NL8002483A - CHLORHEXIDINE SALTS AND PREPARATIONS THEREOF. - Google Patents

Description

* Λ VO 0480 *

Title: Chlorhexidine salts and preparations thereof.

The invention relates to antibacterial compounds of the formula I of the formula sheet, wherein X consists of sorbic acid, nalidixic acid and phosphanilic acid, as well as preparations containing these substances.

More particularly, the invention relates to certain new chloro-5-bexidine salts and antibacterial dermatological preparations containing these salts.

The new salts include chlorhexidine disorbate, chlorhexidine dinalidixate and chlorhexidine diphosphanilate. Preferably, the chlorhexidine disorbate is used as the monohydrate, while the chloro-hexidine diphosphanilate is usually in the form of the dihydrate.

Chlorhexidine, nalidixic acid, phosphanilic acid and sorbic acid are known. In addition, certain chlorhexidine salts, such as the hyrochlorides, gluconates, isethionates, formates, acetates, etc., are known from U.S. Patents 3,960,745 and 3,855-140.

Polyhydroxycarboxylic acid salts of biguanides, such as chlorhexidine di-D-gluconates are known from US patent 2,990,425 and are very soluble in water.

The oral antibacterial use of water-soluble salts of chlorhexidine, such as the gluconates, acetates, fluorides, etc., is shown in U.S. Pat. No. 3-976,765.

An oral antibacterial preparation containing a combination of dodecyldi (aminoethyl} glycine and chlorhexidine or its digluconates, diacetate, etc. is shown in U.S. Patent 3,932,607 ·

Chlorhexidine salts with certain sequestering amino-25 carboxylic acids are shown in U.S. Pat. No. 3,888,947

Preferred salts of these are mcno-daloorhexidine nitrilotriacetic acid, trichlorhexidine di- [diethylene-triaminopentaacetate], mono-chloro-hexidine-di- [U, If-dihydroxyethylaminoacetate], mono-chlorohexidine N-hydroxyethyl-triacethexidine, and mono-trichloro-hexidine ethyl ethylenediaminotriacetate]. Such sequestrates would have a stronger antibacterial activity than the corresponding bis-guanido salts.

Bisguanide hydroxyalkanesulfonic acid salts are shown in British Patent 815,800. Such salts include the isethion-800 2 4 83 9 -2-acid salt, the 2,3-dihydroxypropane-1-sulfonic acid salt, the 3-chloro-2-hydroxypropane-1-sulfonic acid salt and the 2-hydroxypropane-1-sulfonic acid salt and would be beneficial because of their good water solubility.

U.S. Patent 3,152,181 shows monobiguanides having at least one alkoxypropyl group with 11-19 carbon atoms attached to the IJ1 or IF nitrogen atoms. Such compounds are said to be highly antibacterial and used as the free base or their salts with inorganic or organic acids. Examples of this type of acidic salts are hydrochloride, hydrobromide, sulfate, phosphate, acetate, tartrate, picrate and β-ethoxypropionate. Examples of acidic nitrogen compounds are the ofline, purines, saccharin, phthalimide, benzoxazine dions, oxazolidine dions, 1-p-methylbenzenesulfonyl-N * -n-butylurea, barbituric acid derivatives, mercaptobenzothiazole and succinimide. These monobiguanides can also be used with other medicaments.

As mentioned, nalidixic acid, phosphanilic acid and chlorhexidine are known. The nalidixic acid of U.S. Pat. No. 3,590,036 is an antibacterial agent, but has not hitherto been applied topically.

Phosphanilic acid is active against various organisms as described in Berichte 7, 711 (19 ^ 2).

U.S. Patent 3,159 * 537 teaches that certain phosphonic acid compounds such as phosphanilic acid promote oral absorption of tetracycline antibiotics.

Complexes of phosphanilic acid and aminoacrdine compounds are shown in U.S. Pat. Nos. 3,969,717 and 3,779,723 and known antibacterial and antifungal agents.

