US3013007A - Neomycin salt of higher fatty acids - Google Patents

Neomycin salt of higher fatty acids Download PDF

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US3013007A
US3013007A US47916A US4791660A US3013007A US 3013007 A US3013007 A US 3013007A US 47916 A US47916 A US 47916A US 4791660 A US4791660 A US 4791660A US 3013007 A US3013007 A US 3013007A
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neomycin
fatty acids
salt
fatty acid
acid
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US47916A
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Jack K Dale
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/228—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings
    • C07H15/232—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to adjacent ring-carbon atoms of the cyclohexane rings with at least three saccharide radicals in the molecule, e.g. lividomycin, neomycin, paromomycin

Definitions

  • This invention relates to salts of the antibiotic neomycin and more particularly to neomycin higher fatty acid salts and neomycin salts of mixed higher fatty acids.
  • the present invention provides as novel and useful compositions of matter neomycin higher fatty acid salts and neomycin salts of mixed higher fatty acids, wherein the fatty acids contain from 12 to 18 carbon atoms, inclusive.
  • neomycin in either the free base or salt form combines with the said fatty acids and mixed fatty acids to form novel compounds which possess germicidal detergent activity per se and which can be combined with soap and synthetic organic detergents to provide advantageous germicidal detergent combinations.
  • the said compounds and combinations possess germicidal detergent activity generally and are especially advantageous for 'the reduction of both transient and resident bacteria upon human skin.
  • neomycin has reference to the antibiotics more fully described in Waksman, Neomycin, The Williams and Wilkins Company, Baltimore, Maryland, 1958.
  • the term includes the separate closely related antibiotics known as neomycin B and neomycin C and the mixtures thereof.
  • the neomycin reactant can be in the form of the free base or the salts, such as the sulfate and hydrochloride.
  • the fatty acid reactant can be in the form of the free fatty acids, the alkali-metal salts of the acids, the alkali-metal soaps, oil soaps, tallow soaps, and the like.
  • the compounds can be made using a lower alkanol as the solvent for the fatty acid, and an aqueous solution of the neomycin.
  • the reaction can also be accomplished in aqueous solutions of the alkali-metal salts of the fatty acids.
  • Such solutions can take the form of aqueous solutions of soap, for example, 'tallow and coconut oil soaps.
  • Tallow from 'beef contains relatively larger percentages of palmitic acid (C stearic acid (C and oleic acid (C and lesser percentages of lauric'acid (C myristic acid (C 4), palmitoleic acid (C and arachidic acid (C Goat and mutton tallow also contain relatively larger percentages of the palmitic, stearic, and oleic acids.
  • C stearic acid C and oleic acid
  • lauric'acid C myristic acid (C 4)
  • palmitoleic acid C and arachidic acid
  • Goat and mutton tallow also contain relatively larger percentages of the palmitic, stearic, and oleic acids.
  • coconut oil soap contains relatively larger percentages of lauric acid (C and myristic acid (C and lesser percentages of the other higher fatty acids.
  • the neomycin fatty acid compounds can also be prepared, for example, by mixing lower alkanol solutions of neomycin base and of the fatty acid, evapora ing oif the solvent and recovering the solid derivative. Another method comprises mixing an aqueous solution of neomycin acid addition salt and an alkali-metal salt of the fatty acid, recovering the insoluble product and purifying, for example, by washing out soluble by-products such as sodium sulfate, and drying.
  • Example 1 S0ap solution of neomycin salt of coconut oil fatty acids To an aqueous solution of 40% coconut oil soap was added 0.1% neomycin base as a cold solution. A precipitate was formed which became clear in less than one minute. The same result was obtained using 0.143% neomycin sulfate; the precipitate which formed became clear after fifteen minutes.
  • Example 2Ne0mycin higher fatty acid salts Thirty grams of crude neomycin sulfate is dissolved in '90 mls. of distilled water, and then mixed with 9.6 gms. of activated carbon for fifteen minutes followed by filtration and washing of the residue with 25 mls. of distilled Water. This preliminary step can be eliminated if pure neomycin sulfate is being used.
  • neomycin sulfate filtrate solution is then mixed with 300 mls. of barium hydroxide solution (31.55 gms. of Ea(OH) -5H O diluted to 360 mls. with deaerated distilled water) to give a pH of 11.95.
  • barium hydroxide solution 31.55 gms. of Ea(OH) -5H O diluted to 360 mls. with deaerated distilled water
  • the resulting barium sulfate precipitate is removed by filtration and the clear solution is titrated with 22 mls. of one half normal sulfuric acid to precipitate .excess barium ion. Filtering again, followed by washing the filter with water yielded purified neomycin base which was diluted with water to 450 mls.
