Note: Descriptions are shown in the official language in which they were submitted.
:~.44~
2606/76/5301/92 - 2 -
BA 2606/76
The present invention relates to a pharmaceutical
cc~osition and its preparation.
In our British Patent No l,122,284 we have described and
claimed an insufflator device for use in the administration of
pcwdered medicaments by inhalation comprising a propeller-like
device carrying a powder capsule rotatably mounted within a
tubular housing by means of a shaft loosely journalled in a
tapered bearing tube, the housing having a mouthpiece whereby a
user can inhale air through the device. With that device, and
other devices, e.g that described in British Patent
Specification No l,331,216, a user inhales air through -the
device which causes a powder container mounted therein to rotate.
Powder within ~he c3ntainer is fluidised and dispen~ed into the
air stream which is inhaled by the user. For optimum dispensirlg
it has been found that the powdered medicament particles should
be comparatively free-flowing and yet should have an ultimate
particle si~e of less than abcut ten microns to ensure adequate
penetration of the medicament into the lungs of the user. These
two requirements are prima facie mutually exclusive, since such
fine powders are not sufficiently free-flowing. We have now
found that this problem can be mitigated or overcome by forming
the powdered medicament into small soft pellets or granules
which will fluidise satisfactorily within the container and yet
which are oE sufficiently 1GW internal coherence to break ~
~. .
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2606/76/5301/9~ - 3 -
into finer particles o medicament of a therapeutically effectivesize in the turbu]ent airstream around the outside of the
container. The formation of the medicament into soft pellets or
granules also aids the filing of the medicament into capsules
and can enable diluents such as coarse lactose, which have in the
past been incorporated into pcwder inhalation oompositions, to be
omitted from the co~position.
Accordin~ly, the present invention provides a medicament in
pellet or granule form, wherein the pellet or granule is soft, is
lu from 10 to llOOOr preferably 30 to 500, microns in diameter and
cQ~prises an agylcmeration of individual medicament particles, at
least 90% and preferably at least 95% by weight of which have a
diameter of less than 10 microns, characterised in that the pellets
or granules have
(i) a 'Total Transmitted Load Reduction' (as hereinafter
defined) of greater than 100, preferably greater than 400, more
preferably greater than 800 and most preferably greater than
1,000 gms, and/or
(ii) a product of 'Total Transmitted Load Reduction' (as
hereinafter defined) and 'Response Lag' (as hereinafter defined) of
greater than-30, preferably greater than 40, and m~re preferably
betwee~n 40 and 1,000 g/cms, and/or
(iii) a 'Response Lag' (as hereinafter defined) of at least
0.3, preEerably of at least 0.4, c~nd more preferably of between
0.4 and 0.8 cms.
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2606/76/s3nl/s2 - ~ -
The soft pellet or granule preferably has an internalcoherence such that the pellet or granule remains intact when
filled into a container, e.~ a capsule, using au-tomatic or semi-
automatic filling machines, under conditions of transport and
storage, and when fluidised within a container in the device from
which it is intended to dispense the pellets or granules and yet
may be broken up into particles of a therapeutically effective
size outside the container as it discharges from the container.
