CA1176171A - Compositions containing the disodium salt of 1,3- bis(2-carboxychromon-5-yloxy)-propan-2-ol - Google Patents

Abstract

Abstract There is described disodium cromoglycate containing less than 5% by weight of water for use in a pharmaceutical composition comprising finely divided disodium cromoglycate, and a liquified 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

~ ~76171 COMPOSITIONS CONTAINING THE DISODIUM SALT OF 1,3-BIS92-CARBOXY CHROMON-5-YLOXY)-PROPAN-2OL
This application is a division of application no. 270,593, filed January 27, 1977.
This invention relates to disodium cromoglycate in a novel -- form.
Disodium cromoglycate has for a number of years been used in admixture with lactose as a powder for the inhalation therapy 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 containing smaller proportions of water has certain advantageous properties.
Thus according to the invention there is provided disodium cromoglycate containing less than 5% by weight of water.
The disodium cromoglycate preferably 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 mass median diameter of less than 20 microns, more 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.

~g 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 proportion 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 treat-ments. In particular we prefer to dry the disodium cromo-glycate by subjecting it to a combination of heat and vacuum.
It is normally difficult, without using exceptional and expensive techniques, to obtain disodium cromoglycate contain-ing less than about 0.05~ by weight of water, and we thereforeprefer disodium cromoglycate according to the invention to contain more than 0.05% by weight of water.
Disodium cromoglycate according to the invention and of fine particle size may be made by micronising, milling or grinding coarser disodium cromoglycate of appropriate water content.
However, because of the hygroscopic nature of the disodium cromoglycate and because of the electrostatic effects assoc-iated with mechanical working of the dry disodium cromoglycate we prefer to remove the water after the disodium cromoglycate has been reduced to the desired particle size.
More spe¢ifically, disodium cromoglycate containing less than

3~ by weight of water may be made by a method which comprises micronising, milling or grinding disodium cromoglycate until it has a mass median diameter of less than 20 microns, and removing water from the finely divided disodium cromoglycate.
Disodium cromoglycate according to the invention finds use in pharmaceutical formulations and in particular in pressure pack formulations suitable for dispensing powdered disodium cromo-glycate for inhalation.

- 2A -, A pharmaceutical composition comprises disodium cromoglycate, the total formulation containing less than 1.0%, preferably less than 0.5%, more preferably less than 0.2~ and most pre-ferably less than 0.1% by weight of water.

' ~76171 More specifically a pharmaceutical composition comprises from 5 to 35% by weight of finely divided disodium cromoglycate, and a liquified propellent, the composition containing less than 5% by weight o~ 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 substantially anhydrous.

The liquified propellent medium, and indeed the total form-ulation is preferably such that the disodium cromoglycate does not dissolve therein to any substantial extent.

The liquified propellent is preferably a gas at room temper-ature (65F) and atmospheric pressure (760 mm of mercury), i.e.
it should have a boiling point of below 65~F at atmospheric pressure. The liquified propellent should also be non-toxic.
Among the suitable liquified 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 propellents may suitably be employed.
The preferred fluorinated lower alkanes contain not more than two carbon atoms and at least one fluorine atom. The pre-ferred halogenated lower alkanes may be represented generally by the formula CmHnClyFz, wherein m is an integer less than 3, n is an integer or zero, y is an integer or zero, z is an integer, such that n+y+z = 2 m+2. Examples of these propel-lents are dichlorodifluoromethane ('Freon 12'), dichiorotetra-fluoroethane ('Freon 114') CClF2.CClF2, trichloromonofluoro-methane ('Freon 11'), dichloromonofluoromethane ('Freon 21'),monochlorodifluoromethane ('Freon 22'), trichlorotrifluoro-ethane ('Freon 113'), and monochlorotrifluoromethane ('Freon 13'). Propellents with improved vapor pressure characteristics ~ 176171 may be obtained by using certain mixtures of these compounds, e.g. 'Freon 11' with 'Freon 12', or 'Freon 12' with 'Freon 114'.
For example, dichlorodifluoromethane, which has a vapour pressure of about 70 pounds per square inch gauge and 1,2-dichloro-1,1,2,2-tetrafluoro-ethane ('Freon 114'), with a vapour pressure of about 12 pounds per square inch gauge at 70F, may be mixed in various proportions to form a propellent having a desired intermediate vapour pressure. We prefer compositions which do not contain trichloromonofluoromethane.

It is desirable that the vapour pressure of the propellent employed be between 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 65 pounds per square inch at 70F, which are usable safely with metal containers. Two-component propellents, e.g. certain mixtures of 'Freon 12' and 'Freon 11', have been found to give gauge pressures in the range of 20 to 40 pounds per square inch at 70F, which are usable safely with specially reinforced glass containers.