Phosphanilic acid is also said to be synergistically active with trimethoprim against various bacteria. It has also been said that it would be synergistically effective with neomycin and streptomycin against Enterobacteriaceum.

Finally, the topically anti-infective chlorhexidine has long been known, for example, from U.S. Pat. No. 2,668,992.

The new compounds of the formula (I) of the present formula are readily prepared, for example, from the desired acid, dissolved in an appropriate solvent (preferably hot ethanol at 800 2 4 33 ml 0-3-nalidixic acid and sorbic acid and hot water at phosphanilic acid) with the free base of chlorhexidine, dissolved in an appropriate solvent, preferably hot ethanol or methanol.

The precipitate formed is collected, washed and recrystallized by a method known per se, after which the desired salt according to the invention is obtained.

The following examples further illustrate the invention.

Example I

. . . . 3

A solution of 505 mg of chlorhexidine free base with 50 cm @ 3 of warm ethanol was carefully added to a warm solution of

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h6b mg nalidixic acid in 50 cnT ethanol. A precipitate qp immediately occurred, and this was filtered off after the mixture was cooled.

This precipitate was washed successively with ethanol, chloroform and ether. It was then recrystallized from dimethylformamide to obtain 0.6 g of an off-white chlorhexidine dinididate with a melting point of 22k-226 ° C. IH (KBr) bands at 3330-2860 (wide multiplet), 1625, 1 ^ 92, 1UU5, 1252, 1132, 1092, 820, and 7 ^ 5 cm -1.

Analysis: Calculated for C 7 E 14 ClgN Og C, 56.96; H, 5.61; H, 20.21; Cl, 7.31; 0.99.

Found: C, 56.86; H, 5.7 ^; ,2, 20.21; Cl, 7.25.

Example II

A warm solution of 505 mg of chlorhexidine free base in 50 ml of methanol was added to a solution of 3b6 mg of phosphaniline. 3 acid m 250 cm hot water. The resulting solution was evaporated to 3. . .

Approx. 50 cm and cooled, with a waxy material precipitated.

This was filtered off, washed with water and recrystallized from water. After drying, 205 mg of chlorhexidine diphosphanilate dihydrate having a melting point of 172 DEG-17 DEG C. were obtained. This corresponds to a yield of 23.1 *.

30 λ s 255 (Am = 51,600) IR (KBr): bands at 3tó0 to 2930 (wide

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multiplet), 1650 to 16ΟΟ (wide multiplet), 1515, 1 ^ 90, 1 ^ 20, 1130 and -828 cm "1.

Analysis: Calculated for C 12 N 12 8 P 2 C 5 ^ 5.99; H, 5.67;

Cl, 7.98; N, 18.93; 0.1U, U2; P, 6.97.

Found: C, 1 * 5.9 ^; H, 5.75; Cl, 8.25; H, 19.00; P, 6.85.

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Example III

A warm solution of 224 mg sorbic acid in 10 cm ethanol was added to a solution of 505 mg chlorhexidine free base 3 in 50 cm ethanol. The resulting solution was evaporated to dryness. The solid residue was recrystallized from ethanol / isopropanol (1: 1). The crystalline product obtained was dried to 527 mg of chlorhexidine disorbate monohydrate. This material was a white powder that shrank at 90-100 ° C and melted at 100-104 ° C. The yield was 70.5 / λ ^ 0Η = 253 (Am = 79,000) IR (KBr): bands at 3460 to 2870 (wide max 10 multiplet), 1650 to 1600 (wide multiplet), 15 ^ 0.1490, 1390, 1000 and 825 cm "1.

Analysis: Calculated for C 14 H 16 ClN 2 O C, 54.61; H, o. 47;

Cl, 9, 9; N, 18.73; 0, 10.70.

Found: C, 5Mi; H, 6.65; Cl, 9.68; N, 18.49.

