
potassium hydrogen phosphate, potassium hydrogen carbonate, calcium carbonate and
calcium chloride and combinations thereof.
Suitable bulking agents may be employed in the pharmaceutical compositions of the
invention, in particular aerosol compositions that are intended for administration using an
MDI. The bulking agent may comprise one or more of saccharides, including
monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose,
glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran
or mannitol and combinations thereof.
Suitable buffers or pH adjusting agents may be employed in the pharmaceutical
compositions of the invention, in particular aerosol compositions that are intended for
administration using an MDI. The buffer or the pH adjusting agent may comprise one or
more of organic or inorganic acids such as, but not limited to, citric acid, ascorbic acid,
hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid and combinations thereof.
Suitable preservatives may be employed in in the pharmaceutical compositions of the
invention, in particular aerosol compositions that are intended for administration using an
MDI, to protect the formulation from contamination with pathogenic bacteria. The
preservative may comprise one or more of benzalkonium chloride, benzoic acid,
benzoates such as sodium benzoate and such other preservatives which may be known to
the person having a skill in the art and combinations thereof.
Suitable complexing agents may be employed in the pharmaceutical compositions of the
invention, in particular aerosol compositions that are intended for administration using an
MDI, capable of forming complex bonds. The complexing agent may comprise one or
more of, but not limited to, sodium EDTA or disodium EDTA and combinations thereof.
In one embodiment, the pharmaceutical compositions of the present invention are in a
form suitable for administration by a dry powder inhaler (DPI).
The pharmaceutically acceptable excipients suitable for dry powder inhalation according
to the present invention may be selected from suitable carriers which include, but are not
limited to, sugars such as glucose, saccharose, lactose and fructose, starches or starch
derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives,
polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for
example cellulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate,
calcium phosphate, etc. lactose, lactitol, dextrates, , dextrose, maltodextrin, saccharides
including monosaccharides, disaccharides, polysaccharides; sugar alcohols such as
arabinose, ribose, mannose, sucrose, trehalose, maltose, dextran and combinations
thereof.
In an alternative embodiment, the pharmaceutical compositions of the present invention
are in a form suitable for administration by nebulization.
Nebulization therapy has an advantage over other inhalation therapy, since it is easy to
use and does not require co-ordination or much effort. It also works much more rapidly
than medicines taken by mouth. Such compositions may comprise suitable excipients
such as one or more, but not limited to, tonicity agents, p regulators, and chelating
agents in a suitable vehicle.
Examples of suitable isotonicity-adjusting agents include sodium chloride, potassium
chloride, zinc chloride, calcium chloride and mixtures thereof. Other isotonicityadjusting
agents may also include, but are not limited to, mannitol, glycerol, and dextrose
and mixtures thereof.
The pH of pharmaceutical compositions of the invention may be adjusted by the addition
of one or more pH regulators such as pharmacologically acceptable acids.
Pharmacologically acceptable inorganic acids or organic acids may be used for this
purpose. Examples of preferred inorganic acids include one or more acids selected from
the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid
and phosphoric acid and combinations thereof. Examples of particularly suitable organic
acids include one or more acids selected from the group consisting of ascorbic acid, citric
acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic
acid and propionic acid and combinations thereof.
Examples of suitable chelating agents for use in a pharmaceutical compositions of the
invention include editic acid (EDTA) or a salt thereof, e.g. sodium EDTA or disodium
EDTA dihydrate (sodium edetate), and mixtures of such compounds.
In addition to the excipients such as isotonicity-adjusting agents, pH regulators, chelating
agents covered under nebulization therapy, the dosage forma as nasal spay and nasal
drops may comprise thickening agents.
Examples of suitable thickening agents may for use in a pharmaceutical compositions of
the invention include cellulose derivatives (for example cellulose ether) in which the
cellulose-hydroxy groups are partially etherized with lower unsaturated aliphatic alcohols
and/or lower unsaturated aliphatic oxyalcohols (for example methyl cellulose,
carboxymethyl cellulose, hydroxypropylmethylcellulose), gelatin, polyvinylpyrrolidone,
tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl
cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin and equivalent agents.
