Note: Descriptions are shown in the official language in which they were submitted.
CA 02447517 2003-11-19
1
This Application is a Division of Canadian Patxnt Application S:N.
2,367,013, filed April 10, 1996.
BACKGROUND OF THE INVENTION
Drugs for treating respiratory and nasal disorders are frequently administered
in
aerosol formulations through the mouth or nose. One widely used method for
dispensing such aerosol drug formulations involves making a suspension
formulation of the drug as a finely divided powder in a liquefied gas known as
a
propellant. The suspension is stored in a sealed container capable of
withstanding the pressure required to maintain the propellant as a liquid. The
suspension is dispersed by activation of a dose metering valve affixed to the
container.
A metering valve may be designed to consistently release a fixed,
predetermined
mass of the drug formulation upon each activation. As the suspension is forced
from the container through the dose metering valve by the high vapor pressure
of
the propellant, the propellant rapidly vaporizes leaving a fast moving cloud
of very
fine particles of the drug formulation. This cloud of particles is directed
into the
nose or mouth of the patient by a channelling device such as a cylinder or
open
ended cone. Concurrently with the activation of the aerosol dose metering
valve,
the patient inhales the drug particles into the lungs or nasal cavity. Systems
of
dispensing drugs in this way are known as 'metered dose inhalers'(MDI's). See
Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, FL (1990) for a
general background on this form of therapy.
Patients often rely on medication delivered by MDI's for rapid treatment of
respiratory disorders which are debilitating and in some cases, even life
threatening. Therefore, it is essential that the prescribed dose of aerosol
medication delivered to the patient consistently meet the specifications
claimed
by the manufacturer and comply with the requirements of the FDA and other
regulatory authorities. That is, every dose in the can must be the same within
close tolerances.
CA 02447517 2005-12-20
2
Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the
can,
valves, and caps, of the MDI. This can lead to the patient getting
significantly less
than the prescribed amount of drug upon each activation of the MDI. The
problem
s is particularly acute with hydrofluoroalkane (also known as simply
"fluorocarbon") propellant systems, e.g., P 134a and P227, under development
in
recent years to replace chlorofluorocarbons such as P11, P114 and P12.
We have found that coating the interior can surfaces of MDI's with a
fluorocarbon
polymer significantly reduces or essentially eliminates the problem of
adhesion or
to deposition of fluticasone propionate on the can walls and thus ensures
consistent
delivery of medication in aerosol from the MDI.
SUMMARY OF THE INVENTION
A metered dose inhaler having part or all of its internal surfaces coated with
one or
more fluorocarbon polymers, optionally in combination with one or more non-
15 fluorocarbon polymers, more especially fluorinated ethylene propylene
(FEP), for
dispensing an inhalation drug formulation comprising fluticasone propionate,
or a
physiologically acceptable solvate thereof, and a fluorocarbon propellant
optionally in combination with one or more other pharmacologically active
agents
or one or more excipients.
z o Thus, in accordance with one aspect of the invention, there is provided a
metered
dose inhaler comprising a can, said metered dose inhaler having part or all of
its
internal surfaces coated with a polymer blend comprising one or more
fluorocarbon polymers in combination with one or more non-fluorocarbon
polymers, and wherein said can is made of strengthened aluminium and comprises
a 5 a substantially ellipsoidal base, for dispensing an inhalation drug
formulation
comprising fluticasone propionate or a physiologically acceptable solvate
thereof
and a fluorocarbon propellant.
CA 02447517 2005-12-20
2a
In another aspect of the invention, there is provided a metered dose inhaler
system
comprising a metered dose inhaler of the invention in combination with a
suitable
channelling device for oral or nasal inhalation of the drug formulation.
s In still another aspect of the invention, there is provided use of the
aforementioned
system of the invention for the treatment of respiratory disorders.
