CA1120401A

CA1120401A - Composition containing the disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-propan-2-ol

Info

Publication number: CA1120401A
Application number: CA000270593A
Authority: CA
Inventors: Kenneth Brown
Original assignee: Fisons Ltd
Current assignee: Fisons Ltd
Priority date: 1976-01-30
Filing date: 1977-01-27
Publication date: 1982-03-23

Abstract

ABSTRACT

There is described a pharmaceutical composition comprising finely divided disodium cromoglycate, and a liquidified propellent, the composition containing less than 5% by weight of water. The composition is indicated for use in the treatment of allergic conditions such as asthma and rhinitis.

Description

This invention relates to a novel pharmaceutical formulation containing disodium cromoglycate.
Disodium cromoglycate has for a number of years been used in admixture with lactose as a powder for the inhalation the~apy of asthma. For such use -the disodium cromoglycate normally contains between about 8 and 10~ by weight of water;
disodium cromoglycate containing this proportion of water being stable in contact with air of normally encountered humidities.
We have now found that disodium cromoglycate contain-ing smaller proportions of water has certain advantageous properties.
There is provided disodium cromoglycate in a novel form, that is containing less than 5% by weight of water.
The disodium cromoglycate preEerably contains less than 3~, more preferably less than 2% and most preferably less than 1~ by weight of water.
The disodium cromoglycate is preferably finely divided, ` e.g. having a ma~s median diameter of less than 20 microns, more 20 preferably in the range 0.01 to 10 microns, and most preferably at least 50% by weight of the particles having a diameter of 2 to 5 microns.
Disodium cromoglycate according to the invention is strongly hygroscopic and precautions must therefore be taken during its preparation, storage and use to ensure ~in so far as is possible) that the disodium cromoglycate does not pick up water from the environment~
Disodium cromoglycate according to the invention may ,~ ~

be made from disodium cromoglycate containing a larger propor-tion of water by subjecting such disodium cromoglycate to heat, e.g. to temperatures of from about 110 to 150C, to a vacuum, to the action of a dessicant, or to a combination of such treatments. In particular w~ prefer to dry the disodium cromo-glycate by subjecting it to a combination of heat and vacuum.
It i~ normally di~f~cult, without us.ing exceptional and expen-sive techniques, to obtain disodium cromoglycate containing less than about 0.05~ by weight of water, and we therefore pre-fer disodium cromoglyca~e according to the invention to containmore than 0.05% by ~eight of water.
Disodium cromoglycate according to the invention and of fine par~icle size may be made by micronising, milling or grinding coarser disodium cromoglycate of appropriate water content. However because of the hygroscopic nature of the di-sodium cromoglycate and because of the electrostatic effects associaked with mechanical working of the dry diEodium cromogly-; cate we prefer to remove the water after the disodium cromogly-cate has been reduced to the desired particle size.
Disodium cromoglycate according to the invention finds use in pharmaceutical formulations and in particular in pressure pack ~ormulations suitable for dispensing powdered disodlum cromoglycate for inhalation.
Thus according to a further feature of the invention we provide a pharmaceutical composition comprising disodium cromoglycate, the total formulation containing less than 1.0%, preferably less than Q.5%, more preferably less than 0.2% and most preferably less than 0.1~ by weight of water.