Chlorhexidine dinididate and chlorhexidine diphosphanilate were tested for their in vitro activity against 32 strains of Pseudomonas aeruginosa, 26 strains of other gram negative organisms and 18 gram positive organisms. The minimum inhibitory concentration figures of chlorhexidine digluconate, chlorhexidine diacetate, nalidixic acid and phosphanilic acid are also shown. Chlorhexidine base could not be used as a comparative because it is unstable.

The results of this study are shown in Table A.

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The figures in Table A show that the dinalidixate of chlorhexidine is more effective than nalidixic acid and chlorhexidine against most strains investigated. ”The figures further demonstrate that chlorhexidine dinididate is especially active against P. aeruginosa strains and 5 K pneumoniae, 5. cloacae and P. morganii strains, while chlorhexidine diphosphanilate is most effective against P. aeruginosa and a strain of P. mirabilis and P. vulgaris.

The results of Table A also demonstrate that the chloridoxin nalidixic acid salt is more effective than any of its constituents.

To further investigate the synergistic effect of the new salts, these salts were compared in vitro with a number of other compounds against 30 strains of Pseudomonas aeruginosa, 23 strains of other gram-negative organisms and 15 gram-positive organisms. The minimal inhibitory concentrations of the new salts according to the invention and a number of comparators were thereby obtained. In contrast to the procedure used in Table A, all compounds were tested on a direct weight basis and in a medium with a low level of antibiotic antagonists, increasing sensitivity to the antibiotics.

The results are shown in Table B, which shows that chlorhexidine dinididate is most effective compared to chlorhexidine or nalidixic acid against Klebsiella pneumoniae and Enterococcus cloacae as well as 28 of the 30 strains of P. aeruginosa. The chloranxidine phosphanilate is clearly superior to phosphanilic acid and chlorhexidine against four of the 30 P. aeruginosa strains. The results also demonstrate that chlorhexidine diphosphanilate is highly effective against anti-pseudomonas organisms. It inhibits 29 of the 30 strains of P. aeruginosa with MRC values of 8 mg / liter or less, while such a figure is only achieved in 2 strains at 30 chlorhexidine diglueonate, diacetate or disorbate.

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To more clearly explain the differences, the MRC values shown in Tables A and B were converted to MRC values in µl mol / cm ^ using the following molecular formulas and molecular facts: 5 Chlorhexidine di sorbate monohydrate ^ 31 ^ 1 8 ^ 2 ^ 10% 7 ^ 7.72

Chlorhexidine dinididate C ^ H ^ Cl ^ ^ Og 969.9 ^

Chlorhexidine diphosphate anilate Cl, 2 ° 8? 2 dihydrate 5 10 856.72

Chlorhexi dinedigluconate Ο ^ Η ^ Ι ^ Ο ^ Ν, ^ 897.80

Chlorhexidine diacetate ^ 26 ^ 38 ^ 2 ^ 10% 625.56 15 Ealidixic acid ^ 2 ^ 2 ^ 2% 232.23 11 + 2.13

Tables C and D show the results of this conversion 20 and allow a meaningful comparison.

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The results of Table C clearly indicate that the subject salts are active and synergistically effective, especially against P. aeruginosa, with the nalidixate being most synergistically active. The present disorbate salt has a clear synergy against various species. The synergistic effect of chlorhexidinedinali-dixate is evident when comparing the results of Table C in K. pneumonia, E. cloacae, P. mirabilis, P. morganii, P. rettgeri, P. vulgaris, S. marcescens, P. stuartii and P. aeruginosa. For example, chlorhexidine dinalidixate has an MHC of 2.9 against two strains of 10 K. pneumonia and 8.2 against a strain of this organism. The corresponding values for nalidixic acid are 8.7 and 68.9; while those for chlorhexidine digluconate and chlorhexidine diacetate are 70.1 and 35> 6 as well as 5191 and 51.1, respectively.

