U.S. patent application number 10/766857 was filed with the patent office on 2004-09-23 for pharmaceutical aerosol composition containing hfa 227 and hfa 134a.
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. Invention is credited to Brambilla, Gaetano, Ganderton, David, Garzia, Raffaella, Lewis, David, Meakin, Brian, Ventura, Paolo.
Application Number | 20040184993 10/766857 |
Document ID | / |
Family ID | 11381136 |
Filed Date | 2004-09-23 |
United States Patent
Application |
20040184993 |
Kind Code |
A1 |
Lewis, David ; et
al. |
September 23, 2004 |
Pharmaceutical aerosol composition containing HFA 227 and HFA
134a
Abstract
In a solution composition for use in an aerosol inhaler which
comprises an active material, a propellant containing a
hydrofluoroalkane, a cosolvent and optionally a low volatility m
compound the use of a mixture of HFA 134a and HFA 227 allows to
modulate the mass median aerodynamic diameter (MMAD) of the aerosol
particles on actuation of the inhaler to target specific regions of
the respiratory tract. Moreover the fine particle dose (FPD) of the
active ingredient in the composition increases by reducing the
metering chamber volume.
Inventors: |
Lewis, David; (Parma,
IT) ; Ganderton, David; (Devon, GB) ; Meakin,
Brian; (Bath, GB) ; Ventura, Paolo; (Parma,
IT) ; Brambilla, Gaetano; (Parma, IT) ;
Garzia, Raffaella; (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: |
11381136 |
Appl. No.: |
10/766857 |
Filed: |
January 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10766857 |
Jan 30, 2004 |
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09831886 |
Jul 18, 2001 |
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6713047 |
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09831886 |
Jul 18, 2001 |
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PCT/EP99/08959 |
Nov 22, 1999 |
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Current U.S.
Class: |
424/45 |
Current CPC
Class: |
A61K 9/008 20130101;
A61P 11/00 20180101 |
Class at
Publication: |
424/045 |
International
Class: |
A61L 009/04 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 25, 1998 |
IT |
MI98A 002558 |
Claims
1. A composition in form of solution for use in an aerosol inhaler,
the composition comprising an active material, a propellant
containing a hydrofluoroalkane (HFA), a cosolvent, optionally a low
volatility component characterized in that the propellant consists
of a mixture of HFA 227 and HFA 134a.
2. A composition according to claim 1, wherein the ratio of HFA
227/HFA 134a ranges from 10:90 to 90:10.
3. A composition according to claim 1 or 2, wherein the low
volatility component has a vapour pressure at 25.degree. C. lower
than 0.1 kPa.
4. A composition according to claim 3, wherein the low volatility
component has a vapour pressure at 25.degree. C. lower than 0.05
kPa.
5. A composition according to any preceding claim, wherein the
cosolvent has' a vapour pressure at 25.degree. C. lower than 3
kPa.
6. A composition according to any preceding claim, wherein the
cosolvent has a vapour pressure at 25.degree. C. lower than 5
kPa.
7. A composition according to any preceding claim, wherein the
cosolvent is an alcohol.
8. A composition according to any preceding claim, wherein the low
volatility component includes a glycol, oleic acid or isopropyl
myristate.
9. A composition according to any preceding claim, wherein the
composition includes not more than 20% by weight of the low
volatility component.
10. A composition according to any preceding claim, wherein the
composition includes at least 0.2% by weight of the low volatility
component.
11. A composition according to any preceding claim, the composition
being such that, on actuation of the aerosol inhaler in use, the
MMAD of the aerosol particles is not less than 2 .mu.m.
12. An aerosol inhaler containing a solution composition comprising
an active material, a propellant containing one or more
hydrofluoroalkane, a cosolvent and optionally a low volatility
component wherein the particle MMAD is greater than 2 .mu.m and the
fine particle dose (<4.7 .mu.m) is >30%.
13. An aerosol inhaler according to claim 12 wherein the particle
MMAD is greater than 2 .mu.m and the fine particle dose (<4.7
.mu.m) is >40%.
14. An aerosol inhaler according to claims 12 and 13 wherein the
particle MMAD is greater than 0.2 .mu.m and the fine particle dose.
(<4.7 .mu.m) is >50%.
15. An aerosol inhaler according to claims 12 to 14 having a
chamber volume ranging from 25 to 50 .mu.l yielding an increase of
FPD compared to inhalers having chamber volumes larger than 50
.mu.l.
