Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to a process for the production of a
pharmaceutical composition suitable for topical application incorporating a
topically active steroid and a topically active antimicrobial agent. More
particularly, the present invention relates ~o a process for the production
of a composition incorporating a topically active steroid such as 17~-benzoyl-
oxy-9~-fluoro-16~-methyl-~1'4-pregnadiene~ ,21-diol-3,20-dione hereinaEter
referred to as betamethasone 17-benzoate, and a salt of neomycin, typically
neomycin sulfate.
The use of topically active steroid to treat local inflammatory
conditions is a well accepted therapeutic procedure. Generally, the steroid
is suspended or dissolved in a base for application to the inflamed site. In
instances where inflammation is complicated by bacterial infections, a topical- -~
ly active antimicrobial agent is combined with the steroid to ccmbat bacterial
infections. ;
Betamethasone 17-benzoate is a recently discovered topical steroid,
the prepa~ation of which is for instance described in our British specifica-
~ tion No. 1,191,965 published September 16, 1970, and our United States Patent
: 3,529,060 issued September 15, 1970.
- ~ In order to use this compound and to provide maximwm topical
effect of the steroid, a novel ointment base was produced. This forms the
basis of our British complete specification No. 1,316,556 issued February 11,
1912. Briefly, the base disclosed comprises ethanol and propylene glycol,
gelled by the incorporation of a carboxy vinyl polymer neutralized with an
amine. This forms a clear gel with the steroid. It is applied topically and
~ permits maximum absorption of the steroid. However, when such a base contain-
; ~ ing the sterold is used to include an antimicrobial agent such as neomycin
sulfate, a coagulated precipitate forms. This is obviously undesirable.
More lmportantly, in actual microbiological assay by the standard agar cup
method there was no available neomycin sulfate to provide the desired anti-
microbial activity.
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We have now discovered how to prepare a new base containing a
topically active steroid and a salt o neomycin. In accordance with the inven-
tion, there is provided a process for the production of a pharmaceutical com-
position suitable for topical application in the form of a clear stable aqueous
gel incorporating a ~opically active steroid and a pharmaceutically accept-
able salt of neomycin, which comprises the steps of: -
A. dissolving said steroid in a solvent consisting essentially of
a topically acceptable polyol and from 0 to 25% by weight, based on the
weight of the composition, of a topically acceptable alcohol;
B. adding to the glycol solution of step A. from 0.5 % to 5 % by
weight based on the weight of the final composition, of a cellulose ingredi-
ent selected from the group consisting of hydroxypropyl cellulose and hydroxy-
propyl methylcellulose;
C. adding to the product of step B. an aqueous solution of neo-
mycin salt; and, where the neomycin salt is other than neomycin hydrochloride;
D. adding a pharmaceutically acceptable source of chloride ion
in an amount sufficient to produce a clear gel.
In step A there may be present a topically acceptable alcoholic
solvent such as isopropyl alcohol, ethyl alcohol or the like. Preferably
the steroid is dissolved in above 20% to about 60% by weight of the polyol
containing from 0% to about 25% by weight of the alcohol. Still more prefer-
ably, the solvent for the steroid is a mixture of about 35% propylene glycol
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and about 15% ethyl alcohol. The percentages are based on the weight of the
inal composition. ~Iydroxypropyl methylcellulose is the preferred cellulose
ingredient. Suitably, the polyol is glycerin, ethylene glycol, propylene
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glycol, butylene glycol or the like. The source of chloride ion may be an
alkall metal chloride such as sodium chloride. However, when neomycin hydro-
chloride is~employed as the neomycin salt, the step of adding further chloride
` may be unnecessary. The pH of the final composition may be adjusted if ne-
cessary to about ~.0 to 5.0 with a suitable acid, such as hydrochloric acid.
In the process of this invention, about 0.5 to about 5.0%, prefer-
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ably up to 3.0% by weight of the cellulose ingredient is used, depending on
the viscosity of the cellulose ingredient. Typically about 1.5% by weight of
hydroxypropyl methylcellulose having a viscosity of about 80 to 120,000
centipoises is used. The neomycin usually is employed as its sulfate salt
and preferably a sufficient amount is used so as to give a concentration of
about 0.35% by weight of neomycin base in the fina] formulation.
In order to improve the consistency of the final composition,
polyethylene glycol 4000 or other suitable stiffening agents known to the
pharmacist's art may be included. Typically 1 to 2% by weight of polyethylene
.
glycol ~000 may be added.
When a composition, produced in accordance with the foregoing
process, is assayed not only is the steroid totally available, but also the
neomycin is not inactivated.
In order to prevent oxidation a small amount of a suitable anti-
oxidant such as 0.1% by weight of sodium bisulfi~e, and also a chelating agent
may be included in the composition.