Should these substances contain acid groups, the corresponding physiologically
acceptable salts may also be used.
In addition to the aforementioned excipients, one or more anti-microbial preservative
agents may also be added to the pharmaceutical compositions of the invention, in
particular for multi-dose packages.
In an alternative embodiment, the composition according to the present invention may be
included in one or more suitable containers provided with means enabling the application
of the contained formulation to the respiratory tract.
Where the pharmaceutical compositions of the invention are in the form of a powder for
inhalation and are intended to be administered by a DPI, it may be encapsulated in
capsules of gelatin or HPMC, or in blisters. In an alternative embodiment, the dry
powder may be contained as a reservoir either in a single dose or multi-dose dry powder
inhalation device. In a further alternative embodiment, the powder for inhalation may be
suspended in a suitable liquid vehicle and packed in an aerosol container along with
suitable propellants or mixtures thereof. In still a further alternative embodiment, the
powder for inhalation may be dispersed in a suitable gas stream to form an aerosol
composition.
Where the pharmaceutical compositions of the invention are in the form of an aerosol
composition for administration using an MDI, it may be packed in plain aluminium cans
or SS (stainless steel) cans or any such cans suitable for MDI delivery. Some aerosol
drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI.
This can lead to the patient getting significantly less than the prescribed amount of the
active agent upon each activation of the MDI. Such cans may be suitably treated to avoid
any adherence of the active on the walls thereof using techniques known in the art, for
example coating the inner surface of the container with a suitable polymer can reduce this
adhesion problem. Suitable coatings include fluorocarbon copolymers such as FEP-PES
(fluorinated ethylene propylene and polyethersulphone) and PFA-PES
(perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the
inner surfaces of the cans may be anodized, plasma treated or plasma coated.
Where the pharmaceutical compositions of the invention are in the form of nasal sprays
and nasal drops for administration into the nasal passages it may be done by means of a
dropper (or pipette) that includes a glass, plastic or metal dispensing tube. Fine droplets
and sprays can be provided by an intranasal pump dispenser or squeeze bottle as well
known in the art.
The pharmaceutical compositions of the present invention may further comprise, in
addition to those pharmaceutically active ingredients detailed above, one or more
active(s) selected from the group comprising of , antihistamines, antiallergics or
leukotriene antagonists, or their pharmaceutically acceptable salts, solvates, tautomers,
derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
The pharmaceutical compositions of the present invention comprise glycopyrrolate, a
beta2-agonist and, optionally, a corticosteroid. These active ingredients are formulated
for simultaneous, separate or sequential administration. When the active ingredients are
administered sequentially, either glycopyrrolate the long acting beta2-agonist, or where
present, the corticosteroid, may be administered first. When administration is
simultaneous, the active ingredients may be administered either in the same or different
pharmaceutical compositions. Adjunctive therapy, i.e. where one active ingredient is
used as the primary treatment and the other active ingredient(s) is/are used to assist that
primary treatment is also an embodiment of the present invention.
According to a further embodiment of the invention, there is provided a product
comprising (a) glycopyrrolate; (b) a beta -agonist selected from the group comprising
carmoterol, olodaterol, vilanterol; as a combined preparation for simultaneous, separate
or sequential use for treatment and /or prevention of respiratory, inflammatory or
obstructive airway disease
According to a another embodiment of the invention, there is provided a product
comprising (a) glycopyrrolate; (b) a beta2-agonist selected from the group comprising
olodaterol, vilanterol, formoterol, indacaterol (c) a corticosteroid selected from the group
consisting of fluticasone, mometasone, as a combined preparation for simultaneous,
separate or sequential use for treatment and /or prevention of respiratory, inflammatory or
obstructive airway disease
Compositions for use according to the present invention may be presented in a pack or
dispenser device which may contain one or more unit dosage forms containing the active
ingredients. These may for example, comprise metal or plastic foil, such as a blister
pack. Where compositions are intended for administration as two separate compositions
these may be presented in the form of a twin pack.
