Title of Invention

PHARMACEUTICAL METERED DOSE INGALER AND METHODS RELATING THERETO

Abstract A method of manufacturing an MDI comprises providing an MDI sealing gasket (3), providing the other MDI components and a pharmaceutical aerosol formulation and assembling the MDI, wherein the sealing gasket comprises an elastomeric gasket material comprising acrylonitrile butadiene rubber and oleic acid as an extractable compound and the pharmaceutical aerosol formulation comprises salmeterol xinafoate and fluticasone propionate, the method further comprising the step of contacting the elastomeric gasket material (3) with an aqueous solution consisting of ethanol, wherein the solution is at a temperature of from 40°C to the boiling point of said aqueous solution, to extract oleic acid so that the sealing gasket comprises between 0.04 and 0.17% oleic acid prior to assembly of the MDI.
Full Text Pharmaceutical metered dose Inhaler and methods relating thereto
The present invention retetes to methods of treating melerad close inhaler (MDI) sealing
5 gaskets and MDI sealing gasket made from treated matarials. The Invention further
relates to a container far an. MDI with anhanced, characteristics and methods associated
therewith. The MDI is typically one for use in dispensing a quantity of a rnedlcamenl-
containing formulation which may used lo the treatment of respiratory or other
disorders.
10
Background;
The use of aerosols to administer madicaments has been known for severel decades.
Such aerosols generally comprise ihe medicsment. one or more chlorofluorocarbon
propellante and one or more additiivas, for example a surfactant or a co-solvent, such as
15 elhsnol. Historically the most commonly used aerosol propellents for medicaments have
been pnopellant 11 (CCI3F), propellent 114 (CF2CICF2CI). propallant 12 (CC2F2) or
cpmbin ation of those. However replace of those a propellent into the atmosphere is now
believed to contribute to the degradtion of stratospheric ozone and there is thus a need
to provide aerosol formulations for medicaments which employ so called "ozone-friendly"
20 propellants.
Containers for aerosol formulations commonly comprise a vial body (can or canlstor)
coupled to a valve. The valve comprises a valve stem through which the formulations
are dispensed. Generally the valve indudes one or mom rubber vaive seals intended to
25 allow reciprocal movement of the valve stem which prevents leakage of propeliant from
the container. Watered dose Inhalers comprises a valve which is designed to deliver a
metered amount of an aaroscl formulation to the recipient per actuation. Such a
metering valve generaly comprises a mataring chamber which, is of a pce-determined
volume and which causes the dose par acluation to be an accurate, pre-detemined
30 amounrt.
The metering valve in a container is typically coupled to the canister with contact through
a sealing gasket to prevent leakage of propellant and/or drug substance out or the
container at the join. The gasket typically comprises an elastomeric material, for
35 example low density polyethylene, chlorobutyl, acrylanitrile butadiene rubbers, butyl

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rubber, a polymer of ethylane propylene dlene monomer (EPDM), neoprene or
choroprene. Such elastomaric materials may be carbon-black or mineral filled.
Values for use In MDIs are available from various manufactures known in the aerosol
5 industry; for example from Valois, France (e.g. DF10. DF30. DF60), Bespak pic. UK (e.g.
BK300, BK356, BK357) or 3M-neotechnic; Limited, UK (e.g. SpraymiserTM). The
metering valves are used in association with commercially availably canisters, for
example metal canisters. for example aluminium canisters, suitable for delivering
pharmaceutical aerosol forrnulations.
10
MDIS Incorporating a valve seat or a sealing gasket as described above generally
perform adequately with CFC propetiants, such as propatiant 11 (CCI3F), propollant 114
(CF2CICF2CI), propellant 12 (CCI2F2). However, as mentioned above, there is a
requirement to substitute so-colled ozone-friendly propellants for CFC propellents In
15 aerosols. A class of propellants with ere believed to have minimal ozone-deplating
effects in comparison to convenllonal chlorocarbons comprise flurocarbons and
hydrogen-containing chlorolluorocarbons. That dess Incfudes, but is not limited to
hydralluoroalkanes (HFAs), for example 1,1,1,2-tetrafluoroethane (HFA134a).
1.1.1.2.3.3.3-heptafluoro-n-propane (HFA 227) and mixtures thereof However, various
20 problems have arisen witn pharmaceutical aemscl formulations prepared using HFA
propellants. In particular with regard to the stability of the formulations.
Pharmaceutical aercraol formulations generally comprise a solution or a suspension. A
mixture of a suspension and a smsll amount of dissolved medicament is also possible,
25 but generally undesirable (as described below). Some solution formulations have the
disadvantage that the drug substance contained therein is more susceptible to
degradation than when In solid form. Furthermore, solution formulations may be
associated with problems in controlling the size of the droplets which in turn affects the
therapeutic profile. Suspension formulations are tnus generally preferred.
30
To obtain regulatory approval, pharmaceutical aerosol formulation products rnust satisfy
strict specifications. One parameter that must generally be satisfied, and for which a
level is usually specified, is the fine partide mass (FPM). The FPM is a measure of the
amount of drug that has the potential to reach the inner lungs (the small bronchioles and
35 alveoli) based on the proportion of drug particles with a diameter within a certain range,

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usually less than 5 microns. The FPM of an actuation from an MDI is generally
calculated on the basis of the sum of the amount of drug substance deposited on staged
3. 4 and 5 of an Andersen Cascade Impaction stack as determined by standarcf HPLC
analysis, Potential side effects are minimised and a smaller amount of drug substance 13
5 wasted if the FPM constituies as lafge as possible a percentage of the total mass of
drug.
In suspension formulatios, particle size of the emitted dose is generally controlled
during manufacture by the size to which the solid medicament is reduced, usually by
10 micronisation. During storage of some drug suspensions In an HFA, however, various
changes have bean found to take place which have the effect of reducing FPM. A drop
In PPM moans that the therapeulically effective amount of drug available to the patfent is
reduced. That is undesirable and may ultimatety impact on the effectiveness of the
medication. That problem It particularly acute when the dose due to be dispansad is
15 low, which is the case for certain potent drugs such as long acting bete agonists, which
are bronchodilators.
Various mechanisms have been proposed by which the reduction in FPM may be taking
place: particle size growth may occur if the suspended drug has a sufficient solubility in
20 prapellant. a process known as Ostwald Ripening. Alternatively, or additionally, small
particles may have the tendency to aggregate or adhere to parts of the inside of the MDl.
for example the canister or valve. Small particles may also become ebsorbed into of
adsorbed onto rubber components of the valve. As adherence and absorption
processes are more prevalent amongst small particles, those processes lead to a
25 decrease in FPM as a fraction of the administered drug as well as a reduction in the total
drug content (TDC) of the canister available to parent. It has further been found that the
adherence and absorption processes may not only result in loss of available drug, but
may also adversely effect the function of the device, resulting in the valve sticking or
ortflces becoming blocked,
30
It is essential that the prescribed dose of aerosol mediation delivered from the MDl to
the patient consistently meets the specefications claimed by the manufacturer and
complies with the requirements of the FDA and other regulatory authorities. That is,
every dose dispensed from the MDI must be the same within dose tolerances.
35 Therefore It is Important that the formulation be substantially homogenous throughout

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the canistsr and the administered dose at the time of actuation of the metering valve and
that it remains substantially the same even after storage.
Various approaches have been taken to address the problems mentioned above, One
5 approach is the addition of one or more adjuvants to the drug suspension for example
adjuvants selected from alcohols, alkanea, dimethyl other, surfactants (e,g, flurinated or
non-ftuorinated surfacants, carboxylic acids, polyethoxytates. etc.) and even
conventional chiofofiuorocarbon propeilanits in smalI amounts (at levels Intended to Keep
to a minimum potential ozone damage) have been shown to have same effect In
10 mitigaling the FPM problems. Such approaches have been disclosed, for example. In
EP0372777, WO91/04011, WO91/11173. WO91/11495 and WO91/14422-
WO92/00061 discloses non-fluortnalgd surfactants for usa with fluorocarbon propellants.
Fluorineted surfactants may be used to stabilise micronised drug suspensions in
ftuorocarbon propelIants such as 1.1.1.2-tetrafluoroethane (P134a) or 1,1,1.2,3,3,3-
15 heptafluoro-a-pnopane (P227), see for example US4352789, US5126123, US5376358,
US application 09/580008, WO91/11173. WO91/14422, WO92/00062 and WO96/9818,
In WO96/32345. WO96/32151, WO96/32150 and WO96/32099 there are disclosed
aerosol canisters coated with one or more fluorocarbon polymers, optionally in
20 oombination with one or more non-fluorocarbon polymers that reduce the deposition on
the canister walls of drug particles of the pharmacastical alternative propellant aerosol
formulation contained therein.
In WO 03/049786 ft is described that deposition of drug on an elasiomeric seal, and
25 several other problems associated with lubrication, flexibility and sealing, ability of an
elastomeric seal may be overcome by the eddibon of an organotitanium low friction
barrier coating to the seal surface. A pre-treatment step in which the elastomefic seal is
treated as follows is also disclosed therein: the elastomeric substrate is provided in a
bath comprising an alcohol and an alkaline material at a bath temperature eflecflue for
30 treatment, ultrasonic energy is provided to the bath at a treatment effective frequency
and power level for a times sufficient to treat the elastorneric substrate, the treated
elastomeric substrate is rinsed with de-lonised water; and the treated and rinsed
elastomeric substrate is dried, The pre-treatment step to said to permit superior
adhesion and bonding of the organatitaniurn-based coating, in general, however,
35 additional material coating steps add to the expense of manufacturing the final drug

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product and the presence of a coating may cause additional toxicity and safely lasts lo
be necessary.
The present Invention is concerned with an alternative, loss burdensome procedure for
5 treating MDI seals, and methods and articles associated therewith.
Summary of the Invention:
According to embodiments of the present Invention, a method of preparing an
etestomeric gasket material for use in a metered dose Inhaler Includes contracting an
10 elasiomerfc gasket material to be used in a meterad dose inhaler, which gasket material
comprises one or more extractable compounds, with a solution comprising an organic
solvent under conditions sufficient to extract at least a portion of at least one of the one
or more extractable compounds from the elastomeric gasket material. In some
embodiments, at least 10, 15, 20, 25, 30, 35, 40, 45, 50 or more percent of the one or
15 more extractable compounds is extracted fnorn the eteslomertc gasket material.
It has surprisingly boon found that an MDI sealing gasket that has been treated to
accordance with embedments of the present Inveniton has advantageous properties In
use. The drop in FPM after prolonged Storage of drug substance was reduced in an MDI
20 comprising ona or more seating gaskets according to embodiments of the present
invention in comparison with the effects observed after storage in an MDl with untreated
gaskets. It has also been lound that the absolute FPM measurments (before or after
storage) were higher in an MDI comprisirrg one or more treated gaskets according to
embodiments of the present invention than in an MDI with untreated gaskets. Without
25 being bound by any particular theory, it is, at the time of filing., hypothesised that
embodiments of the present Invention provide advantageous stabilisation of tha aerosol
formulation by one or more of the following effects: reducing drug deposition, improving
stability of FPM even after storage, decreasing the Increase in mean mass aerodynamic
diameter (MMAD) during storage, and/or decreasing the GSD (Geometric Standard
30 Deviation)- it is further hypothesised that the one or more effects are caused by removal
from the gasket of fatty adds and/or other teachable material.
Preferably, the MDI sealing gasket is prepared according to embodiments of methods of
the present invention before being utilized in a metering valve. Alternatively, the MDI