The medicament in the soft pellets or granules of the
invention may be selected from a wide range of pGwdered
medicaments and may be in amorphous or crystalline form and may
have been comminuted, e.g ground, and, if necessary, classified
or sieved, e.g on an air jet sieve, to obtain a suitable size
or may have been made by direct crystallisation to the desired
size. However/ it is preferred that the medicament be one which
is to be administered by inhalation and which has a substantial
number o~ particles, e.g greater than 95% by weight, oE less than
10 microns, e.g from 0.01 to 10, and preferably from 1 to 4,
microns diameter, before incorporation into the soft pellets of
the invention. Desirably the individual medicament particles
are self-as~lomerative as is usually the case with a hygroscopic
material. Examples of suitable medicaments include those
suitable for the inhalation treatment of allergic -airway diseases
such as pharmaceutically acceptable salts of lr3-bis(2-carboxy-
chromon-5-yloxy)propan-2-ol, pharmaceutically acceptable salts
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2606/76/5301/92 - 5 -
of 1,3-bis~2-carboxychrom~n-7-yloxy)propan~2-o1, sympathomimetic
amines (e.g iso;orenaline, ephedrine, or isoetharine and salts
thereof), antibiotics (e.g tetracycline), steroids, enzymes,
vitamins and antihistamines. If desired a mixture of medicaments,
e.g a mixture of the disodium salt of 1,3-bis~2-carboxychromon-5-
yloxy)propan-2-ol (o~mmonly known as sodium cromcgly~ate, disodium
cromcglycate or cromolyn sodium) and isoprenaline, may be used.
The pellets or granules may contain other ingredients, e.g
diluents colouring and flavouring agents. Where the medicament
is not self agglomerative, e.g hygrosoopic, it may be desirable
to incDrporate a small portion of a binder into the soft pellets
or granules. Suitable binders include acacia gum, -tragacanth
gum, celluloses such as salts and ethers of carboxymethylcellulose,
dextrans and sugar solutions. Where the medicament is not easily
wetted it may be desira~le to incorporate a small proportion of
a surface active agent into, and/or to use a solvent in the
preparation of, the soft pellets or granules. In general we
prefer nct to use a binder, surface active agent or solvent (other
than water) in the soft pellets or granules.
When the n~dicament is hygrosoopic a small proportion of
w~ter, which, if necessary, is a~ded to the medi~ament in the
vapour phase for pellets and in the liquid phase for granules is
usually sufficient to act as binder. The moisture content of
the material ma~ be adjusted according to the physical properties
of the particular material, for example, for disodium cromoglycate
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26D6/76/5301/92 - 6 -
we prefer the soft pellets or granules to contain less than 15%,and preferably from 8 to 11% by weight of waterO
The size of the soft pellets or granules of the invention
may be varied within the range given above to suit the devices
from which they are to be dispensed. For a given device there
is an optimum pellet or granule size for optimum fluidisation of
the soft pellets or granules ar~ this may be readily determined
by simple tests, e.g by assessing the fluidisation oE extremely
strong pellets or granules within the device which it is
intended to use. We have also found that optimum dispensing of
the soft pellets or granules is related to the size of the hole
in the container through which the pellets or granules are to
issue. We prefer that the pellets or granules have a size of
from one-twentieth td one-fifth of the diame~er of the hole,
which usually has a diameter of from 500 to 2,000, e.g about 700
to 1,500 microns.
As a general guide, we have found that satisfactory soEt
pellets or granules for use in insufflators of the type described
in British Patent No 1,122/284 (oommercially available under the
Registered Trade Mark 'Spinhaler') and powered by human inhalation
have a mean size in the range of from 50 to 250 microns,
preferably a mean size in the range 120 to 160 microns and most
preferably a mean size of about 140 microns.
The soft pellets or granules should be sufEiciently coherent
to be filled into aontainers, transported and stored, since
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2606/76/5301/92 - 7 -
appreciable break-up of the soft pelle-ts or granules should not
occur under these conditions.
From the above, it will be appreciated that soft pellets or
granules having satisfactory properties may be obtaine~ from a
number of permutations of the size and coherence. By way of an
example, we have found that for soft pellets or granules which
- are to be dispensed from a gelatine capsule 6.4 mm in diameter
and having tw~ holes 0.8 mm in diameter in a shoulder thereof
mounted in a device (oommercially available under the Registered
Trade Mark 'Spinhaler') according to British Patent No 1,122,284
havin~ a drawn wire shaft 2.03 mm diameter ~ournalled in a hard
n~lon bearing tube 13 mm long and having an internal diameter of
2008 mm at its inner end (i.e that end housing the free end oE
the shaft) and of ~.44 mm at its other end, and wherein the
capsule is rotated about its axis at a speed of about 1,800 rrm
by an air stream having a flow rate of 60 litres per minute it is
desirable that the pellets have a mean size of about 140 microns.