Pharmaceutical compositions may also be prescribed in "patient packs" containing the
whole course of treatment in a single package. The inclusion of a package insert has
been shown to improve patient compliance with the prescribing physician's instructions.
According to a further embodiment of the present invention, there is provided a patient
pack comprising at least one active ingredient of the combination according to the
invention and an information insert containing directions to use the combination of the
invention. In one embodiment, the present invention provides a fixed dose combination.
The pharmaceutical compositions of the present invention may be conveniently presented
in unit dosage form and may be prepared by any of the methods well known in the art.
Suitable methods include the step of bringing into association the active ingredients with
a carrier which constitutes one or more pharmaceutically acceptable excipients. In
general, compositions may be prepared by uniformly and intimately bringing into
association the active ingredients with one or more liquid carriers or finely divided solid
carriers, or both. It will be appreciated that when the active ingredients are administered
independently, each may be administered by a different means.
The present invention also provides a process to manufacture the compositions according
to the present invention.
In one embodiment, the present invention provides a process of preparing pharmaceutical
compositions for administration by a metered dose inhaler, which process comprises
admixing a pharmaceutically acceptable carrier or excipient with one or more active
pharmaceutical ingredients of the invention and a propellant, and thereafter transferring
the composition to a suitable container, preferably a pre-crimped can.
In another embodiment, the invention provides a process of preparing a pharmaceutical
compositions for administration by dry powder inhalation, which process comprises
admixing of a pharmaceutically acceptable carrier or excipient with one or more active
pharmaceutical ingredients of the invention and providing the composition as a dry
powder.
In a further embodiment, the invention provides a process of preparing pharmaceutical
compositions for administration by nebulisation, which process comprises dissolving the
drugs, optionally chelating agents, osmotic/isotonicity adjusting agents and any other
suitable ingredients in the vehicle and adjusting the pH using a suitable pH adjusting
agent.
In a further embodiment, the invention also provides a method for the prevention and/or
treatment of a respiratory, inflammatory or obstructive airway disease, in particular
chronic obstructive pulmonary disease, in a mammal, such as a human, which method
comprises administration of a therapeutically effective amount of pharmaceutical
compositions according to the present invention.
The present invention also provides pharmaceutical compositions according to the
present invention for use in preventing and/or treating disorders or conditions that
respond to, or are prevented, ameliorated or eliminated by, the administration one or
more bronchodilators and an inhaled corticosteroid (ICS), such as a respiratory,
inflammatory or obstructive airway disease, in particular chronic obstructive pulmonary
disease.
The following examples are for the purpose of illustration of the invention only and are
not intended in any way to limit the scope of the present invention.
Example 1
Process:
1) Fluticasone furoate, Glycopyrronium and Tiotropium were homogenized with part
quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 2
Process:
1) Fluticasone furoate, Indacaterol and Glycopyrronium were homogenized with lactose
and part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 3
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Fluticasone furoate, Indacaterol and Glycopyrronium were homogenized with a part
quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 4
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution
obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 5
Process:
1) Required quantity of HC1 was added to ethanol.
2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution
obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 6
Process:
1) Citric acid anhydrous and glycerol were dissolved in ethanol.
2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution
obtained in step (1).
3) The solution obtained in step (2) was transferred to the main mixing vessel where it
was mixed with entire quantity of HFA134a.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
m l 7
Process:
1) Citric acid anhydrous was dissolved in ethanol.
2) Fluticasone furoate, Indacaterol and Glycopyrronium were dissolved in the solution
obtained in step (1).
3) The solution obtained in step (2) was transferred to the main mixing vessel where it
was mixed with entire quantity of HFA134a.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 8
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Indacaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasone furoate was homogenized with lecithin and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 9
HFA134a or HFA227 q.s.