The present chlorhexidine dinalidixate was found to be very synergistic against P. aeruginosa. Against 26 strains of this organism, chlorhexidinedinalidixate had an MRC of 50.1; an MRC of 1 + 3.2 against five strains; and against a strain of 32.9 * In contrast, nalidixic acid against these strains exhibited MRC values greater than 5 ^ 0, while chlorhexidine digluconate and the diacetate had MRC values greater than 100, respectively greater than 200.

Thus, the synergistic effect of chlorhexidine dinalidixate has been clearly demonstrated with the results of Table D. Synergism appears against K. pneumonia, E. cloacae, P. mirabilis, P. rettgeri, S. marcescens, P. stuartii and P. aeruginosa.

Table C shows that chlorhexidine diphosphanilate is clearly synergistic. active against S. viridans, P. mirabilis, P. vulgaris, a strain P. stuartii and various strains P. aeruginosa.

The results of Table D show a synergy of chlorine-hexidine diphosphanilate against a strain P. rettgeri and various strains of P. aeruginosa.

Table D shows a synergistic effect of chlorhexidine disorbate against S. pyogenes, a strain P. rettgeri and various strains P. aeruginosa.

Compositions in which the present chlorhexidine salt is present can be formed in situ and then form part of the invention.

800 24 83 -13- e

The following preparations further illustrate the invention.

The formulations 1-6 shown in the following Table E were thereby prepared according to the following general procedure.

In a suitable container, stearyl alcohol was dissolved in petrolatum 5 with heating and gentle stirring. The temperature was then brought to between 62 and 68 ° C. Then propylene glycol and about 99% of the water were combined in an appropriate mixing vessel and stirred to a homogeneous solution. This solution was also brought to 62 to 68 ° C and then mixed vigorously, after which the carbomer was slowly added.

The vigorous mixing was continued until the carbomer was completely dispersed (about 1 hour). Sodium lauryl sulfate, sorbic acid and Amphoteric-9 were then added with slow mixing again, and this slow mixing was continued until a homogeneous mixture was formed,

In a suitable container, the rest of the water (approx. 1%) was brought to 15 + 0-1 -1-5 ° C and the dry sodium phosphate was added thereto with good stirring. This stirring was continued until a clear solution was formed. This sodium phosphate solution was then added to the mixture in the main vessel while slowly stirring again.

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Stirring was continued until the soft semi-gel was formed. While gently stirring, it was gently heated while slowly bringing the temperature to 62-68 ° C.

After this, petrolatum and stearyl alcohol, being the oil phase, were slowly added to the main vessel. This took place while the water phase was stirred vigorously. This mixing was continued for another 5 to 10 minutes, then cooled, preferably by circulating cold water through the jacket of the main vessel. During this cooling, the mixture was gently stirred and cooled to a temperature of about 25-30 ° C, after which the finished base material was obtained.

A small amount of this base material, about 5% in the formulations 1 and about 10% in the formulations 2 and 5 and about 15% in the formulations 3 and 6 was then added to a suitable container.

The present chlorhexidine salt was added and mixed with the residue, for example with a spatula or an appropriate mixer, until it was homogeneously dispersed in the finished lotion base. The dispersion 35 was then passed through a roller roller with the aim of obtaining an 800 2 4 83 -1 homogeneous fine non-grit particle size. This procedure was repeated if necessary to obtain a ground concentrate.

This ground concentrate was added to the rest of the finished base and gently mixed with it for 1 hour or until a homogeneous dispersion was obtained.

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The preparations Js 8 and 9 of Table F are prepared according to the following general procedure:

The Peg-8 and the lactic acid were added to a stainless steel container and mixed slowly until homogeneous.

The petrolatum, mineral oil, lanolin oil, cetyl alcohol, the hydrogenated polyisobutene, Peg-2 stearate, benzyl alcohol and sodium lauryl sulfate were added to the main mixing vessel, which is preferably made of stainless steel and contains a steam jacket.