It is especially preferred that the pellets or granules are made
from discdium cromoglycate.
The soft pellets or granules are preferably such that when
put up in gelatine capsules 6.4 mm in diameter each containing
20 mg of the medicament as soft pellets or granules they meet the
criteria set out in the tests (a) and (b) 'oelow:-
(a) Dispersion test
The filled capsules are mounted in the capsule holder of the
2606/76/5301/92 - 8 -
powder insufflator (having the specific dimensions set out
imnediately above) of British Patent Specification No 1,122,284
and pierced to produce -t~ holes of 0.8 ~m diameter in a shoulder
of the capsule. me dispersion of the medicament in the cloud
s delivered by the insufflator is determined using a modified
version of the multistage liquid impin~er described in British
Patent Specification No 1,081,881. m e mcdified impinger is
illustrated in Fig 3 which represents a cross-se~tion through the
impinger.
. In Fig 3 the powder insufflator 1 is situated in the rubber
sleeve 2, and is thereby connected to the bent glass tube 3. The
l~wer end of the glass tube 3 is inserted into a container 4 which
is partially filled with distilled water 5 and has a porous
impinyement disc 6. Connected to one side of container 4 is a
filter unit 7 ~hich in turn is connected to a vacuum pump via
tube 8. The dimentions oE the device are given below:-
a - a 35 mm
b - b 150 mm
c - c lg mm
d - d 30 mm
e --e 55 mm
f - f 100 mm
g _ g 4 m~
h - h 38 m~
i - i 6 mm
j _ j 10 ~[1
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2606/76/5301/92 - 9 -
The insufflator is inserted into the upper, horizontal end
of the glass tube and air drawn through at 60 litres per minute
for 30 seconds. At least five capsules are treated in this
manner and the results are averaged. The weight of the medicament
oollected on the filter, and that in the remainder of the
apparatus and in the insufflator is determined spectrophotometrically
arter solution in an appropriate volume of distilled water (or by
any other appropriate metnod).
Ihe soft pellets or granules disperse satisfactorily if an
average t~tal Eor each capsule of at least 8%, preferably at
least 10% and m3st preferably at least 14~ by weight of the
medicament are found on the filter of the liquid impinger.
(b) Emptying test
The filled capsules are ~unted in the capsule h~lder of the
powder insufflat~r (having the specific dimentions set out above)
of British Patent Specification No l,122,284 and pierced to
produce t~ holes of 0.8 mm diame-ter in a shoulder of the capsule.
The insufflator is placed in a device adapted to suck ~ir t~rough
it for 2.5 seconds, the air flow rate at no time exceeding
60 litres per mi~ute, and being held at 60 litres per minute for
at least 2 seconds. The capsule mounted in the insufflator is
subjected to 4 sucks as described and the weight of the material
r~maining in the capsule is determined. The above procedure is
repeated 20 times and the average of the results determined.
The soft pellets or granules empty satisfactorily if an
_ g _
~L ~3l L~ 4~ ?J
2606/76/5301/92 - 10 -
average of at least 50~, preferably at least 75% and most
preferably at least 90~ by weight oE the material has emptied
from each capsule.
The follcwin3 tests are also of significance in defining the
pellets or granules of the invention:
(c) Response Lag
me respone lag may be measured by means of a device
(available from Instron Limited, Coronation Road~ High Wyc~be,
Buckinghamshire, England as Model lM~SM) ~or the measurement of
10 the stress/strain properties of materials. This device is
illustrated in Fig 2 and c~mprises a punch 1 capable of fitting
tightly into a die 2 oE 4 mms diameter and of 1.55 cms length.
