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GB2118041A - Antibacterial compositions containing chlorhexidine - Google Patents

Antibacterial compositions containing chlorhexidine Download PDF

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GB2118041A
GB2118041A GB08229195A GB8229195A GB2118041A GB 2118041 A GB2118041 A GB 2118041A GB 08229195 A GB08229195 A GB 08229195A GB 8229195 A GB8229195 A GB 8229195A GB 2118041 A GB2118041 A GB 2118041A
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chlorhexidine
acid
salt
microorganism
pharmaceutically acceptable
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Paul L Warner
Grey B Kornegay
George Redl
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Bristol Myers Co
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Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C07C279/265—X and Y being nitrogen atoms, i.e. biguanides containing two or more biguanide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids
    • C07C57/10—Sorbic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3834—Aromatic acids (P-C aromatic linkage)

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  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The invention provides antibacterial compositions comprising synergistic mixtures of 35-65 wt% of (1) chlorhexidine or a pharmaceutically acceptable chlorhexidine salt, and 65-35 wt% of (b) nalidixic or phosphanilic acid or a pharmaceutically acceptable salt thereof.

Description

1 GB 2 118 041 A 1
SPECIFICATION Antibacterial compositions
TECHNICAL FIELD The present invention relates to antibacterial compounds of the formula
NH NH 11 11 CL-0- WC1MHWH (CH2)6. 2X 5 NH NH 11 11 __"/ CL--(NHCNHCNH wherein X is selected from the group consisting of sorbic acid, nalidixic acid and phosphanilic acid, and compositions containing same. More particularly, the invention relates to certain novel chiorhexidine salts and antibacterial dermatological compositions containing such salts.
The novel salts comprise chlorhexidine disorbate, chlorhexidine dinalidixate and chlorhexidine diphosphanilate. Preferably, the chlorhexidine disorbate is employed as the monohydrate while the 10 chlorhexidine diphosphanilate is employed as the dihydrate.
BACKGROUND ART
Chlorhexidine, nalidixic acid, phosphanilic acid and sorbic acid are known in the art. Moreover, as is shown in U.S. Patents 3,960,745, issued June 1, 1976, and 3,855,140, issued December 17, 1974, certain chlorhexidine salts are likewise known. Such salts include the hydrochloride, gluconate, 15 isethionate, formate, acetate, glutamate, succinamate, monodiglycolate, dimethanesulfphonate, lactate, di-isobutyrate and the glucoheptonate. Polyhydroxycarboxylic acid salts of biguanides, such as, for example, chlorhexidine di-Dgluconate, are disclosed in U.S. Patent 2,990,425, issued June 27, 1961, as being highly soluble in water.
The oral antibacterial use of water soluble salts of chlorhexidine, such as the gluconate, acetate, fluoride, dihydrogen fluoride and the dihydrogen chloride, is disclosed in U.S. Patent 3,976,765, issued August 24,1976.
An oral antibacterial composition comprising a combination of dodecyi-di(aminoethyi)giycine and chlorhexidine or its digluconate, diacetate, dichloride or monofluorophosphate salts is disclosed in U.S. 25 Patent 3,932,607, issued January 13, 1976.
Salts of chlorhexidine with certain sequestering amino carboxylic acids are disclosed in U.S.
Patent 3,888,947, issued June 10, 1975. Preferred salts include, monochlorhexidine n itri lotri acetate, trichlorhexidine di-[diethylene triaminepentaacetatel, mono-chiorhexidine- di-[N,N dihydroxyethylaminoacetatel, mono-chlorhexidine Whydroxyethylenedi a mi netri acetate and mono- 30 chlorhexidine di-[N-hydroxyethylethylenediaminetriacetatel. Such sequestrates are disclosed to have greater antibacterial activity than the corresponding bisguanido salt (confer column 3, lines 22 through 42 of the patent).
Bis-guanide hydroxyalkane sulphonic acid salts are disclosed in British Patent Specification
815,800. Such salts (including the isethionic acid salt, the 2:3dihydroxypropane-l-sulphonic acid salt, 35 the 3-chloro-2-hydroxypropane-1 -sulphonic acid salt and the 2- hydroxypropane-1 -sulphonic acid salt) are asserted to advantageously possess high solubility in water.
U.S. Patent 3,152,181, issued October 6, 1964, discloses monobiguanides having at least one alkoxypropyl group having from about 11 to 19 carbon atoms attached to the NI or N5 terminal nitrogen atoms. Such compounds are said to display exceptional antimicrobial activity and may be employed as 40 the free base or, where water solubility is a factor in their use, as their salts with the inorganic and organic acids (such as mono and polycarboxylic and sulfur-containing mono and poly acids and acidic nitrogen compounds). Exemplary of acid salts are the hydrochloride, hydrobromide, sulfate, phosphate, borate, phosphite, sulfite, sulfonate, nitrite, carbonate, nitrate, acetate, tartrate, propionate, oxalate, maleate, malate, picrate and P-ethoxypropionate salts. Examples of suitable acidic nitrogen compounds 45 are theophylline, substituted theophyllines and similar purines, saccharin, phthalimide, benzoxazine-2, 4-diones, oxazolidine-2,4-dione and substituted oxazolidone-2,4-diones, Np-rnethylbenzene sulfonylN'-n-butylurea, barbituric acids, mercaptobenzothiazole, 8-chlorotheophyliine and succinimide. Patentees teach (at column 11, lines 36 through 70) that their monobiguanides can be employed with other medicaments.
As stated heretofore, nalidixic acid, phosphanilic acid and chlorhexidine are known in the art. The 2 -GB 2 118 041 A 2 antibacterial agent, nalidixic acid (1 -ethyl- 1,4-dihydro-7-methyi-4-oxo- 1,8 naphthyridine-3-carboxylic acid) is the subject of U.S. Patent 3,590,036, issued June 29, 1971. Nalidixic acid has not to the instant inventors' knowledge been heretofore utilized topically.
