Note: Descriptions are shown in the official language in which they were submitted.
~ CA 022480~0 1998-09-01
D1518-lWO PCT/ SE 9 7 / O 0 4 7 0
'O 3 ~ 1998
I
COMPONENTS FOR INHALATION DEVICES
The present invention relates to components for inhalation devices for inhaling
medicament, especially those components which can affect airborne particles or come into
contact with medicament.
Inhalation devices include dry powder inhalers, intended to dispense medicament which is
in the form of a dry powder, and pressurised metered dose inhalers, which generally
contain a medicament dissolved or suspended in a liquefied propellant gas, optionally
o together with surfactants and other excipients. The mechanism for dispensing the
medicament varies between inhalers, but in general the medicament must exit the body of
the inhaler and pass through a channel to a mouthpiece. The mouthpiece may connect with
a spacer, that is, a dispersion chamber designed to facilitate inhalation.
Pressurised metered dose inhalers release a metered dose of medicament upon eachactuation, and for maximum benefit with direct inhalation a degree of co-ordination
between actuation and inhalation is required. Powder inhalers are actuated by the air flow
generated at inhalation and for maximum benefit a certain air flow is required. With a
spacer, the medicament is dispensed into the spacer chamber from where it can be inhaled
~o simply by breathing normally. The residence time of the medicament in the spacer can be
from a few seconds to several minutes, for example.
An example of a dry powder inhaler is the Turbuhaler(~) inhaler. Examples of spacers
include the Nebuhaler(~) and Nebuchamber~) spacers.
'5
In the course of inhalation, medicament will come into contact with various parts of an
inhalation device, including for example the body, channel and mouthpiece of an inhaler,
and a spacer. Such components are generally (but not essentially) made of a polymeric
material, for example, a polypropylene or a polyethylene, which is moulded into the
required shape.
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Dls4s-lwo PCT/SE97 /a0470
~ 3 -n6- 1998
Not all of a nominal dose of medicament from an inhaler will reach its intended target,
which may be, for example, the lungs. The medicament which does not reach the target is
lost, for example, in the inhaler, mouth and respiratory tract. Clearly, the amount of
wastage should be as low as possible.
WO-A-91/19524 describes an inhaler for inhaling pulverulent medicament from within a
capsule, including a capsule chamber which may be formed of components made of apolymeric material with low surface resistivity in order to rninimice the extent to which
o released powdered medicament can agglomerate on the surface of the air passage through
the inhaler. The surface resistivity desired is preferably less than 101- Ohms and more
preferably less than 108 Ohms. The polymeric material may incorporate carbon or steel
filler, for example, in the form of fibres or non-fibrous chemical additives. As examples of
the polymeric material are mentioned a polyether block amide product with chemical
additives and a range of polypropylenes with chemical additives. The inhaler also includes
a mouthpiece, which may be integral with the chamber, preferably having at least its inner
wall formed from such a polymeric material of low surface resistivity.
WO-A-95/20414 describes a spacer for children, primarily intended to be used in
conjunction with a pressurised metered dose inhaler. The spacer is made from stainless
steel, which has a surface resistivity such that electrostatic attraction between the respirable
particles and spacer walls is minimised. The surface resistivity is less than 109 Ohm,
preferably less than 106 Ohm and most preferably less than 1 Ohm.
The present invention is concerned with polymeric materials in components for inhalation
devices. It has been found that the amount of medicament which is retained in a device
comprising components made of a polymeric material can be significantly reduced by
incorporating carbon black into the polymeric material. Components according to the
present invention have anti-static properties which minimise the amount of medicament
retained on component surfaces.
A!~ ED SHEr
~ CA 022480~0 1998-09-01 PCT/ SE 9 7 / 0 0 4 7 0
D1548-iWO
O ~ 199~
Carbon blacks are obtainable, for example, from Degussa AG, Frankfurt, Germany. They
are chemically and physically well-defined products, which are manufactured by
incomplete combustion of oils or gases, and are composed of more than 96 percent by
weight of finely dispersed carbon with small amounts of oxygen, hydrogen, nitrogen and
sulphur. They may be produced, for example, as dispersions, pastes, chips or pellets.
Today, the most important method for the manufacture of carbon blacks is the so-called
"furnace black" process. This process can produce a large variety of carbon blacks, for
example, with particular particle sizes and specific surface areas. It also permits the
o control of particle aggregation, that is, the carbon black structure. Carbon blacks consist of
chained-branched aggregates of approximately spherical "primary" particles. Extensive
branching or interlinking produces carbon black having a "high structure", while less
extensive interlinking produces a "low structure" carbon black. One method for the
determination of structure is the "DBP absorption" test, which is described in ISO 4656
and ASTM D-2414. In this method, dibutylphthalate (DBP) is added dropwise to a certain
amount of carbon black that has been placed in a calibrated kneading machine and the
torque exerted by the kneading machine is measured. A change in the torque indicates that
all of the voids between the carbon black aggregates have been filled with DBP and the
surface has been wetted. The consumption of DBP thus allows determination of the degree
of aggregation of the carbon black. In general, the higher the DBP absorption in ml /100 g
(the "DBP number"), the higher the carbon black structure. Carbon blacks with a low
structure have a DBP number of less than 70 ml/100 g of carbon black, those with a
medium structure have a DBP number of between 70 and 100 ml/100 g of carbon black,
and those with a high structure have a DBP number of above 110 ml/100 g of carbon black.
