Note: Descriptions are shown in the official language in which they were submitted.
DESCRIPTIO~
"STEROID COMPOSITIONS"
THIS INVENTIOM relates to steroid compositions
for topical application.
In our British Specification ~o. 1543907, we
ha~e described a novel kind of formulation of hydro-
cortisone which has a much improved effectiveness ascompared with previously known hydrocortisone-containing
compositions. The compositions of our aforesaid
Specification comprise an essentially saturated (iOe.
saturated at the lowest temperature to which the
composition is likely to be subjected during use or
storage, e.g. 0C) solution of hydrocortisone in an
aqueous propylene glycol solution containing at least 15%
but less than 50% by weight of propylene glycol and having
a pH 4.5-5, the proportion of hydrocortisone in the total
15 composition being at least 0.08% but not greater than 0.4%
by weight of the aqueous propylene glycol and from 0.025 to
0.4% based on the total weight of the composition. Such
compositions containing 0.1% of hydrocortisone are more
effective than hydrocortisone cream BP containing 1%
hydrocortisone in the McKenzie ~ Stoughton vasoconstriction
test (Arch. Derm. 86, 608, 1962)~
.: ~
During the last two or three years a new method
of hydrocortisone assay applicable to pharmaceutical
compositions and based on the use of high pressure liquid
chromatography has been introduced~ This method has
shown that the previously used colorimetric method of
hydrocortisone assay has the serious drawback that some
hydrocortisone degradation products give the same colour
reaction as hydrocortisone itself. Consequently the new
method ha~ revealed instability problems with some known
hydrocortisone-containing compositions, particularly those
which are aqueous and including the composition described
in our aforesaid British Specification. While at
temperatures below 15C, the aforesaid composition has
satisfactory storage stability at higher temperatures it .
has a relatively limited shelf life.
It has now surprisingly been discovered that by
very careful and precise alteration of the pH and
constituents of the aforesaid compositions it is possible
to produce a novel hydrocortisone-containing steroid
composition which has a ~ubstantially improved storage
stability, and very surprisingly an even higher activity
than the compositions described in our aforesaid
Specification.
The composit.ions of the present invention comprise
an essentially ~aturated solution of hydrocortisone in an
aqueou~ propylene glycol solution containing at least 15%
but less than 50% by weight of propylene glycol, the
proportion of hydrocortisone in the total composition
being at least 0.0~% but not greater than 0.4% by weight
of the aqueous propylene glycol and from 0.025 to 0.~%
based on the total weight of the composition, the composition
being substantially free of metallic cations and containing
- sufficient of a pharmacologically acceptable compatible
non-toxic acid to bring the pH to within the range 2.7
to ~.3. Very surprisingly, these novel compositions show
a higher degree of activity than the composition described
in our aforesaid Specification (which has a pH of 5), a
substantially higher activity than an otherwise s:imilar
composition having a pH of 2.5, and a higher activity than
a similar composition containing appreciable amounts of a
metallic cation such as sodium ions (which are of course
a frequent constituent of known buffering systems).
Moreover, the new formulation has substantially superior
storage stability as compared with the formulation
described in our aforesaid Specification.
The proportions of water and propylene glycol in
the new compositions are, as in the case of the compositions
described in our aforesaid Specification, very important.
~bout 50% by weight of propylene glycol based on the weight
of aqueous propylene glycol solution, the hydrocortisone is
not sufficiently rapidly released by the composition onto
the skin to ~be very effective, and the concentration of
~L9957
hydrocortisone required for saturation is uneconomically
high, ~hile below 15% by weight propylene glycol
(corresponding to a saturated solution of hydrocortisone
in aqueous propylene glycol containing 0.08% by weight of
hydrocortisone), the satura-ted concentration of hydro-
cortisone in the aqueous propylene glycol is too low for
a satisfactory effect. The solvent therefore contains
at least 15% but less than 50%, preferably about 33%, ~y
weight of propylene glycol, the balance being water.
Because aqueous propylene glycol has a low
viscosity, it is usually convenient to incorporate into
the new composition some kind of thickener. Preferred
thickeners are long-chain paraffins, fatty alcohols, and
waxes, sufficient of the thickener being incorporated in
the ~omposition to give the desired viscosity. Examples
of suitable materials are cetostearyl alcohol, white soft
paraffin, and liquid paraffin. The ointment base called
Emulsifying Ointment (British Pharmacopoea) is especially
convenient. It contains a small porportion of sodium
lauryl sulphate, but not however enough to have a
disadvantageous effect, at least when, as is preferred,
the acid used is o~e capable of chelating metallic cations.
