U.S. patent application number 10/204307 was filed with the patent office on 2003-08-21 for formulations containing an anticholinergic drug for the treatment of chronic obstructive pulmonary disease.
Invention is credited to Brambilla, Gaetano, Ferraris, Alessandra, Ganderton, David, Lewis, David, Meakin, Brian.
Application Number | 20030157028 10/204307 |
Document ID | / |
Family ID | 11444121 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030157028 |
Kind Code |
A1 |
Lewis, David ; et
al. |
August 21, 2003 |
Formulations containing an anticholinergic drug for the treatment
of chronic obstructive pulmonary disease
Abstract
Formulations for the administration through pressurized metered
dose aerosol inhalers containing an anticholineric drug in solution
in a hydrofluorocarbon propellant, a cosolvent and a low volatility
component, and the use thereof in chronic obstructive pulmonary
disease.
Inventors: |
Lewis, David; (Parma,
IT) ; Ganderton, David; (Parma, IT) ; Meakin,
Brian; (Parma, IT) ; Brambilla, Gaetano;
(Parma, IT) ; Ferraris, Alessandra; (Parma,
IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Family ID: |
11444121 |
Appl. No.: |
10/204307 |
Filed: |
November 13, 2002 |
PCT Filed: |
February 19, 2001 |
PCT NO: |
PCT/EP01/01833 |
Current U.S.
Class: |
424/45 ;
514/291 |
Current CPC
Class: |
A61K 31/439 20130101;
A61K 9/008 20130101; Y10S 514/826 20130101 |
Class at
Publication: |
424/45 ;
514/291 |
International
Class: |
A61L 009/04; A61K
031/4745 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 22, 2000 |
IT |
MI2000A000312 |
Claims
1. A pharmaceutical formulation for use in a metered dose aerosol
inhaler, comprising an active ingredient consisting of an
anticholinergic quaternary ammonium salt in solution in a mixture
consisting of a hydrofluoroalkane propellant, a cosolvent and a low
volatility component, wherein the concentration of the active in
gredient ranges from 0.11% to 1.14% by weight and the single dose
delivered on actuation ranges from 60 to 640 .mu.g.
2. A formulation according to claim 1, in which the active
ingredient is ipratropium bromide in concentrations ranging from
0.14 to 0.28% by weight.
3. A formulation according to claims 1-2, in which the propellant
is HFA 134a, the low volatility component is glycerol and the
cosolvent is ethanol.
4. A formulation according to claims 1-3 in which the ethanol
percentage is 13% by weight and that of glycerol is 1% by
weight.
5. Pharmaceutical formulations according to claims 1-4 for use in
pressurized metered dose aerosol inhalers in the treatment of
bronchopulmonary diseases, and in particular chronic obstructive
pulmonary disease.
6. Compositions according to any one of claims 1-5 contained in
metered dose aerosol inhalers having part or all of the inner metal
surfaces made of anodized aluminium, stainless steel or coated with
an inert organic coating agent.
7. A process for the preparation of pharmaceutical formulations
according to claims 1-6 which consists in filling the components
into the metered dose inhaler in the following order: active
ingredient, low volatility component, cosolvent and finally
propellant through the valve.
Description
[0001] The present invention relates to formulations for
administration through pressurized metered dose inhalers containing
a quaternary ammonium salt with anticholinergic action in solution
in a hydrofluorocarbon propellant, a cosolvent and a low volatility
component. More particularly, the invention relates to formulations
containing ipratropium bromide in solution, in which the
concentration of active ingredient corresponds to single doses
ranging from 80 to 320 .mu.g and the amount of respirable particles
is directly related to the dose itself. "Single dose" means the
amount of active ingredient delivered by a single actuation of the
inhaler.
[0002] The formulations of the invention can be useful for the
treatment of any respiratory disease and in particular for the
treatment of the chronic obstructive pulmonary disease.
[0003] The term chronic obstructive pulmonary disease (COPD) refers
to a spectrum of diseases such as chronic bronchitis, asthma and
lung emphysema, characterized by bronchospasm, cough,
hypersecretion and dyspnea which are more and more frequent also
due to tabagism as well as an increase of atmospheric pollution.
