Note: Descriptions are shown in the official language in which they were submitted.
.2
The present invent~on relates to the novel compo-
sition for the treatment of inflammation in mammals which
comprises bis-(2-pyridyl-1-oxide) disulfide alone or in combi-
nation with non-steroidal anti-inflammatory agents or cortico-
steroids in admixture with a pharmaceutical carrier.
Bis-(2-pyridyl-n-oxide) disulfide and its adducts
have been found to be effective for the relieF and inhibition
of inflammatory conditions through their topical adminis-
tration.
It has been further found that even more pronounced
pharmacological properties for the relief and inhibition of
inflammation conditions can be provided by providing a topical
combination of a non-steroidal anti-inflammatory agent or a
corticosteroid and a bis-(2-pyridyl-n-oxide) disulfide com-
pound, that is, bis-(2-pyridyl-1-oxide) disulfide and/or the
adducts of bis-(2-pyridyl-1-oxide) disulfide according to this
invention. More specifically, these adducts have the formula:
(C5H4NOs)2MYt (I)
wherein M represents a member selected from the group consist-
ing of zinc, iron, magnesium, tin, cadmium, zirconium, alkali
and alkaline earth metals; Y is the anion of an inorganic. or
organic acid and t is either 1 or 2. More particularly, the
anion Y is selected from the group consisting of halides, sul-
fates, nitrates, chlorates and acetates~ with the chlorides and
sulfates being most preferable. More particularly preferred
are the water-soluble adducts, especially calcium chloride
(CaC12) or magnesium sulfate (MgS04). Also included in the
adducts of this invention are the hydrates of the afore-
mentioned compounds, i.e., adducts including nH20 groups where
n is an integer of 0 to 10. Additionally, the adducts (I) may
contain one or more substituents on either or both pyridine
- 1 -
~:
8.~
ring structures such as alkyls, halogens and alkoxy groups.
It is further noted that (C5H4NOS)2 as used in (I) above and
throughout the specification and claims represents bis-(2-
pyridyl-l-oxide) disulFide and the structural formula (I).
Among the adducts which may be utilized in combi-
nation with the non-steroidal anti-inflammatory ayents or
corticosteroids in this invention may be mentioned:
Bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate,
bis-(2-pyridyl-1-oxide) disulfide magnesium acetate, bis-(2-
pyridyl-l-oxide) disulfide magnesium chloride, bis-(2-pyridyl-
l-oxide) disulfide magnesium bromide, bis-(2-pyridyl-1-oxide)
disulfide calcium chloride, bis-(2-pyridyl-1-oxide) disulfide
calcium sulfate, bis-(2-pyridyl-1-oxide) disulfide calcium
nitrate, bis-(2-pyridyl-1-oxide) disulfide calcium acetate,
bis-(2-pyridyl-1-oxide) disulfide calcium chlorate, bis-(2-
pyridyl-1-oxide) disulfide barium chloride, bis-(2-pyridyl-1-
oxide) disulfide barium sulfate, bis-(2-pyridyl-1-oxide)
disulfide barium nitrate, bis-(2-pyridyl-1-oxide) disulfide
barium acetate, bis-(2-pyridyl-1-oxide) disulfide barium
chlorate, bis-(2-pyridyl-1-oxide) disulfide strontiu~ chloride,
bis-(2-pyridyl-1-oxide) disulFide strontium sulfate, bis-(2-
pyridyl-l-oxide) disulfide strontium nitrate, bis-(2-pyridyl-1-
oxide) disulfide strontium acetate, bis-(2-pyridyl-1-oxide)
disulfide strontium chlorate, bis-(2-pyridyl-1-oxide) disulfide
potassium chloricle, bis-(2-pyridyl-1-oxide) disulfide potassium
sulfate, bis-(2-pyridyl-1-oxide) disulfide potassium nitrate,
bis-(2-pyridyl-1-oxide) disulfide potassium acetate, bis-(2-
pyridyl-l-oxide) disulfide potassium chlorate, bis-(2-pyridyl-
l-oxide) disulfide sodium chloride, bis-(2-pyridyl-1-oxide)
disulfide sodium sulfate, bis-(2-pyridyl-1-oxide) disulfide
sodium nitrate, bis-(2-pyridyl-1-oxide) disulfide sodium
-- 2
,;
: , ,
acetate, bis-(2-pyridyl-l-oxide) disulfide sodium chlorate,
bis-(2-pyridyl-1-oxide) disulfide zinc chloride, bis-(2-
