Note: Descriptions are shown in the official language in which they were submitted.
CA 02368934 2002-02-07
this Application is a Division of Canadian Patent Application S:N:
2,227,948, filed Apri1 10, 1996:
BACKGROUND OF THE INV'ENTtON
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 seated 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 Papidiy 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 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 02368934 2002-02-07
2
Some aerosol drugs tend to adhere to the inner surfaces, i.e., watts 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 particutarfy acute with hydroftuoroalkane (also known as simply
"ftuorocarbon'~ propellant systems, e.g., P134a and P227, under development in
recent years to replace chloroftuorocarbons such as P11, P114 and P12.
We have found that coating the interior can surfaces of MDt's with a
fluorocarbon
polymer significantly reduces or essentially eliminates the prabtem of
adhesion or
deposition of fluticasone propionate on the can watts and thus ensures
consistent
delivery of medication in aerosol from the MDt.
SUMMARY OF THE lNVENTfON
In one aspect of the invention there is provided an inhalation
pharmaceutical preparation comprising an inhalation drug formulation which
comprises fluicasone 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, in a metered
dose inhaler having part or all of its internal surfaces coated with a polymer
blend comprising one or more fluorocarbon pol~,lmers in combination with one
or more non-fluorocarbon polymers.
CA 02368934 2002-02-07
3
In another aspect of the invention there is provided use of an inhalation
drug formulation comprising fluticasone propionate or a physiologically
acceptable solvate thereof and a fluorocarhon propellant, optionally in
combination with one or more other pharmacologically active agents or one or
more excipients, for the treatment of respiratory and nasal disorders, the
formulation being dispensed in a 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.
DETAILED DESCRIPTION OF TEIE tNVENTiON
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 'MDl system' also includes a suitable channelling
device.
The terms 'MDl 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 actuating device for the valve and a cylindrical or cone-(ike passage tt-
~rough
which medicament may be delivered from the filled MDl can via the MDI valve to
the nose or mouth of a patient, e.g. a mouthpiece actuator. The relation of
the
CA 02368934 2002-02-07
parts of a typical MDi is ihustrated in US Patent 5,261,538:
The temp "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 perfiuorocarbon, hydrofiuorocarbon,
chlorofiuorocarbon, hydro-chioroffuorocarbon 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, 11b, 16a,
i7a)-6, 9-difiuoro-11-hydroxy-16=methyl-3-oxo-1~-(1-oxopropoxy}- androsta-1, 4-
diene-17-carbothioic acid, S-fiuoromethyi ester and the generic name
'fluticasone
propionate'. Fiuticasone 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'. Fiuticasone propionate may also be
used in the form of a physiologically acceptable solvate.
The term 'drug formulation' means fiuticasone propionate (or a physiologically
acceptable solvate thereof) optionally in combination with one or more other
pharmacologically active agents such as other antiinf(ammatory agents,
analgesic agents oc other respiratory drugs and optionally containing one or
more
excipients, and a fluorocarbon propellant. The term "exc(pients" 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 MDl system. For example, excipients include but ace not (invited to
surfactants, preservatives, flavorings, antioxidants, antiaggregating agents,
and
cosoivents, e.g., ethanol and diethyl ether.
3Q
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 02368934 2002-02-07
A~
particularly useful surfactant is 1,2-di[7-(F-hexyl) hexanoytj-glycero-3-
phospho-
N,N,N-trimethylethanolamine also knovsm as 3, ~, 9-trioxa-4-phosphadocosan-1-
aminium, 17, i 7, 18, 18, 19, 19, 20, 20, 21, 21, 22, 22, 22-tridecaftuoro-7-
[(8, 8,
9, 9, 10, 10, 11, 11, 12, 12, 13, 13; 13-tridecafluoro-1-oxotridecyl)oxyj-4-
hydroxy-
N, N,N-trimethyl-10-oxo-, inner salt, 4-oxide.
