U.S. patent application number 10/823533 was filed with the patent office on 2004-09-30 for metered dose inhaler for fluticasone propionate.
This patent application is currently assigned to SmithKline Beecham Corp.. Invention is credited to Ashurst, Ian C., Britto, Ignatius Loy, Herman, Craig Steven, Li-Bovet, Li, Riebe, Michael Thomas.
Application Number | 20040187865 10/823533 |
Document ID | / |
Family ID | 27025486 |
Filed Date | 2004-09-30 |
United States Patent
Application |
20040187865 |
Kind Code |
A1 |
Ashurst, Ian C. ; et
al. |
September 30, 2004 |
Metered dose inhaler for fluticasone propionate
Abstract
A metered dose inhaler having all or part of its internal
surfaces coated with one or more fluorocarbon polymers, optimally
in combination with one or more non-fluorocarbon polymers, for
dispensing an inhalation drug formation comprising fluticasone
propionate or a physiologically acceptable solvate thereof and a
fluorocarbon propellant, optionally in combination with one or more
other pharmacologically active agents or one or more
excipients.
Inventors: |
Ashurst, Ian C.; (Ware,
GB) ; Britto, Ignatius Loy; (Cary, NC) ;
Herman, Craig Steven; (Raleigh, NC) ; Li-Bovet,
Li; (Chapel Hill, NC) ; Riebe, Michael Thomas;
(Raleigh, NC) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
SmithKline Beecham Corp.
|
Family ID: |
27025486 |
Appl. No.: |
10/823533 |
Filed: |
April 14, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10823533 |
Apr 14, 2004 |
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10356591 |
Feb 3, 2003 |
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10356591 |
Feb 3, 2003 |
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09570725 |
May 15, 2000 |
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6546928 |
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09570725 |
May 15, 2000 |
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08829562 |
Mar 31, 1997 |
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6253762 |
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08829562 |
Mar 31, 1997 |
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08584859 |
Jan 5, 1996 |
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08584859 |
Jan 5, 1996 |
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08422111 |
Apr 14, 1995 |
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08829562 |
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PCT/US96/05006 |
Apr 10, 1996 |
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PCT/US96/05006 |
Apr 10, 1996 |
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08584859 |
Jan 5, 1996 |
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08584859 |
Jan 5, 1996 |
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08422111 |
Apr 14, 1995 |
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Current U.S.
Class: |
128/200.14 ;
128/200.23 |
Current CPC
Class: |
A61M 2205/0222 20130101;
A61M 15/009 20130101; A61P 11/00 20180101; B65D 83/54 20130101 |
Class at
Publication: |
128/200.14 ;
128/200.23 |
International
Class: |
A61M 011/00 |
Claims
1-22. (CANCELED)
23. A process for manufacturing a metered dose inhaler for
dispensing an inhalation drug formulation comprising a drug and a
fluorocarbon propellant, comprising: providing a metered dose
inhaler can having a mouth, a cap for covering the mouth of said
can, and a drug metering valve; applying to at least one internal
surface of said can, cap or drug metering valve which comes into
contact with said inhalation drug formulation, without prior
application of a primer thereto, a fluorocarbon polymer, optionally
in combination with one or more non-fluorocarbon polymers, to form
a coating on said at least one internal surface of said can, cap or
drug metering valve; and assembling said can, cap and drug metering
valve into a completed metered dose inhaler.
24. The process according to claim 23, and further comprising the
step of introducing into said metered dose inhaler said drug
formulation.
25. The process according to claim 24, wherein said drug
formulation is introduced into said can through said valve.
26. The process according to claim 23, wherein said fluorocarbon
polymer is applied to said cap.
27. The process according to claim 23, wherein said fluorocarbon
polymer is applied to said valve.
28. The process according to claim 23, wherein said fluorocarbon
polymer is applied as a coating to an internal surface of said can
and said coating is thereafter cured at an elevated
temperature.
29. The process according to claim 28, wherein said can is formed
of strengthened aluminum or an aluminum alloy.
30. The process according to claim 28, wherein said fluorocarbon
polymer is applied to an internal surface of said can at a
thickness of 1 .mu.m to 1 mm.
31. A process for manufacturing a metered dose inhaler for
dispensing an inhalation drug formulation comprising a drug and a
fluorocarbon propellant, comprising: providing a metered dose
inhaler can having a mouth, a cap for covering the mouth of said
can, and a drug metering valve; applying to an internal surface of
said can, which comes into contact with said inhalation drug
formulation, a fluorocarbon polymer, optionally in combination with
one or more non-fluorocarbon polymers, to form a coating on said
internal surface of said can; and assembling said can, cap and drug
metering valve into a completed metered dose inhaler, wherein said
coating has a thickness of 1 .mu.m to 100 .mu.m.