pyridyl-l-oxide) disulfide zinc sulfate, bis-(2-pyridyl-1-
oxide) disulfide zinc nitrate, bis-(2-pyridyl-1-oxide)
disulfide zinc acetate, bis-(2-pyridyl-1-oxide) disulfide zinc
chlorate, bis-(2-pyridyl-1-oxide) disulfide stannous chloride,
bis-(2 pyridyl-l-oxide) disulfide stannous sulfate, bis-(2-
pyridyl-l-oxide) disulfide stannous nitrate, bis-(2-pyridyl-1-
oxide) disulfide stannous acetate, bis-(2-pyridyl-l~oxide)
disulfide stannous chlorate, bis-(2-pyridyl-1-oxide) disulfide
zirconium chloride, bis-(2-pyridyl-1-oxide) disulfide zirconium
sulfate, bis-(2-pyridyl-1-oxide) disulfide zirconium nitrate,
bis-(2-pyridyl-1-oxide) disulfide zirconium acetate, bis-(2-
pyridyl-l-oxide) disulfide zirconium chlorate, bis-(2-pyridyl-
1-oxide) disulfide ferrous chloride, bis-(2-pyridyl-1-oxide)
disulfide ferrous sulfate, bis-(2-pyridy1-1-oxide) disulfide
ferrous nitrate, bis-(2-pyridyl-1-oxide) disulfide ferrous
acetate, bis-(2-pyridyl-1-oxide) disulfide ferrous chlorate,
bis-(2-pyridyl-1-oxide) disulfide lithium sulfate, bis-(2-
pyridyl-l-oxide) disulfide lithium nitrate, bis-(2-pyridyl-1-
oxide) disulfide lithium acetate, and bis-(2-pyridyl-1-oxide)
disulfide lithium chlorate.
Any one of the known effective anti-inFlammatory
corticosteroids may be utilized in this invention. Among the
suitable corticosteroids include hydrocortisone, hydrocortisone
acetate, hydrocortisone butyrate, hydrocortisone valerate,
triamcinolone acetonide, fluocinolone acetonide, 16~-hydroxy-
prednisolone-16~,17~-acetonide, fluorohydrocortisone, 1-
dehydrocortisone, and the like. Preferably, the hydrocortisone
compounds are used in connection with the active adducts I.
A number of known effective anti-inflammatory non-
: . .'
,
.
steroidal agents may be utilized in this invention. Among thesuitable non-steroidal agents may be mentioned l-(p-chloro-
ben~oyl)-5-methoxy-2-methylindole-3-acetic acid d-2-(6-methoxy-
2-naphthyl) propionic acid, 1-methyl-5-(4-methylbenzoyl)-1
H-pyrrole-2-acetic acid, ~-methyl-4-(2-methylpropyl) benzene-
acetic acid, 4-(2-methylpropyl) benzeneacetic acid, ~-methyl-3-
phenoxybenzeneacetic acid, ~,3-dichloro-4-cyclohexylphenyl-
acetic acid, 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic
acid, and the like.
It has been surprisingly found that the anti-
inflammatory activity of corticosteroids or non-steroidal anti-
inflammatory agents are enhanced when combined with bis-(2-
pyridyl-l-oxide) disulfide and/or its adducts.
Additionally, the effective compositions utilized in
the present invention have been shown to have the property of
remaining on the skin and retaining anti-inflammatory activity
over a period of time after washing and rinsing uf the skin.
More specifically the compositions of the present
invention for the anti-inflammatory treatment including skin
conditions such as contact dermatitis, seborrheic dermatitis,
atopic dermatitis, neurodermatitis and the like, as well as
other mammalian conditions where the symptoms of inflammation
and associated pain and fever manifest, such as rheumatic
diseases including arthritis, tendinitis, erythema, sciatic
pain and similar associated veterinary conditions, comprise
from 0.1 to 5% by weight of at least one active compound,
preferably from 0.2 to 1.5% by weight. These compositions can
be in the Form of a solution, a cream, powder, gel, ointment, ~
salve, lotion, or milk. For the treatment of skin conditions `
the active compounds can also constitute make-up products or
dermatological cakes containing the ingredients standard to
this type of composition.
When associated with corticosteroids are utilized the
compositions comprise an amount of 0.01-2.5% by weight of bis-
(2-pyridyl-1-oxide) disulfide compound, preferably 0.1-1% by
weight of bis-(2-pyridyl-1-oxide) disulfide compound present.
