U.S. patent application number 12/487988 was filed with the patent office on 2009-10-22 for pressurised metered dose inhalers containing solutions of beta-2 agonists.
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. Invention is credited to Gaetano Brambilla, Tanya Kathleen Church, Rebecca Jaine Davies, Alessandra Ferraris, David Ganderton, David Andrew Lewis, Brian John Meakin.
Application Number | 20090263488 12/487988 |
Document ID | / |
Family ID | 27790093 |
Filed Date | 2009-10-22 |
United States Patent
Application |
20090263488 |
Kind Code |
A1 |
Davies; Rebecca Jaine ; et
al. |
October 22, 2009 |
PRESSURISED METERED DOSE INHALERS CONTAINING SOLUTIONS OF BETA-2
AGONISTS
Abstract
The present invention relates to a pharmaceutical formulation
for use in the administration of 2(1H)-quinolinone derivatives
long-acting .beta..sub.2-agonists by inhalation. In particular this
invention relates to a chemically stable highly efficient TA 2005
HFA solution formulation to be administered by pressurised metered
dose inhalers (pMDIs) characterized by a deep lung penetration. The
invention also relates to methods for the preparation of said
formulation and to its use in respiratory diseases such as asthma
and chronic obstructive pulmonary disease (COPD).
Inventors: |
Davies; Rebecca Jaine;
(Parma, IT) ; Ganderton; David; (Parma, IT)
; Lewis; David Andrew; (Parma, IT) ; Meakin; Brian
John; (Parma, IT) ; Church; Tanya Kathleen;
(Parma, IT) ; Brambilla; Gaetano; (Parma, IT)
; Ferraris; Alessandra; (Parma, IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Chiesi Farmaceutici S.p.A.
Parma
IT
|
Family ID: |
27790093 |
Appl. No.: |
12/487988 |
Filed: |
June 19, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10505861 |
Mar 8, 2005 |
|
|
|
PCT/EP03/02004 |
Feb 27, 2003 |
|
|
|
12487988 |
|
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Current U.S.
Class: |
424/489 ;
514/312 |
Current CPC
Class: |
A61K 31/4704 20130101;
A61P 11/00 20180101; A61P 11/08 20180101; A61K 47/10 20130101; A61P
43/00 20180101; A61K 9/008 20130101; A61P 11/16 20180101; A61K
31/485 20130101; A61K 45/06 20130101; A61P 11/06 20180101; A61K
31/4704 20130101; A61K 2300/00 20130101; A61K 31/485 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/489 ;
514/312 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/4704 20060101 A61K031/4704; A61P 11/00 20060101
A61P011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 1, 2002 |
EP |
02004786.6 |
Oct 23, 2002 |
EP |
02023589.1 |
Claims
1. A pharmaceutical formulation, which comprises a compound of
formula (I), a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof: ##STR00002## wherein R.sub.1 is methyl and
R.sub.2 is hydrogen or R.sub.1 and R.sub.2 form a methylene bridge
(CH.sub.2).sub.n wherein n is 1 or 2 R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are each independently hydrogen, hydroxyl, C.sub.1-C.sub.4
straight chain or branched alkyl, C.sub.1-C.sub.4 straight chain or
branched alkyl substituted by one or more halogen and/or hydroxyl,
halogen, C.sub.1-C.sub.4 straight chain or branched alkoxy, in a
solution of a liquefied HFA propellant, a co-solvent, and
optionally an amount of water up to 5% based on the total weight of
said formulation, wherein said formulation is contained in a
pressurized metered dose inhaler, wherein a fraction of particles
having a size equal to or less than 1.1 .mu.m delivered on
actuation of said metered dose inhaler is equal to or higher than
30% as defined by the content of stages S6-AF of an Andersen
Cascade Imapctor, relative to the total amount of the fine particle
dose collected in stages S3-AF of said Andersen impactor.
2. The pharmaceutical formulation according to claim 1, wherein
said fraction of particles equal to or less than 1.1 .mu.m
delivered on actuation of said metered dose inhaler is higher than
40%.
3. The pharmaceutical formulation according to claim 1, wherein
said formulation comprises 8-hydroxy
5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]amino]ethyl-
]-2(1H)-quinolinone or a pharmaceutically acceptable salt
thereof.
4. The pharmaceutical formulation according to claim 1, wherein
said formulation comprises
8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]a-
mino]ethyl]-2(1H)-quinolinone hydrochloride.
5. The pharmaceutical formulation according to claim 4 wherein said
compound, stereoisomer thereof, or pharmaceutically acceptable salt
thereof is present in a concentration between 0.0005 and 0.024%
w/v.
6. The pharmaceutical formulation according to claim 4 wherein said
compound, stereoisomer thereof or pharmaceutically acceptable salt
thereof is present in a concentration between 0.001 and 0.008%
w/v.
7. The pharmaceutical formulation according to claim 1, which has
an apparent pH between 2.5 and 5.0.
8. The pharmaceutical formulation according to claim 7 wherein said
apparent pH is adjusted by adding a mineral acid.
9. The pharmaceutical formulation according to claim 8, wherein
said mineral acid is selected from the group consisting of
hydrochloric acid, nitric acid, and phosphoric acid.
10. The pharmaceutical formulation according to claim 1, which has
an apparent pH between 2.8 and 4.0.
11. The pharmaceutical formulation according to claim 10 wherein
said apparent pH is adjusted by adding a mineral acid.
12. The pharmaceutical formulation according to claim 1, wherein
said liquefied HFA propellant comprises one or more
hydrofluoroalkanes selected from the group consisting of HFA 134a
and HFA 227.
13. The pharmaceutical formulation according to claim 1, wherein
said co-solvent is selected from the group consisting of a
C.sub.1-C.sub.4 alkyl alcohol, a polyol, a polyalkylene glycol, a
(poly)alkoxy alcohol, and mixtures thereof.
14. The pharmaceutical formulation according to claim 13 wherein
said co-solvent is ethanol.
15. The pharmaceutical formulation according to claim 14 wherein
said ethanol is present in an amount of from 5 to 30% by
weight.
16. The pharmaceutical formulation according to claim 15, wherein
said ethanol is present in an amount of from 10 to 20% by
weight.