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sealing gasket can be prepared according to embodiments of methods of the present
invention whlist being a part of a metering valve.
According to other embodiments of the present Invention, a method of making an
5 elastomerc sealing gasket for use In a metered dose Inhaler Includes contacting an
elastomaric gasket material configured to be used in a metered dose inhaler, which
gasket material comprises one or more extractable compounds, with a solution
comprising an organic solvent under conditions sufficient to extract a portion of at least
one of the one or more extreclable compounds from the elaslomerlc gasket material,
10 and forming a sealing gasket from the elastomeric gasKet material. In some
embodiment, tha contacting of the elastomeric gasket rnaterial occurs after the forming
of the sealing gasket The process of forming the sealing gasket can include various
processes as will be understood by those skilled In the art including cutting or punching
the sealing gasket material to provide the sealing gasket
15
Preferably, the elastomer is provided as a shsel The sheet preferably has a thickness
between 5 and 2 mm. Optionally, the efastomer may be provided in the form of a tube.
According to still other embodiments of the present Invention, a method of making an
20 elastomeric MDI sealing gasket includes forming an MDI gasket from a piece of
elastamer that comprises one or more extractabla compounds and has bear contacted
with a solution comprising an organic solvent under conditions sufficient to extract a
portion of at least one of the one of more extractable compounds from the elastomeric
gasket material.
25
According to yet other embodiments of the present invention, a method of making an
alestomeric MDI seaTrng gasket Includes contecfing a base polymer starting material that
comprises one or more extractable compounds with a solution comprising an organic
solvent under conditions sufficient to extract at least a portion of at feast one of the one
30 or more extractebte compounds from the base polymer starting material to provide a
treated raw potymer material, producing etestomer fram the treated raw polymer
material; and forming an MDI gasket fnxn the elastomer.
Aocording to still other embodiments of the present Invemian, a method of maxing an
35 elstomeric MDI sealing gasket Includes forming an MDI gasket from 3 piece of

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elastomer that has been produced from base polymer starting material that comprises
one or more extracts ble compounds and has been contacted with a solution comprising
an organic solvent under conditions sufficient to extract at least a portion of at least one
of the one or more extradable compounds from the base polymer starling material,
6
The solution can comprise various organic solvents that am capable of extracting one or
more extractable compounds from the elastomeric gasket material and/or the base
polymer starting material. Such solvents include, but are not limited to, lower alcchote
such as mothanol, ethenol, propanol (e.g., isoproparol), butanol (all isomere) or pantanol
10 (all Isomers), or solvents such as Letrahydrafuran, metnylene chloride, acetone and other
lower Ketones (e.g., methyl ethyl ketone- lsopropymethylkelona, etc.), etnere (e.g.. ethyl
eiter, and other aliphatic and aromatic ethers), aromatic solvents (such as benzene,
tduene. etc) and other common solvents. The organic solvent Is preferably a lower
alcohol, Is more preferably ethanol or isopropanol, and is still more preferably ethanol-
15 The lower alcohol (e.g., etharol) is preferably an anhydrous lower alcohol In some
embodiments, the solution consists essentially of the organic solvent, in other
embodiments, the solution consists of the organic solvent In a preferred embodiment,
the solution consists of anhydrous ethanol.
20 In some embodiments, the solution comprises an additive that may improve the solutions
abiIlity to extract one or more axtractable compounds from the elestomeric gasket
material and/or the base polymer starting matarial. For example. the solution cen further
comprise an acid or a base. The add may be selected from various acids including, but
not limited to, hydrochloric acid, acetic acid, sulfuric acid, nitric acid, and phosphoric
25 acid, The acid is preferably used at a concentration such that the solution has a pH of
from a lower limit of 2.0, 2.1. 2.2, 2.3, 2.4, 2.5, 2.6. 2.7, 2.6, 2,9, 3,0. 3.1, 3.2, 3.3, 3.4,
3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1. 4.2, 4.3, 4.4. 4.5.4.6, 4.7. 4.8. 4.9, 5.0, 5.1. 5.2. 5.3. 5.4,
5.5, 5.6, 5.7, 5.8, 5,9, or 6.0 to an upper Iimit of 2.1, 2.2, 2.3, 2.4, 2.5. 2.6. 2,7, 2.8, 2.9,
3.0, 3.1, 3,2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9. 4.0,4.1, 4.2, 4.3,4.4, 4.5, 4.6, 4,7, 4.8, 4.9,
30 5.0, 5.1, 5.2, 5.3, 5.4, 5.5. 5.6. 5.7. 5.8. 5 9, 6.0, 6.1. 6.2. 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, or
6.9. The base may be selected from various bases Including but not limited to. alkali
metal hydroxidas such as sodium hydroxide. The base Is preferably used at a
concentration such that the solution has a pH of from a lower limit of 7.1, 7.2, 7.3, 7.4,
7.5. 7,6, 7.7, 7.8, 7.9. 8,0, 8.1, 8.2, 8.3, 8.4. 8.5, 8.6, 8.7, 8.8, 8.9, 9.0. 9.1,9.2, 9.3, 9.4.
35 9.5, 9.6. 9.7, 9.8. 9,9, 10.0. 10,1, 10,2. 10.3. 10.4, 10.5. 10.6, 10.7, 10.8, 10.9, 11.0.

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11.1, 11.2, 11.3, 11.4, 11.5, 11.6. 11.7, 11.8, or 11.9 to an upper limit of 8.1, 8.2. 8.3,
8.4. 8.5, 8.6. 8,7, 8.8, 8.9, 9.0. 9.1,.9.2. 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10,2,
10.3, 10.4, 10.5, 10.6,10.7, 10.8, 10.9, 11.0, 11.1, 11.2. 11.3. 11.4, 11.5, 11.6, 11.7.
11.8, 11.9, 12.0, 12.1,12.2, 12.3, 12.4,12.5. 12.6,12.7,12.8,12.9. or 13.0.
5
Preferably, the contacting of the etaslomeric gasket material or {tie bass polymer starting
material with the solution in methods according to embodiments of the present Invention
is carried out at a temperature of from 20oC to the boiling point of the solution. More
preferably, the contacting process is carried out at a temperature of from 40°C to the
10 boiling point. SIM more preferably, the contacting process is carried out at a temperature
of from 60oC to boiling point. Even more preferably, the contacting process takes place
under reflux. Trie present inventors have found that the amount of various extractable
compounds removed from the elastornartc gasket matiarial over a given period of tims Is
temparature dependent, with higher temperatures generally resulting in a large amount
15 of axtractable compounds removed.
In some ambodimenls, the conlacting proecess to carried out for 15 minutes or more (e.g.,
from 15 minutes to 48 hours). Preferably. the contacting process is carried out for fram 1
to 12 hours, more preferably from 2 to 10 hours. still more preferably from 4 to 8 Hours,
20 for example approximately 6 hours.
For a particular elastnmeric gasket material treated by processes according to
embodiments of the present invention to be useful as a seeling gasKet in an MDI, the
contacting process parametert of time, temperature, and solvent should be selected to
25 balance the desire of stabllising the aerosol fofmolation by removing one or more
extractabte compounds from the elastomeric gasket material with the need for the
elasiomeric gasket material to retain its physical properties so that it can function as a
sealing gasket for the MDI For example, when the elastormetic gasket material is EPDM
and the solution is ethanol, the contacting process can be earned out at form 60°C to the
30 boiling point of ethand for 3 period of 12 to 30 hours to provide a seafing gasket that will
aid in stabilising the aerosol forrnulation while retaining its physical properties as a
sealing gasket for an MDl. An elastoameric gasket materials ability to retain its physical
properties as a sealing gasket for an MDI can be determined by various methods as will
be understood by those skilled in the art such as placing the, treatad gasket into an MDI,
35 filling the MDI with HFA propellant (alone or in combination with a medicament), and

WO 2005/016410 PCT/US2004/026252
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measuring the leak rate of the propellent and/or tha moisture Ingress Into the MDI. Leak
rate and moisture ingrass can be determined by methods known to those skilled In the
art. One skilled in the art will be able to use the disclosure provided herein to readily
determine the appropriate process parameters for a given elastomeric gasket material
5 anti a given aerosol pharmaceutical formulation,
The collecting process according to embodiments of tha present Invention can be
performed as a batch process of a continuous process as will be understood by those
skilled in the art, When the contacting process is performed as a batch process, the
methods according to the present Invention may include more than one contacting
10 process (e.g., 2, 3, 4. 5, 6 or more contacting processes) wherein the same elastomeric
material is contacted more than once. A continuous contacting process is preferred.
Equipment for use In batch or continuous contacting processes Is known to those skilled
In the art.
15 In embodimente seconding la the prasent invention methods of preparing a seating,
gasket that includes an elaslameric gasket material comprises contacting the sealing
gasket, which oomprises one or more extractable compounds, with a solution comprising
an organic solvent under conditions sufficient to extract at least a portion of at least one
of the one or more extractable compounds from the sealing gesket. and agitating the
20 sealing gasket. The agitallon process can be perfomed concurrently with the contacting
process or sequentially with the contacting process, in some embodiments, elastomeric
gasket material in the form of sealing gaskets is placed into a column and the solution
comprising an organic solvent is flowed through the column. Alter a perid of time, such
as 2, 3, 4, 5, or 6 hours, the elastomeric sealing gaskets are removed from the colurnn
25 and agitated for a period of time, such as 5, 10, 15, or 20 to 30, 40, 50, or 60 minutes.
The agitation can be provided by various means as with be understood by those in the art
such as, but not limited to placing the sealing gaskets in an explosion proof dryer. The
contacting process and agitation process may be repealed 2, 3, 4, 5, 6, 7, 8 or more
times.
30
The methods according to the present invention can Include the process of distilling the
soluetion after it has contracted the elastomaric gaskst material of the base palymer
starting material and utilizing the distilled solution to be-contact the material (a,g., in the
same or a subsequent batch contacting process of as part of the continuous contacting
35 process). When the material includes an extractable material having a vapor pressure

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that is higher than the vapor pressure of the solution (or, in some embodiments, of the
organic solvent In the solution), it is prefarable not to distill and re-use the solution, but
Instead to use fresh solution (i.e, solution that has not been previously used bo contact
an elastomeric gasket material or a base polymer starting material) for the contacting
5 process(es).
The contracting process according to embodiments of the present Invention can be
performed in an oxygen-containing atmosphere (e.g., air) or in an inert atmosphara. The
Inert atmosphere can be provided by various means such as an inert gas or by
10 performing the contacting process as part of a sealed, continuous process.
The elastomeric gasket material may be one comprising low density polyelhyiene,
chlorobulyl or acrylorrftrfle butadiene rubber, butyl rubber, a polymer of ethylene
propyiene dfene monomer (EPDM), neoprene or chloroprene. The elastomeric rnaterial
15 may be carbon-black or mineral filled. Preferably the elastomeric gasket material is one
made from an acrylonttrlte butadiene potymer (also known as an acrylonitrile butadiene
rubber) or a polymer of ethylene propylene diane monomer (EPDM). More prelerably
the material is an acryIontrille butadiene polymer.