16. An aerosol inhaler according to claims 12 to 15 containing the
compositions of claims 1-11.
17. An aerosol inhaler according to claims 12 to 16 having part or
all of the internal surfaces consisting of stainless steel,
anodised aluminium or lined with an inert organic coating.
18. A delivery system for the administration of drugs to the lung
consisting of aerosol drug solution in a mixture of 134a and 227
HFA propellants, a cosolvent and optionally a low volatility
component, in an aerosol inhaler having a chamber volume ranging
from 25 to 50 .mu.l.
Description
[0001] The invention relates to aerosol compositions for
pharmaceutical use. In particular, this invention relates to
aerosol compositions for use in pressurised metered dose inhalers
(MDIs). The invention also relates to solution aerosol
compositions, wherein the propellant comprises HFA 134a or HFA 227
or their mixtures.
[0002] Another aspect of the invention relates to pressurised MDIs
for dispensing said compositions.
[0003] Inhalers are well known devices for administering
pharmaceutical products to the respiratory tract by inhalation.
[0004] Active materials commonly delivered by inhalation include
bronchodilators such as .beta.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.
[0005] There are a number of types of inhaler currently available.
The most widely used type is a pressurised metered dose inhaler
(MDI) which uses a propellant to expel droplets containing the
pharmaceutical product to the respiratory tract as an aerosol.
Formulations used in MDIs (aerosol formulations) generally comprise
the active material, one or more liquefied propellants and a
surfactant or a solvent.
[0006] 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). Chlorofluorocarbons
have properties particularly suitable for use in aerosols,
including high vapour pressure which generates clouds of droplets
of a suitable particle size from the inhaler.
[0007] 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.
[0008] 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.
[0009] 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 are disclosed in several patent
applications.
[0010] Many of these applications, in which. HFAs are used as
propellant, propose the addition of one or more of adjuvants
including compounds acting as cosolvents, surface active agents
including fluorinated and non-fluorinated surfactants, dispersing
agents including alkylpolyethoxylates and stabilizers.
[0011] Cosolvents which may be used in these formulations include
alcohols such as ethanol and polyols such as propylene glycol.
[0012] Medicinal aerosol formulations using such propellant systems
are disclosed in, for example, EP 0372777. EP 0372777 requires the
use of HFA 134a as a propellant in combination with both a
surfactant and an adjuvant having higher polarity than the
propellant.
[0013] For aerosol suspension compositions, a surfactant is often
added to improve the physical stability of the suspension. EP
0372777 states that the presence of surfactant assists in the
preparation of stable, homogeneous suspensions and may also assist
in the preparation of stable solution formulations.
[0014] Surfactants also lubricate the valve components in the
inhaler device.
[0015] The use of propylene glycol as a solvent having a higher
polarity than the propellant in HFA pressurised metered dose
inhalers formulations has been mentioned in several other patent
applications and for example in:
[0016] EP 504112 relates to a pharmaceutical aerosol formulation
free from CFCs containing a propellant (hydrocarbon, HFA or a
mixture), one or more pharmaceutical active ingredients, a
non-ionic surfactant and optionally other conventional
pharmaceutical auxiliaries suitable for aerosol formulations
comprising solvents having a higher polarity than the propellant,
other non-ionic surfactants as valve lubricants, vegetable oils,
phospholipids, taste masking agents.
[0017] DE 4123663 describes a medical aerosol composition
containing a dispersion or suspension of an active agent in
association with a compound with surface-active or lipophilic
properties, heptafluoropropane as propellant and an alcohol such as
ethanol and/or propylene glycol.
[0018] Other applications propose the addition of dispersing agents
to the composition. U.S. Pat. No. 5,502,076 concerns compositions
used in inhalation aerosols comprising an HFA, leukotriene
antagonists and dispersing agent comprising 3C-linked triesters,
vitamin E acetate, glycerin, t-BuOH, or transesterified
oil/polyethylene glycol.
[0019] EP 384371, describes a propellant for an aerosol, comprising
pressure-liquefied HFA 227 in a mixture with pressure-liquefied
propane and/or n-butane and/or iso-butane and/or dimethyl ether
and/or 1,1-difluoroethane. The document also discloses foam
formulations (shaving and shower foams) containing glycerol as
additive.
