U.S. patent application number 11/289479 was filed with the patent office on 2006-04-20 for stable pharmaceutical solution formulations for pressurised metered dose inhalers.
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. Invention is credited to Gaetano Brambilla, Alessandra Ferraris, David Ganderton, David Lewis, Brian Meakin.
Application Number | 20060083693 11/289479 |
Document ID | / |
Family ID | 8163952 |
Filed Date | 2006-04-20 |
United States Patent
Application |
20060083693 |
Kind Code |
A1 |
Lewis; David ; et
al. |
April 20, 2006 |
Stable pharmaceutical solution formulations for pressurised metered
dose inhalers
Abstract
An aerosol solution composition for use in an aerosol inhaler
comprises an active material, a propellant containing a
hydrofluoroalkane, a cosolvent and optionally a low volatility
component to increase the mass median aerodynamic diameter (MMAD)
of the aerosol particles on actuation of the inhaler. The
composition is stabilized by using a small amount of mineral acid
and a suitable can having part or all of its internal metallic
surfaces made of stainless steel, anodized aluminium or lined with
an inert organic coating.
Inventors: |
Lewis; David; (Parma,
IT) ; Ganderton; David; (Devon, GB) ; Meakin;
Brian; (Bath, GB) ; Brambilla; Gaetano;
(Parma, IT) ; Ferraris; Alessandra; (Parma,
IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Chiesi Farmaceutici S.p.A.
Parma
IT
|
Family ID: |
8163952 |
Appl. No.: |
11/289479 |
Filed: |
November 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10640005 |
Aug 14, 2003 |
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11289479 |
Nov 30, 2005 |
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09860689 |
May 21, 2001 |
6716414 |
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10640005 |
Aug 14, 2003 |
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Current U.S.
Class: |
424/45 ;
128/200.23; 514/171; 514/291 |
Current CPC
Class: |
A61K 31/167 20130101;
A61K 9/008 20130101; A61K 31/573 20130101; A61K 31/5386 20130101;
A61K 9/124 20130101; A61K 31/439 20130101; A61P 11/00 20180101;
A61K 45/06 20130101; A61P 11/08 20180101; A61K 31/4745 20130101;
A61K 31/167 20130101; A61K 2300/00 20130101; A61K 31/439 20130101;
A61K 2300/00 20130101; A61K 31/5386 20130101; A61K 2300/00
20130101; A61K 31/573 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/045 ;
514/291; 128/200.23; 514/171 |
International
Class: |
A61L 9/04 20060101
A61L009/04; A61K 31/573 20060101 A61K031/573; A61K 31/4745 20060101
A61K031/4745; A61M 11/00 20060101 A61M011/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 22, 2000 |
WO |
PCT/EP00/04635 |
Claims
1. An aerosol composition which comprises a .beta..sub.2-agonist
drug of the phenylalkylamino class bearing a functional group
sensitive to oxidative and/or hydrolytic reaction in a solution of
a liquefied HFA propellant, a co-solvent selected from
pharmaceutically acceptable alcohols, wherein the pH of the
solution -is comprised between 2.5 and 5.0 by addition of small
amounts of a mineral acid such as hydrochloric, nitric or
phosphoric acid.
2. A composition according to claim 1 wherein the active ingredient
is a .beta..sub.2-agonist selected from salbutamol, formoterol,
salmeterol and TA-2005, salts thereof or their combination with
steroid such as beclomethasone dipropionate, fluticasone
propionate, budesonide and its 22R-epimer or an anticholinergic
atropine-like derivative such as ipratropium bromide, oxitropium
bromide, tiotropium bromide
3. A composition according to claims 1-2 filled in a container
having part or all of its internal metallic surfaces made of
stainless steel, anodised aluminium or lined with an inert organic
coating.
4. A composition according to claims 1-3, wherein the container is
lined with an inert organic coating selected from epoxy-phenol
resins, perfluoroalkoxyalkane, perfluoroalkoxyalkylene,
perfluoroalkylenes such as polytetrafluoroethylene,
fluorinated-ethylene-propylene, polyether sulfone and a copolymer
fluorinated-ethylene-propylene polyether sulfone
5. A composition according to claims 1-4, wherein the active
ingredient is formoterol fumarate and the pH of the solution -is
comprised between 3.0 and 3.5.
6. A composition according to claims 1-5, wherein the solution
includes a low volatility component with a vapour pressure at
25.degree. C. not more than 0.1 kPa, preferably not more than 0.05
kPa.
7. A composition according to any preceding claim, wherein the
solution includes at least 0.2% by weight of the low volatility
component and not more than 10% by weight.
8. A composition according to claims 6-7, wherein the low
volatility component is selected from a glycol or an ester of
long-chain fatty acids.
9. A composition according to claims -6-8, wherein the low
volatility component is isopropyl myristate.
