CA1116516A - Medicament composition in soft pellet or granule form - Google Patents
Medicament composition in soft pellet or granule formInfo
- Publication number
- CA1116516A CA1116516A CA000270236A CA270236A CA1116516A CA 1116516 A CA1116516 A CA 1116516A CA 000270236 A CA000270236 A CA 000270236A CA 270236 A CA270236 A CA 270236A CA 1116516 A CA1116516 A CA 1116516A
- Authority
- CA
- Canada
- Prior art keywords
- medicament
- granules
- pellets
- soft
- pellet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
Abstract
MEDICAMENT COMPOSITION IN SOFT PELLET OR GRANULE FORM
ABSTRACT
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.
ABSTRACT
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
p~
~A 26l~76 The present Lnvention relates to a pharmaceuticalcomposition 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 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 devioe. ~ith that device, and other devices, e.g that described in British Patent Specification No 1,331~216, a user ir~ales air through the device which causes a powder container mounted therein to rotate.
Pcwder within the container is fluidised and dispensed into the air stream which is inhaled by the user. For optimum dispensing it has been found that the pcwdered 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 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 probl~n can be mitigated or overcome by forming the pcwdered medicament into small soft pellets or granules which will fluidise satisfactorily within the container and yet which are of sufficiently low internal coherence to break up ,, 2606/76/5301/~2 - 3 -into finer particles of medicament of a therapeutically effective size in the turkulent 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 powder inhalation oompositions, to be omitted from the 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, pre~erably 30 to 500, microns in diameter and comprises an agglomeration of individual medicament particles, a-t 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 defined3 and 'Response Lag' ~as hereinafter defined) of greater than 30, preferably greater than 40, and more preferably between 40 and 1,000 g/cms, 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.
2606/76/5301/92 - ~ -The soft pellet or granule preferably has an internal coherence such -that the pellet or gramlle remains intact T~hen filled into a container, e.g a capsule, using automatic or semi-automatic filling machines, under oonditions of transport and S storage, and when fluidised within a container in the devi e from which it is intended to dispense the pellets or granules and yet ma~ 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 pc~dered 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 nunber of particles, e.g greater than 95% by weight, of less than 10 microns, e.g from 0.01 to 10, and preferably from 1 to 4, microns diameter, before incorporati~n into the soft pellets oF
the invention. ~esirably the individual medicament particles are self-agglomerative as is usually the case with a hygroscopic material. Examples of suitable nedicaments include those suitable for the inhalation treatment of allergic airway diseas~s such as pharmaceutically acceptable salts of 1,3-bis(2-carboxy-chromo~-5-yloxy~propan-2-o1, pharmaceutically acceptable salts ~ 3~a $
of 1,3~bis(2-carboxychr~mon-7-yloxy)propan-2-ol, sympathomimetic amines ~e.g isoprenaline, ephedrine, or isoetharine and salts thereof), antibiotics 5e.g tetracycline), steroids, enzymes~
vitamins and antihis~amines. 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 (aommonly kncwn as sodium cromcglycate, disodium cro~oglycate or cromolyn scdium) and isoprenaline, may be used.
m e pellets or granules may contain other ingredients, e~g diluents oolouring and flavouring agents. Where the medicament is not self agglomerative, e.g hygroscopic, it ma~ 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 e-thers of carboxymethylcellulose, dextrans and sugar solutions. Where the medicament is not easily wetted it may be desirable to incorporate a small proportion of a surface active agent intor and/or to use a solvent in the preparation of, the soft pellets or granules. In general we prefer not to use a binder, surface active agent or solvent (other than water) in the ~oft pellets or granules.
When the medicament is hygroscopic a small proportion of water, which, if necessary, is added to the medicament 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 may he adjusted according to the physical properties of the particular material~ for example, for disodium cromoglycate 2hO6/76/5301/92 - 6 -we prefer the soft pellets or granules to c~ntain less than 15~, and preferably from 8 to 11% by weight of water.
The size of the soft peLlets or granules of the invention may be varied within the range giY2n above to sui-t 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 and this may be readily determined by simple tests, e.g by assessing the fluidisation of 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 to one-fifth of the diameter o the hole, which usually has a diameter of from 500 tc) 2,000, e.g about 700 to 1,500 mlcrons.
As a general guide, we have found that satisfactory soft peLlets or granules for use in insufflators of the type described in British Patent No 1,122,284 (c~mmercially 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 lÇO microns and most preferably a mean size of about 140 microns.
The soft pellets or granules should be sufficiently coherent to be filled into containers, transported and stored, since fi~
appreciable break-up of the soft pellets or granules should not occur under these oonditions.