Such disease has social relevance in that it involves repeated,
expensive treatments.
[0004] Anticholinergic quaternary ammonium salts, such as
oxitropium bromide, tiotropium bromide and ipratropium bromide, are
usually prescribed in the form of inhalatory formulations, for
patients suffering from said disease, due to their bronchodilating,
antisecretive and bronchospasm-preventive actions.
[0005] Said drugs, particularly ipratropium bromide, induce less
prompt bronchodilation than conventional P2-agonists, but provide
greater peak response and longer duration of action. Said
characteristics make them particularly suitable for the chronic
treatment rather than the acute one (Ferguson G. et al. N Engl J
Med 1993, 328, 1017-1022).
[0006] Although the single optimal dose for the administration of
nebulized ipratropium bromide in the treatment of COPD has been
established to be 0.4 mg (Gross N J et al Am Rev Respir Dis 1989,
139, 1188-1191), the dosage via pressurized metered dose inhalers
has not yet been univocally established. Some authors (Ferguson G.
et al, passim) have however suggested that treatment of said
disease could benefit from use of higher doses than recommended
ones (54-109 .mu.g). Recent studies (Ikeda A et al. Thorax 1996,
51, 48-53; Shivaram U et al. Resp Med 1997, 91, 327-334; Wood F et
al. Amer J Resp Crit Care Med 1999, 159, A 523) have demonstrated
that the administration of single doses ranging from 80 to 320
.mu.g is beneficial for the improvement in lung function, maximal
workload and oxygen consumption.
[0007] Wood et al also observed for doses of at least 160 .mu.g a
longer duration of action, up to 12 hours: such prolonged effect
would allow for a bis in die (b.i.d.) (twice a day) administration
with evident advantages in terms of patient compliance.
[0008] The formulations currently available on the market in the
form of metered dose aerosols in chlorofluorocarbons (Freon 11 and
Freon 12) suspensions are able of delivering single doses of 20 or
40 .mu.g and the recommended posology envisions the administration
of 1-2 shots 3-4 times a day. Therefore, an increase of the
frequency of administration to 4-6 times a day would be necessary
to guarantee a higher daily dosage regimen, thus adversely
affecting the patient compliance.
[0009] On the other hand, the effectiveness of an aerosol device,
particularly a pressurized metered dose aerosol, is a function of
the dose deposited in the peripheral tract of the pulmonary tree,
that is, in turn mainly affected by the particle size distribution.
The particle size is quantified by measuring a characteristic
equivalent sphere diameter, known as median aerodynamic diameter
(MAD). Particles having a MAD ranging from 0.8 to 5 microns (.mu.m)
are usually considered respirable, i.e. capable of being deposited
into the lower airways. It has also been established that, in the
case of anticholinergic drugs for use in obstructive pulmonary
diseases, the optimal particle size should be approximately 3 .mu.m
(Zanen P et al. Int. J. Pharm. 1995, 114, 111-115; Thorax 1996, 51,
977-980).
[0010] In the suspension formulations, the size distribution of the
delivered particles almost exclusively depends on the particle size
distribution of the suspended particles, and hence on the process
used for preparing them (milling or precipitation). Any kind of
adjustments of the particle size of the delivered aerosol can be
carried out by those skilled in the art, by suitably changing
amounts and types of excipients, surface tension of the propellant,
size of the metering chamber and diameter of the actuator orifice.
The preparation of suspension formulations at higher concentrations
of drugs aimed at delivering higher single doses could however
involve problems intrinsically difficult to be solved. Under high
concentration conditions, the suspended particles could, indeed,
give rise to aggregation, particularly during storage, so to an
increment of the size of particles. Larger size particles deposit
more quickly and can give rise to the formation of compacted and
fuse agglomerates (cakes) which, in turn may impair the possibility
of re-suspending the product by simple agitation. Such drawback,
could jeopardize both physical stability and therapeutic efficacy
of the respective formulations; moreover, even after
aerosolization, said cakes could turn out to be hard to be
re-dispersed, so they will deposit mainly on the oropharynx tract,
to the detriment of the fraction deposited on the peripheral
respiratory tract (respirable fraction).