32. The process according to claim 31, wherein said coating has a
thickness of 1 .mu.m to 25 .mu.m.
33. The process according to claim 31, wherein a primer is applied
to said can before application of said fluorocarbon coating.
34. The process according to claim 31, wherein said fluorocarbon
polymer is applied to said can without prior application of a
primer.
35. The process according to claim 23, wherein said fluorocarbon
polymer is applied to said can by electrostatic dry powder
coating.
36. The process according to claim 23, wherein said fluorocarbon
polymer is applied to said can by spraying a preformed metered dose
inhaler can inside with said fluorocarbon polymer and then curing
at an elevated temperature.
37. The process according to claim 36, wherein curing is conducted
at a temperature of 300.degree. C. to 400.degree. C.
38. The process according to claim 36, wherein curing is conducted
at a temperature of 350.degree. C. to 380.degree. C.
39. The process according to claim 23, wherein said fluorocarbon
polymer is coated on said can by in situ plasma polymerization at
the can walls using fluorocarbon monomer.
40. The process according to claim 39, wherein plasma
polymerization is conducted at a temperature of 20.degree. C. to
100.degree. C.
41. A process according to claim 24, wherein the fluorocarbon
propellant is 1,1,1,2-tetrafluoroethane, or
1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof.
42. A process according to claim 24, wherein the fluorocarbon
propellant is 1,1,1,2-tetrafluoroethane.
43. A process according to claim 23, wherein said can is made of
metal wherein part or all of the internal metallic surfaces of the
can are coated.
44. A process according to claim 43, wherein the metal is aluminium
or an alloy thereof.
45. A process according to claim 23, wherein said fluorocarbon
polymer is a perfluorocarbon polymer.
46. A process according to claim 45, wherein said fluorocarbon
polymer is selected from PTFE, PFA, FEP and mixtures thereof.
47. A process according to claim 24, further comprising fitting
said metered dose inhaler into a suitable channeling device for
oral or nasal inhalation of the drug formulation.
48. The process of claim 23, wherein said can comprises side walls
and a base of a thickness greater than 0.46 mm and said
fluorocarbon polymer is applied to said can.
49. A process for manufacturing a metered dose inhaler having
internal metallic surfaces for dispensing an inhalation drug
formulation comprising a particulate drug and a fluorocarbon
propellant selected from the group consisting of
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and
mixtures thereof, comprising: providing a metered dose inhaler can
having a mouth, a cap for covering the mouth of said can, and a
drug metering valve, wherein said can comprises side walls and a
base having a thickness greater than 0.46 mm; forming a coating
from a polymer composition comprising one or more fluorocarbon
polymers on at least one of said internal metallic surfaces which
comes into contact with said inhalation drug formulation without
prior application of a primer thereto; and assembling said can, cap
and drug metering valve into a completed metered dose inhaler.
50. The process according to claim 49, and further comprising the
step of introducing into said metered dose inhaler said drug
formulation.
51. The process according to claim 49, wherein said fluorocarbon
polymer is applied to said cap.
52. The process according to claim 49, wherein said fluorocarbon
polymer is applied to said valve.
53. The process according to claim 49, wherein said fluorocarbon
polymer is applied as a coating to an internal surface of said can
and said coating is thereafter cured at an elevated
temperature.
54. The process according to claim 49, wherein said fluorocarbon
polymer is applied to said can by spraying a preformed metered dose
inhaler can inside with said fluorocarbon polymer and then curing
at an elevated temperature.
55. The process according to claim 54, wherein curing is conducted
at a temperature of 300.degree. C. to 400.degree. C.
56. The process according to claim 54, wherein said coating has a
thickness of 1 .mu.m to 1 mm.
57. The process according to claim 54, wherein said coating has a
thickness of 1 .mu.m to 100 .mu.m.
58. The process according to claim 54, wherein said coating has a
thickness of 1 .mu.m to 25 .mu.m.
59. The process according to claim 23, wherein said fluorocarbon
polymer is applied as a part of a polymer composition comprising
said fluorocarbon polymer and a non-fluorocarbon polymer.
60. The process according to claim 28, wherein said fluorocarbon
polymer is applied as a part of a polymer composition comprising
said fluorocarbon polymer and a non-fluorocarbon polymer.
61. The process according to claim 31, wherein said fluorocarbon
polymer is applied as a part of a polymer composition comprising
said fluorocarbon polymer and a non-fluorocarbon polymer.
62. The process according to claim 43, wherein said fluorocarbon
polymer is applied as a part of a polymer composition comprising
said fluorocarbon polymer and a non-fluorocarbon polymer.
63. The process according to claim 49, wherein said fluorocarbon
polymer is applied as a part of a polymer composition comprising
said fluorocarbon polymer and a non-fluorocarbon polymer.