[0020] The effectiveness of an aerosol device, for example an MDI,
is a function of the dose deposited at the appropriate site in the
lungs. Deposition is affected by several parameters, of which the
most important are the Fine Particle Dose (FPD) and the aerodynamic
particle size. 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).
[0021] The FPD gives a direct measure of the mass of particles
within a specified size range and is closely related to the
efficacy of the product.
[0022] Particle deposition in the lung depends largely upon three
physical mechanisms: (1) impaction, a function of particle inertia;
(2) sedimentation due to gravity; and (3) diffusion resulting from
Brownian motion of fine, submicrometer (<1 .mu.m) particles. The
mass of the particles determines which of the three main mechanisms
predominates.
[0023] The effective aerodynamic diameter is a function of the
size, shape and density of the particles and will affect the
magnitude of forces acting on them. For example, while inertial and
gravitational effects increase with increasing particle size and
particle density, the displacements produced by diffusion decrease.
In practice, diffusion plays little part in deposition from
pharmaceutical aerosols. Impaction and sedimentation can be
assessed from a measurement of the mass median aerodynamic diameter
(MMAD) which determines the displacement across streamlines under
the influence of inertia and gravity, respectively.
[0024] Aerosol particles of equivalent MMAD and GSD (Geometric
Standard Deviation) have similar deposition in the lung
irrespective of their composition. The GSD is a measure of the
variability of the aerodynamic particle diameters.
[0025] For inhalation therapy there is a preference for aerosols in
which the particles for inhalation have a diameter of about 0.8 to
5 .mu.m. Particles which are larger than 5 .mu.m in diameter are
primarily deposited by inertial impaction in the oropharynx,
particles 0.5 to 5 .mu.m in diameter, influenced mainly by gravity,
are ideal for deposition in the conducting airways, and particles
0.5 to 3 .mu.m in diameter are desirable for aerosol delivery to
the lung periphery. Particles smaller than 0.5 .mu.m may be
exhaled.
[0026] Respirable particles are generally considered to be those
with aerodynamic diameters less than 5 .mu.m. These particles,
particularly those with a diameter of about 3 .mu.m, are
efficiently deposited in the lower respiratory tract by
sedimentation.
[0027] Besides the therapeutic purposes, the size of aerosol
particles is important in respect to the side effects of the drugs.
For example, it is well known that the oropharynx deposition of
aerosol formulations of steroids can result in side effects such as
candidiasis of mouth and throat.
[0028] On the other hand a higher systemic exposure to the aerosol
particles due to deep lung penetration can enhance the undesired
systemic effects of the drugs. For example, the systemic exposure
to steroids can produce side effects on bone metabolism and
growth.
[0029] It has been reported that the particle size characteristics
of HFA aerosol formulations of the state of the art are often very
different from the products to be replaced.
[0030] HFA substitutes may not be pharmaceutically or clinically
equivalent and adjustment of dose and regimen may be necessary,
giving problems for doctor, pharmacist and patient.
[0031] An alternative is the seamless transition from the old to
the new formulas which demands the same deposition of the drug in
the lung. For any product, this can be inferred from the amount of
drug and its particle size distribution in the aerosol cloud.
Matching CFC and HFA formulations with suspension technology is
practicable because the particle size of the aerosol cloud is
dominated by the particle size of the suspended drug, defined by
the milling or precipitation process.
[0032] However, when, as commonly occurs, solution formulations are
unavoidable, the volumetric contribution of suspended particles is
absent and much finer clouds, largely defined by the concentration
of the drug in the solution, are generated. In these circumstances,
a co-solvent, such as alcohol, is often added to ensure
satisfactory solubility. The fine clouds from such formulations
give more extensive deposition in the lung periphery than their CFC
counterparts.
[0033] EP 0553298 describes an aerosol formulation comprising: a
therapeutically effective amount of beclomethasone 17,21
dipropionate (BDP); a propellant comprising a hydrofluorocarbon
selected from the group consisting of HFA 134a, HFA 227, and a
mixture thereof, and ethanol in an amount effective to solubilize
the beclomethasone 17,21 dipropionate in the propellant. The
formulation is further characterized in that substantially all of
the beclomethasone 17,21 dipropionate is dissolved in the
formulation and that the formulation contains no more than 0,0005%
by weight of any surfactant.