[0011] It is known that the chlorofluorocarbon propellants such as
Freon 11 and Freon 12, which for many years have been the preferred
propellants used in the aerosols, are being phased out and also
their use in medicinal formulations, although temporarily exempted,
will be banished.
[0012] Hydrofluoroalkanes (HFAs) and in particular
1,1,1,2-tetrafluoroetha- ne (HFA 134a) and
1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged
to be the best candidates as substitutes for CFCs.
[0013] A number of documents concerning the preparation of HFA
formulations of ipratropium bromide are disclosed in the prior art,
for example WO 91/11495, WO 91/11496 (Boehringer), WO 93/05765
(Fisons), WO 96/19168 (Astra) and WO 98/34595 (Jago); these
examples, however, relate to suspension formulations in which the
active ingredient concentrations (0.08-0.1% by weight) correspond
to single doses of 20-50 .mu.g; furthermore, no data concerning
physical stability during storage are provided. In other documents
(EP 513217, WO 92/00107, EP 587790, EP 588897, WO 94/21228, WO
94/21229, WO 98/34596, WO 98/24420), formulations containing
ipratropium bromide are only cited but not exemplified.
[0014] High-dosage suspension formulations in which CFCs are
replaced with HFAs would nevertheless exhibit the same pitfalls in
term of physical stability and therapeutical efficacy as mentioned
above; moreover, in the case of anticholinergic quaternary ammonium
salts such as ipratropium bromide, the possibility of preparing
formulations of adequate physical stability during storage would
further be compromised or even prevented by the partial solubility
of said active ingredient in HFA (Brambilla et al. Int J Pharm
1999, 186, 53-61); in fact, the size of the suspended particles
could grow during storage as a consequence of the partial or total
recrystallization of the small amount of dissolved solute, thus
worsening the problems deriving from the lack of steady particle
size distribution.
[0015] In this scenario, solution compositions should unavoidably
been used. Said compositions provide a number of advantages in that
they are easier to be prepared and could allow to avoid the
physical stability problems potentially linked to the high dosage
suspension formulations. However, even solution formulation are not
rid of potential drawbacks as they can give rise, for instance, to
more severe problems of chemical instability. Furthermore, since
the suspended particles no longer contribute to the total volume,
the problem of ensuring a direct relationship between increase in
dosage and increase in the drug deposited at the therapeutical site
(respiratory tract) is even more dramatic. The preparation of
homogeneous solution formulations requires indeed the addition of
cosolvents such as ethanol which, due to their vapor pressure
higher than the propellant, increase, proportionally to their
concentration, the velocity of the aerosol droplets leaving the
actuator orifice. The high velocity droplets extensively deposit
into the oropharyngeal tract to the detriment of the dose which
penetrates into the lower airways. The higher the dosage of the
drug the higher is the amount of cosolvent necessary to solubilise,
and hence the lesser is the percentage of therapeutically effective
droplets (respirable dose).
[0016] In consideration of the therapeutical requirements outlined
above and problems thereof, it would be highly advantageous to
provide solution formulations comprising an anticholinergic drug,
such as ipratropium bromide to be used with pressurised metered
dose inhalers, in which the active ingredient concentration
corresponds to single doses ranging from 80 to 320 .mu.g,
characterized by adequate chemical stability for pharmaceutical use
and capable of providing, on actuation, an amount of respirable
particles directly proportional to the delivered dose. Said
formulations would turn out to be useful for the treatment of
respiratory ailments such as chronic obstructive pulmonary
disease.
[0017] The object of the present invention is to provide solution
formulations comprising an anticholinergic quaternary ammonium salt
selected from oxitropium bromide, tiotropium bromide and especially
ipratropium bromide, to be used with pressurized metered dose
inhalers for the treatment of COPD, said solutions being chemically
stable and capable of:
[0018] i) delivering high single doses, of at least 60 .mu.g and
preferably 80 .mu.g;
[0019] ii) provide an amount of respirable particles directly
proportional to the delivered dose;
[0020] iii) allow b.i.d. administration with evident advantages in
terms of patient compliance.