  • neomycin base solution To 30 mls. of this purified neomycin base solution there was added 0.01 equivalents of fatty acid, specifically lauric acid, stearic acid, or palmitic acid dissolved in absolute methanol. The mixture was then vacuum dried to give neomycin laurate, neomycin stearate, or neomycin palmitate.
  • fatty acid specifically lauric acid, stearic acid, or palmitic acid
  • Example 3 Ne0mycin stearate A dispersion of 306 gms. of sodium 'stearate in '6 l. of distilled water at 70 C. was mixed and stirred with a solution of 200 gms. of neomycin sulfate in 600 mls. of distilled water. The white waxy precipitate was separated by filtration and washed with water to yield 340 gms. of neomycin stearate. This neomycin stearate in fine powdered form is suitable as an antiseptic dusting powder possessing detergent properties. Without additional milling, it is incorporated in a soap crutching-operation, as are the other neomycin higher fatty acid salts of Example 2 to produce germicidal soaps.
  • the neomycin compound can be incorporated in shaving cream to prepare a cream possessing advantageous effects in combatting infections resulting from cuts during shaving.
  • the dried neomycin laurate is powdered in a mortar.
  • Example 5 Neomycin myristate Myristic acid gms 2.28 Neomycin base gms 1.4 Ethanol mls A solution of the myristic acid is prepared in 100 mls. of ethanol and the neomycin is added thereto. The re sulting mixture is evaporated to dryness in a vacuum desiccator to obtain dried neomycin myristate. The yield is 2.9 gms.
  • Example 7 A dispersion of 275 gms. of sodium myristate in 6 l. of distilled water at 70 C. is mixed and stirred with a solution of 150 gms. of neomycin sulfate in 600 mls. of distilled water. The white waxy precipitate is separated by filtration and washed with water to yield 300 gms. of neomycin myristate.
  • This product in fine powder form is suitable as an antiseptic dusting powder. Alternatively, it can be incorporated into bar soap at the time of milling the soap chips.
  • Example 8--Ne0mycin salt of coconut oil fatty acids To 4400 mls. of aqueous potash coconut oil soap is added 103 gms. of neomycin base as a cold 10% aqueous solution. The pH is adjusted to 8 with dilute sulfuric acid. The precipitate is recovered, washed with water and dried in a vacuum desiccator. 210 gms. of the neomycin salt of the mixed higher fatty acids are obtained. This neomycin salt can be dissolved in excess soap to provide a liquid soap with effective properties in reducing the resident and transient bacteria upon the skin surface.
  • Example 9.Ne0mycin salt of tallow fatty acids To 5500 mls. of 5% aqueous sodium tallow soap is added 103 gms. neomycin base as a cold 5% aqueous solution. The pH is adjusted to 8 with dilute sulfuric acid. The precipitate is recovered by centrifugation, washed with water and dried in a vacuum desiccator. 300 gms. of the neomycin salt of the mixed higher fatty acids are obtained. The salt can be redissolved in excess soap solution to provide a detergent composition possessing advantageous germicidal properties.
  • Example 1 Following the procedure of Example 8, a mixture of equal parts of coconut oil and tallow soaps is used to prepare the neomycin salt of the mixed fatty acids of coconut oil and tallow.
  • Example 11Neomycin tallowate 17 kgs. of hydrogenated tallow fatty acids are dissolved in a solution of 4150 gms. of 85% potassium hydroxide in 75 gallons of deionized water by stirring at 70 C. After adding a solution of 5.67 kgs. of commercial grade neomycin sulfate in 5 gallons of deionized water the mixture is cooled to 25 C. and adjusted to pH 8.0 with 50% sulfuric acid. The mixture has a thick cream-like consistency. After standing overnight the product filters easily on a filter pot. The optical rotation of the filtrate (+0.05", 4-dm. tube) indicates that less than 2% of the optical activity remains. The moist product weighs 45.5 kgs. A Z-kg. portion is removed.
  • the remainder of moist filter cake is freeze-dried with a shelf temperature of F. and a pressure less than 30 microns. Drying time is 62 hours.
  • the dried product is milled, using a 28 screen.
  • the yield after milling is 18.2 kgs. Assuming that the 2-kg. sample has the same moisture content as the rest of the lot, the total yield is 19.0 kgs.
  • the calculated potency (neomycin base in starting material/ fatty acid neomycin base) is 137 meg/mg. Biological assays show a potency of 137.3 meg/mg.
  • the weight loss on drying is 0.59%
  • the neomycin tallowate is incorporated into bar soap to provide compositions with advantageous stability and germicidal activity.
  • Neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inclusive.
  • composition of matter consisting essentially of neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inclusive.
  • composition of matter consisting essentially of neomycin palmitate.
  • Neomycin stearate 11.
  • Neomycin tallowate 16.
  • Neomycin salt of coconut oil fatty acids 16.

