US3180795A - Actinomycin-c aqueous solutions - Google Patents

Actinomycin-c aqueous solutions Download PDF

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US3180795A
US3180795A US89940A US8994061A US3180795A US 3180795 A US3180795 A US 3180795A US 89940 A US89940 A US 89940A US 8994061 A US8994061 A US 8994061A US 3180795 A US3180795 A US 3180795A
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acid
solution
actinomycin
per
sodium salt
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Schmidt-Kastner Gunter
Frommer Werner
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Bayer AG
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F21/00—Dissolving
    • B01F21/02—Methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/50—Use of additives, e.g. for stabilisation
    • 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
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
    • C07D475/14—Benz [g] pteridines, e.g. riboflavin
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
    • C09B67/0083—Solutions of dyes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the solubilization of insoluble or practically insoluble organic compounds and to the aqueous solutions thereby produced through the use of certain salts, particularly the hereinafter specified salts of cyclohexybsalicylic acid, hippuric acid and cyclohexyl-salicyluric acid, and mixtures thereof, and their alkyl and cycloalkyl substitution products wherein the alkyl group contains 1 to 6 carbon atoms, i.e., is a lower 7 alkyl group, especially those in which the cyclohexyl radical is in the S-position.
  • Typical Water-insoluble organic compounds to which this invention is applicable are cytostatics such as actinomycin C or actinomycin F antibiotics such as nystatin and the antibiotic from Streptomyces resistomycificus (Chemische Berichte 87 (1954) l4601469), sparingly soluble strpetomycin salts, sulfonamides such as 2-sulfanilamid0-4,6-dimethylpyrimidine, diuretics such as diphenylmethane-4,4-disulfonamide and 1,3-dimethyl-2,6- dihydroxypurine (theophylline), vitamins such as lactofiavin and vitamin A acetate, plant protectives such as phyllomycin, natural and synthetic dyestuffs such as alizarin, alkannin and p-dimethylaminoazobenzene, Sudan blue, Sudan red, cosmetics, pest control agents and disinfectants.
  • cytostatics such as actinomycin C or actinomycin F antibiotics such
  • solubilizers not only salts of cyclohexyl-salicylic acid, hippuric acid and cyclohexyl-salicyluric acid, but also alkyl or cycloalkyl substitution products of these compounds with alkyl or cycloalkyl radicals containing l-6 carbon atoms, for example salts of cyclohexyl-o-cresotic acid.
  • mixtures of the said compounds for example aqueous solutions containing, in addition to 20% of cyclohexyl-salicylic acid sodium salt, 10%, or of hippuric acid sodium salt, or, in addition to 20% of hippuric acid sodium salt, 5%, 10%, 15% of cyclohexylic acid sodium salt, or solutions containing sparingly Water-soluble salts, for example cyclohexyl-salicylic acid magnesium salt, and readily water-soluble salts, for example hippuric acid sodium salt.
  • aqueous solutions containing, in addition to 20% of cyclohexyl-salicylic acid sodium salt, 10%, or of hippuric acid sodium salt, or, in addition to 20% of hippuric acid sodium salt, 5%, 10%, 15% of cyclohexylic acid sodium salt, or solutions containing sparingly Water-soluble salts, for example cyclohexyl-salicylic acid magnesium salt, and readily water-soluble salts, for example hippuric acid sodium salt.
  • aqueous solutions of the alkali metal sodium and potassium
  • calcium, magnesium or lithium salts of cyclohexyl-salicylic acid, hippuric acid or cyclohexyl-salicyluric acid the acids are dissolved in an equivalent amount of alkali or the corresponding bicarbonate with slight heating, and the solutions, after cooling, are adjusted topH 7.0i02 and filtered.
  • these compounds are stirred or shaken with an aqueous solution of the solubilizer for a prolonged time, if desired with slight heating; or the Waterinsoluble organic compounds are previously dissolved in a water-miscible organic solvent, e.g., ethanol, acetone, dioxane or tetrahydrofuran, and this solution is added to an aqueous solution of the solubilizer.
  • a water-miscible organic solvent e.g., ethanol, acetone, dioxane or tetrahydrofuran
  • organic solvents or solvent mixtures should preferably be 3,18%,795 Patented Apr. 2?, 1965 used in which the compounds are freely soluble so that after the addition of the pre-dissolved compounds to the aqueous solution of the solubilizer, the proportion by volume of the organic solvent or solvent mixture used for previous-1y dissolving remains small.
  • aqueous solutions of water-insoluble organic compounds prepared with the use of alkali metal, calcium, magnesium or lithium salts ofcyclohexyl-salicylic acid, hippuric acid or cyclohexyl-salicyluric acid are used directly or after removal of'the solvent or solvents.
  • the removal of the solvent or solvents is carried out by vacuum distillation, freeze-drying, spray drying or in a thin layer evaporator.