A polar cosolvent such as Cz~ aliphatic alcohots 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/Hr.
tt will be appreciated by those skilled in the art that the drug formulation
for use in
18 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, dlhydromo~phine,
ergotamine, fentanyl or morphine; anginal preparations, e.g. diitiazem;
antiatlergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g.
cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and
pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories; e.g.
bectomethasone (e.g. the dipropionate), flunisollide, budesonide, tipredane or
2~ triamcinolone acetonide; antitussives, e.g. noscapine; bronchodtlators,
e.g.
salbutamot, salmeterol, ephedrine, adrenaline, fenoterol, formoterol,
isoprenaline,
metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol,
rimiterol, terbutatine, isoetharine, tulobuterol, orc;iprenaline, or (-)-4-
amino-3,5-
d i c h 1 o ro- cc -jj(6-[2-(2-
pyridinyl)ethoxyjhexyljaminojmethyljbenzenemethanol; .
diuretics, e.g. amiloride; anticholinergics e.g. iprat:ropium, atropine or
oxitropium;
hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthine~ e.g. .
aminophyltine, choline theophyltinate, lysine theophyllinate or theophylfine;
and
therapeutic proteins acid 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 02368934 2002-02-07
s
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 andlor 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 salmeterol
{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 fomnulation 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,
y,1,1,2-
tetrafluoroethane also known as "propellant 134x" or "P 134a" and
1,1,1,2,3,3,3-
heptafluoro-n-propane also known as "propellant 227" 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 salmeterol (e.g. in
the form of
the xinafoate salt), and a fluorocarbon propellant. Preferred propellants: and
1,1,i,2-
tetrafluoroethane, 1, l,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof,
and
especially 1,1,1,2-tetrafluoroethane.
CA 02368934 2002-02-07
7
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:
Most often the MDI can and cap are made of alurninurn 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 MDl cans may be
employed. Such strengthened MDl 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 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
v standard MDl 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~), poiycarbonate, polyester, fluorocarbon polymer
(e.g.,
Teflon~) or a combination of these materials. Additionally, seals and "O"
rings of
various materiats (e.g., nitrite rubbers, polyurethane, acetyl resin,
fluorocarbon
polymers), or other elastomeric materials are employed in and around the
valve.
CA 02368934 2002-02-07
Fluorocarbon polymers for use in the invention include fluorocarbon polymers
which are made of multiples of one or more of the following monomeric units:
tetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP),
perfluoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (ETFE),
vinytdienefiuoride (PVDF), and chlorinated ethylene tetrafluoroethylene.
Fluorinated polymers which have a relatively high ratio of #luorine to carbon,
such
as perftuorocarbon polymers e.g. PTFE, PFA, and FEP, are preferred.
The fluorinated polymer may be blended with non-#luorinated polymers such as
. 70 polyamides, polyimides, polyethersulfones; 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, PTFElpolyethersulphone (PES) and FEP-
benzoguanam ine.
Particularly preferred coatings are pure PFA, FEP and blends of PTFE and
polyethersulphone (PES).
Fluorocarbon polymers are marketed under trademarks such as Teflon, Tefzel~,
Halar~ , Hostaflon~ Potyflon~ and Neoflon~. 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 dun to about
1
mm. Suitably the coating thickness is in the range of about 1 Eam to about 100
um, e.g. 1 Fun to 25 Vim. 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
adrninistrntion 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., t-5
microns.
CA 02368934 2002-02-07
9
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 cornprising fluticasone
propionate
y0 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 A~1D1 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 poiyethersulfone for dispensing a drug formulation as
defined
hereinabove. Preferred drug formulations for use in this MDl consist
essentially
of ffuticasone propionate (or a physiologically acceptable solvate, thereof),
optionally in combination with one or more other pharmacoiogically active
agents
particularly salmeterol (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-
tetrafiuoroethane.
Preferably the MDI can is made of aluminium or an alloy thereof.
The MDf 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 rE~asons. 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 02368934 2002-02-07
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 polymerlpolymer blend and then curing. The preformed MDI cans
may also be dipped in the fluorocarbon p~oiymerlpolymer blend coating
formulation and cured, thus becoming coated on the inside and out. The
fluorocarbon polymerlpolymer 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 fluoririated 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 stack.
The appropriate curing temperature is dependent on the fluorocarbon
polymerlpolymer blend chosen for the coating and the coating method employed.
However, for coif coating and spray coating temp~aratures in excess of the
rnetting
point of the polymer are typically required, for example, about 50°C
above the
2D 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 poiymer/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 pofymeri2ation typically temperatures in the range of about 20°C
to about
100°C may be employed.