From the above, it will be appreciated that soft pellets or granules having satisfactory properties may be obtained from a number of permutations of the size and ooherence. By way of an example, we have found that Eor soft pellets or granules which are to be dispensed from a gelatine capsule 6.4 mm in diameter and having twc holes 0.8 mm in diameter in a shoulder thereof mounted in a device (commercia~ly available under the R~gistered Trade Mark 'Spinhaler') according to 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 havin~ an internal diameter of
~A 26l~76 The present Lnvention relates to a pharmaceuticalcomposition 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 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 devioe. ~ith that device, and other devices, e.g that described in British Patent Specification No 1,331~216, a user ir~ales air through the device which causes a powder container mounted therein to rotate.
Pcwder within the container is fluidised and dispensed into the air stream which is inhaled by the user. For optimum dispensing it has been found that the pcwdered 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 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 probl~n can be mitigated or overcome by forming the pcwdered medicament into small soft pellets or granules which will fluidise satisfactorily within the container and yet which are of sufficiently low internal coherence to break up ,, 2606/76/5301/~2 - 3 -into finer particles of medicament of a therapeutically effective size in the turkulent 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 powder inhalation oompositions, to be omitted from the 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, pre~erably 30 to 500, microns in diameter and comprises an agglomeration of individual medicament particles, a-t 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 defined3 and 'Response Lag' ~as hereinafter defined) of greater than 30, preferably greater than 40, and more preferably between 40 and 1,000 g/cms, 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.
2606/76/5301/92 - ~ -The soft pellet or granule preferably has an internal coherence such -that the pellet or gramlle remains intact T~hen filled into a container, e.g a capsule, using automatic or semi-automatic filling machines, under oonditions of transport and S storage, and when fluidised within a container in the devi e from which it is intended to dispense the pellets or granules and yet ma~ 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 pc~dered 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 nunber of particles, e.g greater than 95% by weight, of less than 10 microns, e.g from 0.01 to 10, and preferably from 1 to 4, microns diameter, before incorporati~n into the soft pellets oF
the invention. ~esirably the individual medicament particles are self-agglomerative as is usually the case with a hygroscopic material. Examples of suitable nedicaments include those suitable for the inhalation treatment of allergic airway diseas~s such as pharmaceutically acceptable salts of 1,3-bis(2-carboxy-chromo~-5-yloxy~propan-2-o1, pharmaceutically acceptable salts ~ 3~a $
of 1,3~bis(2-carboxychr~mon-7-yloxy)propan-2-ol, sympathomimetic amines ~e.g isoprenaline, ephedrine, or isoetharine and salts thereof), antibiotics 5e.g tetracycline), steroids, enzymes~
vitamins and antihis~amines. 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 (aommonly kncwn as sodium cromcglycate, disodium cro~oglycate or cromolyn scdium) and isoprenaline, may be used.
m e pellets or granules may contain other ingredients, e~g diluents oolouring and flavouring agents. Where the medicament is not self agglomerative, e.g hygroscopic, it ma~ 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 e-thers of carboxymethylcellulose, dextrans and sugar solutions. Where the medicament is not easily wetted it may be desirable to incorporate a small proportion of a surface active agent intor and/or to use a solvent in the preparation of, the soft pellets or granules. In general we prefer not to use a binder, surface active agent or solvent (other than water) in the ~oft pellets or granules.
When the medicament is hygroscopic a small proportion of water, which, if necessary, is added to the medicament 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 may he adjusted according to the physical properties of the particular material~ for example, for disodium cromoglycate 2hO6/76/5301/92 - 6 -we prefer the soft pellets or granules to c~ntain less than 15~, and preferably from 8 to 11% by weight of water.
The size of the soft peLlets or granules of the invention may be varied within the range giY2n above to sui-t 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 and this may be readily determined by simple tests, e.g by assessing the fluidisation of 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 to one-fifth of the diameter o the hole, which usually has a diameter of from 500 tc) 2,000, e.g about 700 to 1,500 mlcrons.
As a general guide, we have found that satisfactory soft peLlets or granules for use in insufflators of the type described in British Patent No 1,122,284 (c~mmercially 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 lÇO microns and most preferably a mean size of about 140 microns.
The soft pellets or granules should be sufficiently coherent to be filled into containers, transported and stored, since fi~
appreciable break-up of the soft pellets or granules should not occur under these oonditions.
From the above, it will be appreciated that soft pellets or granules having satisfactory properties may be obtained from a number of permutations of the size and ooherence. By way of an example, we have found that Eor soft pellets or granules which are to be dispensed from a gelatine capsule 6.4 mm in diameter and having twc holes 0.8 mm in diameter in a shoulder thereof mounted in a device (commercia~ly available under the R~gistered Trade Mark 'Spinhaler') according to 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 havin~ an internal diameter of
2.08 mm at its inner end (i.e that end housing the free end of the shaft) and of 2.44 mm 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.