The die is open at the top end, save when the punch is inserted
in that end, and is closed at the bottom end by the surface of a
15 load cell 3 oonnected to a recorder adapted ~ reoord loads of from
1 to lOG0 g. In operation the material to be test~d 4 is filled
carefully into the die in such a way as to a~oid bridging, and
the surface made level with the top of the die. The punch is
moved at a oonstant speed into the die from the top end and the
20 load transmited to the load cell is recorded graphically. The
response lag is defined as the distance in cms that the punch
tip travels belcw the top of the die before a response of 1 g is
registered by the load cell.
(d) Total Transmitted Load Reduction
It has also been fcund that with medicaments according to
'
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2606/76/5301/92 - 11 -
the invention which disperse satisfactorily the applied load
transmitted to the load cell in the device described in (c) above
does not increase steadily ~seefor example Fig 1). The back
track of the curve, or the 'easing' of the load in ~ramsr may be
termed the 'Total Transmitted Load Reduction' of the material
under test. Thus 'Total Transmitted Load Reduction' may be
defined as the sum of the reductions in the transmitte~ load
detected by the loQd cell while the load recorded as acting on
the cell proyresses frcm n to 1,000 gms.
We have found that the most useful parame~er in the definition
of the pellets or granules according to the invention is the
product of the 'Total Transmitted Load Reduction' and the 'Response
Lag'.
me pellets and granules according to the invention have a
lower loose bulk density than granules or pell~ts made by
conventional techniques. Thus soft pellets and granules of
discdi~m cromoglycate have a loose bulk density of less than 0.3 g
per cc, preferably from 0.2 to 0.3 g per cc, and ~ost preferably
from 0.22 to 0.28 g per cc.
From another aspect the invention also provides a capsule,
cartridge or~~~like container obntaining soft pel1ets or granules
of the invention, optionally in association with other pellets,
granules or particles. We prefer the container to be loosely
Eilled to less than about 80~ by volume, preferably less than
about 50% by volume, with the soft pellets or granuels of the
,
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~606/76/5301/92 ~ 12 -
invention. The soft pellets or granules should of course not becompacted into the container. We prefer the container~ e.g
capsule, to contain from lO to lO0 mg of the soft pellets or
granules. The container may conveniently be pierced (and
overcapped, e.g with a plastic overcap) during its manufacture
andthe~used, after rem~val of the overcap, in an inhalation
device which bas no piercing mechanism.
Where it is desired t~ use the pellets or granules of the
invention in association with other ingredients such as colourants,
sweeteners or carriers such as lactose, these other ingredients
may be applied, to or admixed with the pelle-ts or granules using
conventional techniques. We prefer the soft pellets ~r granules
of the invention to contain medicament and water only and not to
be mixed with any other ingredients.
The soft pellets or granules of the invention may be made '~y
a number of methods.
m us according to the ~nvention there is provided a method
for the manufacture of soft pellets or granules according to the
invention, which comprises subiecting particles of medicament
(optionally in admixture with any other ingredient it is desired
t~ :;ncorporate into the pellets) which either are intrinsically,
or have been rendered, self-agglomerative to a controlled
agglomeration. This controlled agglomeration may be carried ou-t
~, .
(a) extruding the particles oE medicament through an aperture,
2~06/76/5301/92 - 13 -
(b) controlled agglomeration in a fluidised bed, or
(c) spray drying a solution or slurry oE the medicament.
In method (a) which i5 the preferred method, finely divided
medicament, e.g having a mean particle size in the range 0.01 to
10 micronsmay, if necessary, be subjected to an initial treatment
to cause the powder particles to be self-agglomerative. Thus
where the medicament is of a hygroscopic nature, the treatment may
be carried out by e~posing the poNder particles to water.
When soft pellets are required the powder particles may be
subjected to a humid a-tmosphere, for example at a temperature
of from about 15 to 50C. Whilst the am~unt of water required
to achieve adequate self-agglomerative properties may vary from
medicament to medicament/ it will not usually be necessary ~o
increase the water content of the pcwder beyond about 15%
by weight, e.g to from 5 to 10% when soft pellets are required.
