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Патент USA US2582398

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Patented Jan.‘ 15, 1952
' 2,582,395
UNITED STATES ‘PATENT OFFICE
2,582,395
OINTMENTS CONTAINING OIL- SOLUBLE
AN TIOXIDAN TSv
George W. Rigby, Wilmington, Del., assignor, by
memo assignments, to the United States of
America as represented by the Secretary of War
No Drawing. Application March 6, 1945,
Serial No. 581,323
17 Claims. (01. 167-453)
1
This invention relates to therapeutic composi
tions and more particularly it relates to oint
2
‘tion in greater detail. In these examples pro
portions of ingredients are expressed as parts
ments for arsenic therapy.
by weight unless otherwise speci?ed.
A number of common ointment bases such as,
Example I
for example, those containing peanut oil, lano
lin and the like as the vehicle for the medicament
are suitable in consistency and spreading qual
ity for the preparation of ointments containing
2,3-dimercaptopropanol as the therapeutic agent.
However, these 2,3-dimercaptopropanol oint 10
ments are susceptible to oxidation when exposed
.
Parts
Peanut oil ___________________________ __ 36.95
Lanolin, anhydrous ___________________ __ 8.00
Cetyl alcohol ________________________ __ 10.00
Glyceryl monostearate ________________ __ 10.00
.White petrolatum (soft) ______________ __ 25.00
Benzyl benzoate ______________________ __ 5.00
to air. Oxygen readily reacts with the thiol
Mixed natural tocopherols (4.0%) ______ __ 0.05
groups of the dimercaptopropanol to form poly
2,3-dimercaptopropanol _______________ __
5.00
meric disul?des which are therapeutically inac
tive. Such ointments thus lose their e?icacy on 15 All the above ingredients with the exception of
intermittent or continuous exposure to air. The
the last two mentioned are heated together until
particular sensitivity of the dimercaptopropanol
a uniform melt is obtained. This melt is cooled
and the necessity for keeping these compositions
with stirring to room temperature, and vthe to
' at a precise level of therapeutic activity creates
copherols and 2,3-dimercaptopropanol then
a special problem, to which the application of the 20 Worked into it with a spatula, putty knife, or an
general antioxidant art does not provide a solu
appropriate mechanical mixer designed for han
tion.
dling pasty masses. A composition useful for ex
'An object of this invention is to provide more
ternal arsenic therapy is obtained. Its 10W oxida
useful therapeutic compositions containing 2,3
tion susceptibility is shown by the following test.
dimercaptopropanol than have heretofore been 25 An accurately weighed sample of the ointment
available. A further object is to provide oint
is stored under pure oxygen at 50° C. and atmos
ments containing 2,3-dimercaptopropanol which
retain their e?icacy for long periods, particularly
when they are exposed to air. More speci?cally
it is an object of this invention to retard the rate
of oxidation of 2,3-dimercaptopropanol in oint
ments containing this therapeutic agent.
These objects are accomplished by admixing
with an oily vehicle the desired medicament, viz.,
2,3-dimercaptopropanol, and a small amount of
35
an oil soluble anti-oxidant, whereby there is ob
tained an ointment comprising these components
which is useful in arsenic therapy and more
pheric pressure, and the amount of oxygen ab
sorbed is measured after 48 hours. One part of
the ointment absorbs only 4.6><10—4 part of oxy
gen under these conditions while an equal weight
of an ointment containing the same ingredients
in the same proportions, with the exception that
no tocopherols are present, absorbs 10><10~4 part
of oxygen.
Example II
>
Parts
Lanolin, anhydrous ____________________ __ 80.0
Benzyl benzoate _______________________ __ 10.0
stable than ointments previously available.
Mixed natural tocopherols (40%) _______ __ 0.1
In the practice of the invention, pure 2,3-di 40 2,3-dimercaptopropanol ________________ I- 10.0
mercaptopropanol, obtainable by the reaction of
The above ingredients are made up into an oint
sodium hydrosul?de with glycerol dichlorohy
ment in the manner given in Example I. One
drin, and about 0.5 to 2.0% of its weight of the
part of this ointment when tested as described
oil-soluble anti-oxidant, are compounded at room
Example I, absorbs 2.7><l0-4 part of oxygen
temperature with a cold uniformly melt-blended 45 in
on exposure to pure oxygen for 48 hours at 50° C.
oily base preferably comprising a fatty material
A control ointment containing no added to
such as peanut oil or lanolin or both. The oil
copherols absorbs 15.7><10-4 part of oxygen.