[0021] In the formulations of the invention, to make the transition
from CFC formulations to HFA formulations easier, the respirable
fraction can favorably correspond to that of the CFC suspension
formulations presently available on the market.
[0022] According to a first embodiment of the invention, there is
provided a solution formulation comprising from 0.11% to 1.14% by
weight of an anticholinergic quaternary ammonium salt and a carrier
consisting of a hydrofluoroalkane propellant, a cosolvent and a low
volatility component that also has solvent properties.
[0023] In a preferred embodiment the hydrofluoroalkane propellant
is HFA 134a, the cosolvent is ethanol and the low volatility
component is glycerol.
[0024] According to a more particular embodiment of the invention,
there is provided a solution formulation comprising from
0.14%-0.28% by weight of ipratropium bromide and a carrier
consisting of HFA 134a as a propellant, 13% by weight of ethanol
and 1% by weight of glycerol.
[0025] In WO 98/56349 the Applicant disclosed solution compositions
for use in an aerosol inhaler, comprising an active ingredient, a
propellant containing a hydrofluoroalkane (HFA), a cosolvent and
further comprising a low volatility component to increase the
median aerodynamic diameter (MAD) of the aerosol particles on
actuation of the inhaler; the examples concerning ipratropium
bromide however refer to formulations in which the active
ingredient concentrations corresponded to the usual single doses
(20-40 .mu.g). Said formulations proved to be pharmaceutically
equivalent to the presently marketed formulations, consisting of
CFC suspensions (Ganderton D et al. J. Aerosol Med. 1999, 12,
119).
[0026] It has now been found that by using a low volatility
component with suitable solvent power for the active ingredient,
homogeneous solution formulations are obtained even in the presence
of concentrations of an anticholinergic quaternary ammonium salt
comprised between 0.11% and 1.14% by weight (which equates to
0.11-1.14 g of active ingredient per 100 g of formulation). In
particular, it is possible to prepare homogeneous solution
formulations in the presence of 0.14%-0.28% by weight ipratropium
bromide corresponding to single doses ranging from 80 to 320
.mu.g.
[0027] The use of a low volatility component allows to minimize the
amount of cosolvent, in this case ethanol, added to the formulation
and hence to avoid the negative effects on the
respirable/therapeutically effective dose due to the increase of
its relative percentage.
[0028] In the formulations of the invention, the median aerodynamic
diameter (MAD) of the droplets remains substantially unchanged at
increasing concentrations, therefore the respirable dose is
directly related to the dose obtained on actuation of the inhaler.
As a consequence, the increase in the respirable fraction
concentration remains steady. Contrary to what reported in the
prior art (Dolovich M Aerosol Science and Technology 1995, 22,
392-399) it has in fact surprisingly been found that in the
formulations of the invention the respirable fraction does not
decrease as the single dose increases. Furthermore, by suitably
adjusting the actuator orifice diameter, it is possible, as the
delivered dose increases, to steadily increase the respirable dose
so that this is also linearly related to the dose of the CFC
suspension formulations presently available on the market. Said
feature makes the formulations of the invention therapeutically
preferable as they avoid possible problems related to a non-linear
response, such as accumulation, greater side effects or vice versa
less effective therapeutical action.
[0029] WO 94/13262 generically disclosed and claimed aerosol HFA
solution formulations comprising 0.001%-2.5% of ipratropium bromide
in the presence of ethanol as cosolvent and of small amounts of
organic or inorganic acids. The specific examples however only
relate to formulations with active ingredient concentrations
(0.0187%-0.0748% by weight) corresponding to doses for single
actuation ranging from 10 to 40 .mu.g and containing 15% by weight
of ethanol. Furthermore, organic or inorganic acids are used for
ensuring higher chemical stability of the active ingredient, and
not for solving the technical problem related with the preparation
of high dosage formulations providing a respirable dose
therapeutically effective and directly related to the
concentration.