The composition may also contain a surface active agent. The surface active agent may be a liquid or solid non-ionic sur-face active agent or may be 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. It is pre-ferred to use the solid anionic surface active agent in the form of the sodium salt, and this comprises desirably compounds of formula ROOCCH2CH(SO3Na)COOR where R represents butyl, iso-butyl, octyl or nonyl, or the sodium salt of dodecylbenzene-sulphonic acid or of decylbenzenesulphonic acid.

The preferred solid anionic surface active agent is sodium dioctyl-sulphosuccinate.

~ ~7~171 The amount of the surface active agent required is related to the solids content of the suspension and to the particle size of the solids. In general it is only necessary to use a small amount of the solid anionic surface active agent.

When a liquid, non-ionic surface-active agent is employed it should have an hydrophile-lipophile balance (HLB) ratio of less than 10. The HLB ratio is an empirical number which provides a guide to the surface-active properties of a surface-active agent. The lower the HLB ratio, the more lipophilic is the agent, and conversely, the higher the HLB ratio, the more hydrophilic is the agent. The HLB ratio is well known and understood by the colloid chemist and its method of determin-ation is described by W C Griffin in the Journal of the Society of Cosmetic Chemists, Vol 1, No 5, pages 311-326 (1949). Pre-ferably the surface-active agent employed should have an HLB
ratio of 1 to 5. It is possible to employ mixtures of surface-active agents, the mixture having an ~LB ratio within the prescribed range.

Those surface-active agents which are soluble or dispersible in the propellent are effective. The more propellent-soluble surface-active agents are the most effective.

The surface-active agent should of course be non-irritatiny and non-toxic.

Among the liquid non-ionic surface-active agents which may be employed are the esters or partial esters of fatty acids con-taining from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, oleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the Registered Trade Mark 'Spans') and the polyoxyethylene and !~ 7~ 71 polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides, e.g. olive oil, may be employed. The preferred liquid non-ionic surface-active agents are the oleates of sorbitan, e.g. those sold under the Registered Trade Marks 'Arlacel C' (Sorbitan sesquioleate), 'Span 80' (Sorbitan monooleate) and 'Span 85' (Sorbitan trioleate). Specific examples of other liquid non-ionic surface-active agents which may be employed are sorbitan monolaurate, polyoxyethylene sorbitol tetraoleate, polyoxy-ethylene sorbitol pentaoleate, and polyoxypropylene mannitoldioleate.

Undesirable separation of the suspension may be avoided by the introduction of a sufficient quantity of an additional auxiliary finely divided solid of density greater than that of the liquid phase. ~he auxiliary solid should be compatible with the other ingredients and insoluble 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 auxiliary 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 cromoglycate. The auxiliary powder may also function as a desiccant as in the case of anhydrous sodium sulfate or calcium chloride. The 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 caking or deposition. Higher alkyl halide quaternary salts of substituted pyridines having one or more substituents, for example lower alkyl, on the pyriaine ring are, for the purposes of this specification, the full equivalent of higher alkyl halide quaternary salts of pyridine. Among particularly useful higher ! ~7617 alkyl halide quaternary salts of pyridine and their equivalents are myristyl-gamma-picolinium chloride, cetyl pyridiniurn 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 quater-nary salt of pyridine or an equivalent thereof.

The composition may also contain a suitable dessicant independ-ent of the auxiliary solid, e.g. up to about 100 mg of anhydrous calcium sulphate or silica gel per 10 ml of composition.

The composition may contain other medicaments in addition to the disodium cromoglycate. For example the composition may contain a bronchodilator such as ephidrine, isoprenaline or a suitable salt thereof. The composition preferably contains between about 0.3 and 3.0% by weight of the bronchodilator.

The composition may also 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 composition. The container may also contain a ball bearing to assist in the prevention of caking within the container.

The compositions of the invention may be made by mixing the various components at a temperature and pressure at which the propellent is in the liquid phase and the disodium cromo-glycate is in the solid phase.

In producing the compositions and packages of the invention, ~ ~76171 a container equipped with a valve is filled with a propellentcontaining a finely-divided disodium cromoglycate in suspension.
A container may first be charged with a weighted amount of dry disodium cromoglycate which has been ground to a pre-determined particle size, or with a slurry of powder in thecooled 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, by a ball mill. The homogenization may be carried 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 propellent. 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 of the powder in that component of ihe propellent which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellent may be introduced by pressure filling through the valve nozzie. On operating the valve, the powder will be dispensed in a stream of propellent, which will vapor-ize providing an aerosoi of dry powder. Throughout the pre-paration of the product care is desirably exercised to minimise the absorption of moisture. This may be accomplished by operating in a dehumidified atmosphere using only dry materials and equipment. Under normal operating conditions one expects from about 50 to 100 ppm of moisture to be incorporated in the composition during filling.