So-called "extra-conductive" carbon blacks typically have a DBP number in excess of 300
ml/100 g of carbon black.
The primary use of carbon blacks is in the reinforcement of rubber, for pigmentation, UV
stabilisation and as conductive blacks.
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Accordingly, the present invention provides a component for use in an inhalation device,
said component being made of or coated with a polymeric material loaded with carbon
black having a DBP number of more than 300 ml/l00 g of carbon black and in an amount
of between 3 and 15 percent by weight of the polymeric material to impart to the polymeric
5 material a specific volume resistivity of less than l09 Ohmcm.
The present invention also extends to an inhalation device, in particular a spacer,
incorporating the component as described above.
10 Preferably, the specific volume resistivity of the polymeric material is less than about lo6
Ohmcm, more preferably less than about 104 Ohmcm. In an especially preferred
embodiment the specific volume resistivity of the polymeric material is less than about 102
Ohmcm.
15 Specific volume resistivity may be measured using commercially available apparatuses for
measuring conductivity.
The use of a carbon black dispersion is particularly advantageous as good dispersion of the
carbon black in the polymeric material can be achieved. Preferably, the carbon black-
20 loaded polymeric material comprises a homogeneous distribution of the carbon black.
3 The very low specific volume resistivity values which may be achieved in accordance with
the present invention are particularly valuable when the component is incorporated in a
spacer. In a spacer, a comparatively long medicament residence time is necessary, and the
longer the residence time, the more opportunity there is for the medicament to "attach" to
the spacer walls.
It will be understood that the component of the present invention may be other than that
incorporated in a spacer. For example, the component may comprise the body, a channel,
or the mouthpiece of an inhaler.
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D1548-lWO PCT/ SE97 /00470
O ~ ~ 1998
Preferably, carbon black is included in an amount of between 6 and lO percent and
especially between 8 and lO percent by weight of the carbon black-loaded polymeric
material.
More preferably, carbon black is included in an amount of around lO percent, or around 9
percent, or around 8 percent, or around 7 percent, or around 6 percent, or around 5 percent,
or around 4 percent by weight of the carbon black-loaded polymeric material.
o Suitable carbon blacks are commercially available, for example, from Degussa AG, or
from Cabot Plastics, Belgium. Examples of Degussa AG carbon blacks are the range of
carbon blacks known as Printex(~), for example "Printex L", "Printex L 6", and the extra-
conductive "Printex XE 2".
The polymeric material can be any which can be moulded into the desired shape. For
example, the polymeric material may be a polypropylene, a polyethylene. a polyester, a
polycarbonate, a polystyrene, a polyoxyethylene, a fluoropolymer, or a copolymer thereof.
Suitable polymeric materials may be obtained, for example, from Hoechst AG, Frankfurt,
Germany. As specific examples of polymeric materials may be mentioned the
polyethylenes Hostalen(~) and Hostalen GUR(~); the polypropylenes Hostalen PP(~) and
Hostacen(~); as well as Topas(~), Hostaform(~), Kemetal@), Celanex(~3, Vandar(~), Impet g),
Celstram(~), Fortron( 9, Vectra(~) and Hostaflon~), all available from Hoechst AG.
Preferably, the polymeric material is a polypropylene or a polyethylene.
The carbon black-loaded polymeric material, and the homogeneous mixture, may be
manufactured by conventional methods, for example, by extrusion of the polymericmaterial together with the carbon black. The mixing parameters, flow conditions and
cooling conditions may be optimised easily by methods well known to a person skilled in
the art, according to the particular polymeric material and carbon black used.
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D1548-1WO PCT/ SE 9 7 / 0 0 4 7 0
0 3 -06- 1998
Carbon black-loaded polymeric materials are also commercially available, for example,
from Premix Oy, Rajamaki, Finland.
The components according to the present invention may be made by conventional
moulding techniques, for example, by injection moulding or by blow moulding. Themoulding parameters may be optimised easily by a person skilled in the art, according to
the particular materials used. The preferred method of manufacture is injection moulding.
Typical injection moulding parameters may be for example a cylinder nozzle temperature
of from 200 to 250 ~C, a mould temperature of from 30 to 80 ~C, an injection pressure of
o from 600 to 1800 bar and a moderate injection speed. Preferably, a low moulding speed is
used initially and slowly increased during the moulding process. Preferably, the back
pressure is as low as technically possible. Preferably, the material for injection moulding is
pre-dried, for example, at from 75 to 80 ~C for up to 4 hours, typically from 2 to 4 hours.