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) below:-(a) Dispersion test The filled capsules are m~unted in the capsule holder of the powder insuflator (having the specific dimensions set out immediately above) of British Patent Specification ~o 1,122,284 and pierced to produce two h~les of 0.8 mm diameter in a shoulder of the capsule. The dispersion of the medicament in the cloud delivered by the insufflator is determined using a mKdified version o the multistage liquid .umpinger described in British Patent Specification No 1,08:L,881. The mcdified impinger is illustrated in Fig 3 which represents a cross-section through the impinger.
In Fig 3 the Fcwder insufflator 1 is situated in the rubber sleeve 2, and is thereby connected to the bent glass tube 3. The lower end of the 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 ~nit 7 which in turn is onnected to a vacuun pump via tube 8. The dimentions of the device are given belcw:-a - a 35 mm b - b 150 mm c c 19 mn d - d 30 mm e - e 55 mm f - f 100 mm g _ 9 4 mm h - h 38 mm i - i 6 mm j - j 10 mn ., 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 collected on the filter, and that in the remainder of the apparatus and in the insufflator is determined spectrophotometrically after solution in an appropriate volume of distilled water (or by any other appropriate method)O
The soft pellets or granules disperse satisfactorily if an average total for each capsule of at least 8%, preferably at least 10% and most 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 mounted in the capsule holder of the Ex~wder insufflator (having the specific dimentions 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.
The insufflator is placed in a device adapted to--suck air t~rough it for 2.5 seconds, the air flow rate at no time exceeding ~0 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. The above procedure is repeated 20 times and the average of the results determined.
The soft pellets or granules e~pty satisfactorily if an 5~
2606/76/5301/9~ - 10 -average of at least 50%, preferably at least 75% and most preferably at least ~0~ by weight of the material has emptied from each capsule.
The folLcwing tests are also of significance in defining the pellets or granules of the invention:
(c) Response Lag m e respone lag may be measured by means of a device (available from Instron Limited, Coronation Road, ~ligh Wyccmbe, Buckinghamshire, England as Model IP~5M) for the measurement of the stress/strain properties of materials. This device is illustrated in Fig 2 and comprises a punch 1 capable of fitting tightly into a die 2 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 the 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 surfa oe made level with the top of the die. The punch is moved at a constant speed into the die from the top end and the load transmited b~ the load cell is recorded graphically. The response la~ is defined as the distance in cms that the punch tip travels below the bop of the die before a response of 1 g is registered by the load cell.
~d) Total Transmitted Lcad Reduction It has also been found that with medicaments according to the invention ~hich disperse satisfactorily the applied load transmitted to the load cell in the device described in (c) above d oes not increase steadily ~seefor example Fig 1~. The back track of the curve, or the 'easing' of the load in grams, may be termed the ITotal Transmitted Load Reduction' of the material ~nder test. m us 'Total Transmitted Lcad Reduction' may be defined as the swm of the reductions in the transmitted load detected by the load cell while the load recorded as acting on the oe 11 progresses from 0 to 1,000 gms.
We have found that the most useful para~eter 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'.
The pellets and granules according to the inven-tion have a lower loose bulk density than granules or pellets made by conventional techniques. Thus soft pellets and granules of discdium cromcglycate have a loose bulk density of less than 0.3 g per cc, preferably from 0.2 to 0.3 g per c~, and most preferably frcm 0.22 to 0.28 g per cc.
From another aspect the invention also provides a capsule, cartridge or like container cOntaining soft pellets or gra~ules of the invention, optionally in associa~ion with other pellets, granules or particles. We prefer the container to be loosely filled to less than about 80% by volume, preferably less than about 50% by volume, with the soft pellets or granuels of the 5~
2606/76/5301/9~ ~ 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 10 to 100 mg of the soft pellets or granules. The container may conveniently be pierced (and overcapped, e.g with a plastic overcap) during its manufacture andthen 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 oonventional techniques~ We 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 the 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 oontrolled agglomeration may be carried out by, (a) extruding the particles of medicament through an aperture, ,.~, (b) controlled agglomeration in a fluidised bed, 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 10 micronSmay, if necessary, be subjected to an initial treatment to cause the powder particles to be self-agglcmerative. Thus where the medicament is of a hygroscopic nature, the treatment may be carried out by exposing the powder particles to water.