[0034] It has been reported in literature that these new
formulations of beclomethasone dipropionate (BDP) as a solution in
HFA 134a deliver a particle size distribution with a MMAD of 1.1
.mu.m. This means that the peripheral pulmonary deposition of very
small particles increases and submicronic particles can easily be
directly absorbed from the alveoli into the bloodstream. The rate
and extent of systemic absorption is significantly increased and as
a consequence undesired effects for example certain side effects
can increase. A relatively large fraction of the dose is exhaled.
The implications of this for clinical efficacy and toxic effects
are great. They arise because the principles of formulation using
HFAs may modify the physical form of the respired cloud.
[0035] It has now been surprisingly found that in solution
formulations of the present application comprising an active
material, a propellant containing a hydrofluoroalkane (HFA), a
cosolvent and optionally a low volatility compound, the use of a
mixture of HFA 134a and of HFA 227 allows the modulation of the
MMAD of the aerosol particles on actuation of the inhaler to a
value which is suited for the pulmonary administration.
[0036] Mixtures of hydrofluoroalkanes have been previously used in
suspension-based pMDI compositions to vary the density of the
continuous phase in order to match the density of the suspended
drug and maximize the physical stability of the pMDI
suspension.
[0037] Williams R. O. et al. in Drug Dev. Ind. Pharm. 24(8),
763-770, 1998 investigated the influence of propellant composition
on the characteristics of suspension aerosol compositions. The
results showed that as the density of the propellant blends
approached the density of the suspended drug particles, the
formulation became more physically stable.
[0038] Analogously, WO93/11747 discloses that in suspension aerosol
compositions the density of the propellant may be changed by using
HFA 134a and HFA 227 mixtures so as to bring it to approximately
the same value of the density of the active ingredient, minimizing
thereby the sedimentation of the drug particles.
[0039] Therefore the aerosol compositions using the new propellant
systems disclosed in the known prior art seek to overcome problems
of physical stability of the formulations.
[0040] It has surprisingly been found that in solution compositions
by using a mixture of HFA 134a and HFA 227 and optionally a low
volatility component, the MMAD of the aerosol particles on
actuation of the inhaler can be modulated and thus the compositions
may be formulated so that the aerodynamic particle size
characteristics are optimized.
[0041] Advantageously, the low volatility component has a vapour
pressure at 25.degree. C. not more than 0.1 kPa, preferably not
more than 0.05 kPa.
[0042] The low vapour pressure of the low volatility component is
to be contrasted with that of the cosolvent which preferably has a
vapour pressure at 25.degree. C. not less than 3 kPa, more
preferably not less than 5 kPa.
[0043] The cosolvent has advantageously a higher polarity than that
of the propellant and the cosolvent is used to increase the
solubility of the active material in the propellant.
[0044] Advantageously the cosolvent is an alcohol. The cosolvent is
preferably ethanol. The cosolvent may include one or more
materials.
[0045] The low volatility component may be a single material or a
mixture of two or more materials.
[0046] In general terms the low volatility component can be any
compound, safe and compatible with the propellant system of the
invention capable to influence either the size or the density of
the aerosol particle so affecting the MMAD.
[0047] We have found that glycols are particularly suitable for use
as the low volatility component, especially propylene glycol,
polyethylene glycol and glycerol.
[0048] Other particularly suitable materials are thought to include
other alcohols and glycols, for example alkanols such as decanol
(decyl alcohol), sugar alcohols including sorbitol, mannitol,
lactitol and maltitol, glycofural (tetrahydro-furfurylalcohol) and
dipropylene glycol.
[0049] The low volatility component may include esters for example
ascorbyl palmitate and tocopherol. Among the esters isopropyl
myristate is particularly preferred.
[0050] It is also envisaged that various other materials may be
suitable for use as the low volatility component including
vegetable oils, organic acids for example saturated carboxylic
acids including lauric acid, myristic acid and stearic acid;
unsaturated carboxylic acids including sorbic acid, and especially
oleic acid, which has been previously used in aerosol formulations,
in order to improve the physical stability of drug suspensions, as
a dispersing agent useful in keeping the suspended particles from
agglomerating; saccharine, ascorbic acid, cyclamic acid, amino
acids or aspartame; alkanes for example dodecane and octadecane;
terpenes for example menthol, eucalyptol, limonene; sugars for
example lactose, glucose, sucrose; polysaccharides for example
ethyl cellulose, dextran; antioxidants for example butylated
hydroxytoluene, butylated hydroxyanisole; polymeric materials for
example polyvinyl alcohol, polyvinyl acetate, polyvinyl
pyrollidone; amines for example ethanolamine, diethanolamine,
triethanolamine; steroids for example cholesterol, cholesterol
esters.
