U.S. patent application number 10/502458 was filed with the patent office on 2005-05-19 for novel process for coating inhalation devices.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Badyal, Jas Pal, Rogueda, Philippe.
Application Number | 20050106335 10/502458 |
Document ID | / |
Family ID | 20286854 |
Filed Date | 2005-05-19 |
United States Patent
Application |
20050106335 |
Kind Code |
A1 |
Badyal, Jas Pal ; et
al. |
May 19, 2005 |
Novel process for coating inhalation devices
Abstract
The invention relates to coating inhalation devices and their
components by cold plasma (pulsed or continuous wave) with
fluorinated acrylates. The process gives inhalation devices with
improved product performance by reducing drug deposition on the
coated parts.
Inventors: |
Badyal, Jas Pal; (Durham,
GB) ; Rogueda, Philippe; (Leicestershire,
GB) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
225 FRANKLIN STREET
BOSTON
MA
02110
US
|
Assignee: |
AstraZeneca AB
SE-151 85 Sodertalie
SE
|
Family ID: |
20286854 |
Appl. No.: |
10/502458 |
Filed: |
July 22, 2004 |
PCT Filed: |
January 29, 2003 |
PCT NO: |
PCT/SE03/00158 |
Current U.S.
Class: |
428/2 ; 427/2.1;
427/569 |
Current CPC
Class: |
C09D 4/00 20130101; A61M
15/009 20130101; C09D 4/00 20130101; A61M 2205/0222 20130101; B05D
5/083 20130101; C08F 220/24 20130101 |
Class at
Publication: |
428/002 ;
427/569; 427/002.1 |
International
Class: |
B65D 071/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 1, 2002 |
SE |
0200313-5 |
Claims
1. An device for dispensing a drug by inhalation wherein the device
or components thereof are coated by a cold plasma coating process
characterized in that the coating is a fluorinated acrylate
compound or a mixture thereof.
2. A device according to claim 1 in which the fluorinated acrylate
compound is 1H, 1H, 2H, 2H heptadecafluorodecyl acrylate, 1H, 1H,
2H, 2H perfluoroctyl acrylate or 1H, 1H, 2H, 2H perfluoroctyl
methacrylate.
3. A device according to claim 1 in which the can is coated.
4. A device according to claim 1 in which the stem is coated.
5. A device according to claim 1 in which the actuator is
coated.
6. A device according to claim 1 in which the seals are coated.
7. A device according to claim 1 in which the drug is mometasone,
ipratropium bromide, tiotropium and salts thereof, salemeterol,
fluticasone propionate, beclomethasone dipropionate, reproterol,
clenbuterol, rofleponide and salts, nedocromil, sodium
cromoglycate, flunisolide, budesonide, formoterol fumarate
dihydrate, Symbicort.TM. (budesonide and formoterol),
3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7--
yl)ethylamino]-N-[2-[2-(4-methylphenyl)ethoxy)ethyl]propansulphonamide,
terbutaline, terbutaline sulphate, salbutamol base and sulphate,
fenoterol,
3-[2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[-
2-[2-(4-methylphenyl)ethoxy]ethyl]propanesulphonamide,
hydrochloride.
8. The use of a fluorinated acrylate compound for the cold plasma
coating of a medicinal device.
9. A process for coating a medicinal device with a fluorinated
acrylate which comprises coating the device using a cold plasma.
Description
FIELD OF THE INVENTION
[0001] This invention describes how cold plasma coating can be used
to improve the performance of inhalation devices. In particular, it
describes the use of fluorinated acrylate molecules to reduce drug
adhesion to device components. These compounds conjointly with the
way they are grafted onto surfaces are new to the area of
inhalation devices. This invention can be applied to a range of
surfaces (metals, plastics) and used with a range of drug molecules
for the treatment of local conditions (mouth, lung, nose, throat
and lung diseases). It can also be used in the systemic treatment a
wide range of ailments (lung cancer, migraine, diabetes etc . . .
).
BACKGROUND OF THE INVENTION
[0002] Inhalation treatments of a series of medical conditions rely
on sophisticated devices to deliver the drug to the desired target.
These devices can themselves introduce new variables in the
optimisation of the product performance. These are mainly due to
drug adsorption to the elements constituting the device. For
example, the device can be a pMDI used in the treatment of
respiratory diseases. A pMDI is made up of a canister, an actuator
and a complex valve assembly. All the components of this pMDI are
potential sites of drug adhesion, therefore loss of drug leading to
irregular dosing. Reducing drug adhesion is of primary importance
for the design of a robust product. This can be achieved by
modifying the drug formulation or the surface properties of the
device components.