Description

3 013 007 NEQMYCEQ SALT 6F IillGHER FATTY AClDS Hack K. Dale, Kalamazoo, Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed Aug. 8, 1954 Ser. No. 47,916 17 Claims. (Cl. 26il-2l0) This invention relates to salts of the antibiotic neomycin and more particularly to neomycin higher fatty acid salts and neomycin salts of mixed higher fatty acids.
The present invention is a continuation-in-part of application Serial No. 587,462, filed May 28, 1956.
The present invention provides as novel and useful compositions of matter neomycin higher fatty acid salts and neomycin salts of mixed higher fatty acids, wherein the fatty acids contain from 12 to 18 carbon atoms, inclusive.
It has been found that neomycin in either the free base or salt form combines with the said fatty acids and mixed fatty acids to form novel compounds which possess germicidal detergent activity per se and which can be combined with soap and synthetic organic detergents to provide advantageous germicidal detergent combinations. The said compounds and combinations possess germicidal detergent activity generally and are especially advantageous for 'the reduction of both transient and resident bacteria upon human skin.
As used in the specification and claims of this application, the term neomycin has reference to the antibiotics more fully described in Waksman, Neomycin, The Williams and Wilkins Company, Baltimore, Maryland, 1958. The term includes the separate closely related antibiotics known as neomycin B and neomycin C and the mixtures thereof.
The neomycin reactant can be in the form of the free base or the salts, such as the sulfate and hydrochloride. The fatty acid reactant can be in the form of the free fatty acids, the alkali-metal salts of the acids, the alkali-metal soaps, oil soaps, tallow soaps, and the like.
For complete reaction six molar equivalents of'the fatty acid or mixed fatty acids are theoretically required to react With the neomycin. However, an excess of the fatty acid is preferably used to obtain optimum yields.
The compounds can be made using a lower alkanol as the solvent for the fatty acid, and an aqueous solution of the neomycin. The reaction can also be accomplished in aqueous solutions of the alkali-metal salts of the fatty acids. Such solutions can take the form of aqueous solutions of soap, for example, 'tallow and coconut oil soaps. Tallow from 'beef contains relatively larger percentages of palmitic acid (C stearic acid (C and oleic acid (C and lesser percentages of lauric'acid (C myristic acid (C 4), palmitoleic acid (C and arachidic acid (C Goat and mutton tallow also contain relatively larger percentages of the palmitic, stearic, and oleic acids.
It is preferred to use hydrogenated 'tallow. Coconut oil soap contains relatively larger percentages of lauric acid (C and myristic acid (C and lesser percentages of the other higher fatty acids. The neomycin fatty acid compounds can also be prepared, for example, by mixing lower alkanol solutions of neomycin base and of the fatty acid, evapora ing oif the solvent and recovering the solid derivative. Another method comprises mixing an aqueous solution of neomycin acid addition salt and an alkali-metal salt of the fatty acid, recovering the insoluble product and purifying, for example, by washing out soluble by-products such as sodium sulfate, and drying.
The following examples set forth the best mode contemplated by the inventor of carrying out his invention but are not to be construed as limiting.
Example 1.-S0ap solution of neomycin salt of coconut oil fatty acids To an aqueous solution of 40% coconut oil soap was added 0.1% neomycin base as a cold solution. A precipitate was formed which became clear in less than one minute. The same result was obtained using 0.143% neomycin sulfate; the precipitate which formed became clear after fifteen minutes.
Example 2.Ne0mycin higher fatty acid salts Thirty grams of crude neomycin sulfate is dissolved in '90 mls. of distilled water, and then mixed with 9.6 gms. of activated carbon for fifteen minutes followed by filtration and washing of the residue with 25 mls. of distilled Water. This preliminary step can be eliminated if pure neomycin sulfate is being used.
The neomycin sulfate filtrate solution .is then mixed with 300 mls. of barium hydroxide solution (31.55 gms. of Ea(OH) -5H O diluted to 360 mls. with deaerated distilled water) to give a pH of 11.95. The resulting barium sulfate precipitate is removed by filtration and the clear solution is titrated with 22 mls. of one half normal sulfuric acid to precipitate .excess barium ion. Filtering again, followed by washing the filter with water yielded purified neomycin base which was diluted with water to 450 mls.
To 30 mls. of this purified neomycin base solution there was added 0.01 equivalents of fatty acid, specifically lauric acid, stearic acid, or palmitic acid dissolved in absolute methanol. The mixture was then vacuum dried to give neomycin laurate, neomycin stearate, or neomycin palmitate.