17. The pharmaceutical formulation according to claim 1, which is
contained in a canister having part or all of internal metallic
surfaces of said canister lined with an inert organic coating.
18. The pharmaceutical formulation according to claim 17, wherein
said canister is lined with an inert organic coating selected from
the group consisting of an epoxy-phenol resin, a
perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a
perfluoroalkylene polymer, a polyether sulfone, a copolymer
fluorinated-ethylene-propylene polyether sulfone, and mixtures
thereof.
19. The pharmaceutical formulation according to claim 18, wherein
said inert organic coating is polytetrafluoroethylene.
20. The pharmaceutical formulation according to claim 1, further
comprising at least one additional active ingredient selected from
the group consisting of a steroid, ipratropium bromide, oxitropium
bromide, and tiotropium bromide.
21. A method of preparing a formulation according to claim 1, said
method comprising: a) preparing a solution of said compound,
stereoisomer thereof, or pharmaceutically acceptable salt thereof
in one or more of said co-solvent; b) optionally adding a
pre-determined amount of water and/or adjusting the pH of said
solution; c) filling a metered dose inhaler with said solution; and
d) adding a propellant comprising a hydrofluoroalkane.
22. A method of treating a respiratory disease, comprising
administering an effective amount of a formulation according to
claim 1 with a pressurized metered dose inhaler to a patient in
need thereof, wherein said disease is COPD or asthma.
23. A pharmaceutical formulation, consisting essentially of a
compound of formula (I), a stereoisomer thereof, or a
pharmaceutically acceptable salt thereof: ##STR00003## wherein
R.sub.1 is methyl and R.sub.2 is hydrogen or R.sub.1 and R.sub.2
form a methylene bridge (CH.sub.2).sub.n wherein n is 1 or 2
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each independently
hydrogen, hydroxyl, C.sub.1-C.sub.4 straight chain or branched
alkyl, C.sub.1-C.sub.4 straight chain or branched alkyl substituted
by one or more halogen and/or hydroxyl, halogen, C.sub.1-C.sub.4
straight chain or branched alkoxy, in a solution of a liquefied HFA
propellant, a co-solvent, and optionally an amount of water up to
5% based on the total weight of said formulation, wherein said
formulation is contained in a pressurized metered dose inhaler,
wherein a fraction of particles having a size equal to or less than
1.1 .mu.m delivered on actuation of said metered dose inhaler is
equal to or higher than 30% as defined by the content of stages
S6-AF of an Andersen Cascade Imapctor, relative to the total amount
of the fine particle dose collected in stages S3-AF of said
Andersen impactor.
24. The pharmaceutical formulation according to claim 23, wherein
said fraction of particles equal to or less than 1.1 .mu.m
delivered on actuation of said metered dose inhaler is higher than
40%.
25. The pharmaceutical formulation according to claim 23, wherein
said formulation contains 8-hydroxy
5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]-amino]ethy-
l]-2(1H)-quinolinone or a pharmaceutically acceptable salt
thereof.
26. The pharmaceutical formulation according to claim 23, wherein
said formulation contains
8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxy-phenyl)-1-methylethyl]a-
mino]ethyl]-2(1H)-quinolinone hydrochloride.
27. The pharmaceutical formulation according to claim 23, wherein
said compound, stereoisomer thereof, or pharmaceutically acceptable
salt thereof is present in a concentration between 0.0005 and
0.024% w/v.
28. The pharmaceutical formulation according to claim 27, wherein
said compound, stereoisomer thereof, or pharmaceutically acceptable
salt thereof is present in a concentration between 0.001 and 0.008%
w/v.
29. The pharmaceutical formulation according to claim 23, which has
an apparent pH between 2.5 and 5.0.
30. The pharmaceutical formulation according to claim 29, wherein
said apparent pH is adjusted by adding a mineral acid.
31. The pharmaceutical formulation according to claim 30, wherein
said mineral acid is selected from the group consisting of
hydrochloric acid, nitric acid, and phosphoric acid.
32. The pharmaceutical formulation according to claim 23, which has
an apparent pH between 2.8 and 4.0.
33. The pharmaceutical formulation according to claim 32, wherein
said apparent pH is adjusted by adding a mineral acid.
34. The pharmaceutical formulation according to claim 33, wherein
said mineral acid is selected from the group consisting of
hydrochloric acid, nitric acid, and phosphoric acid.
35. The pharmaceutical formulation according to claim 23, wherein
said liquefied HFA propellant comprises one or more
hydrofluoroalkanes selected from the group consisting of HFA 134a
and HFA 227.
36. The pharmaceutical formulation according to claim 23, wherein
said co-solvent is selected from the group consisting of a
C.sub.1-C.sub.4 alkyl alcohol, a polyol, a polyalkylene glycol, a
(poly)alkoxy alcohol, and mixtures thereof.
37. The pharmaceutical formulation according to claim 36, wherein
said co-solvent is ethanol.
38. The pharmaceutical formulation according to claim 37, wherein
said ethanol is present in an amount of from 5 to 30% by
weight.
39. The pharmaceutical formulation according to claim 38, wherein
said ethanol is present in an amount of from 10 to 20% by
weight.
40. The pharmaceutical formulation according to claim 23, which is
contained in a canister having part or all of internal metallic
surfaces of said canister lined with an inert organic coating.
41. The pharmaceutical formulation according to claim 40, wherein
said canister is lined with an inert organic coating selected from
the group consisting of an epoxy-phenol resin, a
perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a
perfluoroalkylene polymer, a polyether sulfone, a copolymer
fluorinated-ethylene-propylene polyether sulfone, and mixtures
thereof.
42. The pharmaceutical formulation according to claim 41, wherein
said inert organic coating is polytetrafluoroethylene.
43. The pharmaceutical formulation according to claim 23, further
consisting essentially of at least one additional active ingredient
selected from the group consisting of a steroid, ipratropium
bromide, oxitropium bromide, and tiotropium bromide.
44. A method of treating a respiratory disease, comprising
administering an effective amount of a formulation according to
claim 23 with a pressurized metered dose inhaler to a patient in
need thereof, wherein said disease is COPD or asthma.
