Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3l~45~74 `
The present invention is concerned with
improvements in or relating to the formulation of new -~
pharmaceutical cream composltions
,:
Pharmaceu~ical creams have been widely u~ed for ;
S very many years in the medical arts for the topical
application of drugs. It is now believed that the ;
composition of the vehicle may pla~ an important role `~
in determining the rate of reLease of the drug from
the cream and its absorption through the skin on which
it is topically applied, In recent years, there have
been a number of proposals for the formulation of new
pharmaceutical creams which are essentlally
anhydrous in nature and contain non-aqueous solvents
s~ch as glycols.
15We have now discovered that valuable advantages
can be achieved by the use of certain new aqueous cream
compositions (as more particularly described hereinafter)
in the ~ormNlation of topically active drugs.
Thus~ our new cream compositions differ
from the ~bove-mentioned anhydrous compositions in that
they contain significant ~ounts of water.
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In very general ~erms, the new cream composl~ions comprise a dis-
persion of one or more waxe9 or wax-like components in an aqueous phase also
comprising a water miscible solvent compatible with the skin, preferably a
hydroxylic solvent, conveniently at least one glycol and/or glycerol. The
new compositions may advantageously be employed as vehicles for drugs which
it is desired to apply topically to the skin. Indeed, we have found that the
new compositions have certain very valuable advantages, from the point of view
of both formulation and application.
We have further found that particularly advantageous results may
be achieved by the use of wax, water and hydroxylic solvent in the compositions
in the amounts hereinafter specified, the presence of relatively low amounts
of wax in the compositions providing especially favourable results~ -
According to the present invention we provide a substantially oil-
free pharmaceutical cream composition comprising from 0.0001 to 5~ by weight
of a topically-active anti-inflammatory steroid in a vehicle comprising a dis-
hY~o~o~c
C persion of~w~x iTI an aqueous phase comprising water and at least one water~
miscible hydroxylic solvent, the said dispersion further containing a surface
active agent, and the wax, water, the water-miscible hydroxylic solvent and
surface sctive agent being present in amounts of 5.0 to 30%, 7.0 to 75%, 10
to 80% and 0.1 to 10% respectively, based on the total weight of the composi-
tions.
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In our new cream compositions, drugs of low water
solubility can be in solution, at least in part and
preferably to a major extent in the aqueous phase, thus
aiding the release of the drug from the vehicle. Another
factor which has been found to govern the rate of -
release of the drug from the cream is the presence or
absence of oils in the cream. Creams have been
formulated in the past as oily emulsions containing up
to 50% oil. The presence of substantial quantities of
oil in a cream, particularly if the drug has a fair
solubility in the oil, will generally (to a greater
or lesser extent) inhibit release of drug. Even if
the drug is deliberately dissolved in the aqueous phase
of the cream the presence of an oily phase can only
have an adverse effect on the release of the drug, a
proportion of which will partition into it. In
.
contrast, our new cream compositions avoid the use of
substantial quantities of an oil component.
Moreover, the inclusion of substantial quantities
o~ water in our new cream compositions reduces the
potential irritancy to the skin of the vehicle as
compared with the use of prior co~positions based
substantially on such non-aqueous solvents as glycols,
e.g. propylene glycol.
In addition, the inclusion of water in the new
ccmpositions has been found to facilitate their manufacture.
In the manufacture of the above-mentioned prior
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anhydrous compositlons it has been conventional practice
to employ some kind of surface active agent to effect
admixture of the ingredients. ~owever, even when a --
suitable surface active agent is employed, it is still
necessary to employ special manufacturing techniques
since the surface active agent cannot properly exert i`
its normal "wetting effect" in the absence of water.
In contrast, our new compositions contain water and
surface active agents can be readily employed therein,
if so desired. Moreover, our new compositions can be
easily manufactured using conventional techniques such
as mixing, stirring, cooling etc., and do not require
the use of special operating conditions or techniques.
As indicated above, the new compositions contain
one or more waxes. The term "wax" is used herein in
its broadest sense to include not only conventional
waxes but other materials having wax-like physical
and/or chemical characteristics. Examples oE waxes
which may be employed in the new compositions include
long chain (e,g. Cl6-C24) fatty acid monoesters of
glycerol, preferab1y saturated fatty acid esters such
as glycerol monostearate; wa~y triglycerides including
acetoglycerides (i.e. acetylated mono- and di-glycerides);
fatty alcohols, e.g. saturated fatty alcohols preferably
25/ containing 16 to 24 carbon atoms especially cetyl
alcohol, stearyl alcohol, cetostearyl alcohol, behenyl
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alcohol etc; saturated fatty acids o a waxy nature
preferably containing 14 to 26 carbon atoms, especially
stearic acid; and naturaL and sythetic waxes such as
beeswax.