64. The process according to claim 53, wherein said fluorocarbon
polymer is applied as a part of a polymer composition comprising
said fluorocarbon polymer and a non-fluorocarbon polymer.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/356,591 filed on Feb. 3, 2003, which is a continuation of
U.S. application Ser. No. 09/570,725 filed on May 15, 2000, which
is a continuation of U.S. application Ser. No. 08/829,562 (now U.S.
Pat. No. 6,253,762) filed on Mar. 31, 1997, which is a
continuation-in-part of application Ser. No. 08/584,859 filed on
Jan. 5, 1996 (now abandoned), which is a continuation-in-part of
application Ser. No. 08/422,111 filed on Apr. 14, 1995 (now
abandoned). application Ser. No. 08/829,562 is also a continuation
of PCT International Application No. PCT/US96/05006 filed Apr. 10,
1996, which designated the United States, which is a
continuation-in-part of application Ser. No. 08/584,859 filed on
Jan. 5, 1996 (now abandoned), which is a continuation-in-part of
application Ser. No. 08/422,111 filed on Apr. 14, 1995 (now
abandoned). The entire contents of each of the above-identified
applications are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Drugs for treating respiratory and nasal disorders are
frequently administered in aerosol formulations through the mouth
or nose. One widely used method for dispensing such aerosol drug
formulations involves making a suspension formulation of the drug
as a finely divided powder in a liquefied gas known as a
propellant. The suspension is stored in a sealed container capable
of withstanding the pressure required to maintain the propellant as
a liquid. The suspension is dispersed by activation of a dose
metering valve affixed to the container.
[0003] A metering valve may be designed to consistently release a
fixed, predetermined mass of the drug formulation upon each
activation. As the suspension is forced from the container through
the dose metering valve by the high vapor pressure of the
propellant, the propellant rapidly vaporizes leaving a fast moving
cloud of very fine particles of the drug formulation. This cloud of
particles is directed into the nose or mouth of the patient by a
channeling device such as a cylinder or open-ended cone.
Concurrently with the activation of the aerosol dose metering
valve, the patient inhales the drug particles into the lungs or
nasal cavity. Systems of dispensing drugs in this way are known as
"metered dose inhalers" (MDIs). See Peter Byron, Respiratory Drug
Delivery, CRC Press, Boca Raton, Fla. (1990), for a general
background on this form of therapy.
[0004] Patients often rely on medication delivered by MDIs for
rapid treatment of respiratory disorders which are debilitating and
in some cases, even life threatening. Therefore, it is essential
that the prescribed dose of aerosol medication delivered to the
patient consistently meet the specifications claimed by the
manufacturer and comply with the requirements of the FDA and other
regulatory authorities. That is, every dose in the can must be the
same within close tolerances.
[0005] Some aerosol drugs tend to adhere to the inner surfaces,
i.e., walls of the can, valves, and caps, of the MDI. This can lead
to the patient getting significantly less than the prescribed
amount of drug upon each activation of the MDI. The problem is
particularly acute with hydrofluoroalkane (also known as simply
"fluorocarbon") propellant systems, e.g., P134a and P227, under
development in recent years to replace chlorofluorocarbons such as
P11, P114 and P12.
[0006] We have found that coating the interior can surfaces of MDIs
with a fluorocarbon polymer significantly reduces or essentially
eliminates the problem of adhesion or deposition of fluticasone
propionate on the can walls and thus ensures consistent delivery of
medication in aerosol from the MDI.
SUMMARY OF THE INVENTION
[0007] A metered dose inhaler having part or all of its internal
surfaces coated with one or more fluorocarbon polymers, optionally
in combination with one or more non-fluorocarbon polymers, for
dispensing an inhalation drug formulation comprising fluticasone
propionate, or a physiologically acceptable solvate thereof, and a
fluorocarbon propellant optionally in combination with one or more
other pharmacologically active agents or one or more
excipients.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The term "metered dose inhaler" or "MDI" means a unit
comprising a can, a crimped cap covering the mouth of the can, and
a drug metering valve situated in the cap, while the term "MDI
system" also includes a suitable channeling device.
[0009] The term "MDI can" means the container without the cap and
valve. The term "drug metering valve" or "MDI valve" refers to a
valve and its associated mechanisms which delivers a predetermined
amount of drug formulation from an MDI upon each activation. The
channeling device may comprise, for example, an actuating device
for the valve and a cylindrical or cone-like passage through which
medicament may be delivered from the filled MDI can via the MDI
valve to the nose or mouth of a patient, e.g., a mouthpiece
actuator. The relation of the parts of a typical MDI is illustrated
in U.S. Pat. No. 5,261,538, incorporated herein by reference.
