IE45260B1 - Pelletised or granular medicament formulation - Google Patents

Abstract

BA 2606/76 MEDICAMENT COMPOSITION IN SOFT PELLET OR GRANULE FORM 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 hereinafter 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

Tiie present invention relates to a pliaxmaceutical composition and its preparation.

Incur Patent No. 31503 We have described and claimed an insufflator device for use in the administration of powdered medicaments by inhalation comprising a propeller-like device carrying a powder capsule rotatably mounted within a tubular housing by mpans 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 1,331,216, a user inlialcs air through the device which causes a powder container mounted therein to rotate. Powder within tire container is fluidised and dispensed into tiie IS air stream which is inhaled by the user. For optimum dispensing it has been found that the powdered medicament particles should be comparatively free-flowing and yet should have an ultimate particle size of less than about ten microns to ensure adequate penetration Of tile medicament into the lungs of the user. Those two requirements are primn facie mutually exclusive, since such fine powders are not sufficiently free-flowing, life have now found that this problem can be mitigated or overcome by forming tbe powdered medicament into small soft pellets or granules which will fluidise satisfactorily within the container and yet' which aro of sufficiently low internal coherence to break up - 2 4 S 3 S 0 into finer particles of medicament of a therapeutically effective size in tiie turbulent airstream around the outside of the container. The formation of the medicament into soft pellets or granules also aids tlie filling of tiie medicament into capsules and can enable diluents such as coarse lactose, which have in tiie past been incorporated into powder inhalation compositions, to be omitted from tlie composition.

Accordingly, the present invention provides 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 SS”. by weight of which have a L diameter of loss 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 more preferably between 40 and 1,000 g/cras, and/or (iii) a 'Response Lag' (as hereinafter defined) of at least 0.3, preferably of at least 0.4, and more preferably of between 0.4 and 0.8 cms. 4% 2·β0 The soft pellet or granule preferably lias an internal coherence such that the pellet or granule remains intact when filled into a container, e.g a capsule, using automatic or semiautomatic 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 10 invention may bc selected from a wide range of powdered medicaments and may be in amorphous ox· crystalline fonn and may liave 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 bo one which is to be administered by inhalation, and which has particles at least 90% of which, e.g. greater than 95% by weight of which, are of 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 solf-agglomerative as is usually the cose 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 1,5-bis(2-carboxy25 cIiromon-5-yloxy)propan-2-ol, pharmaceutically acceptable salts - 4 45260 - 5 of 1 ;54ds(2-erir<'Oxychron\'«-7~yloxy)pro;K:n-2-ol, sympathomimetic amines (e.g isoprenaliac, ephedrine, ox- isootharine and salts thereof), antibiotics (e.g tetracycline), steroids, enzymes, vitamins and antihistamines. If desired a mixture of medicaments, 5 e.g a mixture of the disodium salt of l,3-bis(2~carboxychromon-Sylaxy)propan-2-ol (commonly known as sodium cromoglycate, disodium cromoglycate or crafielyct sodium) and isoprenalino, may be used.

The pellets or granules may contain other ingredients, e.g diluents colouring and flavouring agents. Where the medicament is not self aggloiiicrative, e.g hygroscopic, it may be desirable to incorporate 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 carboxyractliylccllulosc, dextrans and sugar solutions. Where the medicament is not easily IS wetted it may bo desirable 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 not to use a hinder, surface active agent or solvent (other than water) m tiie soft pellets or granules.

When the medicament is hygroscopic a snail proportion of water, which, if necessary, is added to the medicament in the vapour phase for pellets and .in the liquid phase lor granules is usually sufficient to act as binder. The moisture content of the material may be adjusted according to the physical properties of the particular material, for example, for disodium cromoglycate - 5 4 5 260 - 6 we prefer the soft pellets or granules to contain loss tiian 15«, nnd preferably from 8 to 11¾ by weight of water.

Tiie size of the soft pellets or granules of tho invention may be varied idthin tha range given above to suit tha devices from which they are to be dispensed. For a given device there is an optimum pellet or granule size for optimum fluidisation of tlie soft pellets or granules and this may bo readily determined by simple tests, e.g by assessing tlie fluidisation of extremely strong pellets or granules within tlie 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 to one-fifth of the diameter 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 soft pellets or granules for use in insufflators of the type described in. Patent Na 31503 (commercially available under the 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 340 microns.