scluble anti-oxidants which have given the best
The examples illustrate the use of mixed to
results are the tocopherols, preferably the mix
copherols as the anti-oxidant for 2,3-dimercap
ture of the several isomers available as a ?sh oil 50 topropanol ointments. Instead of the mixed to
distillate. The resulting ointments absorb oxy
copherols, the individual alpha-, beta-, and
gen at a considerably less rapid rate than similar
gamma-tocopherols and other oil-soluble antl
ointments not containing an oil-soluble anti
oxidants, e. g., palmitoyl ascorbate and hydro
oxidant.
quinone, which are not reactive with thiol groups,
The following examples illustrate the inven 55 ‘may be used. The tocopherols are the most ef
2,582,895
4
oxidant for the mercapto compound selected
fective of these oil-soluble anti-oxidants. As pre
viously indicated, they are commercially avail
from the group consisting of tocopherol and
able as a 40% concentrate distilled from ?sh oil.
More specifically, this concentrate is a distilled
palmitoyl ascorbate, the anti-oxidant being
mixture of the alpha-, beta-, and gamma-to
by weight of the said mercapto compound.
2. An anti-vesicant composition containing,
present in an amount of at least 0.5 per cent
copherols, and it may be used in the ointments of
this invention without separation of the isomers
or further puri?cation. The individual to
2,3-dimercaptopropanol, and an anti-oxidant for
said mercapto compound comprising tocopherol
copherols may be used, if desired, but they have
in an amount of at least 0.5 per cent by weight
different degrees of effectiveness. The alpha-to 10 of the said mercapto compound.
copherol, for example, is somewhat less effective
3. An anti-vesicant composition containing,
than the other isomers or the commercial mix
ture. The gamma-tocopherol is the most ef
fective of the individual isomers.
The proportions of oil-soluble anti-oxidant 15
employed in these ointments may vary over a
2, 3-dimercaptopropanol, and an anti-oxidant
for said mercapto compound comprising toco
pherol in an amount of from 0.5-10% of the
weight of said mercapto compound.
4. A stable ointment for arsenic and cadmium
wide range depending on the amount of 2, 3
dimercaptopropanol present and on the degree
of oxygen exposure expected to be encountered.
therapy containing, non-drying oils, 2, 3-di
the weight of the dimercaptopropanol may be
the said mercapto compound.
used. Under mild conditions of exposure, 0.5%
is sufficient, While 10.0% is required when the
therapy containing, non-drying oils, 2, 3-di
ointment is to be exposed to oxygen or air for
mercaptopropanol, and an anti-oxidant for said
mercaptopropanol, and an anti-oxidant for said
mercapto compound comprising tocopherol in an
Thus, amounts ranging from 0.5% to 10.0% of 20 amount of at least 0.5 per cent by weight .of
5. A stable ointment for arsenic and cadmium
long periods at relatively high temperatures. For 25 mercapto compound comprising tocopherol in an
ordinary exposures the preferred amount is 0.5%
amount of from 0.5-10% of the Weight of said
to 2.0% or" the weight of the dimercaptopropanol.
mercapto compound.
2, B-dimereaptopropanol is subject to other
6. A stable ointment for arsenic and cadmium
types of chemical transformation, such to pol
therapy containing, non-drying oils, 2, 3-di
ymeric sul?des by heat in the absence of oxygen, 30 mercaptopropanol, and an anti-oxidant for said
in contrast to disul?des formed by oxidation.
mercapto compound comprising mixed natural
In the present ointments, this type of transior~
tocopherols in an amount of at least 0.5 per cent
mation may be minimized by careful control of
by weight of the said mercapto compound.
water content, iron content, and pH. More
‘2'. A stable ointment for arsenic and cadmium
speci?cally, the ointments of highest heat stabil
ity must (1) contain less than about 0.5% water,
therapy containing, non-drying oils, 2, 3-di
mercaptopropanol, and an anti-oxidant for said
(2) contain less than 1 part per million, and
mercapto compound comprising mixed natural
preferably less than 0.5 part per million, of iron
tocopherols in an amount of from 0.5-,l0% of
and other heavy metals, and (3) have a pH
the weight of said mercapto compound.
within the range of 4-5, an equilibrium value 40
8. A stable ointment for arsenic and cadmium
obtained with a pH meter and glass electrode
therapy containing, non-drying oils, 2, 3-di
on a portion of the aqueous layer obtained by
mercaptopropanol, and an anti-oxidant for said
treating a sample of the ointment with suf?cient
mercapto compound comprising mixed natural
freshly boiled distilled Water to have a ratio or"
Water to dimercaptopropanol of 99 to 1. These
the weight of said mercapto compound.