These compositions can be in the form of a solution, a cream,
powder, gel, ointment, salve, lotion, or milk. For the
treatment of skin conditions they can also constitute make-up
products or dermatological cakes containing the ingredients
standard to this type of composition.
When associated with non-steroidal anti-in~lammatory
agents the compositions comprise bis-(2-pyridyl-1-oxide)
disulfide or one of its adducts I in an amount of from about
0.05-10% by weight of the composition, preferably from about
0.25-5.0% by weight. The non-steroidal agents are utilized in
the composition in an amount of 1-40% by weight of bis-(2-
pyridyl-l oxide) disulfide compound in the composition, prefer-
ably 5-25% by weight of the compound present. These compo-
sitions can be in the form of a solution, a cream, powder, gel,
ointment, salve, lotion, or milk. For the treatment of skin
conditions, they can also constitute make-up products or
dermatological cakes containing the ingredients standard to
this type of composition.
The following examples will further illustrate the
formulations containing the bis-(2-pyridyl-1-oxide) disulfide
compound and/or its adducts of Formula I but are not to be
considered as limiting the scope of this invention. -
EXAMPLE 1
A cream was prepared as follows:
Bis-(2-pyridyl-1-oxide)
disulfide calcium chloride2 9.
Hydrocortisone 0.05 g.
Titanium oxide 10 g
Red iron oxide 0.3 g.
Yellow iron oxide 0.2 g.
Brown iron oxide 0.4 g.
Chestnut iron oxide 0.2 g.
Several stearyl alcohols oxyethylenated with 33 mols
of ethylene oxide 7 9.
Polyglycol stearate 6 g.
Propyl parahydroxybenzoate0.2 g.
Water, 4.S.P. 100 g.
EXAMPLE 2
Testing of the synergistic effect of the combination
of hydrocortisone and the adducts of Formula I, using as a
representative compound bis-(2-pyridyl-1-oxide) disulfide ~ ;
magnesium sulfate was performed utilizing a modiFication of the
experimental technique described by Tonelli, G., Thibault, L.
and Ringler, L., A Bioassay for the Concomitant Assessment of
the Anti-phlogistic and Thymolytic Activities of Topically
Applied Corticoids. Endocrinology 77, 625 (1965) and
Roszkowski, A.P., Rooks, W.H. II, Tomolonis, A.J. and Miller,
L.M., Anti-inflammatory and Analgetic Properties of d-2-(6'-
Methoxy-2'-Naphthyl~ Propionic Acid (Naproxen). J. Pharm. Exp.
Ther. 179, 11~ (l971). Mathematical determination of the
synergistic effects of combinations of bis-(2-pyridyl-1-oxide)
disulfide magnesium sulfate and hydrocortisone was done using a
modification of the method described by Van Arman, C.G., Nuss,
.. . . .
:. ' . ; : "
.. . ~,
~ 6 ~
G.W. and Risley. E.A., Interactions of Aspirin, Indomethacin
and Other Drugs In Adjuvant-induced Arthritis in the Rat
(appendix). J. Pharmacol, Exp. Therap. 187, 400, (1973).
Hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide
magnesium sulfate were suspended or dissolved in ethanol U.S.P.
(200 proof) at concentrations of 20, 40 and 80 mg/ml oF b1s-
(2-pyridyl-1-oxide) disulfide magnesium sulfate and 0.01, 1 and
10 mg of hydrocortisone. In experiments where the interaction
of hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide mag-
nesium sulfate were to be determined, equipotent doses of eachagent were simultaneously co-applied after admixture in the
alcohol vehicle. Bis-(2-pyridyl-1-oxide)disulfide magnesium
sulfate formed a fine suspension, while hydrocortisone was
completely soluble in the alcohol.
Therapeutic effects of bis-(2-pyridyl-1-oxide)
disulfide magnesium sulfate at topical doses of 2, 4 and 8
mg/ear (0.01 ml) of hydrocortisone at doses of 0.01, 0.1 and
1 mg/ear (0.1 ml) were measured after application to the left
ear of mice, 1 hour after inflammation was induced by the
topical application of an irritant solution containing 2%
croton oil (Amend Drug and Chemical Co., Irvington, N.J. Lot
710034), 73% diethyl ether, U.S.P. (Corco Chemical Corp.,
Fairless Hills, PA), 20% pyridine (J.T. Baker Chemical Co.,
Phillipsburg, PA, Lot 3348) and 5% distilled water. Groups of
mice treated with only the croton-oil irritant solution served
as controls. The right ear of mice in any group was not
treated.