  • Example 1 10 g. of actinomycin C are dissolved in 50 ml. of acetone. The acetone solution is added to 450 ml. of a 2% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid. The solution contains 20 mg. of actinomycin C per ml.
  • Example 3 10 g. of actinomycin C are dissolved in 50 ml. of acetone, the acetone solution is added to ml; of a 10% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid and the solution freeze-dried. The residue after freeze-drying dissolves clearly in 100 ml. of Water. The solution contains 100 mg. of actinomycin C per ml.
  • Example 4 10 g. of actinomycin C are dissolved in 50 ml. of tetrahydrofuran. The solution is added to 1380 ml. of a 4% aqueous solution of the sodium salt of S-cyclohexyl-ocresotic acid. The solution contains 7 mg. of actinomycin C per ml.
  • Example 5 6 g. of actinomycin C are dissolved in 50 ml. of tetrahydrofuran. The solution is added to 950 ml. of a 13% aqueous solution of the magnesium salt of hippuric acid. The solution contains 6 mg. of actinomycin C per ml.
  • Example 6 8.5 g. of actinomycin C are dissolved in 30 ml. of tetrahydrofuran and added to a 10% aqueous solution of the lithium salt of hippuric acid. The solution contains 17 mg. of actinomycin C per ml.
  • Example 7 5 g. of actinomycin C are dissolved in 25 m1. of tetrahydrofuran, the solution is added to 100 ml. of a 7% aqueous solution of the lithium salt of S-cyclohexylsalicylic acid and freeze-dried. The residue after freezedrying dissolves clearly in 100 ml. of Water. The solution contains 50 mg. of actinomycin C. per ml.
  • Example 8 12 g. of actinomycin C are dissolved in 50 ml, of tetra hydrofuran and the solution is added to 950 ml. of an aqueous solution containing g. of hippuric acid magnesium salt and g. of hippuric acid sodium salt. 7 The final solution contains 12 mg. of actinomycin C per ml.
  • Example 9 25 g. of actinomycin C are dissolved in 75 ml. of tetrahydrofuran and the solution is added to 925 ml. of an aqueous solution containing 25 g. of S-cyclohexylsalicylic acid magnesium salt and 150 g. of hippuric acid sodium salt. The solution contains 25 mg. of actinomy- 'cin C per ml.
  • Example 10 3.5 g. of actinomycin C are shaken with 500 ml. of a solution containing 20 g. of S-cyclohexyl-salicyluric acid sodium salt (sodium salt of 2-hydroXy-S-cycloheXylbenzoyl-glycine) and 20 g. of S-cyclohexyl-salicylic acid sodium salt in water until the actinomycin dissolves.
  • the solution contains 70 mg. of actinomycin C per ml.
  • Example 11 2g. of actinomycin F are previously dissolved in 30 ml. of tetrahydrofuran and to this solution are added 170 ml. of a 4% aqueous solution of the sodium salt of S-cyclohexyl-salicyluric acid (sodium salt of 2-hydroxy-S-cyclohexylbenzoyl-glycine). The solution contains 10 mg. of actinomycin F per ml. The normal solubility of actinomycin F in water is the same as actinomycin C.
  • Example 13 260 mg. of the antibiotic from Streptomyces resistomycificus are dissolved in 5 ml. of tetrahydrofuran and 995 ml. of a 12.5% aqueous solution of the sodium salt of S-cyclohexyl-salicylic acid are added thereto.
  • the solution contains 260 of the antibiotic of Streptomyces resistomycificus per ml.
  • the normal solubility in Water is only 27 per ml.
  • Example 14 30 g. of the streptomycin salt of S-cyclohexyl-o-cresotic acid (1 mol of streptomycin per 3 mols of S-cyclohe'xyl-o-cresotic acid) are stirred with 100 ml. of a 40% aqueous solution of the sodium salt of hippuric acid until the streptomycin salt dissolves.
  • the solution contains 300 mg. of streptomycin salt per ml.
  • the normal solubility in water is 0.8 mg. per ml.
  • Example 15 16 g.'of the streptomycin salt of S-cyclohexyl-o-cresotic acid (1 mol of streptomycin per 3 mols of S-cyclohexyl-o-cresotic acid) are stirred with 100 ml. of a 15% aqueous solution of the sodium salt of 5-cyclohexylsalicylic acid until the streptomycin salt dissolves.
  • the solution contains 160 mg. of streptomycin salt per ml.
  • the normal solubility in water is 0.8 mg. per ml.
  • Example 16 10 g. of diphenylmethane-4,4-disulphonamide are dissolved in 30 ml. of acetone, and 470 ml. of a 12.5% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid are added. The solution contains mg. of diphenylmethane-4,4'-disulphonamide per ml.
  • Example 18 g. of 2'sulphonamido-4,6-dimethylpyrimidine are shaken with 2000 ml. of a aqueous solution of the sodium salt of hippuric acid at room temperature until the 2-sulphonamid0 4,6 dimethylpyrimidine dissolves completely.