Phosphanilic acid (p-NH2C,H,P03H2, 4-aminobenzene phosphonic acid) has been synthesized (inter alia Doak et a]. JACS 74 (1952)) and found to be active against various organisms (see for 5 example Kuhn et al., Ber. 75,711 (1942); Klotz et al., JACS 69,473 (1947); and Thayer et al., Antibiotics and Chemotherapy, 3,256 (1953)).
U.S. Patent 3,159,537, issued December 1, 1964, teaches that certain phosphonic acid compounds, including phosphanilic acid, increase the oral absorption (viz. increase blood level) of tetracycline antibiotics.
Complexes of phosphanilic acid and an aminoacridine compound (preferably, 9-amino, 3-amino or 6-amino acridine) are disclosed in U.S. Patents 3,694, 447, issued September 26, 1972 and 3,794,723 issued February 26, 1974, as having antibacterial and antifungal activity.
Phosphanilic acid has also been reported to show synergistic action with trimethoprim against a variety of bacteria (see U.S. Patent 4,125,610, issued November 14, 1978). It has also been reported to15 show synergistic action with neomycin and with streptomycin against Enterobacteriaceae (see Ciencia (Mexico) 17, 71-73 (1957)).
Finally, it should be noted that the topical anti-infective, chlorhexidine, (1,6-di(N-pchlorohenyidianido)hexane) is long known to the prior art having been disclosed in U.S. Patent 20 2,684,924, issued July 27,1954.
DETAILED DESCRIPTION OF INVENTION
The novel antibacterial compounds of the fo'rmula NH NH 11 11 CL--0NHCNHCNH (CH2)6.2X NH NH 11 11 "I cl --G- WCNHCW wherein X is selected from the group consisting of sorbic acid, nalidixic acid and phosphanilic acid, are readily prepared by for example reacting the desired acid, dissolved in suitable solvent therefor 25 (preferably hot ethanol in the case of malidixic acid and sorbic acid and hot water in the case of phosphanilic acid) with chlorhexidine free base, dissolved in a suitable solvent, preferably hot ethanol or hot methanol.
The resultant precipitate is recovered, washed then recrystallized according to methods known per se whereby the desired novel salt of the present invention is obtained.
The following examples more fully illustrate the method of preparation of the novel salts of the present invention.
EXAMPLE 1
A solution of 505 mg. (1.0 mmole) of chlorhexidine free base in 50 mi. hot ethanol is cautiously added to a hot solution of 464 mg. (2.0 mmole) of nalidixic acid in 50 mi. hot ethanol. An immediate 35 precipitate results and is filtered off after the mixture has cooled. The recovered precipitate is successively washed with ethanol, chloroform then ether. The washed solid precipitate is then recrystallized from dimethylformamide (DMF) whereby 0.6 g. (representing a yield of 6.19% of theoretical) of off-white solid chlorhexidine dinalidixate having a meltirfg point of 2241 to 2261C is obtained. IR (KBr disc): bands at 3330-2860 (broad multiplet), 1625, 1492, 1445, 1252, 1132, 1092, 820 and 745 cm-1 AnaL CalcA for C461-1.4C12N1406 C, 56.96; H, 5.61; N, 20.21; Cl, 7.3 1; 0, 9.90 Found. C, 56.86; H, 5.74; N, 20.2 1; Cl, 7.25.
EXAMPLE 2
K_ r 20 dk P 'p, A warm solution of 505 mg. (1.0 mmole) of chlorhexidine free base in 50 mi. methanol is added to 45 a solution of 346 mg. (1.0 mmole) of phosphanilic acid in 250 mi. of hot water. The resultant solution is then evaporated to approximately 50 mi. and cooled whereby a waxy solid separates. The waxy solid is filtered off, washed with water then recrystallized from water. After drying, 205 mg. of chlorhexidine diphosphanilate dihydrate, having a melting point of 1 720-1740C, are produced. This represents a 3 GB 2 118 041 A 3 yield of 23.1 % of theoretical. A ROH = 255 (Am = 51,600) I'R (KBr disc): bands at 3460 to 2930 (broad max multiplet), 1650 to 1600 (broad multiplet), 1515, 1490, 1420, 1130 and 828 em--'.
AnaL Cale'd for C34HWC1,1\1,0,P, C, 45.99; H, 5.67; Cl, 7.98; N, 18.93; 0, 14.42; P, 6.91. Found C, 45.94; H, 5.75; Cl, 8.25; N, 19.00; P, 6.85.
EXAMPLE 3
A hot solution of 224 mg. (2.0 mmole) of sorbic acid in 10 mi. ethanol is added to a hot solution of 505 mg. (1.0 mmole) of chlorhexidine free base in 50 mi. ethanol. The resulting solution is evaporated to a solid. The solid is then crystallized from ethanol/isopropanol (1 A by volume). The thus crystallized product is dried whereby 527 mg. chlorhexidine disorbate monohydrate are produced. The chlorhexidine disorbate monohydrate is produced as a white powder which shrinks 901-1 OOIC and 10 melts at 1000-1 041C. The amount of chlorhexidine disorbate monohydrate recovered represents a yield of 70.5% of theoretical. X E10H = 253 (Am = 79,000) IR (KBr disc): bands at 3460 to 2870 (broad max multiplet), 1650 to 1600 (broad multiplet), 1540,1490,1390, 1000 and 825 em-'.
AnaL Calc'd for C3,1H41C12N1,0, C, 54.61; H, 6.47; Cl, 9.49; N, 18.73; 0, 10.70.
Found C, 54.87: H, 6.65; Cl, 9.68; N, 18.49.
