GB2089659A - Compositions containing silver salts - Google Patents

Compositions containing silver salts Download PDF

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Publication number
GB2089659A
GB2089659A GB8138117A GB8138117A GB2089659A GB 2089659 A GB2089659 A GB 2089659A GB 8138117 A GB8138117 A GB 8138117A GB 8138117 A GB8138117 A GB 8138117A GB 2089659 A GB2089659 A GB 2089659A
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Prior art keywords
silver
acid
pharmaceutical composition
salt
mole
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GB8138117A
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GB2089659B (en
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University of Strathclyde
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University of Strathclyde
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/12—Saturated polycyclic compounds
    • C07C61/125—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system
    • C07C61/135—Saturated polycyclic compounds having a carboxyl group bound to a condensed ring system having three rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition comprises a water-insoluble silver salt of a physiologically benign organic acid in admixture with a pharmacologically acceptable vehicle or carrier. Particularly useful salts disilver pamoate, silver-2-furoate, silver-3-hydroxy-2-naphthoate, silver orotate, silver adamantoate and silver-o-benzoylbenzoate. The composition may be applied topically to burn wounds for the eradication and prevention of Pseudomonas aeruginosa infections therein.

Description

SPECIFICATION Silver-containing pharmaceutics This invention relates to pharmaceutical compositions containing silver compounds.
Silver compounds have been widely used for their astringent and antiseptic properties. The silver ion in higher concentrations has a protein precipitant action and hence exerts its biological action. In lower concentrations where protein precipitation is not obvious, they presumably act by interference with essential metabolic activities of bacteria to produce a bacteriostatic effect.
Inorganic silver salts are highly germicidal e.g.
silver nitrate destroys most organisms at concentrations of 1:1000. Silver proteinate compounds act bacteriocidally at higher concentrations (10%) and are bacteriostatic in concentrations as low as 1:20,000.
The silver salt of sulphadiazine is widely used topically for the eradication and prevention of Pseudomonas aeruginosa infections in burns, see for example, U.S. Patent No. 3761590. In formulation this compound has the advantages of being painless on application, requiring a single daily application and not producing electrolyte disturbances (seen with mafenide). Sensitivity reactions and accumulation with renal and hepatic disease although of low incidence must be taken into consideration in clinical practice.
It has recently been put forward that the sulphonamide component of the silver sulphadiazine salt exerts little or no antimicrobial action (unpublished work). The use of an alternative anionic base of negligible sensitising ability and showing an absence of accumulation in disease could present advantages over the currently used silver sulphadiazine salt.
According to the present invention there is provided a pharmaceutical composition comprising in admixture with a pharmacologically acceptable vehicle or carrier a water-insoluble silver salt of a physiologically benign organic acid.
The expression "physiologically benign" as used herein means having no harmful effect. Thus the expression includes materials which are inert to the human or animal body and also materials which have beneficial effects thereon.
The phrase "water-insoluble" means of very low solubility and is thus to be construed in its normal technical rather than literal meaning. The very low solubility of the silver salt provides a means for slow-release of silver ions.
The carrier or vehicle may be an inert powder or an ointment base which may or may not contain other additives conventional in the application envisaged.
The composition of the invention is particularly suitable for the treatment of burn wounds.
The following Examples illustrate compounds useful in their invention and describe how they may be prepared.
Example 1 Disilverpamoate (embonate) The parent compound of the disilver salt is disodium pamoate.
M.W. 450.3548 4,4'-methylenebis(3hydroxy-2-naphthoate) disodium salt The sodium salt exhibits a reasonable degree of aqueous solubility. Both the acid form and the potassium salt show poor aqueous solubility and low solubility in most organic solvents.
A multiplicity of therapeutically active pamoate salts have been prepared. There are several examples from this list currently on the market. The success of the pamoate ion can be attributed to: its apparent low toxicity; the lack of evidence of any therapeutic effect; its ready and rapid ability to form salts of low solubility with many cationic species.
Method of manufacture 0.01 mole (4.50359) of disodium pamoate was dissolved in approximately 70ml of freshly distilled water. To this were added, with stirring, 20ml of 1 mole silver nitrate solution (0.02 mole). The precipitate which formed was immediately filtered off and thoroughly washed with chilled, freshly distilled water. The product was dried at room temperature in a vacuum oven over phosphorus pentoxide.
Micro-organic analysis Theoretical Experiment C 45.88 C 46.52 H 2.34 H 2.10 % yield 47.3. Melting point 229 - 233"C (with decomposition).
The preparation was carried out under light restricted circumstances to prevent oxidation (which occurs with all silver salts).
Example 2 Silver-2-furoate The precursor for this compound was the acid parent compound.