  • the solution contains 15 mg. of 2-sulphonamido-4,6-dimethylpyrimidine per ml.
  • the normal water-solubility of 2-sulphonamido-4,6-dimethylpyrimidine is 0.6 mg. per ml.
  • Example 19 g. of theophylline (1,3-dimethyl 2,6 dihydroxypurine) are shaken with 500 ml. of a 40% aqueous solution of the sodium salt of hippuric acid at room temperature until the theophylline dissolves completely.
  • the solution contains 100 mg. of theophylline per ml.
  • the solubility of theophylline in water is 4 mg. per ml.
  • Example 20 15 g. of lactofiavin (vitamin B are kneaded with 1000 ml. of a 40% solution of the sodium salt of hippuric acid until the lactofiavin dissolves completely.
  • the solution contains 15 mg. of lactofiavin per ml.
  • the normal solubility in water is 0.2 mg. of lactofiavin per ml.
  • Example 21 17 g. of lactofiavin (vitamin B are shaken with 1000 ml. of a 15% aqueous solution of the sodium salt of 5- cyclohexyl-salicylic acid until the lactofiavin dissolves completely.
  • the solution contains 17 mg. of lactofiavin per ml.
  • Example 22 1.1 g. of vitamin A acetate are dissolved in 10 ml. of acetone and slowly introduced into 190 ml. of a 15% aqueous solution of the sodium salt of 5-cyclohexylsalicylic acid. The solution contains 5.5 mg. of vitamin V A acetate per ml., i.e., 16,000 immunization units of vitamin per ml.
  • Example 23 1.2 g. of vitamin A acetate are dissolved in 10 ml. of acetone and the solution is added to ml. of a 20% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid in which 13.5 g. of sodium hippurate are also dissolved.
  • the solution contains 12 mg. of a vitamin A acetate per ml., i.e., 35,000 I.U. of vitamin A per ml.
  • Example 24 10.7 g. of phyllomycin are dissolved in ml. of dioxane and diluted with 15 ml. of 1 N sodium hydroxide solution. This solution (93mg. of phyllomycin per ml.) is poured into 2480 ml. of a 10% aqueous solution of the sodium salt of 5-cyclohexyl-salicylic acid. The solution contains 4.12 mg. of phyllomycin per ml. Phyllomycin is practically water-insoluble.
  • Example 25 4.92 g. of phyllomycin are dissolved in ml. of dioxane and diluted with 75 ml. of 0.1 N sodium hydroxide solution and 25 ml. of water. This solution (19.7 mg. of phyllomycin per ml.) is poured into 2250 ml. of a 2.2% aqueous solution of the sodium salt of S-cyclohexylsalicyluric acid (sodium salt of Z-hydroxy- S-cyclohexylbenzoyl-glycine). The solution contains 1.97 mg. of phyllomycin per ml.
  • Example 26 10.2 g. of phyllomycin are dissolved in 300 ml. of dioxane and diluted with 150 ml. of 0.1 N sodium hydroxide solution and 50 ml. of water. This solution (20.4 mg. of
  • phyllomycin per ml. is poured into-a second solution containing 350 g. of hippuric acid sodium salt and 150 g. of 5-cyclohexyl-salicylic acid sodium salt in4500 ml. of water.
  • the final solution contains 7% of hippuric acid sodium salt, 3% of S-cyclohexyl-salicylic acid sodium salt and 2.04 mg. of phyllomycin per ml.
  • Example 27 33 g. of alizarin (1,Z-dihydroxyanthraquinone) are shaken with 1000 ml. of a 15 aqueous solution of the sodium salt of hippuric acid until the alizarin dissolves completely. The solution contains 33 mg. of alizarin per ml. The solubility of alizarin in distilled water is 0.08 mg. per ml.
  • Example 28 1.1 g. of alizarin (1,Z-dihydroxyanthraquinone) are shaken with 1000 ml. of a 15% aqueous solution of the sodium salt of S-cyclohexyl-salicylic acid, pH 73:0.1, until the dyestutf dissolves completely.
  • the solution contains 11 mg. of alizarin per ml.
  • Example 29 3.5 g. of alkannin [3-(Z-methoxy-S-hydroxy-pentene- 2-yl)-5,8,-dihydroxy-naphthoquinone-1,4] are shaken with 1000 ml. of a 15% aqueous solutionof the sodium salt of S-cyclohexyl-salicylic acid until the dyestutt dissolves completely.
  • the solution contains 3.5 mg. of alkannin per ml.
  • Alkannin is insoluble in water.
  • Example 30 7.6 g. of alkannin [3-(Z-methoxy-S-hydroxy-pentene-Z- yl)-5,8-dihydroxynaphthoquinone-1,4] are shaken with 1000 ml. of an aqueous solution containing 200 g. of cyclohexyl-salicylic acid sodium salt and 150 g. of hippuric acid sodium salt until the dyestufi dissolves completely. The final solution contains 20% of S-cyclohexylsalicylic acid sodium, 15 of hippuric acid sodium salt and 7.6 mg. of allrannin per ml.