Example 3. Ne0mycin stearate A dispersion of 306 gms. of sodium 'stearate in '6 l. of distilled water at 70 C. was mixed and stirred with a solution of 200 gms. of neomycin sulfate in 600 mls. of distilled water. The white waxy precipitate was separated by filtration and washed with water to yield 340 gms. of neomycin stearate. This neomycin stearate in fine powdered form is suitable as an antiseptic dusting powder possessing detergent properties. Without additional milling, it is incorporated in a soap crutching-operation, as are the other neomycin higher fatty acid salts of Example 2 to produce germicidal soaps.
Alternatively, the neomycin compound can be incorporated in shaving cream to prepare a cream possessing advantageous effects in combatting infections resulting from cuts during shaving.
Example 4.Neomycin 'laurate Laurie .acid
evaporated to dryness.
The dried neomycin laurate is powdered in a mortar.
Example 5.Neomycin myristate Myristic acid gms 2.28 Neomycin base gms 1.4 Ethanol mls A solution of the myristic acid is prepared in 100 mls. of ethanol and the neomycin is added thereto. The re sulting mixture is evaporated to dryness in a vacuum desiccator to obtain dried neomycin myristate. The yield is 2.9 gms.
Example 7.-Nemycin myristate A dispersion of 275 gms. of sodium myristate in 6 l. of distilled water at 70 C. is mixed and stirred with a solution of 150 gms. of neomycin sulfate in 600 mls. of distilled water. The white waxy precipitate is separated by filtration and washed with water to yield 300 gms. of neomycin myristate. This product in fine powder form is suitable as an antiseptic dusting powder. Alternatively, it can be incorporated into bar soap at the time of milling the soap chips.
Example 8.--Ne0mycin salt of coconut oil fatty acids To 4400 mls. of aqueous potash coconut oil soap is added 103 gms. of neomycin base as a cold 10% aqueous solution. The pH is adjusted to 8 with dilute sulfuric acid. The precipitate is recovered, washed with water and dried in a vacuum desiccator. 210 gms. of the neomycin salt of the mixed higher fatty acids are obtained. This neomycin salt can be dissolved in excess soap to provide a liquid soap with effective properties in reducing the resident and transient bacteria upon the skin surface.
Example 9.Ne0mycin salt of tallow fatty acids To 5500 mls. of 5% aqueous sodium tallow soap is added 103 gms. neomycin base as a cold 5% aqueous solution. The pH is adjusted to 8 with dilute sulfuric acid. The precipitate is recovered by centrifugation, washed with water and dried in a vacuum desiccator. 300 gms. of the neomycin salt of the mixed higher fatty acids are obtained. The salt can be redissolved in excess soap solution to provide a detergent composition possessing advantageous germicidal properties.
Example 1 0 Following the procedure of Example 8, a mixture of equal parts of coconut oil and tallow soaps is used to prepare the neomycin salt of the mixed fatty acids of coconut oil and tallow.
Example 11.Neomycin tallowate 17 kgs. of hydrogenated tallow fatty acids are dissolved in a solution of 4150 gms. of 85% potassium hydroxide in 75 gallons of deionized water by stirring at 70 C. After adding a solution of 5.67 kgs. of commercial grade neomycin sulfate in 5 gallons of deionized water the mixture is cooled to 25 C. and adjusted to pH 8.0 with 50% sulfuric acid. The mixture has a thick cream-like consistency. After standing overnight the product filters easily on a filter pot. The optical rotation of the filtrate (+0.05", 4-dm. tube) indicates that less than 2% of the optical activity remains. The moist product weighs 45.5 kgs. A Z-kg. portion is removed.
The remainder of moist filter cake is freeze-dried with a shelf temperature of F. and a pressure less than 30 microns. Drying time is 62 hours. The dried product is milled, using a 28 screen. The yield after milling is 18.2 kgs. Assuming that the 2-kg. sample has the same moisture content as the rest of the lot, the total yield is 19.0 kgs. The calculated yield (fatty acid plus neomycin base) is 17.0+2.69=19.69 kgs. The calculated potency (neomycin base in starting material/ fatty acid neomycin base) is 137 meg/mg. Biological assays show a potency of 137.3 meg/mg. The weight loss on drying is 0.59%
The neomycin tallowate is incorporated into bar soap to provide compositions with advantageous stability and germicidal activity.
What is claimed is:
1. Neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inclusive.
2. Solid neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inclusive.
3. Pulverulent neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inelusive.
4. Dried neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inclus1ve.
5. A composition of matter consisting essentially of neomycin higher fatty acid salt wherein the fatty acid contains from 12 to 18 carbon atoms, inclusive.
6. Neomycin palmitate.
7. Solid neomycin palmitate.
8. Pulverulent neomycin palmitate.
9. Dried neomycin palmitate.
10. A composition of matter consisting essentially of neomycin palmitate.
11. Neomycin stearate.
12. Solid neomycin stearate.
13. Neomycinlaurate.
14. Pulverulent neomycin laurate.
15. Neomycin salt of mixed fatty acids wherein the fatty acids contain from 12 to 18 carbon atoms, inclus1ve.
16. Neomycin tallowate.
17. Neomycin salt of coconut oil fatty acids.
References Cited in the file of this patent OTHER REFERENCES OKeefe: J.A.C.S., July 1949, 71 pages 2452-7. Swart: A. 8., July 1951, 73, pages 3253-5