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Extraetable compounds according to embodiments of the present Invention Include
various compounds typically found In alastomeric gasket materials that are capable of
being extracted from the materials using an organic solvent. Such compounds include,
but are not limited to, fatty acids, antioxidaiants, light stabillizing compounds, rubber
5 synthesis byproducts, and other rubber extractebles. The extractable compounds are
preferably nonylphenol lsomers. 2.2'-memytenebis(6-terbutyl-4-methylphenol),
2.2,4.5.6,-pentemelhythept3-ene. 3-oxybisepropantfrile,cleic acid. palmitic acid, elaidlc
acid and stearic acid, and are more prefarably 2t2-methyenebis (6-terbutyl-4)-
methylphanol), 2.2,4.6,-pentamethylhapt-3-ene. 3-oxybispropgnitrits. and oleic add. In
10 some embodiments the extractable compounds include this (2,4-dI -tert-
butylphenyl)phosphate. this (2.4-di-tert-butyphenyl)phosphate, 3,5-di-tert-butytphenol,
2.4-dI-tert-butylphenol, and/or 4-methyl-2.8-di tert-butylpbenol in addition to ono or more
of tne foregoing extractable compounds. In other embodiments, the extractable
compounds include eicosanol, docosano, dodecanol, or other telly alcohols In addition
15 to one or more of the foregoing extrseteble compounds. In some embodiments
according to the present invention the extractable compounds include one or more
compounds having a vapor pnessure that is greater than 45 torr (6,000 Pa), such as
2.2,4.6.6-pentamethyltept-3-ene, and 3-oxybispropanitrile.
20 In some embedments, tne contacting process is the last treatment process that
significantly affects the properties of the elestomeric gasket material. Further optional
steps may include rising the treated elastomeric gasket material with a neutrallisng
solution (which is preferred when the solution includes a pH modifier), rising the treated
elastomeric gasket material with water (for example disttlled or de-lonised water), or
25 rising the treated elastomeric gasket material with a rising solution comprising an
organic solvent such as those described above with respect to the contacting process,
and drying the rised elastormeric gasket material (e.g., by exposing the material to heat
in for example, a drying oven). The organic solvent in the rising solution may be the
same as or different from the organic solvent Iin the contacting solution. Preferably, the
30 organic solvent in the rinsing solution and the contacting sofuton ana the same, in an
embodiment of the present invention, the cotracting solution consists essenitially of an
organic solvent as described above and the preparation or treatment method does not
Include a rinsing process. In a preferred embodiment of the present invention, the
contracting solution consists essentially of an organic solvent as described above and the
35 preparation or trealment method Includes a rinsing process that comprises rinsing the

WO 2005/016410 PCT/US2004/026252
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treated elastomeric gasket material with a rinsing solution comprising an organic solvent
In such methods, the drying process may be performed by exposing the elastomeric
gasket material to a vacuum, such as a vacuum of fees than 1,2. 3, 4, or 5 mm Hg. This
vacuum drying process may be more efficient (e.g., energy and/or time efficient) than the
5 heat drying process that may be needed if a rinse process is utilized.
Other treatment steps may be Included in the overall treatment process. The
elastomeric gasket material may, for example, be washed with detergent and or bleach,
Such a washing process preferably occurs priot to the contracting of the elastomers
10 gasket material with the solution comprising the organs solvenl. It is pretarred that the
elaslomaric gasket material is not coated with an organotitanium coating. It is preferred
that the treatment in acconlanco with the Invention doss not Indude providing ultrasonic
energy to the elastomer.
15 According to embodiments of the present invention, a sealing gasket for use in an
Inhaler is provided which seal has been prepared by a method in accordance with
embodiments of thg pnesent invention or has been made by a method in accordance
with embodiments of the present invention. As used herein, the term "gasket" is used
Interchangeably with Vie terms "seating gasket" or "seal".
20
In some embodiments, the seating gasket for use in a metered dose Inhater Includes a
treated alastornerrc gasket material comprising one or mere extractable compounds,
wherein the level of at least one of the ore or more extractable compounds present in
the treated elastomeric gasket material is at least 5 percent fess than the Eevel of the at
25 least one of the one or more extra enable compounds that woutd be present if the
elastomeric gasket material were untreated. As used herein, the term "treated
elsstomeric gasket material" Includes elastomeric gasket matertai prepared or made
according to embodiments of the present invention. In some embodiments, the level of
at least one of the one or more extractable compounds is at least 10. 15, 20, 25, 30, 35,
30 40. 45. 50 or more percent less man the level of the at least one of the one or more
extractable compounds thet would be present If the elastomeric gasket material were
untreated. The extractable compounds are as described above. In some embodiments,
at least one of the one or more extraclable compounds has a vapor pressure that is
greater than 45 forr (6.000 Pa) as described above.
35

WO 2005/016410 PCT/US2004/026252
13
In some embodiments, a gasket for use In a rnetered dose inhalar comprises an
elastomeric gasket material and between about 0.001 and 1 percent (by weight or the
gasket) of on a of more extractable compounds. The extraetable compounds are as
described above, in some embodiments, the gasket comprises an amount between a
5 lower limit of 0.001. 0.005, 0.01 0.02. 0 .03, 0.04. 0.05. 0.06. 0.07, 0,06, 0.09, 0.1. 0.15,
0.2, 0.25, 0,3, 0.35. 0.4, 0.45. 0.5, 0.55, 0.6, 0..65, 0.7. 0.75, 0.8. 085 or 0,8 and an
upper Iimit of 0.005. 0.01. 0.02, 0.03. 0.04, 0.05. 0.06, 0.07. 0.08, 0.09. 0.1, 0.15, 0.2.
0.25, 03. 0.35. 0.4 0.45. 0.5, 0.55. 0.6, 0.65, 0.7. 0.75, 0,8, 0,85, 0.9, 0.95. 1. 2, 3,4, 5.
6. 7, 8. 9, or 10 percent (by weight of the gasket) of one or more of the extractable
10 compounds. In some embodiments, at least one of the one or more extractable
compounds has a vapor pressure that is greater than 45 torr (6.000 Pa) such as those
described above.
According to some embodiments of the present Invention, a method of manufacturing an
15 MDI comprises providing an MDI sealing gasket that has been treated in accordance
with the Invention, providing the other MDI components and a pharmacautical aerosol
fomulation and assenting the MDI One skilled in the art will understand that the
sealling gaskets according to embodiments of the present Invention can be substituted
for untested gasket is in conventional MDIs.
20
The pharmaceutiacal aerosol fornulation may comprises any suitable medicament, for
exampte an anti-astymatic, for example a branchodllator or an antt-infiammatory,
particularly of sterold lype, having a local therapeutic action in the lungs and/or a
systemic action after absorption Into the blood. The pharmaceutical aerosol formulation
25 may comprise salbutamof perticularly as the sulphate, 3-(4-{(6-(((2R)-2-hydroxy-2-[4-
hydrony-3-(hydroxymethyl)phenynethyl} amino)haxyi]oxybuttyl} benzenesulfonamlda, 3-
(3[7-{{(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymathyl }phenyl]ethyl}-
amino)heptynoxylpropyl) benzeneeulfonamida, 4-((1R)-2-((6-(2-{(2,6-
dichlorobenzyl )oxy]ethoxy)hexy)amino)1 -hydroxyeiaiyl-2-(hydroxymethyl phenol.
30 6.9-difluoro-17-{(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-
1,4-diene-17-carbomfolc add S-fluoromethyl ester, 6,8difluoro-11-hydroxy-16
methyl-17-[(4-methyl 1,3-thiazaole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17-
carbothiolc acid S-fluoromethyl easter. N-(3,5-dichloropyridth-4-yl)-2-[1-(4-fluorobenzyl)-5-
hyroxyindol-3-yl]-2-oxoacelamide, a compound of formula (II) as disclosed in