The soft pellets or granules should be sufficiently coherent to be filled into containers, transported and stored, since 3 6 Ο - 7 appreciable break-up of tbe soft pellets or granules should not occur under those conditions.

From ihe above, it will te appreciated that soft pellets or granules having satisfactory properties way be obtained from a number of permutations of tbe 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 sr; in diameter and having two holes 0.8 nm in diameter in a shoulder thereof mounted in a device (commercially available under the Trade Mark 'Spinhaler') according, to Patent No. 31503 having a drawn wire shaft 2.03 ran diameter journalled in a bard?, nylon bearing tube 13 nm long and having an internal diameter of 2.08 nm at its inner end (i.e that end housing the free end of the shaft) and of 2.44 nsn at its other end, and wherein the capsule is rotated about its axis at. a speed of about 1,800 rpm 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 disodium cromoglycate.

Tiie soft pellets or granules are preferably such that when put up in gelatine capsules 6.4 ran 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) below:(a) Dispersion test Tiie filled capsules are mounted in tho capsule holder of the - 7 - 8· powder insufflator (having tho specific dimensions sot out immediately above) of Patent Specification No 31503 and pierced to produce two holes of 0.8 ran diameter in a shoulder of the capsule. The dispersion of tbe medicament in the cloud delivered by tlie insufflator is determined using a modified version of tbe multistage liquid impinger described in Patent Specification No. 31503. The modified impinger is illustrated in Fig 3 which represents a cross-section 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 lower end of tlie glass tube 3 is inserted into a container 4 which is partially filled with distilled water 5 and has a porous impingement disc 6. Connected to one side of container 4 is a filter unit 7 whicli in turn is connected to a vacuum pump via tube 8. The dimensions of the device are given below:- a - a 35 mm b - b 150 mm c - c 19 mm d-d 30 mm e - e 55 ran £ - £ 100 mm s - g 4 mm h - h 38 mm i - i 6 mm j “ 5 10 mm - 8 0S26G - 9 The insufflator is inserted into the upper, horizontal end of the glass tube and air dram through at GO litres per minute for 30 seconds. At least five capsules are treated in this manner and the results are averaged, lhe weight of th.e medicament collected on tiie filter, and that in the remainder of the apparatus and in tiie insufflator is determined r-poctrophotomctrically after solution in an appropriate volume of distilled water (or by any other appropriate method).

Tiie soft pellets or granules disperse satisfactorily if an 10 average total for each capsule of at least 81, preferably at least 10Ί and most preferably at least 141 hy weigiit of the medicament arc found on the filter of tiie liquid impingcr. (h) Emptying test Tho filled capsules are mounted in the capsule holder of the 15 pewder insufflator (having tho specific dimensions set out above) of Patent Specification Lo. 31503 and pierced to produce two holes of 0,8 mn diameter in a shoulder of the capsule.

Tiie insufflator is placed in a device adapted to suck air through it fcr 2.5 seconds, the air flow rate at no time exceeding 60 litres per minute, 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 remaining in the capsule is determined. Tiie above procedure is repeated 20 times and the average of the results determined.

Tiie soft pellets or granules empty satisfactorily if an - 9 45S60 - 10 average of at least 50s, preferably at least 75¾ and most preferably at least 90¾ by weight of the material has emptied from each capsule.

The following tests arc also of significance in defining the 5 pellets or granules of the invention: (c) Response lag The response lag may bs measured by limans of a device (available from Instron Limited, Coronation Road, High tycombe, Buckinghamshire, England as Ifodcl 1M-S4) for the measurement of the stress/strain properties of materials. This device is illustrated in Fig 2 aiid comprises a punch 1 capable of fitting tightly into a die 2 of 4 mus diameter and of 1.55 ems length.