45. A pharmaceutical aerosol formulation, which is contained in a
pressurized metered dose inhaler and which comprises TA2005 in a
solution consisting of a liquefied HFA propellant, a co-solvent, a
mineral acid and optionally an amount of water up to 5% based on
the total weight of said formulation, wherein a fraction of
particles having a size equal to or less than 1.1 .mu.m delivered
on actuation of said metered dose inhaler is equal to or higher
than 30% as defined by the content of stages S6-AF of an Andersen
Cascade Imapctor, relative to the total amount of the fine particle
dose collected in stages S3-AF of said Andersen impactor and
wherein said TA2005 is present in said formulation in an amount of
0.001 to 0.008% w/v to deliver 1 to 2 .mu.g of TA2005 per actuation
of said inhaler.
46. A method of treating a respiratory disease, comprising
administering an effective amount of a formulation according to
claim 45 with a pressurized metered dose inhaler to a patient in
need thereof, wherein said disease is COPD or asthma.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/505,861, which is the U.S. national stage
of International Patent Application No. PCT/EP03/02004, filed on
Feb. 27, 2003, and claims priority to European Patent Applications
No. 0200476.6, filed Mar. 1, 2002, and No. 02023589.1, filed Oct.
23, 2002, all of which are incorporated herein by reference in
their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a pharmaceutical
formulation for use in the administration of 2(1H)-quinolinone
derivatives long-acting .beta..sub.2-agonists by inhalation. In
particular this invention relates to a chemically stable highly
efficient TA 2005 HFA solution formulation to be administered by
pressurised metered dose inhalers (pMDIs) characterized by a deep
lung penetration. The invention also relates to methods for the
preparation of said formulation and to its use in respiratory
diseases such as asthma and chronic obstructive pulmonary disease
(COPD).
[0004] 2. Discussion of the Background
[0005] Asthma is a disease which is becoming more prevalent and is
the most common disease of childhood. It can be identified by
recurrent wheeze and intermittent air flow limitation. Despite many
advances in its understanding, said pathology remains a poorly
understood and often poorly treated disease. Previously,
contraction of airway smooth muscles has been regarded as the most
important feature of asthma. Recently there has been a marked
change in the way asthma is managed, stemming from the fact that
asthma is recognized as a chronic inflammatory disease.
Uncontrolled airway inflammation may lead to mucosal damage and
structural changes giving irreversible narrowing of the airways and
fibrosis of the lung tissue. Therapy should therefore be aimed at
controlling symptoms so that normal life is possible and at the
same time provide basis for treating the underlying
inflammation.
[0006] Another respiratory disease whose incidence is steadily
increasing throughout the world is chronic obstructive pulmonary
disease (COPD). Most patients with COPD have acquired their lung
disease through smoking cigarettes. Depending upon trends in
tobacco smoking, it is set to rise to fifth most prevalent cause of
disability, worldwide by 2020 (Leckie M et al Exp Opin Invest Drugs
2000, 9, 3-23).
[0007] Chronic obstructive pulmonary disease (COPD) is defined as a
disease state characterized by the presence of airflow obstruction
due to chronic bronchitis or emphysema.
[0008] Chronic bronchitis is characterized by excessive secretion
of bronchial mucus, whereas emphysema denotes abnormal, permanent
enlargement of air spaces distal to the terminal bronchiole, with
destruction of their walls and without obvious fibrosis (American
Thoracic Society). Each condition is treated as specific
diseases.
[0009] Chronic obstructive bronchiolitis is due to obstruction of
the peripheral airways as a result of inflammation in the
bronchioles.
[0010] .beta..sub.2-Adrenoceptor agonists have been the mainstay of
treatment for asthma for many years in view of their prompt
bronchodilation effects. Previous researches have also shown that
.beta..sub.2-agonists have potent anti-inflammatory capabilities,
e.g. represented by suppression of release of the pro-inflammatory
cytokines.
[0011] The first generation drugs such as salbutamol or fenoterol
were characterized by a relatively short duration of action which
has been considered as a disadvantage particularly for patients
with nocturnal asthma. Moreover, they have limited effects in COPD,
since this disease involves `irreversible` airways obstruction. The
development of longer acting .beta..sub.2-agonists such as
formoterol, salmeterol and TA 2005 has therefore been heralded as a
major new development in the treatment of asthma. According to some
authors, long-acting .beta..sub.2-agonists (LABAs) may have acute
anti-inflammatory activity in vivo (Johnson M Clin Exp Allergy
1992, 22, 177-181; Stelmach I et al Ann Allergy Asthma Immunol
2002, 89, 67-73). These drugs are a new interesting therapeutic
option for patients with chronic obstructive pulmonary disease
(COPD) as well since they have been shown to significantly improve
lung function and symptom control.
[0012] .beta..sub.2-adrenergic agonists can also stimulate alveolar
fluid clearance in several animal species and in ex vivo rat and
human lungs. In view of these findings beta-adrenergic agonist
therapy has been proposed as a possible treatment for accelerating
the resolution of pulmonary edema in patients with acute pulmonary
edema (Sacuma T et al Am J Respir Crit Care Med 1997, 155,
506-512). Treatment with .beta..sub.2-agonists may also increase
the secretion of surfactant and perhaps exert an anti-inflammatory
effect, thus helping to restore vascular permeability of the lung
(Ware L et al New Eng. J Med 2000, 342, 1334-1349.
[0013] Drugs intended for the treatment of lung diseases such as
asthma and COPD are currently administered by pulmonary delivery
which relies on inhalation of an aerosol through the mouth and
throat so that the drug substance can reach the lung. They can be
administered as aqueous or hydroalcoholic formulations through a
nebuliser, as dry powders by means of Dry Powder Inhalers or in
halogenated hydrocarbon propellants. The propellant-based systems
require suitable pressurized metered-dose inhalers (pMDIs) which
release a metered dose of medicine upon each actuation. The
relevant formulations can be in the form of solutions or
suspensions. Solution formulations, with respect to suspensions, do
not present problems of physical stability of the suspended
particles and so could guarantee a higher dose uniformity and
reproducibility. As far as the type of propellant is concerned,
hydrofluoroalkanes [(HFAs) known also as hydro-fluoro-carbons
(HFCs)] would be mandatory propellants as chlorofluorocarbons
(known also as Freons or CFCs), which were for many years the
preferred propellants aerosols for pharmaceutical use, have been
implicated in the destruction of the ozone layer so their use is
being phased out. In particular, 1,1,1,2-tetrafluoroethane (HFA
134a) and 1, 1, 1, 2, 3,3,3-heptafluoropropane (HFA 227) have been
acknowledged to be the best candidates for non-CFC propellants and
a number of pharmaceutical aerosol formulations using such HFA
propellant systems have been disclosed.