10. A composition according to any preceding claim, wherein the
propellant includes one or more HFAs selected from the group
comprising HFA 134a and HFA 227.
11. A composition according to any preceding claims, wherein the
cosolvent is an alcohol, preferably ethanol.
12. A method of preparing the formulations of claims 1-10, the
method comprising: (a) preparation of a solution of one or more
active ingredients in one or more co-solvents optionally containing
an appropriate amount of a low volatility component; (b) filling
the device with said solution; (c) adding a pre-determined amount
of a strong mineral acid; (d) adding a propellant containing a
hydrofluoroalkane (HFA); (e) crimping with valves and gassing.
Description
[0001] The invention relates to stable pharmaceutical solution to
be used with pressurised metered dose inhalers (MDIs) suitable for
aerosol administration. In particular, the invention relates to
solution to be used with pressurised metered dose inhalers (MDIs),
suitable for aerosol administration containing
.beta..sub.2-agonists and stable at room temperature for a
pharmaceutically acceptable shelf-life.
[0002] Pressurised metered dose inhalers are well known devices for
administering pharmaceutical products to the respiratory tract by
inhalation.
[0003] Drugs commonly delivered by inhalation include
bronchodilators such as .beta..sub.2-agonists and anticholinergics,
corticosteroids, anti-leukotrienes, anti-allergics and other
materials that may be efficiently administered by inhalation, thus
increasing the therapeutic index and reducing side effects of the
active material.
[0004] MDI uses a propellant to expel droplets containing the
pharmaceutical product to the respiratory tract as an aerosol.
Formulations for aerosol administration via MDIs can be solutions
or suspensions. Solution formulations offer the advantage of being
homogeneous with the active ingredient and excipients completely
dissolved in the propellant vehicle or its mixture with suitable
co-solvents such as ethanol. Solution formulations also obviate
physical stability problems associated with suspension formulations
so assuring more consistent uniform dosage administration.
[0005] For many years the preferred propellants used in aerosols
for pharmaceutical use have been a group of chlorofluorocarbons
which are commonly called Freons or CFCs, such as CCl.sub.3F (Freon
11 or CFC-11), CCl.sub.2F.sub.2 (Freon 12 or CFC-12), and
CClF.sub.2-CClF.sub.2 (Freon 114 or CFC-114).
[0006] Recently, the chlorofluorocarbon (CFC) propellants such as
Freon 11 and Freon 12 have been implicated in the destruction of
the ozone layer and their production is being phased out.
[0007] Hydrofluoroalkanes [(HFAs) known also as
hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered
less destructive to ozone and these are proposed as substitutes for
CFCs.
[0008] HFAs and 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 medicinal aerosol formulations using such HFA
propellant systems have been disclosed.
[0009] Due to the higher polarity of the HFA propellants, in
particular of HF A 134a (dielectric constant D.gtoreq.9.5), with
respect to CFC vehicles (D.ltoreq.2.3), HFA solution formulations
may suffer to a greater extent of chemical stability problems with
respect to the corresponding CFC formulations.
[0010] Preparation of stable HFA solution formulations is even more
critical when bronchodilator .beta..sub.2-agonists belonging to the
class of the phenylalkylamino derivatives are concerned; said
drugs, like formoterol,
8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]am-
ino]ethyl]-2(1H)-quinolinone (hereinafter referred as TA 2005), and
salbutamol (albuterol) and others, may suffer of inherent chemical
stability problems due to their susceptibility to oxidative
conditions; moreover, in the view of the presence of some
functional groups like formamide, a higher polarity of the vehicle
may accelerate the rate of solvolysis reactions.
[0011] As far as formoterol, the currently marketed CFC
solutionformulation (Foradil.RTM.) exhibits a limited shelf life,
i.e. 12 months at refrigerator temperature, 4.+-.2.degree. C., and
only 3 month at room temperature.
[0012] As far as salbutamol, no formulation as HFA solution for
aerosol administration currently on the market.
[0013] In the case of TA 2005, no formulation at all is currently
available for aerosol administration.
[0014] In consideration of the problems outlined, it would be
highly advantageous to provide a formulation in the form of HFA
solution to be administered by MDI's aimed at providing
pharmaceutical doses of .beta..sub.2-agonists characterised by
adequate shelf-life.
OBJECT OF THE INVENTION
[0015] It is an object of the invention to provide a formulation in
the form of HFA solution to be administered by MDI's for providing
pharmaceutical doses of .beta..sub.2-agonists into the low
respiratory tract of patients suffering of pulmonary diseases such
as asthma, characterised by adequate shelf-life. In particular, it
is an object of the invention to provide a formulation in the form
of HFA solution to be administered by MDI's for providing
pharmaceutical doses of formoterol with a greater shelf-life of
that of the formulation currently on the market.