DETAILED DESCRIPTION OF THE INVENTION
The term "metered dose inhaler" or "MDI" means a unit comprising a can, a
crimped cap covering the mouth of the can, and a drug metering valve situated
in
to the cap, while the term "MDI system" also includes a suitable channelling
device.
The terms "MDI can" means the container without the cap and valve. The term
"drug metering valve" or "MDI valve" refers to a valve and its associated
mechanisms which delivers a predetermined amount of drug formulation from an
MDI upon each activation. The channelling device may comprise, for example, an
i 5 actuating device for the valve and a cylindrical or cone-like passage
through which
medicament may be delivered from the filled MDI can via the MDI valve to the
nose or mouth of a patient, e.g., a mouthpiece actuator. The relation of the
CA 02447517 2003-11-19
3
parts of a typical MDI is illustrated in US Patent 5,281,538:
The term "fluorocarbon polymers" means a polymer in which one or more of the
hydrogen atoms of the hydrocarbon chain have been replaced by fluorine atoms.
Thus, "fluorocarbon polymers" include perfluorocarbon, hydrofluorocarbon,
chlorofluorocarbon, hydro-chlorofiuorocarbon polymers or other halogen
substituted derivatives thereof. The "fluorocarbon polymers" may be branched,
homo-polymers or co-polymers.
U.S. Patent No. 4,335,121, teaches an
antiinflammatory steroid compound known by the chemical name [(6a, 11 b, 16a,
17a)-6, 9-difluoro-ll-hydroxy-16-methyl-3-oxo-i7-(1-oxopropoxy) androsta-1, 4-
diene-17-carbothioic acid, S-fiuoromethyl ester and the generic
name'fluticasone
propionate'. Fluticasone propionate in aerosol form, has been accepted by the
medical community as useful in the treatment of asthma and is marketed under
the trademarks 'Flovent " and "Ffonase". Fluticasone propionate may also be
used in the form of a physiologically acceptable solvate.
The term 'drug formulation' means fluticasone propionate (or a physiologically
acceptable solvate thereof) optionally in combination with one or more other
pharmacologically active agents such as other antiinfiammatory agents,
analgesic agents or other respiratory drugs and optionally containing one or
more
excipients, and a fluorocarbon propellant. The term °excipients" as
used herein
means chemical agents having little or no pharmacological activity (for the
quantities used) but which enhance the drug formulation or the performance of
the MDI system. For example, excipients include but are not limited to
surfactants, preservatives, flavorings, antioxidants, antiaggregating agents,
and
cosoivents, e.g., ethanol and diethyl ether.
Suitable surfactants are generally known in the art, for example, those
surfactants
disclosed in EP 0327777, published 16.08.89. The amount of surfactant employed
is desirably in the range of 0.0001% to 50% weight to weight ratio relative to
the drug, in particular 0.05 to 5% weight to a weight ratio. A
CA 02447517 2003-11-19
4
particularly useful surfactant is 1,2-di[7-(F-hexyl) hexanoyl]-giycero-3-
phospho
N,N,N-trimethylethanolamine also known as 3, 5, 9-trioxa-4-phosphadocosan-1
aminium, 17, 17, 18, 18, 19, 19, 20, 20, 21, 21, 22, 22, 22-tridecafluoro-7-
[(8, 8,
9, 9, 10, 10, 11, 11, 12, 12, 13, 13, 13-tridecafluoro-1-oxotridecyl)oxy]-4-
hydroxy
N, N,N-trimethyl-10-oxo-, inner salt, 4-oxide.
A polar cosolvent such as C~~ aliphatic alcohols and polyois e.g. ethanol,
isopropanol and propylene glycol, preferably ethanol, may be included in the
drug
formulation in the desired amount, either as the only excipient or in addition
to
other excipients such as surtactants. Suitably, the drug formulation may
contain
0.01 to 5% w/w based on the propellant of a polar cosoivent e.g. ethanol,
preferably 0.1 to 5% w/w e.g. about 0.1 to 1 % w/w.