The mixture was gently stirred and heated. Mixing and heating 10 'was continued until all solid materials had melted. The temperature was then brought to 65-70 ° C. Mixing was continued for a further 10 minutes after which heating and stirring were stopped. The mixture was then cooled, preferably by passing cold water through the jacket, and stirred slowly. The mixture cooled to approx.

15 h - 5 ° C, during which time was mixed continuously.

The lactic acid and Peg-8 solution was then added to the main mixing vessel components, which constituted the oil phase. This addition was done slowly with slow but constant mixing. Mixing and cooling was continued until the temperature reached 25-30 ° C to obtain the finished base.

A small amount of finished base, approx. 5 # in preparation 7, approx. 10% in preparation 8 and approx. In preparation 9 was added to an appropriate mixer, and then the chlorhexidine diphosphanilate was added thereto. The combination of this diphosphanilate and the finished base 25 were slowly mixed until an almost homogeneous dispersion was obtained. This dispersion was passed through a roller roller until the particle size no longer felt gritty; thus a well-ground concentrate was obtained. This ground concentrate was added to the rest of the finished base and mixed slowly with it, for example, about 1 hour 30 until a homogeneous dispersion was obtained.

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The preparations 10, 11 and 12 of Table G were generally prepared as follows:

The glyceryl oleate / propylene glycol, Peg-7 hydrogenated castor oil, sorbitan oleate, oleoyl hydrogenated animal protein, Arlacel U81, 5 light mineral oil, hydrogenated polyisobutene, lanolin oil / mineral oil, Capryl / caprine triglycerides, propyl paraben and beeswax. holder with jacket. This mixture was then gently heated and mixed, bringing the temperature to 75-85 ° C and forming an oil phase.

Water, lactic acid, propylene glycol and dried sodium phosphate were added to a main mixing vessel, which was made of stainless steel and jacketed. This combining took place with heating and moderate stirring. This stirring was continued until a clear solution was formed, then sorbitol, methyl paraben and titanium dioxide were added. Mixing and heating were continued until a homogeneous mixture was obtained. The temperature was brought to 75-85 ° C to obtain an aqueous phase.

When the oil phase is slowly added to the water phase at an appropriate temperature, with constant medium stirring, a good emulsion is obtained. The magnesium stearate is added to this and the mixture is stirred for another 20 minutes at 75-5 ° C. Thereafter, no more heating, slow stirring and then this is also finished until the temperature has reached 25-30 ° C, and the finished base, approx. 5 $ for preparation 10, approx. 10 $ for preparation 11 and approx. 15 $ for formulation 12 was added to a suitable container, the chlorhexidine salt added thereto and mixed using a spatula or other mixer until a fairly well uniform dispersion was obtained. This dispersion was then rolled and ground until the material no longer felt gritty. A ground concentrate was thus obtained.

This ground concentrate was added to the remainder of the base and mixed well but slowly with it for 1 hour until a homogeneous dispersion was obtained. The Arlacel U81 of preparation 10 is a mixture of sorbitan oleate, hydrogenated castor oil, beeswax and stearic acid.

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Mixtures of chlorhexidine or pharmaceutically suitable salts of chlorhexidine with nalidixic acid or a pharmaceutically suitable salt of nalidixic acid also exhibit good synergy in avoiding the growth of microorganisms such as 5 Klepsiella pneumoniae, Enerobacter cloacae and Pseudomonas aeruginosa.

The calculated synergistic indices show that these mixtures contain 35-65% by weight chlorhexidine or a salt thereof and 65-35% by weight nalidixic acid or a salt thereof. Preferably, such mixtures contain equal amounts of both compounds. Mixtures of this kind have a synergistic effect against ant organisms such as Staph, aureus, Str. pyogenes. Str. faeealis and Pseudomonas aeruginosa. These mixtures preferably contain 35-65% by weight of chlorhexidine or a salt thereof and 65-35% by weight of phosphanilic acid or a salt thereof. Preferably, these mixtures should preferably contain equal amounts by weight of both compounds.