The above waxes are all of a hydrophobic nature
and with an appropriate surfactant produce a dispersion
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in water. Hydrophilic waxes may~if desired be additLonally ~ -~
present; these dissolve in the water component. Examples
of such hydrophilic waxes include polyethylene glycols ~ ~
of a waxy nature, e.g. of molecular weight 1500-6000.
The wax components are preferably employed in a
total amount of 10 to 20% o the composi~ion.
With regard to the hydroxylic solvent, this may
for example consist of or include one or more glycols,preferably
ones in which the intended drug is soluble at least to
some extent, whereby the drug can be mobilised in the
vehicle to reach the surface being treated. Thus,
the identity and quantity of glycol solvent may be
conveniently selected to ensure partial or complete
dissolution of the drug therein. Examples of
particularly preferred glycol so~lvents for use in our
new compositions include propanediols such as
1,2-propanediol, 1,3-propanediol; liquid polyethylene
glycols particularly those having a molecular weight
::
; of from 100 to 800; dipropylene glycols; and mixtures
~ thereof.
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The hydroxylic solvents may consist of or include
trihydric alcohols such as glycerol, the latter
material being particularly useful for those
dermatological purposes where a bland composition is
desirable, e.g. in compositions for pediatric usage.
In general the hydroxylic solvent preferably
constitutes 25 - 70% of the compositions, particularly
when the solvent is a glycol. However, in theparticular
case of such trihydric alcohols as glycerols, these
preferably constitute up to only 40% (more preferably
25%) of the composition.
The new compositions preferably contain 20 to
60% of wa~er.
As mentioned above, the new compositions may, if
desired, contain a surface active agent serving as
a dispersing agent for the wax and also as a stabiliser
for the resulting dispersion. The surface active agent,
which may be a single substance or a mixture, may be
non-ionic and preferably has an HLB value of at least
8.
Examples of surface active agents include
polyoxyekhylene ethers or esters such as Cetomacrogol 1000
(i.e. polyethylene glycol 1000 monocetyl ether),
~ ~r~ lPm ~r
97~ :
polyoxyethylene s~earat~ ~or a mlxture of s~earatfls) ospeclally polyoxyethy-
lene 40 stearate, or polyoxyetllylene lanolin derivAtives especially polyoxy-
ethylene 25 lanolin. Alternati~ely, one may employ an anionic surace active
agent such as sodium lauryl sulphate, sodium dioctyl ~ulphosuccinate etc. The
new compositions advantageously contain 0~1 to 10~ ~preferably 1 to 5%~ of
surface active agent, ~he propo~tion and nature o the sur~ace active agent
being chosen by preliminar~ experiment to give satis~actor~ release of the
drug
The cream compositions described abo~e may be advantageously em- ~-
ployed in the formulation of drugs or mixtures o~ drugs which are in~ended for
topical application, for example, to a~flicted areas of the skin. Such drugs ~-
include in particular d~ugs for the topical alleviation of inflammatory con-
ditions, for example anti-inflammatory steroids, particul~rly o~ the corticoid
type~ Particular classes o~ anti-inflammatory steroid compounds which may be
adYantageously ~ormulated with the new composltions include those described
in British Patents Nos, 1,047,518; 1,047,519; 1,070,751; 1,139,S06; 1,253,831;
1,281,689; 1,261,650; and Canadian Applications Nos. 132~814J 176~804 and
178,557,
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Particular steroid compounds which may be ~o
formulated include betamethasone 17-valerate; 21-chloro- :
21-desoxybetamethasone 17-propionate (21-chloro-9a-
fluoro~ hydroxy-16~-methyl 17~-propionyloxy-pregna-
1,4-diene-3,20-dione);betamethasone 17-benzoate; fluocinolone
acetonide (6a,9a-difluoro~ ,21-dihydroxy-16a,17a ~ -
isopropylidenedioxy pregna-1,4-diene-3,20-dione) and
the corresponding 21-acetate; 9a-fluoro-16-methylene
prednisolone-21-acetate; 6a,9a-difluoro-prednisolone-21-
acetate-17-butyrate; 9a,11~-dichloro-6a,21-difluoro- ~:
16a,17a-isopropylidenedioxy pregna-1,4-diene-3,20-
dione; 11~, 21-dihydroxy-16a,17a-isopropylidenedioxy ;`~
pregna-1,4-diene-3,20-dione, 9a,11~-dichloro-6a-fluoro-
21-hydroxy-16~,17a-isopropylidenedioxy pregna-1,4-diene-3, :.
20-dione, beclomethasone 17J21-dipropionate (9a-chloro- `~
:~ 16~-me~hyl-prednisolone 17,21-dipropionate); 21-chloro-21 soxy~
ll~dehydro-betamethasone 17-butyrate; 21-desoxy- ;
betamethasone 17-propionate; betamethasone 17-isobutyrate
21~acetate; ~8(9)-16~-methyl-prednisolone 17,21-dipropionate;
and methyl ll~-hydrox~-3-oxo-17~-propionyloxy-androst-
4-ene 17~-carboxylate.