[0016] According to the invention there is provided a
pharmaceutical composition comprising a .beta..sub.2-agonist
belonging to the class of phenylalkylamino derivatives in a
solution of a liquefied HFA propellant, a co-solvent selected from
pharmaceutically acceptable alcohols, solution whose apparent pH
has been adjusted to between 2.5 and 5.0 by addition of small
amounts of a mineral acid. The composition of the invention shall
be contained in a pressurised MDI having part or all of its
internal metallic surfaces made of stainless steel, anodised
aluminium or lined with an inert organic coating.
[0017] In fact, it has been found that, in the case of certain
active ingredients such as .beta..sub.2-agonists, their chemical
stability in HFA solution formulations could be dramatically
improved by a proper and combined selection of the kind of cans as
well as the apparent pH range. The attribution `apparent` is used
as pH is indeed characteristic of aqueous liquids where water is
the dominant component (Mole Fraction>0.95). In relatively
aprotic solvents such as the HFA-ethanol vehicles used in these
studies, protons are non-hydrated; their activity coefficients
differ significantly from those in aqueous solution. Although the
Nernst equation with respect to EMF applies and the pH-meter glass
electrode system will generate a variable milli-volt output
according to proton concentration and vehicle polarity, the "pH"
meter reading is not a true pH value. The meter reading represents
an apparent pH or acidity function (pH').
[0018] When formoterol fumarate was titrated with a strong acid in
a model vehicle system commercially available (HFA 43-10MEE,
Vertrel XF, Dupont), according to a method developed by the
applicant, the pH' profile exhibits a shallow negative to about
pH'=5.5; thereafter the acidity function drops abruptly.
Surprisingly the corresponding HFA formulations turned out to much
more stable below pH' 5.5. As far as TA 2005 is concerned, the pH'
profile exhibits a shallow negative to about pH'=5.0; thereafter
the acidity function drops quite abruptly.
[0019] On the other hand, the use of inert containers allows to
avoid the leaching of metal ions or alkali as a consequence of the
action of the acid contained in the formulation onto the inner
walls of the cans. Metal ions such Al.sup.3+ or alkali respectively
deriving from the conventional aluminium or glass cans could in
turn catalyse radical oxidative or other chemical reactions of the
active ingredient which give rise to the formation of degradation
products.
[0020] According to an embodiment of the invention there is also
provided a pharmaceutical composition further containing a low
volatility component in such a way as to, besides increasing the
mass median aerodynamic diameter (MMAD) of the aerosol particles on
actuation of the inhaler as explained in the following, further
improving the stability of the formulation. In fact, the addition
of a low volatility component with a reduced polarity with respect
to the co-solvent such as an ester may allow either to reduce the
amount of acid to be added for adjusting the pH and diminish the
polarity of the medium so limiting the possible uptake of
environmental water. In the case of active ingredients such as
formoterol, it is well known that the latter (e.g. humidity) could
be detrimental to the stability of the active ingredient during
storage. According to a particular embodiment of the invention,
there is provided a pressurised MDI for administering
pharmaceutical doses consisting of an anodised aluminium container
filled with a pharmaceutical composition consisting of a solution
of formoterol fumarate in HFA 134a as a propellant in turn
containing 12% w/w ethanol as a co-solvent and optionally isopropyl
myristate as a low volatility component in an amount less/equal
than 1.0% w/w, the apparent pH of said solution having been
adjusted to between 3.0 and 3.5 by addition of small amounts of
hydrochloric acid. The expression `% w/w` means the weight
percentage of the component in respect to the total weight of the
composition.
[0021] The shelf-life of the formulation put in the device of the
invention could be predicted to be greater than two years at the
refrigerator temperature (4-10.degree. C.) and three months at room
temperature.
[0022] According to another particular embodiment of the invention,
there is provided a pressurised MDI consisting of a coated
container filled with a pharmaceutical composition consisting of a
solution of a combination of formoterol fumarate and beclometasone
dipropionate (hereinafter BDP) in HFA 134a as a propellant in turn
containing 12% w/w ethanol as a co-solvent with or without
isopropyl myristate as low volatility component, the apparent pH of
said solution having been adjusted to between 3.0 and 3.5 by
addition of small amounts of hydrochloric acid.
[0023] According to a further particular embodiment of the
invention, there is provided a pressurised MDI consisting of a
coated container filled with a pharmaceutical composition
consisting of a solution of TA 2005 in HFA 134a as a propellant in
turn containing 12% w/w ethanol as a co-solvent with or without
ispropyl myristate as a low volatility component, the apparent pH
of said solution having been adjusted to between 3.0 and 5.0 by
addition of small amounts of hydrochloric acid.
[0024] However, a person sufficiently skilled in the art can easily
apply the teaching of the present invention to the preparation of
HFA solution formulations containing other active ingredients
bearing functional groupssensitive to hydrolytic and/or oxidative
reactions, such as formamide and cathecol respectively.