When soft pellets are required the powder particles may be subjected to a humid atmcsphere, for example at a temperature o from about 15 to 50C. Whilst the amount of water required to achieve adequate self-agglGmerative properties may vary from m~dicament to medicamentf it will not usually be necessary to increase the water content of the powder beyond about 15%
by weight, e.g to from 5 to 10% when soft pellets are required.
Where the medicament is non-hygroscopic, the necessary self-agglomerative properties may be imparted 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 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 the nature of the binder may affect the coherence of the resultant pellet or granule formed ~ m treated medicament.
A binder solution may, if desired, be used with a hygrosoopic i medica~ent 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 dr~uD 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. The product of this passage through an aperture are shaped pre-pellets of the medicament.
When soft granules are required the powder particles may be mixed with an excess of a suitable solvent, e.g. liquid water, and the m~istened material passed through an aperture, e.g a sieve such as a vibrating sieve, of approximately equal to or larger than the mesh size required in the final granules and then drying the resulting sieved material to the desired final solvent, e.g. water, content. The materia] may then be dry granulated to give the required product.
When it is desired to incorp~rate another ingredient, e.g.
a binder, inb~ 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 m~isten the medicament.
The amount of water, or other solvent, used in the granulation can, under certain circumstances, be critical. Thus we have found that with di-sodium crom~glycate (DSCG) use of 2606/76/5301/92 ~ 15 -greater than about 25~ by weight of water (measured on dry DSCG) causes the granules to be too strong and not to have sakisfac~ory dispersion properties. We therefore prefer to use from about 12 to 25~, and preferably from 17 to 23% by weight of water in the granulation of di~sodium cromoglycate.
The dryin~ is preferably effected in a preheated forced convection hot air oven. The temperature of drying is desirably from 60 to 100C, and more especially from 80 to 90 & .
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 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. When a hygrosoopic 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 water into the bed. The medicament may be treated in the fluidised bed for a time and under oonditions sufficient to produce pre pellets or granules of the desired internal ooherence and size.
In process (c) a solution or more preferably a slurry, of the medicament may be spray-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 medi~ament particles during the spray drying.
When a controlled amount of water is desired in the produc-t 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 vary according to the method and pcwder used in the agglomeration. However, as a guide, we have found that suitable pre-pellets may be formed by process (a) from a powder of disodium cromoglycate containing from about 8 to 10 by weight of water, by 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, shape and coherence of the pellets are achieved. We prefer a proportion~
e.g a majority, of the soft pellets, and especially soft pellets of disodium cromoglycate, to be approximately spherical.
Conveniently the t~nbling 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.
r.33~;
2606/76/5301/g2 - 17 -The size of the pre-pellets used and the conditions used in their agitatlon and tumbling may be varied in known 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 si2e slightly and to make them more nearly spherical in shape.
As indicated above the final product which issues from the agitation or tu~bling 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 the pellets or granul~es of the invention in asscciation 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. We prefer the soft pellets or granules of the invention to contain medicament and water only. The soft pellets or granules may also be u æ d in admixture with up to 75% b~ weight of free particles of medicament having a dianeter of from 0.01 to 10 microns.
- 17 ~
'~
~ccording to our invention we also provide a method of 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 containi~q soft pellets or granules according to the invention is rotated and vibrated in 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 cromGglycate is known to be of u æ in the treatment of asthma and rhinitis.
In this specification the ~erm 'pellet' is used to denote an agglGmerate which is held together by interparticulate (e.g Van der Waal's) forces and is typically made by a process involving water vaFx~lr. Pellets are in general spherical in shape. The term 'granule' is used to denote an agglomerate which is held together b~ interparticle bridges. In the case o 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 some of the solvent.
The invention will now be illustrated by the following Exa~ples in which all parts and percentages are by weight unless otherwise stated.
Example 1 The moisture content of micronised disodium croncglycate having at least 98% thereof of particle size less than 10 nucrons ~, 2606/76/5301/'92 - 19 -and having a mass median diameter of from 1 to 3 nucrons was adjusted from an initial 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 isture content had been achieved, the treated pcwder was (after an optional initial rolling in a drum pelletiser) tipped onto a 150 micron aperture stainless s-teel sieve screen mounted in a Russel vibratory sifter operating at a frequency of 1,000 ~ycles per second. The pKwder on the screen 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 150 microns was fed directly to a drum pelletiser adapted -to rotate about a horizontal axis. The c~ of the pelletiser was approximately 0.3 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 orifi oe through which material could be charged to or removed from the drum~ 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 0.38 m per second + 0.025 m per second 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~ by weight was retained on a 63 mlcron aperture sieve. The moisture content of the final soft pellets was in the range 8.5 t.o 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 pc~der should be carri~d out under oonditions of controlled humidity so as not to alter the water content of the powder appreciably. The water used in the process should be sterile and the air used in the process should be Class 100 air.
m e soft pellets produced by the above procedure are approximately spherical, and have an open and loose structure and a fluffy surface when viewed under a microscope.