WO 2005/016410 PCT/US2004/026252
WO01/42193, a compound of formula (I) as disclosed in WO03/042160, or a compound
of formula (I) as disclosed in WO03/042164.
preferably, the pharmaceutical aerosol fornulation comprises salmeterot xinafoate,
5 fluticasone proplonate or a combination of those with each other and/or with one or more
further medicaments.
According to other embodiment of the present, invention, a container comprises a
canister sealed with a metering valve and a sealing gasket, when canister contains a
10 pharmaceutical aerosol formulation comprising a propellant and a medicament, wherein
the sealing gasket is one in accordance witn the present invention. A container
according to embodiments of the present Invention is preferably a sealed container
capable of withstanding the pressure required to maintain the propellent aa a liquid. In
some embodiments, the canister contains a pharmaceutics aerosol formulation
15 comprising a propellant a medicament and between a lower limit of 0.7, 0.6, 0.9, 1.0,
1.1, 1.2, 1.3, 1.4, or 1.5 and an Upper limit of 2.0, 2.1. 2.2, 2.3, 2.4, 2.5. 2.6. 2.7, 2.8, 2.9,
3.0, 3,1, 3.2. 33. 3.4, 3,5, 3.6, 3.7, 3.8, 3 9, 4.0. 4.1. 4.2, 4.3,4.4, 4.5, 4.6, 4.7, 4.8 4.9,
5.0, 5.1, 5.2, 5.3. 5.4. 5.5, 5.6. 5.7, 5.8. 5.9. 6,0. 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6,7, 6.8. 6.9,
or 7.0 pg of palmilic acid after storage at 40°C tor 2, 4, 8. or more weeks, in other
20 embodiments, the canister contains a pharmaceutical aerosol formulation comprising a
propefiant, a medicament and between a lower limit of 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3,
1.4. or 1.5 and an upper limit of 2.0, 2.1. 2.2, 2.3. 2.4, 2.5,2.6, 2.7, 2.8. 2.9. 30, 3.1, 3.2,
3.3, 3.4, 3.5. 3.6, 3.7. 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5. 4.6, 4.7. 4.8, 4.9. 5 0, 5.1, 5.2.
5.3, 5.4, 5.5, 5.6, 5.7, 5.3, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 67, 6.8, 6.9, or 7.0 pg of
25 oleic acid after storage at 40oC for 2. 4. 8, or more weeks. In still other embodiments,
the canister contains a pharmaceutical aerosol fomulation comprising a propelleant, a
medicament and between a lower limit of 0.0, 0.1, or 0.2 and an upper limit of 0.2, 0.3, or
0-4 pg of elaidic acid after storage at 40°C for 2. 4. 8, or more weeks. In some
embodiments, the canister contains a pharmaceutical aerosol formulation comprising a
30 propelIant. a medicament and between a lower limit of 0.0, 0.1. 0.2. 0.3. 0.4, 0.5. 0.6,
0.7. 0.8, 0.9. 1.0. 1.1. 1.2,1.3,1.4, or 1.5 and an upper limit of 2,0,2.1.2.2,2.3, 2.4 2.5.
2.6, 2.7, 2.8. 2.9. 3.0. 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, of 4.0 Hg of stearic adcid
after storage at 40oC for 2. 4. 8. or more weeks According to some embodiments of the
present Invention, the canister contains a pharmaoeutical aerosol formulation comprising
35 a propellent, a medicament, end two or more of palmrtic acid, oleic acid, elasIdic acid and

WO 2005/016410 PCT/US2004/026252
15
stearic add, which fatty acids are present in the formulation in the applicable amount
described above.
Especially preferred is a container with a metering valve comprising a metering chamber
5 defined by walls and an upper and a lower sealing gasket through which passes a valve
stem Optionally, the one or more of the sealing gaskats within the metering valve may
be sealing gaskets In accordance with the present invention.
In some embodiments, a medicament container for use In a rneterad dose inhaler
10 includes a Canister having an open end and a closed end, a metering valve that includes
a valve body, a valve stem, and one of more stem seale in contact with the valve stem,
wham the value body and at least nng of the one or mom stem seals define a metering
chamber, a cap configured to seal the open end of the canister such that the sealed
canister is adapted to contain an aarcsd pharmaceutical composition and a canister
15 seal positioned between ihe open end of Ine canister and the cap, where at least one of
the canister seal and the one or more stem seals comprise a sealing gsskel according to
the. present invention, In some embodiments, the medicament porttainar cortbalms a
pharmaceutical aerosof formulation as described herein, In other embodiments, the
medicament container is empty and has not yet been filled with a pnarmaceuiScal
20 aerosol formulation.
According to other embodiments of the present invention, a process for making a
container configured to contain a pharrraaceuticaf aerosol formulation and provide
metered doses thereof includes coupling a metering valve that comprises one or mare
25 stem seals to a canister to provide the container, wherein at least one of the one or more
stem seals comprises a sealing gasket according to the present invention. The coupling
process preferably indudes coupling the metering valve to the canister utilizing a cap (or
ferule) and canister seal configured to seal the canister such that the canister Is adapted
to contain an aerosol pharmaceutical compositon,
30
Acceding to still other embodiments of the present invention, a mete ring valve suitabte
for metering a drug suspension comprising a meditcament and a propellant Is provided,
which metering valve comprises a valve body, a metering chamber, a valve stem and
one or more sealing gaskets in accordsnos with the present invention. A metering valve
35 according lo embodiments of the invention incorporates a gasket to prevenl leakage of

WO 2005/016410 PCT/US2004/026252
16
prapellant through the vslve. Such a metering valve is preferably designed to deliver a
matered amount of the formulation par actuation.
In some embodiments, the metering valve includes a valve body, a valve stem, and one
5 or more stem seals in contact with the valve stem. at least one of ttve one or more stem
seals comprising a sealing gasket according to the present invention, wherein the valve
body and at least one of the one or more slam seals define a metering chamber.
In other embodiments, a process for making a metering valve Is provided thai includes
10 assembling a valve body, a valve stem, and one or more slam seals to form s metering
valve, wherein the valve body and at least ane of the one or more slam seals define a
metering chamber, and wnerein at least one of the one or more stem seals is a sealing
gasket according to the present Invention.
15 According to yet other embodiments of the present invention, a metered dosa Inhelar
comprises a canister In communication with a metering valve suitable for metering a
drug suspension comprising a rnedicament; and a liquid propellant, wherein the rnetering
valve includes and/or the canister is sealed with a sealing gasket In accordance with the
present invention. Matered dose inhalers are designed to deliver a fixed unit dosage of
20 medicament per actuation or "puff" for example, in the range of 2.5 to 5000 micrognamfl
of medicament per puff, preferably in the range of from 5.0 to 3500 micrograms per puff.
According to some embodiments of the invention, a drug product comprises a canister
containing a drug suspension cornprising a propeflant end a medicament in
25 communrcation with a metering valve suitable for metering e drug suspension
comprising a medicament and a liquid propellant, wheiein the metering valve and/or the
canister are seated with one or more sealing gaskets according to the present invention.
In some embodiments, a drug product includes a canister navlng an open end and a
30 dosed end, a metenng valve that Includes a vefve body, a valve stem, and one or more
stem seals in contact with the valve stem, where the valve body and at least one of the
one or more stem seals define a metering chamber, a cap configured to seal the open
end of the canister such that the sealed canister is adapted to contain an aerosol
pharmaceutical composition, a canister seal postponed between the open end of the
35 canister and the cap, end a valve acluator configured to acluate the metenng valve and

WO 2005/016410 PCT/US2004/026252
17
dispense a metered dose of the pharmaceutical aerosol formulation, where at least one
of the canister seal and the one or more stem seals comprise a scaling gasket according
to the present invention.
5 In other embodiments, a pnpcess for making a drug product includes assembling an
actuator and a canister containing a pharmaceutical aerosol formulation to provide the
drug product, wherein the canister comprises a canister seal and a metering valve
comprising one or more stem seals, wherein one or more of the canister seal and the
one or more stem seals comprise a seeing gasket according to the present invention.
10
According to some embodiments of the present Invention, a package comprises a
metered dose Inhaler to accordance with the present Invention cotained wthin a flexible
wrapper, said wrapper being composed of a material that is substantialy permeasbla to
evacuation of proponent gas and substantially Impermable to Intrusion of atmospheric
15 moisture e.g. as described In USP 6.119,853. Preferably the package will also contain
within it a deslccant material. The desiccant material may be inside the MDl and/or
outside the MDI.
According to embodiments of the present Invention, a method of treating a respiratory
20 disease such as asthma, rhinitis or COPD in a patent comprises use by the patent of a
metered dose inhaler in accordance with the present invention.
In some embodiment, a method of treating and/or preveniing the onset of a raspiratory
disease includes administertng an effective amount of a pnarmaceutfcal aerosol
25 formulation to a person In need of treatment or prophylaxis of the respiratory disease,
wherein the effective amount of the pharmaceutical aerosol formulation is administered
from a metered dose Inhaler that comprises a canister containing the pharmaceutical
aerosol formulation, wherein the canister comprises a canister seal and a metering valve
comprising one or more stem seals, wherein one or more of the canister seal and the
30 one or more stem seals composes a sealing gasket according to the present invention.
Io a further aspect, embodiments of the invention provide a method of prolonging the
shelf-life of a melered dose inhaler draug product comprising assembling the metered
doss inhaler from parts inducing one or more Sealing gaskets in accordance with the
35 present Invention.

WO 2005/016410 PCT/US2004/026252
18
In some embodiments, a method gf prolonging the self-life of a metered close inhaler
drug product comprises assembling an actuator and a canister containing a
pharmacautical aerosol formulation to provide the metered dose Inhaler drug product.
5 wherein the canister comprises a canister seal and a metering valve comprising one or
more stem seals, wherein one or more of the canister seal and the one or more stem
seals comprise a seaffng gastol according to the present Invention.
Some embodimehts of the Invention provide the use of a gasket In accordance with the
10 invention in a method of manufacturing an MDI for providing a dispensed drug aerosol
with higher FPM then an MDI with an untreated seal of gasket. Embodiment of the
Invention provide Ihe use of a gasket fn accordance with embodiments of the Invention in
a method of marmfaduring an MDI for providing a dispensed aerosol with an Improved
FPM storage stability in comparison with an MDI with an untreated sealing gasket
15 Some embodiments of the Invention provide the use of a gasket in accordanca with
embodiments of the invention for increasing the self-Iife of a HFA suspension
formulation In comparison witn a corresponding formulation stored in a MDI with an
untreated gasket.
20 Embodiments of the invention provide a seating gasket comprising an efasttmer
characterised in that said gasket is a washed gasket from which 0.5% by weight or less
such as 0.001 to 0.1% by weight of the gasket has been extracted with solution
comprising an organic solvent.
25 According to other embodiments of the present invention, a container comprises a
sealing gasket according to the present invention wherein said container is sealed with a
mate ring valve and contains a pharmaceutical aerosol formulation comprising a
particulate medicament and a liquefied HFA propelIant, said container characterised in
that the FPM of the participate medicament is maintained within 15% more preferably
30 within 10% and especially within 5% of its original level after 4, 8, or preferably 12 weeks
storage at 40oC and 75% relative humidity. In some embodiments of the present
invention, the particulate medicament comprises salmetrol, or a salt (a.g. xinafoale)
thereof) and flutcasone prapfonste. In embodiments of the present Invention In which
the container is packaged in a flexible wrapper as described above with respect to the
35 packaging of a matenacf dose inhaler, the container is preferably characterised In that the