Chlorhexidine dinalidixate and chlorhexidine diphosphanilate produced in Examples 1 and 2, were tested for their activity in vitro against 32 strains of Pseudomonas aeruginosa, 26 strains of other gramnegative organisms and 18 gram-positive organisms. Minimum inhibitory concentration data for the reference standards, chlorhexidine digluconate, chlorhexidine diacetate, nalidixic acid and phosphanilic acid, were also obtained. Chlorhexidine base could not be employed as a reference as it is unstable. The 20 results of the study are reported in Table 1 as follows:
TABLE 1 Antibacterial Activity of Chlorhexidine Di Nalidixate and Chlorhexidine Di Phosphanilate Salts MIC (jug/mi) Chlorhexidine Number Gram of Nalidixic Phosphanilic Nalidixic Phosphanilic Organism Stain Strains Acid Salt Acid Salt Digluconateb Diacetateb Acid Acid S. aureus + 6 6.4 4 4 2 44.8 >125 S. pneumoniae + 4 19 16 16 13.5 >125 >125 S.pyogenes + 3 a 5 5 4 >125 >125 S. Viridans. + 1 63 32 63 32 125 >125 Streptococcus (p-hemolytic) + 2 11.3 8 5.7 5.7 >125 >125 S. faecalis + 2 16 8 8 5.7 >125 >125 E. col! 3 8 10 10 5 16 79.4 K. pneumoniae 2 2.8 88.7 63 32 11.3 32 1 8 63 32 32 16 >125 E. cloacae 3 6.4 32 32 16 25.4 >79.4 1 1, Ir -Pb G) W N CD 0 -P.
-P.
A TABLE 1 (continued) Antibacterial Activity of Chlorhexidine Di Nalidixate and Chlorhexidine Di Phosphanilate Salts MIC (Pg/M0a Chlorhexidine Number Gram Of Nalidixic Phosphanilic NaHdixic Phosphanilic Organism Stain Strains Acid Salt Acid Salt Digluconate b Diacetate b Acid Acid P. mirabilis - 2 16 22.6 88.7 88.7 11.3 8 1 16 32 >125 >125 16 125 P. morganii - 2 2.8 22.6 16 5.7 8 44.7 P. rettgeri - 1 1 63 63 32 2 32 2 11.3 11.3 >125 >125 11.3 1.4 P. vulgarls - 2 2.8 8 >125 >89 4 2.8 1 16 16 125 125 16 63 S. marcesceus - 3 4 1.3 50.3 >125 6.4 0.5 P. stuartii - 2 11.3 5.7 44.9 32 16 2.8 1 16 16 125 >125 16 2 P. aeruginosa - 26 48.6 3.2 >125 >125 >125 1.5 42 72.5 >125 125 >125 36.4 1 32 63 125 125 >125 >125 Geometric mean MIC values where applicable b In terms of chlorhexidine content G) m N (n 6 GB 2 118 041 A 6 The data of Table 1 shows that the dinalidixic acid salt of chlorhexidine is more effective than either nalidixic acid or chlorhexidine alone as against many of the strains tested. The data shows chlorhexidine dinalidixate to be particularly active against all strains of P. aeruginosa as well as against individual strains of K pneumoniae, E. cloacae and P. morganfl while chlorhexidine diphosphanilate is seen to be effective against 26 out of 32 strains of P. aeruginosa and a strain of P. mirabilis and P. vulgaris.
The results of Table 1 indicate that the nalidixic acid salt of chlorhexidine is more effective than either of its two components alone.
To more fully investigate the synergistic effect of the novel salts of the present invention, chlorhexidine dinalidixate, chlorhexidine disorbate and chlorhexidine diphospha ni late, as well as nalidixic acid, phosphanilic acid, chlorhexidine diacetate and a 1:1 mixture of chlorhexidine digluconate 10 and nalidixic acid, were tested for activity in vitro against 30 strains of Pseudomonas aeruginosa, 23 strains of other gram-negative organisms and 15 gram-positive organisms. Minimum inhibitory concentrations of the novel salts of the instant invention as well as the reference standards (viz. chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine disorbate, nalidixic acid, phosphanilic acid and the 1:1 mixture of chlorhexidine digluconate and nalidixic acid) were obtained. In contrast to the procedure employed in obtaining the results of Table 1, all compounds were tested on a straight weight basis and in a medium low in antibiotic antagonists (viz. Mueller-Hinton Broth + 1 % lonager), thus.increasing antibiotic sensitivity.
The results, as reported in Table 11 which follows, show chlorhexidine dinalidixate to be more effective than either chlorhexidine or nalidixic acid, particularly against strains of Klebsiella pneumoniae, 20 and Enterococcus cloacae and 28 of 30 strains of P. aeruginosa. The phosphanilic acid salt of chlorhexidine shows clear improvement over phosphanilic acid and chlorhexidine alone as against 4 of 30 strains of P. aeruginosa. The results also show chlorhexidine diphosphanilate to be a very effective antipseudomonal. It inhibits 29 of the 30 strains of P. aeruginosa at MIC values of 8 pg/mi or less as compared to chlorhexidine digluconate, diacetate and disorbate, which inhibit only 2 strains below 8 pg/mi.