[0025] WO 97/47286, EP 513127, EP 504112, WO 93/11747, WO 94/21228,
WO 94/21229, WO 96/18384, WO 96/19198, WO 96/19968, WO 98/05302, WO
98/34595 and WO 00/07567 disclose HFA formulations in the form of
suspensions in which .beta..sub.2-agonists such formoterol and
salbutamol are either exemplified and/or claimed.
[0026] WO 99/65464 refers to HFA formulations containg two or more
active ingredients in which at least one is in suspension. The
preferred formulations comprises salbutamol sulphate in
suspension.
[0027] In WO 98/34596, the applicant described solution
compositions for use in an aerosol inhaler, comprising an active
material, a propellant containing a hydrofluoroalkane (HFA), a
cosolvent and further comprising a low volatility component to
increase the mass median aerodynamic diameter (MMAD) of the aerosol
particles on actuation of the inhaler. Said application does not
address the technical problem of the chemical stability of the
active ingredient but it rather concern the drug delivery to
lungs.
[0028] In the international application n.degree.PCT/EP99/09002
filed on Nov. 23, 1999 published on Jun. 2, 2000 as WO 00/30608 the
applicant has disclosed pressurised MDI's for dispensing solution
of an active ingredient in a hydrofluorocarbon propellant, a
co-solvent and optionally a low-volatility component characterized
in that part or all of the internal surfaces of said inhalers
consist of stainless steel, anodised aluminium or are lined with an
inert organic coating. The examples are referred only to steroids
and anticholinergic agents. As demonstrated in the example 1 of the
present application, the use of coated containers, even in the
presence of an organic acid, is not sufficient for providing stable
solution formulations of a phenylalkylamino derivative such as
salbutamol.
[0029] EP 673240 proposes the use of acids as stabilisers
preventing the chemical degradation of the active ingredient in
aerosol solution formulations comprising HFAs. Most examples relate
to ipratropium bromide, an anticholinergic drug and only an example
is presented for a .beta..sub.2-agonist, i.e. fenoterol. Although
salbutamol is claimed, no exemplary formulations are provided.
Moreover, the stability data are reported only for ipratropium and
the patentee does not either make difference between the use of
organic and inorganic acids. It is indeed evident from the data
reported in the example 1 of the present application, that
salbutamol cannot be stabilised at all by addition of organic acids
even when stored in coated cans. Furthermore, apart from
ipratropium bromide, in EP 673240 no guidance is given 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.
[0030] WO 98/34596 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.
[0031] WO 00/06121 refers to propellant mixtures for aerosol
dinitrogen monoxide and a hydrofluoroalkane in the preparation of
suspension and solution aerosols. The use of dinitrogen monoxide
may improve the stability at storage of oxidation-sensitive active
ingredients. As far as .beta..sub.2-agonist such as levosalbutamol
sulphate, formoterol fumarate and salmeterol xinafoate, only
examples referred to suspensions are reported.
[0032] WO 99/65460 claims pressurised MDI's containing stable
formulations of a .beta.-agonist drug in suspension or solution.
Examples refer to solutions of formoterol fumarate containing an
HFA propellant and ethanol as co-solvent, filled in conventional
aluminium or plastic coated glass cans.
[0033] Samples stored under accelerated conditions (40.degree. C.,
75% relative humidity) for a very short period, one month,
exhibited about 10% loss of drug. According to pharmaceutical
guidelines on stability, loss of 10% of active ingredient does not
meet the criteria of acceptance. Moreover, as it is evident from
the data reported in Example 2 of the present application,
following the teaching of WO 99/65460 stable formoterol solution
formulations cannot be provided. The applicant has indeed
demonstrated that the presence of low-volatility components does
not substantially affect the chemical stability of the
compositions. In some cases, they could even improve it.
[0034] According to a further aspect of the invention there is
provided a method of filling an aerosol inhaler with a composition
of the invention, the method comprising: [0035] (a) Preparation of
a solution of one or more active ingredients in one or more
co-solvents optionally containing an appropriate amount of a low
volatility component [0036] (b) Filling of the device with said
solution [0037] (c) Adding a pre-determined amount of a strong
mineral acid [0038] (d) Adding a propellant containing a
hydrofluoroalkane (HFA) [0039] (e) Crimping with valves and
gassing
[0040] Active ingredients which may be used in the aerosol
compositions of the invention are short- and long-acting
.beta..sub.2-adrenergic agonists such as salbutamol, formoterol,
salmeterol, TA 2005 and salt thereof and their combinations with
steroids such as beclomethasone dipropionate, fluticasone
propionate, budesonide and its 22R-epimer or with anticholinergic
atropine-like derivatives such as ipratropium bromide, oxitropium
bromide, tiotropium bromide.