When it is necessary to employ an auxiliary solid or powder to prevent surface deposit or cakingr it is desirably introduced into the composition at the time that powdered active solids are introduced. Alternatively, the auxiliary solid can be added to the composition after pre-wetting it with the surface-active agent or propellant.

The compositions of the invention may be used in the treatment of a number of allergic conditions in mammals r e.g. the ~ 176171 g inhalation treatment of allergic conditions of the airways, such as asthma or allergic rhinitis (hay fever). The treatment is preferably by oral or nasal inhalation and is preferably treatment of man.

Disodium cromoglycate is sometimes known as sodium cromoglycate or cromolyn sodium and is the disodium salt of l,3-bis(2-carboxychromon-5-yloxy)-propan-2-ol.

The invention is illustrated, but in no way limited by the following Examples in which the parts and percentages are by lO weight.

Example l Micronized disodium cromoglycate 5%

Ethanol anhydrous 30%

15Propellant 144 60 parts ) ) to 100%
Propellent 12 40 parts ) The composition may be made up using the following procedure:-Form a smooth, homogeneous paste of the disodium cromoglycatein half the ethanol by ball-milling for l hour. Pour the paste into a suitable vessel cooled to -40C and wash out the ball mill with the remaining ethanol adding the washings to the bulk.
Stirring continuously, cool to -40C and add the propellent mixture also at -40C. Stir for a further lO minutes, cold fill into suitable cans, apply valves and crimp.

I ~761~1 Example 2 Micronized disodium cromoglycate 8~

Sorbitan trioleate (Arlacel 85) 5%

Propellent 11 5%

Propellent 114 60 parts ) ) to 100%
Propellent 12 40 parts ) The composition may be made up as follows:

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

15 Example 3 Micronised disodium cromoglycate 25%

Sodium chloride qs "Span" 85 10%

Cetylpyridinium bromide 1 Peppermint flavour qs Propellent 11 30 parts ) Propellent 12 30 parts ) to 100%
) Propellent 114 40 parts ) ~ l76171 The Composition may be made up as follows:-Dissolve the flavour and the Span 85 in the Propellent 11 andadd the disodium cromoglycate, sodium chloride and cetyl pyridinium bromide. Disperse using a high dispersion stirrer, and dispense suitable volumes of the concentrate into suitable cans using a metering pump. Add the Propellent 12/Propellent 114 mixture cooled to -40C, apply the valves and crimp.

Example 4 Micronised disodium 10cromoglycate 30%

Sodium diocty~sulphosuccinate 0.25 Propellent 114 60 parts ) ) to 100%
Propellent 12 40 parts ) The composition may be made up as follows:-Dissolve the sodium dioctyl sulphosuccinate in half the Propellent 114 cooled to below -15C. Place in a ball mill cooled to below -15C with the disodium cromoglycate and roll for 15 minutes at a temperature below -15C. Pour into a suitable container chilled to -40C, and rinse out 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. Using heat alone 1 kg of micronised disodium cromoglycate at a moisture content I 176~71 of 5.8% w/w was spread in layers approximately 2 cm thick, and heated for 42 hours at 120DC. After removal from the oven, cooling under conditions preventing ready access to atmospheric moisture, and mixing, the moisture content was 0.25% w/w.

2. Using dessicant alone lOg of micronised disodium 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 disodium cromoglycate" we mean disodium cromoglycate that has been subjected to a process of attrition in a fluid energy'mill, for example that manufactured by CHRISPRO LIMITED, 3 ST MARGARET'S STREET, CANTERBURY, XENT, ENGLAND.

Claims (7)

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

1. Disodium cromoglycate containing less than 3% by weight of water.

2. Disodium cromoglycate according to Claim 1 and containing less than 2% by weight of water.

3. Disodium cromoglycate according to Claim 1 and containing less than 1% by weight of water.

4. Disodium cromoglycate according to Claim 1 and containing more than 0.05% by weight of water.

5. Disodium cromoglycate according to Claim 1 having a mass median diameter in the range 0.01 to 10 microns.

6. Disodium cromoglycate according to Claim 5, wherein at least 50% by weight of the particles have a diameter of 2 to 5 microns.

7. A method of making disodium cromoglycate containing less than 3% by weight of water, which comprises micronising, milling or grinding disodium cromoglycate until it has a mass median diameter of less than 20 microns, and removing water from the finely divided disodium cromoglycate.