More specifically we provide a pharmaceutical composi-tion comprising rom 5 to 35~ ~y weight of finely divided diso-dium cromoglycate, and a liquified propellent, the composition containing less than 5~ by weight of water.
We prefer the composition to contain from 5 to 25 and more preferably from 5 to 20~ by weight of disodium cromoglycate The composition is preferably su~stantially anhydrous.
The liquified propellent medium, and indeed the total formulation is preferably such that the disodium cromoglycate does not dissolve therein to any substantial extent.
The liquified propellent is preferably a gas at room temperature (65F) and atmospheric pressure (760 mm of mercury), i.e. it should have a boiling point of below 65F at atmospheric pressure. The liquified propellent should also be non-toxic.
Among the suitable li~uified propellents which may be employed are alkanes containing up to five carbon atoms, e.g. butane or pentane, or a lower alkyl chloride, e~g. methyl, ethyl or propyl chlorides. The most suitable liquified propellents are the fluorinated and fluorochlorinated lower alkanes such as are sold under the Registered Trade Mark "Freon". Mixtures of the above mentioned propellent~ may suitably be employed. The preferred fluorinated lower alkanes contain not more than two carbon atoms and at least one fluorine atom. The preferred halogenated lower alkanes may be represented generally by the formula CmEnClyFz, wherein m is an integer less than 3, n is an integer or zero, y i.s an integer or zero, z is an integer, such that n~y+z - 2 m+2.
Examples of - - -these propellents are (lic1l10rodi~1uorolllethane ('Freon 12t), dichlorotetrafluoroetl~e ('~reon ll~') CC1l2.CClI:2, trichloro-n~nofluorometl}~le ('Freon 11'), dicllloromonoLluorometllane t'Frcon 21'), n~nochlorodifluorolneth.~le ('Freon 22'), trichlorotri1lloro-etllane ('~reon 113'), and monoclllorotrifluorolnet3~ane ('~reon 13').
Propellents ~itll improved vapor pressure characteristics ~Iy be obtained by using certain mixtures of these compounds, e.g.
'Freon 11' with 'Freoll 12', or 'I1reon 12' with 'Freon 114'. For - example, dichlorodi~luorome~llane, l~lich has a vapour pressure of about 70 pounds per square inch gauge and 1,2-dichloro-1,1,2,2-tetra:~uoro-ethalle ~'Freon 114'~, with a vapour pressure of about 12 pOWldS per square inch gauge at 70F, may be mixed .in various proportions to form a ~ropellent having a desired int~rmediate vapour pressure. ~Ye prefer compositions l~lich clo not contain lS trichloromono1uorometllc~e.
It is desirable that the vapour pressure of the propellent employed be be~een 25 and 65, and preferably between 30 and 65 pounds per square inch gauge at 70F. A one-component propellent can give a composition with gauge pressures in the range of 55 to ~5 pounds per square inch at 70F, l~lich are usable safely with metal containers. n~o-component propellents, e.g. certain mixtures of 'Freon 12' and '~reon 11~9 have been found to give gauge pressures in the range o~ 20 to 40 pounds per square inch at 70F, whi~l are usa~le safely with specially rein~orced glass containers.

06/C/]~3 Tlle composition may also contain a surface active agent.
The surace active agerlt may be a li~uid or solid non-ionic surface active agen~ or nlay be a solid alliOlliC surface acl:ive agent selec~cd from the group comllrisillg alkali metal, cu~lonium ~Id amine salts o dialkyl sulphosuccinate, where th~ alkyl ~roups have 4-12 carbon atoms, c~nd alkylbenzene sulpllonic acid l~here the alkyl group has 8-l~ carbo~l a~oms. It is preferred to use the solid anionic surface active agent m the ~onn of the sodium salt, and tllis comprises desirably compounds of ~or~ula ROOCal2~-l(S03Na) COOR l~lere R represents butyl, iso-butyl, octyl or nonyl, or the sodi~ml salt of clodecylbenzenesulphonic acicl or o~ decylbenzene-sulphonic acicl.
The preferred solid cmionic surEace active ageIlt is sodi~n dioctyl-sulphosuccinate.
The amount of the surace active agent required is related to the solids conten~ of the suspension and to the particle size o-f the solids. In general it is only necessary to use a sm~ll amount of tlle solid ani ic surEace active agent.
l~hen a liquid, non-ionic surface-active agent is employed it should have an hydrophile-lipophile balance (~ILB) ratio oE less than 10. The ~LB ratio is an empirical number l~nich provides a guide to the surface-active ploperties of a sur~ace~active agent.
The lower the WLB latio, the more lipophilic is the agent, and conversely, the hi~ler the ~-LB ratio, the more hyclrop]lilic is the agent. The l-LB ratio is well knol~m ancl understood by the colloid 07/C/1~3 7 x emist c~nd its method of determination is described by ~ C Griffin in t}le Journal of the Society of Cosmetic Chemists, Vol l, IYo 5~ pages 311-326 (1949). Preferably the surface-actlve agent employed should have an ~LB ratio of 1 ~o 5. It is possible S $o en~loy mixtures of surface-active agents, the mixture having an ~;
HLB ratio wi~lin the prescribed range.
Those sur~ace-active agents which are soluble or dispersible in the propellent are effective~ The more propellent-soluble surface-active agents ar~ the most effective.
1~ The surfa~e-acti~e agent should of course be non-irritating and non-toxic.
Among the liquid n~n-ionic surface-active agents which may be `,r'' employed are the esters or partial esters of atty acids containing from 6 to 22 carbon atoms, suc~ as caproic, oc~oic, lauric, palmitic, stearic, linoleic, l molenic, oleostearic and oleic acids ; with an aliphatic polyhydric alcohol or its cyclic anhydride suchas, ~or example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbîtan esters sold under the Registered Trade ~k 7Spansl) and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters9 such as mixed or natural glycerides, e.g.
olive 3il, m~y be employed. The preferred liquid n~n-ionic surface-active agents are the oleates of sorbitan, e.g. those sold under ~he Registered Trade ~arks 'Arlacel Cl (Sorbitan sesquioleate).
'Span 80' (Sorbitan monooleate3 and 'Spk~n 85' (Sorbi~an ~rioleate).