[0014] In developing a therapeutic aerosol, the aerodynamic size
distribution of the inhaled particles is the most important
variable in defining the site of droplet or particle deposition in
the lungs of the patient; in short, it will determine whether drug
targeting succeeds or fails. See P. Byron, "Aerosol Formulation,
Generation, and Delivery Using Nonmetered Systems, "Respiratory
Drug Delivery, 144-151, 144 (CRC Press, 1989).
[0015] Thus, a prerequisite in developing a therapeutic aerosol is
a preferential particle size.
[0016] When the formulation is in the form of suspension, the
particle size of the cloud is dominated by the particle size of the
suspended drug, defined by the milling/micronization process. When
the formulation is in the form of solution, the volumetric
contribution of suspended drug particles is absent and much finer
liquid droplets clouds, largely defined by the drug concentration
in the solution, are generated.
[0017] Solid particles and/or droplets in an aerosol formulation
can be characterized by their mass median aerodynamic diameter
(MMAD, the diameter around which the mass aerodynamic diameters are
distributed equally).
[0018] Particle deposition in the lung depends largely upon three
physical mechanisms:
[0019] i) impaction, a function of particle inertia;
[0020] ii) sedimentation due to gravity; and
[0021] iii) diffusion resulting from Brownian motion of fine,
submicrometer (<1 microns) particles.
[0022] The mass of the particles determines which of the three main
mechanisms predominates.
[0023] For aerosol therapy of drugs which topically act on the
smooth muscle of the conducting airways, and in particular for
.beta..sub.2-agonists, it has been reported in the past that
particles should preferentially deposit in the upper- to
mid-pulmonary region (bronchiole region), so they should have a
MMAD of about 1.5 (2.0) to about 5.0 microns, preferably
approximately 3 microns (Zanen P et al Int J Pharm 1994, 107,
211-217; Int J Pharm 1995, 114, 111-115; Thorax, 1996, 51,
977-980).
[0024] In fact, particles having aerodynamic diameters of greater
than about 5 microns generally do not reach the lung since they
tend to impact the back of the throat and are swallowed and
possibly orally absorbed, while particles smaller than 1.5 (2.0)
micron, i.e., about 0.5 to about 2 microns, capable of reaching the
alveolar region, have been considered undesirable because they can
be absorbed into the bloodstream and might enhance the undesired
systemic effects of the drugs. Particles having diameters smaller
than about 0.5 microns have been generally considered as not
therapeutically useful as they can be exhaled.
[0025] Accordingly, pMDI formulations of 2-agonist have
traditionally been formulations able to deliver particles whose
larger fraction is comprised between 2 and 5 microns and the amount
of those below 1 micron is very limited since the former are small
enough to reach the upper- to mid-pulmonary region, but are too
large to reach the alveoli. This is also the inherent particle size
of the formulation in the form of suspensions as conventional
micronization (air-jet milling) of pure drug substance can reduce
the drug particle size to about 2-3 microns.
[0026] On the other hand, it is known that the density of the
beta-adrenergic receptors is higher in the distal tract of the
bronchioles (Barnes P et al Am Rev Respir Dis 1983, 127, 758-762),
a region which is better reached by smaller particles. Moreover
inflammation in asthma in not merely confined to the large central
airways but also extends to small peripheral airways. The
eosinophilic inflammation process which has been seen to be
associated to asthma concerns both the bronchial and the alveolar
districts (Wang S J Immunol 2001, 166, 2741-2749). Recently, Martin
R in J Allergy Clin Immunol 2002, 109 (Suppl 2), 447-460 reported
that distal lung diseases appear to increase the risk of recurrent
asthma exacerbation, while disease-related anatomic changes in the
small airways of the distal lung are prominent in fatal asthma. In
this respect, in his opinion, the administration of drug with
particles of a diameter of about 1 micron (referred as "extrafine"
aerosols) could be advantageous. The clinical significance of
distal lung disease makes this region an important therapeutic
target so particles able to reach and deposit into such region
could better contribute to the management of the disease. It has
been also reported that, among the particles smaller than 0.5
micron, those with a diameter less or equal than 0.3 micron,
preferably between 5 and 300 nm, can be deposited in the alveolar
region of the lung by sedimentation. This range of particle has
been referred to in the literature as "ultrafine" particles.
[0027] "Ultrafine" particles generated from di-2-ethylhexyl
sebacate (DEHS) as a model, have also been reported to have a good
airway penetration (Anderson P et al Chest 1990, 97, 1115-1120).
Amirav I et al in J Nucl Med 2002, 43, 487-491 emphasize the need
for improvement in aerosol delivery by targeting narrow peripheral
airways with superfine aerosols in the treatment of inflammation
airways diseases and in particular in acute bronchiolitis.
[0028] Therefore medicinal aerosol particles having a diameter
<0.1 .mu.m can be particularly effective in case of airway
obstruction in asthmatic subjects wherein the pathology is
associated with mucus hypersecretion which hinders the diffusion of
the drug or in patients affected by obstructive lung diseases such
as COPD. Intuitively indeed, one would expect the reduction in the
lumen of airways by mucus and permanent constriction would require
finer clouds for perfusion.
[0029] Nevertheless, sub-micron aerosol formulations (including HFA
formulations) have only been reported until now as microemulsions
containing surface active agents such as lecithin (WO 01/78689, WO
00/27363; Dickinson P et al J Drug Target 2001, 9, 295-302).
[0030] In virtue of the inherent anti-inflammatory properties of
LABAs, relevant formulations capable of delivering a significant
fraction of fine particles would be expected to be of great
advantage in patients affected by broncho-pulmonary obstructive
diseases.
[0031] 2(1H)-quinolinone derivatives .beta..sub.2-agonist have been
described as potent and long-acting compounds (EP 147 719; WO
00/75114).