The proportion of hydrocortisone in the new
compositions is from 0.025 to 0.4%, preEerably 0.05 to
0.3%, by weight of the total composition. The proportion
of hydrocortisone in the total composition based on the
;~ a5~7
weight of aqueous propylene glycol must be at least 0,08%
but not greater than 0.4%. For most uses, good reRults
are obtained with a hydrocortisone concentration in the
total cornposition of about 0.1% by weight of the total
composition, and of 0.167% by weight of the aqueous
propylene glycol.
Any pharmacologically acceptable compatible non-
toxic acidic material may be used to bring the pH of the
composition to within the range of 2.7 to 3.3. It should
be borne in mind in this connection that the amount of acid
used should not be so great that after application of the
composition to the skin the p~ is still held at 2.7 to 3.3
rather than the normal physiological pH of the skin.
Non-toxic organic carboxylic acids which are sufficiently
acidic to achieve the desired pH when used in small amount
are preferably used. Since acids by themselves are not
buffers it is difficult to ensure that a precisely fixed
pH is always obtained because of slight variations in the
quality of the ingredients used. However if the
proportions of the ingredients used are such as to give in
most ca~es a pH of 2.8 to 3.0, it will only rarely be
found that the pH obtained is outside the desired range
of 2.7 to 3.3. Becau~e of the possibility that some of
the ingredients used may contain small amounts of metallic
cations (e.g. the sodium ions in Emulsifying Qintment BP
already mentioned), it is preferred to use an acid which
S~
has the ability to ehelate metallic cations, i.e. is also
a ehelating agent. Citrie acid is partieularly well
suited for this purpose, and a concentration of about
0.167% based on the aqueous propylene glycol normally
gives a pH within the desired range.
An anti-bacterial agent may if desired be
ineluded in the composition in an appropriate concentration.
The following Example illustrates the invention.
E X_A M P L E
Hydroeortisone (0.1 g) was dissolved in propylene
glycol (20 g~. 5eparately citric acid (Ool g~ was dissolved
in deionised water (40 g). The two solutions were warmed
to 60C and then mixed. This mixture was then poured into
emulsifying ointment BP (37.9 g~ which had previously
lS been melted at 60C. The eomposition was stirred until
eool. The emulsifying ointment forms a discontinuous
phase in the aqueous propylene glycol. The citric acid
adjusts the pH of the ~omposition to 2.8.
This formulation has been compared for storage
stability with that deseribed in our aforesaid British
Speeifieation No. 1543907. Samples of the two eompositions
were stored at ambient temperature (about 20C) or at
~0C Eor periods up to 13 months, and were periodieally
analysed during the storage period for their hydrocortisone
eontent. The following results were obtained:
Composition Temperature Storaqe Period % ~ydrocortisone
( oriqinal - 1Oo/o
CompositionAmbient6 weeks 102.3
of the
present " 3 months 101.4
invention
" 6 months 104.1
" 9 months 98.6
13 months 98.6
" 40C 6 weeks 9~3.7
" 3 months 95.0
" 6 months 89.1
" 9 months 80.9
CompositionAmbient6 weeks 93.2
of British
Specification " 3 months 91
~o. 1543907
" 6 months 90.0
" 9 months 80.9
" 13 months 70.5
40C 6 weeks 70.5
" 3 months 52.3
" 6 months 29.5
" 9 months 13.6
These figures clearly show the superior storage stability
of the formulation in accordance with the present invention.
The prior composition had to be stored at 15C or below in
order to achieve satisfactory shelf life. The composition
of the present invention, on the other hand, can be stored
safely at ambient temperature or even slightly above.
In a ser.ies of tests based on the above-mentioned
9~
Mc~enzie & Stoughton vasoconstriction test, the aforesaid
composition in accordance with the present invention was
compared with a number of similar compositions including
the composition described in our aforesaid British
Specification No. 1543907. The results obtained showed
that the composition in accordance with the present invention
was, in this test, at least twice as active as the
composition of our prior Specification. Similar
compositions having a pH of about 3.2 but containing sodium
dihydrogen phosphate were significantly less active than
the composition of the present invention unless the
hydrocortisone content is raised to 0.25%. nn the other
hand, a composition having a pH of 2.5 and containing 0.1%
of hydrocortisone was substantially less active than the
composition of the present invention and indeed less active
than the composition of the prior Specification. It is
thus critically necessary to keep within the above specified
pH range and to keep down the concentration of metallic
cations in order to achieve the superior activity of the
compositions of the present invention.
