PRODUITS PHARMACEUTIQUES

PHARMACEUTICAL COMPOSITIONS

Abrégé anglais

A B S T R A C T
Title: PHARMACEUTICAL COMPOSITION
A pharmaceutical composition is described which
contains as active ingredient the .beta.-stimulant
salbutamol or one or more of its physiologically
acceptable salts. The stability of aqueous
formulations of the composition is improved by
including a cellulose derivative which provide
an optically transparent or opalescent colloidal
dispersion. Preferred compositions are liquid
formulations suitable for oral administration
in which the cellulose derivative also serves as
a thickening agent.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A pharmaceutical composition comprising an
aqueous dispersion of one or more cellulose derivatives
containing salbutamol and/or one or more of its
physiologically acceptable salts.
2. A pharmaceutical composition according to
claim 1, which comprises the one or more cellulose
derivatives in a total amount of at least 0.1% w/v.
3. A pharmaceutical composition according to
claim 1 or 2, wherein the cellulose derivative is an
alkyl and/or hydroxyalkyl ether.
4. A pharmaceutical composition according to any
of claims 1 or 2, in which the cellulose derivative is
selected from ethyl cellulose, methyl cellulose, ethyl-
methyl cellulose, hydroxymethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxyethyl methyl-
cellulose, hydroxypropyl methylcellulose, hydroxyethyl
ethylcellulose,carboxymethylcellulose and salts of
carboxymethylcellulose.
5. A pharmaceutical composition according to claim
1 or 2, wherein the cellulose derivative is hydroxypropyl
methylcellulose.
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6. A pharmaceutical composition according to claim
1, which is formulated as a liquid preparation suitable
for oral administration.
7. A pharmaceutical composition according to
claim 6, which contains the one or more cellulose
derivatives in a total amount such as to provide the
liquid preparation with a viscosity in the range of from
5 to 10,000 centipoises.
8. A pharmaceutical composition according to claim
7, wherein the viscosity is in the range of from 10 to
100 centipoises.
9. A pharmaceutical composition according to any
of claims 6 to 8, which contains salbutamol and/or one or
more of its physiologically acceptable salts in a
concentration of 1 mg to 4 mg, expressed as salbutamol
free base per 5 ml of liquid.
10. A pharmaceutical composition according to claims
6 to 8 which contains salbutamol and/or one or more of
its physiologically acceptable salts in a concentration
of 2 mg, expressed as salbutamol free base per 5 ml of
liquid.
11. A pharmaceutical composition according to
claim 1 or 2, having a pH of 3.5.
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12. A pharmaceutical composition according to claim
6, 7 or 8, having a pH of 73.5.
13. A method of preparing an aqueous based pharm-
aceutical composition comprising salbutamol and/or one or
more of its physiologically acceptable salts wherein the
salbutamol and/or one or more of its physiologically
acceptable salts has improved stability, which methods
comprises mixing one or more cellulose derivatives with
salbutamol and/or one or more of its physiologically
acceptable salts in the presence of water and introducing
before, during or after mixing any optional components of
the composition.
14. A method of improving the stability of salbut-
amol and/or its physiologically acceptable salts in an
aqueous based pharmaceutical composition containing as
active ingredient salbutamol and/or one or more of its
physiologically acceptable salts which method comprises
mixing one or more cellulose derivatives with salbutamol
and/or one or more of its physiologically acceptable salts
in the presence of water and introducing before, during or
after mixing any optional components of the composition.
15. A method according to claim 13 or 14 wherein the
one or more cellulose derivatives are dispersed in water
and then mixed with salbutamol and/or one or more of its
physiologically acceptable salts.
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16. A method according to claim 13 or 14 which
comprises selecting the amount of cellulose derivative
such that the resulting pharmaceutical composition
contains the one or more cellulose derivatives in a total
amount of at least 0.1% w/v.
17. A method according to claim 13 or 14 wherein
the cellulose derivative is an alkyl and/or hydroxyalkyl
18. A method according to claim 13 or 14 in which
the cellulose derivative is selected from ethyl cellulose,
methyl cellulose, ethylmethyl cellulose, hydroxymethyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methyl-
cellulose, hydroxyethyl ethylcellulose, carboxymethyl-
cellulose and salts of carboxymethylcellulose.
19. A method according to claim 13 or 14 wherein the
cellulose derivative is hydroxypropyl methylcellulose.
20. A method according to claim 13 which comprises
formulating the resulting pharmaceutical composition as a
liquid preparation suitable for oral administration
containing the one or more cellulose derivatives in a total
amount such as to provide the liquid preparation with a
viscosity in the range of from 5 to 10,000 centipoises.
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21. A method according to claim 20 wherein the
viscosity is in the range of from 10 to 100 centipoises.
22. A method according to claim 20 which comprises
selecting the amount of salbutamol or physiologically
acceptable salts such that the resulting pharmaceutical
composition contains salbutamol and/or one or more of its
physiologically acceptable salts in a concentration of 1
mg to 4 mg, expressed as salbutamol free base per 5 ml
of liquid.
23. A method according to claim 22 wherein the
concentration is 2 mg expressed as salbutamol free base
per 5 ml of liquid.
24. A method according to claim 13, 14 or 20 which
comprises controlling the pH such that the resulting
pharmaceutical composition has a pH of 3.5.
25. A method according to claim 21, 22 or 23
which comprises controlling the pH such that the result-
ing pharmaceutical composition has a pH of 3.5.
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Description