Up to 90 m~, e.g 40 to 60 mg, of the above soft pellets ~ere 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 1,122,284 having the detailed construction and dimensions referred to above. When air at a flow 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 micronised pcwder from which the pellets had been prepared was tested under identical conditions, oomparatively little of the pcwder was dispensed Erom test to test.
Similar results were obtaine when 1,3-bis(2-carboxychromon-~ 20 -, .. .
2606/76/53~1/92 - 21 -7-yloxy)propan-2-o1 disodium salt (6~ water), isoprenaline sulphate and tetracycline were subjected to the procedure of the Example to obtain soft pellets.
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 Tbtal Transmitted Load Reduction of greater than 900 gms and a dispersion of greater than 10~ were obtained.
~
l,OOOg of micronised disodium cromoglycate of determined water content was placed in the bowl of a planetary mixer. The calculated amount of water to bring the moisture oontent of the disodium cromoglycate to within the desired range was then added gradually, the sides of the mixer bcwl being scraped regularly to ensure even m~isture distribution. The damp disodium crom~glycate ~as then passed through 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 isture content of the granules was in the range 5 to 8% by weight. The granules were then sieved through a 250 micron screen. The resulting granules were found to flow well and could be filled easily into gelatine capsules.
Example 4 Using the devioe illustrated in Eig 2I granules of disodium . , .
~ f~ J~
260~/76/5301/92 - 22 -cron~glycate produced according to Example 3, and the Dispersion Test as previously described, dispersions of greater than lO~
were obtained for gram~les made using from 10 to 25% by weight water at the granulation stage. m ese granules had response lags of greater than 0.3 cms and a Total Transmitted Load Reduction of greater than lO0 gms.
2~
It is especially preferred that the pellets or granules are made from disodium 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) below:-(a) Dispersion test The filled capsules are m~unted in the capsule holder of the powder insuflator (having the specific dimensions set out immediately above) of British Patent Specification ~o 1,122,284 and pierced to produce two h~les of 0.8 mm diameter in a shoulder of the capsule. The dispersion of the medicament in the cloud delivered by the insufflator is determined using a mKdified version o the multistage liquid .umpinger described in British Patent Specification No 1,08:L,881. The mcdified impinger is illustrated in Fig 3 which represents a cross-section through the impinger.
In Fig 3 the Fcwder insufflator 1 is situated in the rubber sleeve 2, and is thereby connected to the bent glass tube 3. The lower end of the 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 ~nit 7 which in turn is onnected to a vacuun pump via tube 8. The dimentions of the device are given belcw:-a - a 35 mm b - b 150 mm c c 19 mn d - d 30 mm e - e 55 mm f - f 100 mm g _ 9 4 mm h - h 38 mm i - i 6 mm j - j 10 mn ., 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 collected on the filter, and that in the remainder of the apparatus and in the insufflator is determined spectrophotometrically after solution in an appropriate volume of distilled water (or by any other appropriate method)O
The soft pellets or granules disperse satisfactorily if an average total for each capsule of at least 8%, preferably at least 10% and most 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 mounted in the capsule holder of the Ex~wder insufflator (having the specific dimentions 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.
The insufflator is placed in a device adapted to--suck air t~rough it for 2.5 seconds, the air flow rate at no time exceeding ~0 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. The above procedure is repeated 20 times and the average of the results determined.
The soft pellets or granules e~pty satisfactorily if an 5~
2606/76/5301/9~ - 10 -average of at least 50%, preferably at least 75% and most preferably at least ~0~ by weight of the material has emptied from each capsule.
The folLcwing tests are also of significance in defining the pellets or granules of the invention:
(c) Response Lag m e respone lag may be measured by means of a device (available from Instron Limited, Coronation Road, ~ligh Wyccmbe, Buckinghamshire, England as Model IP~5M) for the measurement of the stress/strain properties of materials. This device is illustrated in Fig 2 and comprises a punch 1 capable of fitting tightly into a die 2 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 the 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 surfa oe made level with the top of the die. The punch is moved at a constant speed into the die from the top end and the load transmited b~ the load cell is recorded graphically. The response la~ is defined as the distance in cms that the punch tip travels below the bop of the die before a response of 1 g is registered by the load cell.
