CA1116082A - Pharmaceutical compositions and method of use - Google Patents
Pharmaceutical compositions and method of useInfo
- Publication number
- CA1116082A CA1116082A CA311,816A CA311816A CA1116082A CA 1116082 A CA1116082 A CA 1116082A CA 311816 A CA311816 A CA 311816A CA 1116082 A CA1116082 A CA 1116082A
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- Prior art keywords
- oxide
- pyridyl
- bis
- disulfide
- c5h4nos
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4933—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having sulfur as an exocyclic substituent, e.g. pyridinethione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/59—Mixtures
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Birds (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
A B S T R A C T
The present invention relates to a novel synergistic composition for the treatment of inflammation in warm blooded animals which comprises an effective amount of bis-(2-pyridyl-1-oxide) disulfide and/or at least one adduct of bis-12-pyridyl-1-oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents a member selected from the group con-sisting of zinc, iron, magnesium, tin, cadmium, zirconium, alkali and alkaline earth metals; Y is the anion of an inor-ganic or organic acid and t is either 1 or 2 in admixture with a pharmaceutical carrier. Bis-(2-pyridyl-1-oxide) disulfide or its adducts have been further found to enhance the anti-inflammatory activity of corticosteroids and non-steroidal anti-inflammatory agents.
The present invention relates to a novel synergistic composition for the treatment of inflammation in warm blooded animals which comprises an effective amount of bis-(2-pyridyl-1-oxide) disulfide and/or at least one adduct of bis-12-pyridyl-1-oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents a member selected from the group con-sisting of zinc, iron, magnesium, tin, cadmium, zirconium, alkali and alkaline earth metals; Y is the anion of an inor-ganic or organic acid and t is either 1 or 2 in admixture with a pharmaceutical carrier. Bis-(2-pyridyl-1-oxide) disulfide or its adducts have been further found to enhance the anti-inflammatory activity of corticosteroids and non-steroidal anti-inflammatory agents.
Description
.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 ~:
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 ,;
: , , 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-
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 ~:
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 ,;
: , , 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. -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.
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.
.~. .
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.
~x~
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.
A tincture is prepared as Follows:
Bis-(2-pyrjdyl-1-oxide) disul~ide barlum acetate1%
Ethanol 20%
Propylene glycol 10%
Water ~ 69%
Bis-(Z-pyridyl-l-oxide) disulfide magnesium chloride 1%
Vitamin E 2%
Propylene glycol 20%
Ethanol 20%
Water 57%
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.
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.
.
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.
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 " ~
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).
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. -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.
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.
.~. .
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.
~x~
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.
A tincture is prepared as Follows:
Bis-(2-pyrjdyl-1-oxide) disul~ide barlum acetate1%
Ethanol 20%
Propylene glycol 10%
Water ~ 69%
Bis-(Z-pyridyl-l-oxide) disulfide magnesium chloride 1%
Vitamin E 2%
Propylene glycol 20%
Ethanol 20%
Water 57%
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.
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.
.
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.
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 " ~
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).
Claims (13)
1. A topical composition for treating inflammation in warm blooded animals characterized by an effective amount of bis-(2-pyridyl-1-oxide) disulfide or the adducts of bis-(2-pyridyl-1 oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a suitable pharmaceutical carrier.
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a suitable pharmaceutical carrier.
2. The composition of Claim 1, characterized by the fact that M is magnesium, Y is sulfate and t is 1.
3. The composition of Claim 1, characterized by the fact that M is calcium, Y is chloride and t is 2.
4. The composition of Claim 1, characterized by the fact that M is calcium, magnesium or barium.
5. The composition of Claim 1, characterized by the fact that the formula is (C5H4NOS)2CaC12, (C5H4NOS)2MgSO
(C5H4NOS)2 SrC12, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca (NO3)2 or (C5H4NOS)2 Ba(C103)2.
(C5H4NOS)2 SrC12, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca (NO3)2 or (C5H4NOS)2 Ba(C103)2.
6. The composition of Claim 1, characterized by the fact that said adducts are water-soluble.
7. The composition of Claim 1, characterized by the fact that Y is selected from the group consisting of halides, sulfates, nitrates and acetates.
8. A topical composition for treating inflammation in warm blooded animals characterized by an effective amount of bis-(2-pyridyl-1-oxide) disulfide or the adducts of bis-(2-pyridyl-1-oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a non-steroidal anti-inflammatory agent.
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a non-steroidal anti-inflammatory agent.