7~
--1--
Title: P~ARMAC~UTIC~L COMPOSITIONS
The present invention relates to a pharmaceutical
composition containing as active ingredient the
~-stimulant salbutamol.
Salbutamol [(~l-tert-butylaminomethyl)-~-hydroxy-
m-xylene~ 3-diol)~ and its physiologically acceptable
salts are described in British Patent Specification
No. 1200886. In that specification there is reference
to pharmaceutical compositions containing salbutamol
and there is a description of solid and liquid
preparations for oral and intravenous use.
Liquid preparations of salbutamol and/or a
physiologically acceptable salt thereof are conveniently
water based and for oral use the preparations contain
sucrose or sorbitol which acts both as a sweetener and
thickening agent.
Such pharmaceutical compositions have been
successfully marketed. However, it is known that the
presence of a substance such as sucrose,
or sorbitol or glycerol in aqueous compositions of
salbutamol or a physiologically acceptable salt thereof
is associated with an accelerated deterioration in
the stability of the salbutamol in the composition.
We have now surprisingly found that the stability

03~7i
of salbutamol in aqueous formulations may he significantly
enhanced by the presence of a cellulose derivative
which forms a colloidal dispersion in water.
Thus, the present invention provides an
improved pharmaceutical composition which comprises
an aqueous dispersion of one or more cellulose
derivatives containing salbutamol and/or one or more
of its physiologically acceptable salts.
According to a preferred embodiment of the
invention, the pharmaceutical composition is
formulated as a liquid preparation suitab]e for oral
administration in which the cellulose derivative
is advantageously used as thickening agent.
Suitable cellulose derivatives are those which
form an optically transparent or opalescent dispersion
in water, preferably an optically transparent colloidal
dispersion.
Preferred cellulose derivatives include non-ionic
derivatives such as alkyl and/or hydroxyalkyl ethers
of cellulose, particularly Cl 4 alkyl and/or hydroxy
Cl 4 alkylethers of cellulose for example, e~hyl
cellulose, methyl cellulose, ethylmethyl cellulose,
hydroxymethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxyethyl methylcellulose,
hydroxypropyl methylcellulose and hydroxyethyl
ethylcellulose.