It will be appreciated by those skilled in the art that the drug formulation
for use in
the invention may, if desired, contain fluticasone propionate (or a
physiologically
acceptable solvate thereof) in combination with one or more other
pharnnacologically active agents. Such medicaments may be selected from any
suitable drug useful in inhalation therapy. Appropriate medicaments may thus
be
selected from, for example, analgesics, e.g. codeine, dihydromorphine,
ergotamine, fentanyl or morphine; anginai preparations, e.g. diltiazem;
antiallergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g.
cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and
pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g.
beclomethasone (e.g. the dipropionate), flunisolide, budesonide, tipredane or
triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators, e.g.
saibutamoi, salmeteroi, ephedrine, adrenaline, fenoterol, formoterol,
isoprenaline,
metaproterenol, phenylephrine, phenylpropanolamine, pirbuteroi, reproterol,
rimiterol, terbutaline, isoetharine, tulobuteroi, orciprenaline, or (-)-4-
amino-3,5-
dichioro- a -[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;
diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or
oxitropium;
hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthine:; e.g.
aminophylline, choline theophyliinate, lysine theophyllinate or theophyliine;
and
therapeutic proteins and peptides, e.g. insulin or glucagon. it will be clear
to a
person skilled in the art that, where appropriate, the medicaments may be used
in
CA 02447517 2003-11-19
5
the form of salts (e.g. as alkali metal or amine salts or as acid addition
salts) or as
esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise
the
activity and/or stability of the medicament and/or to minimise the solubility
of the
medicament in the propellant.
Particularly preferred drug formulations contain fluticasone propionate (or a
physiologically acceptable solvate thereof) in combination with a
bronchodilator
such as salbutamol (e.g. as the free base or the sulphate salt) or salmeteroi
(e.g.
as the xinafoate salt).
A particularly preferred drug combination is fiuticasone propionate and
salmeterol
xinafoate.
'Propellants' used herein mean pharmacologically inert liquids with boiling
points
from about room temperature (25°C) to about -25°C which singly
or in
combination exert a high vapor pressure at room temperature. Upon activation
of
the MDI system, the high vapor pressure of the propellant in the MDI forces a
metered amount of drug formulation out through the metering valve then the
propellant very rapidly vaporizes dispersing the drug particles. The
propellants
used in the present invention are low boiling fluorocarbons; in particular,
1,1,1,2-
tetrafluoroethane also known as 'propellant 134a" or "P 134a' and
1,1,1,2,3,3,3-
heptafluoro-n-propane also known as 'propellant 227' or 'P 22T.
Drug formulations for use in the invention may be free or substantially free
of
formulation excipients e.g. surfactants and cosoivents etc. Such drug
formulations ace advantageous since they may be substantially taste and odour
free, less irritant and less toxic than excipient-containing formulations.
Thus, a
preferred drug formulation consists essentially of fluticasone propionate, or
a
physiciologically acceptable solvate thereof, optionally in combination with
one or
more other pharmacologically active agents particularly salmeterol (e.g. in
the form of
the xinafoate salt), and a fluorocarbon propellant. Preferred propellants and
1,1,1,2-
tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof,
and
especially 1,1,1,2-tetrafluoroethane.
CA 02447517 2003-11-19
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Further drug formulations for use in the invention may be free or
substantially free of
surfactant. Thus, a further preferred drug formulation comprises or consists
essentially of albuterol (or aphysiciologically acceptable solvate thereof),
optionally
in combination with one or more other pharmacologically active agents a
fluorocarbon propellant and 0.01 to S% w/w based on the propellant of a polar
cosolvent, which formulation is substantially free of surfactant. Preferred
propellants
and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures
thereof,
and especially 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-
propane.