.

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Specific examples of other liquid non-ionic surface-active agents which may be employed are sorbitan monolaurate, polyoxy-ethylene sorbitol tetraoleate, polyoxyethylene sorbitol penta-oleate, and polyoxypropylene mannitol dioleate.
Undesixable separation of the suspension may be avoi-ded by the introduction of a sufficient quantity o an additional auxiliary finely divided solid of density greater than that of the li~uid phase. The auxiliary solid should be compatible with the other ingredients and insolu~le in the propellent. For example, we may use an inorganic compound such as sodium sulfate, calcium chloride or sodium chloride. We may also use an organic material such as powdered lactose or sucrose. The awciliary solid should of course be non-toxic and non-irritant. The particle size of the auxiliary solid should be of the same order of magnitude as the disodium cromogl~cate. The auxiliary powder may also functicn as a desiccant as in the case of anhydrous sodium sulfate or calcium chloride. ~he desired proportion of the auxiliary solid can be calculated using well known techniques.
It has also been found that the inclusion of a minor amount of a higher alkyl halide quaternary salt of pyridine, or an equivalent thereof, can help to overcome undesirable cakin~
or deposition. ~Iigher alkyl halide quaternary salts of substi-tuted pyridines having one or more substituents, for example lower alkyl, on the pyridine ring are, for the purposes of this specification, the full equivalent of higher alkyl halide t~

_g quaternary salts of pyridine. Among particularly useful higher alkyl halide quaterllary salts of pyridine and their equivalents are myristyl-gamma-picolinium chloride/ cetyl pyridinium bro-mide and cetyl pyridinium chloride. Such higher alkyl halide quaternary salts of pyridine may, if desired, be used in the form of their monohydrates. The compositions preferably contain between 0.01 and 1% by weight of the higher alkyl halide ~uater-~ nary salt of pyridine or an e~uivalent thereof.
; The composition may also contain a suitable dessicant independent of the auxiliary solid, e.g. up to about lOD mg ofanhydrous calcium sulpha~e or silica gel per 10 ml of composi-tio~.
The composition may contain other medicaments in addi-tion to the disodium cromoglycate. For example the composition may contain a bronchodilator such as ephidrine, isoprenaline or a suitable salt thereof. The composi~ion preferably contains between about 0.3 and 3.0% hy weight o the bronchodilator.
The composition may al50 contain an anti-oxidant, e.g.
ascorbic acid, preferably in a proportion of from 0.5 to 2.0% by weight. In addition the composition may contain a sufficient quantity of a suitable flavour. We prefer compositions which do not contain ethanol.
We prefer packages containing from about 8 to 30 ml of composition, e.g. a conventional aerosol pressure pack of 10 ml. The pack preferably has a valve adapted to deliver unit dosages of compositions of between 0.025 and 0.25 mls of compo-sition~ The container may also contain a ball bearing to assist in the preven-tion of caking within the container~
The compositions of the invention may be made by mix-ing the various components at a temperature and pressure at which the propellent is in the liquid phase and the disodium cromoglycate is in the solid phase.
In producing the compositions and packages of the invention, a container e~uipped with a valve is Eilled with a propellent containing a finely-divided disodium cromoglycate in suspension. A container may first be charged with a weighted amount of dry disodium cromoglyca~e which has been ground to a predetermined particle size, or with a slurry of powder in the cooled liquid propellent~ Alternatively and preferably the disodium cromoglycate and the surface-active agent are tritu-rated or homogenized first into a uniform paste, for instance, b~ a ball mill. The homogeniæation may be carriea out in the presence of a suitable liquid, e.g. ethanol, to prevent agglo-meration of the particles. This paste is then dispersed in the cooled liquified propellentu This procedure fosters uniform wetting of the powder particles. A container may also be filled by introducing powder and propellent by the cold filling method, or a slurry o~ the powder ln that component of the propellent which boils above room temperature may be placed in the contai-ner, the valve sealed in plac~/ and the balance of the propel-lent may be introduced by pressure filling through the valve nozzle. On operating the valve, the powder will be dispensed in a stream of propellent, - -'~

