Note: Descriptions are shown in the official language in which they were submitted.
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5012550J.20
Apparatus and process for metering powder
The invention relates to an apparatus and a process
for metering small amounts of finely divided powder.
Small amounts of finely divided, preferably
micronised powder are used particularly for therapeutic
purposes, mainly in the form of aerosols for the
treatment by inhalation of respiratory complaints such
as asthma.
Powders of this kind are conveyed to the patient's
lungs~in amounts which are usually well below 50 mg in
the air breathed in. It has been found that the
particles of active substance should be less than 10 ~,m
in size to ensure that they penetrate deep into the
lungs. However, this does not rule out the use of some
larger particles in the preparations, particularly for
any excipients. If particles of different sizes are
used, a significant difference in size is sometimes even
desirable or in any case not harmful; cf. DE-OS
17 92 207.
Two main methods have been developed for
administering fine powders without the aid of propellant
gases in respiratory tract therapy.
One method makes use of hard gelatine capsules each
of which contains a dose of active substance and
possibly also excipients, whilst the other, using a
measuring chamber, removes a specific amount of powder
from a storage container and mixes it with the air
breathed in. Devices for both methods have been
described in large numbers, cf. for example DE-OS
23 46 914; EP-OS 166 294.
The invention now provides a new method of
administering fine powders. In this method, the ease of
manufacture of carriers charged with active substance is
advantageously combined with accuracy of metering and
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the possibility of producing an aerosol suitable for inhalation
by simple means.
According to the invention, there is provided carrier
charged with powdered pharmaceutical preparation for the
production of aerosols for inhalation, characterized in that it
consists of a substantially planar material layer on which
fibres of a length of 0.1 to 3 mm are provided being secured on
one end or at the centre on or in the carrier, the free end or
the two free ends being directed upwardly, predominantly form-
ing angles of 45 to 90°, wherein the powder is incorporated
between the fibres. When used for inhalation, the powder
released is mixed with the air breathed in, optionally via an
inhalation device such as the one described for example in
German Utility Model 89 08273.
When the dry powder is spread into the velour
material, the movement of the fibres under the doctor blade
causes a preliminary break-up. The particles are then in a
very loose state and are correspondingly less inclined to clump
together. When the powder is applied by means of a suspension,
this preliminary break-up is achieved by running an edge over
the powder, so that once again only some of the energy for the
breaking-up has to be supplied by the gas jet. Moreover, the
previously broken up particles present a large surface area for
contact with the gas jet, which again has a favourable effect
on dispersal.
The carrier consists of a substantially planar
material on which thin fibres are provided. The fibres are
secured by one end or at the centre on or in the carrier. The
free end or the two free ends of the fibres are directed
upwardly, predominantly forming angles of 45 to 90°, more
particularly 60 to 90° with one another. The material which
carries the fibres may be, for example, paper, plastics film or
a textile fabric; the fibres may be natural or synthetic, e. g.
cotton, wool, silk, viscose, perlon, nylon or polyacrylic.
The fibres are preferably up to about 1 mm long.
They should not be too matted, to ensure that the powder
applied, which is essentially
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embedded between the fibres, can be blown out again
relatively easily. The lower limit for the length o.f
the fibres is about 0.1 mm. Generally, the length of
the fibres should be such that the powder applied can be
accommodated in the desired quantities per unit of
surface area.
Accordingly, a carrier material with longer fibres
is appropriate for relatively large quantities of powder
per unit of surface area, whereas, for very small
quantities of powder per unit of surface area, shorter
fibres are usable or, even, advantageous. The quantity
of powder which can be applied per unit of surface area
'depends mainly on the nature (density) of the powder and
its compaction, as well as the carrier material used.
If the powder is to be administered by inhalation, care
must however be taken to ensure that the dispersal of
the powder in the gas or air jet used is not affected by
excessive compaction.