Most often the MDI can and cap are made of aluminum or an alloy of aluminum,
although other metals not affected by the drug formulation, such as stainless
steel, an alloy of copper or tin plate, may be used. An MDI can may also be
fabricated from glass or plastic. Preferably, however, the MDI cans employed
in
the present invention are made of aluminium or an alloy thereof.
Advantageously, strengthened aluminium or aluminum alloy MDI cans may be
employed. Such strengthened MDI cans are capable of withstanding particularly
stressful coating and curing conditions, e.g. particularly high temperatures,
which
may be required for certain fluorocarbon polymers. Strengthened MDI cans
which have a reduced tendency to malform under high terr~peratures include MDI
cans comprising side walls and a base of increased thickness and MDI cans
comprising a substantially ellipsoidal base (which increases the angle between
the side walls and the base of the can), rather than the hemispherical base of
standard MDI cans. MDI cans having an ellipsoidal base offer the further
advantage of facilitating the coating process.
The drug metering valve consists of parts usually made of stainless steel, a
pharmacologically inert and propellant resistant polymer, such as acetal,
polyamide (e.g., Nylon°), polycarbonate, polyester, fluorocarbon
polymer (e.g.,
Teflonm) or a combination of these materials. Additionally, seals and "O"
rings of
various materials (e.g., nitrite rubbers, polyurethane, acetyl resin,
fluorocarbon
polymers), or other elastomeric materials are employed in and around the
valve.
CA 02447517 2003-11-19
7
Fluorocarbon polymers for use in the invention include fluorocarbon polymers
which are made of multiples of one or more of the following monomeric units:
tetrafiuoroethylene (PTFE), fluorinated ethylene propylene (FEP),
perfluoroaikoxyalkane (PFA), ethylene tetrafluoroethylene (ETFE),
vinyldienefluoride (PVDF), and chlorinated ethylene tetrafluoroethylene.
Fluorinated polymers which have a relatively high ratio of fluorine to carbon,
such
as perfluorocarbon polymers e.g. PTFE, PFA, and FEP, are preferred.
The fluorinated polymer may be blended with non-fluorinated polymers such as
polyamides, polyimides, polyethersulfones, polyphenylene sulfides and amine-
formaldehyde thermosetting resins. These added polymers improve adhesion of
the polymer coating to the can walls. Preferred polymer blends are
PTFE/FEP/polyamideimide, PTFE/polyethersulphone (PES) and FEP-
benzoguanamine.
Particularly preferred coatings are pure PFA, FEP and blends of PTFE and
polyethersulphone (PES).
Fluorocarbon polymers are marketed under trademarks such as Tefiono, Tefzelm,
Halarm , Hostaflonm Poiyfion~ and Neofionm. Grades of polymer include FEP
DuPont 856-200, PFA DuPont 857-200, PTFE-PES DuPont 3200-100, PTFE
FEP-polyamideimide DuPont 856P23485, FEP powder DuPont 532, and PFA
Hoechst 6900n. The coating thickness is in the range of about 1 Eun to about 1
mm. Suitably the coating thickness is in the range of about 1 Irm to about 100
pm, e.g. 1 Eun to 25 pm. Coatings may be applied in one or more coats.
Preferably the fluorocarbon polymers for use in the invention are coated onto
MDI
cans made of metal, especially MDI cans made of aluminium or an alloy thereof.
The particle size of the particular (e.g., micronised) drug should be such as
to
permit inhalation of substantially all the drug into the lungs upon
administration of
the aerosol formulation and will thus be less than 100 microns, desirably less
than 20 microns, and, ~in particular, in the range of 1-10 microns, e.g., 1-5
microns.
CA 02447517 2003-11-19
8
The final drug formulation desirably contains 0.005-10% weight to weight
ratio, in
particular 0.005-5% weight to weight ratio, especially 0.01-1.0% weight to
weight
ratio, of drug relative to the total weight of the formulation.