Where the medicament is non-hygrosoopic, the necessary self-
agglomerative properties may be imparted by the additi~n o~ a
pharmaceutically acceptable binder, e.g ~e selected from those
mentioned earlier, or by treating the pawder with a liquid (under
carefully controlled conditions), which may be evaporated to
prcduce bridges of a solid residue binding the powder particles,
or which causes adequate interparticle contact. It will be
appreciated that the nature of the ~inder may affect the coherence
of the resultant pellet or granule formed fi~mtreated medicament.
A binder solution may, if desired, be used with a h~groscopic
- 13 -
.: . . . .. .
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2606/76/5301/92 - 14 -
medicament in order to improve the internal coherence of theresultant pellet or granule. After the particles have been
rendered self-agglomerative, they are passed (optionally after
being rolled in for example a drum or pan for a oontrolled time)
s through an aperture of approximately the size of the desired
pellets, e.g they are forced through the apertures of a vibrating
sieve which is of similar mesh aperture to the desired final
pellet or granule size. ~he product of this passage through an
aperture are shaped pre-pellets of the medicament.
When sat granules are required the pcwder particles may be
mixed with an excess of a suitable solvent, e.g. liquid water,
and the moistened material passed through an aperture, e~g a
sieve SUG~ as a vibrating sieve, of approximately equal to or
larger than the mesh size required in the final granules ~nd
then drying the resulting sie~ed material to the desired final
solvent, e.g. water, oontent. The material may then be dry
granulated to give the required product.
When it is desired to incorporate another ingredient, e.g.
a binder, into the soft granules the other ingredient may
conveniently either be mixed with the medicament before it is
moistened or may be incorporated in the solvent used to moist~n
the medicament.
The am~unt of water, or other solvent, used in the
granulation can, under certain circumstances, be critical. Thus
we have found that with di-sodium cromoglycate ~DSOG) use of
2606/76/5301/92 - 15 -
greater than about 25% by weight of water (measured on dry DSOG)
causes the granules to be tco strong and not to have satisfactory
dispersion properties. We therefore prefer to use from about 12
to 25%, and preEerably from 17 to 23~ by weight of water in the
granulation of di-sodium cromoglycate.
The drying is preferably effected in a preheated forced
convection hot air oven. The temperature of drying is desirably
from 60 to No&, and ~re especially from 80 to 90C.
The soft granules may also be made by controlled agglomeration
of the medicament in a fluidised bed or by spray drying a solution
or slurry of the medicament.
In process (b) the fine particles of medicament to be formed
into pellets OL granules may be suspended, together with any
other ingredients it is desired to incorporate in the pellets or
granules, in a gas stream in a fluidised bed apparatus. When a
hygroscopic material is to be formed into pellets or granules
the water content of the solid material may be adjus-ted by variation
of the humidity of the gas stream passing through the fluidised
bed or by spraying water into the bed. The medicament ma~ be
treated in the fluidised bed for a time and under oonditions
sufficient to produce pre-pe U ets or granules of the desired
internal coherence and si2e.
In process (c) a solution or more preferably a slurry, of
the medicament may be spra~-dried to produce a soft granule. We
prefer to use a slurry of discrete medicament particles of the
2606/76/5301/92 - 16 -
desired fine particle size, the slurry also containing any other
ingredients it is desired to incorporate in the granules. The
liquid in the slurry is preferably a non-solvent or a pcor solvent
for the medicament so that no or not many, medicament bridges are
formed between the medicament particles during the spray drying.
When a controlled amount of water is desired in the product a
correspondingly greater amount of water may be included in the
liquid in the slurry.