The die is open af the top end, save when the punch is inserted in that end, and. is closed at the bottom end by tho surface of a load cell 3 connected to a recorder adapted to record loads of from 1 to 1000 g. In operation the material to be tested 4 is filled carefully into the die in such a way as to avoid bridging, and the surface made level with the top of the die. The punch is moved at a constant speed into the die from the top end and tbe load transmitted to the load cell is recorded graphically. The response lag is defined as the distance in eras that the punch tip travels below 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 found that with medicaments according to - 10 4S36 -lithe invention which disperse satisfactorily the applied load transmitted to the load cell in the device described in (c) above does not increase steadily (see for example Fig 1). 'Πιο hack track of the curve, or the easing' of the load in grams, may te $ tciincd the 'Total Transmitted tend Reduction' of tho material under test. Thus 'Total Transmitted tend Reduction' nay he defined as tho sum of eke reductions in tiie transmitted load detected by tiie load cell while the load recorded as acting on the cell progresses from 0 to 1,090 tnns.

We Jiave found tiiat the aast useful parameter in tho definition of the pellets or granules according to tlie invention is the product of tiie 'Total Transmitted Load Reduction' and the 'Response Lag'.

The pellets and granules according to tlie invention have a IS lower loose bulk density than granules or pellets made by conventional techniques. Tims soft pellets and granules of disodium 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 most preferably from 0.22 to 0.28 g per cc. 2° From another aspect the invention also provides a capsule, cartridge or like container containing soft pellets or granules of ths invention, optionally in association witii oilier pellets, granules or particles. Ife prefer the container to be loosely filled to less than about 80¾ by volume, preferably less than about SO; by voiiims, with the soft pellets or granules of the 4S360 - 12 invention. The soft pellets or granules should of course not be compacted into the container. Vb prefer the container, e.g capsule, to contain from 10 to 100 mg of the soft pellets or granules. Tho container may conveniently be pierced (and overcapped, e.g with a plastic overcap) during its manufacture and then used, after removal of the overcap, in an inhalation device which has no piercing mechanism.

Where it is desired to 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 pellets or granules using conventional techniques. Wb prefer the soft pellets or 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 tho invention may be made by a number of methods.

Thus according to the invention there is provided a method for the manufacture of soft pellets or granules according to the invention, which comprises subjecting particles of medicament (optionally in admixture with any other ingredient it is desired to incorporate into the pellets) which either are intrinsically, or have been rendered, self-agglomerative to a· controlled agglomeration. This controlled agglomeration may be carried out by, (a) extruding the particles of medicament through an aperture, - 12 4 52 6 0 - 33 (b) controlled agglomeration in a fluidised ned, or (c) .spray drying a solution or slurry of the medicament.

In method (a) which is the preferred method, finely divided medicament, e.g having a mean particle size in the range 0.01 to microns may, if necessary, be subjected to an initial treatment to cause the powder particles to be self-agglomerative. Thus where the wedi.cament is of a hygroscopic nature, the treatment may ta carried out hy exposing the powder particles to water.

Mien soft pellets are required the powder particles may he 10 subjected to a humid atmosphere, for example nt a temperature of from about 15° to 50°C. Whilst the amount of water required to achieve adequate self-agglowcrative properties may vary from medicament to medicament, it will not usually be necessary to increase the water content of tiie powder beyond about 15’ IS by weight, e.g to from 5 to 101 when soft pellets are required. Where tiie medicament is non-hygroscopic, the necessary selfagglomerative properties may be imparted by tiie addition of a pharmaceutically acceptable hinder, e.g one selected from those mentioned earlier, or by treating the powder with a liquid (under carefully controlled conditions), which may be evaporated to produce bridges of a solid residue binding the powder particles, or which causes adequate interparticle contact. It will be appreciated that tho nature of the binder may affect the coherence of the resultant pellet or granule formed from treated medicament. Λ binder solution may, if desired, be used with a hygroscopic - 14 - medicament in. order to improve the internal coherence of the I resultant 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 controlled time) 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. Tiie product of this passage through an aperture are shaped pre-pellets of the medicament.

Mien soft granules are required tiie powder particles may te mixed with an excess of a suitable solvent, e.g. liquid water, • and tho moistened material passed through an aperture, e.g. a sieve such as a vibrating sieve, of approximately equal to or larger than tiie mesh size required in the final granules and then drying the resulting sieved material to the desired final solvent, e.g. water, content. The material may then te 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 bc mixed with tho medicament before it is moistened or may be incorporated in the solvent used to moisten the medicament.