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Indacaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasone furoate was homogenized with oleic acid and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 10
Process:
1) Glycopyrronium, Indacaterol and Fluticasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 1
Process:
1) Glycopyrronium, Indacaterol and Fluticasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 12
Process:
1) Glycopyrronium, Indacaterol and Fluticasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 13
Process:
1) Fluticasone furoate, Glycopyrronium and Formoterol were homogenized with part
quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 14
Process:
1) Fluticasone furoate, Formoterol and Glycopyrronium were homogenized with lactose
and part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 15
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Fluticasone furoate, Formoterol and Glycopyrronium were homogenized with a part
quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 16
formulation
5. Glycerol 1% of total
formulation
6. HCL ( 0.08N) pH 2.5 - 3.5
7. HFA134a q.s.
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Fluticasone fiiroate, Formoterol and Glycopyrronium were dissolved in the solution
obtained i step .
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 17
Process:
1) Required quantity of HC1 was added to ethanol.
2) Fluticasone furoate, Formoterol and Glycopyrronium were dissolved in the solution
obtained in step .
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 18
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Formoterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasoen furoate was homogenized with lecithin and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 19
6. HFA134a or HFA227 q.s.
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Formoterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasone furoate was homogenized with oleic acid and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 20
Process:
1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 21
Process:
1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 22
Process:
1) Glycopyrronium, Formoterol and Fluticasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 23
Process:
1) Fluticasone furoate, Glycopyrronium and Vilanterol were homogenized with part
quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 24
Process:
1) Fluticasone furoate, Vilanterol and Glycopyrronium were homogenized with lactose
and part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 25
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Fluticasone furoate, Vilanterol and Glycopyrronium were homogenized with a part
quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 26
W
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Fluticasone furoate, Vilanterol and Glycopyrronium were dissolved in the solution
obtained in step .
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 27
Process:
1) Required quantity of HC1 was added to ethanol.
2) Fluticasone furoate, Vilanterol and Glycopyrronium were dissolved in the solution
obtained in step .
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 28
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasoen furoate was homogenized with lecithin and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 29
W
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasoen furoate was homogenized with oleic acid and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 30
Process:
1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone furoate were sifted with
quantity of lactose.
2) The co-sift of step 1was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 3 1
Process:
1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone furoate were sifted with
quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 32
Process:
1) Glycopyrronium, Vilanterol Trifenatate and Fluticasone furoate were sifted with a part
quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 33
Process:
1) Fluticasone furoate, Glycopyrronium and Olodaterol were homogenized with part
quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 34
Process:
1) Fluticasone furoate, Olodaterol and Glycopyrronium were homogenized with lactose
and part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 35
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Fluticasone furoate, Olodaterol and Glycopyrronium were homogenized with a part
quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 36
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Fluticasone furoate, Olodaterol and Glycopyrronium were dissolved in the solution
obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 37
Process:
1) Required quantity of HC1 was added to ethanol.
2) Fluticasone furoate, Olodaterol and Glycopyrronium were dissolved in the solution
obtained in step .
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 38
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasone furoate was homogenized with lecithin and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
W
Example 39
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Fluticasone furoate was homogenized with oleic acid and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 40
Process:
1) Glycopyrronium, Olodaterol and Fluticasone furoate were sifted with a part quantity of
lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 41
Process:
1) Glycopyrronium, Olodaterol and Fluticasone furoate were sifted with a part quantity of
lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 42
Process:
1) Glycopyrronium, Olodaterol and Fluticasone furoate were sifted with a part quantity of
lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 43
Process:
1) Mometasone furoate, Glycopyrronium and Olodaterol were homogenized with part
quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 44
HFA134A OR HFA227 q.s.
Process:
1) Mometasone furoate, Olodaterol and Glycopyrronium were homogenized with lactose
and part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 45
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Mometasone furoate, Olodaterol and Glycopyrronium were homogenized with a part
quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 46
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Mometasone furoate, Olodaterol and Glycopyrronium were dissolved in the solution
obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 47
Process:
1) Required quantity of HC1 was added to ethanol.
2) Mometasone furoate, Olodaterol and Glycopyrronium were dissolved in the solution
obtained in step .
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 48
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Mometasone furoate was homogenized with lecithin and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 49
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) Mometasone furoate was homogenized with oleic acid and ethanol.