A further aspect of the present invention is a metered dose inhaler having
part or
all of its internal metallic surfaces coated with one or more fluorocarbon
polymers, optionally in combination with one or more non-fluorocarbon
polymers,
for dispersing an inhalation drug formulation comprising fluticasone
propionate
and a fluorocarbon propellant optionally in combination with one or more other
pharmacologically active agents and one or more excipients.
A particular aspect of the present invention is an MDI having part or
essentially all
of its internal metallic surfaces coated with PFA or FEP, or blended
fluoropolymer
resin systems such as PTFE-PES with or without a primer coat of a
polyamideimide or polyethersulfone for dispensing a drug formulation as
defined
hereinabove. Preferred drug formulations for use in this MDI consist
essentially
of fluticasone propionate (or a physiologically acceptable solvate, thereof),
optionally in combination with one or more other pharmacologically active
agents
particularly salmeterot (e.g. in the form of the xinafoate salt), and a
fluorocarbon
propellant, particularly 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-
heptafluoropropane or mixtures thereof, and especially 1,1,1,2-
tetrafluoroethane.
Preferably the MDI can is made of aluminium or an alloy thereof.
The MDI can may be coated by the means known in the art of metal coating. For
example, a metal, such as aluminum or stainless steel, may be precoated as
coil
stock and cured before being stamped or drawn into the can shape. This method
is well suited to high volume production for two reasons. First, the art of
coating
coil stock is well developed and several manufacturers can custom coat metal
coil stock to high standards of uniformity and in a wide range of thicknesses.
Second, the precoated stock can be stamped or drawn at high speeds and
precision by essentially the same methods used to draw or stamp uncoated
stock.
CA 02447517 2003-11-19
9
Other techniques for obtaining coated cans is by electrostatic dry powder
coating
or by spraying preformed MDI cans inside with formulations of the coating
fluorinated polymer/potymer blend and then curing. The preformed MDI cans
may also be dipped in the fluorocarbon polymer/polymer blend coating
formulation and cured, thus becoming coated on the inside and out. The
fluorocarbon polymer/polymer blend formulation may also be poured inside the
MDI cans then drained out leaving the insides with the polymer coat.
Conveniently, for ease of manufacture, preformed MDI cans are spray-coated
with the fluorinated polymer/polymer blend.
The fluorocarbon polymer/polymer blend may also be formed in situ at the can
walls using plasma polymerization of the fluorocarbon monomers. Fluorocarbon
polymer film may be blown inside the MDI cans to form bags. A variety of
fluorocarbon polymers such as ETFE, FEP, and PTFE are available as film stock.
The appropriate curing temperature is dependent on the fluorocarbon
polymer/polymer blend chosen for the coating and the coating method employed.
However, for coil coating and spray coating temperatures in excess of the
melting
point of the polymer are typically required, for example, about 50°C
above the
melting point, for up to about 20 minutes such as about 5 to 10 minutes e.g.
about 8 minutes or as required. For the above named preferred and particularly
preferred fluorocarbon polymer/polymer blends curing temperatures in the range
of about 300°C to about 400°C, e.g. about 350°C to
380°C are suitable for
plasma polymerization typically temperatures in the range of about 20°C
to about
100°C may be employed.
The MDI's taught herein may be prepared by methods of the art (e.g., see
Byron,
above and U.S. patent 5,345,980) substituting conventional cans for those
coated
with a fluorinated polymer/polymer blend. That is, fluticasone propionate and
other components of the formulation are filled into an aerosol can coated with
a
fluorinated pofymedpolymer blend. The can is fitted with a cap assembly w~iich
is
crimped in place. The suspension of the drug in the fluorocarbon propellant in
liquid form may be introduced through the metering valve as taught in U.S.
5,345,980 .