k -j TABLE 11 Antibacterial Activity of Various Salts of Chlorhexidine in Mueller-Hinton Broth Supplemented with 1 % lonagar MIC (AgIM1)a Chlorhexidine Digluco-' Number nate + Gram Of Nalidixic Nali- PhosphanDiglu- Diace- Disor- Nalidixic Phosphan- Organism Stain Strains Acid 0/1) dixate ilate conate tate bate Acid ilic Acid S. aureus + 4 1.2 0.21 0.25 0.25 0.21 0.21 32 >125 S. pneumoniae + 3 99.5 12.7 10.1 10.1 6.4 12.7 >125 >125 S.pyogenes + 3 16 4 3.2 3.2 3.2 1.6 >125 >125 S. viridans + 1 63 16 16 16 8 16 >125 >125 Streptococcus (B-hemolytic + 2 16 4 4 1.4 1.4 1.4 >125 >125 S. faecalis + 2 11.3 8 4 2 2 2 >125 >125 E. coli 3 1 0.63 0.63 0.63 0.32 0.63 2 32 K. pneumoniae 2 1.4 1 2.8 4 2.8 4 2.8 16 1 2 1 4 4 4 4 4 >125 E. cloacae 1 1 1 4 4 1 4 4 16 2 1.4 1 2.8 2.8 1 2.8 4 >125 r') 0 t 0D TABLE 11 (continued) Antibacterial Activity of Various Salts of Chlorhexidine in Mu61ler-Hinton Broth Supplemented with 1 % lonagar MIC (pg/mi)o Chlorhexidine Digluco Number nate + Gram of Nalidixic, NailPhosphan- Diglu- Diace- Disor- Nalidixic Phosphan- Organism Stain Strains Acid 0/1) dixate ilate conate tate bate Acid ilic Acid P. mirabilis 3 6.4 4 4 12.7 8 16 4 3.2 P. rettgeri 1.0.5 - 0.5.1 1. 8 4. 4 0.25 1 3 5 4 6.4 16 8 16 2.5 1.3 P. vulgaris 1 4 1 4 2 1 2 0.5 >125 S. marcescens 3 2,5 2.5 2 6.4 12.7 6.4 1.3 0.5 stu.artil 2 4 2.8 2 4 2 4 2 2.8 1 8 4 4 16 16 16 4 4 11 4 v G) W N 00 1 (D TABLE 11 (continued) Antibacterial Activity of Various Salts of Chlorhexidine in Mueller-Hinton Broth Supplemented with 1 % lonagar MIC (,4g/M1)a Chlorhexidine Digluco Number nate + Gram of Nalidixic Nali- Phosphan- Diglu- Diace- Disor- Nalidixic PhosphanOrganism Stain Strains Acid 0/1) dixate ilate conate tate bate Acid ilic Acid P. aeruginosa - 1 8 2 2 4 4 4 63 1 1 8 4 8 4 4 4 63 63 1 8 4 16 32 32 32 63 >125 1 8 4 2 16 16 16 >125 63 19 8.9 4.5 1.9 19.2 18.5 19.2 65.3 0,77 12.1 8 2.6 18.4 18.4 18.4 >125 1.2 2 8 8 5.7 16 16 16 63 63 b geometric MIC values where applicable.' Inocula: The majority of cultures were diluted 1 000-fold; all the streptococci, except S. faecalis were used undiluted.
G) m N) W GB 2 118 041 A 10 To more fully amplify the unexpected synergism of the novel salts of the present invention the MIC values, reported in Tables 1 and 11 inug/mi, were converted to MIC values of p moles/mi using the following molecular formulae and molecular weights:
Chlorhexidine disorbate monohydrate C34H4BC12N1005 747.72 Chlorhexidine dinalidixate C461-154C12N1406 969.94 Chlorhexidine diphosphanilate dihydrate C34H50C12N1208P2 856.72 Chlorhexidine digluconate C341-154C12014N10 897.80 Chlorhexidine diacetate C261-138C12N1004 625.56 4 Nalidixic acid C12H12N203 232.23 Phosphanilic acid C61-18N03 142.13 Tables Ill and W show the results of such conversion and enable a comparison of potencies on a more meaningful molecule to molecule basis rather than gram to gram basis.
TABLE Ill Antibacterial Activity of Chlorhexidine as a Nalidixic Acid and Phosphanilic Acid Salt MIC (pmoles/mix 103) Chlorhexidine Number Gram of Nalidixic Phosphanilic Nalidixic Phosphanilic Organism Stain Strains Acid Salt Acid Salt Digluconate Diacetate Acid Acid S. aureus + 6 6.6 4.6 4.5 3.2 193 >880 S. pneumoniae + 4 19.6 18.6 17.8 21.5 >539 >880 S.pyogenes + 3 8.2 5.8 5.6 6.4 >539 >880 S. viridans + 1 64.9 37,3 70.1 51.1 539 >880 Streptococcus (P-hemolytic) + 2 11.6 9.3 6.3 9.1 >539 >880 S. faecalis + 2 16.5 9.3 8.9 9.1 >539 >880 E. coli - 3 8.2 11.7 11.1 8.0 68.9 559 K. pneumoniae - 2 2.9 103.5 70.1 51.1 48.7 225 1 8.2 73.5 35.6 51.1 68.9 >880 E. cloacae - 3 6.6 37.3 35.6 25.6 109 >559 P. mirabilis - 2 16.5 26.3 98.8 141.6 48.7 56.3 1 16.5 37.3 >139 >200 68.9 880 P. morgaffil - 2 2.9 26.3 17.8 9.1 34.4 315 G) m N) hi TABLE Ill (continued) Antibacterial Activity of Chlorhexidine as a Nalidixic Acid and Phosphanilic Acid Salt MIC,(,umoleWmi x 103) Chlorhexidine Number Gram of Nalidixic Phosphanilic Nalidixic Phosphanilic Organism Stain Strains Acid Salt Acid Salt Digluconate Diacetate Acid Acid P. rettgeri 1 1 73.5 70.1 51.1 8.6 225 2 11.6 13.0 >139 >200 48.7 9.8 P. vulgarls 2 2.9 9.3 >139 >142 17.2 19.7 1 16.5 18.6 139 200 68.9 444 S. marcescens - 3 4 2. 