The extent of compaction of the treated pcwder during the
controlled agglQmeration will vary according to the method and
pawder used in the agglomeration~ However, as a guide, we have
found that suitable pre-pellets may be formed by process (a) from
a pcwder of disodium cromoglycate containing from about 8 tv 10%
by weight of water, by forcing the powder through a sieve ha~ing
apertures of about 150 micron size.
The pre-pellets produced by any of the above processes may,
if desired or necessary be subjected to tumbling and agitation
using conventional method~ until the desired size, shape and
coherence of the pellets are achieved. We prefer a proportion,
e.g a majorityr of the soft pellets, and especially soft pellets
of disodium cromoglycate, to be approximately spherical.
Conveniently the tumbling and agitation are carried out in a
pan or drum type of pelletising machine. The treatment of the
pre-pellets in such a machine is carried out until the majority
of pellets in the charge have a size within the desired rangeO
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2606/76/5301/92 - 17 -
The size of the pre-pellets used and the conditions used in their
agitation and tumbling may be varied in kncwn manner to achieve
the desired final size of soft pellet. The time for which the
pellets are tumbled is, in certain circumstances, of importance
to the production of viable soft pellets. The effect of the
tumbling and agitation of the pellets is in general to strengthen
them and increase their size slightly and to make them more nearly
spherical in shape.
As indicated above the final product ~hich issues ~rom the
agitation or tumbling step will have a range of sizes about the
desired mean size. The product may be classified, e.g sieved,
to remove over and under sized material. The over and under
sized materially may be broken down into very fine particles and
recycled to the agglomeration stage if desired.
The final soft pellets or granules may be put up in any
suitable form of container such a capsule or cartridge. Where
it is desired to use tne pellets or granules of the invention in
association with other ingredients such as o~lourants, sweeteners
or carriers such as lac~ose, these other ingredients ma~ be applied
to or admixed with the pellets or granules using conventional
techniques. We prefer the soft pellets or granules of ~he
invention to contain medicament and water only. The soft pellets
or granules may also be used in admixture with up to 75% by weight
of free particles of medicament having a diameter of from 0.01 to
10 microns.
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?6o6/7~/s3ol/g2 - 18 -
According to OUL- invention we also provide a method oE
application of a medicament, e.g disodium cro~oglycate, to a
patient by way of inhalation, the medicament being dispersed
into an air stream, characterised in that a pierced container
c~ntaining soft pellets or granules according to the invention
is rotated and vibrated in an air stream which is inhaled b~ the
patient~ The rotation and vibration may conveniently be produced
by any one of a number of devices, e.g the device of British
Patent Speci~ication ~o l,122,2840 Disodium crom~glycate is
known to be o use in the treatment of asthma and rhinitis.
In this specification the tenm 'pellet' is used to denote an
agglomerate which is held together by interparticulate ~e.g ~an der
Waal's) forces ~nd is typically made by a process involving water
vapour. Pellets are in general spherical in shape. The term
'granule' is used to denote an ~gglomerate which is held together
by interparticle bridgesO In the case of a soft granule these
bridges are brittle. Granules can be of almost any shape.
Granules are typically made by overwetting the medicament with
solvent, e.g water, and then removing ~-ome of the solvent.
The invention will now be illustrated by the following
~samples in which all parts and percentages are by weight unless
otherwise stated.
Eisample_ 1
The moisture content of micronised disodium cromoglycate
having at least 98%i thereoE of particle size less than 10 microns
- 18 -
2606/76/5301/92 - l9 -
and havin~ a mass median diarneter of from l to 3 microns was
adjusted from an initial value of from 4 to 6% by weight to a
value of about 9.5% by weight by expc6ure of the powder on a
tray in an atmosphere of relative humidity 33% at 18 to 24C.