WO 2005/016410 PCT/US2004/026252
19
FPM of the parttculats medicament is maintained within 15%, more preferably within
10% and, especially wthin 5% of the original level after 4. 8, or preferably 12 weeks
storage at 40°C, or 8, 24, or 52 weeks at room temperature.
5 According to stilt other embodiments of the present invention, a meterad dose Inhaler
comprises a canister having an open end and a closed end a metering velve that
includes a valve body,a valve stem; and one or more stem seels in contact wtlh the
velve stem, where the valve body and at least one of the one or more slam seals define
a metering chamber, a cap configuired to seal the open end of the canister such that the
10 sealed canister is adapted to contain an aerosol pharmacautical composition, a canister
seal positioned between the opert end of the canister and the cap. and a valve actuator
configured to actuate the metering velve and dispense a metered close of the
pharmaceutical aerosol formulation. At least one of the canister seal and the one or
more stem seals composes a sealing gasket according to the present Invention, and the
15 metered dose inhaler exhibits a change in the particle mass (FPM) of less than 1, 5, 10,
15, 20, 30, 40, or 50 percent of the Initial FPM after storage at 40oC and 75 percent
humidity for at least, 4, 8, or 12 weeks.
According to embodiments of the present Invention, a sealing gasket for use in an MDI
20 includes an elastomeric gasket material and between a lower limit of 0-04, 0.05, 0.06,
0.07, 0.08, 0.09, 0.10. 0.11, 0.12, 0.13, or 0.14 and an upper limit of 0.09, 0.10. 0.11,
0.12, 0.13, 0.14. 0.15, 0,16. or 0.17 % oleic acid by weight of the gasket. According to
other embodiments of the present invention, a sealing gasket for use in an MDl Includes
an alastomeric gasket material as described above and between a lower limit of 0.05,
25 0.06, 0.07, 0.08, 0.09, 0.10. 0.11. 0.12, 0.13, 014. or 0.15 and an upper limit of 0.11,
0.12, 0.13. 0.14, 0.15. 0.16, 0.17; 0.18, 0.19, 0.20. 0.21, 0.22, 0.23, 0.24, 0.25, 0.26,
0.27, 0.28. 0.29, 0.30, 0.31, 0,32, 0.33, 0.34 and 0,35 % palmitic grid by weight of the
gasket According to still other embodiments of trie present invention, a sealing gasket
for use in an MDl includes an elastomeric gasket matenal as described above and
30 between a lower limit of 0.03,0.04,0.05,0.06,0.07,0.08,0.09,0.10,0.11,0.12,or 0.13
and an upper limit of 0.08, 0.09, 0.10. 0.11, or 0,12 % elaldic acid by weight of the
gasket. According to yet other embodiments of the present invention, a sealing gasket
for use in an MDl Includes an elastormeric gasket material as described above and
between a lower limit of 0.06, 0.07, 0.05, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16,
35 0.17,0.18. 0.19, 0.20 and an upper limit of 0.12, 0.13, 0.14, 0.15, 0,16, 0.17, 0.18,0.19,

WO 2005/016410 PCT/US2004/026252
20
0.20, 0.21. 0.22, 0.23. 0.24. 0.25. 0.26. 0.27, 0.28, 0.29, 0.30. 0.31, 0.32, 0.33, 0.34, or
0,35 % stearic add by weight of the gasket According to still other embodiments of the
present invention, a sealing gasket for usa in an MDI includes an etagiomeric gasket
material as described above and a mixture of two or more of oleic acid, palmitic add,
5 olsldic acid, and slearic acid, which acids are present in the applicable foregoing ranges.
In a preferred embodiment, the sealing gasket for use in an MDI Includes EPDM and 2,
3, or 4 of olelc acid, palmitic acid, elaidic acid, and alsaric acid, which acids are present
In the applicable foregoing ranges. While not wishing to be bound by theory, It is
believed at this time that sealing gaskets for use in an MDI that have bean subjected to
10 an extraction process that results in the removal of one or more of the fatty acids
described above to such an extent that the fatty acids are present In amounts below the
foregoing lower limits may also result in Ihe removal of other compounds, such as
anfloxidantg, that act to stabilize the sealling gasket material As a result of the removal
of these other compounds, the sealing gaskets may expertence a decrease in physical
15 properties that may make the sealing gasket unsuitable for use in an MDI, It is also
believed that sealing gaskets for use in an MDI that Include more than the foregoing
amounts of fatty acids may result in a decreased stabilitiy of the aerosol pharmaceutical
formulation over time.
20 The Invention further provides the use of pure ethanol In a gasket extraction process for
providing a seal or a gasket which, when incorporated into an MDI provides an MDI
Which has s dispensed drug aerosol with higher FPM than an MDI with an untreated
sealing gasket. There is also provided the use of pure ethanol In a seal or gasket
extraction process for providing a seal of a gasket which, when incorporated into an MDI
25 provides an MDI which has a dispensed drug aerosol with an Improved FPM storage
stability in comperison with an MDI with an untreated sealing gasket.
The present invention finds particular application In MDls for use with therapeutic agents
that are antiasthmatics, Including bronchodliators and XXX, particularly of
30 steroid type, having a local therapeutic action In the lungs and/or a systemic therapeutic
action after absorption in the blood. 4-Hydroxy--[{(6-(4-phenylbutoxy)hexyl]
amlinomethyl]-1,3-benzene dimethanol was described as one of a wide range of
bronchodilators In GB-A-2140800. Thet com pound is also known by the ganeric name
of salmeterol, the xinafoate salt of which has become widely Known as a highly affective
35 treatment of inflammatory diseases, such 35 asthma and chronic obstructive pulmonary

WO 2005/016410 PCT/US2004/026252
21
disease (COPD). Fluticasone propolnate is one of a range of topical anti-Inflammatory
corticostaroids with minimal liability to undesired systemic side effects which is described
in GB-A-2088877, and is systematically named S-fluoromothyl 6, 9-difluoro-11-
hydroxy-16- methyl-17-propeonyloxy-3-oxoandiosta-1.4-diene-17-carbothioate.
5
Preferably, the medicament is a combination of salmeterol xinsfoete and flulfcasane
pfofuonsto. Prateiably, no further medircament substances are present.
However, further to the medicaments already disciosed in the specification, MDIs of the
10 present Invention are atso suitable for diEpensing any medicaments which may be
administered In aerosol fomiutetons and useful in inhalation therapy e.g.; anti-allergics,
e.g. cromoglycate (e.g. as the sodium salt), kelotifon or nedocromll (e.g. as sodium salt);
anti-lnflammatory steroids, e.g. beclomothasone (e.g. as diproplanate), flulicasone (e.g.
as propionate), flunisollde, budesonlde, rofleponide, momelasone (e.g as furoate),
15 ciclesonide, XXX acetonide; antichollnorglcs, e.g. ipratroplum (e.g. as bromide),
tiotreplum, atropine or oiltroplum and salts thereof. It will be clear to a person skilled in
the art that, where appropriate, the medicaments may be used in the form of salts, (e.g.
as alkali matal or amine salts or as add addition salts) or as asters (e.g. lower alkyI
eslera) or as solvates (e.g- hydrates) to optimise the activity and/or stability of the
20 medicament and/or to minimise the solubility of the medicament In the propeIIant
Medicament may be used in the form of racemate or in the form of a pure isomer e.g, R-
salmeterol or S-salmeterol, Formulations combining one or mone the disclosed
medicaments are also within the remit of this disclosure.
25 The container, MDI and valve described heretn are particularly useful for medicaments
which present similar formulation difficulties to those described above e.g. because of
their susceptibility to water ingress, drug deposition, and other drug losses, Genarally,
those difficulties are especially severs for potent madicaments which are administered at
low those (i.e., less than about 1 mg per dose).
30
The particle sizs of the particulate (e.g. micronised) medicament should be such as to
permit inhalation of substancially all of the medicament into the lungs uport administration
of the aerosol formulation and wili thus be less than 100 microns, desirably less than 20
microne, and preferably in the tange 1-10 microns, e.g.1-5 microns.
35

WO 2005/016410 PCT/US2004/026252
22
The concentration of medicament In the formulation will generally be 0.01-10% such as
0.01-2%, particularly 0.01-1%, especially 0.03-0.25% w/w. When slametercl xinafoate is
the only medicament. its concentration in the formulation will generaily be 0.03-0.15%
w/w
5
The formulations according to the present Invention may optionally contain one or more
furthar ingredients conventionally used In the art of pharmaceutical aerosol formuistion.
Such optional ingredients include, but am not limited to, taste masking agents, sugars,
buffers, antioxwidants, water and chemical stabilisers.
10
It is described that the formulations of the Invention contain no components which may
provoke the degradation of stratospneric ozone, In particular it is desirable that the
formulations are substantially free of chlorofiuorocarbons such as CCI3F. CCI2F2 and
CF3CCI3. If desired the propellant may additionally contain a volatile adjuvant such as a
15 saturated hydrocarbon, for example, propane, n-butane. isobutone, pentane and
isopentane or a dialkyl other, for example, dimethyl ether, in general, up to 50% w/w of
the propelant may comprise a volatile hydrocarbon, for example 1 to 30% w/w.
However, formulations which are substantially frea of volatile adjuvants are preferred, in
certain cases, it may be desirable to include appropriate amounts or water, which can be
20 advantageous In modifyng the dialectric properties of the propellant.
Polar adjuvants which may, if desired, be incorporated into the formulations according to
the present invention include, for example, C2aliphatic alcohols and potyols such as
etnanol, isopropanol and propytene glycol and mixtures thereof Preferably, ethanol will
25 be employed in general onty small quantitiies (e.g, 0.05 to 3.0% w/w) of polar adjuvants
are required and the use of quantities in excess of 5% w/w may disadvantageously tend
to dissolve the medicament. Formulations praferably contain less than 1% w/w, for
example, about 0.1% w/w of poler adjuvant. Polarity may be determined, far example,
by the method described in European Patent Application Publication No. 0327777, in
30 some embodiments. It is desirable that the formualations of the invention are substantially
free of polar adjuvants, "Substantially free" will generally be understood to mean
containing less than 0.01% especialy less than 0.0001% based on weight of formulation.
Preferably a single propellant is employed, for example, 1,1,1,2-telrafluorthane (HFA
35 134 a) or 1,1,1.2.3,3.3-heptafluoro-n-propane (HFA 227), especially 1.1,1,2-

WO 2005/016410 PCT/US2004/026252
23
tetrafluoroethane, It is desirable that the formulations of the invention ocntain no
components which may provoke the degradation of stratospheric ozone. In particular It
Is desirable that the Formulations are substantially free of chlorofluorocarbons such as
CCI3F, CCI2F2 and CF3CCI3.
5
Whilst a suitable surfactant may be employed preferably the formulations or the
invention are substantially free of surfactant. "Substantially free" will generally be
understood to mean confining less than 0,01% w/w especially less than 0.0001%
based on weight of forrnulation.
10
The formulations for use in the Invention may be prepared by dispersal of the
medicament In the selected propellent in an appropriate container, for example, with the
aid of sonicatfon or a high-shear mixer. The process Is desirably carried out under
controlled humidity conditions.
15
The term "sealing gasket' when used in this specification will be understood to mean a
neck/canister gasket and/or lower sealing gasket and/or upper sealing gasket The latter
two gaskets being those associated with the metering chamber. According to some
embodiment, in canisters according to the present Invention the neck/canister gasket is
20 the only gasket prepared according to the present Invention.
The term "metered dose Inhaler or "MDI" means a unit comprising a canister, a secured
cap covering the canister and a formulation rnetering valve situated in the cap. A fully
assembled MDI includes a suitable channelling device. Suitable channelling devices
25 comprise, for example. a varve actuator and a cylindrical or cone-like passage through
which mad teamen t may be delivared from the filled canister via the metering valve to
the nose or mouth of a patient e.g. a mouthpleca actuator,
MDI canisters generally comprise a container capable of withstanding the vapour
30 pressure of the propellant used such as a plastic or plastics-coated glass bottle or
preferably a metal canister, for example, of aluminium or an sfloy thereof which may
optionaly be anodised, lacquer-coated and/or plastic-coated (e.g. incorporated herein by
reference WO96/32150 wherein part or all of the internal surfaces of the can are coated
with one or more fluorocarbon polymers optionally in combination with one or more non-
35 fluorocarban polymera).

WO 2005/016410 PCT/US2004/026252
24
The cap may be secured onto the canister via welding such as ultrasonic warding or
laser welding, screw fitting or crimping. MDIs taught herein may be prepared by
methods of the art (e.g.. see Byron, above and WO/96/32150), Preferably the canister is
5 fitted with a cap assembly, wherein a formulation metering valve is situated in the cap.
and said cap is crimped in place.
The metering chamber (especially when composed of a plastics material) may be
surface treated so as to presant a substantially fluoridated surface to the fomulation.
10 Alternatively the metering chamber (especially when composed of a plastics material)
may be surface treated with a siloxane such as dimethyl silloxane. As a further
alternative, the metering chamber presents a substantialy fluorinated surface to the
formulation by virtue of being composed of a suitable substantially fluorinated material,
Suitable metering chambers and surface treatments for metering chambers are
16 described In WO 02/51483 at page 7, line 15 to page 11. line 18.
According to some embodiments of the present invention, a container as described
above Includes a valve stem that presents a substantially fluoronated surface to the
formulation. Suitable valve stems and surface treatment for valve stems are described
20 in WO 02/51483 at page 11, line 21 to page 12, line 3.
Preferably, containers according to embodiments of the invention comprise a canister
composed of aluminium. Suitable surface treatments for a canister are described in WO
02/51483 at page 12, lines 10 to 16.
25
Conventional bulk manufacturing methods and machinery well known to those skilled in
the art of pharmaceutical aeposol manufacture may be employed for ihe preparation of
large scale batches for the commercial production of filled canisters. Thus, for example,
in one bulk manufaturing method a metering valve is crimped onto an aluminium can to
30 form an empty canister, The particulates medicament to added to a charge vessal and
liquefied propellant is pressure filled through the charge vessel into a manufacturing
vessel, together with liquefied propellant containing the surfactant. Tne drug suspension
is mixed before recirculation to a filling machine and an aliquot of the drug suspension is
then filled througn the metering valve into the canister.
35

WO 2005/016410 PCT/US2004/026252
25
In an alternative process, an aliquot of the liquefied formulation is added to an open
canister under conditions which are sufficiently cold such that ihe formulation does not
vaporise, and then 3 metering valve Crimped onto the canister.
5 Typically, In batches prepared for pharmacaetitical use, each filled canister is check-
weighed. coded with a batch number end packed into a tray for storage before release
testing
Each fitted canister is conventently fated into a suitable channelling device, prior to use,
10 to form a meterad dose inhaler system for administration of the medicament into the
lungs or nasal cavity or a patient.
The chemical and physical stability and the phamrtacaulical acceptability of the aerosol
formulations seconding to the invention may be determined by techniques well Known to
15 those skilled in the art. Thus the chemical stability of the components may be
determined by HPLC assay, for example, after prolonged storage of the product,
Physical stability data may be gained from other conventional analytical techniques such
as by leak testing, by valve delivery assay (average shot weights per actuation), by dose
reproductibtlity assay (active Ingredient per actuation) and spray distributor analysis.
20
The Suspension stability of the aerosol formulation according to the invention may be
measured by conventional techniques, for example, by measuring figculation size
distribution using a back light scattering instrument or by measuring aerodynamic
particle size distribution by cascade Impaction, next generation Impactor, multistage
25 liquid Impinger. or by the "twin impinger" analytical process. As used herein reference to
the "twin Impinger" assay rneans Determination of the deposition of the emitted dose in
pressurised inhafations using spparstus A" as denned in British Pharmacopaeta 1986^
pages A204-207 Appendix XVII C. Such techniques enable the "respirable fraction" of
the aerssol formulations to be calcufated. One method used to calculate the "respireble
30 fraction" is by reference to line particle friction' which is the amount of active ingredtent
collected in the lower impirgement chamber per actuation expressed as a percentage of
the total amount of active ingredient delivered per actuation using the twin impinger
method described above. As discusaed above, the absolute "fine particte mass" (FPM)
is an important panameter in relation to the present invention. The FPM may be
35 assessed using the same apparatus as the fine particle fraction.

WO 2005/016410 PCT/US2004/026252
26
Administration of medicament in a container or MDI in accordance with the Invention
may be Indicated for the treatment of mild, moderate, severe acute or chronic symptoms
or for prophylactic treatment. It will be appreciated that the precise dose administered
5 will depend on the ape and condition of the patient, the particular particular medicament
used and the frequency of administration and will ultimetely be at the discretion or the
attendant physician. When combinations of medicaments are employed the dose of
each component of the combination will In general be that employed for each component
when used alone. Typically, administration may be one or more times, for example,
10 from 1 to 8 times per day. giving for example 1. 2, 3 or 4 puffs each time.
Suitable dally doses, may be, for example in the range 50 to 200 micrograms of
salmetarol or 50 to 2000 micnograms of fiutlcasone propfonsts, depending on the
severity of the disease. Thus, for exemple, each valve acluation may delivar 26
15 micrograrns of salmelerol or 25, 50. 125 or 250 mlcrograme of fluticasona proplonate.
Doses far Seratid, which is a combination of salmetaral (e,g, as xinafoata salt) and
fluticasone proplonate, will usually be those given for the corresponding Individual
component drugs. Typically each filled canister for use in a metered dose inhaler
contains 60,100, 120, 160 or 240 metered doses or puffs of medicament.
20
An appropiate dosing regine for other medicamants will be known or readilly available
to persons skilled in the art.
Excapt as otherwise noted, all references including patent and published patent
25 applications referred to hereto are Incorporated henain by reference in their entireties.
The Invention will now be described further with reference the following Examples which
serve to illustrafe the invefition but is not Intended to be limitng.
30 Figure 1 shows part of a cross-section view of the valve end of en MDI container with the
valve pointing downward. The main sealing gasket is represented by 3 the can/heck
seal; The figure also shows the kwer metering chamber seal 9 and the upper metering
chamber seal 12.
Figure 2 shows part of a cross-section view of the valve end of an alternative MDI
35 container with the valve pointing downward.

WO 2005/016410 PCT/US2004/026252
27
Referring to Figure 1, the valve body 1 is formed at its lower part with a metering
chamber 4, and its upper part with a sampling chamber 5 which also acts as a housing
for a return spring 6. The metering chamber is constnjcted from a fluortnaied polymer at
5 least in part and/or a fluoridated coating. The words "upper' and "lower" am used tor the
container wnen it is in a use orientation with the neck of the container and vatva at the
lower end of the container which corresponds to the orientation of the valve as shown in
Figure 1. Inside tho valve body 1 Is disposed a valve stem 7, a part 8 of which extends
outside the valve through lower stem seal 9 and ferrule 2. The stem part a Is formed
10 with an Inner axial or longitudinal canal 10 opening at the outer end of The stem and in
common cation with a radial passage 11.
The upper portion of slam 7 has a diameter such that it can slide through an opening In
an upper stem seal 12 and will engage the periphery of that opening sufficiently to
15 provide a seal. Upper stem seal 12 is held in position against a step 13 formed in the
valve body 1 bdtwaen the said lower and upper parts by a sleeve 14 which defines the
metering chamber 4 between lower stem seal 9 and upper stem seal 12. The valve
stem 7 has a pssasge 15 which, when the stem is in the Inoperative position shown,
provides a communication between itie metering chamber 4 and sampling chamber 5,
20 which Itself communicates with the Interior of the container via orifice 20 formed in the
side of the valve body 1,
Valve stem 7 is biased downwardly to Ihe inoperative position by return spring 6 and is
provided with a shoulder 17 which abuts sgalnst lower siem seal 9. In the inoperative
25 position as shown in Figure 1 shoulder 17 abuts against tower stem seal 9 and radial
passage 11 opens below lower stem seal 9 so that the metering chamber 4 te isolated
from canal 10 and suspension inside cannot escape.
A ring 18 having a "U" shaped cross section extending in a radial directior is disposed
30 around the valve body below orhice 26 so as to form a trough 19 arouncf the valve body
As seen In Figure 1 the rtng is farmed as a separate component having an Inner annular
contacting, rim of a diameter suitable in provide a fiction fit over trig upper part of valve
body 1, the ring seating against step 13 betow the orifice 26. However, the ring 18 may
alternatively be formed as an integrally moulted part of valve body 1.
35

WO 2005/016410 PCT/US2004/026252
28
To use the device the container is first shaken to homogenise the suspension within the
container. Trie user then depresses the valve stem 7 against the force of the spring 6.
When the valve stem is depressed both ends of the passage 15 come to lle on the side
of upper slem seal 12 remote from the metering chamber 4. Thus a dose Is metered
6 within the fluorinated metering chamber. Container depression of the valve stem will
move the radial passage 11 into the metering chamber 4 while Ihe upper atom seat 12
seals against the valve atam body. Thus, tha metered dose can exit through the radial
passage 11 and the outfet canal 10.
10 Releasing the valve stem causes it to return to the illustrated positton under the force of
the spring 6. The passage 15 then once again provides communication between the
metering chamber 4 and sampling chamber 6. Acconrtngly. at this stage liqued passes
under pressure from the the container through orifica 26, througri the passage 15 ertd
thanoe into the moisting chamber 4 to filed.
15
Figure 2 shows a view of a different valve in which the gasket seal end lower and upper
stem seals are labelled 3, 9 and 12 respectively.
Examples
20
Examplge1
25 The valves used In the following experiments were DF60 valves from Valois (France).
The cap sealing gasket (acrylonitrile butadiene polymer) was removed from the valve for
treatment.
Experiment A
30 A 250ml round bottomed flask was charged with 120 ml ethanot (anhydrousUSP grade),
40 gaskets were planed in the solution and a condenser was attached to the flask. The
solution was then heated under reflux for 1-5 hours with the exclusion of air The hot
ethanol was decanted and the gaskets were rs-axtracted using the same procedure. The
gesket was then washed one time with 50 ml ethanol (anhydrous USP grade), removed
35 from the round bottomed flash and dried in a vaeuo over CaSO4.