56 >200 27.5 3.5 P. stuartii - 1 11.6 6.6 50 51.1 68.9 19.7 2 16.5 18.6 139 >200 68.9 14.1 P. aeruginosa - 26 50.1 3.6 >139 >200 >539 10.6 43.2 84.3 >139 200 >539 256 1 32.9 73.5 139 200 >539 >880 1 1 G) C0 N N W TABLE W Antibacterial Activity of Various Salts of Chlorhexidine in Mueller-Hinton Broth Supplemented with 1 % lonagar MIC (iumole/mi x 103) Chlorhexidine Chlorhexi dine Diglu Number conate + Gram of Nalidixic Nali- Phosphan- Diglu- Diace- DisorNalidixic Phosphan- Organism Stain Strains Acid (1:1) dixate ilate conate tate bate Acid ilic Acid S. aureus + 4 2.3 0.2 0.3 0.3 0.3 0.2 137 >880 S. pneumoniae + 3 193 13 11.7 11.2 10.2 17.0 >539 >880 S.pyogenes + 3 31 4 3.7 3.5 5.1 2.1 >539 >B80 S. viridans + 1 12 1.6 18.6 17.8 12.7 21 >539 >880 Streptococcus (p-hemolytic) + 2 31 21.9 8.2 4.6 2.2 3.1 >539 >880 S. faecalis + 2 21.9 8.2 4.6 2.2 3.1 2.6 >539 >880 E. coli - 3 1.9 0.6 0.7 0.7 0.5 0.8 8.6 225 K. pneumoniae - 2 2.7 1 3.2 4.4 4.1 5.4 12 112 1 3.8 1 4.6 4.4 1.5 5.4 17.2 >880 E. colacae - 1 1.9 1 4.6 4.4 1.5 5.4 17.2 112 2 2.7 1 3.2 3.1 12.7 3.7 17.2 >880 P. mirabills - 3 12.4 4 4.6 14.1 6.4 21 17.2 22.5 a) W hi h 1 TABG IV (contin'Ued) Antibacterial Activity of Various Salts of Chlorhexidine in Mueller-Hinton Broth Supplemented with 1 % lonagar MIC (iumole/mi x 103) Chlorhexidine Chlorhexi dine biglu Number conate + Gram of Nalidixic Nali- Phosphan- Diglu- Diace- Disor- Nalidixic Phosphan- Organism Stain Strains Acid W1) dixate ilate conate tate bate Acid ilic Acid P. rettgeri 1 0.9 0.5 1 8.9 12.7 5.4 1 7 3 9.7 4 7.4 17.8 1.5 21 10.7 9 P. vulgaris 1 7.7 1 4.6 2.2 20.3 2.6 2.1 >880 S. marcescens 3 1.9 2.5 2.3 7.1 3.1 8.6 5.6 3.5 P. stuatii 2 7,71 2.8 2.3 4.4 1.6 5.4 8.6 19.7 1 15.5 4 4.6 17.8 6.4 21 17.2 28 P. aeruginosa 1 15.5 2 2.3 4.4 6.4 5.4 271 7 1 15.5 4 9.3 4.4 51.1 5.4 271 443 1 15.5 4 18.6 35.6 25.5 4.3 271 >880 1 15.5 4 2.3 17.8 29.6 2.4 >539 443 19 17.2 4.5 2.2 21.4 29.4 25 281 5.4 23.4 12.1 2.8 20.5 29.3 24 539 8.4 2 15.5 8 6.1 17.8 32.4 21 271 443 1 - 1 a) m rIj 0.P.
41 GB 2 118 041 A The results of Table Ill clearly indicate that the novel chlorhexidine dinalidixate and diphosphanilic salts of the instant invention are potent and exhibit synergistic effect particularly against P. aeruginosa with the nalidixate salt being the most widely synergistic. The novel disorbate salt of the present invention demonstrates clear synergism against several species. The synergisitc effect of chlorhexidine 5 dinalidixate is clearly seen by comparison of the results of Table Ill for K. pneumonia, E. cloacae, P. mirabilis, P. morganfl, P. rettgeri, P. vulgaris, S. marcescens, P. stuartilandP. aeruginosa. For example, chlorhexidine dinalidixate is seen to have an MIC of 2.9 as against two strains of K. pneumonia and 8.2 against one strain of this organism. The corresponding values for nalidixic acid are 48.7 and 68.9; while those for chlorhexidine digluconate and chlorhexidine diacetate are respectively 70.1 and 35.6 and 51.1 and 5 1. 1.
The novel chlorhexidine dinalidixate of the present invention is seen to display a most impressive synergistic effect as against P. aeruginosa. Against 26 strains of this organism chlorhexidine dinaladixate exhibited an MIC of 50.1; against five strains of such organism, it exhibited an MIC of 412; while against one strain of such organism, it exhibited an MIC of 32.9. In contrast thereto, nalidixic acid exhibited against these strains, MIC values, in each case, of more than 539 while chlorhexidine 15 digluconate and chlorhexidine diacetate exhibited, as against the same strains, MIC values of respectively more than 139, more than 139 and 139 and more than 200, 200 and 200.
The synergistic effect of chlorhexidine dinalidixate is also clearly demonstrated from the results of Table IV. Synergisim is seen as against K. pneumoniae, E. cloacae, P. mirabills, P. rettgeri, S.
marcescens, P. stuartil and P. aeruginosa.
Referring again to Table Ill, chlorhexidine diphosphanilate of the present invention demonstrates marked synergism against S. viridans, P. mirabilis, P. vulgaris, one strain of P. stuartif and numerous strains of P. aeruginosa.
The results of Table IV demonstrate the asserted synergism of chlorhexidine diphosphanilate as against one strain of P. rettgeri and numerous strains of P. aeruginosa.
Referring again to Table IV, the synergistic effect of chlorhexidine disorbate is most clearly demonstrated as against S. pyogenes, one strain of P. rettgeri and numerous strains of P. aeruginosa.