[0051] The amount of low volatility component in the composition
depends to some extent upon its density and the amount of active
material and cosolvent in the composition. Advantageously, the
composition includes not more than 20% by weight of the low
volatility component. Preferably the composition includes not more
than 10% by weight of the low volatility component.
[0052] On actuation of the inhaler, the propellant and the ethanol
vaporise but because of the low vapour pressure of the low
volatility component, that component generally will not.
[0053] It is thought that it is preferable for the composition to
contain at least 0.2%, preferably at least 1% by weight of the low
volatility component. The composition may contain between 1% and 2%
by weight.
[0054] According to the present invention, as it can be noticed
from the results reported in the tables, the influence on the MMAD
of the particles is correlated to the ratio of the two HFA
components (as well as to the amount and density of the low
volatility component).
[0055] The MMAD can be modulated by changing the ratio between HFA
134a and HFA 227; said ratio may range from 10:90 to 90:10.
[0056] From the data reported in Table 1, it is clear that MMAD is
increased by increasing the proportion of HFA 227 in the
mixture.
[0057] Most advantageously, the composition is such that, on
actuation of the aerosol inhaler in use, the MMAD of the aerosol
particles is not less than 21m. For some active materials the MMAD
is preferably not less than 2.5 .mu.m and for a few formulations,
the preferred MMAD will be greater than 3 .mu.m or even greater
than 4 .mu.m.
[0058] 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.
[0059] The active material may be one or more of any biologically
active material which could be administered by inhalation. Active
materials commonly administered in that way include .beta.2
agonists, for example salbutamol and its salts, steroids for
example beclomethasone dipropionate or anti-cholinergics for
example ipratropium bromide and combinations thereof.
[0060] As indicated above, on actuation of the inhaler, the aerosol
particles advantageously have an MMAD of not less than 2 .mu.m, for
many formulations more preferably not less than 2.5 .mu.m.
[0061] It has also been found, and it is a further object of the
invention, that it is possible to increase the "fine particle dose"
or FPD of the active ingredients in the compositions of the
invention, without affecting MMAD, by decreasing the metering
chamber volume of the metered dose inhaler (increasing thereby the
space above it named "sump") and/or changing the ratio between the
metering chamber and the space above by increasing the sump. In
particular, by reducing the metering chamber volume from 50 .mu.l
to 25 .mu.l at sump volume constant, it is possible to increase the
fine particle delivery up to 40%.
[0062] This result could be only obtained with solution
compositions in which the MMAD of the particles is higher than 2
.mu.m and it is particularly surprising since it is known from
Williams R. O. et al. in Pharmaceutical Research 14(4), 438-443,
1997 that in suspension based PMDI containing HFA 134a the
aerodynamic particle size distribution was not influenced as the
metering chamber volume of the valve was increased.
[0063] The solution formulations with MMAD>2 may be obtained by
using a metering chamber <40 .mu.l, preferably 25 .mu.l: the
fine particle delivery (Stage 3 to filter; <4.7 .mu.m)
determined through a Andersen Cascade Impactor is increased by at
least 10% in comparison with the same formulation packaged with a
valve with a metering chamber of at least 50 .mu.l and the same
sump, as it will be shown hereinbelow.
[0064] Using a reduced metering chamber volume (e.g. about 40 .mu.l
or lower for a conventional inhaler), favourable results are
obtained even with aerosol compositions wherein the propellant
consists either in HFA 227 or in HFA 134a alone.
[0065] Also provided is a method of filling an aerosol inhaler with
a composition, the method comprising filling the following
components into the inhaler
[0066] (a) one or more active materials,
[0067] (b) optionally one or more low volatility components,
[0068] (c) one or more cosolvents
[0069] followed by the addition of a propellant containing a
hydrofluoroalkane (HFA) or a mixture of HFAs.
[0070] Embodiments of the invention will now be described by way of
example.