The amount of water, or other solvent, used in the granulation can, under certain circumstances, be critical. TIius we have found that with di-sodium cromoglycate (DSCG) use of - 14 greater tiian about 251 by weight of water (measured on dry DSCG) causes the granules to be too strong and not. to have satisfactory dispersion properties. Re therefore prefer to use from about 12 to 25“, and preferably from 17 to 23¾ by weight of water in the granulation of di-sodium cromoglycate.

The drying is preferably effected in a preheated forced convection 1«H air oven. The tenperauire of drying is desirably from CO to vri'C, and wore especially from 80 tc 90°C.

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 ib) tire fine particles of medicament to be formed into pellets or 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. Mien a hygroscopic material is to be formed into pellets or granules the water content of the solid material may be adjusted by variation of the humidity of the gas stream passing through the fluidised bed or by spraying vzater into the bed. The medicament may be treated in the fluidised bed for a time and under conditions sufficient to produce pre-pellets or granules of the desired internal coherence and size.

In process (c) a solution or more preferably a slurry, of the medicament may he spray-dried to produce a soft granule. I'.’e prefer to use a slurry of discrete medicament particles of the - 15 - 16 desired fine particle size, the slurry also containing any other ingredients it is desired to incorporate in the granules. Tlie liquid in the slurry is preferably a non-solvent or a poor solvent for the medicament so that no, or not many, medicament bridges are formed between the medicament particles during tho spray drying. Mien a controlled amount of water is desired in the product a correspondingly greater amount cf water may be included in tho liquid in the slurry.

Tlie extent of compaction of the treated powder during the controlled agglomeration will vary according to the method and powder used in the agglomeration. However, as a guide, wo have found that suitable prc-pel.lets may be formed by process (a) from a powder of disodium cromoglycate containing from about 8 to 10» by weight of water, hy forcing the powder through a sieve having 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 methods until the desired size, single and coherence of the pellets are achieved. Ife prefer· a proportion, e.g a majority, 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 range. - 16 d £i S 0 0 - 17 Tiie size of the pre-pellets mud and tiie conditions used in their agitation ami tumbling may bo varied in known manner to achieve t.he desired final size of soft pellot. Tho time for which tho 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 then; and increase their size slightly and' to «.ike them more nearly spherical in shape.

As indicated above tho final product which issues from the agitation or tumbling step will have a range of sizes about the desired mean size. 'Flic product may iio classified, e.g sieved, to remove over and under sized material. The over and under sized materially may be broken down into very fine particies and. recycled tc tho agglomeration stage if desired.

T.he final soft pellets or granules may he put up in any suitable form of container such as a capsule or cartridge. Micro it is desired to use the pellets or granules of tiic 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 pellets or granules using conventional techniques, hfe prefer the soft pellets or granules of the invention to contain medicament and water only. The soft pellets or granules may also be used in admixture with up to 755 by weight of free particles of Medicament having a diameter of from 0.01 to 10 microns. - 17 According to our invention was also provide a method of dispersing a medicament, e.g. disodium cromoglycate, into an air stream wherein a pierced capsule containing a plurality of soft pellets or granules according to the invention is rotated and vibrated in an air stream.

The rotation and vibration may conveniently be produced by any one of a number of devices, e.g. the device of Eafcest Specification No. 31503. Disodium cromoglycate is known to ba of use in ths treatment of asthma and rhinitis. m this Specification the term 'pellet' is used to denote an 10 agglomerate which is held together by interparticulate (e.g. Van der Waal's) forces and is typically made by a process involving water vapour. Pellets are in general spherical in shape. Ths term 'granule* is used to denote an agglomerate which is held together hy interparticle bridges. 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 sate of the solvent.

Pellets or granules comprising sodium crcsnoglycate and having a loose bulk density of less than 0.3 g per cc and particulate discdim cromoglycate containing 12 to 25% by weight of water are described and claimed in Patent Specifications Nos. 45251 and 45262.