ll/C/193 ~. B.2~3L9~

wllich will vaporize providing an aerosol of dry po~der. Throughoutthe preparation of ~le product care is desirahly exercised to min~se the absorption of moisture. This may be accomplished -by operating in a dehumidified atmospllere using only dry n~terials and equipment. Under normal operating conditions one expects from about 50 to 100 ppm of moisture to be incorporated in the con~osition durin~ fillung.
~hen it is necessary to employ an auxiliary solid or powder ` to prevent surface deposit or caking, it is d~sirably introduced into the composition at the time that po~*~ered active solids are introduced. Altsrnatively, the auxiliary solid can be added to the c3mposition after pre-wetting it with the surface-active agent or propellant.
The compositions of the invention ~ay be used Ln the ~5 treabment of ~ number o~ allergic conditions in xammals, e.g. thc inhal~tion trea~nent of allergic conditions ~f the airw~ysy such as asthma or allergic r~initis ~hay fever). ~ne trea~ment is pTeerably by oral or nasal inhalation and is pre~erably treatment o~ man.
.
Disodium cromoglycate is sometimes known as sodium cromoglycate or cromolyn sodium and is the disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-propan 2-ol~
The invention is illustrated, bu~ in no way limited by the following Examples in which the parts and percentages are by weight.

Micronized disodium cromoglycate 5%
Ethanol anhydrous 30 Propellant 144 60 parts ) ~ to 100%
Propellent 1~ 40 parts ) The composition may be made up using the following procedure:-Form a smooth, homgeneous paste of the disodium cromo-glycate in halE the ethanol by ball-milling for 1 hour. Pour the paste into a suitable vessel cooled to -40C and wash out the ball mill with the r~maining ethanol adding the ~ashings to the bulk. 5tirring continuously, cool to ~40C and add the pro-pellent mixture also at -40C. Stir for a further 10 minutes, cold fill into suitable cans, apply valves and cximp.
15 Example 2 -Micronized dis~dium cromoglycate 8~

Sorbitan trioleate (Arlacel 85) ~%

Propellent 1~ 5 Propellent 114 60 parts ) ) to 100 20Propellent 12 40 parts ) The composition may be made up as follows:

Dissolve the Sorbitan trioleate in the Propellent 11, add the disodium cromoglycate and disperse using a high disper-sion stirrer (e.gO Silverson). R~frigerate to -40C add the remaining propellents (cooled to ~40C) and stir for a further 10 minutes. Cold fill into suitable cans, apply valves and r r~crimp.

