CA1072569A

CA1072569A - Pellet form medicament

Info

Publication number: CA1072569A
Application number: CA232,477A
Authority: CA
Inventors: John H. Bell
Original assignee: Fisons Ltd
Current assignee: Fisons Ltd
Priority date: 1974-08-10
Filing date: 1975-07-29
Publication date: 1980-02-26
Also published as: IL47829A; NL7509080A; DK145654C; HK17780A; IL47829A0; GB1520247A; DK360875A; HU175594B; NL177980B; DK145654B; CY1049A; BE832097A; LU73182A1; BR7505055A; MY8100034A; FI752232A; FI65547B; KE3034A; ZA754765B; IE41586B1

Abstract

ABSTRACT
There is described a medicament in pellet form characterised in that the pellet is soft, is from 10 to 1000, 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. Processes for making the soft pellets are also described.

Description

;9 12/C/107 ~A 35334/74 -The present invention relates to a pharmaceutical composition and its preparation.
In our British Patent No 1,122,284 we have described and claimed an insufflator device for use in the administration of powdered medicaments by inhalatioD compris~ng a propeller-like device carrying a powder capsule rotatably m~unted within a ~ubular ; housing by means o a shaft loosely journalled in a tape~ed bearing tube, the housing having a mouthpiece whereby a useT 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 inhales air through the device which causes a powder container mDunted therein to rotate. Pcwder within the conta m er is fluidised and dispensed into the air stream which is inhaled by the user.
For optimum dispensing it has been found that the powdered medicament particles should be comparatively free-~lowqng and yet should have an ultimate particle size of less than about ten microns to ensure adequate penetration of the medicament into the lungs o~
the user. These two requirements are ~ facie m~tually exclusive, since such fine powders are not suficiently free-~lowing.
We have n~w ~ound that ~his problem can be mitigated or overcome by foTming the powdered medicament into small sot pellets which will ~luidise satisfactorily within the container and yet whi~h are of sufficiently l~w internal coherence to bTeak up into f-iner particles of medicament of a therapeutically effective size in the turbulent ~' 3L6) 7 ~5 6 g 15/C/107 In general we prefer not to use a binder, surface active agent or solvent in the soft pellets.
When ~he medicament is hygroscopic a small proportion of water, which, if necessary, is added to the medicament in the vapour phase 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 we prefer the soft pellets to contain less than 15~9, and preferably from 8 to 11% by weight of water.
The size of the soft pellets of the invention may be varied within the range given abo~e to suit the devices from which they are to be dispensed. For a gi~en device there is an optimum pellet size ~or optimim fluidisation of the soft pellets and this may be readily determined by simple tests9 e.g. by assessing the fluidisation of extremely strong pellets within ~he device which it is intended to use. We have also ~ound that optimum dispensing of the soft pe~lets is related to the size of ~he hole in the container through which the pellets are to issue. We prefer that the pellets ha~e a size of from one-twentieth to one-fifth of the diameter of ~he hole, which usually has a diameter of from 50D *o ;`~ 2000, e.g. about 700 to 15~0 nicrons.
However, the inte~nal coherence of the soft pellets may affect the desired size of the soft pellets since, as a generality~ the larger the pellet the more internally coherent it must be ~n order ' .
_ 5 _ '' ' ' : . ' ~ ~
' -''. '~ ' .' ' . , .
,' , LC~72569 16/c/107 to survive the forces experienced during fluidisation and it may be that the optimlm pellet size (as determined by criteTia other than internal coherence) would require that the pellet be so internally coherent for fluidisation ~hat it is not broken up after it leaves the container. The optimum size of ~he soft pellet may therefoTe have to be reduced in order that a suitable internal coherence value may be used. H~wever, as a general guide9 we have found that satisfactory sot pellets for use in insuf1ators of the type described in British Patent No 1,122,284 (commercially available under the Registered Trade Mar~ 'Spinhaler') and powered by human inhalation have a mean size in the range of from 50 ~o 250 niCroDS~ preferably a mean size in the range 120 to 160 microns and most p~eferably a m~an size of about 140 nicrons.
As indicated abovej the necessary internal coherence to be possessed by the soft pellet is a function of ~he conditions to be experienced both inside the container during fluidisation and outside the c~ntainer for achieving break-up o the soft pellets.
Large soft pelle~s mus~ be of comparatively high internal coherence to withstand the forces generated during fluidisation in the con~ainer and yet m~st not be so strong that they do not break-up outside the container to form finer particles of a therapeutically effective size, which is preferably less than about 10 nicrons, e.g. from about 0.01 ~o 10, and preferably from 1 to 4, n~crons in diameter, for medicaments which are to penetrate deep ~nto the lungs of a subject. The internal coherence of the soft - ~LC~7~569 15/C/107 , In general w~ prefer not to use a binder, surface active agent or solvent in the soft pellets.
When the medicament is hygroscopic a small proportion of water, which, if necessary, is added to the medicament in the vapour phase is usually suffici0nt to act as binder. The moisture content of the material m~y be adjusted according to the physical properties of the particular material, for example, for disodium cromoglycate we prefer the soft pellets to contain less than 15~, and preferably from 8 to 11~ by weight of wate~ -The size of the soft pellets of the in~ention may be varied within the range given above to suit the devices from which they are to be dispensed. FOT a given deYice there is an optLmum pellet size for optimNm fluidisation o~ the soft pellets and this may be Teadily determined by simple tests9 e.g. by assessing the fluidisation of extremely strong pellets within ~he device which it is intended to use. We have also found that optimun dispensing of the sof~ pellets is related to the size of ~he hole in the container through which the pellets are to issue. We prefer that ; 20 the pellet5 ha~e a size of from one-twentieth to one-fifth of the diameter of the hole? which usually has a diamete~ of from 500 to 2000, e.g. about 700 to 1500 microns.
However, the internal coherence of the soft pellets m~y affect the desired size of the soft pe31ets since, as a generality, the larger the pellet ~he more internally coherent it must be in order .