[0003] The problem is particularly acute in pMDI. The requirement
to use HFA propellants, for the treatment of asthma for instance,
imposed by the Montreal protocol has led to a series of unexpected
hurdles in the development of new products. This is mostly due to
the characteristics of the liquid HFA and the behaviour of the drug
suspensions prepared with them. HFA propellants have very low
surface tensions and wet solid surfaces with remarkable efficiency.
This means that due to capillary forces, the propellants spread up
can walls very easily, and leave a thin film of caked particles.
Furthermore, because of the poor solvent properties of the
propellants, drug particles have a tendency to move to the
propellant/device interface to have a more energetically favourable
contact than they would by remaining in the bulk. Both phenomenon
can be reduced by coating the device and its components with
appropriate chemicals. A range of coatings can be applied in a
variety of fashion with a varying degree of success.
[0004] One of the early forms of coating is spray coating. It is a
process akin to painting and is used successfully in the food and
paint industry. For example PCT/SE/01/01606 discloses the spray
coating of fluorinated alkylpolyglycosides. Most spray coating
methods suffer from the drawback to rely on multiple steps
processes. The can has to be sprayed and dried before use.
Anodisation of the aluminium parts is often required as well. The
uniformity and integrity of such coating can be an issue, since
spray guns cannot access the intricate details of some components
design. Finally, the coating layer thus deposited can be scraped
off the surface, and introduces leachables and unwanted chemicals
in the medicament composition.
[0005] Silanisation is another way of modifying surface properties.
For example PCT/SE/01/12749 indicates how such treatment can be
used to reduce drug adhesion. This treatment is a solvent based
method and require the cans to be washed after treatment and tested
for cleanliness before being put to use for medical treatment.
[0006] Plasma coating is known in the art, for example WO 99/64662
and WO 00/05000 disclose plasma coating of a surface such as a
fabric. GB 2 355 252 discloses plasma coating of a medicinal device
with certain silicon based polymers. However Fluorinated acrylates
are not disclosed nor suggested.
[0007] Reducing the attraction between drug particles and solid
surfaces will lead to a reduce particle adhesion, since the
particles will not reach the surfaces.
SUMMARY OF THE INVENTION
[0008] It has been found that drug adhesion to the elements (i.e.
can, stem, valves, seals etc . . . ) of inhalation devices (nasal,
nebulisers, pMDIs, DPIs . . . ) can be dramatically reduced by
coating these elements by cold plasma with fluorinated acrylates.
The process can either be pulsed or continuous. Some or all of the
above components can be coated using the processes of the
invention.
[0009] In a first aspect, the invention provides a device for
dispensing a drug by inhalation wherein the device or components
thereof are coated by a cold plasma coating process characterised
in that the coating is a fluorinated acrylate compound or a mixture
thereof.
[0010] In a further aspect, the invention provides use of a
fluorinated acrylate compound for the cold plasma coating of a
medicinal device.
[0011] In a further aspect, the invention provides a process for
coating a medicinal device with a fluorinated acrylate which
comprises coating the device with a cold plasma.
[0012] The term "cold plasma" means that the temperature within the
body of the plasma is ambient.
[0013] The advantages of the invention are that no spray guns are
used for the coating. Henceforth, problems associated with
conventional coating methods such as spray blockage can be avoided.
In addition since the present invention employs cold plasma,
polymers can be used that could not otherwise be used with
conventional spraying such as unstable polymers The medicinal
devices can be coated in a batch process. Cold plasma is also
better than standard coating in that a more uniform coat is
achieved and the coating can reach in the intricate part of the
device design that standard spray coating fails to reach. Finally,
a chemical bond is achieved between substracte and coating, which
provides a longer lasting and more efficient coated layer.
[0014] The chemicals with which the device components can be coated
are fluorinated acrylates suitable for plasma coating. Short chain
acrylates are preferred. The molecules can be straight of branched
chains. Most preferably 1H, 1H, 2H, 2H heptadecafluorodecyl
acrylate, 1H, 1H, 2H, 2H perfluoroctyl acrylate and 1H, 1H, 2H, 2H
perfluoroctyl methacrylate can be used. Any other homologous
compound in the acrylate family can also be used. This list does
not pretend to be exhaustive, and any person skilled in the art
could identify other compounds with similar structures as being
covered in this invention. These would include homologous series of
the previous molecules (i.e. with a varying chain length, or
branching), and other straight chain fluorinated acrylates and
methacrylates. Chain length less than 25 carbon atoms long are
preferred, most preferably they should have less than 20 carbon
atoms, most most preferably less than and including 16.
[0015] The thickness of the coated layer can range from 1 nm to 500
.mu.m Preferably between 5 nm and 100 .mu.m.