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Example 3 Micronised disodium cromoglycate 25 Sodium chloride qs "Span" 85 10-~
Cetylpyridinium bromide 1%
Peppermint Elavour qs Propellant 11 30 parts ) Propellent 12 30 parts )to 100%
Propellent 114 40 parts ) The composition may be made up as follows:-Dissolve the flavour and tha Span 85 in the Propellent 11 and add the disodium cromoglycate, sodium chloride and cetyl pyridinium bromide. Disperse usin~ a high dispersion st.irrer, and dispense suitable volumes of the concentrate into suitable 15 cans using a metering pump~ Add the Propellent 12/Propellent 114 mixture cooled ~o -40~C, apply the valves and crimp.
_xample 4 Micronised disodium cxomoglycate 30%
: Sodium dioctylsulphosuccinate 0. 25%
Propellent 114 60 parts ) )to 10~%
Propellent 12 40 parts ) The composition may be made up as follows:-Dissolve the sodium dioctyl sulphosuccinate in halE
the Propellent 114 cooled to below -15C. Place in a ball mill cooled to below -15C with the disodium cromoglycate and roll Eor 15 minutes at a temperature b~low -15C. Pour into a ; ' suitable container chilled to -40C, and rinse ou-t the container with the remaining Propellent 114 cooled to below -15C. Add the Propellent 12, suitably cooled, and mix at -40C for 10 minutes. Cold fill into suitable cans, apply valves and crimp.
Example 5 (a) Drying of micronised disodium cromoglycate 1. Usln~ heat alone 1 kg of micronised disodium cromoglycate at a moisture content of 5.8% w/w was spread in layers approximately

2 cm thick, and heated for 42 hours at 120C. After removal from the oven, cooling under conditions preventing ready access to atmospheric moisture, and mixing, the moisture content was 0 35~ w/~.
2. Using dessicant alone l~g of micromseddisodium cromoglycate at a moisture content of 6.3% w/w was spread in a thin layer and placed in an enclosed container in which was also placed fresh phosphorous pentoxide, also in a thin layer. After 7 days, the moisture content of the micronised disodium cromoglycate had fallen to 0.13% w/w~

(b) Determination of moisture content of micronised : disodium cromoglycate The water content of disodium cromoglycate may be determined by loss on drying or by Karl-Fischer titration.
(c) Micronising of disodium cromoglycate By the term `'micronised di60dium cromoglycate' we mean disodium cromoglycate that has been subjected to a process of attrition in a fluid energy mill, for i~
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ex~nple that ma:nu~act-lrecl by C~ISPRD l,I~IITED, 3 ~ST ~fARGA~.T'S
~REF~T, C~ER~URY, KENT, E~NG~

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.'-Supplementary Disclosure Accordi~g to the invention we provide a pharmaceutical composition c~mprising from 1 ko 20% by weight of finely divided disodium cromoglycate, and a liquified propellent, the composi-tion containing less than 5~ by weight of water.
We prefer the composition to contain from 2 to 12 and more preferably from 4 to 7% by weight of disodium cromoglycate.
The composition is preferably substantially anhydrous~
We have found that, in ~eneral, use of dried disodium cromogly-cate in the composition enables freer and easier working of the~alve, better dispersion from the valve, and less los~ cf pro-pellent when the composition has been filled into pressurized packs. We prefer the percentage of water in the formulation expressed as a percentage by weight of the disodium cromoglycate to be less than 2.
I~ is desirable that the vapourp.ressure`of the propel-lent employed be between 35 and 70, and preferably between 50 and 6S pounds per s~uare inch gauge at 70F.
In general it is only necessary to use 5 - 15%, and preferably 5 - 8%, of the solid anioni~ surface active agent by weight of the solids content of the suspension. We have found that, under certain conditions, use of a solid anionic surface active agent gives a better dispersion of medicament when the composition is released from a pressurized pack than does the use of a liquid non-ionic surface active agent.