' : ~
' :

, :

~L0 7 z 5 ~9 16/C/107 to survive the forces experienced during fluidisation and it may ~e ~hat ~he optimum pellet size tas determined by criteria othe~
than internal coherence) would require that the pellet be so internally coherent for fluidisa~ion that it is not broken up after it leaves the container. The optimum size o~ the soft pellet may therefore have to be reduced in order that a suitable internal coherence value may be used. Hcwever, as a general guide~ we have found that satisfactory soft pellets for use in insuf1ators of the type described in British Patent No 1,122,284 (commercially a~ailable under the Registered Trade MarX '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.
As indicated above~ the necessary internal coherence to be possessed by the soft pellet is a function of the conditions to be experienced both inside the container during fluidisation and outside the container for achieving break-up of the soft pellets.
Large soft pellets nus~ be of comparatively high internal coherence to withstand the forces generated durLng fluidisation in the con~aine~ and yet must not be so strong that t~ey do not break-up outside the container to form finer particles of a therapeutically effective size, which is preferably less than about 10 nicrDns, e.g. from about 0.01 to 107 and prefeTably from 1 to 4 microns in diameter, for medicaments which are to penetrate deep into the lungs of a subject. The inte~nal coherence of ~he soft , `''' , .
.
.

iL~7~S6~ 17/C/107 pellet may therefore be varied o~er quite a wide range depending upon the ener W available for breaking-up the soft pellet, and its size. The minimum internal coherence which may be possessed by the soft pellets will depend on their size and density, and on the forces to which the soft pellets are subject during fluidisation within the container~ The internal coherence for a given case may be dete~mined by simple test and modified as appropriate.
It will of course be appreciated that the method by which the soft pellets are to be filled into ~he container and under which the filled~containers are transported and stored will also affect the minim~m acceptable internal coherence in a given case, since appreciable bTeak-up of the soft pellets should not occur under these conditions.
From the above, it will be appreciated that soft pellets having satisfactory prDpeTties may be obtained from a number of permutations of the size and coherence and optimum permutations within the above guide lines may be readil~ determined in each case by simple empirical tests. By way of an example5 we have found that fo~ soft pellets which are to be dispensed from a gelatine capsule 6.4 ~m in diameter and having two holes 0.8 mm in diameter in a shoulder thereof mounted in a device tcommerci~lly available under the Registered Trade Mark 'Spinhaler') according ~o British Patent No 1,122,284 having a drawn wire shaft 2.03 mm diameter journalled in a hard nylon bearing tube 13 mm long and having an internal diameter of 2.08 r~ at its inner end (i.e. that ~.' ' ~L~7;~56~