[0041] Preferably the active ingredient is a long acting
.beta..sub.2-agonists belonging to the formula sketched below
##STR1##
[0042] wherein R is more preferably
1-formylamino-2-hydroxy-phen-5-yl (formoterol) or
8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) or one of their
corresponding stereoisomers. Other amino type drugs bearing
functional groups sensitive to oxidative and/or hydrolytic
reactions can be advantageously used. Although the preferred
formulations of the invention are in the form of solutions, in case
of the combinations, one of the two active ingredients could be
present in suspension.
[0043] We prefer the formulation to be suitable for delivering a
therapeutic amount of the active ingredient in one or two
actuations. Preferably the formulation will be suitable for
delivering 6-12 .mu.g/dose of formoterol fumarate either alone or
in combination. In the case of TA 2005, the formulation will be
advantageously suitable for delivering 2-10 .mu.g/dose, preferably
3-5 .mu.g/dose. For "dose" we mean the amount of active ingredient
delivered by a single actuation of the inhaler.
[0044] The formulations of the invention will be contained in cans
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,
perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes
such as polytetrafluoroethylene, 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.
[0045] To further improve the stability, cans having a rolled-in
rim and preferably a part or full rollover rim are used.
[0046] The formulation is actuated by a metering valve capable of
delivering a volume of between 50 .mu.l and 100 .mu.l.
[0047] Metering valves fitted with gaskets made of
chloroprene-based rubbers can preferably be used to reduce the
ingress of moisture which, as previously mentioned, can adversely
affect the stability of the drug during storage. Optionally,
further protection can be achieved by packaging the product in a
sealed aluminium pouch.
[0048] The hydrofluorocarbon propellant is preferably selected from
the group of HFA 134a, HFA 227 and mixtures thereof.
[0049] The co-solvent is usually an alcohol, preferably
ethanol.
[0050] The low volatility component, when present, has a vapour
pressure at 25.degree. C. lower than 0.1 kPa, preferably lower than
0.05 kPa. Advantageously, it could be selected from the group of
glycols, particularly propylene glycol, polyethylene glycol and
glycerol or esters, for example ascorbyl palmitate, isopropyl
myristate and tocopherol esters.
[0051] The compositions of the invention may contain from 0.1 to
10%. w/w of said low volatility component, preferably between 0.3
to 5% w/w, more preferably between 0.4 and 2.0% w/w.
[0052] Propylene glycol, polyethylene glycol, glycerol with
residual water less than 0.1% w/w and esters of long-chain fatty
acids are the preferred low-volatility components. More preferred
are those with a dipole moment less than 2.0 or with a dielectric
static constant less than 20, preferably less than 10. Particularly
preferred is isopropyl myristate.
[0053] The function of the low volatility component is to modulate
the MMAD of the aerosol particles and optionally to further improve
the stability of the formulation. With respect to the latter
aspect, particularly preferred is the use of isopropyl
myristate.
[0054] The apparent pH range is advantageously comprised between
2.5 and 5.0, preferably between 3.0 and 4.5, even more preferably
between 3.0 and 3.5. Strong mineral acids such as hydrochloric,
nitric, phosphoric are preferably used to adjust the apparent
pH.
[0055] The amount of acid to be added to reach the desired apparent
pH will be pre-determined in the model vehicle reported before and
it will depend on the type and concentration of the active
ingredient. In the case of the preferred formulations of formoterol
fumarate and its combination with beclometasone dipropionate, an
amount comprised between 3 and 3.5 .mu.l of 1.0 M hydrochloric acid
should be added.
[0056] The following examples further illustrate the invention.
EXAMPLE 1
[0057] Stability of salbutamol (100 .mu.g/dose)-HFA 134a solution
as such and in the presence of different organic acids.
[0058] Compositions containing 24 mg of salbutamol (100
.mu.g/dose), 10-20% (w/w) ethanol in HFA 134a put in 12 mL epoxy
phenol resin lacquered cans, with or without addition of different
organic acids, were stored at 40-50.degree. C.
[0059] The results in term of stability expressed as percentage of
remaining drug determined by HPLC, are reported in Table 1.
TABLE-US-00001 TABLE 1 % SALBUTAMOL Acid t = 42 days t = 1.5 months
at 4.degree. C. None 69% -- Oleic 69-70% -- Xinafoic 70% -- Citric
(0.41 w/w) -- 40.0 Citric (0.02 w/w) -- 55.1 30% Acetic acid (0.4%
w/w) -- 49.6 30% Acetic acid (0.14% w/w) -- 73.8
[0060] The results show that the addition of organic acids does not
improve the stability of salbutamol even when coated cans are
used.
EXAMPLE 2
[0061] Stability of formoterol (12 .mu.g/100 .mu.l) -HFA 134a
compositions in epoxy-phenol resin lacquered cans.