The present invention also contemplates dermatological compositions comprising a novel chlorhexidine salt of the instant invention and a dermatological ly acceptable carrier therefor.
Suitable compositions include creams, lotions, suspensions, emulsions, ointments and pastes. 30 Compositions in which a novel chlorhexidine salt of the present invention is produced in such compositions, in situ, are also within the scope of the invention.
The following formulations are offered to illustrate the compositions of the invention. Although a particular formulation utilizes one of the novel compounds of the invention, it should be readily appreciated that any of the novel compounds or, for that matter, a mixture of such compounds, could be 35 employed in lieu thereof.
Formulations 1 through 6, set forth in Table V which follows, are prepared according to the following general procedure.
In a suitably sized premixed container, the Stearyl Alcohol is dissolved in the Petrolatum with the aid of heat and gentle stirring. The temperature is then adjusted to about 62 to 6WC.
The Propylene Glycol and about 99% of the purified water are combined in a suitably sized, preferably jacketed, main mix vessel and stirred until a homogeneous solution is obtained. The resultant solution is heated to 62 to 681C then subjected to high speed mixing (preferably utilizing a suitable propeller mixture such as the Lightnin model ARL air mixer or similar type apparatus). The Carbomer is then slowly added thereto. High speed mixing is continued until the Carbomer is completely dispersed 45 (approximately one hour). The Sodium Lauryl Sulfate, Sorbic Acid and the Amphoteric-9 are then added, while mixing slowly, and the resultant mixture is mixed slowly until it is homogeneous.
In a suitably sized container, the remainder of the water (about 1 %) is heated to about 40 to 450C then the Dried Sodium Phosphate is added thereto under rapid stirring. The stirring is continued until a clear solution results. The clear Sodium Phosphate solution is then added to the mixture in the main mix 50 vessel while mixing slowly. Mixing is continued until a smooth semi-gel is formed. While mixing slowly, heating is initiated. The temperature is adjusted to about 62 to 680C.
The Petrolatum and Stearyl Alcohol, constituting the oil phase, are then slowly added to the main mix vessel containing the ingredients constituting the aqueous phase. This addition is made while mixing the aqueous phase at high speed. Mixing is continued for a period of about 5 to 10 minutes then 55 cooling is initiated (preferably by circulation of cold water in the outer jacket of the main mixed vessel).
During this cooling operation, the mixture is subjected to slow speed agitation (preferably using a side scraping sweep agitator of the Groen type or the like). The mixture is cooled to a temperature of about to 301C whereby a finished base is produced.
A small amount of the finished base (an amount sufficient to produce a workable consistency: 60 About 5% in the case of Formulations 1 and 4; about 10% in the case of Formulations 2 and 5 and about 15% in the case of Formulations 3 and 6) is added to a suitably sized container. The novel chlorhexidine salt of the present invention is added thereto and mixed therewith (with the aid of a spatula or suitable mixer) until it is uniformly dispersed in the finished lotion base. The dispersion is passed through a roller mill (preferably of the Asra type or the like) at an appropriate setting to produce 65 16 GB 2 118 041 A 16 a fine non-gritty particle size. This procedure is repeated if necessary whereby a milled concentrate is obtained.
The milled concentrate is then added to the remaining finished base and mixed therewith at slow speed (preferably using a sweep agitator) for one hour or until the uniform dispersion is formed.
TABLE V
Formulation Chlorhexidine Disorbate Chlorhexidine Dinalidixate Chlorhexidine Diphosphanilate Propylene Glycol, USP Petrolatum, LISP Stearyl Alcohol, LISP Amphoteric-9 Carbomer-940 Sodium Lauryl Sulfate, LISP Sorbic Acid, N F Dried Sodium Phosphate Purified Water qs to No. 1 1.00 2 Percentage (by weight) 3 4 5.00 3.00 12.00 12.00 5.84 5.84 2.00 2.00 0.66 0.66 0.20 0.20 0.10 0.10 0.10 0.10 0.10 0.10 100.00 100.00 1.00 12.00 5.84 2.00 0.66 0.20 0.10 0.10 0.10 100.00 3.00 5.00 12.00 12.00 12.00 22.50 22.50 22.50 15.00 15.00 15.00 0.66 0.66 0.66 0.50 0.50 0.50 0.10 0.10 0.10 0.10 0.10 0.10 0.25 0.25 0.25 1bo.oo loom loom Formulations 7, 8 and 9, sat forth in Table V1 which follows, are prepared according to the following general procedure:
The Peg-8 and the Lactic Acid are added to a, preferably stainless, premix container of suitable size and mixed slowly until a homogeneous solution is obtained.
The Petrolatum, Mineral Oil, Lanolin Oil, Cetyl Alcohol, Hydrogenated Polyisobutene, Peg-40 10 Stearate, Benzyl Alcohol and Sodium Lauryl Sulfate are added to a main mix vessel which is preferably of stainless steel and steam jacketed (e.g. Groen Model TX/2-20 or the like). The mixture is agitated slowly (preferably using a Lightnin air mixer or a similar type mixture equipped with a propeller type blade) and heated. Miging and heating is continued untiltall solids are melted. The temperature is iadjusted to about 65 to 700C. Mixing is continued for about 10 minutes then heating and agitation are discontinued. The mixture is then cooled (preferably by introduction of cold water into the outer jacket) and slow speed mixing is initiated (preferably with a side scraping sweep agitator). The mixture is permitted to cool to about 40 to 450C during which time continuous mixing is maintained. The solution of Lactic Acid and Peg-8 is then added to the ingredients
contained in the main mix vessel, said ingredients constituting the oil phase. The addition is carried out slowing and with constant 20 mixing. Mixing and cooling are continued until a temperature of about 25 to 300C is attained whereby a finished base is produced.