  • Example 31 0.7 g. of p-dimethylaminoazobenzene are shaken with 1000 ml. of a 15 aqueous solution of the sodium salt of 5-cyclohexyl-salicylic acid until the dyestufl dissolves completely.
  • the solution contains 700 mg. of p-dimethylaminoazobenzene/litre.
  • the normal solubility of p-dimethylaminoazobenzene in water is 1 mg./litre.
  • Example 32 125 mg. of Sudan blue are shaken with 1000 ml. of a 15% aqueous solution of the sodium salt of 5-cyclohexylsalicylic acid until the dyestufl dissolves completely.
  • the solution contains 125 mg. of Sudan blue/litre.
  • the normal solubility in water is 0.4 mg./litre.
  • Example 33 80 mg. of Sudan red B are shaken with 1000 ml. of a 15 aqueous solution of the sodium salt of S-cyclohexylsalicylic acid until the dyestufi dissolves completely.
  • the solution contains 80 mg. of the Sudan red/litre.
  • the normal solubility in Water is 0.5 mg./litre.
  • Example 34 5 g. of 3 methoxy 4 N,N diethyl carbamidomethoxyphenylacetic acid-n-propyl ester are dissolved While shaking in 66.7 ml. of a 60% aqueous solution of the sodium salt of hippuric acid and the volume is made up with water to a total of ml. The solution contains 50 mg. of 3-methoxy-4-N,N-diethyl-carbamidomethoxyphenylacetic acid-n-propyl ester per ml.
  • Example 36 5 g. of 3-methoxy-4-N,N-diethyl-carbamidomethoxyphenylacetic acid-n-propyl ester are dissolved while shaking in 50 ml. of a 60% aqueous solution of the sodium salt of hippuric acid, 10 ml. of 1,2-propane-diol are added and the volume is made up with water to a total of 100 ml.
  • the solution contains 50 mg. of 3-methoxy-4-N,N- diethyl carbamidomethoxyphenylacetic acid n propyl ester per ml.
  • the invention thus makes it possible to prepare true, clear, aqueous solutions of many water-insoluble or sparingly soluble organic compounds in a comparatively simple but highly elfective manner, thereby widening the range and efficacy of usefulness of such compounds, particularly since relatively concentrated solutions can be produced.
  • True aqueous solutions of the kind provided by this invention have manifold advantages not heretofore available as will be understood.
  • the solubilized compounds have enhanced or increased utility for the purposes for which said compounds are intended to be used.
  • the aqueous solutions of the invention may or may not contain an organic solvent in which the organic compound is readily soluble and which solvent is miscible with water.
  • true solution means that the organic compound is actually dissolved as distinguished from a colloidal solution or a suspension.
  • An aqueous solution of actinomycin C containing at least about 12 times as much actinomycin C in solution as is normally soluble in the same amount of water, said solution comprising, in addition to water and actinomycin C, a solubilizing agent selected from the group consisting of the sodium, potassium, calcium, magnesium and lithium salts of cyclohexyl-salicylic acid, hippuric acid and cyclohexylsalicyluric acid and their alkyl and cycloalkyl substitution products wherein the alkyl group has 1 to 6 carbon atoms, and mixtures of said solubilizing agents.
  • a solubilizing agent selected from the group consisting of the sodium, potassium, calcium, magnesium and lithium salts of cyclohexyl-salicylic acid, hippuric acid and cyclohexylsalicyluric acid and their alkyl and cycloalkyl substitution products wherein the alkyl group has 1 to 6 carbon atoms, and mixtures of said

Description

United States Patent 3,180,795 ACTINOMYCIN-C AQUEOUS SOLUTIONS Giinter Schmidt-Kastner and Werner Frommer, Wupper- 2 Claims. a. 167-65) The present invention relates to the solubilization of insoluble or practically insoluble organic compounds and to the aqueous solutions thereby produced through the use of certain salts, particularly the hereinafter specified salts of cyclohexybsalicylic acid, hippuric acid and cyclohexyl-salicyluric acid, and mixtures thereof, and their alkyl and cycloalkyl substitution products wherein the alkyl group contains 1 to 6 carbon atoms, i.e., is a lower 7 alkyl group, especially those in which the cyclohexyl radical is in the S-position.
. Because of theirinsolubility in water, many organic compounds are prevented from finding their full range of uses and/ or are utilizable only with partial effectiveness. In numerous instances it has been impossible to prepare true aqueous solutions of such compounds although such are greatly to be desired.