CA 02447517 2003-11-19
The MDI's with fluorocarbon polymer/polymer blend coated interiors taught
herein
may be used in medical practice in a similar manner as non-coated MDI's now in
clinical use. However the MDI's taught herein are particularly useful for
containing
5 and dispensing inhaled drug formulations with hydrofluoroalkanefluorocarbon
propellants such as 134a with little, or essentially no, excipient and which
tend to
deposit or cling to the interior walls and parts of the MDI system. In certain
cases
it is advantageous to dispense an inhalation drug with essentially no
excipient,
e.g., where the patient may be allergic to an excipient or the drug reacts
with an
10 exciptent.
MDI's containing the formulations described hereinabove, MDI systems and the
use of such MDI systems for the treatment of respiratory disorders e.g. asthma
comprise further aspects of the present invention.
It will be apparent to those skilled in the art that modifications to the
invention
described herein can readily be made without departing from the spirit of the
invention. Protection is sought for all the subject matter described herein
including any such modifications.
The following non-limitative Examples serve to illustrate the invention.
EXAMPLES
Standard 12.5 ml MDI cans (Presspart Inc., Cary, NC) were spray-coated
(Livingstone Coatings, Charlotte, NC) with primer (DuPont 851-204) and cured
to
the vendor's standard procedure, then further spray-coated with either FEP or
PFA (DuPont 856-200 and 857-200, respectively) and cured according to the
vendor's standard procedure. The thickness of the coating is approximately 10
~m to 50 Vim. These cans are then purged of air (see PCT application number
W094/22722 (PCTIEP94/0092~)), the valves crimped in place, and a suspension
CA 02447517 2003-11-19
11
of about 20 mg fluticasone propionate in about 12 gm P134a is filled through
the
valve.
Standard 0.46 mm thick aluminum sheet (United Aluminum) was spray-coated
(DuPont, Wilmington, DE) with FEP (DuPont 856-200) and cured. This sheet
was then deep-drawn into cans (Presspart Inc., Cary, NC}. The thickness of the
coating is approximately 10 Eun to 50 Ir,m. These cans are then purged of air,
the
valves crimped in place, and a suspension of about 40 mg fluticasone
propionate
in about 12 gm P134A is tilled through the valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with
PTFE-PES blend (DuPont) as a single coat and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1 pm
and approximately 20 N.m. These cans are then purged of air, the valves
crimped
in place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg
micronised fluticasone propionate in about 12 g P134a is filled through the
valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with
PTFE-FEP-polyamideimide blend (DuPont) and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1 Nm
and approximately 20 Vim. These cans are then purged of air the valves crimped
in place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg
micronised fluticasone propionate in about 12 g P134a is filled through the
valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the
CA 02447517 2003-11-19
12
coating is between approximately 7 lun and approximately 20 ~Cm. These cans
are then purged of air, the valves crimped in place, and a suspension of about
41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg micronised fluticasone propionate in about
12 g P134a was filled through the valve.
Standard 0.46 mm thick aluminium sheet is spray coated with FEP-
Benzoguanamine and cured. This sheet is then deep-drawn into cans. These
cans are then purged of air, the valves crimped in place, and a suspension o1
about 41.0 mg, 21.0 mg, 8.8 mg, or 4.4 mg micronised fluticasone propionate in
about 12 g P134a is filled through the valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spraycoated with an
aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of
the coating is between approximately 1 lun and approximately 20 ~.m. These
cans are then purged of air, the valves crimped in place, and a suspension of
about 41.0 mg, 21.0 mg, 8.8 mg, or 4.4 mg micronised fluticasone propionate in
about 12 g P134a is filled through the valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with
PTFE-PES blend (DuPont) as a single coat and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1
fun
and approximately 20 um. These cans are then purged of air, the valves crimped
in place, and a suspension of about 8.8 mg, 22 mg or 44 mg of micronised
34 fluticasone propionate with about 6.4 mg micronised saimeteroi xinafoate in
about 12 g P134a is filled through the valve.