[0062] Solution formulations were prepared by dissolving 1.44 mg of
formoterol fumarate in HFA 134a in turn containing 15% w/w ethanol
and 1.3% w/w glycerol. pMDIs were stored upright over the range
4-50.degree. C. for up to 28 days. Formoterol content was
determined by HPLC and the percent residual concentrations
calculated relative to the 12 .mu.g/shot nominal dose. The percent
residual formoterol concentration is reported in Table 2. Derived
Arrhenius parameters were used to estimate rate constants at
ambient temperature (18-25.degree.) and solutions stored in a
domestic refrigerator (4-10.degree.); these rate constants were
used to calculate predicted shelf-life for 5% and 10% degradation
of formoterol (Table 3).
[0063] The calculated shelf-life data in Table 3 indicates that
formoterol is not stable in this HFA 134a-ethanol-glycerol vehicle.
TABLE-US-00002 TABLE 2 Degradation Rate Data for Formoterol-HFA
134a pMDI Solutions (12 .mu.g/100 .mu.l) Vehicle: HFA 134a with
1.3% w/w Glycerol, 15.0% w/w Ethanol Epoxy-phenol lacquered cans
stored upright Percent Residual Conc. Formoterol Time (days)
50.degree. C. 43.degree. C. 40.degree. C. 25.degree. C. 4.degree.
C. Initial 99.7 99.7 99.7 99.7 99.7 2 92.5 -- -- -- -- 4 87.2 89.4
-- -- -- 6 80.6 -- -- -- -- 7 -- -- 89.0 -- -- 10 74.9 -- -- -- --
12 72.1 79.4 -- -- -- 14 67.0 -- 81.7 92.0 -- 16 64.4 75.7 -- -- --
18 59.5 -- -- -- -- 20 59.5 74.5 -- -- -- 24 54.6 68.6 -- -- -- 28
47.2 63.3 71.3 86.6 96.7 r 0.995 0.989 0.993 0.997 -- Rate Constant
2.53 1.49 1.17 0.51 0.11 (day.sup.-1 .times. 10.sup.2) Arrhenius
Plot Parameters: K = Ae.sup.E/RT A = 2.28 .times. 10.sup.6
day.sup.-1: E = 49.4 kJ mol.sup.-1; r = 0.9985
[0064] TABLE-US-00003 TABLE 3 Predicted Shelf Life Data for
Formoterol-HFA 134a pMDI Solutions (12 .mu.g/100 .mu.l) Vehicle:
HFA 134a with 1.3% w/w Glycerol, 15% w/w Ethanol Epoxy-phenol
lacquered cans stored upright Rate Constant Shelf-Life (days)
Temperature (day.sup.-1 .times. 10.sup.3) t.sub.10% t.sub.5%
4.degree. C. 1.10 95 47 10.degree. C. 1.74 60 29 20.degree. C. 3.51
30 15 25.degree. C. 4.93 21 10
EXAMPLE 3
[0065] Effect of hydrochloric acid on solution pH' (acidity
function)
[0066] (a) 1.0 M hydrochloric acid was added incrementally to 50 mL
of HFA 43-10MEE (Vertrel XF) containing 20% w/w ethanol and pH'
measured after each aliquot of acid. FIG. 1 shows the resultant
titration curve normalised to the usual fill volume of a pMDI can
(12 L). The pH' profile exhibits a shallow negative slope to about
pH'=5.5; thereafter the acidity function drops abruptly.
[0067] (b) Experiment (a) was repeated with formoterol formulations
containing a lower concentration of ethanol (12% w/w) and with the
addition of 1.0% isopropyl myristate. The resultant pH profile, for
replicate bulk solutions, shown in FIG. 2 is similar in shape with
the abrupt fall in pH' per unit increment of acid again commencing
at about pH'=5.5. However, only about half the acid is required to
achieve the same reduction in pH'. This is largely due to the
reduction in ethanol content; FIG. 2 also shows similarity in the
profiles obtained with and without isopropyl myristate.
EXAMPLE 4
[0068] Effect of pH' on Stability of Formoterol Solutions in HFA
43-10MEE containing 20% w/w ethanol
[0069] Aliquots of 1.0 M hydrochloric acid were added to 12 mL of
formoterol solution in glass vials. After measurement of pH, valves
were crimped on and the vials stored upright at 50.degree. C. Vial
samples containing different concentrations of acid were assayed
for residual formoterol after 10 and 20 days storage. The pH' of a
third vial was determined after 40 days storage. Results are shown
in Table 4. Table 4 shows changes in pH on storage; this is
probably largely associated with leaching of alkali from the soft
glass of the vials. However, overall consideration of the pH' and
formoterol content data implies that the stability of a solution
formulation of the drug in HFA can be improved by the addition of
mineral acid to provide a formulation with pH' between 2.5-5.0.