4) The suspension obtained instep (3) was transferred to the main mixing vessel where
the remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 50
Process:
1) Glycopyrronium, Olodaterol and Mometasone furoate were sifted with a part quantity
of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 51
Process:
1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 52
Process:
1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 53
Process:
1) Glycopyrronium and Vilanterol Trifenatate were sifted with a part quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 54
Process:
1) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 55
Process:
1) Vilanterol and Glycopyrronium were homogenized with lactose and part quantity of
HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 56
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Vilanterol and Glycopyrronium were homogenized with a part quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 57
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Vilanterol and Glycopyrronium were dissolved in the solution obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 58
formulation
4. HCL ( 0.08N) pH 2.5-3.5
5. HFA134a q.s.
Process:
1) Required quantity of HC1 was added to ethanol.
2) Vilanterol and Glycopyrronium were dissolved in the solution obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 59
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) The solution obtained in step (1) was homogenized with part quantity of HFA
4) The mixture obtained in step (3) was transferred to the main mixing vessel where the
remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 60
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Vilanterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) The solution obtained in step (1) was homogenized with part quantity of HFA
4) The mixture obtained in step (3) was transferred to the main mixing vessel where the
remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 61
Process:
1) Glycopyrronium and Olodaterol were sifted with a part quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 62
Process:
1) Glycopyrronium and Olodaterol were sifted with a part quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 63
Process:
1) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
W
Example 64
Process:
1) Olodaterol and Glycopyrronium were homogenized with lactose and part quantity of
HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 65
Process:
1) PVP was dissolved in PEG and part quantity of HFA 34A or HFA227.
2) The solution obtained in Step 1 was transferred to a mixing vessel.
3) Olodaterol and Glycopyrronium were homogenized with a part quantity of HFA.
201
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 66
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC was added.
2) Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 67
HFA134a q.s.
Process:
1) Required quantity of HC1 was added to ethanol.
2) Olodaterol and Glycopyrronium were dissolved in the solution obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 68
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) The solution obtained in step (1) was homogenized with part quantity of HFA
4) The mixture obtained in step (3) was transferred to the main mixing vessel where the
remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 69
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Olodaterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) The solution obtained in step (1) was homogenized with part quantity of HFA
4) The mixture obtained in step (3) was transferred to the main mixing vessel where the
remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 70
Process:
1) Glycopyrronium and Carmoterol were sifted with apart quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 71
Process:
1) Glycopyrronium and Carmoterol were sifted with a part quantity of lactose.
2) The co-sift of step 1 was then sifted with the remaining quantity of lactose and
blended.
3) The blend of step 2 was then filled in capsules.
Example 72
Process:
1) Glycopyrronium and Carmoterol were homogenized with part quantity of HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
W
Example 73
Process:
1) Carmoterol and Glycopyrronium were homogenized with lactose and part quantity of
HFA.
2) The suspension obtained in step 1 was transferred to the mixing vessel where
remaining quantity of HFA was added.
3) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 74
Process:
1) PVP was dissolved in PEG and part quantity of HFA134A or HFA227.
2) The solution obtained in Step 1was transferred to a mixing vessel.
3) Carmoterol and Glycopyrronium were homogenized with a part quantity of HFA.
4) The suspension obtained in step 3 was transferred to the mixing vessel where
remaining quantity of HFA was added.
5) The resulting total suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 75
Process:
1) Glycerol was dissolved in ethanol and required quantity of HC1 was added.
2) Carmoterol and Glycopyrronium were dissolved in the solution obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 76
HFA134a q.s.
Process:
1) Required quantity of HC1 was added to ethanol.
2) Carmoterol and Glycopyrronium were dissolved in the solution obtained in step 1.
3) The resulting solution was transferred to the mixing vessel where HFA was added.
4) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 77
Process:
1) Lecithin was dissolved in ethanol.
2) Glycopyrronium and Carmoterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) The solution obtained in step (1) was homogenized with part quantity of HFA
4) The mixture obtained in step (3) was transferred to the main mixing vessel where the
remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
Example 78
Process:
1) Oleic acid was dissolved in ethanol.