Four hours after application of the irritant vehicle
(three hours after drug application) both ears were amputated
and one circular section was excised from each ear using a
No. 4 cork borer (7 mm i.d.). The ear sections were then
weighed. The increase in weight due to edema formation caused
by the croton-oil in the treated ear and reduction of the edema
caused by treatment with bis-(2-pyridyl-1-oxide) disulfide
magnesium sulfate hydrocortisone or combinations thereof was
determined by subtracting the weight of the untreated right ear
section from that of the treated left ear section.
The anti-inflammatory eflects of either bis-(2-
pyridyl-l-oxide) disulfide magnesium sulfate or hydrocortisone
or of co-applied equipotent dose pair combinations of the two
agents expressed as percent inhibition were calculated by:
Edema weight (controls) - Edema wei ~ (treated) X 100
Edema weight controls
The immediate anti-inflammatory effects of bis-(2-
pyridyl-l-oxide) disulfide magnesium sulfate were measured by
direct application to the ear of the drug suspended in a 2%
solution of croton-oil in 95% ethanol. Ethanol was used as the
vehicle; pyridine contained in the usual irritant vehicle as
described previously produces an alkaline reaction. Controls
were treated with only the croton-oil vehicle.
TABLE I
THE INTERACTION OF BTS-(2-PYRIDYL-l-OXIDE)
DISULFIDE MAGNESIUM SULFATE WITH HYDROCORTISONE
AFTER IMMEDIATE CO-ADMINISTRATION TO CROTON-OIL
INDUCED INFLAMMATION TO THE MOUSE'S EAR
-
Ear Percent
Treatmenta Topica1 Dose Edema Weight Inhibition
mg/ear mg ~ S.D.b oF Ear
Control - 16.9 -~ 3.0 -
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 4 12.7 ~ 3.0 24.9
sulfate
Hydrocortisone 0.01 13.0 + 3.8 23.1
0.1 7.9 + 2.3 53.3
1.0 5.5 + 2.6 67.5
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 4 14.3 + 2.2 15.4
sulfate
20 Hydrocortisone 0.01
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 4 10.2 + 2.6 39.6
sulfate
Hydrocortisone 0.1
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 4 8.4 + 2.1 50.3
sulfate
Hydrocortisone 1.0
a 2% Croton-oil in 95% ethanol as irritant, bis-(2-pyridyl-1-
oxide) disulfide magnesium sul-Fate alone or bis-(2-pyridyl-
l-oxide) disulfide magnesium sulfate and hydrocortisone
suspended in the same vehicle.
b Standard Deviation.
- .
,. .
.. . ,,
:. . . ~ ~ :
&~
The potential synergistic effects induced by topical
co-application of doses of hydrocortisone and bis-(2-pyridyl-1-
oxide) disulfide magnesium sulfate were investigated by both
immediate application (Table I) and by delayed application to
an existing inflammation (Table II).
A. _ynergism after Immediate Application
A fixed dose of 4 mg/ear of bis-(2-pyridyl-1-oxide)
disulfide magnesium sulfate was co-applied with 0.01, 0.1 and
1 mg/ear of hydrocortisone. Such co-application at the time of
induction of the inf`lammatory process (Table I) resulted in
effects that were less than those which would be expected from
simple addition, i.e., there was evidence that some antagonism
of therapeutic effects occurred under these conditions. At the
dose of 0.01 mg/ear, hydrocortisone produced 53.3% inhibition.
When that same dose of hydrocortisone was co-applied with 4 mg/
ear of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate
(24.9% inhibition by itself), a response of only 39.6% was
obtained; a response of 58.5% inhibition was expected. This
reduction in response obtained after co-application of combi-
nations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate
and hydrocortisone was evident at all dose levels.
B. Synergism after Delayed Application
When equipotent dose-pair combinations of bis-(2-
pyridyl-l-oxide) disulfide magnesium sulfate and hydrocortisone
were co-applied to an existing inflammation in the mouse's ear,
the results in Table II were obtained. The observed responses
at each dose level of the combinations were compared with the
expected responses calculated on the basis of simple addition.
The type of interaction between bis-(2-pyridyl-1-oxide)
disulfide magnesium sulfate and hydrocortisone was dose-
dependent and varied from potentiation to simple addition.
-- 1 0
.~. .