end housing the free end of the shaft3 and of 2.4 mm at its other end, and wherein the capsule is ~otated about its axis at a speed of about 18C0 rpm by an air stream having a fl~w rate of 60 litres per minute it is desirable that the pellets have a mean size of - S about 140 microns. It is especially preferred that the pellets are made from disodium cromoglycake.
The soft pellets are pre~erably such that when put up in gelatine capsules 6.4 mm in diameter each contamlng 20 mg of the medicamen~ as soft pellets they m~et the criteria set out in the two tests below:- -~a) Dispersio~ test The filled capsules are mDunted in the capsule holder of the powder lnsufflator (having the specific dimensions set out imnediately above) o British Patent Specification No 1,122,284 and pierced to produce two holes of 0.8 mm diameter m a shoulder of the capsule. The dispersion of the nedicament in the cloud delivered by the insufflator is determined using a modified version of ~he multistage liquid i~pinger described in British Patent Specification No 1,081,881. The m~difications incorporated in the present design are ~he addition of an ext~a impingement stage, and - of a glass tube wi~h a ri~ht angled bend approxinately mid-way along its leng~h. The extra impingement stage was added prior to the ~hree stages described in British Patent Specificati~n No 1,081,881 and consists essentially of a jet of internal diameter 2.5 cm and a collection plate of diameter 5 cm designed ~o give an effec~ive ~7;Z56gl cut-o~ o approximately 12 m~crons at an air flcw rate of 60 litres per minute. lhe glass tube, also of internal diameter 2.5 cm abutts the external end of the jet of the extra stage, and is coated internally with a film of polyethylene glycol 40D to provide a retentive surface for impinging particles. The insufflator is inserted into the upper, horizontal end of the glass tl~e and air drawn through at 60 litres per minute for 30 seconds. At least ive capsules are treated in ~his manner and the results are averaged. The weight of the medicament collected on each stage of the impinger, on the glass tube, and on a filter paper positioned after the inal stage is determined spectrophotometricaily after solution in an appropriate volume of distilled water (or by any other appropriate method).
The soft pellets disperse satisfactorily if an average total for each capsule of at least 0.5 mg, preferably at least 1.0 mg and most preferably at least 1.5 mg of the medicament are found on a combination of the last two stages and filter paper of the multi-stage liquid impinger.
: (b) Emptying test The filled capsules are mounted in ~he capsule hol~er o the powder insufflator ~having ~he specific dimensi~ns set out above) of British Patent Specification No 1,122,284 and pierced to produce two holes of 0.8 mm diameter in a shoulder of the capsule. Tle insu~Çlator is placed in a device adapted to suck air through ît for 2.5 seconds, the air ~low rate at no tine exceeding 60 litres '' _ g_ 1~7Z~6~

--~o--per minute~ and be~ng held at 60 litres per minu~e for at least

2 seconds. The capsule unted in the insufflator is subjected to 4 sucks as described and the weight of the material remaining in ~he capsule is determined. The above procedure is repeated 20 times and the average of the results determined.
The soft pellets empty satisfactorily if an average of at least 50~, preferably at least 75~ and mcst preferably at least 90~ by weight of the material has emptied from each capswleO
~ he follcwing Strength test is also of relevance:-A measure of the strength of the soft pellets of the invention may be achieved by means of a device (available ~rom Instron Llmited, Coronation Road, High Wyco~be, ~uckinghamshire, England as M~del IM-SM~ for the measurement of the stress/strain proper~ies o~ materials. This device comprises a punch capable of fitting tigh~ly into a die of 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 a pressure sensitive plate.
In operation the material to be tested is filled loosely into the die, the punch is mDved at a constant speed into the die from the top end and the pressure on the pressure sensitive pla~e is recorded , . .
graphically. We have found ~hat with soft pellets accord m g to our inventi~n a ~easurement of lOg on the pressure sensitive plate occurs ~hen ~he volume of the soft pellets has been reduced by about 25 to 35~, preferably about 30~, of the original volume of the soft pellets and ~hat a measurement of 1 kg on ~he pressure 1~72S6~ ll/C/236 sensitiYe plate occurs when the vDlume of the soft pellets has been reduced by about 50 to 70%, preferably about 60~, of the original v~lume of the soft pellets. It is also noticeable that the measurement of the force on the pressure plate does not increase regularly, but in an approxImately stepwise fashion.
The increase in force on the pressure sensitive plate is not continuous, and decTeases in the ~orce with increasing penetration of the die may occur, as well as the expected increases in force with increaSLng penetration. It is believed that this irregular response to the applied pressure is due to the breakdown of the soft pellets.
From another aspect the invention also provides a capsule, cartridge or li~e container containing soft pellets of the m vention, optionally in association with other pellets or particles. We prefer the container to be loosely filled to less than about 80% by volume, preferably less than about 50~ by volune, with the soft pellets of ~he invention. The soft pellets should of course not be compacted into the container. ~e prefer the container, e.g. capsule, to contaLn from 10 to 100 mg of the soft pellets. The container may oonveniently be pierced (and overcapped, e.g. with a plastic overcap) durung its manufacture and then used, after removal of the overcap, in an inhalation device which has no piercing mechanism.
The soft pellets of the invention may be made by a number of ~- 25 methods.