The invention wd.ll now? be illustrated by the following Exaitples in which all parts and percentages are by wseight unless otherwise stated. Example 1 - The moisture content of finely ground disodium crcsnoglycate having at least 98% thereof of particle size less than 10 micrcns - 18 4 5360 - 19 and having a mass median diameter of frcm 1 to 3 microns was adjusted from an initial value of frora 4 to bl by weight to a value of about 9.31 by weight by exposure of tlie powder on a tray in an atmosphere of relative humidity .3.31 at 18 to 24°C.

After the desired moisture content had been achieved, the treated powder was (after an optional initial rolling in a drum pelletiser) tipped onto a ISO micron aperture stainless steel sieve screen mounted in a Russel vibratory sifter operating at a frequency of 1,000 cycles per second. Tlie powder on the screen was forced through the sieve apertures using a stainless stool spatula pushed across the surface of tlie screen. The material issuing frora the sifter as particles with a mean particle diameter of about ISO microns was fed directly to a drum pelletiser adapted to rotate about a horizontal axis. Tiie drum of tlie pelletiser was IS approximately 0..3 nt in internal diameter and 0.37 m long witii one end closed and tiie other end provided witii frusto conical shoulder leading to a 0,18 in orifice through which material could be charged to or removed from tiie drum. Tho interior of the drum was highly polished. Two kilograms of tlie material from tlie sifter were loaded into tlie drum which was then*rotated at a peripheral speed of 0.3S is per second j 0.025 m per second for 15 minutes.

At the end of this time the soft pellets liad a moan 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’ by weight was retained on a 63 micron aperture sieve. Tlie moisture content of tho - 19 - 20 final soft pellets was in tho range 8.5 to 10.5¾ by weight. .

It v/ill bo appreciated that those stops of the process carried out after adjustment of the moisture content of the initial powder should be carried out under conditions of controlled humidity so as not to alter the v/ater content of the powder appreciably. The water used in the process should be sterile and the air used in the process should be clean air.

The soft pellets produced by the above procedure are * approximately spherical, and have an open and loose structure •10 and a fluffy surface when viewed under a microscope. tip 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 mn in diameter pierced in the shoulder' thereof which was mounted in a device as described in Patent No. 31503 having tiie detailed construction nnd dimensions referred to above. Mien air at a flow1 rate of 60 litres per minute was passed through this device, it was found that the charge in the capsule was consistently completely dispensed into the airstream and broken up to provide a cloud of very fine particles suitable for inhalation.

By way of contrast, when the initial-finely ground powder fran which tiie pellets had been prepared was tested under identical conditions, comparatively little of the powder was dispensed from test to test.

Similar results were obtained when 1,3-bis(2-carboxychromon- 20 - 21 7-yloxy)propan-2~ol disodium salt (6 water), isoprenalino sulphate and tetracycline were subjected to the procedure of tho Example to obtain soft pellets.

Example 2 Using the device illustrated in Fig 2 and, pellets of di-sodium cromoglycate according to Example 1 a Response lag of greater than 0.4 cms, a Total Transmitted Load Reduction of greater tlian 900 <>ns and a dispersion of greater than IOS were obtained. Ιθ Example 3 l,OOOg of finely ground disodium cromoglycate of determined water content was placed in the bowl of a planetary mixer. The calculated amount of water to bring the moisture content of the disodium cromoglycate to within the desired range was then added gradually, the sides of the mixer bowl being scraped regularly to ensure even moisture distribution.· The damp disodium cromoglycate was then passed through a vibrating sieve having a mesh size of 1,000 microns. Hie product was then dried in a preheated forced convection hot air oven at 8S°C for 2 hours until the moisture content of tiie granules was in the range 5 to S« by weight. The granules were then sieved through a 250 micron screen. Tlie resulting granules were found to flow well and could be filled easily into gelatin capsules.

Example 4 Using the device illustrated in Fig 2, granules of disodiuin - 21 453θθ - 22 cromoglycate produced according to Example 3, and the Dispersion Test as previously described, dispersions of greater than 101 were obtained for granules made using from 10 to 251 by weight water at the granulation stage. These granules had response lags of greater than 0.3 cms and a Total Transmitted Load Reduction of greater than 100 gins.