Typical Water-insoluble organic compounds to which this invention is applicable are cytostatics such as actinomycin C or actinomycin F antibiotics such as nystatin and the antibiotic from Streptomyces resistomycificus (Chemische Berichte 87 (1954) l4601469), sparingly soluble strpetomycin salts, sulfonamides such as 2-sulfanilamid0-4,6-dimethylpyrimidine, diuretics such as diphenylmethane-4,4-disulfonamide and 1,3-dimethyl-2,6- dihydroxypurine (theophylline), vitamins such as lactofiavin and vitamin A acetate, plant protectives such as phyllomycin, natural and synthetic dyestuffs such as alizarin, alkannin and p-dimethylaminoazobenzene, Sudan blue, Sudan red, cosmetics, pest control agents and disinfectants.
According to the invention there are used as solubilizers not only salts of cyclohexyl-salicylic acid, hippuric acid and cyclohexyl-salicyluric acid, but also alkyl or cycloalkyl substitution products of these compounds with alkyl or cycloalkyl radicals containing l-6 carbon atoms, for example salts of cyclohexyl-o-cresotic acid. It is also possible to use mixtures of the said compounds, for example aqueous solutions containing, in addition to 20% of cyclohexyl-salicylic acid sodium salt, 10%, or of hippuric acid sodium salt, or, in addition to 20% of hippuric acid sodium salt, 5%, 10%, 15% of cyclohexylic acid sodium salt, or solutions containing sparingly Water-soluble salts, for example cyclohexyl-salicylic acid magnesium salt, and readily water-soluble salts, for example hippuric acid sodium salt.
In order to produce aqueous solutions of the alkali metal (sodium and potassium), calcium, magnesium or lithium salts of cyclohexyl-salicylic acid, hippuric acid or cyclohexyl-salicyluric acid, the acids are dissolved in an equivalent amount of alkali or the corresponding bicarbonate with slight heating, and the solutions, after cooling, are adjusted topH 7.0i02 and filtered.
For producing true aqueous solutions of water-insoluble organic compounds, these compounds are stirred or shaken with an aqueous solution of the solubilizer for a prolonged time, if desired with slight heating; or the Waterinsoluble organic compounds are previously dissolved in a water-miscible organic solvent, e.g., ethanol, acetone, dioxane or tetrahydrofuran, and this solution is added to an aqueous solution of the solubilizer. For previously dissolving the Water-insoluble organic compounds, organic solvents or solvent mixtures should preferably be 3,18%,795 Patented Apr. 2?, 1965 used in which the compounds are freely soluble so that after the addition of the pre-dissolved compounds to the aqueous solution of the solubilizer, the proportion by volume of the organic solvent or solvent mixture used for previous-1y dissolving remains small.
The true aqueous solutions of water-insoluble organic compounds prepared with the use of alkali metal, calcium, magnesium or lithium salts ofcyclohexyl-salicylic acid, hippuric acid or cyclohexyl-salicyluric acid are used directly or after removal of'the solvent or solvents. The removal of the solvent or solvents is carried out by vacuum distillation, freeze-drying, spray drying or in a thin layer evaporator.
Thetollowing non-limitative examples illustrate the invention:
Example 1 10 g. of actinomycin C are dissolved in 50 ml. of acetone. The acetone solution is added to 450 ml. of a 2% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid. The solution contains 20 mg. of actinomycin C per ml.
Example 3 10 g. of actinomycin C are dissolved in 50 ml. of acetone, the acetone solution is added to ml; of a 10% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid and the solution freeze-dried. The residue after freeze-drying dissolves clearly in 100 ml. of Water. The solution contains 100 mg. of actinomycin C per ml.
Example 4 10 g. of actinomycin C are dissolved in 50 ml. of tetrahydrofuran. The solution is added to 1380 ml. of a 4% aqueous solution of the sodium salt of S-cyclohexyl-ocresotic acid. The solution contains 7 mg. of actinomycin C per ml.
V Example 5 6 g. of actinomycin C are dissolved in 50 ml. of tetrahydrofuran. The solution is added to 950 ml. of a 13% aqueous solution of the magnesium salt of hippuric acid. The solution contains 6 mg. of actinomycin C per ml.
Example 6 8.5 g. of actinomycin C are dissolved in 30 ml. of tetrahydrofuran and added to a 10% aqueous solution of the lithium salt of hippuric acid. The solution contains 17 mg. of actinomycin C per ml.
Example 7 5 g. of actinomycin C are dissolved in 25 m1. of tetrahydrofuran, the solution is added to 100 ml. of a 7% aqueous solution of the lithium salt of S-cyclohexylsalicylic acid and freeze-dried. The residue after freezedrying dissolves clearly in 100 ml. of Water. The solution contains 50 mg. of actinomycin C. per ml.
Example 8 12 g. of actinomycin C are dissolved in 50 ml, of tetra hydrofuran and the solution is added to 950 ml. of an aqueous solution containing g. of hippuric acid magnesium salt and g. of hippuric acid sodium salt. 7 The final solution contains 12 mg. of actinomycin C per ml.
Example 9 25 g. of actinomycin C are dissolved in 75 ml. of tetrahydrofuran and the solution is added to 925 ml. of an aqueous solution containing 25 g. of S-cyclohexylsalicylic acid magnesium salt and 150 g. of hippuric acid sodium salt. The solution contains 25 mg. of actinomy- 'cin C per ml.