' 9L~97Z569 12/C/236 Thus according to the invention ~here is provided a method for the m~nufacture of soft pellets according to the inventionf which comprises subjectLng particles of medicament which either aTe intrLnsically, 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 apeTture, (b) contTolled agglomeration in a fluidised bed, or (c) spray d~ying a solution or slur~y of the medicament.
In method (a) which is the pre~erred method, finely divided medicament, e.g. having a mean particle size in the range 0.01 to 10 microns may, 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 wetting the powder particles by exposing them to a humid atmosphere, for example at a temperature of from about 15 to 50C. Whilst *he amount of water required to achieve adequate self-agglomerative properties may vary from m~dic~ment to medicam~nt9 it will not usually be necessary to increase the free water content of the pcwder beyond about 15~ by weight, e.g. to ~rom 5 to 10~. Uhere the medicament is non-hygroscopic, the necessary self-agglomerative properties may be Lmparted by the addition of a pharmaceutically acceptable binder, e.g. one selected from those mentioned earlier, or by treating the powder with a liquid ~under carefully co~trolled condit;ons~, which may - _~ 13/C/236 ~L~)7Z56~ ' ~ 13 -be evaporated to produce bridges of a solid residue binding the p~wder particles, or which causes ~dequa~e interparticle con~act.
It will be appreciated that the nature of the binder may affect the coherence of the resultant pellet fo~med from treated medicament.
A binder solu~ion may, if desired, be used with a hygroscopic medicament in order to improve the internal coherence of the resultant pellet.
After t~he particles have been rendered self-agglomeratiYe, they are passed through an aperture of approximately the size of the desired pellets, e.g. they are forced ~hrough the apertures of a vibrating sieve which is of similar mesh aperture to the desired final pelle~ size. The product of this passage through an aperture are shaped pre-pellets of the medicament.
In process (b) the fine particles of medicament to be form~d - 15 into pellets may be suspended, together with any other ingredients it is desired to incorporate in the pellets, in a gas st~eam in a fluidised bed apparatus. When a hygxoscopic material is to be formed into pellets the water conte~t of the solid material may be adjusted by variation of the humidity of the gas strean passing through the fluidised bed. The medicament may be treated in the fluidised bed for a time and under conditions sufficient to produce pre-pellets of the desiTed internal coherence and size.
In process (c) a solution or nNre preferably a slurry, of the medicament may be spray-dried. We prefer ~o use a slurry of discrete medicament particles of the desired fine particle size, ' .
~ 13 -~,` 14/C/236 ~137Z~i6~31 ~ 14 the slurry also containLng any other ingredients it is desired to incorporate in ~he pellets. The 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 par~icles 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 powder during the ~ controlled agglomeration will va~y according to the method and - 10 powder used~in the agglomeration. However, as a guide, we have found that suitable pre-pellets may be formed by process (a) ~rom a powder of disodium cromoglycate co~taining from abou~ 8 to 10~
by weight of water, by forcing the powder through a seive 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 co~ventional methods until the desired size, shape and coherence of the pellets are achieved. We prefer a proportion9 e.g. a majori~y, of the soft pellets, and especially sof~ pelle~s of disodium cromoglycate, to be approximately spherical.
Conveniently the tumbling and agitation are carried out in a pan or drum type of pelletis;ng machLne. The treatment of the pre-pellets in such a machine is carried out until ~he majority of pellets in the charge have a size within the desired range.
The size of the pre-pellets used and the conditions used in their ~ 107Z569 15/C/236 agitation and tumbling may be varied in known manner ~o 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. ~he effect of the tumbling and agitation of the pellets is in general to strengthen them and increase their size slightly and ~o make them more nearly spherical ` in shape.
: As indicated above, the final product which issues from the ; agitation or tumbling step wQll have a range of sizes about thedesired mean size. The product may be classified, e.g. sieved, to remo~e over and under sized material. The over and under sized material nay be broken down into very fine particles and recycled to the agglomeration stage if desired.
The final so~t pellets may be put up Ln any suitable form of container such as a capsule or cartridge. Where it is desired to use the pellets 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 using conventional techniquesO We prefer the soft pellets of the invention to contain medicament and water only.
According to our invention we àlso proYide a method of application of a medicament, e.g. disodium cro glycate, to a patient by way of inhalation, the medicament being dispersed into an air stream, characterised in that a pierced capsule containing soft pellets according to the L~ention is rota~ed and vibrated in ~ 15 -:' , ~7~:~6~