My. 112.08 2-furoic acid 2-furan carboxylic acid (pyromucic acid) Solubility: 1:26 water, soluble in ethanol and ether. Several 5-substituted -2-furan compounds are clinically useful e.g. nitrofurantoin, nitrofurazone, furazolidone, nifuroxime.
Little information is available in the literature on the clinical use or toxicity of 2-furoate salts or the parent acid. In India furoic acid has been investigated as a preservative. The acid and its ethyl, propyl and butyl esters were shown to be effective against Pseudomonas aeruginosa in concentrations of 0.22, 0.20, 0.12 and 0.13%. They are considered non-toxic to rabbits.
Furoic acid has been demonstrated to have a hypocalcaemic action by antagonising parathyroid hormone. Oral administration produced a much lower response than parenteral routes. Topical administration was not investigated.
Method of manufacture 0.01 mole (1.12089) of 2-furoic acid was dissolved in 30 ml of freshly distilled water (pH = 1.0). Sufficient quantities of 4N sodium hydroxide were added until a pH of 6.0 was attained. (Precipitation occurred at higher pH). To this solution 1 Oml of 1 mole silver nitrate solution (0.01 mole) were added with stirring.
The resulting precipitate was immediately filtered off and washed thoroughly with chilled freshly distilled water. The mushroom coloured product was then dried in a vacuum oven at room temperature over phosphorus pentoxide.
Micro-organic analysis Theoretical Experiment C 27.43 C 27.84 H 1.38 H 1.53 % yield 82.0. Melting point 296"C (with decomposition).
Example 3 Silver-3-hydroxy-2-naphthoate This compound was prepared from the parent acid3 - hydroxy - 2 - naphthoic acid.
M.W. 188.17 Solubility: almost insoluble in cold water, freely soluble in alcohol, benzene, ether and alkali.
The sodium salt has been used to solubilise ribof lavin for the poultry industry.
There is little literature information available on this compound. The 3-hydroxy derivative appears to be less toxic than the 1-hydroxy derivative. It has shown some anthelmintic properties. Changes in stomach mucosa have been shown with repeated oral administration but these are believed to be reversible.
Method of manufacture 0.01 mole (1.8817g) of 3 - hydroxy - 2 - naphthoic acid was suspended in 50ml of freshly distilled water. The suspension was neutralised with 4N sodium hydroxide to pH 8.0. The solution was fil tered and then 10ml of 1 mole silver nitrate were added with stirring. The buff coloured precipitate was immediately filtered off and washed thoroughly with chilled freshly distilled water. The precipitate was dried in a vacuum oven at room temperature over phosphorus pentoxide.
Micro-organic analysis Theoretical Experimental C 44.78 C 41.90 H 2.39 H 1.93 % yield 94. Melting point 270"C.
Example 4 Silver orotate This compound is derived from orotic acid.
M.W. 156.10 (1 ,2.3,6-tetrah yd ro-2,6-di oxo4- pyrimidine carboxylic acid.
Orotic acid is a pyrimidine precursor found in animals. It occurs in milk and is classified as a vitamin. It has been reported to be linked to fatty liver, a precancerous condition. Therapeutically it is classed as a uricosuric agent.
It normally occurs as the monohydrate which is soluble to the extent of 1.7g/nl in water.
Its use as a solubilising agent for insoluble quaternary drugs e.g. nicotinamide and nicotinic acid has been reported.
Method ofmanufacture 0.01 mole (1.5610g) of orotic acid was suspended in 50ml of freshly distilled water. An excess amount of 4N sodium hydroxide was added to solubilisethe acid and the pH was then adjusted to pH 8.0 with 0.1 mole HCI. To this solution 1 Oml of 1 mole silver nitrate were added. The resulting white precipitate was stirred and then rapidly filtered off and washed thoroughly with chilled freshly distilled water The product was dried in a vacuum oven at room temperature phosphorus pentoxide.
Micro-organic analysis Theoretical Experimental C 22.84 C 13.75 H 1.15 H 1.07 N 24.34 N 6.45 % yield (mono silver compound) 86.3.
Example 5 Silver adamantoate This compound was prepared from adamantoic acid.
1-adamantane carboxylic acid.
M.W. 180.25.
M.W.180.25.
Adamantoic acid is structurally related to amantidine, however it shows little or no anti-viral activity.
It has been used to form esters with betamethazone and chloramphenicol. Salts have been produced with antidiabetic biguanide compounds and a psychotropic agent.
Method of manufacture 0.01 mole (1.80259) of adamantoic acid was sus pended in 50ml of freshly distilled water. The sus pension was neutralised to pH 7.0 by the addition of 4N sodium hydroxide solution. To this, 10ml of 1 mole silver nitrate solution were added with stirring.
The resulting white precipitate was filtered off and washed thoroughly with chilled freshly distilled water. The product was dried in a vacuum oven at room temperature over phosphorus pentoxide.
Micro-organic analysis Theoretical Experimental C 43.98 C 35.58 H 4.80 H 3.75 % yield 196.68.
Example 6 Silver-o-benzoylbenzoate This compound was prepared from o-benzoylbenzoic acid.
M.W. 226.23.
Very little information is available on this compound. A methadone salt has been produced by refluxing the acid with the drug base. This compound was intended for prolongation of the therapeutic action of methadone.
Method of manufacture 0.01 mole (2.26239) of o-benzoylbenzoic acid was suspended in 50 ml of freshly distilled water. The pH of the solution was adjusted to approximately 7.0 by the addition of 4N sodium hydroxide solution. To this solution 1 Oml of 1 mole silver nitrate solution were added with stirring. The resulting precipitate was immediately filtered off and washed with chilled freshly distilled water. The product was dried in a vacuum oven at room temperature over phosphorus pentoxide.
Micro-organic analysis Theoretical Experimental C 50.48 C 39.56 H 2.72 H 2.23 %yield 159.61.