[0030] The Applicant has also proved that formulations prepared
according to the teaching of said application, with high
concentrations of ipratropium bromide, require the use of ethanol
in remarkable percentages which significantly jeopardize the
performances in terms of respirable fraction. It has been indeed
demonstrated that, in solution formulation only consisting of HFA
as a propellant and ethanol as a co-solvent, the amount of ethanol
necessary to solubilize ipratropium bromide in concentrations
corresponding to single doses ranging from 80 to 160 .mu.g is of at
least about 19% by weight. On the other hand, formulations
containing such a large amount of ethanol, of at least 19% by
weight, give rise to a reduced respirable dose and a decrease in
the MAD.
[0031] The formulations of the invention can be prepared as
described in WO 98/56349 and comprise a quaternary ammonium salt
provided of anticholinergic action, such as oxitropium bromide,
tiotropium bromide, ipratropium bromide in a concentration that,
depending on the characteristics of the active ingredient, ranges
from 0.11% to 1.14% by weight and which, in turn, could give rise,
by suitably adjusting the volume of the metering chamber, to single
doses ranging from 60 to 640 .mu.g. More preferably, the active
ingredient is a quaternary ammonium salt provided with
anticholinergic action in a concentration ranging from 0.12% to
0.56% by weight.
[0032] Even more preferably, the active ingredient is ipratropium
bromide in a concentration ranging from 0.14% to 0.28% by weight.
According to the volume of the metering chamber, the formulation
containing 0.14% ipratropium bromide can be used for delivering
single doses of 80 and 160 .mu.g, while that containing 0.28% for
single doses of 160 and 320 .mu.g. Advantageously, the low
volatility component has a vapor pressure at 25.degree. C. not
above 0.1 kPa, preferably not above 0.05 pKa. Particularly suitable
for the use of the invention are glycols, in particular propylene
glycol, polyethylene glycol and most preferably glycerol. However,
the invention also comprises all the substances, alone or in
admixture, having similar vapor pressure characteristics and
suitable solvent power for the active ingredients belonging to the
anticholinergic quaternary ammonium salts. The composition
preferably contains at least 0.2%, more preferably 1% by weight of
said component and anyway no more than 6%.
[0033] The cosolvent has advantageously higher polarity than the
propellant and is preferably an alcohol, more preferably ethanol.
In this case, the amount of cosolvent in the composition is below
19% by weight, preferably it does not exceed 15% by weight more
preferably it does not exceed 13% by weight.
[0034] All the percentages are expressed as gram per 100 g of
formulation.
[0035] Preferred hydrofluoroalkane propellants are HFA 134a, HFA
227 or mixtures thereof.
[0036] The formulations of the invention are preferably stored in
pressurized inhalers for aerosol, part or all of their inner metal
surfaces being made of anodized aluminium, stainless steel or
coated with an inert organic coating agent. It has, in fact, been
observed that in this type of cans the active ingredient remains
chemically stable during storage, even at concentrations higher
than 0.11% by weight. The inhalers can be equipped with any
suitable conventional or unconventional dispensing valve,
preferably a metered dose valve as well as any suitable
conventional or unconventional metering chamber. Advantageously,
the inhalers are equipped with an actuator with orifice diameter
from 0.25 to 0.50 mm, preferably 0.3 mm and with a metering chamber
with a volume from 25 .mu.l to 100 .mu.l. However, the volume of
metering chamber and the orifice diameter of the actuator will be
suitably selected by the person skilled in order to deliver the
desired single dose as well as to the best performances in term of
respirable dose.
[0037] Finally, the invention relates to, the use of said
formulations in the treatment of bronchopulmonary diseases, in
particular chronic obstructive pulmonary disease.
[0038] Specific embodiments of the invention are described in
detail in the following.
[0039] The invention refers also to a process for the preparation
of pharmaceutical formulations according to claims 1-6 which
consists in filling the components into the metered dose inhaler in
the following order: active ingredient, low volatility component,
cosolvent and finally propellant through the valve.