TABLE-US-00004 TABLE 4 pH' and Formoterol Content of
Formoterol-Vertrel XF/HFA Solutions (12 .mu.g/100 .mu.l) Vehicle:
Vertrel XF/HFA with 20% Ethanol and Hydrochloric Acid St Gobain
glass vials stored upright Acidity Percent Residual Function (pH')
Conc. Formoterol Initial 40 days Initial 10 days 20 days 1.8 2.8
100 4.8 Nil 2.1 4.4 100 75.1 70.7 2.6 4.2 100 97.2 86.7 3.3 4.2 100
97.1 89.9 5.6 6.6 100 95.8 92.1 7.4 6.7 100 85.4 67.2
EXAMPLE 5
[0070] Stability of acidified formoterol-HFA 134a solutions in
anodised cans
[0071] Formoterol formulations (12 .mu.g/100 .mu.l) were prepared
by dissolving 1.44 mg of formoterol fumarate in HFA 134a containing
12% w/w ethanol with and without 1.0% w/w isopropyl myristate. The
latter was included as a non-volatile excipient with the potential
for increasing MMAD if so desired. It also improves the solubility
of formoterol in the vehicle and reduces polarity of the vehicle
compared to the addition of glycerol.
[0072] pMDI cans containing 3.1-3.41 .mu.l 1.0 M hydrochloric acid
were set down on storage, upright and inverted, at 4.degree. C. to
50.degree. C. and samples taken for analysis of formoterol content
at appropriate intervals.
[0073] Stability data obtained after 70 days of storage are given
in Table 5.
[0074] A matrix of formulations containing 1.44 mg (12 .mu.g/100
.mu.l) formoterol fumarate were prepared in HFA 134a containing
12.0% w/w ethanol with or without 1.0% w/w isopropyl myristate as
non-volatile excipient. Aliquots of drug concentrate were
transferred to anodised cans and 3.15-3.35 .mu.l of 1.0M
hydrochloric acid added prior to crimping with 50 .mu.l valves and
gassing between 22 and 28 replicates at each acid strength were
prepared.
[0075] To determine residual formoterol, 30.times.50 .mu.l shots
were discharges into DUSA tubes. The acid range selected was
anticipated to give pH' values of 3.0-3.5 and to determine the
formulation sensitivity to small changes in acid concentration.
Cans were placed on stored upright and inverted (valve up and down
respectively) at 25-50.degree. C.
[0076] Table 5 shows the results obtained at 40.degree. and
50.degree. after 11-40 day's storage. Each value (expressed as
percent nominal drug concentration) is obtained from a different
can.
[0077] Initial values were obtained for two cans of each acid
strength. Inspection of the data shows all assay values to within
the reproducibility of the HPLC assay and independent of acid
strength. A similar conclusion was drawn for the storage time point
replicates, i.e., independent of acid strength (3.2-3.3 .mu.l) or
whether cans were stored upright or inverted. Consequently for
kinetics calculation the mean value for initial (n=10) and
subsequent time points (n=6) was used.
[0078] In Table 6 are reported the Arrhenius parameters together
with estimated shelf lives at 4, 10 and 25.degree. C. The t.sub.5%
is predicted to be greater than 3 months at ambient temperature and
approximately 2 years at 4.degree. C. TABLE-US-00005 TABLE 5
Stability Data for Formoterol Fumarate Solutions (12 .mu.g/100
.mu.l) in HFA 134a containing 12.0% Ethanol .+-. 1.0% Isopropyl
Myristate (values are expressed as percent nominal) Anodised cans
fitted with 50 .mu.l valves/30 doses collected per can Different
cans assessed at each condition Cans stored upright (* inverted)
STORAGE CONDITION/No isopropyl myristate 1.0M HCl Initial
40.degree. C.; 40 days 50.degree. C.; 11 days 50.degree. C.; 33
days .mu.l per Can 1.sup.st Can 2.sup.nd Can 1.sup.st Can 2.sup.nd
Can 1.sup.st Can 2.sup.nd Can 1.sup.st Can 2.sup.nd Can 3.15 99.8
99.6 -- -- -- -- -- -- 3.20 100.8 99.7 96.0 93.2* 96.7 96.5 88.5
89.9* 3.25 97.9 98.8 93.9 94.3* 96.4 96.5 92.2 91.5* 3.30 97.3 98.9
93.7 93.7* 97.0 89.1 90.9 92.8* 3.35 100.0 98.3 -- -- -- -- -- --
Mean 99.1 94.1 95.4 91.0 C.V. 1.1% 1.0% 3.2% 1.8% STORAGE
CONDITION/1.0% isopropyl myristate 1.0M HCl Initial 40.degree. C.;
33 days 50.degree. C.; 11 days 50.degree. C.; 31 days .mu.l per Can
1.sup.st Can 2.sup.nd Can 1.sup.st Can 2.sup.nd Can 1.sup.st Can
2.sup.nd Can 1.sup.st Can 2.sup.nd Can 3.15 101.1 99.3 -- -- -- --
-- -- 3.20 97.0 100.2 94.4 93.2* 93.8 93.6 90.6 92.7* 3.25 101.4
100.2 98.6 95.0* 96.1 95.9 91.6 89.7* 3.30 99.9 100.8 92.8 95.3*
95.6 95.7 90.0 89.6* 3.35 99.2 97.2 -- -- -- -- -- -- Mean 99.6
94.9 95.1 90.7 C.V. 1.5% 2.2% 1.2% 1.4%
[0079] TABLE-US-00006 TABLE 6 Shelf Life Prediction for Acidified
Formoterol Fumarate Solution (12 .mu.g/100 .mu.l) in HFA 134a
containing 12% w/w Ethanol .+-. 1.0% w/w isopropyl Myristate (IPM)
Anodised aluminium cans FORMOTEROL FUMARATE (percent nominal) TIME
40.degree. C. (days) Nil IPM 1% IPM Nil IPM 1% IPM 0 99.1 99.6 99.1
99.6 11 95.4 95.1 -- -- 31 -- 90.7 -- -- 33 91.0 -- -- 94.9 40 --
-- 94.1 -- Rate Const. 2.52 2.94 1.29 1.46 (day.sup.-1 .times.