The resultlng gel is substantially clear and has a substantially
uniform conslstency and iS further characterized by the fac~ that it is self-
preserving in that there is no need to include in the composition the usual
preservatives such as the parabens.
In order to further illustrate the practice of this invention the
following examples are included:
EXAMPLE 1
An 0.025% by weight of betamethasone 17-benzoate is prepared from
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- the following ingredients:
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% Ingredients 1000.00 g
.025 1. Betamethasone 17-benzoate*0.2625
.35 2. Neomycin sulfate USP, adjustt
or about 5.00 g
3. Hydroxypropyl methylcellulose15.00 g
4. Propylene glycol USP 350.00 g
5. Alcohol USP **166.67 g
6. Polyethylene glycol 4000USP10.00 g
7. Disodium Edetate USP 1.00 g
8. Sodium Bisulfite USP 1.00 g
9. Sodium Chloride USP granular10.00 g
10. Hydrochloric Acid N/l q.s. or about 3.00 m
11. Water~ Purified USP q.s. to1000.00 g
*5% excess for processing losses
~ adjust to give 0.35% by weight as neomycin base
**11% excess for manufacturing losses
The gel is prepared by dissolving betamethasone 17-benzoate in the
alcohol and propylene glycol employing a suitable mixer. To this is added the
hydroxy propyl methylcellulose. It is mixed until the methylcellulose is
wetted.
In a separate vessel neomycin sulfate is mixed together with poly-
ethylene glycol 4000, the disodium edetate and sodium bisulfite and approxi~
20mately 400 grams of water. When the solution is complete, it is added to the
betamethasone 17-benzoate solution. The sodiu~ chloride dissolved in -~
approximately 40 grams of water is added to the resulting mixture. With mix- ~;
ing, the pH is then adjusted with hydrochloric acid to about 4.0 to 5Ø
Sufficient water is added to make 1000 grams. There is obtained a clear gel
,
containing 0.025% by weight of betamethasone 17-benzoate and 0.35% by weight
of neomycin.
EXAMPLE 2
By employing the procedure described in Example 1 but substituting
fluocinolone acetonlde for the betamethasone 17-benzoate, a clear gel is also -
30obtained.
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EXAMPLE 3
The biological activity of the gel produced in accordance with
Example 1 is compared with an aqueous solution of neomycin sulfate. The test
procedure utilized is the agar cup method utilizing S. aureus ATCC 6538P as
the test organism. The following results were obtained:
Zone of Zone of
FormulationInhibition ¦ Neomycin Base Inhibition ;
(mm)* (mcg/ml) (mm)*
Composition of
Example 1 8.6 l 3,500 8.0
Placebo N.Z.** ¦ 3,000 7.8
1 2,500 7.4
1 2,000 7.1
1,000 6.7
500 5.9
250 5.2
2 6
~_ 10 2.1
* Average of two observations ''
** No zone
; ~ The placebo utilized in the above test comprises all the ingredients
except neomycin and~betamethasone 17-benzoate. The above results show that
utlll~zing the process of this invention the neomycin sulfate retains its ant
mlcrobial activlty as the zone of inhi~ition approximates the zone of inhibit- `
ion produced by an aqueous solution of neomycin sulfate.
EXAMPLE 4
In order to illustrate the clinical effectiveness o:E the composi-
tion a double blind study involving 10 normal adults was made. The two pre-
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parations labeled A and B were applied to the volar aspects o~ the forearms
of 10 patients in random fashion, three applications of each preparation being
made to each patient.
The arms were then covered for 20 hours and the areas were then
read one hour and eight hours after the removal of the covering.
Blanching of an area, i.e.~ vasoconstriction was regarded as
positive, i.e., absorption of the steroid had occurred. I`he results obtained
were as follows:
TOTAL NO. OF NUMBERS WITH POSITIVF.
APPLICATIONS BLANCHING
1 Hour 8 Hours
GEL A 30 23 27
GEL B 30 19 2
S~MMARY:
Patients receiving preparation A in the 20 hour test
. ~23 showed positive
1 hour after uncoverm g: l 7 showed negative
27 showed positive
8 hours after uncovering: 3 sho~ed negative
Patients receiving preparation B in the 20 hour test:
. ~19 sho~ed positive
1 hour after uncoVerlng: l 11 showed negative
r 2~ showed positive
8 hours after uncover m g: l 6 showed negative
Preparation A utilized in the above test contained betamethasone
2017-benzoate in a gel formulation previously known. Preparation B was prepared
in accordance with the process of Example 1.
From the foregoing results, it is clearly shown that in utilizing
the present process the addition of neomycin did not inactivate or interfere
with the absorption of the steroid~ and moreover the neomycin retained its
activity.
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