3L2~3~L'76
--3--
Suitable ionic cellulose derivatives include
carboxymethylceullose and salts thereof such as
the calcium or sodium salts.
Particularly preferred cellulose derivatives
S are hydroxyethyl cellulose and more especially
hydroxypropyl methylceullose.
A preferred salt of salbutamol for use in
the pharmaceutical composition according to the
invention is the sulphate.
The total amount of dispersible cellulose
derivatives present in the pharmaceutical composition
accordin~ to the invention is such that the resulting
colloidal dispersion has the desired enhanced
stability and has a viscosity suitable for its
proposed mode of administration. Preferably, the
pharmaceutical composition contains at least 0.1~ w/v
of the cellulose derivatives.
~or liquid preparations suitable for oral
administration the total amount of cellulose
derivatives will be determined primarily by the
requirement to obtain a solution with a viscosity
suitable for oral administration, preferably
within the range 5 to lO,000 centipoises~ more
preferably from 10 to 100 centipoises.
The concen'tration of the salhutamol or its salts
in the formulation may be adjusted to suit the use

~2g33~
for which the form~lation is required and/or the
patient's requirements. For example, for oral
use the concentration is conveniently equivalent
to lmg to 4mg, preferably 2mg, of salbutamol,
expressed as salbutamol free base, per 5 ml of the
liquid.
Preferably the pH of the pharmaceutical
composition is in the range of from 2.5 to 7, more
particularly 3.5 and this is conveniently achieved
by the use of a buffer. For oral compositions,
suitable buffers include a sodium citrate/citric acid buffer.
The pharmaceutical composition according to
the invention may also contain an antimicrobial
preservative, such as benzoic acid or a salt thereof
which generates the acid in situ, or a methyl, ethyl,
propyl or butyl hydroxybenzoate. For oral use the
composition preferably also contains a flavouring;
a sweetening agent such as saccharin sodium or
sodium cyclamate and~or a colouring.
The pharmaceutical composition according to
the invention may be prepared by disperslng one
or more cellulose derivatives in water, and then
adding or mixing with the salbu~amol or physiologically
acceptable salts thereof, conveniently dissolved in
water,together with any optional components of the
composition.

~Z~:~3~71E;
~5-
Illustrative examples of formulations
~expressed as a 5 ml dose for oral administration
according to the invention are as follows:-
Example 1
5 Salbutamol sulphate 2.40 mg
Hydroxyethyl cellulose
~Natrosol*250H) 22.5 mg
Distilled water to 5 ml
To prepare the formulation the hydroxyethyl~0
cellulos~ is dispersed in water and then mixed with
a solution of salbutamol sulphate in water.
Example 2
Salbutamol sulphate 2~40 mg
Sodium citrate dihydrate 9.60 mg
Citxic aoid monohydrate 15.15 mg
Natrosol 250H 15.0 mg
Distilled water to 5.0 ml
To prepare the formulation the hydroxyethyl
cellulose is dispersed in water, and then mixed
with a solution of salbutamol and the buf~ers
salts in water.
* Trade Mark

~Z~3~76
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Example 3
Salbutamol sulphate2.40 mg
Sodium citrate dihydxate9.60 mg
Citric acid monohydrate15.25 mg
Hydroxypropyl methylcellulose
viscosity type 400022.5 mg
Distilled water to 5 ml
Example 4
Salbutamol sulphate B.P.2.40 mg
Sodium citrate B.P.7.5 mg
Citric acid monohydrate ~.P. 25.0 mg
Hydroxypropyl methylcellulose
(viscosity type 4000)22.5 mq
Sodium benzoate B.P.10.0 mg
15 Saccharin sodium B.P.2.5 mg
Flavouring qS
Purified water to 5 ml
To prepare the formulations of ~xamples 3 and 4
the hydroxypropyl methylcellulose is dispersed in hot
water, cooled and then mixed with an aqueous
solution containing the salbutamol sulphate and the
other components of the ~ormu].ation.