Doses of bis-(2-pyridyl-1-oxide) disulfide magnesium
sulfate (0.87 mg/ear) and hydrocortisone (0.00125 mg/ear) each
by themselves would be expected, by extrapolation of their
respective dose-response lines, to produce little, if any,
significant anti-inflammatory response. When the expected
response that would result in simple addition was calculated
from that dose-pair combination, a value of 10.6% inhibition
was obtained; the observed response was 46.3%. In order to
achieve a similar response from either hydrocortisone or bis-
(2-pyridyl-1-oxide) disulfide magnesium sulfate by themselves,
it would have been necessary to apply 0.25 mg/ear or 17.7 mg/
ear, respectively.
Similar potentiation was observed with combinations
of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1/5 mg/
ear and hydrocortisone 0.004 mg/ear, or bis-(2-pyridyl-1-oxide)
disulfide magnesium sulfate 1.9 mg/ear and hydrocortisone 0.005
mg/ear. Higher doses of bis-(2-pyridyl-1-oxide) disulfide
magnesium sulfate in combination with equipotent doses of
hydrocortisone resulted in simple addition.
..
,;
TABLE II
T~IE INTERACTION OE BIS-(2-PYRIDYL-l-OXIDE)
DISULFIDE ~AGNESIUM SULFATE WITH HYDROCORTISONE
AFTER DELAYED CO-APPLICATION TO CROTON-OIL
INDUCED INFLAMMATION TO THE MOUSE'S EAR
Ear Percent
Treatmenta Topical Dose Edema Weight Inhibition
mg/earmg -~ S.D.b oF Ear
Control - 14.9 L 3.8
Bis-(2-pyridyl-1-oxide)
disulFide magnesium 2 12.7 -~ 2.4 14.8
sulfate
4 11.4 ~ 2.8 23.5
8 9.6 ~ 2.2 35.6
Hydrocortisone 0.01 12.3 -~ 3.3 17.5
(free alcohol)
0.1 8.9 -~ 2.3 40.3
1.0 6.2 ~ 2.4 58.4
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 0.87 7.9 ~ 2.5 47.3
sulfate
Hydrocortisone 0.00125
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 1.5 9.2 ~ 2.7 38.1
sulfate
Hydrocortisone 0.004
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 1.9 9.5 ~ 2.4 36.4
sulfate
Hydrocortisone 0.005
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 3.7 9.87 ~2.7 34.0
sulfate
Hydrocortisone 0.02
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 7.0 8.7 ~ 2.4 41.6
sulfate
Hydrocortisone 0.08
a Drug suspended or dissolved in 95% ethanol and applied 1 hour
after 2% croton-oil.
b Standard Deviation.
- 12 -
~x~
EXAMPLE 3
A dermatological cleansing cake is prepared by mixingtogether the following components:
Esters o-f sodium isothionate and coprafatty acids
(sold under the name "IG~PON A"(Trademark)having the :Eormula
R-COO-CH2~ H2-SO Na, wherein R equals fatty acid derivatives
having 12-15 carbon atoms) 75 g
Lanolin derivatives 22.75 g
(CsH~Nos)2 MgC12 2 g
Hydrocortisone
acetate 0.02 g
Other dermatologicalclean3ing cakes, identical to
the above, are prepared by replacing the magnesium chloride
salt of bis-(2-pyridyl-1-oxide) disulfide with any one of the
aforementioned active compounds. Also, any one of the cortico-
steroids mentioned may be utilized.
EX~PLE ~
A powder comprising the following mixtures:
Talc 86.85 g
Glycerine oleate 3 g
Isopropyl myristate 7 g
Bis-(2-pyridyl-1-oxide)
disulfide magnesium
sulfate 1 g
l-methyl-5-(4-methyl-
benzoyl)-l H-pyrrole-2-
acetic acid 1 g
Perfume 2 cc ('_,approx. 1.9 g)
~ ther equally~effective powder compositio~ns identical
to the above are prepared except that the active ingredient
component bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate
is replaced by any of the other aforementioned active compounds.
EXAMPLE 5
A tincture is prepared as Follows:
Bis-(2-pyrjdyl-1-oxide)
disul~ide barlum acetate1%
Ethanol 20%
Propylene glycol 10%
Water ~ 69%
EXAMPLE 6
Bis-(Z-pyridyl-l-oxide)
disulfide magnesium chloride 1%
Vitamin E 2%
Propylene glycol 20%
Ethanol 20%
Water 57%
EXAMPLE 7
The following ointment base was utilized as a vehicle
for the active ingredients of this invention:
Ingredient Amount in grams
Polyoxyethylene stearyl
ether 5.0
White petrolatum 5.0
Stearyl alcohol 15.0
Distilled water 63.5
The ointment containing the above active ingredients
were manufactured in the following manner. 3.0 grams bis-(2-
pyridyl-l-oxide) disulfide magnesium sulfate were dissolved in
a heated mixture of 59 ml of distilled water and 11.50 9 of
propylene glycol. This solution was heated to a temperature of ~ ~
75C and added to a mixture having a like temperature consist- ~:
ing of 15.0 g of stearyl alcohol, 5.0 9 of white petrolatum,
1.0 ml of concentrated ammonia solution and 5.0 9 of polyoxy-
ethylene stearyl ether, molecular weight about 700. While the
- ... , .~ : .