Claims (1)

1. NEOMYCIN HIGHER FATTY ACID SALT WHEREIN THE FATTY ACID CONTAINS FROM 12 TO 18 CARBON ATOMS, INCLUSIVE.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3226329A (en) * 1961-09-14 1965-12-28 Procter & Gamble Germicidal cleansing composition
US3311607A (en) * 1963-12-23 1967-03-28 Angeli Inst Spa Neomycin pamoate
WO2019023392A1 (en) * 2017-07-25 2019-01-31 Elektrofi, Inc. Formation of particles including agents
US11459376B2 (en) 2019-09-13 2022-10-04 Elektrofi, Inc. Compositions and methods for the delivery of therapeutic biologics for treatment of disease
US11654112B2 (en) 2016-11-22 2023-05-23 Elektrofi, Inc. Particles comprising a therapeutic or diagnostic agent and suspensions and methods of use thereof
US11717488B2 (en) 2019-01-31 2023-08-08 Elektrofi, Inc. Particle formation and morphology

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA474055A (en) * 1951-05-29 Welch Henry Fatty acid salts of streptomycin and dihydrostreptomycin
US2631143A (en) * 1947-07-19 1953-03-10 Olin Mathieson Purification of antibiotics with water soluble salts of water insoluble carboxylic acids
US2799620A (en) * 1956-06-29 1957-07-16 Rutgers Res And Educational Fo Neomycin and process of preparation
US2891943A (en) * 1954-03-10 1959-06-23 Chemie Grunenthal G M B H Stol Novel antibiotically active products

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA474055A (en) * 1951-05-29 Welch Henry Fatty acid salts of streptomycin and dihydrostreptomycin
US2631143A (en) * 1947-07-19 1953-03-10 Olin Mathieson Purification of antibiotics with water soluble salts of water insoluble carboxylic acids
US2891943A (en) * 1954-03-10 1959-06-23 Chemie Grunenthal G M B H Stol Novel antibiotically active products
US2799620A (en) * 1956-06-29 1957-07-16 Rutgers Res And Educational Fo Neomycin and process of preparation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3226329A (en) * 1961-09-14 1965-12-28 Procter & Gamble Germicidal cleansing composition
US3311607A (en) * 1963-12-23 1967-03-28 Angeli Inst Spa Neomycin pamoate
US11654112B2 (en) 2016-11-22 2023-05-23 Elektrofi, Inc. Particles comprising a therapeutic or diagnostic agent and suspensions and methods of use thereof
WO2019023392A1 (en) * 2017-07-25 2019-01-31 Elektrofi, Inc. Formation of particles including agents
US11077059B2 (en) 2017-07-25 2021-08-03 Elektrofi, Inc. Electrospraying formation of particles including agents
US11717488B2 (en) 2019-01-31 2023-08-08 Elektrofi, Inc. Particle formation and morphology
US11459376B2 (en) 2019-09-13 2022-10-04 Elektrofi, Inc. Compositions and methods for the delivery of therapeutic biologics for treatment of disease

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