[0010] The term "fluorocarbon polymers" means a polymer in which
one or more of the hydrogen atoms of the hydrocarbon chain have
been replaced by fluorine atoms. Thus, "fluorocarbon polymers"
include perfluorocarbon, hydrofluorocarbon, chlorofluorocarbon,
hydrochlorofluoro-carbon polymers or other halogen substituted
derivatives thereof. The "fluorocarbon polymers" may be branched,
homo-polymers or co-polymers.
[0011] U.S. Pat. No. 4,335,121, incorporated herein by reference,
teaches an antiinflammatory steroid compound known by the chemical
name [(6a, 11b, 16a, 17a)-6,
9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)-
-androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester and
the generic name "fluticasone propionate". Fluticasone propionate
in aerosol form, has been accepted by the medical community as
useful in the treatment of asthma and is marketed under the
trademarks "Flovent" and "Flonase". Fluticasone propionate may also
be used in the form of a physiologically acceptable solvate.
[0012] The term "drug formulation" means fluticasone propionate (or
a physiologically acceptable solvate thereof) optionally in
combination with one or more other pharmacologically active agents
such as other antiinflammatory agents, analgesic agents or other
respiratory drugs and optionally containing one or more excipients,
and a fluorocarbon propellant. The term "excipients" as used herein
means chemical agents having little or no pharmacological activity
(for the quantities used) but which enhance the drug formulation or
the performance of the MDI system. For example, excipients include
but are not limited to surfactants, preservatives, flavorings,
antioxidants, antiaggregating agents, and cosolvents, e.g., ethanol
and diethyl ether.
[0013] Suitable surfactants are generally known in the art, for
example, those surfactants disclosed in European Patent Application
No. 0 327 777. The amount of surfactant employed is desirably in
the range of 0.0001% to 50% weight to weight ratio relative to the
drug, in particular 0.05 to 5% weight to weight ratio. A
particularly useful surfactant is 1,2-di [7-(F-hexyl)
hexanoyl]-glycero-3-phospho-N,N,N-trimethyl-ethanolamine also known
as 3,5,9-trioxa-4-phosphadocosan-1-aminium,
17,17,18,18,19,19,20,20,21,21,22,22,22-trideca-fluoro-7-[(8,8,9,9,10,10,1-
1,11,12,12,13,13,13-tri-decafluoro-1-oxotridecyl)oxy]-4-hydroxy-N,N,N-trim-
ethyl-10-oxo-, inner salt, 4-oxide.
[0014] A polar cosolvent such as C.sub.2-6 aliphatic alcohols and
polyols e.g., ethanol, isopropanol and propylene glycol, preferably
ethanol, may be included in the drug formulation in the desired
amount, either as the only excipient or in addition to other
excipients such as surfactants. Suitably, the drug formulation may
contain 0.01 to 5% w/w based on the propellant of a polar cosolvent
e.g., ethanol, preferably 0.1 to 5% w/w, e.g., about 0.1 to 1%
w/w.
[0015] It will be appreciated by those skilled in the art that the
drug formulation for use in the invention may, if desired, contain
fluticasone propionate (or a physiologically acceptable solvate
thereof) in combination with one or more other pharmacologically
active agents. Such medicaments may be selected from any suitable
drug useful in inhalation therapy. Appropriate medicaments may thus
be selected from, for example, analgesics, e.g., codeine,
dihydromorphine, ergotamine, fentanyl or morphine; anginal
preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate,
ketotifen or nedocromil; antiinfectives, e.g., cephalosporins,
penicillins, streptomycin, sulphonamides, tetracyclines and
pentamidine; antihistamines, e.g., methapyrilene;
anti-inflammatories, e.g., beclomethasone (e.g., the dipropionate),
flunisolide, budesonide, tipredane or triamcinolone acetonide;
antitussives, e.g., noscapine; bronchodilators, e.g., salbutamol,
salmeterol, ephedrine, adrenaline, fenoterol, formoterol,
isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,
pirbuterol, reproterol, rimiterol, terbutaline, isoetharine,
tulobuterol, orciprenaline, or
(-)-4-amino-3,5-dichloro-.alpha.-[[[6-[2-(2-pyridinyl)e-
thoxy]hexyl]amino]methyl]benzene-methanol; diuretics, e.g.,
amiloride; anticholinergics, e.g., ipratropium, atropine or
oxitropium; hormones, e.g., cortisone, hydrocortisone or
prednisolone; xanthines, e.g., aminophylline, choline
theophyllinate, lysine theophyllinate or theophylline; and
therapeutic proteins and peptides, e.g., insulin or glucagon. It
will be clear to a person skilled in the art that, where
appropriate, the medicaments may be used in the form of salts
(e.g., as alkali metal or amine salts or as acid addition salts) or
as esters (e.g., lower alkyl esters) or as solvates (e.g.,
hydrates) to optimize the activity and/or stability of the
medicament and/or to minimize the solubility of the medicament in
the propellant.