~d) Total Transmitted Lcad Reduction It has also been found that with medicaments according to the invention ~hich disperse satisfactorily the applied load transmitted to the load cell in the device described in (c) above d oes not increase steadily ~seefor example Fig 1~. The back track of the curve, or the 'easing' of the load in grams, may be termed the ITotal Transmitted Load Reduction' of the material ~nder test. m us 'Total Transmitted Lcad Reduction' may be defined as the swm of the reductions in the transmitted load detected by the load cell while the load recorded as acting on the oe 11 progresses from 0 to 1,000 gms.
We have found that the most useful para~eter 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'.
The pellets and granules according to the inven-tion have a lower loose bulk density than granules or pellets made by conventional techniques. Thus soft pellets and granules of discdium cromcglycate have a loose bulk density of less than 0.3 g per cc, preferably from 0.2 to 0.3 g per c~, and most preferably frcm 0.22 to 0.28 g per cc.
From another aspect the invention also provides a capsule, cartridge or like container cOntaining soft pellets or gra~ules of the invention, optionally in associa~ion with other pellets, granules or particles. We prefer the container to be loosely filled to less than about 80% by volume, preferably less than about 50% by volume, with the soft pellets or granuels of the 5~
2606/76/5301/9~ ~ 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 10 to 100 mg of the soft pellets or granules. The container may conveniently be pierced (and overcapped, e.g with a plastic overcap) during its manufacture andthen 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 oonventional techniques~ We 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 the 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 oontrolled agglomeration may be carried out by, (a) extruding the particles of medicament through an aperture, ,.~, (b) controlled agglomeration in a fluidised bed, 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 10 micronSmay, if necessary, be subjected to an initial treatment to cause the powder particles to be self-agglcmerative. Thus where the medicament is of a hygroscopic nature, the treatment may be carried out by exposing the powder particles to water.
When soft pellets are required the powder particles may be subjected to a humid atmcsphere, for example at a temperature o from about 15 to 50C. Whilst the amount of water required to achieve adequate self-agglGmerative properties may vary from m~dicament to medicamentf it will not usually be necessary to increase the water content of the powder beyond about 15%
by weight, e.g to from 5 to 10% when soft pellets are required.
Where the medicament is non-hygroscopic, the necessary self-agglomerative properties may be imparted 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 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 the nature of the binder may affect the coherence of the resultant pellet or granule formed ~ m treated medicament.
A binder solution may, if desired, be used with a hygrosoopic i medica~ent 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 dr~uD 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. The product of this passage through an aperture are shaped pre-pellets of the medicament.
When soft granules are required the powder particles may be mixed with an excess of a suitable solvent, e.g. liquid water, and the m~istened material passed through an aperture, e.g a sieve such as a vibrating sieve, of approximately equal to or larger than the mesh size required in the final granules and then drying the resulting sieved material to the desired final solvent, e.g. water, content. The materia] may then be dry granulated to give the required product.
When it is desired to incorp~rate another ingredient, e.g.
a binder, inb~ 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 m~isten the medicament.
The amount of water, or other solvent, used in the granulation can, under certain circumstances, be critical. Thus we have found that with di-sodium crom~glycate (DSCG) use of 2606/76/5301/92 ~ 15 -greater than about 25~ by weight of water (measured on dry DSCG) causes the granules to be too strong and not to have sakisfac~ory dispersion properties. We therefore prefer to use from about 12 to 25~, and preferably from 17 to 23% by weight of water in the granulation of di~sodium cromoglycate.
The dryin~ is preferably effected in a preheated forced convection hot air oven. The temperature of drying is desirably from 60 to 100C, and more especially from 80 to 90 & .
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 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. When a hygrosoopic 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 water into the bed. The medicament may be treated in the fluidised bed for a time and under oonditions sufficient to produce pre pellets or granules of the desired internal ooherence and size.
In process (c) a solution or more preferably a slurry, of the medicament may be spray-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 medi~ament particles during the spray drying.
When a controlled amount of water is desired in the produc-t 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 vary according to the method and pcwder used in the agglomeration. However, as a guide, we have found that suitable pre-pellets may be formed by process (a) from a powder of disodium cromoglycate containing from about 8 to 10 by weight of water, by 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, shape and coherence of the pellets are achieved. We prefer a proportion~
e.g a majority, of the soft pellets, and especially soft pellets of disodium cromoglycate, to be approximately spherical.
Conveniently the t~nbling 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.
r.33~;
2606/76/5301/g2 - 17 -The size of the pre-pellets used and the conditions used in their agitatlon and tumbling may be varied in known 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 si2e slightly and to make them more nearly spherical in shape.
As indicated above the final product which issues from the agitation or tu~bling 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 the pellets or granul~es of the invention in asscciation 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. We prefer the soft pellets or granules of the invention to contain medicament and water only. The soft pellets or granules may also be u æ d in admixture with up to 75% b~ weight of free particles of medicament having a dianeter of from 0.01 to 10 microns.