[0016] The invention can be applied successfully to any part of an
inhalation device where drug adhesion can occur. For pMDIs, the
actuator, the stem, the valve components, the measuring chamber,
the seals, and the canister can all be treated. The invention
relates to inhalation therapy therefore includes also nebulisers,
nasal sprays and dry powder inhalers (DPI's).
[0017] The invention is particularly successful with drugs suitable
for the inhaled route. Examples of specific drugs which can be used
according to the invention include mometasone, ipratropium bromide,
tiotropium and salts thereof, salemeterol, fluticasone propionate,
beclomethasone dipropionate, reproterol, clenbuterol, rofleponide
and salts, nedocromil, sodium cromoglycate, flunisolide,
budesonide, formoterol fumarate dihydrate, Symbicort.TM.
(budesonide and formoterol),
3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(4-met-
hylphenyl)ethoxy)ethyl]propansulphonamide, terbutaline, terbutaline
sulphate, salbutamol base and sulphate, fenoterol,
3-[2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[24-methy-
lphenyl)ethoxy]ethyl]propanesulphonamide, hydrochloride. All of the
above compounds can be in free base form or as pharmaceutically
acceptable salts as known in the art.
[0018] The coating process can be carried out using the techniques
described in WO 99/64662 and WO 00/05000.
[0019] The full potential of this invention is revealed for
particles with a size distribution between 100 nm and 1000 .mu.m,
most preferably between 500 nm and 500 .mu.m, even more preferably
between 900 nm and 100 .mu.m, most preferably between 900 n=and 30
.mu.m.
[0020] The invention works particularly well when the particles are
dispersed in a non-aqueous pressurised medium such as the
propellants HFA227 and BFA134a, or any mixture thereof. The
invention can also be applied successfully to devices having
formulations with HFA propellants, or propellant mixtures to which
have been added polymers or co-solvents.
[0021] The invention is illustrated by the following examples.
EXAMPLES
[0022] To assess the usefulness of the coating technique for
inhalation a series of tests were performed. Aluminium surfaces
were coated with 3 types of polymers under 2 types of conditions.
Interactions between drug particles and the treated surfaces were
then measured by Atomic Force Microscopy (also known as AFM). The
strength and range of these interactions were compared with the
ones obtained from an uncoated surface.
[0023] The materials used to exemplify the invention were: 1H, 1H,
2H, 2H Heptadecafluorodecyl acrylate, 1H, 1H, 2H, 2H Perfluoroctyl
Acrylate and 1H, 1H, 2H, 2H Perfluoroctyl Methacrylate.
[0024] The chemicals were cold plasma coated onto aluminium sheets.
These Aluminium surfaces are the one currently used to manufacture
pMDI canisters. With 3 different chemicals and 2 methods of
production, a total of 6 coatings were investigated. In addition,
an anodised aluminium surface and a non-anodised one were studied
to provide a reference for the interactions.
[0025] The drug used in these tests was formoterol fumarate
dihydrate (abbreviated as FFD). Its size distribution was centred
around 2 .mu.m.
[0026] The extent of the adhesion between the particles and the
treated surfaces was tested in a fluorinated solvent, 2H, 3H
perfluoropentane (abbreviated as HPFP). This liquid is a very good
substitute for both propellants HFA227 and BFA134a. It is used when
tests can not be performed in situ in pressurised liquids, such as
AFM.
[0027] Substrate surfaces were imaged in air with a Digital
Instruments Nanoscope III AFM in TappingMode.TM. operation, using
standard silicon TBSP cantilevers (Nanoprobes, Digital Instruments,
Santa Barbara). Typical scan rates for all images were between
1-1.5 Hz with a pixel resolution of 512.times.512. Force-distance
interactions and force volume data were recorded under in-situ
conditions, via a hermetically sealed contact mode in-situ cell
(Digital Instruments, Santa Barbara). Drug particles were glued on
a tipless cantilever to act as a colloidal probe.
[0028] The adhesion force was calculated from the retracting
force-distance curve. The adhesion energy is the product of the
maximum force by the distance to which the cantilever retracts when
going away from the surface (see FIG. 1, do you have the figure,
they should have been sent with the previous e-mail???). The AFM
technique used in this study records a series of force-distance
curves on a finite surface and for each points calculates an
adhesion energy. When a repulsion is felt, no calculation is
possible. The energy values quoted are average values over a finite
element of the surface (on average 20 .mu.m.times.20 .mu.m).
[0029] Reference Sample: Non Anodised Aluminium Surface:
[0030] A non anodised aluminium surface was used as a reference.
The force distance curve for this sample can be found on FIG.