A small amount of the finished base (viz. an amount sufficient to produce a workable consistency; approximately 5% in the case of Formulation 7, approximately 10% in the case of Formulation 8 and approximately 15% in the case of Formulation 9) is added to a suitably sized mixing container (for example a Hobart Model A-200D or the like) and the Chlorhexidine Diphosphanilate is added thereto. The combination of the Chlorhexidine Diphosphanilate and finished base is mixed slowly until a fairly uniform dispersion of the salt results. The dispersion is passed through a roller mill (preferably of the Asra type or the like) at an appropriate setting to produce a fine non-gritty particle size whereby a milled concentrate is obtained.
The milled concentrate is added to the finished base and mixed therewith at slow speed (preferably employing a side scraping sweep agitator, for example of the Groen type or the like) for about one hour or until a homogeneous dispersion is obtained.
1 17 GB 2 118 041 A 17 TABLE VI
Percent (by weight) Formulation No. 7 8 9 Chlorhexidine Diphosphanilate 1.000 3.000 5.000 Mineral Oil USP 10.000 10.000 10.000 Peg-8 8.000 8.000 8.000 Lanolin Oil 4.000 4.000 4.000 Cetyl Alcohol 3.000 3.000 3.000 Hydrogenated Polyisobutene 3.000 3.000 3.000 Peg-40 Stearate 2.000 2.000 2.000 Benzyl Alcohol 0.500 0.500 0.500 Sodium Lauryl Sulfate USP 0.100 0.100 0.1000 Lactic Acid (88%) 0.002 0.002 0.002 Petrolatum LISP qs to 100.000 100.000 100.000 Formulations 10, 11 and 12, set forth in Table VII which follows, are produced according to the following general procedure:
The Glyceryl Oleate/Propylene Glycol, Peg-7-Hydrogenated Castor Oil, Sorbitan Oleate, Oleoyl Hydrogenated Animal Protein, Arlacel 481, Light Mineral Oil, Hydrogenated Polyisobutene, Lanolin 5 Alcohol/Mineral Oil, Caprylic/Capric Triglycerides, Propyl Paraben and Beeswax are added to a, preferably stainless steel and jacketed, premix container or suitable size. The mixture is subjected to heating and slow mixing (preferably with a Lightnin Model ARL air mixer with propeller type agitator or similar apparatus). The temperature is adjusted to about 75 to 851C whereby an oil phase is produced.
The water, Lactic Acid, Propylene Glycol and Dried Sodium Phosphate are added to a main mixing 10 vessel which is preferably of stainless steel and jacketed (for example the Groen Model T13C/2-20 or similar apparatus). This addition is made while heating and mixing at moderate speed (preferably employing a Lightnin Model ARL air mixer or the like). Mixing is continued until a clear solution is formed, then the Sorbitol, Methyl Paraben and the Titanium Dioxide are added. Mixing and heating are continued until a homogeneous mixture is produced. The temperature is adjusted to about 75 to 851C 15 whereby a water phase is produced. When the water phase and the oil phase are at a proper temperature, the oil phase is added slowly to the water phase while mixing constantly at moderate speed (preferably employing a Lightnin Model ARL air mixer or similar apparatus) whereby an emulsion is produced. The Magnesium Stearate is added to the emulsion and mixed therewith for about 20 minutes at a temperature of about 75 to 851C. The heating is then discontinued (preferably by 20 introduction of cold water into the outer jacket of the main mixing vessel). Slow speed mixing is initiated (preferably using a side scraping sweep agitator (such as the Groen Model TX/2-20 style agitator or similar apparatus). Mixing and cooling is permitted to continue until the temperature reaches about 25 to 301C whereby a finished base is produced.
A small amount of the finished base (viz. an amount sufficient to produce a workable consistency; 25 about 5% in the case of Formulation 10, about 10% in the case of Formulation 11 and about 15% in the case of Formulation 12) is added to a suitably sized container. The novel chlorhexidine salt of the present invention is then added thereto and mixed therewith using a spatula or other suitable mixer until a fairly uniformed dispersion of the salt in the ointment base results. This dispersion is passed one or more times through a roller mill of suitable capacity (preferably of the Asra type or the like) at an 30 appropriate mill setting to produce a fine non-gritty particle size whereby a milled concentrate is produced.
The milled concentrate is added to the remaining finished base and mixed therewith (preferably using a Groen sweep agitator or similar equipment) at slow speed for about one hour or until a homogeneous dispersion is formed.
It should be noted that as employed in Formulation 10, Arlacel 481 is a trademark of [Cl America Inc. and is a mixture of Sorbitan Oleate, Hydrogenated Castor Oil, Beeswax and Stearic Acid.
18 GB 2 118 041 A 18 TABLE V1 I
Percent (by weight) Formulation No. 10 11 12 Chlorhexidine Disorbate 1.00 - - Chlorhexidine Dinalidixate - 3.00 - Chlorhexidine Diphosphanilate - 5.00 Propylene Glycol 12.00 12.00 12.00 Light Mineral Oil USP 10.84 10.84 10.84 Hydrogenated Polylsobutene 10.00 10.00 10.00 Caprylic/Capric Triglycerides 10.00 10.00 10.00 Beeswax 10.00 10.00 10.00 Peg-7-Hydrogenated Castor Oil 8.00 8.00 8.00 Lanolin Alcohol/Mineral Oil 6.00 6.00 6.00 Arlacel 481 4.00 4.00 4.00 Sorbitol 3.00 3.00 3.00 Glyceryl Oleate/Propylene Glycol 2.00 2.00 2.00 Sorbitan Oleate 2.00 2.00 2.00 Oleoyl Hydrogenated Animal Protein 2.00 2.00 2.00 Magnesium Stearate 2.00 2.00 2.00 Titanium Dioxide 1.00 1.00 1.00 Methyl Paraben 0.25 0.25 0.25 Propyl Paraben 0.20 0.20 0.20 Dried Sodium Phosphate 0.11 0.11 0.11 Lactic Acid (88%) 0.1Q 0.10 0.10 Purified Water qs to 100.00 100.00 100.00 Mixtures of chlorhexidine or pharmaceutically acceptable salts of chlorhexidine (e.g. chlorhexidine digluconate) with nalidixic acid or pharmaceutically acceptable salts of nalidixic acid display synergism when used to prevent growth of microorganisms such as klebsiella pneumoniae, enerobacter cloacae, and pseudomonas aeruginosa. The calculated synergism indices show that said mixtures should contain from 35 to 65 weight percent of chlorhexidine or a pharmaceutically jacceptable chlorhexidine salt and from 65 to 35 weight percent of nalidixic acid or a pharmaceutical ly, acceptable salt of nalidixic acid. Preferably said mixtures should contain an approximately equal weight percent of each of the above acceptable compounds selected.