The number of fibres per unit of surface area may
vary considerably. Various commercially available
carriers have proved suitable (velour-film, velvet,
niki). These products also provide a guide to the
suitable fibre density of other carriers. The fibre
thickness also varies within wide limits. Generally,
fibres with a~diameter of from 0.002 to 0.05, preferably
0.004 to 0.03 mm are used. The velvet-like carrier
itself may also be attached, e.g. by glueing, to a stiff
layer. It is also possible to attach an absorbent
under-layer.
The carrier may be correspondingly flexible or
rigid and rectangular or circular, for example.
Preferably, the carrier is in the form of a strip. This
may be charged with the powder over its entire surface
or over individual areas. In the latter case, the strip
may be charged with the powder by means of a template
over small individual areas, e.g. in the form of
circular areas a few millimetres in diameter and clearly
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spaced apart, so that when the powder is blown out from
one of these areas the powder on the neighbouring areas
remains unaffected.
Thus, the dose can be accurately fixed by means of
the quantity of powder on each of the small charged
areas.
Tf the entire surface of the carrier is coated with
powder, the quantity of powder which is blown out can
simply be determined by the size of the area exposed to
the gas jet during each separate removal operation and
defined, for example, by means of a mask. However, a_
mask is not essential. It has been found, in fact, that
the quantity of powder blown downwards from the
uniformly charged carrier by means of the gas jet is
substantially constant. Consequently, the quantity of
powder dispersed can also be regulated by the intensity
of the gas jet and the geometry of the nozzle.
In order to protect the layer of powder it may be
appropriate to cover or laminate the carrier with a
plastics film, for example, in such a way that only that
part of the carrier from which powder is to be taken is
exposed. Particularly in moisture-sensitive powders, an
aluminium lamination on both sides might be considered.
Finally, it is also possible to use carriers, e.g.
strips, in which there are alternating areas filled with
fibres and smooth areas.
In order to charge the carrier, first of all a
layer of powder 1 to 2 mm high is distributed as
uniformly as possible thereon (in the case of highly
effective pharmaceutical powders and in the case of
carriers with very short fibres the layer may be
considerably thinner). The powder is pressed into the
strip by means of a doctor blade and excess powder is
wiped away. This process is repeated once or several
times, as necessary, with the doctor blade being set
progressively lower. As a result of the movement of the
fibres under the pressure of the doctor blade, the
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agglomerated areas of powder are broken up.
If only certain parts of the carrier are to be
charged, the carrier may be covered, for example, with a
template, e.g. a suitably perforated film. If the
powder is then applied as described above, the carrier
will be charged with it only at those points where the
perforations are located.
The powder may also be applied to the carrier in
the form of a suspension. In the case of pharmaceutical
compositions for inhalation, the dosage of active
substance is generally so small that the quantity of _
active substance contained in one drop of suspension is
sufficient. One drop of the suspension is then applied
at the desired spacing from the next drop. The spacing
is selected so that the spot of powder which remains
after evaporation of the suspension agent is clearly
separated from the adjacent spot. The aim is to be able
to separate only the exact quantity of powder applied in
one drop from the carrier when the powdered active
substance is transferred into the stream of air breathed
in.
It is particularly satisfactory to charge the
carrier with an accurately metered quantity of powder
over a small area using a suspension.
The suspending agents used may be liquid organic
compounds in which the powder to be applied does not
dissolved readily and which can be eliminated as
completely as possible.
Examples of suspending agents of this kind which
are selected in accordance with the solubility
characteristics of the substance or mixture of
substances to be suspended include dichlorome~thane,
ethyl acetate, 1,1,1-trichloroethane or petrol (e.g. the
fraction 60/95 or 80/110). As a rule, suspension
adjuvants such as lecithin are added to the suspension.
The solids content in the suspension is usually between
3 and 30 percent by weight, preferably from 5 to 25
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percent by weight; the quantity of suspension adjuvants varies
between about 0.5 and 3 percent by weight, based on the solids.