EXAMPLE 1
Ipratropium Bromide Aerosol Solution Formulation in a Carrier
Constituted of HFA 134a as a Propellant, Ethanol as a Co-Solvent
and Glycerol as a Low Volatility Component
[0040] The aerosol formulations of the invention described below
are prepared according to the following method. The components
necessary to the formulation are transferred into 12 ml aerosol
cans in the following order: drug, low volatility component,
absolute ethanol.
[0041] After crimping the valve onto the can, the propellant is
added through the valve. The weight gain of the can after addition
of each component is recorded to evaluate the weight percentage of
each component in the formulation.
1 Amounts Dose of a single Per unit actuation Components mg % by
weight .mu.g Ipratropium bromide 19.2-38.4 0.14-0.28 80-320
Absolute ethanol 13 -- Glycerol 1 -- HFA 134a q.s. to 13714 --
--
[0042] The aerodynamic particle size distribution of each tested
formulation was 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 used.
[0043] Results were obtained as a mean of 3-4 cans. For each
device, 5-25 cumulative actuations were carried out after
discarding the first 5.
[0044] Deposition of the drug on each ACI plate was determined by
high pressure liquid chromatography (HPLC). Mean metered dose was
calculated from the cumulative deposition in the actuator and ACI
(stages); 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 to filter
corresponding to particles .ltoreq.4.71 .mu.m, divided by the
number of actuations per experiment.
[0045] MAD and associated GSD (standard geometric deviation) values
were obtained from probit transformation of cumulative percent
undersize--log (ACI effective cut-off particle size diameter) and
linear regression analysis of the resultant data, (Ph. Eur. Supp
1999).
[0046] The delivery characteristics of formulations containing
increasing amounts of ipratropium bromide present in cans equipped
with standard Bespack BK 360 actuators with 0.3 mm orifice diameter
and a metering chamber volume of 50 .mu.l are reported in Table 1.
The use of a metering chamber volume of 100 .mu.l allows a 320 kg
strength variant of the 160 .mu.g formulation.
[0047] It can be observed that MAD is substantially unaffected by
the active ingredient concentration, so that the amount of droplets
with size lower than 4.7 .mu.m (respirable dose) is linearly
related to the nominal dose.
[0048] Only at a nominal dose of 320 .mu.g, a slight decrease of
the respirable fraction is observed.
2TABLE 1 Performances of formulations containing as active
ingredient ipratropium bromide at different concentrations, such as
to give raise to the reported nominal doses. Nominal Metered
Delivered Respirable Respirable Dose.sup.(1) dose.sup.(2)
dose.sup.(3) dose.sup.(4) fraction.sup.(5) MAD (.mu.g) (.mu.g)
(.mu.g) (.mu.g) (%) (.mu.m) GSD 20 20.6 .+-. 1.6 18.8 .+-. 1.6 6.8
.+-. 1.1 33.3 .+-. 3.8 2.4 .+-. 0.3 2.1 .+-. 0.8 40 42.2 .+-. 1.8
38.7 .+-. 1.9 11.7 .+-. 1.2 31.5 .+-. 3.8 2.2 .+-. 0.1 2.1 .+-. 0.1
80 78.5 .+-. 0.4 72.7 .+-. 0.6 23.3 .+-. 4.5 32.0 .+-. 6.1 2.7 .+-.
0.3 2.2 .+-. 0.1 160 161.1 .+-. 12.5 149.2 .+-. 10.7 45.2 .+-. 2.5
30.4 .+-. 3.5 2.5 .+-. 0.2 2.3 .+-. 0.1 320 321.4 .+-. 2.0 290.5
.+-. 1.9 73.2 .+-. 3.0 25.2 .+-. 1.2 2.9 .+-. 0.2 2.6 .+-. 0.1
.sup.(1)Nominal dose: theoretical dose per single actuation
.sup.(2)Metered dose: sum of the dose delivered through the device
plus the active ingredient residue deposited on the device
actuator. .sup.(3)Delivered dose: amount of active particles
deposited into the various ACI stages .sup.(4)Respirable dose (fine
particle dose): amount of active particles of size less than 4.7
.mu.m .sup.(5)Respirable fraction (fine particle fraction): ratio
between the delivered dose and the respirable dose.