Claims (58)

1. CLAIMS:1. Λ medicament in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 1,000 microns in diameter and comprises an agglomeration of individual medicament particles at 5 least 901 of which have a diameter of less than 10 microns, characterised in that the pellets or granules have (i) a ’Total Transmitted Load Reduction’ of greater tiian lOOg,. :ind/or (ii) a product of 'Total Transmitted Load Reduction' and 10 'Response Lag' of greater tiian 30 g/ems, and/or (iii) a 'Response Lag' of at least 0.3 cms. .

2. A medicament according to Claim 1, wherein the 'Total Transmitted Load Reduction' is greater than 400 g.

3. A medicament according to Claim 2, wherein the 'Total 15 Transmitted Load Reduction* is greater tiian 800 g.

4. A medicament according to claim 3, wherein the 'Total Transmitted Load Reduction* is greater.than 1,000 g.

5. A medicament according to any one of tiie preceding claims, wherein tiie product of 'Total Transmitted Load Reduction 1 and 20 ’Response Lag' is greater than 40 g/ems.

6. A medicament according to any one of tho preceding claims, wherein the product of 'Total Transmitted Load Reduction' and 'Response Lag' is between 40 nnd 1,000 g/ems.

7. Λ medicaine.it according to any one of the preceding claims, 25 wherein the 'Response Lag' is at least 0.4 cms. - 23 - 24

8. A medicament according to any one of the preceding claims, wherein the 'Response Lag* is between 0.4 and 0.8 cms.

9. A medicament according to any one of the preceding Claims, wherein, in the Dispersion test as hereinbefore described, an S average total of at least 8» by weight of medicament is found on the filter of the liquid impinger.

10. A medicament according to Claim 9, wherein an average total of at least 10» by weight of medicament is found on the filter of the liquid impinger. 10

11. , A medicament according to Claim 10, wherein an average total Of at least 14¾ by weight of medicament is found on the filter of . the liquid impinger.

12. Λ medicament according to any one of the preceding Claims, wherein, in the Emptying test as hereinbefore described, an IS average of at least 50¾ by weight of the material has emptied from each capsule.

13. A medicament according to Claim 12, wherein an average of at least 75¾ by weight of the material has emptied from each capsule.

14. A medicament according to Claim 13, wherein an average of at 20 least 90¾ by weight of the material has emptied from each capsule.

15. A medicament according to any one of the preceding claims, wherein the pellet or granule is from 30 to 500 microns in diameter.

16. A medicament according, to Claim 15, comprising a plurality of soft pellets or granules of mean size of from 50 to 250 microns. 25

17. A medicament according to Claim 16, wherein the mean size is - 24 43260 - 25 from 120 to 160 microns.

18. A medicament according to Claim 17, wherein the moan, size is 140 microns.

19. A medicament according to any one of the preceding Claims, 5 wherein at least 95¾ by weight of the medicament particles have a diameter of less than 10 microns,

20. A medicament according to Claim 19, wherein at least 951 by v/eight of tho medicament particles have a diameter of from 0.01 to 10 microns. 10

21. A medicament according to Claim 19, wherein at least 95¾ by weight of the medicament particles have a diameter of from 1 to , • 4 microns. '

22. A medicament according to any one of the preceding claims, wherein the individual medicament particles are sclf-agglomcrative.

IS 23, k medicament according to any one of the preceding claims, wherein the medicament is hygroscopic.

24. A medicament according to any one'of the preceding claims comprising an inhalation medicament for the treatment of allergic airway disease. 20

25. A medicament according to Claim 24, wherein the inhalation medicament comprises a pharmaceutically acceptable salt of 1,3bis(2-carboxychro$on-S-yloxy)propan-2-ol.

26. A medicament according to Claim 25, wherein the inhalation medicament comprises disodium cromoglycate. 25

27. A medicament according to Claim 26, wherein the inhalation - 25 - 26 medicament comprises disodium cromoglycate and isoprenaline.

28. Λ medicament according to Claim 26, comprising less than 15¾ by weight of wateT.