- 17 ~
'~
~ccording to our invention we also provide a method of 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 containi~q soft pellets or granules according to the invention is rotated and vibrated in 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 cromGglycate is known to be of u æ in the treatment of asthma and rhinitis.
In this specification the ~erm 'pellet' is used to denote an agglGmerate which is held together by interparticulate (e.g Van der Waal's) forces and is typically made by a process involving water vaFx~lr. Pellets are in general spherical in shape. The term 'granule' is used to denote an agglomerate which is held together b~ interparticle bridges. In the case o 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 some of the solvent.
The invention will now be illustrated by the following Exa~ples in which all parts and percentages are by weight unless otherwise stated.
Example 1 The moisture content of micronised disodium croncglycate having at least 98% thereof of particle size less than 10 nucrons ~, 2606/76/5301/'92 - 19 -and having a mass median diameter of from 1 to 3 nucrons was adjusted from an initial 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 isture content had been achieved, the treated pcwder was (after an optional initial rolling in a drum pelletiser) tipped onto a 150 micron aperture stainless s-teel sieve screen mounted in a Russel vibratory sifter operating at a frequency of 1,000 ~ycles per second. The pKwder on the screen 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 150 microns was fed directly to a drum pelletiser adapted -to rotate about a horizontal axis. The c~ of the pelletiser was approximately 0.3 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 orifi oe through which material could be charged to or removed from the drum~ 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 0.38 m per second + 0.025 m per second 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~ by weight was retained on a 63 mlcron aperture sieve. The moisture content of the final soft pellets was in the range 8.5 t.o 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 pc~der should be carri~d out under oonditions of controlled humidity so as not to alter the water content of the powder appreciably. The water used in the process should be sterile and the air used in the process should be Class 100 air.
m e soft pellets produced by the above procedure are approximately spherical, and have an open and loose structure and a fluffy surface when viewed under a microscope.
Up to 90 m~, e.g 40 to 60 mg, of the above soft pellets ~ere 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 1,122,284 having the detailed construction and dimensions referred to above. When air at a flow 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 micronised pcwder from which the pellets had been prepared was tested under identical conditions, oomparatively little of the pcwder was dispensed Erom test to test.
Similar results were obtaine when 1,3-bis(2-carboxychromon-~ 20 -, .. .
2606/76/53~1/92 - 21 -7-yloxy)propan-2-o1 disodium salt (6~ water), isoprenaline sulphate and tetracycline were subjected to the procedure of the Example to obtain soft pellets.
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 Tbtal Transmitted Load Reduction of greater than 900 gms and a dispersion of greater than 10~ were obtained.
~
l,OOOg of micronised disodium cromoglycate of determined water content was placed in the bowl of a planetary mixer. The calculated amount of water to bring the moisture oontent of the disodium cromoglycate to within the desired range was then added gradually, the sides of the mixer bcwl being scraped regularly to ensure even m~isture distribution. The damp disodium crom~glycate ~as then passed through 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 isture content of the granules was in the range 5 to 8% by weight. The granules were then sieved through a 250 micron screen. The resulting granules were found to flow well and could be filled easily into gelatine capsules.
Example 4 Using the devioe illustrated in Eig 2I granules of disodium . , .
~ f~ J~
260~/76/5301/92 - 22 -cron~glycate produced according to Example 3, and the Dispersion Test as previously described, dispersions of greater than lO~
were obtained for gram~les made using from 10 to 25% by weight water at the granulation stage. m ese granules had response lags of greater than 0.3 cms and a Total Transmitted Load Reduction of greater than lO0 gms.
2~
Claims (11)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A medicament in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 1000 microns in diameter and comprises an agglomeration of individual medicament particles at least 90% 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 than 100g, or (ii) a product of 'Total Transmitted Load Reduction' and 'Response Lag' of greater than 30g/cms, or (iii) a 'Response Lag' of at least 0.3cms.
2. A medicament according to Claim 1 wherein the product of 'Total Transmitted Load Reduction' and 'Response Lag' is between 40 and 1,00 a g/cms.
3. A medicament according to Claim l,wherein, in a Dispersion test, an average total of at least 8% by weight of medicament is found on filtration.
4. A medicament according to any one of Claims 1, 2 or 3 wherein, in an Emptying test, an average of at least 50% by weight of the material has emptied from each capsule filled with the granules.
5. A medicament according to any one of Claims 1, 2 or 3 comprising an inhalation medicament for the treatment of allergic airway disease.