factors are controlled by (1) use of only an
tocopherols in an amount of from 0.5—2.0% of
9. A stable ointment for arsenic and cadmium
hydrous ingredients, (2) use of ingredients to
gether containing less than the above-speci?ed
quantity of heavy metals, and formulating the
captopropanol, and
ointments in vessels WhiCh'dO not introduce any
more of these metals, and (3) the use of in
in an amount of at least 0.5 per cent by weight
gredients having a neutral or slightly acid re
action or by adding su?icient acid to the final
ointment to bring its pH Within the preferred
therapy containing, non-drying vegetable oils,
range.
In place of the speci?c oily vehicles disclosed
in the examples, other oily bases may be used
in these ointments. For example, other non
drying vegetable oils such as olive oil and castor
oil, non-drying animal oils, or other types of
non-drying oils such as mineral oils may be
used if desired.
The ointments of this invention are of great
value in neutralizing chemical warfare vesicants
containing arsenic, particularly the arsines, and
in arsenic and cadmium therapy in general. The
presence of the oil-soluble anti-oxidant renders
them sufficiently inert to oxidation to permit
their use under practical conditions Without ex
cessive loss in ef?cacy.
Having thus described my invention, what I
claim as new and wish to secure by Lettefs
Patent is:
l. A stable ointment comprising an oily vehicle,
2,3-dimercaptopropanol, and an oil-soluble anti
therapy containing, non-drying oils, 2, 3-dimer
anti-oxidant for said mer
capto compound consisting of gamma-tocopherol
of the said mercapto compound.
10. A stable ointment for arsenic and cadmium
2, B-dimercaptopropanol, and an anti-oxidant
for said mercapto compound comprising mixed
natural tocopherols in an amount of from 0.5
10% of the weight of said mercapto compound.
11. A stable ointment as set forth in claim 9
characterized in that it-has a pH range of from
4-5 and contains less than about 0.5% water and
less than 1 part per million of heavy metals.‘
12. A stable ointment for arsenic and cadmium
therapy containing, non-drying animal oils,
, 2, 3-dimercaptopropanol, and an anti-oxidant
for said mercapto compound comprising mixed
natural tocopherols in an amount of from 0.5
10% of the weight of said mercapto compound.
13. A stable ointment as set forth in claim 11
characterised in that it has a pH range of from
4—5 and contains less than about 05% water
and less than 1 ‘part per million of heavy metals.
14. A stable ointment for arsenic and cadmium
therapy containing, peanut oil, 2, 3-dimercapto
75 propanol, and an anti-oxdiant for said mercapto
2,688,895
“
5
compound comprising mixed natural tocopherols
in an amount of from 05-10% of the weight of
said mercapto compound.
15. A stable ointment for arsenic and cadmium
therapy containing, anhydrous lanolin, 2, 3-di
mercaptopropanol, and an anti-oxidant for said
mercapto compound comprising mixed natural
6
17. A stable ointment for arsenic and cadmium
therapy comprising in parts by Weight:
Lanolin, anhydrous ____________________ .._ 80.0
Benzyl benzoate _______________________ __ 10.0
Mixed natural tocopherols, 40% _________ __ 0.1
2, 3-dimercaptopropanol ________________ .._ 10.0
tocopherols in an amount of from 05-10% of the
GEORGE W. RIGBY.
weight of said mercapto compound.
REFERENCES CITED
16. A stable ointment for arsenic and cadmium 10
therapy comprising in parts by weight:
Peanut 011 ____________________________ __ 36.95
Lanolin, anhydrous _______ __‘ __________ __
8.00
The following references are of record in the
?le of this patent:
UNITED STATES PATENTS
Cetyl alcohol _‘ ________________________ __ 10.00 15 Number
Glyceryl monostearate ________________ __ 10.00
2,267,224
White petrolatum, soft __________________ _. 25.00
2,317,353
Benzyl benzoate ______________________ __ 5.00
2,333,655
Mixed natural tocopherols _____________ __ 0.05
2,333,657
2, 3-dimercaptopropanol _______________ __ 5.00 20
2,361,624
2,363,722
_ Name
Date
Taylor et a1 _______ __ Dec. 23,
Baxter ___________ __ Apr. 27,
Mattill et a1 ________ __ Nov. 9,
Mattill et a1 ________ __ Nov. 9,
Hamilton et a1 _____ __ Oct. 31,
Faust et a1 ________ __ Nov. 28,
1941
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1944
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