The carriers and suspension should be such that the
particles of powder are left behind at the point where the
drop penetrates into the carrier, whilst the suspending agent
spreads out and then evaporates. The evaporation can be
promoted by pressure reduction and/or by heating.
The material from the dried drop of suspension cannot
generally be released and dispersed simply by means of a jet
of air. However, if the fibres of the carrier are moved, e. g.
by running an edge over them the bonds between the particles
of powder are broken up again and the powder is "activated".
The individual particles which adhere to one another or to the
fibres of the carrier with only slight adhesive force after
activation can then be released by means of an air jet and
dispersed, to a large extent, into the lungs.
Instead of releasing the loosened powder from the
carrier by means of a jet of air, it is also possible to loosen
it by running an edge over it or by brushing, immediately
before or while the flow of breathed-in air is passing the
carrier, and thereby transferring the powder into the air which
is breathed in.
Apart from the high degree of accuracy of metering,
the application of a drop of suspension has the further
advantage over the application of dry powder that the powder is
protected from being released by acceleration (impact,
vibrations) by the encrustation. The activation by running
along an edge should only be carried out immediately before the
powder is released for inhalation.
The invention will further be described, by way of
example only, with reference to the accompanying drawings
wherein:
Figure 1 is a somewhat schematic illustration of an
apparatus for applying the powdered suspension;
Figure 2 is a sectional view showing a valve for use
in the apparatus;
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Figure 3 is a side elevation of a device for utiliz-
ing a carrier in accordance with the invention; and
Figure 4 is a front elevation corresponding to
Figure 3.
As shown in Figure 1, the suspension 1 is initially
in the storage container 2. From there it flows through the
line 3 to
a magnetic valve 4 and passed the valve surfaces through
the line 5 into the storage container 6. In the resting
position the plunger 7 seals off the inlet port of the
line 8 from which the suspension is applied to the
carrier 11. At the sides, the suspension is able to
flow passed the plunger from the line 3 to the line 5.
When the plunger is pulled back by an electromagnet, it
exposes the opening so that the suspension can reach the
carrier 11. The suspension is pumped out of the
container 6 by means of the pump 9 into the storage
container 2. To ensure that the suspension in the
storage container 2 is always at the same level, there
'is a connecting line 10 between these two storage
containers, through which suspension can flow from
storage container 2 into storage container 6 when the
liquid level is higher than the entry port of this
connecting line. The cross-section of the lines 3 and
is made so small that the volume flow of suspension
flowing through the two lines is less than 'the volume
flow delivered by the pump 9. In the storage containers
2 and 6 are stirrers which keep the particles constantly
suspended. For uniform metering, the magnetic valve
is controlled by an electronic timer. Details of the
valve are illustrated in Figure 2.
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Example of the application of the pharmaceutical
composition as a suspension:
A suspension of micronised fenoterol (proportion of
fenoterol: 10 percent by weight) in dichloromethane
with the addition of (0.1 percent by weight)
lecithin was applied to velvet with a fibre length
of 1.2 mm over the basic fabric, dropwise at
spacings of about 10 mm and then dried. The powder
was then activated by running an edge over it and
blown out of the carrier with a gentle jet of
compressed air. _
The inhalable portion of the particles (particle
diameter < 5.8 Vim) was 41.4% of the dosage
expelled.
A relatively small amount of gas, e.g. 10 cc or
air, forced through a 0.5 mm diameter nozzle, is
sufficient to disperse (blow out) the powder.
The gas jet required for dispersal can be produced
in various ways, e.g. using a cylinder provided with a
nozzle out of which air is forced by a spring-operated
piston, or by means of conventional small COZ containers
which can be used to generate pressure. Instead of.a
cylinder with a piston it is also possible to use
bellows.
A simple device in which carriers charged according
to the invention can be used is diagrammatically shown
in Figures 3 and 4. The main constituents are two
bobbins, one of which receives the charged strip whilst
the other receives the used strip. The strip is guided
over a panel, whilst being guided passed an edge to
activate the powder. Here, the jet of gas or air makes
contact with the strip and carries the powder along.