[0032] In particular,
8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am-
ino]ethyl]-2(1H)-quinolinone has been reported as a highly potent
.beta..sub.2-agonist, also characterized by a rapid onset of
action, which by virtue of its peculiar long duration of action can
be administered once a day. Its hydrochloride salt is known under
the experimental code TA 2005.
[0033] HFA solution formulations of .beta..sub.2-agonists for
aerosol delivery through pressurized metered-dose inhalers are
known.
[0034] WO 94/13262, in the name of Boehringer Ingelheim, provides
aerosol solution formulations comprising a medicament, an HFC
propellant, a cosolvent and an inorganic or an organic acid as a
stabiliser for preventing the chemical degradation of the active
ingredient. Most examples relate to ipratropium bromide, an
anticholinergic drug. As far as .beta..sub.2-agonists are
concerned, only formulations containing fenoterol, a short acting
derivative not chemically related to the compounds of the invention
are exemplified. Furthermore, apart from ipratropium bromide, WO
94/13262 gives no guidance with respect to the amount of acid which
has to be added in order to stabilise the medicaments without
compromising the stability of the whole composition in the can. The
only hint can be found on page 5, lines 15 to 16 which says that an
amount of inorganic acid should be added to obtain a pH value from
1 to 7, so a very broad and generic range. As far as the water
content is concerned, in the application it is stated that a small
amount of water (up to about 5% by weight) may also be present in
the propellant/cosolvent system. In the case of ipratropium
bromide, it is reported that addition of 1% water reduces the
decomposition due to dehydration.
[0035] WO 98/34596, in the name of 3 M, refers to solution
formulations containing a propellant and a physiologically
acceptable polymer which could help the solubilisation and the
stability as well of the active ingredients.
[0036] In WO 98/56349 the applicant described solution compositions
for use in an aerosol inhaler, comprising an active material, a
propellant containing a hydrofluoroalkane (HFA), a co-solvent and
further comprising a low volatility component to increase the mass
median aerodynamic diameter (MMAD) of the aerosol particles on
actuation of the inhaler. In some cases a small quantity of water
may be added to the composition to improve the solution of the
active material and/or the low volatility component in the
cosolvent.
[0037] In EP 1157689 the applicant disclosed aerosol pharmaceutical
compositions comprising a .beta..sub.2-agonist belonging to the
class of phenylalkylamino derivatives in solution in a HFA
propellant, a co-solvent whose apparent pH has been adjusted to
between 2.5 and 5.0 in order to guarantee an adequate shelf-life.
In a particular embodiment of the invention, isopropyl myristate
(IPM) as a low-volatility is added in order to either increase the
MMAD of the aerosol particles and further improving the stability
of the formulation. As far as the role of water is concerned, it is
only reported that humidity, in the case of certain active
ingredients could be detrimental to the chemical stability during
storage. In EP 1 157 689 it is generically stated that TA 2005
formulations will be advantageously suitable for delivering 2-10
.mu.g/dose, preferably 3-5 .mu.g/dose. A 3.5 .mu.g/dose HFA 134a
formulation containing 12% w/w ethanol and 1.0% IPM in order to
increase the MMAD of the delivered particles and to improve the
stability of the formulation is reported in example 7.
[0038] In view of the above considerations, it would be highly
advantageous to provide highly efficient 2(1H)-quinolinone
derivatives long acting .beta..sub.2-agonist formulations to be
administered by pMDI characterized by a deeper lung penetration and
a low systemic exposure.
SUMMARY OF THE INVENTION
[0039] The object of the present invention is to provide a
pharmaceutical aerosol solution formulation to be administered by
pMDI, having a suitable shelf-life for pharmaceutical use,
comprising an active ingredient selected from 2(1H)-quinolinone
derivatives long acting .beta..sub.2-agonists of formula (I)
##STR00001##
[0040] where R.sub.1 is methyl and R.sub.2 is hydrogen or R.sub.1
and R.sub.2 form a methylenic bridge (CH.sub.2).sub.n
[0041] n is 1 or 2
[0042] R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each independently
hydrogen, hydroxy, C.sub.1-C.sub.4 straight chain or branched
alkyl, C.sub.1-C.sub.4 straight chain or branched alkyl substituted
by one or more halogen and/or hydroxy, halogen, C.sub.1-C.sub.4
straight chain or branched alkoxy, enantiomers, salts and solvates
thereof;
[0043] a HFA propellant and a suitable amount of co-solvent wherein
the active ingredient is completely dissolved in the
propellant-cosolvent system.
[0044] Said solution provides on actuation of the formulation a
fraction of particles equal or less than 1.1 micron of at least 30%
as defined by the content stages S6-AF of an Andersen Cascade
Impactor relative to the total amount of the fine particle dose
collected in the stages S3-AF of the impactor.
[0045] The formulation of the invention is able to deliver a
significant fraction of particles having a diameter equal or less
than 1.1 micron, comprising both extrafine particles, according to
the definition of Martin R in J Allergy Clin Immunol 2002, 109
(Suppl 2), 447-460 and particles having a diameter equal or less
than 0.3 micron (ultrafine particles, according to the definition
of other authors). By virtue of these characteristics the
formulation of the invention will be hereinafter referred to as
superfine formulation.
[0046] As a particular aspect of the present invention, we provide
a pharmaceutical aerosol formulation comprising 0.005-0.016% w/v
8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am-
ino]ethyl]-2(1H)-quinolinone or one of its pharmaceutically
acceptable salt or solvates as active ingredient in solution in a
liquefied HFA propellant and a co-solvent preferably selected from
a pharmaceutically acceptable alcohol, characterized in that the
fraction of particles equal or less than 1.1 micron is higher than
or equal to 30% as defined by the content of stages S6-AF of an
Andersen Cascade Impactor relative to the total amount of the fine
particle dose collected in the stages S3-AF of the impactor. The
preferred active ingredient is
8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am-
ino]ethyl]2(1H)-quinolinone hydrochloride from now onwards defined
as TA 2005. In certain formulations a proper amount of water up to
5% w/w of the total weight of the formulation can be added.
Advantageously the pH of the formulation is to between 2.5 and 5.0
as determined in the model vehicle system reported in EP
1157689.