800 2 4 83

Claims (17)

A compound of the formula 1 of the formula sheet wherein X represents sorbic acid, nalidixic acid or phosphanilic acid. A compound according to claim 1, characterized in that X is sorbic acid. Compound according to claim 2, characterized in that X is the monohydrate of sorbic acid. k. A compound according to claim 1, characterized in that X is nalidixic acid. Compound according to claim 1, characterized in that X 10 is phosphanilic acid. A compound according to claim 5, characterized in that X is a dihydrate of phosphanilic acid. 7. An antibacterial composition containing an effective amount of a compound of the formula 1, wherein X has the meaning as defined in claim 1, and a dermatologically suitable carrier therefor. Preparation according to claim 7, characterized in that the compound is present in the carrier in an amount of 0.1-10% by weight. 9. Preparation according to claim 7, characterized in that the active compound is present therein in an amount of 0.25-5% by weight. Preparation according to claim 7, characterized in that the active compound is present therein in an amount of 0.75-2.5% by weight. 11. A composition according to claim 7S, characterized in that the active compound is formed therein in situ, namely by a reaction of chlorhexidine with sorbic acid, nalidixic acid or phosphanilic acid. 12. Mixtures of chlorhexidine or its salts with nalidixic acid or phosphanilic acid or its salts, which mixtures are synergistically active against a large number of harmful micro-organisms. Process for preparing a compound according to claim 30 1, characterized in that sorbic acid, nalidixic acid or phosphanilic acid are dissolved in an appropriate solvent, preferably warm ethanol or warm water and this solution is reacted with the free base of chlorhexidine, dissolved in an appropriate solvent, preferably warm ethanol or ethanol, binds the precipitate formed, washes and recrystallizes if desired. 800 2 4 83 -22- Μ 1¼. Process for the preparation of an antibacterial preparation, characterized in that an effective amount of a compound of the formula 1 of the formula sheet is incorporated in a dermatologically suitable carrier. 800 2 4 83% UNIFIED PATENT OFFICES No. 80.02483 • s -GRAVENHAGE (HOLLAND) Belongs to writers dated ΐβ June 1980 vL / AH -23— ê CHANGES SHEET The following conclusions are added: An antibacterial composition comprising 35-65 wt.% Chlorhexidine or a pharmaceutically acceptable chlorhexidine salt and 65-35 wt.% Nalidixic acid or a pharmaceutically acceptable salt thereof, wherein the chlorhexidine or pharmaceutically acceptable salt thereof and the nalidixin or pharmaceutically acceptable salt thereof are preferably present in the mixture in a weight ratio of about 1: 1. An antibacterial composition comprising 35-65% by weight of chloro-10-hexidine or a pharmaceutically acceptable salt thereof, and 65-35% by weight of phosphanilic acid or a pharmaceutically acceptable salt thereof, wherein the chlorhexidine or pharmaceutically acceptable salt thereof and phosphanilic acid or pharmaceutically acceptable salt thereof, preferably present in the mixture in a weight ratio of about 1: 1. Preparation according to claim 15 or 16, characterized in that chlorhexidine digluconate is used. 18. A method of inhibiting the growth of a susceptible microorganism, characterized in that the microorganism is contacted with an amount sufficient to inhibit its growth of the compound according to one or more of claims 1-6. 19. A method of inhibiting the growth of a susceptible microorganism, characterized in that the microorganism is contacted with an amount sufficient to inhibit its growth of the composition according to one or more of claims 7-12 and 15-17 · On page 20, line 9 becomes; "this kind of mixtures" changed to: Q "mixtures of chlorhexidine or pharmaceutically acceptable salts of chlorhexidine (eg chlorhexidine digluconate) with phosphanilic acid or pharmaceutically acceptable salts of phosphanilic acid". fi nh nh d-Q-NHCNHClIH. (CH2) 5. 2X NH NH / Cl-NH-NHCNH 800 2 4 83