Example 10 3.5 g. of actinomycin C are shaken with 500 ml. of a solution containing 20 g. of S-cyclohexyl-salicyluric acid sodium salt (sodium salt of 2-hydroXy-S-cycloheXylbenzoyl-glycine) and 20 g. of S-cyclohexyl-salicylic acid sodium salt in water until the actinomycin dissolves. The solution contains 70 mg. of actinomycin C per ml.
Example 11 2g. of actinomycin F are previously dissolved in 30 ml. of tetrahydrofuran and to this solution are added 170 ml. of a 4% aqueous solution of the sodium salt of S-cyclohexyl-salicyluric acid (sodium salt of 2-hydroxy-S-cyclohexylbenzoyl-glycine). The solution contains 10 mg. of actinomycin F per ml. The normal solubility of actinomycin F in water is the same as actinomycin C.
Examp e 12 33.7 g. of crystalline nystatin (125 X 10 units of nystatin) are stirred with 30 ml. of dimethyl-sulphoxide and added to 970 ml. of a 10.4% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid. The solution contains 33.7 mg. of nystatin per ml. The normal solubility in Water of nystatin is only 0.23 mg. per ml.
Example 13 260 mg. of the antibiotic from Streptomyces resistomycificus are dissolved in 5 ml. of tetrahydrofuran and 995 ml. of a 12.5% aqueous solution of the sodium salt of S-cyclohexyl-salicylic acid are added thereto. The solution contains 260 of the antibiotic of Streptomyces resistomycificus per ml. The normal solubility in Water is only 27 per ml.
Example 14 30 g. of the streptomycin salt of S-cyclohexyl-o-cresotic acid (1 mol of streptomycin per 3 mols of S-cyclohe'xyl-o-cresotic acid) are stirred with 100 ml. of a 40% aqueous solution of the sodium salt of hippuric acid until the streptomycin salt dissolves. The solution contains 300 mg. of streptomycin salt per ml. The normal solubility in water is 0.8 mg. per ml.
Example 15 16 g.'of the streptomycin salt of S-cyclohexyl-o-cresotic acid (1 mol of streptomycin per 3 mols of S-cyclohexyl-o-cresotic acid) are stirred with 100 ml. of a 15% aqueous solution of the sodium salt of 5-cyclohexylsalicylic acid until the streptomycin salt dissolves. The solution contains 160 mg. of streptomycin salt per ml. The normal solubility in water is 0.8 mg. per ml.
Example 16 10 g. of diphenylmethane-4,4-disulphonamide are dissolved in 30 ml. of acetone, and 470 ml. of a 12.5% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid are added. The solution contains mg. of diphenylmethane-4,4'-disulphonamide per ml.
1 Example 18 g. of 2'sulphonamido-4,6-dimethylpyrimidine are shaken with 2000 ml. of a aqueous solution of the sodium salt of hippuric acid at room temperature until the 2-sulphonamid0 4,6 dimethylpyrimidine dissolves completely. The solution contains 15 mg. of 2-sulphonamido-4,6-dimethylpyrimidine per ml. The normal water-solubility of 2-sulphonamido-4,6-dimethylpyrimidine is 0.6 mg. per ml.
Example 19 g. of theophylline (1,3-dimethyl 2,6 dihydroxypurine) are shaken with 500 ml. of a 40% aqueous solution of the sodium salt of hippuric acid at room temperature until the theophylline dissolves completely. The solution contains 100 mg. of theophylline per ml. The solubility of theophylline in water is 4 mg. per ml.
Example 20 15 g. of lactofiavin (vitamin B are kneaded with 1000 ml. of a 40% solution of the sodium salt of hippuric acid until the lactofiavin dissolves completely. The solution contains 15 mg. of lactofiavin per ml. The normal solubility in water is 0.2 mg. of lactofiavin per ml.
Example 21 17 g. of lactofiavin (vitamin B are shaken with 1000 ml. of a 15% aqueous solution of the sodium salt of 5- cyclohexyl-salicylic acid until the lactofiavin dissolves completely. The solution contains 17 mg. of lactofiavin per ml.
Example 22 1.1 g. of vitamin A acetate are dissolved in 10 ml. of acetone and slowly introduced into 190 ml. of a 15% aqueous solution of the sodium salt of 5-cyclohexylsalicylic acid. The solution contains 5.5 mg. of vitamin V A acetate per ml., i.e., 16,000 immunization units of vitamin per ml.
About 0.05 mg. of vitamin A acetate per ml. are normally soluble in water.
Example 23 1.2 g. of vitamin A acetate are dissolved in 10 ml. of acetone and the solution is added to ml. of a 20% aqueous solution of the sodium salt of S-cyclohexylsalicylic acid in which 13.5 g. of sodium hippurate are also dissolved. The solution contains 12 mg. of a vitamin A acetate per ml., i.e., 35,000 I.U. of vitamin A per ml.