[0047] The formulations of the invention can also comprise a
further active ingredient. In particular, the addition of a
corticosteroid to a long-acting 2-agonist gives optimal control of
asthma in most patients and relevant fixed combinations are
increasingly used as a convenient controller in patients with
persistent asthma. It has also been reported that each class of
drug enhances the beneficial actions of the other. In fact,
corticosteroids increase the expression of .beta..sub.2-receptors
and protect them against down-regulation in response to long-acting
.beta..sub.2-agonist exposure, whereas .beta..sub.2-agonist may
enhance the anti-inflammatory actions of corticosteroids (Barnes P
et al. Eur Respir J 2002, 19, 182-191).
[0048] Accordingly, another object of the present invention is to
provide highly efficient formulations containing a
2(1H)-quinolinone derivative .beta..sub.2 agonist as active
ingredient, further comprising a steroid. The high fraction of
superfine particles of the formulation of the invention can allow
both drugs to reach the small peripheral airways region in such a
way as to better exercise their synergic effects in distal lung
diseases. Moreover, in view of the aforementioned characteristics,
it might be possible to develop formulations comprising fixed
combinations of the .beta..sub.2 agonist and a steroid wherein the
latter one could be present in a lower dose, by maintaining the
same therapeutic effect.
[0049] A further aspect of the present invention is to provide
highly efficient 2(1H)-quinolinone derivatives long-acting
.beta..sub.2-agonist formulations in combination with an
anticholinergic atropine-like derivative such as ipratropium
bromide, oxitropium bromide and tiotropium bromide in order to
provide a medicament particularly effective for the treatment of
COPD.
[0050] It is also provided a method of filling an aerosol inhaler
with a composition of the invention, the method comprising:
[0051] (a) preparation of a solution of one or more active
ingredients in one or more co-solvents;
[0052] (b) optionally adding a pre-determined amount of water
and/or adjusting the pH of the solution;
[0053] (c) filling of the device with said solution;
[0054] (d) crimping with valves and gassing;
[0055] (e) adding a propellant containing a hydrofluoroalkane
(HFA).
[0056] A still further aspect of the invention comprises the use of
the .beta..sub.2 agonist fully dissolved in the
propellant/co-solvent system and capable of providing on actuation
a fraction of at least 30% of emitted particles with an aerodynamic
diameter equal or less than 1.1 microns, for the preparation of a
medicament for the treatment of respiratory disorders such as
asthma and COPD.
[0057] In view of its technical feature of providing on actuation a
fraction of particles with an aerodynamic diameter of less than 1.1
micron, of at least 30%, the formulation of the invention can be
particularly effective for the treatment of asthma, COPD and,
generally, of airway obstruction conditions wherein the pathology
is associated with mucus hypersecretion which hinders the diffusion
of the drug.
[0058] Furthermore, it may be clinically useful as a treatment to
hasten the resolution of alveolar edema and of
surfactant-deficiency related diseases such as acute lung injury
(ALI) and acute respiratory distress syndrome (ARDS).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0059] A more complete appreciation of the present invention and
many of the attendant advantages thereof will be readily obtained
as the same becomes better understood by reference to the following
detailed description
[0060] The aerosol formulations of the invention comprise a
2(1H)-quinolinone derivative long acting .beta..sub.2-agonist of
formula (I) as active ingredient, an HFA propellant and a
co-solvent wherein the active ingredient is fully dissolved in such
a way that the formulations are able of providing on actuation a
fraction of emitted particles of equal or less than 1.1 microns
higher or equal to 30% as defined by the content stages S6-AF of an
Andersen Cascade Impactor relative to the total fine particle dose
collected in the stages S3-AF of the impactor, advantageously
higher than 40%, preferably higher than 50%, more preferably higher
than 60%, even more preferably higher than 70%. Advantageously, the
formulations of the invention are free of other excipients such as
surfactants besides the solubilisation agent, the propellant and,
optionally, water.
[0061] The formulations may contain up to 5% w/v of the active
ingredient, for example 0.0001% to 5%, 0.0005% to 3%, 0.001% to 1%,
0.001 to 0.005% w/v.
[0062] Examples of HFA propellants include
1,1,1,2-tetrafluoroethane (HFA 134a) and
1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) and mixtures thereof.
The preferred propellant is 1,1,1,2-tetrafluoroethane (HFA134a). An
alternative propellant of interest is
1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227).
[0063] The co-solvent is selected from the group of lower alkyl
(C.sub.1-C.sub.4) alcohols, polyols, polyalkylene glycols and their
combinations. Other suitable co-solvents are (poly)alkoxy
derivatives including polyalkoxy alcohols, [such as
2-(2-ethoxyethoxy)ethanol available under the trademark
Transcutol.RTM.].
[0064] Preferably the co-solvent is an alcohol. The preferred one
is ethanol. The concentration of the co-solvent (e.g. ethanol) will
vary depending on the final concentration of the active ingredients
in the formulation and on the propellant. The amount of ethanol
should not exceed around 40% w/w of the total weight of the
formulation. Advantageously it is comprised between 5 and 30% w/w,
preferably between 10 and 20% w/w, even more preferably between 12
and 15% w/w.
[0065] Active ingredients which may be used in the aerosol
compositions of the invention are 2(1H)-quinolinone derivatives
long acting .beta..sub.2 adrenergic agonists of formula (I),
stereoisomers, physiologically acceptable salts and solvates
thereof.
[0066] The preferred active ingredient is
8-hydroxy-5-[(1R)-1-hydroxy-2-[[-(1R)-2-(4-methoxyphenyl)-1-methylethyl]a-
mino]ethyl]-2(1H)-quinolinone, in the form of hydrochloride salt
(TA 2005).
[0067] Said active ingredients can be used alone or in combination
with steroids such as beclometasone dipropionate (BDP),
flunisolide, mometasone furoate, fluticasone propionate,
ciclesonide, budesonide and its 22R-epimer, with anticholinergic
atropine-like derivatives such as ipratropium bromide, oxitropium
bromide, tiotropium bromide or with drugs useful for the management
of respiratory diseases such as methylxanthines, anti-leukotrienes
and phosphodiesterase inhibitors.
[0068] The concentration of the active ingredient in the HFA
formulation will depend on the therapeutic amount to be delivered
preferably in one or two actuations.