WO 2005/016410 PCT/US2004/026252
29
The gasket was then re-attached to the valve.
Experiment B
5 Tha treatment described above in respect of Experiment A was repeated using sn
elhanol-hydrooWoric aefd solution with an HCI concentration of 0.01M HCI.
Experiment C
The treatment described above In respect of Experiment A was repeated using an
10 ethanol-eoetlc acid solution with on AcOH concentration or 5% (v/v).
Experiment D
The treatment described above in respect of Experiment B was repeated, Instead of
rinsing five gasket with athanol, the gaskets were immersed in de-lonized water and
15 sodium hydroxide was added until the solution and gaskets were neutmlized. The
gaskets were dried over phosphorus pentoxide in vacuum.
Experiment E
The treatment describe above in respect of Experiment C was respected. Instead of
20 ringing the gaskets with ethanol. the gaskets were immersed in de-tonized water and
sodioum hydroxide was added until the solution and gaskets were neutralized. The
gaskets were dried dried over phosphorus pentoxide In vacuum.
Experiment F
25 Neck gaskets were placed in a Duran bottle and immersed in ethanol sufficient for total
coverage. The botlles were then placed in an Ultrasonic batch (Decon FS2008) and
sonicated on the high setting for 59 minutes. The ethanol was decanted off than
replaced with fresh elhanol and allowed to stand for 2 hours with occasional swfriling.
The ethanol was again decanted off and the components then rinsed twice with fresh
30 ethanol ard then the components dried. The treated gaskets were then Inserted into the
valves.
Comparative Experiment G
The velve was left unseated.
35

WO 2005/016410 PCT/US2004/026252
30
2. Sample Preparation
The MDls for which date ara presented in Tables 1 and 2 were prepared in aluminium
carUsters coated with g PTFE/PES polymer blend as described In WO96/32150 and
sealed with a valve prepared as described In 1 above. The aluminium canisters
5 cantetaed 3 pharmaceutical aerosofl formulation comprising 4-2mg of salmelerol In the
form of its xinafoale salt, 3.4 mg of fluticasore pnoplonte and 12a of HFA 134a.
3. Sample storogo conditions
Each dovice was stored at 40°C and 75% relative humidity unless otherwise stalad.
10 FPM was determined shortly after praparabon finltar) and afar the passage of the
Indicated time period.
4. Method for Determining FPM
Each MDl canister tested was put into a clean actuator and primed by filling 4 shots,
15 Then 10 snois ware fired into an Anderser Cascade Impector which was quantitatively
washed and the amount drug deposited tnereon wea quarrtified by HPLC analysis of
the washings From this the dose delivered (the sum of the amount of drug deposited on
the cascade impactor) and the FPM (the sum of drug depoaftecf on stages 3, 4 and 5)
data were calculated.
20
5. Results of FPM studies with gaskets from section 1 above
Table 1 (FPM denotes FP on stages 3.4.5. in microgrant)

25 The data in Table 1 show that the inttial fPM and the FPM after storage are both higher
in an MDl with a gasket treated in accordance with the invetion than In the control MDI

WO 2005/016410 PCT/US2004/026252
31
which utilized urttraated gaskets. The data also show that FPM is more stable to an MDI
with that inductee a gasket treated in accordence with the Invention that In the control
MDI.
5 Table2(FPM denotes FP on stages 3,4,5, in mterograms)

The data in Table 2 show that the FPM is more stable in an MDI with a gasket treated in
accordant with the invention than In the control MDl.
10 Example 2
1. Treatment of valve gaskets
The valvee used in the following experiments were DF60 valves from Valots (Franco),
15 The cap sealling gasket (acrylonthile butadiene polymer) was removed from the valve for
treatment
Treated Valves
20 The gaskets were extracted at 60°C with ethanol In a flow-through Column, The ethanol
was distilled during the process to remove extractable materials, then recyded. Neck
gaskets were extracted for 15-24 hours and the stem gasKets were extracted far 4-8
hours. All data are combined in the results.
25 The gaskets were thenra-attached to tha valve.
Control
The valve was left untreated.
30 2. Sample Preparation

WO 2005/016410 PCT/US2004/026252
32
The MDls for which data are presented in Figure 1 ware prepared In aluminium canisters
coated with a PTFE/PES polymer blend as described in WO96/32150 and seated with a
valve prepared as described in 1 above. The slumtoium cantetere contelrrad a
pharmaceutical aerosol formulation comprising 4.2mg of salmeterol in the form of its
5 xinefoate sail 8.4g of fluticasone propionate and 12g of HFA 134a.
3 Sample storage conditions
Each device was stored at 40oC and 75% relative humidity unless otherwise stated
FPM was determined shortly after preparation ('intial') and after the passage of the
10 indicated time period.
4. Method for determining FPM
Each MDI canfalaf tested was put Inio a clean actuator and primed by firing 4 shots.
Then 10 shots were firtd into an Andersen Cascade impactor which was quantitavely
15 washed and the amount of drug doposited thereon was quantified by HPLC analysis of
the washings. From this the dose delivered (the sum of the amount of drug deposited art
the cascade Impact or) and the FPM (the Burn of drug deposited on stages 3, 4 and 5)
data were calculated.
20 5. Results of FPM studies [FPM ehoivn for fluticasone propfonate (FP))
Figure 1


WO 2005/016410 PCT/US2004/026252
33
The data In Figure 1 show Inat FPM is more stable In an MDI that Includes a gasket
treated fn accordance with the invention than in the control MDI.
Example 3
5
1. Treatment of valva gaskets
The valves used In the following experiments were DF60 vstves from Vatools (France).
The cap seating gasket (acrylontrite butadiene polymer) was removed from the valve for
10 treatment,
Treated Valves
The cap sealing gaskets were extracted by flowing ethanol (60-80oC) in a glass column
over the gasket for 24 houre. than dried in a commercial dryer undw parttet vacum.
15 The stem gaskets were extracted for 8 hours at 60oC by the method described in
Example 1,
The gasket was than re-attached to the valve.
20 Control
The valve was left untreated.
2. Sample Preparation
The MDIs for which data are presented in figure 1 were prepared In aluminium canisters
25 coated with a PTFE/PES polymer blend as described in WO96/32150 and sealed with a
valve praparsd as described in 1 above. The aluminium caniatere contained
pharmaceutical aerosol formulation comprising 4-2mg of salmelerai In the form of its
xinafoate saft, 8.4 mg of fluttoasone proptonste gncl 12g of HFA 134a.
30 3, Sample storage conditions
Each device was stored at room temparature and orientation (valve down). FPM was determined short/ after preparation ("Initief") and
after the passage of the indicated line period
35 4. Method for DslermiriidS FPM

WO 2005/016410 PCT/US2004/026252
34
Each MDl canister tested was put into a clean actuator and primed by flring 4 shots.
Then 10 shots were lined Into an Andersen Cescsde impactor which was quantitatvely
wasnad and the amount ot drug deposited mereon was quantified by HPLC analysis of
the washings. From thats the dose delivered (the sum of the amount of drug deposited on
5 that cascade impactor) and the FPM (the sum of drug deposited on stages 3, 4 and 5)
data were calculaed.
5. Results of FPM studies (FPM shown for fluflcasone proplonale (FP))
FIgure2

The data in Figure 2 show that FPM is more stable in art MDI that incfudes a gasket
15. treatment of valve gastete
20

WO 2005/016410 PCT/US2004/026252
35
The valves used in the following experiments were DF60 valves from Vafole (France).
The cap sealing gasket and stern sealing gaskets all acryfoniIa butadtene potymer)
were removed from the velve for treatment.
5
Approximately 10 kg of neck gaskets fn a mesh bag were placed into a column. Ethanel
at 80oC was flowed through the column for 4 hours. with the ethanal axiting the column
being distilled prior 1o flowing back Into the column. The mesh bag containing the
10 gaskets was removed from the column and pieced Into an explosion proof dryer, where
the gaskets were agitated for 5 minutes at 20°C. The gaskete wane then placed back
into the column end the processes of ethand extraction and agitation wene repealed four
Mines. The gaskets wefe then placed back into the column for a final repeat at the
extraction process. The gaskets were then riefnoved from the column. rinsed twice with
15 ethanol. and dried In vacuum. Stem gaskets were prepared in a similar manner with
total extraction time of 8 hours.
The gasket was then re-attached to the valve.
20 Experiment I
A 250ml round bottomed flask was charged with 120 ml ethanol (anhydrous USP grade),
40 necfc gaskets were placed in lha sdutiort and a condenser was attached to the flask.
The solution was than heated under reflux for 1.6 hours with the exclusion of air. The
25 hot ethanol was decanted and the gaskets were re-extracted using the same procedure.
The gasket was then washed one lime with 50 ml ethanel (anhydrous USP grade).
removed from the nqund bottomed flask and dried in a vacuo over CaSO4. Stem gaskets
were extracted fn the same manner but fore hours.
30 The gasket wss than ns-attached so the valve,
Approximately 140.000 neck gaskets were placed In a column. Ethanol at 60"C was
35 nowod through the column for 24 hours, with the ethanol exiting the column being

WO 2005/016410 PCT/US2004/026252
36
distilled prior to flowing back into the column. Stem gskete were extracted in the same
manner but for a twins.
The gasket wes then re-attached to the valve,
5
Control
The valve was left untreated.
2. Sample Prepare lion
10 The MDI for which data are presented In Figuras 3-6 were pfeparad in, aluminium
canfsters coated with a PTFE/PES polymer blend as described In WO8G/32150 and
sealed with a valve prepared as described in 1 above The aluminium canisters
coretained a pharmgcetitlcal aerosol fcumufatfon comprtsing 4.2mg of sstmetsrol fn [ho
form of Its xinafoate sail, 84 mg of fluflcasone propfonate and 12g or HFA 134a.
15
3. Sample storage condtions
Each device was stored at 40oC and 75% relative humidity in air inverted orientation
(valve down). PPM was determined shortly after preparation (initial) and after the
passage of Ihe indicated time period.
20
4. Method for Determining FPM
Each MDI canister tested was put into a clean aduaior and primed by firing 4 shots.
Then 10 shots were fined into an Andersen Cascade Impactcr which was quantitatively
washed and the amount of drug deposited thereon was quantified by HPLC analysis of
25 the washfngs. From this the dose dslivered the sum of the amount of drug deposited on
the cascade Impaelor) and the FPM (the sum of drug deposited on stages 3, 4 and 5)
data were calculated.
5. Method for Determinng Total Fatty Acids (FA)
Fatty adds mrene determined using a precolumn derivization witn 4-
bromophenylacstyfpromitde, and analysed via HPLC using a C18 column, ACN gradianl,
and UV detection at 260 nm.
35 6.Results of FPM studies.