EXAMPLE 2
Ipratropium Bromide Aerosol Solution Formulation in HFA 134a as a
Propellant and Ethanol as a Co-Solvent
[0049] Determination of the Solubility of Ipratropium Bromide in
Ethanol
[0050] 20.1.+-.0.2 mg of ipratropium bromide is weighed into
Saint-Gobain aerosol bottles.
[0051] Increased volumes of absolute ethanol are added to the same
aerosol bottle using a Gilson variable pipette.
[0052] A Bespak BK357 valve is crimped onto the same aerosol
bottle. Shaking and ultra-sonication ensured a homogeneous solution
was formed before a pre-determined mass of HFA 134a is filled
through the valve.
[0053] The individual weight of ipratropium bromide, ethanol, and
HFA134a addition is recorded using a four-figure analytical
balance.
[0054] Final formulations have a total volume into cans having a
volume of 12.+-.0.3 ml (20.degree. C.), corresponding to that of
the standard aerosol cans. The components are expressed as
percentages by weight of the total formulation. Visual appearance
of all manufactured formulations is assessed using a polarized
light source immediately after preparation and again after 3 weeks
storage at 4.0.+-.0.4.degree. C. Observations where further
confirmed after 10 months storage at 4.0.+-.0.4.degree. C.
[0055] Ipratropium bromide is found to crystallise for the
following ethanol levels (% by weight): 14.7, 15.0, 16.8, 17.2,
17.5, 17.9 while is found not to crystallise for the following
ethanol levels: 18.9, 19.2, 20.6, 21.0, 21.3, 22.2, 22.6, 23.0,
23.4, 24.5, 29.7, 38.9, 40.1.
[0056] Therefore about 19% by weight of ethanol is required to
solubilise an amount of ipratropium bromide (0.14% by weight) which
could give rise, by suitably selecting the volume of the metering
chamber, to single doses of 80 and 160 .mu.g within a HFA 134a
formulation.
[0057] The formula of the corresponding composition is reported
below.
3 Amount Dose of a single Per unit actuation Components mg % by
weight .mu.g Ipratropium bromide 20.1 0.14 80-160 Absolute ethanol
2735 19 -- HFA 134a q.s. to 14397 -- --
[0058] Delivery performances of the HFA formulations corresponding
to single nominal doses of 80 and 160 .mu.g
[0059] The delivery characteristics of the formulation in cans
equipped with standard Bespack BK 360 actuators with 0.3 mm orifice
diameter and a metering chamber volume of 50 .mu.l are reported in
Table 2. The use of a metering chamber volume of 100 .mu.l allows a
160 .mu.g strength variant of the 80 .mu.g formulation.
[0060] The relevant parameters were determined as described in
Example 1.
[0061] It can be observed that, the formulation containing an
ethanol level of 19% by weight depresses the respirable dose
(.ltoreq.4.7 .mu.m); it also reduces the MAD from 2.2-2.9 .mu.m to
1.2-1.3 .mu.m; and increases the Geometric Standard Deviation (GSD)
from 2.1-2.6 to 4.3-6.2.
4TABLE 2 Performances of a the formulation without the low
volatility component containing as active ingredient ipratropium
bromide corresponding to nominal doses of 80 and 160 .mu.g. Nominal
Metered Delivered Respirable Respirable Dose dose dose dose
fraction MAD (.mu.g) (.mu.g) (.mu.g) (.mu.g) (%) (.mu.m) GSD 80
76.6 .+-. 1.6 70.0 .+-. 1.0 20.0 .+-. 1.3 28.7 .+-. 1.5 1.2 .+-.
0.1 4.3 .+-. 0.4 160 158.5 .+-. 2.0 144.2 .+-. 1.7 31.4 .+-. 1.3
21.8 .+-. 1.1 1.3 .+-. 0.2 6.2 .+-. 0.2
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