Claims (4)

.CLAIMS
1. A pharmaceutical composition comprising in admixture with a pharmacologically acceptable vehicle or carrier a water-insoluble silver salt of a physiologically benign organic acid.
2. A pharmaceutical composition according to claim 1 wherein the silver salt is selected from dis ilver pa moate, silver-2-furoate, silver-3-hydroxy-2naphthoate, silver orotate, silver adamantoate and silver-o-benzoylbenzoate.
3. A pharmaceutical composition according to claim 1 or claim 2 wherein the carrier or vehicle is an inert powder or an ointment base.
4. A pharmaceutical composition for use in the treatment of burn wounds comprising in admixture with a pharmacologically acceptable vehicle or carrier a water-insoluble silver salt of a physiologically benign organic acid.
GB8138117A 1980-12-19 1981-12-17 Compositions containing silver salts Expired GB2089659B (en)

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Application Number Priority Date Filing Date Title
GB8138117A GB2089659B (en) 1980-12-19 1981-12-17 Compositions containing silver salts

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Application Number Priority Date Filing Date Title
GB8040834 1980-12-19
GB8138117A GB2089659B (en) 1980-12-19 1981-12-17 Compositions containing silver salts

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GB2089659A true GB2089659A (en) 1982-06-30
GB2089659B GB2089659B (en) 1984-07-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0125858A1 (en) * 1983-05-06 1984-11-21 University of Strathclyde Improved compositions for treating infected burn wounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0125858A1 (en) * 1983-05-06 1984-11-21 University of Strathclyde Improved compositions for treating infected burn wounds
WO1984004456A1 (en) * 1983-05-06 1984-11-22 Univ Strathclyde Improved compositions for treating infected burn wounds

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PCNP Patent ceased through non-payment of renewal fee