[0016] Particularly preferred drug formulations contain fluticasone
propionate (or a physiologically acceptable solvate thereof) in
combination with a bronchodilator such as salbutamol (e.g., as the
free base or the sulphate salt) or salmeterol (e.g., as the
xinafoate salt).
[0017] A particularly preferred drug combination is fluticasone
propionate and salmeterol xinafoate. "Propellants" used herein mean
pharmacologically inert liquids with boiling points from about room
temperature (25.degree. C.) to about -25.degree. C. which singly or
in combination exert a high vapor pressure at room temperature.
Upon activation of the MDI system, the high vapor pressure of the
propellant in the MDI forces a metered amount of drug formulation
out through the metering valve. Then the propellant very rapidly
vaporizes dispersing the drug particles. The propellants used in
the present invention are low boiling fluorocarbons; in particular,
1,1,1,2-tetrafluoroethane also known as "propellant 134a" or
"P134a" and 1,1,1,2,3,3,3-heptafluoro-n-pro- pane also known as
"propellant 227" or "P227".
[0018] Drug formulations for use in the invention may be free or
substantially free of formulation excipients, e.g., surfactants and
cosolvents, etc. Such drug formulations are advantageous since they
may be substantially taste and odor free, less irritant and less
toxic than excipient-containing formulations. Thus, a preferred
drug formulation consists essentially of fluticasone propionate, or
a physiologically acceptable salt thereof, optionally in
combination with one or more other pharmacologically active agents
particularly salmeterol (e.g., in the form of the xinafoate salt),
and a fluorocarbon propellant. Preferred propellants are
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-pr- opane or
mixtures thereof, and especially 1,1,1,2-tetrafluoroethane.
[0019] Further drug formulations for use in the invention may be
free or substantially free of surfactant. Thus, a further preferred
drug formulation comprises or consists essentially of albuterol (or
a physiologically acceptable salt thereof), optionally in
combination with one or more other pharmacologically active agents,
a fluorocarbon propellant and 0.01 to 5% w/w based on the
propellant of a polar cosolvent, which formulation is substantially
free of surfactant. Preferred propellants are
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or
mixtures thereof, and especially 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoro-n-propane.
[0020] Most often the MDI can and cap are made of aluminum or an
alloy of aluminum, although other metals not affected by the drug
formulation, such as stainless steel, an alloy of copper or tin
plate, may be used. An MDI can may also be fabricated from glass or
plastic. Preferably, however, the MDI cans employed in the present
invention are made of aluminium or an alloy thereof.
Advantageously, strengthened aluminium or aluminum alloy MDI cans
may be employed. Such strengthened MDI cans are capable of
withstanding particularly stressful coating and curing conditions,
e.g., particularly high temperatures, which may be required for
certain fluorocarbon polymers. Strengthened MDI cans which have a
reduced tendency to malform under high temperatures include MDI
cans comprising side walls and a base of increased thickness and
MDI cans comprising a substantially ellipsoidal base (which
increases the angle between the side walls and the base of the
can), rather than the hemispherical base of standard MDI cans. MDI
cans having an ellipsoidal base offer the further advantage of
facilitating the coating process.
[0021] The drug metering valve consists of parts usually made of
stainless steel, a pharmacologically inert and propellant resistant
polymer, such as acetal, polyamide (e.g., Nylon.RTM.),
polycarbonate, polyester, fluorocarbon polymer (e.g., Teflon.RTM.)
or a combination of these materials. Additionally, seals and "O"
rings of various materials (e.g., nitrile rubbers, polyurethane,
acetyl resin, fluorocarbon polymers), or other elastomeric
materials are employed in and around the valve.
[0022] Fluorocarbon polymers for use in the invention include
fluorocarbon polymers which are made of multiples of one or more of
the following monomeric units: tetrafluoroethylene (PTFE),
fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA),
ethylene tetrafluoroethylene (ETFE), vinyldienefluoride (PVDF), and
chlorinated ethylene tetrafluoroethylene. Fluorinated polymers
which have a relatively high ratio of fluorine to carbon, such as
perfluorocarbon polymers e.g., PTFE, PFA, and FEP, are
preferred.
[0023] The fluorinated polymer may be blended with non-fluorinated
polymers, such as polyamides, polyimides, polyethersulfones,
polyphenylene sulfides and amine-formaldehyde thermosetting resins.
These added polymers improve adhesion of the polymer coating to the
can walls. Preferred polymer blends are PTFE/FEP/polyamideimide,
PTFE/polyethersulphone (PES) and FEP benzoguanamine.
[0024] Particularly preferred coatings are pure PFA, FEP and blends
of PTFE and polyethersulphone (PES).