9. The composition of Claim 8, characterized by the fact that the formula is (C5H4NOS)2CaC12, (C5H4NOS)2MgSO4, (C5H4NOS)2SrCl2, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca (NO3) or (C5H4NOS)2Ba(Cl03)2
10. The composition of Claims 8 or 9, characterized by the fact that said non-steroida] agent is l-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, d-2-(6-methoxy-2-naphthyl) propionic acid, l-methyl-5-(4-methylbenzoyl)-1 H-pyrrole-2-acetic acid, .alpha.-methyl-4-(2-methylpropyl) benzene-acetic acid, 4-(2-methylpropyl) benzeneacetic acid, .alpha.-methyl-3-phenoxybenzeneacetic acid, .alpha., 3-dichloro-4-cyclohexylphenyl-acetic acid and 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid.
11. A topical composition for treating inflammation in warm blooded animals characterized by an effective amount of bis-(2-pyridyl-1-oxide) disulfide or the adducts of bis-(2-pyridyl-l oxide)disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earch metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a corticosteroid having anti-inflammatory activity and a suitable pharmaceutical carrier.
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earch metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a corticosteroid having anti-inflammatory activity and a suitable pharmaceutical carrier.
12. The composition of Claim 11, characterized by the fact that the formula is (C5H4NOS)2CaC12, (C5H4NOS)2MgSO4, (C5H4NOS)2SrCl2, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca(NO3) or (C5H4NOS)2Ba(C103)2.
13. The composition of Claims 11 or 12, characterized by the fact that said corticosteroid is hydrocortisone, hydrocor-tisone acetate, hydrocortisone butyrate, hydrocortisone valerate, triamcinolone acetonide, fluocinolone acetonide, 16.alpha.-hydroxy-prednisolone-16.alpha.,17.alpha.-acetonide, fluorohydrocortisone or 1-dehydrocortisone.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83559477A | 1977-09-22 | 1977-09-22 | |
| US05/835,596 US4137311A (en) | 1977-09-22 | 1977-09-22 | Synergistic compositions and method of use |
| US835,596 | 1977-09-22 | ||
| US835,595 | 1977-09-22 | ||
| US05/835,595 US4152430A (en) | 1977-09-22 | 1977-09-22 | Synergistic compositions and method of use |
| US835,594 | 1986-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1116082A true CA1116082A (en) | 1982-01-12 |
Family
ID=27420252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA311,816A Expired CA1116082A (en) | 1977-09-22 | 1978-09-21 | Pharmaceutical compositions and method of use |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5455732A (en) |
| CA (1) | CA1116082A (en) |
| DE (1) | DE2840684A1 (en) |
| FR (1) | FR2403798A1 (en) |
| GB (1) | GB2004742B (en) |
| NL (1) | NL7809562A (en) |
| SE (1) | SE7809906L (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5636411A (en) * | 1979-08-31 | 1981-04-09 | Sumitomo Chem Co Ltd | Liquid agent for external use |
| JPS59137408A (en) * | 1983-01-27 | 1984-08-07 | Taisho Pharmaceut Co Ltd | Ointment |
| JPS59139315A (en) * | 1983-01-31 | 1984-08-10 | Taisho Pharmaceut Co Ltd | Cream agent |
| DE3508666A1 (en) * | 1985-03-12 | 1986-09-18 | Hoechst Ag, 6230 Frankfurt | HETEROCYCLIC DISULFIDES AND THEIR USE AS IMMUNO MODULATORS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE790244A (en) * | 1971-10-18 | 1973-04-18 | Olin Corp | BIS- (2-PYRIDYL-1-OXIDE) DISULPHIDE ADDITION PRODUCTS, THEIR PREPARATION AND USES |
| JPS5212207A (en) * | 1975-07-21 | 1977-01-29 | Kao Corp | Shampoo composition having ecxcellent effect for preventing dandruff |
-
1978
- 1978-09-18 FR FR7826729A patent/FR2403798A1/en active Granted
- 1978-09-19 DE DE19782840684 patent/DE2840684A1/en not_active Withdrawn
- 1978-09-20 SE SE7809906A patent/SE7809906L/en unknown
- 1978-09-20 NL NL7809562A patent/NL7809562A/en not_active Application Discontinuation
- 1978-09-21 CA CA311,816A patent/CA1116082A/en not_active Expired
- 1978-09-22 GB GB7837779A patent/GB2004742B/en not_active Expired
- 1978-09-22 JP JP11606878A patent/JPS5455732A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5455732A (en) | 1979-05-04 |
| GB2004742B (en) | 1982-07-07 |
| SE7809906L (en) | 1979-03-23 |
| GB2004742A (en) | 1979-04-11 |
| FR2403798B1 (en) | 1981-12-11 |
| FR2403798A1 (en) | 1979-04-20 |
| DE2840684A1 (en) | 1979-04-05 |
| NL7809562A (en) | 1979-03-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |