Note: Descriptions are shown in the official language in which they were submitted.
CA 02367013 2002-O1-21
Zhi.s Applicatiaci is a Division of Canadian Patent Application S:N:
2,217,948, 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
genera! background on this foml 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
cEaimed
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 02367013 2005-04-21
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
is particularly acute with hydrofluoroalkane (also known as simply
s "fluorocarbon") propellant systems, e.g., P134a and P22'7, under development
in
recent years to replace chlorofluorocarbons such as P 11, P 114 and P 12.
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
z o deposition of fluticasone propionate on the can walls and thus ensures
consistent
delivery of medication in aerosol from the MDI.
SUMMARY OF THE INVENTICIN
is In accordance with the invention, there is provided an inhalation
pharmaceutical
preparation comprising an inhalation drug formulation which comprises
fluticasone propionate or a physiologically acceptable solvate thereof and a
fluorocarbon propellant selected from the group consisting of 1,1,1,2-
tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof,
in a
a o metered dose inhaler comprising a can, a crimped cap covering the mouth of
the
can, and a drug metering valve situated in the cap, said metered dose inhaler
having part or all of its internal surfaces coated wiith fluorinated ethylene
propylene and wherein said can is made of strengthened aluminium or aluminium
alloy.
CA 02367013 2005-04-21
2a
There is also provided 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-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.
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
the cap, while the term "MDI system" also includes a suitable channeling
device.
The term "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 channeling device may comprise, fox example, an
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
a o nose or mouth of a patient, e.g., a mouthpiece actuator. The relation of
the
CA 02367013 2002-O1-21
3
parts of a typical MDi is illustrated in US Patent 5;261,538:
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, hydrofiuorocarbon,
chiorofiuorocarbon, 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
antiinfiammatory steroid compound known by the chemical name [(6a, 11 b, 16a,
17a}-6; 9-difiuoro-11-hydroxy-16-methyl-3-oxo-i7-(1-oxopropoxy} androsta-1, 4-
diene-17-carbothioic acid, S-fluoromethyl ester and the generic
name'fluticasone
propionate". Ftuticasone 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 "Flonase". Ftuticasvne propionate may also be
used in the form of a physiologically acceptable solvate.
The term "drug formulation" means _fluticasone propionate (or a
physiologically
acceptable sotvate thereof) optionally in combination with one or more other
pharmacologically active agents such as other antiinflammatory 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 tittle 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
' cosotvents, 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 02367013 2002-O1-21
4
particularly useful surfactant is 1,2-di[7-(F-hexy!) hexanoyl]-glycero-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 CZ~ aliphatic alcohols and polyols 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 surfactants. Suitably, the drug formulation may
contain
0.01 to 5% w/w based on the propellant of a polar cosolvent 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
pharmacologically 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, dihydramorphine,
ergotamtne, fentanyl or morphine; anginai preparations, e:g. diltiazem;
antiallergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g.
cephalosporins, penicillins, streptomycin, sulphonamides, tetracyctines and
pentamidine; antihistamines, e.g. methapyritene; anti-inftammatories, e.g.
beclomethasone (e.g, the dipropionate), fiunisolide, budesonide, tipredane or
triamcinotone acetonide; antitussives, e.g. noscapine; bronchoditators, e.g.
salbutamol, safmeterol, ephedrine, adrenaline, fenoterot, formoterol,
isoprenaline,
metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol,
rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline; or (-)-4-
amino-3,5-
dichloro- a -j[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;
diuretics, e.g. amiloride; anticholinergics e.g. ipratropiurn, atropine or
oxitropium;
hormones, e.g. cortisone, hydrocortisone or prednisolone; xantfiines e.g. .
aminophylline, choline theophyllinafie, lysine theophyllinate or theophyfline;
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 02367013 2002-O1-21
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
bronchodiiator
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 ftuticasone 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 22T or'P 227".
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 are 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 salineterol (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 02367013 2002-O1-21
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 5% 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.
~o
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 aiso be
fabricated from glass or plastic. Preferably, however, the MDI cans employed
in
15 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 ace 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
20 which have a reduced tendency to matform under high temperatures include
MDl
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
25 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.,
30 Teflon~) or a combination of these materials. Additionally, seals and
°(J" rings of
various materials (e.g.; nitrite rubbers, polyurethane, acetyl resin,
fluorocarbon
polymers), or other elastomeric materials are employed in and around the
valve.