~r~ -~ prefer the liquid non-iunic surface-active agent to comprise from 1 to 7, and more pref~rably ~rom 4 to 6~, by weight o$ the total composition. Such co~ositions tend to be more ~hysically stable on storage. -~
A solid non-ionic sur~ace active agent which may be mentioned is lecithin, e.g. soya lecithin, a vegetable lecithin extracted rom soya beans, but lecithin is not preferred. The co~position preferably contains between about 0.1 and 1.0% by wei~ht u the bronchodilator when a bronchodilator is included.
Xhe invention is illustrated, but in no w~y limited by ~le fDllowing Examples in which the parts and percentages are by w~ight.
E~mple 1 ~hods of pre~aration (a) Dissol~e the surface-active agen~(s) in the prDpellant 11 and add the micronised disodium cromDglycate. Disperse by us mg a high-sh~ar miOYer or a homDgeniser, Cool to -S0C and add the ; p~pellants 114 and 12, also cooled to -50C. Remix, cold fill into suitable cans, apply valYes and cr~mp.
~b~ Cool ~he propellant 114 to -15C and dissolve ~he surface acti~e agent~s) in it. Add the micronised disodium cron~glycate and mix with a high shear mixer. Cool to -50C, add the prope:llalnt 12 cooled to -50C and remix. Cold fill into suitable cans, apply lves and crimp.
Suitable ~oDlations are shown in Table 1 in which the _ 17 -~ . .

, 18/B/63 _ 18 -figures represent the percentages by weight of the various ingredien~s. I
~ le ~orl~llations have been found to be stable when stored f~r 3 m~n~hs, to ha~e a high LD50 in rats and tu provide satisfactory dispersionbs of disodium cromoglycate.
CDmpositions 26 and 31 are pre~e~redO
Cbmpositions 6, 16, 29, 30 and 3. were made up usi~g both dried and undried disodium cronoglycate. When dried disodium cromoglycate was used the percentage of water in the formulation expressed as a percentage by weight of disodium crom~glycate was l~ss than 2. ~en ~dried disodi~n cron~glycate was used the yercentage of water, e~ressed on the same basis, was from 4 to 7.

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Claims

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

1. A pharmaceutical composition comprising disodium cromoglycate and a pharmaceutically acceptable diluent excipient or carrier, the composition containing less than 1.0% by weight of water.

2. A composition according to Claim 1 containing less than 0.5% by weight of water.

3. A composition according to Claim 2 containing less than 0.2% by weight of water.

4. A composition according to Claim 3 containing less than 0.1% by weight of water.

5. A pharmaceutical composition according to Claim 1 comprising from 5 to 35% by weight of finely divided disodium cromoglycate, and a liquified propellant.

6. A composition according to Claim 5 containing from 5 to 20% by weight of disodium cromoglycate.

7. A composition according to Claim 5 comprising disodium cromoglycate containing less than 3% by weight of water.

8. A composition according to Claim 5 comprising a liquid or solid non-ionic surface active agent or a solid anionic surface active agent selected from the group comprising alkali metal, ammonium and amine salts of dialkyl sulphosuccinate, where the alkyl groups have 4-12 carbon atoms, and alkylbenzene sulphonic acid where the alkyl group has 8-14 carbon atoms.

9. A composition according to Claim 8, where the surface active agent is sodium dioctyl-sulphosuccinate.

10. A composition according to Claim 8, wherein the surface active agent is sorbitan trioleate.

CLAIMS BASED ON SUPPLEMENTARY DISCLOSURE

11. A pharmaceutical composition comprising from 1 to 20% by weight of finely divided disodium cromoglycate, and a liquified propellent, the composition containing less than 5% by weight of water.

12. A composition according to Claim 11, containing from 2 to 12% by weight of disodium cromoglycate.

13. A composition according to Claim 12, containing from 4 to 7% by weight of disodium cromoglycate.

14. A composition according to Claim 11, comprising disodium cromoglycate according to Claim 1.

15. A composition according to Claim 11, wherein the vapour pressure of the propellent employed is between 35 and 70 pounds per square inch gauge at 70°F. .

16. A composition according to Claim 11, comprising from 5 to 15% of solid anionic surface active agent by weight of the solids content of the formulation.

17. A composition according to Claim 16, comprising from 5 to 8% of solid anionic surface active agent by weight of the solids content of the formulation.

18. A composition according to Claim 11, wherein from 1 to 7%
by weight of the total compostition comprises non-ionic surfactant.

19. A composition according to Claim 18, wherein the surfactant comprises from 4 to 6% by weight of the total composition.