2) Glycopyrronium and Carmoterol were homogenized with part quantity of HFA and
transferred to the mixing vessel.
3) The solution obtained in step (1) was homogenized with part quantity of HFA
4) The mixture obtained in step (3) was transferred to the main mixing vessel where the
remaining quantity of HFA was added.
5) The resulting suspension was mixed, recirculated and filled in into pre-crimped
aluminum cans.
It will be readily apparent to one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the
spirit of the invention. Thus, it should be understood that although the present invention
has been specifically disclosed by the preferred embodiments and optional features,
modification and variation of the concepts herein disclosed may be resorted to by those
skilled in the art, and such modifications and variations are considered to be falling
within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose
of description and should not be regarded as limiting. The use of "including,"
"comprising," or "having" and variations thereof herein is meant to encompass the items
listed thereafter and equivalents thereof as well as additional items.
W
It must be noted that, as used in this specification and the appended claims, the singular
forms "a," "an" and "the" include plural references unless the context clearly dictates
otherwise. Thus, for example, reference to "an excipient" includes a single excipient as
well as two or more different excipients, and the like.
Claims
1. A pharmaceutical composition comprising glycopyrrolate in combination with a
beta2-agonist selected from indacaterol, formoterol, vilanterol, carmoterol olodaterol,
optionally, one or more pharmaceutically acceptable excipients.
2. A pharmaceutical composition according to claim 1, wherein the beta -agonist is
indacaterol.
3. A pharmaceutical composition according to claim 2 or 3, wherein indacaterol is
an amount ranging from 25-800mcg.
4. A pharmaceutical composition according to claim 1, wherein the beta2-agonist is
formoterol.
5. A pharmaceutical composition according to claim 4, wherein formoterol is an
amount ranging from 12-24mcg.
6. A pharmaceutical composition according to claim 1, wherein the beta2-agonist is
vilanterol.
7. A pharmaceutical composition according to claim 6, wherein vilanterol is an
amount ranging from 3-50mcg.
8. A pharmaceutical composition according to claim 1, wherein the beta2-agonist is
carmoterol.
9. A pharmaceutical composition according to claim 8, wherein carmoterol is an
amount ranging from 1—4mcg.
10. A pharmaceutical composition according to claims 8 or 9, wherein the carmoterol
is in the form of carmoterol hydrochloride.
11. A pharmaceutical composition according to claim 1, wherein the beta2-agonist is
olodaerol.
12. A pharmaceutical composition according to claim 1, wherein olodaterol is an
amount ranging from 3-50mcg.
13. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate and vilanterol.
14. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate and carmoterol.
15. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate and olodaterol.
16. A pharmaceutical composition comprising in combination glycopyrrolate in
combination with a beta2-agonist, and one or more corticosteroid, optionally with one or
more pharmaceutically acceptable excipients.
17. A pharmaceutical composition according to claim 16, wherein the beta2-agonist is
selected from indacaterol, formoterol, vilanterol, carmoterol olodaterol.
18. A pharmaceutical composition according to claim 17, wherein the corticosteroid
is selected from fluticasone, mometasone.
19. A pharmaceutical composition according to claim 16 or 18, wherein the
corticosteroid is fluticasone.
20. A pharmaceutical composition according to claim 16, 8 or 19, wherein the
fluticasone is in the form of an ester of fluticasone.
21. A pharmaceutical composition according to claim 16, 18 or 20, wherein the
fluticasone is present in an amount ranging from 25 -800mcg.
22. A pharmaceutical composition according to claim 19, 20 or 21, wherein the
fluticasone is in the form of fluticasone furoate.
23. A pharmaceutical composition according to claim 16 or 18, wherein the
corticosteroid is mometasone.
24. A pharmaceutical composition according to claim 16, 18 or 23, wherein the
mometasone is in the form of an ester of mometasone
25. A pharmaceutical composition according to claim 16, 18 or 24, wherein the
mometasone is present in a amount ranging from 400-800mcg.
26. A pharmaceutical composition according to any one of the preceding claims,
wherein glycopyrrolate is present in an amount ranging from 0.5-1 Omcg.
27. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate indacaterol and fluticasone furoate.
28. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate, indacaterol and fluticasone furoate.
29. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate, formoterol and fluticasone furoate.
30. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate, vilanterol and fluticasone furoate.
31. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate, olodaterol and fluticasone furoate.
32. A pharmaceutical composition according to any of the preceding claims,
comprising glycopyrrolate, olodaterol and mometasone.
33. A pharmaceutical composition according to any one of the preceding claims
wherein pharmaceutical composition along with any excipients are formulated in a single
pharmaceutical composition
34. A pharmaceutical composition according to any one of the preceding claims,
formulated as a composition for inhalation.
35. A pharmaceutical composition according to claim 34, formulated as a
composition for inhalation in the form of a metered dose inhaler (MDI), dry powder
inhaler (DPI), nebulizer, nasal spray, nasal drops or an insufflation powder.
36. A pharmaceutical composition according to any one of claims 1 to 35, formulated
for use in a metered dose inhaler.
37. A pharmaceutical composition according to claim 34, 35 or 36, further
comprising a propellant.
38. A pharmaceutical composition according to claim 34, 35, 36 or 37, further
comprising an excipient selected from a cosolvent, an antioxidant, a surfactant, a bulking
agent and a lubricant.
39. A pharmaceutical composition according to any one of claims 1 to 35, formulated
for use as a dry powder inhalation formulation.
40. A pharmaceutical composition according to claim 39, further comprising at least
one finely divided pharmaceutically acceptable carrier suitable for use in dry powder
inhalation formulations.
41. A combination composition according to claim 40, wherein said carrier includes a
saccharide and/or a sugar alcohol.
42. A combination composition according to any one of claims 1 to 35, formulated
for use as an inhalation solution/suspension.
43. A combination composition according to claim 42, further comprising an
excipient selected from a wetting agent, osmotic agent, a pH regulator, a buffering agent
and a complexing agent, provided in a pharmaceutically acceptable vehicle.
44. A pharmaceutical composition according to any one of the preceding claims for
once daily administration.
45. A process for manufacturing a pharmaceutical composition according to
according to any one of claims 1 to 44, comprising combining glycopyrrolate with a
beta2-agonist selected from indacaterol, formoterol, vilanterol, carmoterol olodaterol, and
optionally, one or more pharmaceutically acceptable excipients.
46. A process for manufacturing a pharmaceutical composition according to any one
of claims 1 to 44 comprising combining glycopyrrolate with a beta2-agonist selected from
indacaterol, formoterol, vilanterol, carmoterol olodaterol, and corticosteroid is selected
from fluticasone, mometasone, optionally, one or more pharmaceutically acceptable
excipients.
47. The use of glycopyrrolate with a beta2-agonist selected from indacaterol,
formoterol, vilanterol, carmoterol olodaterol, in the manufacture of a medicament for the
prophylaxis or treatment of a respiratory, inflammatory or obstructive airway disease.
48. The use of glycopyrrolate with a beta -agonist selected from indacaterol,
formoterol, vilanterol, carmoterol olodaterol, and corticosteroid is selected from
fluticasone, mometasone, in the manufacture of a medicament for the prophylaxis or
treatment of a respiratory, inflammatory or obstructive airway disease.
49. The use according to claim 48 wherein the fluticasone is provided in the form of
fluticasone furoate
50. The use according to claim 47, 48 or 49, wherein said medicament is for once
daily administration.
51. The use according to claim 47, 48, 49 or 50 wherein the disease is COPD or
asthma.
52. A method of prophylaxis or treatment of a respiratory, inflammatory or
obstructive airway disease, comprising administering a therapeutically effective amount
of a pharmaceutical composition according to any one of claims 1 to 44 to a patient in
need thereof.
53. A method according to claim 52, wherein said pharmaceutical composition is
administered once daily.
54. A method according to claim 52, or 53, wherein the disease is COPD or asthma.
55. A pharmaceutical composition substantially as herein described with reference to
the examples.
56. A process for making a pharmaceutical composition substantially as herein
described with reference to the examples.