CA1144862A - Composition - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

There is described a medicament in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 1,000, preferably 30 to 500, microns in diameter and comprises an agglomeration 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 herein-after defined) of greater than 100 gms, or (ii) a product of "Total Transmitted Load Reduction"
(as hereinafter defined) and "Response Lag" (as hereinafter defined) of greater than 30 g/cms, or (iii) a "Response Lag" (as hereinafter defined) of at least 0.3 cms.
The pellets and granules are particularly suitable for inhalation, e.g. in the treatment of asthma or hay fever.

Description

:~.44~

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.

i2 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 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 ;2 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 - 6 ~

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 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 4~

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

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 ' 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 , t;f~
~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 .: . . . .. .

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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 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 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

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 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 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-- 20 ~

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 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.

Claims (3)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Di-sodium cromoglycate characterized in that it contains from 12 to 25% by weight of water.

2. Di-sodium cromoglycate in pellet or granule form characterized in that it has a loose bulk density of less than 0.3 g per cc.

3. Di-sodium cromoglycate according to claim 2 char-acterized in that it has a loose bulk density of from 0.2 to 0.3 g per cc.