6. A medicament according to any one of Claims 1, 2 or 3, wherein the medicament comprises a pharmaceutically acceptable salt of 1,3-bls(2-carboxychromon 5-yloxy)propan-2-ol.
7. A medicament according to any one of Claims 1, 2 or 3, wherein the medicament comprises disodium cromoglycate.
8. A medicament according to any one of Claims 1, 2 or 3, comprising disodium cromoglycate and less than 15% by weight of water.
9. A container containing a medicament according to any one of Claims 1, 2 or 3, and loosely filled to less than 80% by volume with the medicament in soft pellet or granule form.
10. A method for the manufacture of a medicament in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 1000 microns in diameter and comprises an agglomeration 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, characterised in that the pellets or granules have (i) a 'Total Transmitted Load Reduction' of greater than 100g, or (ii) a product of 'Total Transmitted Load Reduction' and 'Response Lag' of greater than 30g/cms, or (iii) a 'Response Lag' of at least 0.3cms.
11. A method according to Claim 10 for the production of a soft granule which comprises mixing the individual medicament particles with an excess of a solvent, passing the moistened material through 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000388621A CA1144862A (en) | 1976-01-23 | 1981-10-23 | Composition |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2608/76 | 1976-01-23 | ||
| GB2606/76 | 1976-01-23 | ||
| GB260676A GB1569611A (en) | 1976-01-23 | 1976-01-23 | Pelletised or granular medicament formulation |
| GB260876 | 1976-01-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1116516A true CA1116516A (en) | 1982-01-19 |
Family
ID=26237614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000270236A Expired CA1116516A (en) | 1976-01-23 | 1977-01-21 | Medicament composition in soft pellet or granule form |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5294413A (en) |
| AU (1) | AU506878B2 (en) |
| CA (1) | CA1116516A (en) |
| DK (1) | DK27177A (en) |
| ES (1) | ES455273A1 (en) |
| FI (1) | FI67663C (en) |
| FR (1) | FR2361104A2 (en) |
| IE (1) | IE45260B1 (en) |
| LU (1) | LU76618A1 (en) |
| NO (1) | NO148542C (en) |
| SE (1) | SE442950B (en) |
| ZA (1) | ZA77327B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6102036A (en) * | 1994-04-12 | 2000-08-15 | Smoke-Stop | Breath activated inhaler |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3268533D1 (en) * | 1981-07-24 | 1986-02-27 | Fisons Plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
-
1977
- 1977-01-05 IE IE14/77A patent/IE45260B1/en not_active IP Right Cessation
- 1977-01-11 FI FI770070A patent/FI67663C/en not_active IP Right Cessation
- 1977-01-20 ZA ZA770327A patent/ZA77327B/en unknown
- 1977-01-20 FR FR7701501A patent/FR2361104A2/en active Granted
- 1977-01-21 SE SE7700665A patent/SE442950B/en not_active IP Right Cessation
- 1977-01-21 CA CA000270236A patent/CA1116516A/en not_active Expired
- 1977-01-21 LU LU76618A patent/LU76618A1/xx unknown
- 1977-01-21 NO NO770198A patent/NO148542C/en unknown
- 1977-01-21 DK DK27177A patent/DK27177A/en not_active Application Discontinuation
- 1977-01-22 ES ES455273A patent/ES455273A1/en not_active Expired
- 1977-01-24 AU AU21589/77A patent/AU506878B2/en not_active Ceased
- 1977-01-24 JP JP597877A patent/JPS5294413A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6102036A (en) * | 1994-04-12 | 2000-08-15 | Smoke-Stop | Breath activated inhaler |
Also Published As
| Publication number | Publication date |
|---|---|
| SE442950B (en) | 1986-02-10 |
| ZA77327B (en) | 1977-12-28 |
| DK27177A (en) | 1977-07-24 |
| IE45260L (en) | 1977-07-23 |
| NO148542C (en) | 1983-11-02 |
| LU76618A1 (en) | 1977-08-12 |
| FI770070A (en) | 1977-07-24 |
| FI67663B (en) | 1985-01-31 |
| AU2158977A (en) | 1978-08-03 |
| IE45260B1 (en) | 1982-07-28 |
| NO148542B (en) | 1983-07-25 |
| NO770198L (en) | 1977-07-26 |
| JPS5294413A (en) | 1977-08-09 |
| SE7700665L (en) | 1977-07-24 |
| JPS6228124B2 (en) | 1987-06-18 |
| ES455273A1 (en) | 1978-04-01 |
| AU506878B2 (en) | 1980-01-24 |
| FR2361104A2 (en) | 1978-03-10 |
| FI67663C (en) | 1985-05-10 |
| FR2361104B2 (en) | 1982-09-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |