US3888947A - Bis-biguanides - Google Patents

Bis-biguanides Download PDF

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US3888947A
US3888947A US254440A US25444072A US3888947A US 3888947 A US3888947 A US 3888947A US 254440 A US254440 A US 254440A US 25444072 A US25444072 A US 25444072A US 3888947 A US3888947 A US 3888947A
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chlorhexidine
mono
hedta
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solution
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Ronald Arthur Stephenson
Bente Lissy Laursen
Ove Henning Mattsson
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Kemanord AB
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    • 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

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  • PATENTEDJUH 10 I975 SHEET com 256 a 5535 No BIS-BIGUANIDES
  • This invention concerns novel bis-biguanides, processes for their preparation, and compositions incorporating them. More specifically, the invention relates to certain novel bis-biguanide salts which appear to have interesting bactericidal properties, and which may thus be of use in human or veterinary medicine.
  • Bis-biguanides are known (in general) to have certain bactericidal properties, and one such compound in particular l,6-bis-(N -p-chlorophenyldiguanido-N hexane, which has the open name chlorohexidine has found considerable use in medicine as a bactericide, and primarily as a general disinfectant.
  • the known bis-biguanide bases and most of their salts are only sparingly soluble in water (which is the solvent of choice for making up disinfectant compositions), and therefore have a limited use from a commercial point of view.
  • this invention provides a salt of a known bactericidally active bis-biguanide base with a sequestering amino-carboxylic acid falling within the general formula:
  • R represents hydrogen, an alkyl group, a carboxymethyl group, a hydroxyethyl group or a hydroxypropyl group
  • R represents a carboxymethyl group, a hydroxy ethyl group or a hydroxypropyl group
  • Z represents the group [CH ,.CH .N(R)],,- (wherein R is defined as R, though is not necessarily identical thereto, and n is 0,1,2 or 3), or Z represents the group (Ill) (wherein R" is as defined hereinbefore), subject to the proviso that, when n is l R,, R and R are carboxymethyl groups.
  • Typical amino-carboxylic acids falling within general formula II are:
  • EDDA N,N'-ethylenediaminediacetic acid
  • HEDTA N-hydroxyethylethylenediaminetriacetic acid
  • HEDDA N,N-dihydroxyethylenediaminediacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • CDTA l,2-diaminocyclohexanetetraacetic acid
  • NTA nitrilotriacetic acid
  • HIMDA N-hydroxyethyliminodiacetic acid
  • DAA N,N-dihydroxyethylaminoacetic acid
  • iminodiacetic acid n O, R hydrogen and R carboxymethyl
  • HPIMDA 3-hydroxypropyliminodiacetic acid
  • HEDTA DTPA aminocarboxylic acids
  • NTA aminocarboxylic acids
  • DAA aminocarboxylic acids
  • the compounds may essentially be regarded as the reaction product between the acidic sequestering amino-carboxylic acid and the basic bis-biguanide (and can, thus, be referred to generally not only as salts but also as sequestrates) may contain the two compounds (the acid and the base) in varying proportions, because the acids are mostly poly-acidic (they have two or more acid groups) and chlorhexidine is dibasic, and because all of the basic/acidic groupings may not necessarily be used up.
  • the acidic amino-carboxylic acids tend to act either as monoacidic acids or as di-acidic acids (wherein either one or two acidic groupings are used).
  • the particularly preferred aminocarboxylic acid HEDTA acts either in a monoor diacidic fashion, and so far as can be determined the only salts formed are chlorhexidine mono- HEDTAcetate (wherein the HEDTA is di-acidic) and chlorhexidine di-HEDTAcetate (wherein the HEDTA is mono-acidic).
  • the sequestrates of this invention may be made by any of the conventional methods employed for the preparation of salts.
  • they may be prepared by a straight acid/base reaction, or they may be prepared by a metathesis (or double decomposition) reaction between another salt of the acid and another salt of the base.
  • this invention provides a process for the preparation of a bisbiguanide/amino-carboxylic acid sequestrate of the invention, in which chlorhexidine (or salt thereof) is reacted in an aqueous medium with an appropriate amino-carboxylic acid (or salt thereof) to give the desired sequestrate.
  • the reaction be effected in the pres- (chlorhexence of a medium in which the bis-biguanide is soluble, which medium is easily miscible with the water present.
  • mediums are the alkanols, and particularly suitable alkanols are methanol and ethanol.
  • the reaction is preferably effected in aqueous methanol or ethanol.
  • both the bis-biguanide and the aminocarboxylic acid may be dissolved in the aqueous alka' no], or the former may be dissolved in alkanol, the latter in water, and the two solutions mixed.
  • the former is preferably one of these with common organic acids (for example, the diacetate) and the latter is preferably an alkali-metal salt (for example, a sodium salt).
  • an alkali-metal salt for example, a sodium salt.
  • the formed salts may be isolated by conventional techniques, but for some purposes they need not be isolated at all (the prepared solution containing them may be used as it is), and this is discussed hereinafter.
  • the novel bis-biguanide sequestrates of this invention appear to exert a useful anti-bacterial activity.
  • the bis-biguanides of general formula l are known to have anti-bacterial activity in salt form, the sequestrates derived from them have a greater anti-bacterial activity and this can be manifest in several ways. Firstly, the spectrum of activity of the bis-biguanide salts at a given concentration can be extended"; that is to say, a given bis-biguanide salt may be inactive against a particular species of bacteria at a given concentration, whereas a corresponding sequestrate will be active when applied at the same concentration expressed in terms of the bis-biguanide base.
  • any of the sequestrates of this invention may be used in medicine, they should preferably be formed into compositions by association with suitable vehicles.
  • suitable vehicle isused herein to exclude any possibility that the nature of the vehicles, considered of course, in relation to the use to which the composition is to be put, could be harmful rather than beneficial.
  • the choice of a suitable mode of presentation, together with an appropriate veprobably by far the most important use of the compositions will be as disinfectants, primarily for use in hospitals, and as such the composition will generally be liquid, the vehicle being, for instance, water.
  • compositions of this invention may be administered orally, perlingually, topically, or rectally, and in respect of these modes, the vehicle is preferably:-
  • the ingestible excipient of a tablet, coated tablet, sublingual tablet or pill the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier of a powder; or the ingestible liquid medium of a syrup, solution, suspension or elixir;
  • solid or liquid carrier medium of an ointment, paste, gel, salve, lotion, balm, unguent, wash, cream, solution, emulsion or dusting powder;
  • a base material of low melting point capable of releasing an active ingredient to perform its pharmacological function which base material when appropriately shaped forms a suppository.
  • compositions of this invention that are prepared by formulating an isolated sequestrate will, naturally, contain the two moieties involved the bis-biguanide moiety on the one hand, and the amino-carboxylic acid moiety on the other hand in stoichiometric molar proportions.
  • a composition made from chlorhex/HEDTA contains the two moieties in the molar ratio 1:1
  • a composition made from chlorhex/2 HEDTA contains the two moieties in the molar ratio 1:2.
  • compositions containing an excess of either moiety or, rather, containing an additional quantity of either the bisbiguanide itself or the amino-carboxylic acid itself
  • an excess particularly an excess of amino-carboxylic acid is advantageous and appears to give rise to somewhat better bactericidal properties than might be expected.
  • aminocarboxylic acid for example, excesses of the order of half a mole per mole of bis-biguanide give compositions which perform quite satisfactorily.
  • the sequestrates of this invention are not all equally soluble in water. Indeed, some of them are so poorly soluble that it is difficult, if possible at all, to form a liquid aqueous composition that contains enough sequestrate to act properly as a bactericide without using a solubilizing agent (discussed hereinafter). Accordingly, this invention does not extend to sequestrate-containing compositions which are aqueous and liquid, and which do not incorporate a solubilizer, where the sequestrate is incapable, without the aid of a solubilizer, of being dissolved in water to a concentration of more than 1000 ppm.
  • compositions of the invention meet this criterion it is highly desirable that they should contain, in addition, a solubilizing agent for the sequestrate, and a class of solubilizing agents which is particularly suitable (partly because most of the agents are themselves bactericidal, partly because the agents have detergent properties useful in a disinfectant composition and partly because, as is discussed below, the thus-formed compositions appear to exhibit synergism) is the quaternary ammonium compounds.
  • Y is an alkyl group containing from 8 to carbon atoms, a di-isobutyl-phenoxy-ethoxyethyl group, or a diisobutyl-cresoxyethoxyethyl group;
  • Y is an aralkyl group, preferably a benzyl group, optionally substituted in the aromatic nucleus) especially those having the benzalkonium cation (which is described in the literature as alkyldimethylbenzyl ammonium wherein the alkyl is the well known cocogroup being a mixture of alkyl groups mainly in the C -C range such as lauryl, myristyl, etc.), and the compounds sold under the trade names Hyamine LOX and Hyamine 1622 in the USA (which are described as having the cations di-isobutylcresoxyethoxyethyl dimethyl benzyl ammonium and di-isobutylphenoxyethoxyethyl dimethyl benzyl ammonium), and the myristyldimethylbenzyl ammonium compounds;
  • Y and Y which may be the same or different, are each an alkyl group containing from 8 to 18 carbon atoms), especially the didecyldimethyl ammonium and the dioctyl-dimethyl ammonium cations,
  • Y isan alkyl group of 8 to 20 carbon atoms; and Y and Y are the same or different, and each is a hydroxy-substituted alkyl or hydroxyalkoxyalkyl group), especially alkyl dihydroxyethyl) benzyl ammonium, wherein the alkyl is, for example, a cocogroup; andthose having a cation of the general formula 9 Y (vm) (wherein: Y is an alkyl group of 8 to 20 carbon atoms), especially the cetylpyridinium cation.
  • the particularly preferred quaternary ammonium cations are benzalkonium, myristyldimethylbenzyl amammonium, and coco dihydroxyethyl)benzyl ammonium.
  • a not-so-good solubilizing quaternary may only solubilize as much sequestrate as will give a 5 percent solution, and at that level may be solubilizing perhaps only l/ 10 its weight of sequestrate.
  • a few general examples of maximum solubilizing power of various quaternary ammonium compounds with various bis-biguanide sequestrates are as follows (the percentages are by weight based on the final solution, and the formed solutions were stable):
  • solubilizing power of a particular quaternary to a particular sequestrate may easily be determined by trial.
  • compositions of this invention may be made simply by mixing the sequestrate with the vehicle (and with excess sequestrate moiety and/or with quaternary ammonium compound as appropriate). However, as intimated above the formed sequestrates need not necessarily be isolated from their reaction media; the reaction solution may well constitute a suitable aqueous liquid composition.
  • compositions of this invention can be prepared simply by dissolving the bisbiguanide and the amino-carboxylic acid in water or an aqeous alkanol to which also may be added (ifdesired) the quaternary ammonium compound.
  • compositions of this invention by dissolving in water or an aqueous alkanol the bis-biguanide and the quaternary ammonium sequestrate.
  • EXAMPLE 3 Mono(chlorhexidine) mono(nitrilotriacetate) 25 ml of a 0.04 M solution of chlorhexidine diacetate in distilled water were added to 25 ml of a 0.04 M solution of disodium nitrilotriacetate in distilled water. Thus, the acid and base were present in equimolar proportions. A fine, oily precipitate was formed which at first remained suspended in the liquid, but which solidified on standing. This precipitate was filtered, washed with distilled water and dried to give mono(chlorhexidine) mono(nitrilotriacetate). The solubility of the salt in water at 20C is 0.3% w/w,
  • a differential scanning calorimeter showed the formation of the salt, and this was confirmed by melting point tests, which gave the following melting points:
  • anti-bacterial compositions are less active against gram negative bacteria than against gram positive bacteria. Furthermore, their anti-bacterial activity is reduced in the presence of hard water and/or organic matter such as blood serum.
  • a particularly stringent anti-bacterial test is one against the highly resistant gram negative bacterium, Pseudomonas pyocyanea in the presence of hard water.
  • Standard Hard Water (W.H.O. Formulation) 10% CaCl 6H O (wt/vol) 10% Mg SOJH O (wt/vol) Distilled water 17.5 mls. 5.0 mls. 3,300 mls.
  • the inactivator stopped the further action of the anti-bacterial agent, and each live bacterium left on addition to the activator produces a colonly on the agar plate. The number of colonies on each plate was counted, multiplied by the Table I Final concentration of bactericide p.p.m. 200 300 400 600 Bactericide Mono(chlorhexidine) Di(I-IEDTA) 21,818 2,909 16 Chlorhexidine dihydrochloride (control) u/c u/c Chlorhexidine digluconate (control) u/c u/c u/c u/c u/c u/c number of survivors too great to be counted.
  • EXAMPLE 7 Mono( chlorhexidine) mono(hydroxyethylethylenediaminetriacetate a. Preparation of the compositions Solid mono(chlorhexidine) mono(hydroxyethylethylenediaminetriacetate, prepared as in Example 1, was dissolved in standard hard water (W.H.O. formulation) to yield solutions containing 400, 800, 1200, 1600 and 2000 ppm of the salt.
  • EXAMPLE 8 Mono( chlo rhexidine) mono( nitrilo-triacetate a. Preparation of the compositions Solid mono(chlorhexidine) mono(nitrilo-triacetate), prepared as in Example 3, was dissolved in standard hard water (W.H.O. formulation) to yield solutions containing 400, 800, 1200, 1600 and 2000 p.p.m. of the salt.
  • EXAMPLE 9 Tri(chlorhexidine) di(diethylenetriaminepentaacetate) a. Preparation of the compositions Solid tri(chlorhexidine) di(diethylenetriaminepentaacetate) prepared as in Example 4 was dissolved in standard hard water (W.H.O. formulation) to yield solutions containing 400, 800, 1200, 1600 and 2000 p.p.m. of the salt. b. Bactericidal tests The solutions prepared in a) were tested for bactericidal activity in the same manner as in Example 6. Control examples were provided using the same concentrations of chlorhexidine digluconate. Results The results are shown in Table IV below.
  • l1 Mono(chlorhexidine) mono(l-IEDTA) lCetrimide a. Preparation of the composition 14.3 G of chlorhexidine, 20.4 g of cetyltrimethyl ammonium bromide and 7.8 g of hydroxyethylethylenediaminetriacet'ic acid (HEDTA) were allowed to react in 57.5 g water'under agitation, until a clear solution was obtained which was dilutable with water in all concentrations and contained a mixture of mono(- chlorhexidine) mono(hydroxyethylethylenediaminetriacetate) and cetyltrimethylammonium bromide.
  • HEDTA hydroxyethylethylenediaminetriacet'ic acid
  • Nutrient Broth No. 2 is used as in Example 6 above.
  • Preparation of Culture A culture from agar of the organism was prepared in nutrient broth, and incubated at 37C for 24 hours. Daily subcultures were continued, and cultures between the third and seventh generation were used for the test.
  • the broth culture of Pseudomonas pyocyanea was filtered aseptically before use, or shaken, allowed to settle for 15 minutes, and the supernatant liquor used for the test.
  • Culture dilution One part of the broth culture was diluted with 24 parts of distilled water, i.e. 4 ml. broth culture 96 ml of distilled water. The average count of bacteria in such a dilution would be 5 X 10 organisms per ml.
  • Baclericide gPP )PP q lpp PP Organic One can determine the concentration of the various g'g e ffiggf gg z m gfifg mixtures made according to the Examples (expressed in terms of parts per million of total organic material z g g g [bis-biguanide plus quaternary ammonium compound p p 75 75 45 195 aminocarboxylic acid]) and hence, knowing the relalive quantities of Components, One-Can Calculale
  • These results should be compared to those given for from the Antiseptic Test results the killing dilution in hl h i i digluconate and Q AC sequestrate in terms of bls'biguamde and/0T quaternary ammonium Table VI above, whereupon it will be seen that the compoundcomposition of this invention is markedly superior as a Results I bactericide to both these conventional agents.
  • EXAMPLE l2 Mono(chlorhexidine) mono(HEDTA) lCetrimide b. Bactericidal tests The composition obtained in a) was tested for bactericidal activity in the same manner as in Example 11, and the results are shown in Table VIII below.
  • EXAMPLE 15 Mono(chlorhexidine) di(I-IEDTA) di(myristyldimethylbenzylammonium) mono(I-IEDTA)
  • Myristyldimethylbenzylammonium hydroxide was prepared using essentially the following method. 367.5 Gm (1 mole) of myristyldimethylbenzylammonium chloride was dissolved in the smallest possible quantity of isopropyl alcohol. A saturated solution of 56 gm (1 mole) of potassium hydroxide in absolute ethanol was added under agitation. After a few hours, the precipitate of potassium chloride which had formed was filtered off and washed with isopropyl alcohol, the washings being returned to the main solution.
  • the resultant alcoholic solution contained myristyldimethylbenzylammonium hydroxide. This solution was divided into aliquots each containing 0.1 mole (34.9 gm) of the quaternary ammonium hydroxide.
  • the mono(myristyldimethylbenzylammonium) salt of hydroxyethylethylenediaminetriacetic acid was prepared by taking one of the aliquots containing 0.1 mole of myristyldimethylbenzylammonium hydroxide and adding 27.8 gm (0.1 mole) of a solution of HEDTA in water, then making the solution up to 418 ml.
  • di(myristyldimethylbenzylammonium) mono(hydroxyethylethylenediaminetriacetate) was prepared by using 0.1 mole of the quaternary ammonium hydroxide and 13.9 gm (0.05 mole) of HEDTA, and this was made up to 314 ml to give a 15 percent w/w solution containing 10.6 percent of quaternary ammonium cation and 4.4 percent of dibasic HEDTA anion.
  • EXAMPLE l7 Mono(chlorhexidine) di( I-IEDTA )/Myris tyldimethylbenzylammonium hydroxide/HEDTA salt a. Preparation of the composition By the same method as in Example 16, mono(chlorhexidine di(hydroxyethylethylenediaminetriacetate), containing 1 molar proportion of chlorhexidine to 2 molar proportions of HEDTA anion, was prepared by taking 2 m1 of the 15 percent solution of di(myristyldimethylbenzylammonium) mono( hydroxymethylethylenediaminetriacetate) and adding 0.08 gm of chlorhexidine. The product was a clear solution which could be further diluted with water.
  • EXAMPLE l8 Mono(chlorhexidine )mono-and di( HEDTA )/di(myristyldimethylbenzylammonium) mono(HEDTA) a.
  • Preparation of the composition Using exactly the same method as in Example 16, compositions were prepared from the 15 percent w/w solution of di(myristyldimethylbenzylammonium) mono(hydroxyethylethylenediaminetriacetate) and chlorhexidine base which corresponded to mixtures of the mono(chlorhexidine) mono(HEDTA) salt and the mono(chlorhexidine) di(HEDTA) salt with excess of the di(quaternary ammonium) mono(HEDTA) salt.
  • Example 16 the mono(chlorhexidine) mono (HEDTA) salt was made from 15 percent quaternary ammonium HEDTA salt and 8 percent chlorhexidine
  • Example 17 the mono (chlorhexidine) di( HEDTA) salt was made from 15 percent quaternary ammonium salt 4 percent chlorhexidine
  • Didecyldimethylammonium chloride is commercially available in the form of a concentrated solution containing 50 percent of the salt and 50 percent of water. A 0.2 percent solution of the salt was made up by dissolving 4.0 gm of this concentrate in 1000 ml of distilled water.
  • the test results would be along the line A, but in fact all the observations lie on a curve B lying wholly below A.
  • the bactericidal properties of the mixtures are greater than would be expected from the properties of the single components, and thus the mixtures are synergistic.
  • the curve B of the killing dilutions of mixtures of the two compounds always lies below the straight line A which shows the results which would be obtained if the bactericidal effects of the two compounds behaved additively (the tests indicated that the killing dilution of the quaternary ammonium compound alone was about 2500 ppm and the line A is drawn on this basis).
  • EXAMPLE 20 Mono(chlorhexidine) I
  • EXAMPLE 2i Mono(chlorhexidine) di(I-IEDTA)/Hyamine 10X 7 di(I-IEDTA)/l-Iyamine 1622 a. Preparation of the composition a.
  • compositions prepa e n were tested for and are also presented graphically in FIG. 3 of the actericidal activity in the same manner as in Example I l. companying drawings.
  • EXAMPLE 22 Mono(chlorhexidine) di(HEDTA)/Cetylpyridinium chloride a. Preparation of the compositions The 0.2 percent w/w solution of chlorhexidine di( HEDTA) prepared in Example was mixed with 0.2 percent w/w solution of cetylpyridinium chloride in the following ratios. I I
  • compositions prepared in a) above were tested, .for bactericidal activity in the same way as in Example 1 1.
  • chlorhexidine digluconate was also tested. The results are shown in Table XVI below.
  • EXAMPLE 24 Chlorhexidine HEDTA
  • EXAMPLE 25 Chlorhexidine HEDTA sequestrate/Dioctyldimethylammonium chloride sequestrate/Cetyltrimethyl-ammonium bromide mixtures mixtures a. Preparation of the composition 25 As shown above mono(chlorhexidine) mono Using the same technique as 1n Example 23, the fol- (HEDTA) is soluble in water at 20 C to the extent of lowing solutions were prepared: only 0.2 percent, and the mono(chlorohexhdine) di Solution l (HEDTA) is soluble to the extent of only about 0.3 per- Dioctyldimethylammonium chloride 0.65 gm cent.
  • the solutions can be prepared by adding The compositions produced in a) above were tested the solid chlorohexidine sequestrate to water and addfor bactericidal activity in the same manner as in Examing the ammonium compound until dissolution takes ple l l To provide a control, chlorhexidine digluconate place. was also tested. The results are shown in Table XVII In this way, the following solutions were prepared: below.
  • EXAMPLE 26 Chlorhexidine DTPA Sequestrate/Cetrimide mixtures.
  • EXAMPLE 27 Efficacy of compositions of this invention against various bacteria
  • solution A from Example 25 and solution A from Example 26 were tested with chlorhexidine digluconate, for their killing power against a wide range of bacteria.
  • the tests were conducted in the same manner These results Show that h Compositions of this as in Example 11 in distilled water containing 10 vention are markedly superior to chlorhexidine diglucent of bovine serum, and the bacteria used were as folconate against a wide range of bacterla' lows:- EX
  • AMPLE 28 1. Pseudomonas pyocyanea N.C.T.C. 6749
  • tests of the bactericidal properties of compositions of this lnvention against E.coli were carried out by the 3 Salmonella hi N C T C 3390 method of British Standard 3286:1960 described above w in standard hard water (W.H.O formulation) contain- 4. Escherichia coli N.C.T.C. 8196 mg percent of bovine serum.
  • the solutions used were as follows, chlorhexidine digluconate being pro- 5.

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DE3016110A1 (de) * 1979-04-26 1980-11-06 Bristol Myers Co Antibakterielle verbindungen, verfahren zu ihrer herstellung und daraus hergestellte mittel
US4836853A (en) * 1986-10-24 1989-06-06 Dentsply Gmbh Algin based dental impression material containing biocidal component
EP1203531A2 (de) * 2000-10-21 2002-05-08 Degussa Aktiengesellschaft Wasserlösliche chlorhexidinhaltige Zusammensetzungen und deren Verwendung
US20060018847A1 (en) * 2001-09-25 2006-01-26 Beiersdorf Ag Active ingredient combinations of polyhexamethylenebiguanidine hydrochloride and distearyldimethylammonium chloride and preparations comprising said active ingredient combinations
US20070254854A1 (en) * 2006-05-01 2007-11-01 Medi-Flex, Inc. Aqueous Antiseptic Solution and Compatible Anionic Dye for Staining Skin
US20080108674A1 (en) * 2006-05-01 2008-05-08 Enturia, Inc. Cationic antiseptic and dye formulation
WO2010010345A2 (en) * 2008-07-22 2010-01-28 Polybiotech Limited Sanitising compositions and methods
WO2020055716A1 (en) * 2018-09-14 2020-03-19 3M Innovative Properties Company Antimicrobial compositions comprising chlorhexidine
CN112368022A (zh) * 2018-04-11 2021-02-12 新墨西哥科技大学研究园公司 抗感染制剂

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US4051234A (en) 1975-06-06 1977-09-27 The Procter & Gamble Company Oral compositions for plaque, caries, and calculus retardation with reduced staining tendencies
DE2611957C2 (de) * 1976-03-20 1985-06-13 Henkel KGaA, 4000 Düsseldorf Antimikrobielle Mittel
SE425043B (sv) * 1977-05-10 1982-08-30 Kenogard Ab Fungicid komposition, foretredesvis for anvendning som treskyddsmedel, innehallande minst en kvarter ammoniumforening i blandning med en aminkomponent
AT381001B (de) * 1983-11-28 1986-08-11 Arcana Chem Pharm Verfahren zur herstellung klarer waesseriger desinfektionsmittelloesungen
DE3528209C2 (de) * 1984-08-07 1993-10-28 Fresenius Ag Desinfektionsmittel

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US3468898A (en) * 1966-05-26 1969-09-23 Sterling Drug Inc Bridged bis-biguanides and bis-guanidines

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FR1265808A (fr) * 1956-02-10 1961-07-07 Ici Ltd Biguanides

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US3272863A (en) * 1964-03-27 1966-09-13 Sterling Drug Inc 1, 1'-(alkylene) bis
US3468898A (en) * 1966-05-26 1969-09-23 Sterling Drug Inc Bridged bis-biguanides and bis-guanidines

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3016110A1 (de) * 1979-04-26 1980-11-06 Bristol Myers Co Antibakterielle verbindungen, verfahren zu ihrer herstellung und daraus hergestellte mittel
US4836853A (en) * 1986-10-24 1989-06-06 Dentsply Gmbh Algin based dental impression material containing biocidal component
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Also Published As

Publication number Publication date
NL7206762A (de) 1972-11-21
FR2157775B1 (de) 1975-12-26
DE2223766A1 (de) 1972-12-14
FR2157775A1 (de) 1973-06-08
CA1003750A (en) 1977-01-18
JPS5911562B1 (de) 1984-03-16
SE370003B (de) 1974-09-30
BE783598A (fr) 1972-09-18
FI58423B (fi) 1980-10-31
FI58423C (fi) 1981-02-10
GB1381361A (en) 1975-01-22
ZA723225B (en) 1973-03-28

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