[0025] Fluorocarbon polymers are marketed under trademarks such as
Teflon.RTM., Tefzel.RTM., Halar.RTM., Hostaflon.RTM.,
Polyflon.RTM., and Neoflon.RTM.. Grades of polymer include FEP
DuPont 856-200, PFA DuPont 857-200, PTFE-PES DuPont 3200-100,
PTFE-FEP-polyamideimide DuPont 856P23485, FEP powder DuPont 532,
and PFA Hoechst 6900n. The coating thickness is in the range of
about 1 .mu.m to about 1 mm. Suitably the coating thickness is in
the range of about 1 .mu.m to about 100 .mu.m, e.g., 1 .mu.m to 25
.mu.m. Coatings may be applied in one or more coats.
[0026] Preferably the fluorocarbon polymers for use in the
invention are coated onto MDI cans made of metal, especially MDI
cans made of aluminium or an alloy thereof.
[0027] The particle size of the particular (e.g., micronised) drug
should be such as to permit inhalation of substantially all the
drug into the lungs upon administration of the aerosol formulation
and will thus be less than 100 microns, desirably less than 20
microns, and, in particular, in the range of 1-10 microns, e.g.,
1-5 microns.
[0028] The final drug formulation desirably contains 0.005-10%
weight to weight ratio, in particular 0.005-5% weight to weight
ratio, especially 0.01-1.0% weight to weight ratio, of drug
relative to the total weight of the formulation.
[0029] A further aspect of the present invention is a metered dose
inhaler having part or all of its internal metallic surfaces coated
with one or more fluorocarbon polymers, optionally in combination
with one or more non-fluorocarbon polymers, for dispersing an
inhalation drug formulation comprising fluticasone propionate and a
fluorocarbon propellant optionally in combination with one or more
other pharmacologically active agents and one or more
excipients.
[0030] A particular aspect of the present invention is an MDI
having part or essentially all of its internal metallic surfaces
coated with PFA or FEP, or blended fluoropolymer resin systems such
as PTFE-PES with or without a primer coat of a polyamideimide or
polyethersulfone for dispensing a drug formulation as defined
hereinabove. Preferred drug formulations for use in this MDI
consist essentially of fluticasone propionate (or a physiologically
acceptable solvate thereof), optionally in combination with one or
more other pharmacologically active agents, particularly salmeterol
(e.g., in the form of the xinafoate salt), and a fluorocarbon
propellant, particularly 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoropropane or mixtures thereof, and
especially 1,1,1,2-tetrafluoroethane. Preferably the MDI can is
made of aluminium or an alloy thereof.
[0031] The MDI can may be coated by the means known in the art of
metal coating. For example, a metal, such as aluminum or stainless
steel, may be precoated as coil stock and cured before being
stamped or drawn into the can shape. This method is well suited to
high volume production for two reasons. First, the art of coating
coil stock is well developed, and several manufacturers can custom
coat metal coil stock to high standards of uniformity and in a wide
range of thicknesses. Second, the precoated stock can be stamped or
drawn at high speeds and precision by essentially the same methods
used to draw or stamp uncoated stock.
[0032] Other techniques for obtaining coated cans is by
electrostatic dry powder coating or by spraying preformed MDI cans
inside with formulations of the coating fluorinated polymer/polymer
blend and then curing. The preformed MDI cans may also be dipped in
the fluorocarbon polymer/polymer blend coating formulation and
cured, thus becoming coated on the inside and out. The fluorocarbon
polymer/polymer blend formulation may also be poured inside the MDI
cans then drained out leaving the insides with the polymer coat.
Conveniently, for ease of manufacture, preformed MDI cans are
spray-coated with the fluorinated polymer/polymer blend.
[0033] The fluorocarbon polymer/polymer blend may also be formed in
situ at the can walls using plasma polymerization of the
fluorocarbon monomers. Fluorocarbon polymer film may be blown
inside the MDI cans to form bags. A variety of fluorocarbon
polymers such as ETFE, FEP, and PTFE are available as film
stock.
[0034] The appropriate curing temperature is dependent on the
fluorocarbon polymer/polymer blend chosen for the coating and the
coating method employed. However, for coil coating and spray
coating temperatures in excess of the melting point of the polymer
are typically required, for example, about 50.degree. C. above the
melting point, for up to about 20 minutes such as about 5 to 10
minutes, e.g., about 8 minutes or as required. For the above-named
preferred and particularly preferred fluorocarbon polymer/polymer
blends curing temperatures in the range of about 300.degree. C. to
about 400.degree. C., e.g., about 350.degree. C. to 380.degree. C.
are suitable for plasma polymerization typically temperatures in
the range of about 20.degree. C. to about 100.degree. C. may be
employed.