Other drugs which can conveniently be included in
the compositions according to the invention include ~ :
antibiotics, local anaesthetics, antibacterials,
antifungals and otherdermatological drugs. ~ ~
The new compositions may also contain, if desired, ~ .
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1045974
further conven~ional ingredients and/or additives as
desired, e.g. preservatives such as chlorocresol,
parabens, such as methyl and propyl parabens, and
mercury compounds, humectants such as sorbitol, or
suitable stabilisers where required such as sodium
metabisulphite or ethylene diamine tetracetic acid.
Although the compositions of the invention are
substantially oil-free, they may contain relatively
small amounts of oily lubricants i.e. up to about
5% (preferably 1-2%) of the composition; such lubricants
include silicone oil, liquid paraffin, castor oil,
isopropyl myristate etc. The compositions may also
contain one or more buffer compounds.
;;; ; The base compositions of the invention may for
example contain 0~0001 to 5%, conveniently 0.005 to
0.50% and preferably 0.01 to 0.10% o~ an anti-
Lnflammatory steroid, the precise percentage to be used
being readily chosen by reference to the potency of the
steroid. In the case of 21~chloro- 21-desoxybetamethasone
17-propionate a convenient proportion is 0.05%.
Our new cream compositions may be readily manufactured
for example by suitable admixture of the components,
e.g. in conventional manner, as illustrated by the
following Examples. It should be noted that the topically
active drug component may be added to the preformed
cream or, more preferably, may be incorporated into one
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of the components of the cream prior to emulsification.
The following Examples illustrate the present
invention;
Example 1
Composition
Cetostearyl alcohol 10~/o
Acetoglyceride 10%
Cetomacrogol 1000 1,5% ~;~
1,2 Propanediol 35%
Methyl paraben 0.08%
Propyl paraben 0.02%
Sodium dihydrogen phosphate0.10%
Water to 100.00%
Method of Preparation
Melt the three waxes together and heat to 75C.
` Mix most of the 1,2 propanediol and water and dissolve
the other ingredients, heating to effect solution of the
parabens. Heat this solution to 75C and mix with the
molten waxes. Stir and cool to 40C.
21-chloro-21-desoxy-betamethasone 17-propionate
is either dissolved in a small portion of the 1,2-
propanediol which is added after the waxes and a~ueous
phase have been mixed. Alternatively the steroid is
ball milled in an aqueous solution of the surfactant
and the resul~ant microfine suspension added to the
other components as above `~
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:~0~5~317g~
The same method of preparation is employed for
the composition of Example 2 below.
Example 2
Stearic acid 8.0%
Cetostearyl alcohol 8.0%
1,2-Propanediol 45.0%
Cetomacrogol 1000 0.5%
Polyoxyethylene 40 stearate . 2.00
Chlorocresol 0~05
Sodium citrate 0.15
Citric acid 0.15
Water to 100.00
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Glyceryl rnonostearat;e (G.t~ .) 10.0%
Cetostearyl alcohol (C.S.A.) 8.0%
Polyoxyethylene 25 lanolin deri.va~ve 3.0%
1, 2 Propanediol 67.0%
Thiomersal - 0,01%
Sodium dihydroge~ phosphate 0.05i~
Disodium hydrogen phosphate 0.05% ; ;~
.
Water to100.0%
Method of Preparation_
Melt the G.M.S., C.S.A. and ]anolin derivative
together and heat to 75C. Mix most of the propanediol
and water, add the other ingredients and heat to efEect
solution. Mix both solutions at 75C, stir and cool to
40C. . ;
Dissolve the steroid in the remaining propanediol and
add to the above after the phases have been mixed.
xam~ 4
Glyceryl monostearate (G.M.S.) 10.0% ;
Cetostearyl alcohol (C.S.A,) S.0%
Beeswax ~r 2~ 0%
Acid stable self-emulsifying mono-
stearin ) 2.0%
. ~.
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:~.04~
Glycerol 10.0%
Sodium citlate 0.05/O
Citric acid 0.05%
Chlorocresol 0.10%
Water to 100.0% :
_ethod O~ e~
Melt the G.M~S., C.S.A., Beeswax and monostearin
togethQr and heat to 75C. Mix most of the glycerol and
water, add the other ingredients and heat to aid
solution. Mix the two phases at 75C, stir and cool
to 40C.
Ball mill the steroid in the remaining glycerol ànd
add to the above atter tbe two phases have been mixed,
Example 5
As Example 4 with addition of 1% dimethylpolysilvxane
o-L:L.
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