After the desired m~isture content had been achieved, the
treated powder was tafter an optional initial ro Uing in a drum
pelletiser) tipped onto a 150 micron aperture stainless steel
sieve screen mounted in a Russel vibratory sifter operating at a
frequency of l,000 cycles per secondO The powder on the screen
1~ was forced through the sieve apertures using a stainless steel
spatula pushed across the surface of the screen. The material
issuing from the sifter as particles with a mean particle diameter
of about lS0 m~crons was fed directly to a dnmn pelletiser adapted
to rotate about a horizontal axis. The drurn of the pelletiser was
a~roximately ~.3 m in internal diameter and 0.37 m long with one
end closed and the other end provided with frusto conical
shoulder leading to a 0.18 m orifice through which material could
be charged to or removed from the drum. The interior of the drum
was highly polished. Two kilograr~ of the material frcm the sifter
were loaded into the drum which was then rotated at a peripheral
speed of ~.38 m per second + 0.025 m per secon~ for 15 minutes.
At the end of this time the soft pellets had a mean particle
diameter of 135 microns and not more than 10% by weight was retained
on a 350 micron aperture sieve and not less than 90~ b~ weight was
retained on a 63 micron aperture sieve. The moisture content of the
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2606/76/5301/92 - ~0 -
final soft pellets was in the range 8.5 to 10.5% by weight.
It will be appreciated that those steps of the process
carried out after adjustment of the moisture content of the
initial powder should be carried out under c3nditions of
controlled humidity so as not to alter the water content oE
the pcwder appreciably. The water used in the process should be
sterile and the air used in the process should be Class lO0 air.
The soft pellets produced by the abo~e procedure are
approximately spherical, and have an open and loose structure
and a fl~ffy surface when viewed under a microscope.
Up to 90 mg, e.g 40 to 60 mg, of the above soft pellets
were placed in a gelatine capsule having two holes 0.8 mm in
diameter pierced in the shoulder thereof which was mounted in a
device as described in British Patent No lrl22,284 having the
detailed construction and d~nensions referred to above. When
air at a flow rate oE 60 litres per minute was passed through
this de~.Tice, it was found that the charge in the capsule was
consistently completely dispensed into the airstream and broken
~p to provide a cloud oE very fine particles suitable for
inhalation.
By way of contrast, when the initial micronised p~wder fr~m
which the pellets had been prepared was tested under identical
conditions, oomparati~ely little of the pcwder was dispensed from
test to test.
Similar results were obtaine when 1,3-bis(2-carboxychromon-
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2606/76/5301/~2 - 21 -
7-yloxy)propan-2-ol disodium salt (6% water), isoprenaline
sulphate and tetracycline were subjected to the prccedure of
the Example to obtain soft pellets.
Example 2
Usin~ the device illustrated in Fig 2 and, pellets of
di-sodium cromcglycate according to Example 1 a Response Lag of
greater than 0.4 cmst a Total Transmitted Load Reduction oE
greater than 900 gms and a dispersion of greater than 10~ were
obtained.
Example 3
l,OOOg of micronised discdium cromoglycate of determined
water content was placed in the bcwl of a planetary mixer. The
calculated amount of water to bring the moisture content of the
disodium cromoglycate to within tne desired range was then added
gradually, the sides of the mixer bowl bein~ scraped regularly
to ensure even moisture distribution. The damp di~odium
cromoglycate was ~hen passed ~lrough a vibrating sieve having a
mesh size of 1,000 microns. The product was then dried in a
preheated forced convection hot air oven at 85C for 2 hours until
the moisture content of the granules was in the range 5 to 8~ by
~ight. The granules were then sieved through a 250 micron
screen. The resulting granules were found to flcw well and
oould be filled easily into gelatine capsules.
_ mple 4
Using the device illustrated in Fig 2, granules of disodium
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2606/76/5301/92 ~ ~2 -
cromoglycate produced according to Example 3, and khe Dispersion
Test as previously described, dispersions of greater than 10~
were obtained for g~anules made using from 10 to 25~ by weight
water at the granulation staqe. These granules had response lags
of greater than 0.3 cms and a Total Tran~nitted Load ~educticn
of greater than 100 gms.
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