10.sup.3) Frequency Activation Arrhenius Parameters Factor
(day.sup.-1) Energy (kJ mol.sup.-1) Nil IPM 3.19 .times. 10.sup.6
56.3 1% w/w IPM 9.63 .times. 10.sup.6 58.9 Nil IPM 1.0% w/w IPM
Rate Rate Const. t.sub.10% t.sub.5% Const. t.sub.10% t.sub.5%
TEMPERATURE (day.sup.-1) (days) (day.sup.-1) (days) 4.degree. C.
7.8 .times. 10.sup.-5 1344 657 7.8 .times. 10.sup.-5 1360 664
10.degree. C. 1.3 .times. 10.sup.-4 802 392 1.3 .times. 10.sup.-4
789 386 25.degree. C. 4.4 .times. 10.sup.-4 240 117 4.4 .times.
10.sup.-4 225 110
EXAMPLE 6
[0080] Stability of acidified formoterol/BDP-HFA 134a solutions in
cans coated with a fluorocarbon polymer (DuPont 3200-200).
[0081] Formoterol and BDP combination formulations equivalent to
doses of 6 .mu.g/50 .mu.l and 100 .mu.g/50 .mu.l respectively, were
prepared by dissolving 1.44 mg of formoterol fumarate and 24 mg of
BDP in HFA 134a containing 12% w/w ethanol and 0.4% w/w of
isopropyl myristate. pMDI coated cans containing 3.25 .mu.l 1.0 M
hydrochloric acid were set down on storage inverted, at 4.degree.
C. and samples taken for analysis of formoterol and BDP contents at
appropriate intervals.
[0082] Stability data obtained are given in Table 7.
[0083] Each value is expressed as per cent nominal drug
concentration.
[0084] The results indicate that the formulation is stable for at
least 4 months at 4.degree. C.
EXAMPLE 7
[0085] Stability of acidified TA 2005-HFA 134a solutions in cans
coated with a fluorocarbon polymer (DuPont 3200-200).
[0086] TA 2005 (3.5 .mu.g/50 .mu.l) were prepared by dissolving
0.84 mg of the active ingredient in HFA 134a containing 12% w/w
ethanol and 1.0% w/w of ispropyl myristate. pMDI coated cans
containing 1.0, 1.4 and 1.8 .mu.l 0.08 M hydrochloric acid
(corresponding respectively to an apparent pH of about 4.8, 3.2 and
2.9) were set down on storage, upright at 50.degree. C., and
samples taken for analysis of TA 2005 contents at appropriate
intervals.
[0087] Stability data obtained are given in Table 8.
[0088] Each value is expressed as per cent nominal drug
concentration.
[0089] The results indicate that the formulations in which the
apparent pH is comprised between 3.0 and 5.0 are stable (i.e give
rise to much less than 10% loss of drug) for almost three months at
50.degree. C., while that corresponding to an apparent pH of less
than 3, not. TABLE-US-00007 TABLE 7 Formoterol/BDP combination
formulations of Ex 6 - Stability data at 4.degree. C. Storage
Condition 4.degree. C.; 64 days 4.degree. C.; 123 days Initial
inverted inverted Formoterol 104.7 95.10 99.9 BDP 99.4 100.10
102.6
[0090] TABLE-US-00008 TABLE 8 TA 2005 formulations of Ex 7 -
Stability data at 50.degree. C. Storage Condition 0.08M HCl
50.degree. C.; 22 days 50.degree. C.; 83 days .mu.l per can Initial
upright upright 1.0 100.0 98.3 99.4 1.4 100.0 98.2 98.8 1.8 100.0
90.2 88.1
* * * * *