~. . , ~. .. .
..6~82
resulting mixture was still hot, lactic acid was added to
adjust the pH thereof to about 5.5 to approximate the pH oF
skin. The resulting mixture was thereafter cooled to form a
cream which was further worked utilizing a three-roller frame
and filled into tubes.
In an analogous manner, o;ntments were prepared
ukilizing the following ingredients to form the initial
solutions:
a. 2.27 grams bis-(2-pyridyl-1-oxide) disulFide
ferrous chloride in 53.23 ml of distilled water and 11.5 g of
propylene glycol;
b. 2.51 grams of bis-(2-pyridyl-1-oxide) disulfide
lithium acetate in 56.19 ml of distilled water and 11.5 g of
propylene glycol;
c. 2.62 grams of bis-(2-pyridyl-1-oxide) disulfide
zirconium chloride in 56.35 ml of distilled water and 11.5 g of
propylene glycol,
d. 1.0 gram of bis-(2-pyridyl-1-oxide) disulfide
strontium chloride in 60.7 ml of distilled water and 11.5 g
propylene glycol and 0.80 sodium hydroxide. In this example
the solution was heated to 75C and added to a mixture having a
like temperature and containing 1.0 gram of bis-(2-pyridyl-1-
oxide) disulfide magnesium sulfate, 13.0 grams of stearyl
alcohol, 5.0 grams of polyoxyethylene stearyl ether, molecular
weight about 700 and 5.0 grams of white petrolatum, the pH
adjusted with lactic acid and the mixture cooled to form a
cream which was worked up as above.
EXAMPLE 8
2.5 g of bis-(2-pyridyl-1-oxide) disulfide magnesium
sulfate and 0.05 9 hydrocortisone are predispersed in 30.0 g of
propylene glycol. The mixture is then homogenized into 97.
- 15
.
grams of finished crearn, ointment or lotion following a modifi-
cation of any one of the procedures of Examples 2, 6 and 7 or
as described in F.W. Martin et al, "Remlngton's Pharmaceutical
Sciences", 14th Ed., Mack Publishing Co., Easton, Pa., 1965.
Other agents which have medic~nal or therapeutic
value may be incorporated in the compositions of this
invention.
EXAMPLE 9
An anti-inflammatory composition in milk form having
the following composition:
ngredient Weight in grams
l~ydrogenated, ethoxylated
(10 mol) lanolin 1.8
Triglyceride of fatty acid
of coconut 7.0
Cetylalcohol 0.6
Stearylalcohol 0.6
Paraffin oil (lightweight) 5.0
Hydrocortisone 0.05
Stearic acid 3.0
Bis-(2-pyridyl-1-oxide)
disulfide magnesium 2.0
sulfate
Demineralized water72.2
Triethanolamine 0.8
Perfume 0.5
Carboxyvinylpolymer 2.0
Conservation agent 2.0
was manufactured as follows:
A mixture of 1.8 9 hydrogenated, ethoxylated (10 mol)
lanolin, 7.0 9 triglyceride of fatty acid of coconut, 0.6 g
cetylalcohol, 0.6 9 stearyl alcohol, 5.0 g paraffin oil, 0.05 9
hydrocortisone and 3.0 9 of stearic was blended at 70C. After
- 16 -
" ~
addition of 2.0 g bis-(2-pyridyl-l-oxide) disulfide magnesium
sulfate, 2.0 g carboxyvinylpolymer in 72.2 9 demineralized
water were added at 70C with stirring to the resulting
suspension. The mixture was stirred for 15 minutes and then
cooled. 0.8 g of triethanolamine and 0.5 g of perfume were
added at 60C and 45C respectively. The resulting mixture was
stirred until cold and a white milk, which was stable at 3,000
Rpm for l hour was obtained. Viscosity: 6,000 Cp (Brockfield,
Spindel, 5, 10 Rpm).