[0069] In the foregoing formulations are provided for TA 2005 and
drug concentrations are given as w/v. The corresponding percentages
as (w/w) can be calculated by determining the density of the
vehicle.
[0070] The formulations will be filled in a canister fitted with a
suitable metering valve. We prefer that the formulation is actuated
by a metering valve capable of delivering a volume of between 25
.mu.l and 100 .mu.l, e.g. 50 .mu.l or 63 .mu.l. 100 .mu.l is also
suitable.
[0071] TA 2005 concentration will vary between 0.0005% and 0.024%
w/v in order to deliver 0.5-6 .mu.g per actuation, preferably
between 0.001% and 0.016% w/v, in order to deliver 1-4 .mu.g per
actuation, more preferably between 0.001% and 0.008% w/v in order
to deliver 1 or 2 .mu.g per actuation. If needed, a drug overage
can be done. For instance, for 1 and 2 .mu.g/dose, wherein a 63
.mu.l metering volume is used, the final concentrations of TA 2005
hydrochloride delivered per actuation would be 0.0016% and 0.0032%
w/v, respectively.
[0072] The intended dose regimen for TA 2005 is twice or once
daily, preferably once daily where the suitable daily dose may
range up to 8 .mu.g and advantageously ranges from 0.5 to 6 .mu.g,
preferably from 1 to 6 .mu.g, more preferably from 2 to 4
.mu.g.
[0073] The apparent pH range is advantageously between 2.5 and 5.0,
preferably between 2.8 and 4.0. Strong mineral acids preferably
selected from the group of hydrochloric, nitric, phosphoric acid
are used to adjust the apparent pH, more preferably hydrochloric
acid.
[0074] The amount of acid to be added to reach the desired apparent
pH will be pre-determined in the model vehicle reported in EP
1157689 and it will depend on the type and concentration of the
active ingredient and the amount of the co-solvent.
[0075] For 0.001-0.008% w/v TA 2005 in HFA 134a and 15% w/w
ethanol, a concentration between 0.01% and 0.05%, preferably
between 0.01% and 0.03% on the total weight of the formulation of
0.1 M hydrochloric acid is preferably added.
[0076] The presence of water can be especially advantageous when
the formulation further contains another active ingredient such as
a steroid.
[0077] In these cases an amount of water up to 5.0% w/w on the
total weight of the formulation might be present, preferably from
0.05% to 3% w/w, even more preferably from 1% to 2% w/w.
[0078] The formulations of the invention will be filled into
canisters suitable for delivering pharmaceutical aerosol
formulations such as plastic or plastic coated glass bottle or
preferably a metal can, for example an aluminium can. The
formulations can also be filled in canisters having part of all of
the internal surfaces made of anodised aluminium, stainless steel
or lined with an inert organic coating. Examples of preferred
coatings are epoxy-phenol resins, perfluorinated polymers such as
perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes
such as poly-tetrafluoroethylene (TEFLON.RTM.),
fluorinated-ethylene-propylene, polyether sulfone and a copolymer
fluorinated-ethylene-propylene polyether sulfone. Other suitable
coatings could be polyamide, polyimide, polyamideimide,
polyphenylene sulfide or their combinations.
[0079] Canisters having the internal surface lined with Teflon
might be preferred for the TA 2005 formulations.
[0080] To further improve the stability, cans having a rim with
rounded edges, preferably a rolled neck or rolled-in rim, a part or
full rollover rim can be used according to the teaching of WO
02/72448.
[0081] The canister is closed with a metering valve. The metering
valves are designed to deliver a metered amount of the formulation
per actuation and incorporate a gasket to prevent leakage of
propellant through the valve.
[0082] The gasket may comprise any suitable elastomeric material
such as for example low density polyethylene, chlorobutyl, black
and white butadiene-acrylonitrile rubbers, butyl rubber, neoprene,
EPDM (a polymer of ethylenepropylenediene monomer) and TPE
(thermoplastic elastomer). EPDM and TPE rubbers are preferred. EPDM
rubbers are particularly preferred. Suitable valves are
commercially available from manufacturers well known in the aerosol
industry, for example, from Valois, France (e.g., DF10, DF30,
DF60), Bespak plc, UK (e.g., BK300, BK356, BK357) and 3M-Neotechnic
Ltd, UK (e.g., SPRAYMISER.RTM.). The DF31 valve of Valois, France
is also suitable. Valve seals, especially the gasket seal, and also
the seals around the metering chamber, will preferably be
manufactured of a material which is inert to and resists extraction
into the contents of the formulation, especially when the contents
include ethanol.
[0083] Valve materials, especially the material of manufacture of
the metering chamber, will preferably be manufactured of a material
which is inert to and resists distortion by contents of the
formulation, especially when the contents include ethanol.
Particularly suitable materials for use in manufacture of the
metering chamber include polyesters e.g. polybutyleneterephthalate
(PBT) and acetals, especially PBT.
[0084] Materials of manufacture of the metering chamber and/or the
valve stem may be fluorinated, partially fluorinated or impregnated
with fluorine containing substances in order to resist drug
deposition.
[0085] Conventional bulk manufacturing methods and machinery well
known to those skilled in the art of pharmaceutical aerosol
manufacture may be employed for the preparation of large-scale
batches for the commercial production of filled canisters. Thus,
for example, in one bulk manufacturing method a metering valve is
crimped onto an aluminum can to form an empty canister. The
medicament is added to a charge vessel and a mixture of ethanol,
optionally water and liquefied propellant is pressure filled
through the charge vessel into a manufacturing vessel. An aliquot
of the formulation is then filled through the metering valve into
the canister.
[0086] In an alternative process, an aliquot of the liquefied
formulation is added to an open canister under conditions which are
sufficiently cold that the formulation does not vaporize, and then
a metering valve crimped onto the canister.
[0087] In an alternative process, an aliquot of medicament
dissolved in the solubilising agent is dispensed into an empty
canister, a metering valve is crimped on, and then the propellant
is filled into the canister through the valve. The processes can be
carried out an in inert atmosphere, for instance by insufflating
nitrogen, in order to avoid the uptake of humidity from the
air.
[0088] Each filled canister is conveniently fitted into a suitable
channeling device prior to use to form a metered dose inhaler for
administration of the medicament into the lungs of a patient.