Example 24 10.7 g. of phyllomycin are dissolved in ml. of dioxane and diluted with 15 ml. of 1 N sodium hydroxide solution. This solution (93mg. of phyllomycin per ml.) is poured into 2480 ml. of a 10% aqueous solution of the sodium salt of 5-cyclohexyl-salicylic acid. The solution contains 4.12 mg. of phyllomycin per ml. Phyllomycin is practically water-insoluble.
Example 25 4.92 g. of phyllomycin are dissolved in ml. of dioxane and diluted with 75 ml. of 0.1 N sodium hydroxide solution and 25 ml. of water. This solution (19.7 mg. of phyllomycin per ml.) is poured into 2250 ml. of a 2.2% aqueous solution of the sodium salt of S-cyclohexylsalicyluric acid (sodium salt of Z-hydroxy- S-cyclohexylbenzoyl-glycine). The solution contains 1.97 mg. of phyllomycin per ml.
Example 26 10.2 g. of phyllomycin are dissolved in 300 ml. of dioxane and diluted with 150 ml. of 0.1 N sodium hydroxide solution and 50 ml. of water. This solution (20.4 mg. of
phyllomycin per ml.) is poured into-a second solution containing 350 g. of hippuric acid sodium salt and 150 g. of 5-cyclohexyl-salicylic acid sodium salt in4500 ml. of water. The final solution contains 7% of hippuric acid sodium salt, 3% of S-cyclohexyl-salicylic acid sodium salt and 2.04 mg. of phyllomycin per ml.
Example 27 33 g. of alizarin (1,Z-dihydroxyanthraquinone) are shaken with 1000 ml. of a 15 aqueous solution of the sodium salt of hippuric acid until the alizarin dissolves completely. The solution contains 33 mg. of alizarin per ml. The solubility of alizarin in distilled water is 0.08 mg. per ml.
Example 28 1.1 g. of alizarin (1,Z-dihydroxyanthraquinone) are shaken with 1000 ml. of a 15% aqueous solution of the sodium salt of S-cyclohexyl-salicylic acid, pH 73:0.1, until the dyestutf dissolves completely. The solution contains 11 mg. of alizarin per ml.
Example 29 3.5 g. of alkannin [3-(Z-methoxy-S-hydroxy-pentene- 2-yl)-5,8,-dihydroxy-naphthoquinone-1,4] are shaken with 1000 ml. of a 15% aqueous solutionof the sodium salt of S-cyclohexyl-salicylic acid until the dyestutt dissolves completely. The solution contains 3.5 mg. of alkannin per ml. Alkannin is insoluble in water.
Example 30 7.6 g. of alkannin [3-(Z-methoxy-S-hydroxy-pentene-Z- yl)-5,8-dihydroxynaphthoquinone-1,4] are shaken with 1000 ml. of an aqueous solution containing 200 g. of cyclohexyl-salicylic acid sodium salt and 150 g. of hippuric acid sodium salt until the dyestufi dissolves completely. The final solution contains 20% of S-cyclohexylsalicylic acid sodium, 15 of hippuric acid sodium salt and 7.6 mg. of allrannin per ml.
Example 31 0.7 g. of p-dimethylaminoazobenzene are shaken with 1000 ml. of a 15 aqueous solution of the sodium salt of 5-cyclohexyl-salicylic acid until the dyestufl dissolves completely. The solution contains 700 mg. of p-dimethylaminoazobenzene/litre. The normal solubility of p-dimethylaminoazobenzene in water is 1 mg./litre.
Example 32 125 mg. of Sudan blue are shaken with 1000 ml. of a 15% aqueous solution of the sodium salt of 5-cyclohexylsalicylic acid until the dyestufl dissolves completely. The solution contains 125 mg. of Sudan blue/litre. The normal solubility in water is 0.4 mg./litre.
Example 33 80 mg. of Sudan red B are shaken with 1000 ml. of a 15 aqueous solution of the sodium salt of S-cyclohexylsalicylic acid until the dyestufi dissolves completely. The solution contains 80 mg. of the Sudan red/litre. The normal solubility in Water is 0.5 mg./litre.
Example 34 Example 35 5 g. of 3 methoxy 4 N,N diethyl carbamidomethoxyphenylacetic acid-n-propyl ester are dissolved While shaking in 66.7 ml. of a 60% aqueous solution of the sodium salt of hippuric acid and the volume is made up with water to a total of ml. The solution contains 50 mg. of 3-methoxy-4-N,N-diethyl-carbamidomethoxyphenylacetic acid-n-propyl ester per ml.
Example 36 5 g. of 3-methoxy-4-N,N-diethyl-carbamidomethoxyphenylacetic acid-n-propyl ester are dissolved while shaking in 50 ml. of a 60% aqueous solution of the sodium salt of hippuric acid, 10 ml. of 1,2-propane-diol are added and the volume is made up with water to a total of 100 ml. The solution contains 50 mg. of 3-methoxy-4-N,N- diethyl carbamidomethoxyphenylacetic acid n propyl ester per ml.