[0071] The aerosol compositions of the invention described below
were prepared by the following method. The required components of a
composition were added into a can in the following order: drug,
non-volatile additive, absolute ethanol. After crimping of the
valve on to the can, the propellant was added through the valve.
The weight gain of the can after each component was added was
recorded to allow the percentage, by weight, of each component in
the formulation to be calculated.
[0072] The aerodynamic particle size distribution of each
formulation was characterized using a Multistage Cascade Impactor
according to the procedure described in the European Pharmacopoeia
2nd edition, 1995, part V.5.9.1. pages 15-17. In this specific case
an Andersen Cascade Impactor (ACI) was used. Results represented
were obtained from ten cumulative actuations of a formulation.
Deposition of the drug on each ACI plate was determined by high
pressure liquid chromatography. The mass median aerodynamic
diameter (MMAD) and geometric standard deviation (GSD) were
calculated from plots of the cumulative percentage undersize of
drug collected on each ACI plate (probit scale), against the upper
cut off diameter for each respective ACI plate (log10 scale). The
fine particle dose of each formulation was determined from the mass
of drug collected on Stages 3 through to Filter (<4.7 .mu.m)
divided by the number of actuations per experiment.
[0073] Table 1 shows the MMAD characteristics of aerosol
formulations containing beclomethasone dipropionate (BDP) (active
material), glycerol as low volatility component and different
mixtures of HFA 134a and HFA 227. As can be seen, the MMAD is
substantially influenced by the ratio of the two fluorocarbons
whereas FPD is substantially unaffected.
[0074] The presence of the low volatility component contributes to
the modulation of the MMAD: its percent content (w/w) can be
properly adapted to obtain the desired MMAD.
[0075] Table 2 shows the effects of valve chamber (also known as
metering chamber) volumes at sump volume constant on the generation
of aerosol clouds.
[0076] In particular, the data shown in Table 2 show that FPD
increases with decreasing valve chamber volume and that FPD can be
increased by more that 40% by reducing the volume of a valve
metering chamber. MMAD or GSD are not conversely affected by
changing the volume of the valve-metering chamber.
[0077] Therefore, the compositions of the invention consisting of
aerosol drug solution in a mixture of 134a and 227 HFA propellants,
a cosolvent and optionally a low volatility component, added into
an aerosol inhaler having a chamber volume ranging from 25 to 50
.mu.l, constitute a delivery system which allow improvement of the
delivery characteristics of drugs to the lung by modulating the
aerodynamic particle size and size distribution so that the pattern
of deposition gives the desired clinical effect.
[0078] To obviate possible chemical stability problems of active
ingredients in solution in HFA propellants metered-dose inhalers
having part or all of their internal metallic surfaces consisting
of stainless steel, anodized aluminium or lined with an inert
organic coating can be employed.
1TABLE 1 Effect of HFA 134a/HFA 227 mixtures upon the MMAD of pMDI
solution formulation BDP 250 .mu.g/shot Ethanol 15% (w/w) Glycerol
1.3% (w/w) HFA to 12 ml Actuator = 0.30 mm HFA 227/ MMAD FPD
FPD.sub.3 < 4.7 .mu.m* HFA 134a (.mu.m) (%) (.mu.g) 100:0 4.2,
3.9, 3.8 20, 20, 24 47, 45, 50 75:25 3.7, 3.7 25, 25 56, 57 50:50
3.4, 3.7 25, 25 56, 56 25:75 3.3, 3.2 27, 28 60, 62 0:100 2.8, 2.8
27, 27 58, 59 *Results normalized for 250 nominal dose.
[0079]
2TABLE 2 Effect of Valve Chamber Volume upon the FPD of pMDIs
containing HFA 134a and HFA 227 Solutions Formulations BDP 50
.mu.g/shot Ethanol 13% (w/w) Glycerol 1.3% (w/w) HFA to 12 ml
Chamber Metered Volume FPD < 4.7 .mu.m MMAD Dose (.mu.l)
Propellant (.mu.g) (.mu.m) GSD (.mu.g) actuator orifice 0.30 mm 25
HFA 134a 19.2 2.6 2.0 57 50 13.9 2.8 2.1 49 100 11.7 2.7 2.2 51 25
HFA 227 16.4 3.6 2.1 58 50 13.1 3.5 2.2 51 100 12.6 3.5 2.2 49
actuator orifice 0.25 mm 25 HFA 134a 26.0 2.8 1.9 55
* * * * *