Mixtures of chlorhexidine or pharmaceutical ly acceptable salts or chlorhexidine (e.g. chlorhexidine 10 digluconate) with phosphanilic acid or pharmaceutically acceptable salts of phosphanilic acid display synergism when used to prevent growth of microorganisms such as staphylococcus aureus, streptococcus pyogenes, streptococcus faecalis, and pseudomonas a6ruginosa. Said mixtures should contain from 35 to 65 weight percent of chlorhexidine or a pharmaceutically acceptable- chlorhexidine salt and from 65 to 35 weight percent of phosphanilic acid or a. phcjrmaceutically acceptable salt of is phosphanilic acid. Preferably said mixtures should contain an approximately equal weight percent of 0 A 1 1 19 GB 2 118 041 A 19 each of the above acceptable compounds selected.

Claims (8)

  1. CLAIMS of 1. An antibacterial composition comprising a synergistic mixture
    of from 35 to 65 weight percent (a) chlorhexidine or a pharmaceutically acceptable chlorhexidine salt, and from 65 to 35 weight 5 percent of (b).
    of Of (b) nalidixic acid or a pharmaceutically acceptable salt of nalidixic acid.
  2. 2. A composition according to claim 1 comprising approximately equal weight percents of (a) and
  3. 3. An antibacterial composition comprising a synergistic mixture of from 36 to 65 weight percent 10 (a) chlorhexidine or a pharmaceutically acceptable chlorhexidine salt, and 65 to 35 weight percent (b) phosphanilic acid or a pharmaceutically acceptable salt of phosphanilic acid.
  4. 4. A composition according to claim 3 comprising approximately equal weight percents of (a) and 15
  5. 5. A composition according to claim 1, 2, 3 or 4 wherein (a) is chlorhexidine digluconate.
  6. 6. An antibacterial composition according to claim 1, substantially as hereinbefore described in any one of the Examples.
  7. 7. A method of inhibiting the growth of a microorganism wherein the microorganism is one sensitive to a composition according to any of claims 1 to 6, and wherein the microorganism is contacted with an amount of the said composition sufficient to inhibit its growth.
  8. 8. A method according to claim 6, wherein the microorganism is Klebsiella pneumoniae, Enterobacter cloacae or Pseudomonas aeruginosa, and wherein the said composition comprises chlorhexidine, or a pharmaceutical ly acceptable chlorhexidine salt, with nalidixic acid, or a pharmaceutically acceptable nalidixic acid salt.
    Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa. 1983. Published by the Patent Office, 25 Southampton Buildings. London, WC2A lAY, from which copies may be obtained.
    8. A method according to claim 7, wherein the microorganism is Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis or Pseudomonas aeruginosa, and wherein the said composition comprises chlorhexidine, or a pharmaceutical ly acceptable chlorhexidine salt, with phosphanilic acid, or a pharmaceutically acceptable phosphanilic acid salt.
    9. A method according to claim 7, wherein the microorganism is Klebsiella pneumoniae, Enterobacter cloacae or Pseudomonas aeruginosa, and wherein the said composition comprises chlorhexidine, or a pharmaceutical ly acceptable chlorhexidine salt, with nalidixic acid, or a pharmaceutically acceptable nalidixic acid salt.
    New or amended claims:- Claim 6 deleted and appendant claims and appendancies revised.
    CLAIMS Of (b).
    percent of of of (b).
    1. An antibacterial composition comprising a synergistic mixture of from 35 to 65 weight percent (a) chlorhexidine or a pharmaceutically acceptable chlorhexidine salt, and from 65 to 35 weight (b) nalidixic acid or a pharmaceutically acceptable salt of nalidixic acid.
    2. A composition according to claim 1 comprising approximately equal weight percents of (a) and 3. An antibacterial composition comprising a synergistic mixture of from 35 to 65 weight percent (a) chlorhexidine or a pharmaceutical ly acceptable chlorhexidine salt, and 65 to 35 weight percent (b) phosphanilic acid or a pharmaceutically acceptable salt of phosphanilic acid.
    4. A composition according to claim 3 comprising approximately equal weight percents of (a) and 5. A composition according to claim 1, 2, 3 or 4 wherein (a) is chlorhexidine digluconate.
    6. A method of inhibiting the growth of a microorganism on an inanimate surface, wherein the microorganism is one sensitive to a composition according to any of claims 1 to 5, and wherein the 50 microorganism is contacted with an amount of the said composition sufficient to inhibit its growth.
    7. A method according to claim 6, wherein the microorganism is Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis or Pseudomonas aeruginosa, and wherein the said composition comprises chlorhexidine, or a pharmaceutical ly acceptable chlorhexidine salt, with phosphanilic acid, or a pharmaceuticaliy acceptable phosphanilic acid salt.
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