2.
[0031] An attractive force was felt on approaching the surface. The
attractive force led to an adhesion force on contact of .about.8
nN. For each point measured an adhesion energy was calculated from
the retraction experiment (i.e. when the cantilever is taken away
from the surface). The adhesion energy spread can be found on FIG.
3. Because of the roughness of the surface, the adhesion energy
spreads over a range of energy values. Two areas of adhesion are
seen: a low adhesion centred around 5.8 nJ and a high adhesion
region centred on 36.4 nJ. The energy spread is due to the
variations in surface roughness.
[0032] Reference Sample: Anodised Aluminium Surfaces:
[0033] A second reference sample was studied. This was an anodised
aluminium surface. Anodised aluminium sheets are also used in the
process of making pMDI canisters.
[0034] As with the previous sample, an attractive force was felt on
approaching the drug particle to the surface. This attractive force
was translated into and adhesive force on contact for which an
adhesive energy can be calculated. The adhesion force was on
average 51.5 nN, yielding adhesion energies between 5 and 1500 nJ.
(see FIG. 4 for energy diagram). The high adhesion energies are
centred on 1038 nJ.
[0035] Sample 1: Aluminium Surface Cold Plasma Coated with 1H, 1H,
2H. 2H heptadecafluorodecyl acrylate with a Continuous Wave.
[0036] As can be seen from the force-distance profile for this
sample (see FIG. 5), no attractive force was detected on
approaching the particle to the coated surface.
[0037] There was however a weak and irregular adhesion force on
retraction. Probably due to some drag caused by the extension of
the fluorinated chain. The drug and cantilever on retraction
dragged the chain with them and created what appears to be an
attractive force. This force however is mechanical in nature, and
is not of the van der Waals type. i.e. its extent stops where the
molecular chain finishes, it is a contact force. The system was
essentially non attractive and no adhesion energy could be
calculated.
[0038] The plasma coating is therefore an effective way of reducing
particle adhesion.
[0039] Sample 2: Aluminium Surface Cold Plasma Coated with 1H, 1H,
2H, 2H heptadecafluorodecyl acrylate with a Pulsed Wave.
[0040] The same observation were done on this sample as on sample
1. No attraction is detected, and an irregular adhesion is
seen.
[0041] Therefore, the 1H, 1H, 2H, 2H heptadecafluorodecyl acrylate
coating, either applied as a continuous wave or a pulsed one, is an
effective hindrance to particle adhesion to surfaces in a
fluorinated environment.
[0042] Sample 3: Aluminium Surface Cold Plasma Coated with 1H, 1H,
2H, 2H perfluoroctyl acrylate with a Continuous Wave.
[0043] No attraction was detected on approaching the particle to
the coated surface. On retraction, no adhesion was observed.
[0044] This coating is a very effective way of preventing drug
adhesion.
[0045] Sample 4: Aluminium Surface Cold Plasma Coated with 1H, 1H,
2H, 2H perfluoroctyl acrylate with a Pulsed Wave.
[0046] No attraction was detected on approaching the particle to
the coated surface. On retraction, no adhesion was observed.
[0047] This coating is a very effective way of preventing drug
adhesion.
[0048] Sample 5: Aluminium Surface Cold plasma coated with 1H, 1H,
2H, 2H perfluoroctyl methacrylate with a Continuous Wave.
[0049] No attraction was detected on approaching the particle to
the coated surface. On retraction, no adhesion was observed.
[0050] This coating is a very effective way of preventing drug
adhesion.
[0051] Sample 6: Aluminium Surface Cold Plasma Coated with 1H, 1H,
2H, 2H perfluoroctyl methacrylate with a Plused Wave.
[0052] No attraction was detected on approaching the particle to
the coated surface. On retraction, no adhesion was observed.
[0053] This coating is a very effective way of preventing drug
adhesion.
[0054] FIG. 6 summarises the average energies for all samples. No
adhesion energy could be calculated for any of the coated samples,
whereas uncoated samples had strong adhesive energies and
attractive forces.
LIST OF FIGURES
[0055] FIG. 1: Calculation of adhesion energy from AFM
measurements.
[0056] FIG. 2: Force vs distance curve for FFD against a non
anodised aluminium surface in HPFP.
[0057] FIG. 3: Energy map for the interaction between FFD and a non
anodised aluminium surface in HPFP.
[0058] FIG. 4: Energy map for the interaction between FFD and an
anodised aluminium surface in HPFP.
[0059] FIG. 5: Force vs distance curve for FFD against the surface
of sample 1 in HPFP.
[0060] FIG. 6: Summary of adhesion energies for coated and uncoated
samples.
* * * * *