The jet is generally released at a time when air is
being breathed in through the mouthpiece. It is
advisable to actuate the stream of gas or air by means
of the air breathed in so as to coordinate the dispersal
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of the powder with the inhalation of the process.
Figure 3 shows an inhalation device viewed from in
front. The carrier strip 12 with the powder, which is
applied in individual dots at regular intervals on the
strip, is unwound from the bobbin 13 and, once empty,
wound onto the bobbin 14. By means of a transporting
mechanism constructed in conventional manner, the strip
is wound on, on each actuation of the device, by an
amount such that a new spot arrives on the flat surface
15. The flat surface 15 is located in a mouthpiece 16
through which the patient breathes in. The slot through
which the carrier strip 12 is guided into the mouthpiece
is somewhat narrower than the thickness of the carrier
strip 12. The upper boundary of the slot is constructed
as an edge for activating the powder. Air is passed
onto the dot of powder through a nozzle from a cylinder
17 in which there is a piston subjected to spring
pressure with a handle 18. The spring which urges the
piston towards the flat surface 15 is biased by pulling
the handle 18. The dispersing step is prepared by means
of a locking mechanism 19 which can be released by
pressing the knob 20. Whilst breathing in through the
mouthpiece 16 the patient presses the knob 20 and thus
ensures that the piston propels the quantity of air
contained in the cylinder through the nozzle onto the
dot of powder, so that the powder is dispersed in the
air breathed in.
Figure 4 diagrammatically shows the apparatus from
the side, the mouthpiece 16 being shown in section. The
nozzle 21 guides the jet of air out of the cylinder 17
onto the dot of powder.
The bobbins with the carrier are in this case.
contained in a cassette similar to that used in cassette
recorders. Their movement is advantageously coupled
with the movement of the handle 18, so that, each time
the piston is put under tension, the carrying strip is
moved on until the next dot reaches the flat surface 15.
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Instead of the cylinder and spring it is also
possible to use a bellows or a C02 cartridge of
conventional construction which releases a few cc of COZ
every time the device is used, in order to generate a
gas current, as mentioned above. The COZ is then again
guided through a nozzle onto the carrier surface coated
with powder. The volume of gas needed to disperse a
quantity of powder required for therapeutic purposes is
generally 3 to 20 cc (under normal conditions).
Nozzles are used which have a mouth shaped to suit
the type of carrier. In the case of circular dots of
powder, the nozzle has a small, preferably circular
aperture. In the case of larger, powder-coated carrier
surfaces, a slot-shaped or rectangular nozzle may be
more appropriate. In this case, a larger quantity of
gas is used, if necessary, in order to ensure the
required speed of outflow.
The accuracy of metering was measured in a series
of tests in which either (tests 1, 2, 3) a carrier strip
was continuously coated by the application of dry powder
and a sharply defined section of the strip was
investigated in each case or else a strip was used in
which only certain places had a coating of powder.
The following surface coatings and relative
standard deviations were found:
Material Surface Relative standard
covering deviation
1. Velour-film 6.6 mg/cmz 6.3%
2. Velvet 2.2 mg/cmZ 6.Oo
3. Nicki 5.4 mg/cm2 6.2%
4. Velour-film with
individual circular
dots of powder* 2.1 mg/dot 11.2%
* When the powder was applied the carrier was covered
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with a perforated film. The perforations were 4 mm in
diameter and spaced 10 to 15 mm apart. By improving the
charge, the standard deviation could be reduced still
further in subsequent tests.
For virtually complete dispersal on blowing out the
powder, a relatively small amount of gas is sufficient,
e.g. 10 cc of air which is forced through a 0.8 mm
diameter nozzle (in the case of the dots of powder
according to test number 4). Excellent break-up is
found.
As was established by means of the Andersen
impactor using micronzsed fenoterol, 400 of the
' particles of the dosage expelled were in the particle
size range below 5.8 ~.m.