., ~
an air stream which is inhaled by 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 Specification No 1,122,284.
Disodium cromoglycate is Xnown to be of use in the ~reatment of S asthma and hay fever.
~ le invention will now be illustrated by the following Example in which all parts and percentages are by weight unless otherwise stated.
EXample ' ` 10 The moisture content of micronised disodium cromDglycate having at least 98~ thereof of particle size less than lO macrons and having a mass median diameter of from 1 to 3 microns was adjusted f~om an i~itial value of from 4 to 6~ by weight to a value of about 9.5~ by weight by exposure of the powder on a tray in an atmosphere of relative humidity 33~ at 18 to 24C.
After the desired moisture content had been achieved, the treated powder was tipped onto a 150 micron aperbure stainless steel sieve scree~ mounted in a Russel vibratory sifter operating at a frequency of 1,000 cycles per second. The powder on the screen was forced through the sieve apertures usLng a stainless steel spatula pushed across the surface o the screen. The material issuing from the sifter as particles with a mean particle diam~ter of about lS0 microns was fed directly to a drum pelletiser adapted to rotate about a horizontal axis. The drun o~ the pelletiser was approximately 0.3m in internal diameter and ~' - 16 _ ' ' ~7Z569 i .
0.37m long with one end closed and the other end provided with frusto conical shoulder leading to a 0.18m orifice through which material could be charged to or removed from the dr~m. The interior of the drum was highly polished. Two kilograms of the material from the sifter were loaded into the drum which was then rotated at a peripheral speed of 0.38m per second ~ 0.025m per second for 15 minutes. At th~ end of this time the soft pellets : had a mean particle diame~er of 135 microns and not more than 10%
by weight was retained on a 350 micron apertuTe sieve and not less than 90~ by weight was retained on a 63 micron aperture sieve.
Ihe moisture content of the 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 isture content of the ; 15 initial pawder should be carried out under conditions of controlled humidi~y so as not to alter the water content of ~he powder appreciably.
The soft pellets produced by the above procedure are approximately spherical, and have an open and loose struc~ure and a fluf~y surface when viewed under a microscope.
Up bo ~0 mg, e.g. 40 or 60 mg, of the abo~e soft pe~lets were plaçed 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 1~122,284 having the detailed construction and dimensions referred to above. When air at a flow . . , .. .

, ., ~L~37~2S6~ 18/C/236 rate of 60 litres per minute was passed through this devise,`it was found that the charge in the capsule was consistently completely dispensed into ~he airstream and broken up to provide a cloud of very fine particles suitable for inhalation.
S By way of contrast, when the initial micronised powder from which the pellets had been prepared was tested under identical conditions, comparatively little of the powder was dispensed ~rom the capsule and the amount dispensed varied inconsistently from test to test.
Similar results weTe obtained when 1,3-bis(2-carboxychromon -7-yloxy)propan-2-ol disodium salt (6% water), isoprenaline sulphate and tetracycline were subjected to the procedure of the Example to obtain soft pellets.

: . ~

: 20 . 25 ,. . ,. ., ' , -

Claims

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

1. An inhalation medicament for the treatment of allergic airway disease in pellet form characterised in that the pellet is soft, is from 10 to 1,000 microns in diameter and comprises an agglomeration of individual medicament particles at least 90% of which have a diameter of less than 10 microns.

2. A medicament according to claim 1, comprising a plurality of soft pellets of mean size of from 120 to 160 microns.

3. A medicament according to claim 1 or claim 2, comprising an inhalation medicament for allergic airway disease.

4. A medicament according to claim 1 wherein the inhalation medicament comprises disodium cromoglycate.

5. A medicament according to any one of claims 1, 2 or 4 comprising less than 15% by weight of water.

6. A medicament according to any one of claims 1, 2 or 4 wherein the soft pellet is spherical.

7. A capsule containing a medicament according to any one of claims 1, 2 or 4, the capsule containing from 10 to 100 mg of the medicament in soft pellet form and being loosely filled to less than 80% by volume with the medicament in soft pellet form.

8. A method for the manufacture of an inhalation medicament, comprising disodium cromoglycate, for the treatment of allergic airway disease in pellet form, wherein the pellet is soft, is from 10 to 1000 microns in diameter and comprises an agglomera-tion of individual medicament particles at least 90% of which have a diameter of less than 10 microns, which comprises controlled agglomeration of medicament comprising individual medicament particles at least 90% of which have a diameter of less than 10 microns, the controlled agglomeration comprising (a) extruding the medicament comprising individual medicament particles through an aperture, or (b) passing the individual medicament particles through a fluidised bed, or (c) spray drying a solution or slurry of the medicament.

9. A method according to Claim 8 wherein the controlled agglomeration comprises forcing the particles of medicament through a sieve of similar mesh size to the desired final pellet size.