23. A medicament according to Claim 28, comprising from 5 to 10¾ 5 by weight of water.

30. A medicament according to any one of the preceding claims, wherein the soft pellet is spherical.

31. A medicament according to any one of the preceding claims, in association with a colourant, sweetener or diluent. 10

32. A container containing a medicament according to any one of the preceding claims.

33. A container according to Claim 32 whicli is a capsule.

34. A container according to Claim 32 or 33 wiiich is loosely filled to less than 80¾ by volume irith the medicament in soft

IS pellet or granule form. 35. A container according to Claim 34 wiiich is loosely filled to less than 50¾ by volume with the medicament in soft pellet or granule form.

36. A container according to any one of Claims 32 to 35 containing 20 from 10 to 100 mg of the medicament in soft pellet or granule form.

37. A container according to any one of Claims 32 to 36 which is pierced.

38. A method for the manufacture of a medicament in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 24. 25 1,000 microns in diameter and comprises an agglomeration of - 26 d S 3 6 0 - 27 individual medicament particles at least 90¾ of which have a diameter of less tiian 10 microns, which comprises controlled agglomeration of medicament comprising individual medicament particles at least 901 of which have a diameter of less than 5 10 microns, characterised in tint the pellets or granules have (i) a 'Total Transmitted Load Reduction’ of greater than 100 g, and/or (ii) a product of 'Total Transmitted load Reduction' and 'Response Lag' of greater than 30 g/ems, and/or 10 (iii) a 'Response Jog' of at least 0.3 cms.

39. A method according to Claim 38, wherein the controlled agglomeration comprises extruding the medicament comprising individual medicament particles through ;m aperture.

40. Λ method according to Claim 39, wherein the controlled 15 agglomeration comprises forcing the medicament comprising individual medicament particles through a sieve of similar mesh size to the desired final pellet size..

41. A method according to any one of Claims 38 t.o 40, wherein the medicament comprising individual medicament particles is subjected 20 to an initial treatment to cause the particles to be selfagglomerative.

42. A method according to Claim 41, wherein the medicament is hygroscopic and the initial· treatment comprises wetting the powder particles by exposing them to a humid atmosphere. 25

43. A method according to Claim 42, wherein the particles are - 27 48360 - 28 exposed, to the humid atmosphere at a temperature of from 15 to 50°C.

44. A method according to any one of Claims 38 to 41, wherein the medicament is non-hygroscopic and self-agglomerative properties are imparted by the addition of a pharmaceutically acceptable 5 binder.

45. A method according to Claim 38, wherein the controlled agglomeration is effected in a fluidised bod.

46. A method according to Claim 38, wherein tho controlled agglomeration comprises spray drying a solution Or slurry of the 10 medicament.

47. A method according to any one of Claims 38 to 46, wherein the product of the controlled agglomeration .is subjected to tumbling and agitation.

48. A method according to Claim 47, wherein the tumbling and 15 agitation are carried out in a pan or drum type of pelletising machine.

. 49. A method according to Claim 38 for the production of a soft granule which comprises mixing tho individual medicament particles with an excess of a solvent, passing tiie moistened material through 20 an aperture of equal to or larger than the size required in the final granules and then drying the resulting material to the desired final solvent content.

50. A method according to Claim 49, wherein the solvent is v/ater.

51. A method according to Claim 50, wherein the medicament is di25 sodium cromoglycate and the water content of the di-sodium - 28 <ί Β 8 8 0 »» 23 * cromoglycate before the drying is from 12 to 251 by weight.

52. A method according to Claim 51, wherein the water content of the di-sodium cromoglycate before drying is from 17 to 231 by weight. 5

53. A method according to any one of Claims 49 to 52, wherein the temperature of drying is from 60 to 100°C.

54. A method according to any one of Claims 38 to 53, wherein the product is classified to remove over and under sized material.

55. A netted according to Claim 38 and substantially as 10 hereinbefore described.

56. A method according to Claim 38 and substantially as hereinbefore described in any one of tte Examples.

57. A medicament is soft pellet or granule form when made by a process according to any one of Claims 38 to 56. IS

58. A method of dispersing a medicament into an air stream, wherein a pierced capsule containing a plurality of soft pellets or granules according ts any one of Claims 1 to 31 or a container according to any one of Claims 32 to 37 is rotated and vibrated in an air stream.