CA 02447517 2003-11-19
13
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with
PTFE-FEP-potyamideimide blend (DuPont) and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1
I,tm
and approximately 20 um. These cans are then purged of air the valves crimped
in place, and a suspension of about 8.8 mg, 22 mg or 44 mg of micronised
fluticasone propionate with about 6.4 mg micronised salmeterol xinafoate in
about 12 g P134a is filled through the valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with FEP
powder (DuPon! FEP 532) using an electrostatic gun. The thickness of the
coating is between approximately 1 lun and approximately 20 p.m. These cans
are then purged of air, the valves crimped in place, and a suspension of about
8.8 mg, 22 mg or 44 mg of micronised fluticasone propionate with about 6.4 mg
micronised salrneterol xinafoate in about 12 g P134a is filled through the
valve.
Example 11
Standard 0.46 mm thick aluminium sheet is spray coated with FEP-
Benzoguanamine and cured. This sheet is then deep-drawn into cans. These
cans are then purged of air, the valves crimped in place, and a suspension of
about 8.8 mg, 22 mg or 44 mg of micronised fluticasone propionate with about
6.4 mg micronised salmeterol xinafoate in about 12 g P134a is filled through
the
valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with an
aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of
the coating is between approximately 1 lun and approximately 20 pm. These
cans are then purged of air, the valves crimped in place, and a suspension of
CA 02447517 2003-11-19
14
about 8.8 mg, 22 mg or 44 mg of micronised fluticasone propionate with about
6.4 mg micronised salmeterol xinafoate in about 12 g P134a is filled through
the
valve.
Exam nle 13
Standard 12.5 ml MDI cans (Presspart int., Cary NC) are spray-coated with
PTFE-PES blend (DuPont) as a single coat and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1
!un
and approximately 20 u.m. These cans are then purged of air, the valves
crimped
in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised
fiuticasone propionate with about 4 mg micronised salmeterol xinafoate in
about
8 g P134a is filled through the valve.
Fxamole 14
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with
PTFE-FEP-polyamideimide blend (DuPont) and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1
Eun
and approximately 20 pm. These cans are then purged of air the valves crimped
in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised
fluticasone propionate with about 4 mg micronised salmeterol xinafoate in
about
8 g P134a is fitted through the valve.
Example 15
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the
coating is between approximately 1 Nm and approximately 20 pm. These cans
are then purged of air, the valves crimped in place, and a suspension of about
5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with about 4 mg
micronised salmeteroi xinafoate in about 8 g P134a is filled through the
valve.
CA 02447517 2003-11-19
Standard 0.46 mm thick aluminium sheet is spray coated with FEP-
Benzoguanamine and cured. This sheet is then deep-drawn into cans. These
5 cans are then purged of air, the valves crimped in place, and a suspension
of
about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with about
4
mg micronised salmeterol xinafoate in about 8 g P134a is filled through the
valve.
Standard 12.5 ml MDI cans (Presspart Inc., Cary NC) are spray-coated with an
aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of
the coating is between approximately 1 Erm and approximately 20 Vim. These
cans are then purged of air, the valves crimped in place, and a suspension of
about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with about
4
mg micronised salmeterol xinafoate in about 8 g P134a is filled through the
valve.
Examples 3 to 7 are repeated except that a suspension of about 13.3 mg
micronised fluticasone proprionate in about 21.4 g P227 is filled through the
valve.
Examples 3 to 7 are repeated except that 66 mg, or 6.6 mg micronised
fluticasone proprionate in about 182 mg ethanol and about 18.2 g P134a is
filled
through the valve.
Examples 28-52
Examples 3 to 27 are repeated except that modified 12.5 ml MDI cans having a
substantially ellipsoidal base (Presspart Inc., Cary NC) were used.
CA 02447517 2003-11-19
16
Dose delivery from the MDis tested under simulated use conditions is found to
be
constant, compared to control MDis filled Into uncoated cans which exhibit a
significant decrease in dose delivered through use.