[0035] The MDIs taught herein may be prepared by methods of the art
(e.g., see Byron, above, and U.S. Pat. No. 5,345,980) substituting
conventional cans for those coated with a fluorinated
polymer/polymer blend. That is fluticasone propionate and other
components of the formulation are filled into an aerosol can coated
with a fluorinated polymer/polymer blend. The can is fitted with a
cap assembly which is crimped in place. The suspension of the drug
in the fluorocarbon propellant in liquid form may be introduced
through the metering valve as taught in U.S. Pat. No. 5,345,980,
incorporated herein by reference.
[0036] The MDIs with fluorocarbon polymer/polymer blend coated
interiors taught herein may be used in medical practice in a
similar manner as non-coated MDIs now in clinical use. However the
MDIs taught herein are particularly useful for containing and
dispensing inhaled drug formulations with
hydrofluoroalkanefluorocarbon propellants such as 134a with little,
or essentially no, excipient and which tend to deposit or cling to
the interior walls and parts of the MDI system. In certain cases it
is advantageous to dispense an inhalation drug with essentially no
excipient, e.g., where the patient may be allergic to an excipient
or the drug reacts with an excipient.
[0037] MDIs containing the formulations described hereinabove, MDI
systems and the use of such MDI systems for the treatment of
respiratory disorders, e.g., asthma, comprise further aspects of
the present invention.
[0038] It will be apparent to those skilled in the art that
modifications to the invention described herein can readily be made
without departing from the spirit of the invention. Protection is
sought for all the subject matter described herein including any
such modifications.
[0039] The following non-limitative Examples serve to illustrate
the invention.
EXAMPLES
Example 1
[0040] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) were
spray-coated (Livingstone Coatings, Charlotte, N.C.) with primer
(Du Pont 851-204) and cured to the vendor's standard procedure,
then further spray-coated with either FEP or PFA (DuPont 856-200
and 857-200, respectively) and cured according to the vendor's
standard procedure. The thickness of the coating is approximately
10 .mu.m to 50 .mu.m. These cans are then purged of air (see PCT
Application No. WO 94/22722 (PCT/EP94/00921)), the valves crimped
in place, and a suspension of about 20 mg fluticasone propionate in
about 12 gm P134a is filled through the valve.
Example 2
[0041] Standard 0.46 mm thick aluminum sheet (United Aluminum) was
spray-coated (DuPont, Wilmington, Del.) with FEP (DuPont 856-200)
and cured. This sheet was then deep-drawn into cans (Presspart
Inc., Cary, N.C.). The thickness of the coating is approximately 10
.mu.m to 50 .mu.m. These cans are then purged of air, the valves
crimped in place, and a suspension of about 40 mg fluticasone
propionate in about 12 gm P134A is filled through the valve.
Example 3
[0042] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with PTFE-PES blend (DuPont) as a single coat and
cured according to the vendor's standard procedure. The thickness
of the coating is between approximately 1 .mu.m and approximately
20 .mu.m. These cans are then purged of air, the valves crimped in
place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg
micronised fluticasone propionate in about 12 g P134a is filled
through the valve.
Example 4
[0043] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with PTFE-FEP-polyamideimide blend (DuPont) and cured
according to the vendor's standard procedure. The thickness of the
coating is between approximately 1 .mu.m and approximately 20
.mu.m. These cans are then purged of air, the valves crimped in
place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg
micronised fluticasone propionate in about 12 g P134a is filled
through the valve.
Example 5
[0044] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with FEP powder (DuPont FEP 532) using an
electrostatic gun. The thickness of the coating is between
approximately 1 .mu.m and approximately 20 .mu.m. These cans are
then purged of air, the valves crimped in place, and a suspension
of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg micronised fluticasone
propionate in about 12 g P134a was filled through the valve.
Example 6
[0045] Standard 0.46 mm thick aluminium sheet is spray coated with
FEP-Benzoguanamine and cured. This sheet is then deep-drawn into
cans. These cans are then purged of air, the valves crimped in
place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg, or 4.4
mg micronised fluticasone propionate in about 12 g P134a is filled
through the valve.
Example 7
[0046] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with an aqueous dispersion of PFA (Hoechst PFA-6900n)
and cured. The thickness of the coating is between approximately 1
.mu.m and approximately 20 .mu.m. These cans are then purged of
air, the valves crimped in place, and a suspension of about 41.0
mg, 21.0 mg, 8.8 mg, or 4.4 mg micronised fluticasone propionate in
about 12 g P134a is filled through the valve.
Example 8
[0047] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with PTFE-PES blend (DuPont) as a single coat and
cured according to the vendor's standard procedure. The thickness
of the coating is between approximately 1 .mu.m and approximately
20 .mu.m. These cans are then purged of air, the valves crimped in
place, and a suspension of about 8.8 mg, 22 mg or 44 mg of
micronised fluticasone propionate with about 6.4 mg micronised
salmeterol xinafoate in about 12 g P134a is filled through the
valve.