WO 2005/016410 PCT/US2004/026252
37
FPM shown for flutfcasone propioftele (Fp)
FA is lolal fatty acid content in the Inhaler
5 Figure. 3 (Control)


WO 2005/016410 PCT/US2004/026252
38

5
Comparison between the control date in Figure 3 end the data according to the present
invention shown in Figures 4-8 illustafe that MDIs that utilized gaskets prepared in
accordant with the present invention exhibit more stable FPM than conventional MDls
ihat utilize untreated gaskete. The data in Figures 3-6 also illtustrate that thaca is a
10 XXX between the total fatty acid content in the aerosol pharmaceutical formulation
and the resulting FPM of the formulation.
Example 5
15 1. Treatment of valve gaskets

WO 2005/016410 PCT/US2004/026252
39
The valves usad in the following experiments were MK96 valvess from Valois (France).
The cap seeing gasket (EPDM) was removed from the valve for treatment.
Exgerjmapl K
5
Approximately 140,000 nsck gaskete were placed in a column. Ethanol at 60°C was
flowed through the column for 24 hours., with the ethanal exiting the column being
distilled prior to flowing back into the column.
10 The gasket was then re-arttached to the valve,
Control
The valve was lefl untreated. ControI is provided for comparison purposes and Is not
part of the present invention.
15
2. Sample Preparation
The MDIs for which data are presented in Tables 3 and 4 warn prepared in aluminium
canisters coated with a PTFE/PES polymer blend as deacdbed in WO96/32150 and
sealed with a valve prepared as described in 1 above. The aluminium canisters
20 contained 3 pharmaceutical aerosol formulation comprising 4.2mg of salmtiterol in the
form of Its xinaloate salt, B.4 mg ot fiubcasone propionste and 12g of HFA 134a. For
each storage condition, the oontrol and Experinwnt K canistars were filled frofn the samg
suspenstion.
25 3. Sample storage conditions
Each device was stored at the Indicated conditions. Permeabiltily and leak rate were
determined at initial time point from weight change over 7 days at arrtotent storage and
determined by weight change during storage at all other tfmepoints.
30 4. Method for Pernieability
Samples ana stored at confcnited temperature and relative humidity conditions (as
specified in line tables) for the indicated pertod of time then assay for moisture using a
modified Kart Fiscner trtration.
35

WO 2005/016410 PCT/US2004/026252
40
5 Method for Determining Leak Rate
Samples are weighed and stored a I the indicated conditions, At the end of the test
period, the samples are rewefghed and a leak rate is calculated from the differences in
5 initial weight and the weight at the test date, divided by lime, and normalized to mg of
propellant leaked/year of storage.
10 Table 3 Comparative permeability data for salmeterol/fluticassone propionate MDl
walar content (ppm)


WO 2005/016410 PCT/US2004/026252
41


WO 2005/016410 PCT/US2004/026252
42
These data show that the physical properties of the gasket, which allow the gasket to act
as a sealing gasket In an MDI, are not adversely effected by ethanol extraction of the
5
It is to be understood that the present invention covere all combinations of
particular and preferred groups described herein above.
The application of which this description and claims forms part may be used as a
10 basis for priority in respect of any subsequent application. The claims of such
subsequent application may bo directed to any feature or combination of features
described herein. They may take the form of prtsduct, composition, process, or
use claims and may include, by way example and without limitation the
following claims.

WO 2005/016410 PCT/US2004/026252
43
We claim:
1. A method of manufacturing a metered dose inhaler (MDI) comprising providing an MDI
sealing gasket, providing the other MDI components and a pharmaceutical aerosol formulation and
assembling the MDI, wherein the sealing gasket comprises an elastomeric gasket material comprising
acrylonitrile butadiene rubber and oleic acid as an extractable compound and the pharmaceutical
aerosol formulation comprises salmetero! xinafoate and fluticasone propionate, the method further
comprising the step of contacting the elastomeric gasket material with an aqueous solution consisting
of ethanol, wherein the solution is at a temperature of from 40°C to the boiling point of said aqueous
solution, to extract oleic acid so that the sealing gasket comprises between 0.04 and 0.17% oleic acid
prior to assembly of the MDI.
2. The method as claimed in claim 1, wherein sealing gasket comprises at least one additional
compound selected from the group consisting of nonylphenol isomers, 2,2'- methylenebis(6-tertbutyl-
4-methylphenol), 2,2,4,6,6-pentamethylhept-3-ene,3'-oxybispropanitrile, palmitic acid, and stearic
acid.
3. The method as claimed in claim 1, wherein the elastomeric gasket material is contacted with the
aqueous solution for at least 1 hour.
4. The method as claimed in claim 1, wherein the elastomeric gasket material is contacted with the
aqueous solution at a temperature of at least 60°C .
5. The method as claimed in claim I, wherein the elastomeric gasket material is contacted with
the aqueous solution under reflux conditions for the solution.
6. The method as claimed in claim I, wherein the elastomeric gasket material is contacted with
the aqueous solution in the presence of ultrasonic energy.
7. The method as claimed in claim 1, wherein the elastomeric gasket material is contacted with
the aqueous solution under conditions sufficient to extract at least 20 percent of at least one of the one
or more extractable compounds.


8. The method as claimed in claim 1, wherein the elastomeric gasket material is contacted with
the aqueous solution under conditions sufficient to extract at least 40 percent of at least one of the one
or more extractable compounds.
9. The method as claimed in claim 1, comprising agitating the elastomeric gasket material.
10. The method as claimed in claim 1, wherein the agitating of the elastomeric gasket material is
performed subsequent to the contacting of the elastomeric gasket material with the aqueous solution.
11. The method as claimed in claim 1, comprising contacting the elastomeric gasket material with
the aqueous solution subsequent to the agitating of the elastomeric gasket material.




A method of manufacturing an MDI comprises providing an MDI sealing gasket (3),
providing the other MDI components and a pharmaceutical aerosol formulation and assembling the
MDI, wherein the sealing gasket comprises an elastomeric gasket material comprising acrylonitrile
butadiene rubber and oleic acid as an extractable compound and the pharmaceutical aerosol
formulation comprises salmeterol xinafoate and fluticasone propionate, the method further
comprising the step of contacting the elastomeric gasket material (3) with an aqueous solution
consisting of ethanol, wherein the solution is at a temperature of from 40°C to the boiling point of
said aqueous solution, to extract oleic acid so that the sealing gasket comprises between 0.04 and
0.17% oleic acid prior to assembly of the MDI.

Documents:

00498-kolnp-2006-abstract.pdf

00498-kolnp-2006-claims.pdf

00498-kolnp-2006-description complete.pdf

00498-kolnp-2006-drawings.pdf

00498-kolnp-2006-form 1.pdf

00498-kolnp-2006-form 3.pdf

00498-kolnp-2006-form 5.pdf

00498-kolnp-2006-gpa.pdf

00498-kolnp-2006-international publication.pdf

00498-kolnp-2006-international search report.pdf

00498-kolnp-2006-pct request.pdf

498-KOLNP-2006-ABSTRACT.1.1.pdf

498-kolnp-2006-abstract.pdf

498-KOLNP-2006-AMANDED CLAIMS.pdf

498-kolnp-2006-assignment.pdf

498-kolnp-2006-claims.pdf

498-KOLNP-2006-CORRESPONDENCE.pdf

498-kolnp-2006-correspondence1.1.pdf

498-KOLNP-2006-DESCRIPTION (COMPLETE).1.1.pdf

498-kolnp-2006-description (complete).pdf

498-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

498-kolnp-2006-examination report.pdf

498-KOLNP-2006-FORM 1.1.1.pdf

498-kolnp-2006-form 13.1.pdf

498-KOLNP-2006-FORM 13.pdf

498-kolnp-2006-form 18.pdf

498-KOLNP-2006-FORM 2.pdf

498-KOLNP-2006-FORM 3.1.1.pdf

498-kolnp-2006-form 3.pdf

498-kolnp-2006-form 5.pdf

498-KOLNP-2006-FORM-27.pdf

498-kolnp-2006-gpa.pdf

498-kolnp-2006-granted-abstract.pdf

498-kolnp-2006-granted-claims.pdf

498-kolnp-2006-granted-description (complete).pdf

498-kolnp-2006-granted-drawings.pdf

498-kolnp-2006-granted-form 1.pdf

498-kolnp-2006-granted-form 2.pdf

498-kolnp-2006-granted-letter patent.pdf

498-kolnp-2006-granted-specification.pdf

498-KOLNP-2006-OTHERS DOCUMENTS.pdf

498-kolnp-2006-others.pdf

498-KOLNP-2006-PETETION UNDER RULE 137.pdf

498-KOLNP-2006-PETITION UNDER RULE 137-1.1.pdf

498-KOLNP-2006-PRIORITY DOCUMENT.pdf

498-kolnp-2006-reply to examination report.pdf

498-kolnp-2006-specification.pdf

498-kolnp-2006-translated copy of priority document.pdf

abstract-00498-kolnp-2006.jpg


Patent Number 244126
Indian Patent Application Number 498/KOLNP/2006
PG Journal Number 48/2010
Publication Date 26-Nov-2010
Grant Date 18-Nov-2010
Date of Filing 03-Mar-2006
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREENFORD, MIDDLESEX, UB6 ONN, GREAT BRITAIN
Inventors:
# Inventor's Name Inventor's Address
1 MILLER, JOHN, FRANCIS C/O GLAXOSMITHKLINE, FIVE MOORE DRIVE, PO BOX 13398, RESEARCH TRIANGLE PARK, NC 27709, U.S.A
2 SOMMERVILLE, MARK, LEE C/O GLAXOSMITHKLINE, FIVE MOORE DRIVE, PO BOX 13398, RESEARCH TRIANGLE PARK, NC 27709, U.S.A
PCT International Classification Number A61M
PCT International Application Number PCT/US2004/026252
PCT International Filing date 2004-08-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/494,450 2003-08-11 U.S.A.