Suitable channeling devices comprise, for example a valve actuator
and a cylindrical or cone-like passage through which medicament may
be delivered from the filled canister via the metering valve to the
mouth of a patient e.g. a mouthpiece actuator.
[0089] In a typical arrangement the valve stem is seated in a
nozzle block which has an orifice leading to an expansion chamber.
The expansion chamber has an exit orifice which extends into the
mouthpiece. Actuator (exit) orifice diameters in the range
0.15-0.45 mm especially 0.2-0.45 mm are generally suitable e.g.
0.25, 0.30, 0.33 or 0.42 mm. 0.22 mm is also suitable. For certain
formulations it would be useful to utilize laser-drilled actuator
orifices having a diameter ranging from 0.10 to 0.22 mm, in
particular from 0.12 to 0.18 mm as those described in the
co-pending application n. EP 1130521.6.
[0090] The use of such fine orifices also increases the duration of
cloud generation and lowers its velocity. These changes facilitate
the coordination of cloud generation with the slow inspiration of
the patient.
[0091] The aerodynamic particle size distribution of each tested
formulation of the invention can be characterized using a
Multistage Cascade Impactor according to the procedure described in
European Pharmacopoeia 2.sup.nd edition, 1995, part V.5.9.1, pages
15-17. In this specific case, an Andersen Cascade Impactor (ACI)
was utilized operating at a flow rate of 28.3 l/min. Deposition of
the drug on each ACI plate was determined by high pressure liquid
chromatography (HPLC). Mean delivered dose was calculated from the
cumulative deposition in the ACI. Mean respirable dose (fine
particle dose) was obtained from the deposition on Stages 3 (S3) to
filter (AF) corresponding to particles .ltoreq.4.7 microns, divided
by the number of actuation per experiment, while mean "superfine"
dose was obtained from the deposition on Stages 6 to filter
corresponding to particles .ltoreq.1.1 microns.
[0092] Administration of the formulations of the invention may be
indicated for the treatment of mild, moderate or severe, acute or
chronic symptoms or for prophylactic treatment of respiratory
diseases such as asthma and chronic obstructive pulmonary disease
(COPD). Other respiratory disorders characterized by obstruction of
the peripheral airways as a result of inflammation and presence of
mucus such as chronic obstructive bronchiolitis and chronic
bronchitis can also benefit of this kind of formulation.
EXAMPLES
[0093] Having generally described this invention, a further
understanding can be obtained by reference to certain specific
examples which are provided herein for purposes of illustration
only and are not intended to be limiting unless otherwise
specified.
Example 1
Superfine TA 2005 HFA Formulations
[0094] A formulation for delivering a nominal dose of 1 .mu.g per
actuation of active ingredient was prepared with the composition as
follows:
TABLE-US-00001 Amounts Per unit Nominal Components mg % dose .mu.g
TA 2005 0.15 0.0016 w/v 1 Ethanol 1650 15 w/w -- HCl 0.1 M 2.0*
0.018 w/w -- HFA 134a q.s. to 9.45 ml 9347.85 -- -- *equivalent to
2.0 .mu.l
[0095] The formulation (120 actuations/canister, overage of 30
actuations) was filled in aluminum canisters having the internal
surface coated with TEFLON.RTM. (two stage pressure filling) and
fitted with a metering valve having a 63 .mu.l metering chamber. An
actuator with an orifice diameter of 0.22 mm was used. Results were
obtained as a mean of 2 cans.
[0096] Analogously, formulations able of delivering a nominal dose
of 2, 3 or 4 .mu.g per actuation of active ingredient can be
prepared. The aerodynamic particle size distribution was measured
by ACI, according to page 16 lines 10 to 18 and the delivery
characteristics of each formulation were determined in terms of the
following parameters i) nominal dose: theoretical dose per single
actuation; ii) delivered dose: amount of active particles deposited
into the all ACI stages; iii) respirable dose (fine particle dose):
amount of active particles of size less than 4.7 microns (S3-AF);
iv) respirable fraction (fine particle fraction): ratio between the
respirable dose and the delivered dose; v) "superfine" dose: amount
of active particles equal or less than 1.1 microns (S6-AF); iv)
"superfine" fraction: ratio between the "superfine" dose and the
respirable dose.
[0097] The formulation of the invention gives rise upon actuation
to a very high percentage of particles with a diameter less than
1.1 microns. For certain formulations depending on the percentage
of active ingredient and amount of co-solvent, superfine fractions
of more than 80% can be achieved.
[0098] Despite the presence of such a high fraction of particles
having a diameter equal or less than 1.1 micron in the formulation,
at the therapeutic doses the drug has been well tolerated.
[0099] A stability study on a formulation able to deliver 4 .mu.g
per actuation was initiated storing the cans upright at 5.degree.
C.
[0100] After nine months the TA 2005 assay is higher than 95% and
therefore meets the requirements of the ICH guideline Q1A referring
to "Stability Testing of new Active Substances (and Medicinal
Products)".
Example 2
Superfine HFA Formulation Comprising TA 2005 and 22R-Budesonide
[0101] A formulation for delivering, respectively, a nominal dose
of 1 .mu.g of TA 2005 and 80 .mu.g of 22R-budesonide per actuation
was prepared with the composition as follows:
TABLE-US-00002 Amounts Per unit Nominal Components mg % dose .mu.g
TA 2005 0.15 0.0016 w/v 1 22R-budesonide 12.00 0.127 w/v 80 Ethanol
1650 15 w/w -- HCl 0.1 M 3.3* 0.03 w/w -- Water 220.05 2.0 w/w HFA
134a q.s. to 9.45 ml 9114.5 -- -- *equivalent to 3.3 .mu.l
The formulation (120 actuations/canister, overage of 30 actuations)
was filled in aluminum canisters having the internal surface coated
with Teflon (two stage pressure filling) and fitted with a metering
valve having a 63 .mu.l metering chamber.
[0102] Where a numerical limit or range is stated herein, the
endpoints are included. Also, all values and subranges within a
numerical limit or range are specifically included as if explicitly
written out.
[0103] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that, within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described herein.
[0104] All patents and other references mentioned above are
incorporated in full herein by this reference, the same as if set
forth at length.
* * * * *