The MDl'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 ini;o an aerosol can coated
with a
fluorinated polymerlpolymer blend. The can is fitted with a cap assembly waich
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 02368934 2002-02-07
~1
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 p~articulariy useful for
containing
and dispensing inhaled drug formulations with hydrofluoroalkaneftuorocarbon
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 excip~ient or the drug reacts
with an
i0 excipient.
MDI's containing the formulations described hereinabove, MDI systems and the
use of such MDl systems for the treatment of respiratory disorders e.g. asthma
comprise further aspects of the present invention.
18
1t 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-iimitative Examples serve to iltustrate the invention.
EXAMPLES
Example ~
Standard 12.5 ml MDI cans (Presspart Lnc., Cary, NC) were spray-coated
(Livingstone Coatings, Charlotte, NC) with primer (DuPont 85i-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 Ir.m. These cans are then purged of air {see PCT application number
W094122722 (PCT/EP94/00921 )); the valves crimped in place, and a suspension
CA 02368934 2002-02-07
12
of about 20 mg fluticasone propionate in about 12 gm P134a is filled through
the
valve.
~xars
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 um to 50 u.m. These cans are then purged of air,
the
valves crimped in place, and a suspension of about 40 mg fituticasone
propionate
in about 12 gm 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
Eun
and approximately 20 um. 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.
Exasn~ lp a 4
Standard 12.5 mi MDf 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
dun
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.
' ~camr~te 5
Standard 12.5 mi MDi cans (Presspart Inc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the
CA 02368934 2002-02-07
13
coating is between approximately 1 Nm and appro;~cimately 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 ftuticasone 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 heel is then deep-drawn 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 ftuticasone 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 an
aqueous dispersion ~of PFA (Hoechst PFA-6900n) and cured. The thickness of
the coating is between approximatefy~ 1 iun and approximately 20 Vim. 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 fluticasone propionate in
about 12 g P134a is filled through the valve.
Standard 12.5 mI 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 ~
irm
and approximately 20 ~.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 satmeterol xinafoate in
about 12 g P134a is filled through the valve.
CA 02368934 2002-02-07
~.4
Standard 12.5 ml MDl 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 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 filled through the valve.
Example 10
Standard 12.5 ml MDl 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 l.im 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 saimeterol 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 propioriate with about
6.4 mg micronised salmeterol xinafoate in about 12 g P134a is filled through
the
valve.
.. exam fp a 12
3a
' Standard 12.5 ml MDt 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 ~.~m and approximately 20 ~.m. These
cans are then purged of air, the valves crimped in place, and a suspension of
CA 02368934 2002-02-07
about 8.8 mg, 22 mg or 44 mg of n'~icronised fluticasone propionate with about
6.4 mg micronised salmeterol xinafoate in about i2 g P134a is filled through
the
valve.
5 Example 13
Standard 12.5 ml MDI cans (Presspart Inc., Caiy 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
Izm
10 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 filled through the valve.
15 Exam Ire 14
Standard 12.5 ml MDI cans (Presspart~ Inc., Cary NC) are spray-coated with
PTFE-FEP-poiyamideimide blend (DuPont} and cured according to the vendor's
standard procedure. The thickness of the coating is between approximately 1 um
and approximately 20 ~.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 saimeterot xinafoate in
about
8 g P134a is filled through the valve.
Exam Ip a 15
Standard 12.5 ml MDI cans (Presspart Inc., Cary INC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the
coating is between approximately i lam 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 abou~ 4 mg
micronised salmeterol xinafoate in about 8 g P134a is filled through the
valve.
, CA 02368934 2002-02-07
36
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 5.5 mg, 13.8 mg or 27.5 mg micronised fiuticasone propionate with about
4
mg micronised salmeterol xinafoate in about 8 g I'134a is filled through the
valve.
Example 17
Standard 12.5 ml MDI cans (Presspart lnc., 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 Nm 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 about
4
mg micronised saimeterol 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.
,ExamQles 23-27
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
fitted
through the valve.
ExamQles 28-52
Examples 3 to 27 are repeated except that modified 72.5 m! MDl cans having a
substantially ellipsoidal base (Presspart (nc., Cary fJC) were used.
CA 02368934 2002-02-07
17
r
Dose delivery from the MDIs tested under simulated use conditions is found to
be
constant, compared to control MDts filled into uncoated cans which exhibit a
significant decrease in dose delivered through use.