~ 02367013 2002-O1-21
7
Fluorocarbon polymers for use in the invention include fluorocarbon polymers
which are made of muEtiples of one or more of the following monomeric units:
tetrafluoroethytene (PTFE), fluorinated ethylene propylene (FEP),
perftuoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (ETFE),
vinyidienefluoride (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
'10 polyamides, poiyimides;=poiyethersulfones, poiyphenylene 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 Teflon, Tefzel~,
Hatar~ , Hostaflonm Polyflon~ and Neoflon~. Grades of polymer include FEP
DuPont 856-200, PFA DuPont 857,-200, PTFE-PES DuPont 3200-100, PTFE-
FEP-potyamideimide DuPont 856P23485, FEP powder DuPont 532, and PFA
Hoechst 6900n. The coating thickness is in the range of about 1 pm to about 1
mm. Suitably the coating thickness is in the range of about 7 (rm to about 100
um, e.g. 1 E,Em to 25 uxn. Coatings may be applied in one or ri~ore 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 ahoy 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 tongs upon
administration of
the aerosol formulation and wilt 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 02367013 2002-O1-21
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 MDl consist
essentiatly
of fluticasone propionate (or a physiologically acceptable solvate, thereof),
optionally in combination with one or more other pharmacologically active
agents
particutarly safmeterol (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 welt developed and several manufacturers can custom coat metal
coif 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 02367013 2002-O1-21
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/polymer blend and then curing. The preformed MDI cans
may also be dipped in the fluorocarbon polymerlpolymer blend coating
formulation and cured, thus becoming coated on the. inside and out. The
fluorocarbon poiymer/poiymer 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 MDl cans are spray-coated
with the fluorinated polymerlpofymer blend.
The fluorocarbon polymer/poiymer 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
polymerlpolymer 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 polymerlpolymer 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 poiymer/polymer blend. That is, fluticasone propionate and
other components of the formulation are filled into an aerosol can coated with
a
' fluorinated polymedpolymer blend. The can is fitted with a cap assembly
w;~ich is
crimped in place. The suspension of the drug in the fluorocarbon propellant in
liquid form may be introduced through the metering waive as taught in U.S.
5,345,980
CA 02367013 2002-O1-21
The MDI's with fluorocarbon polymerlpolymer 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 wails 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 excipient.
MD('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
Examgle 1
Standard 12.5 ml MDl 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 pm. These cans are then purged of air (see PCT application number
W094/22722 (PCT/EP94/00921 )), the valves crimped in place, and a suspension
CA 02367013 2002-O1-21
11
of about 20 mg fluticasone propionate in about 12 gm P134a is fined through
the
vaive.
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 E.im to 50 arm. 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 filled through the valve.
Ex~m~le 3
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
l.~m
and approximately 20 N,m. These cans are then purged of air, the valves
crimped
in place, ancJ 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 th .rough the
valve.
Example 4
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 pm
and approximately 20 p.m. These cans are then purged of air the valves crimped
in place, and a suspension of about 4i.0 mg, 21.0 mg, 8.8 mg or 4.4 mg
micronised flcrticasone propionate in about 12 g P134a is filled through the
valve.
Standard 12.5 m1 MDI cans (Presspart lnc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the
CA 02367013 2002-O1-21
12
coating is between approximately 1 irm and approximately 20 p.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 was filled through the valve.
Example 6
Standard 0.46' mm thick aluminium sheet is spray coated with FEP-
Benzoguanamine and cured. This sheet is then deep-drawrt into cans. 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 fitted through the valve.
Standard 12.5 m! MDi cans (Presspart Inc., Cary NC) are spray-coated with an
aqueousdispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of
the coating is between approximately 1 L~m and approximately 20 p.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.
Example 8
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
Lun
and approximately 20 N.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 satmeteroi xinafaate in
about 12 g P134a is filled through the valve.
CA 02367013'2002-O1-21 .,
13
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
tim
and approximately 20 u.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 salmeterol xinafoate in
about 12 g P134a is fiitled through the vahre.
Standard 12.5 ml MD1 cans (Presspart tnc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the
coating is between approximately 1 trm arid approximately 20 ~tm. These cans
are then purged of air, the valves crimped in ptace, 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.
Exam a 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.
_ .. ~ Exam2p 12
Standard 12.5 ml MDf 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 ~l.un and approximately 20 ~.m. These
cans are then purged of air, the valves crimped in place, and a suspension of
CA 02367013 2002-O1-21
14
about 8.8 mg, 22 mg or 44 mg of micronised fluticasone propionate with about
6.4 mg micronised saimeterol xinafoate in about 12 g P134a is filled through
the
valve.
xam 13
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 ~m
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
fluticasone propionate with about 4 mg micronised safmeterol xinafoate in
about
8 g P134a is filled through the valve.
Exams !a a 14
Standard 72.5 ml MDI cans (Pressp~.rt lnc., Cary NC) are spray-coated with
PTFE-FEP-polyarnideimide bleed (DuPont) and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1
I,~m
and approximately 20 N.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
fluticasone propionate with about 4 mg micronised salmeterol xinafoate in
about
8 g P134a is filled through the valve.
Exam 1Q a 15
Standard 12.5 ml MD! 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 i irm and approximately 20 p.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 fluticasone propionate with abou~ 4 mg
micronised salmeterol xinafoate in about 8 g P134a is filled through the
valve. '
CA 02367013 2002-O1-21
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 ofi 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 tHoechst PFA-s900n) and cured. 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 satmeterof xinafoate in about 8 g. P134a is filled though 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 fitted through the
valve.
Examg_le~~~2_7
Examples 3 to 7 are repeated except that 66 mg, or 6.6 mg micronised
fiuticasone proprionate in about 182 mg ethanol and about 18.2 g P134a is
filled
through the valve.
r
Exami~les 28-52
Examples 3 to 27 are repeated except that modified 12.5 ml MDt cans having a
substantially ellipsoidal base (Presspart Inc., Cary NC) were used.
CA 02367013 2002-O1-21
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.