The present invention also provides a method of forming the component for use in an
inhalation device as described above, comprising the step of moulding the component at
least in part from a carbon black-loaded polymeric material.
When the carbon black-loaded polymeric material is a coating on another polymeric
material, it may be co-moulded with the other polymeric material, for example, using two
extruders, to produce a moulded component in which the carbon black-loaded polymeric
material is surrounded by the other material; that is, the "inner" surface of the component is
of the carbon black-loaded polymeric material and the "outer" surface of the component is
of the other polymeric material. The outer material may be provided with any desired
pigmentation to mask the black colour of the carbon black in circumstances where this
would be considered undesirable.
~ The thickness of the component or carbon black-loaded polymeric layer may vary
according to the nature of the moulded component. Where the component is incorporated
A~DED SHEET
CA 022480~0 1998-09-01
D1548-lWO PCT/SE97 /00470
0 3 ~ 1998
in a spacer, for example, the thickness of the carbon black-loaded polymeric material may
be, for example, up to about 10 mm, preferably betw~en 1 and 5 mm thick.
The present invention will be further described with reference to the following non-limiting
Examples.
Example I
A carbon black-loaded polymeric material, "PP 1381 " (formerly "Pre-Elec TP 4474"),
o Premix Oy, comprising polypropylene "Hostalen PPU 1734S 1 ", Hoechst AG, and 9percent by weight of "Printex XE 2" carbon black, Degussa AG, was used to manufacture a
spacer for use with a dry powder inhaler, by injection moulding using a "Ferromatic"
injection moulder, with a cylinder nozzle temperature of 240 ~C, a mould cavity
temperature of 30 ~C, an injection pressure of 1700 bar, a back pressure of 1600 bar and a
moderate injection speed.
The specific volume resistivity obtained was 100 Ohmcm. (Surface resistivity 1300 Ohm.)
Example 2
A carbon black-loaded polymeric material, "Pre-Elec TP 4479", Premix Oy, comprising
polypropylene "Hostalen PPU 1734Sl", Hoechst AG, and 22 percent by weight "Black'~ Pearls 4750" carbon black, Cabot Plastics, was used to manufacture a spacer for use with a
dry powder inhaler, by injection moulding as in Example 1.
The specific volume resistivity obtained was 30 Ohmcm. (Surface resistivity 800 Ohm.)
Example 3
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D15~8-lWO PCT/ SE 9 7 t 0 0 4 7 0
0 3 ~6- 1998
A carbon bl~ck-loaded polymeric material, "Pre-Elec TP 4480", Premix Oy, comprising
polypropylene "Hostalen PPU 1734S l", Hoechst AG, and 37 percent by weight "Channel
Black MPC" carbon black, Cabot Plastics, was used to manufacture a spacer for use with a
dry powder inhaler, by injection moulding as in Example 1.
The specific volume resistivity obtained was 10000 Ohmcm. (Surface resistivity 100000
Ohm.)
Example 4
Doses of budesonide from a dry powder inhaler (Pulmicort Turbuhalertg)) containing 200
unit doses each comprising 400 ~g of budesonide were expelled by means of a suction flow
into a spacer according to Example I above After a 2 second delay, suction flow means
were employed to expel the dose from the spacer onto a filter.
The experiment was repeated using a spacer constructed of polypropylene only. The means
of manufacture of the polypropylene-only spacer was as in Example 1, but with aninjection pressure of 900 bar and a back pressure of 600 bar.
~o The amount of budesonide on the filter after expulsion from the carbon black-loaded
polypropylene spacer of Example 1 was 2.4 times greater than the amount resulting from
expulsion from the conventional polypropylene spacer. This was taken as an indication of
~ the greatly reduced amount of medicament which had been retained in the spacer according
to the present invention as compared with a conventional spacer.
~5
Example 5
Doses of budesonide from a dry powder inhaler (Pulmicort Turbuhalertg)) containing 200
unit doses each comprising 400 llg of budesonide were expelled by means of a suction flow
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D15~8-lwO PCT/ SE97 / OC470
0 3 ~ 1998
into a spacer according to Example 1 above. After a 30 second delay, suction flow means
were employed to expel the dose from the spacer ont~ a filter.
The experiment was repeated using a spacer constructed of polypropylene only. The means
of manufacture of the polypropylene-only spacer was as in Example 1, but with aninjection pressure of 900 bar and a back pressure of 600 bar.
The amount of budesonide on the filter after expulsion from the carbon black-loaded
polypropylene spacer of Example 1 was 2.8 times greater than the amount resulting from
o expulsion from the conventional polypropylene spacer. This was taken as an indication of
the greatly reduced amount of medicament which had been retained in the spacer according
to the present invention as compared with a conventional spacer.
D S~