Example 9
[0048] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with PTFE-FEP-polyamideimide blend (DuPont) and cured
according to the vendor's standard procedure. The thickness of the
coating is between approximately 1 .mu.m and approximately 20
.mu.m. These cans are then purged of air, the valves crimped in
place, and a suspension of about 8.8 mg, 22 mg or 44 mg of
micronised fluticasone propionate with about 6.4 mg micronised
salmeterol xinafoate in about 12 g P134a is filled through the
valve.
Example 10
[0049] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with FEP powder (DuPont FEP 532) using an
electrostatic gun. The thickness of the coating is between
approximately 1 .mu.m and approximately 20 .mu.m. These cans are
then purged of air, the valves crimped in place, and a suspension
of about 8.8 mg, 22 mg or 44 mg of micronised fluticasone
propionate with about 6.4 mg micronised salmeterol xinafoate in
about 12 g P134a is filled through the valve.
Example 11
[0050] Standard 0.46 mm thick aluminium sheet is spray coated with
FEP-Benzoguanamine and cured. This sheet is then deep-drawn into
cans. These cans are then purged of air, the valves crimped in
place, and a suspension of about 8.8 mg, 22 mg or 44 mg of
micronised fluticasone propionate with about 6.4 mg micronised
salmeterol xinafoate in about 12 g P134a is filled through the
valve.
Example 12
[0051] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with an aqueous dispersion of PFA (Hoechst PFA-6900n)
and cured. The thickness of the coating is between approximately 1
.mu.m and approximately 20 .mu.m. These cans are then purged of
air, the valves crimped in place, and a suspension of about 8.8 mg,
22 mg or 44 mg of micronised fluticasone propionate with about 6.4
mg micronised salmeterol xinafoate in about 12 g P134a is filled
through the valve.
Example 13
[0052] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with PTFE-PES blend (DuPont) as a single coat and
cured according to the vendor's standard procedure. The thickness
of the coating is between approximately 1 .mu.m and approximately
20 .mu.m. These cans are then purged of air, the valves crimped in
place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg
micronised fluticasone propionate with about 4 mg micronised
salmeterol xinafoate in about 8 g P134a is filled through the
valve.
Example 14
[0053] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with PTFE-FEP-polyamideimide blend (DuPont) and cured
according to the vendor's standard procedure. The thickness of the
coating is between approximately 1 .mu.m and approximately 20
.mu.m. These cans are then purged of air, the valves crimped in
place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg
micronised fluticasone propionate with about 4 mg micronised
salmeterol xinafoate in about 8 g P134a is filled through the
valve.
Example 15
[0054] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with FEP powder (DuPont FEP 532) using an
electrostatic gun. The thickness of the coating is between
approximately 1 .mu.m and approximately 20 .mu.m. These cans are
then purged of air, the valves crimped in place, and a suspension
of about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone
propionate with about 4 mg micronised salmeterol xinafoate in about
8 g P134a is filled through the valve.
Example 16
[0055] Standard 0.46 mm thick aluminium sheet is spray coated with
FEP-Benzoguanamine and cured. This sheet is then deep-drawn into
cans. These cans are then purged of air, the valves crimped in
place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg
micronised fluticasone propionate with about 4 mg micronised
salmeterol xinafoate in about 8 g P134a is filled through the
valve.
Example 17
[0056] Standard 12.5 ml MDI cans (Presspart Inc., Cary, N.C.) are
spray-coated with an aqueous dispersion of PFA (Hoechst PFA-6900n)
and cured. The thickness of the coating is between approximately 1
.mu.m and approximately 20 .mu.m. These cans are then purged of
air, the valves crimped in place, and a suspension of about 5.5 mg,
13.8 mg or 27.5 mg micronised fluticasone propionate with about 4
mg micronised salmeterol xinafoate in about 8 g P134a is filled
through the valve.
Examples 18-22
[0057] Examples 3 to 7 are repeated except that a suspension of
about 13.3 mg micronised fluticasone propionate in about 21.4 g
P227 is filled through the valve.
Examples 23-27
[0058] Examples 3 to 7 are repeated except that 66 mg, or 6.6 mg
micronised fluticasone propionate in about 182 mg ethanol and about
18.2 g P134a is filled through the valve.
Examples 28-52
[0059] Examples 3 to 27 are repeated except that modified 12.5 ml
MDI cans having a substantially ellipsoidal base (Presspart Inc.,
Cary, N.C.) were used.
[0060] Dose delivery from the MDIs tested under simulated use
conditions is found to be constant, compared to control MDIs filled
into uncoated cans, which exhibit a significant decrease in dose
delivered through use.
* * * * *