The invention thus makes it possible to prepare true, clear, aqueous solutions of many water-insoluble or sparingly soluble organic compounds in a comparatively simple but highly elfective manner, thereby widening the range and efficacy of usefulness of such compounds, particularly since relatively concentrated solutions can be produced. True aqueous solutions of the kind provided by this invention have manifold advantages not heretofore available as will be understood. The solubilized compounds have enhanced or increased utility for the purposes for which said compounds are intended to be used. As mentioned above, the aqueous solutions of the invention may or may not contain an organic solvent in which the organic compound is readily soluble and which solvent is miscible with water. Where the organic solvent is not desired in the final solution, it is removed in any suitable or convenient manner and its removal does not throw the dissolved organic compound out of solution. The expression, true solution, as used herein means that the organic compound is actually dissolved as distinguished from a colloidal solution or a suspension.
What is claimed is:
1. An aqueous solution of actinomycin C containing at least about 12 times as much actinomycin C in solution as is normally soluble in the same amount of water, said solution comprising, in addition to water and actinomycin C, a solubilizing agent selected from the group consisting of the sodium, potassium, calcium, magnesium and lithium salts of cyclohexyl-salicylic acid, hippuric acid and cyclohexylsalicyluric acid and their alkyl and cycloalkyl substitution products wherein the alkyl group has 1 to 6 carbon atoms, and mixtures of said solubilizing agents.
2. An aqueous solution according to claim 1, wherein there is present an organic solvent in which the actinomycin'C is readily soluble and which solvent is miscible with water.
References Cited in the file of this patent UNITED STATES PATENTS 2,447,363 Rabinowitz Aug. 17, 1948 2,800,426 Kaellner et al. July 23, 1957 2,971,889 Swintosky Feb. 14, 1961 FOREIGN PATENTS 491,567 Great Britain Sept. 5, 1938 OTHER REFERENCES Dale et al.: J.A.P.A., Proc. Pharm. Ed., July 1957,

Claims (1)

1. AN AQUEOUS SOLUTION OF ACTINOMYCIN C CONTAINING AT LEAST ABOUT 12 TIMES AS MUCH ACTINOMYCIN C IN SOLUTION AS IS NORMALLY SOLUBLE IN THE SAME AMOUT OF WATER, SAID SOLUTION COMPRISING, IN ADDITION TO WATER AND ACTINOMYCIN C, A SOLUBILIZING AGENT SELECTED FROM THE GROUP CONSISTING OF THE SODIUM, PORASSIUM, CALCIUM, MAGNESIUM AND LITHIUM SALTS OF CYCLOHEXYL-SALICYLIC ACID, HIPPURIC ACID AND CYCLOHEXYLSALICYLURIC ACID AND THEIR ALKYL AND CYCLOALKYL SUBSTITUTION PRODUCTS WHEREIN THE ALKYL GROUP HAS 1 TO 6 CARBON ATOMS, AND MIXTURES OF SAID SOLUBILIZING AGENTS.
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FR2411188A1 (en) * 1977-12-12 1979-07-06 Parcor Anti-spasmophilic magnesium 2-and 3-thenoyl glycinate(s) - are prepd. from glycine and thenoyl halide followed by magnesium hydroxy-carbonate
IL59083A (en) * 1979-01-10 1983-12-30 Israel Marcus Pharmaceutical composition containing thymidine and a salicyclic acid derivative as a solubilizing agent therefor
AU541247B2 (en) * 1979-12-20 1985-01-03 R.P. Scherer Corporation Adjuvants for rectal delivery of drug substances
EP2286908A3 (en) 2010-11-19 2011-06-01 Symrise AG Solubilizer for cosmetic preparations

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GB491567A (en) * 1937-03-03 1938-09-05 Felix Koenigsberger Improvements in and relating to the production of aqueous solutions of phenols whichare difficultly soluble in water
US2447363A (en) * 1945-06-15 1948-08-17 Harold M Rabinowitz Compound of urobilinogen and hippuric acid as antipressor
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GB491567A (en) * 1937-03-03 1938-09-05 Felix Koenigsberger Improvements in and relating to the production of aqueous solutions of phenols whichare difficultly soluble in water
US2447363A (en) * 1945-06-15 1948-08-17 Harold M Rabinowitz Compound of urobilinogen and hippuric acid as antipressor
US2800426A (en) * 1953-06-12 1957-07-23 Upha Chemische Pharmazeutische Stable khellin solutions and method of preparing same
US2971889A (en) * 1958-03-18 1961-02-14 Smith Kline French Lab Press coated enteric tablets and process for preparing them

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387712A1 (en) * 1989-03-14 1990-09-19 Fujisawa Pharmaceutical Co., Ltd. WS 7622 A,B,C and D substances, derivatives thereof, processes for preparation thereof and use thereof

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