IE60364B1 - Composition inhibiting at least one unicellular living creature and/or virus, process of manufacture of such composition and applications thereof - Google Patents

Abstract

Pharmaceutical or cosmetic substance or composition inhibiting or destroying at least one monocellular living being and/or at least one virus, medicament or product including such composition, process for producing such composition, chemical compound entering in such composition, and process for the inhibition or destruction of at least one unicellular living being and/or at least one virus. The inhibiting or destroying substance, according to the invention, is characterized in that it comprises at least one basic active principle inhibiting or destroying said unicellular living being and a principle for inhibiting or destroying at least one enzyme associated with said living being, forming an activator - particularly acting by synergy - of the basic active principle.

Description

The invention relates to the inhibition or destruction of unicellular living beings such as protozoans, microbes, bacteria, gametes, fungi and the like and viruses. It thus relates in particular to the technical fields of local contraception, antibiotic therapy and antisepsis. In the context of both pharmacy or cosmetics and disinfection.

In the following, inhibition3* of a unicellular living being or of a virus is understood as meaning the act either of preventing its proliferation or of rendering it unable to perform certain functions which it usually performs. «Destruction83 is understood as meaning the act of killing unicellular living beings or viruses.

«Substance83 in the context of the invention and below is understood as meaning any chemical compound or combination of chemical compounds having at least one function attributed to or common to the compounds and capable of occurring in the composition of a finished product, generally in combination with an excipient and possibly other substances. Moreover, the term «product33 designates a finished, usable product. In general, a finished product thus constitutes at least one excipient and several substances, each substance consisting of one or more chemical compounds having similar or identical functions. This term «substance·13 may correspond to a practical reality, but may also be purely theoretical and functional in the case of complex mixtures where the compounds have multiple actions where one interferes with the other. This functional classification into compounds, substances and products does not necessarily correspond to the production process for the product and to mixtures effectively realized in practice. The term composition*’ is used here and below to designate a pharmaceutical or cosmetic substance in the usual manner.

Substances which inhibit or destroy unicellular living beings are already known, both in the biological, pharmaceutical and cosmetic fields and also in more general fields, such as disinfection and the like.

Spermicidal compositions are known, in particular, from U.S. Patents 4 339 and 4 359 ^75.

Numerous chemical compounds which can be used in local contraception methods on th® living being are also known. In particular, it is known ί) that surface-active surfactants (for example quaternary ammoniums, nonoxynols, derivatives of amido-ethylglycinate on fatty acids, sodium salt oxide methyltauride...) and certain other compounds, such as phenylmercury nitrate, paramenthanylphenyl:polyoxyethylene ether or the trisodium salt of polysaccharide ether-sulphate, have actions which inhibit or destroy unicellular living beings, in particular spermicidal actions.

Sub3taacea which act mechanically on spermatozoa, for example by immobilizing them, are also known. American Patent 4 368 186 describes such effects, and more particularly the combination of poloxaaer with inhibitors of spermatozoa, in order to control gelling and solubilisation of the products and thus to increase the efficacy of the inhibitors mechanioally by addition or synergism.

Local contraceptive compositions, in particular spermicides,, which contain such chemical compounds and can be used locally to inhibit the reproductive capacity of gametes, in particular spermatozoa of the human or animal being, are also known. These known compositions have a certain concentration of the inhibiting chemical compound which is greater than the minimum inhibitory concentration. or MIC, in solution or suspension in a pharmaoeutioal excipient, which depends on the galenical form used. In fact, it is known that to achieve the death of all the spermatozoa contained in 0.2 millilitre of sperm within less than 5 seconds (conditions of the total spermicide test according to IPPP, International Planned Parenthood Federation, specifications), it is necessary for the concentration of the spermicidal active principle in 1 millilitre of pharmaceutical composition to be greater than ©r equal fe© the minimum inhibitory concentration, or MIC, of this active principle. Ihe MIC of a chemical compound depends on this chemical compound, and also on the conditions under which it is used, that is to say the galenical forms which contain the composition.

More generally, pharmaceutical or cosmetic compositions containing at least one base active principle which inhibits or destroys at least one unicellular living being and medicaments or oosaetios containing such compositions ar® known, Suaerous active principles are already known in the field of antisepsis and disinfection: halogens (derivatives of chlorine ©r iodine...), aldehydes, alcohols, phenols, acids, metals (salts of silver, copper, sine, mercury...), amidines, biguanides, carbanilides, oxidising agents (hydrogen peroxide, permanganates of potassium...), colouring agents and surface-active and wetting agents (cationic, anionic, amphoteric or organic).

Antiseptic and/or disinfectant and/or antiprotosoic and/or antifungal and/or antibiotic and/or antiviral products containing such inhibitory or destructive substances and processes for the preparation of these substances or compositions are also known.

American Patents US-A-4 097 590, US-A-3 996 350 and US-A-3 995 029 describe the use of sodium fluoride with, in a lesser proportion with respect to the fluoride, a wetting agent consisting of an anionic surfactant for the treatment of acne and the mycosis of athlete's foot.

European Patent Application EP-A-0 226 187 and PCT Application WO-A-87 03482 describe a pharmaceutical product intended for topical application to combat the herpes virus, which contains a bensoic acid, phenol and an alkali metal fluoride.

The known substances or compositions are in general satisfactory but present practical problems when used.

The problems presented by these known substances or compositions are mainly the following: Firstly, it is generally desirable to have a total efficacy of the inhibition or destruction of the proposed unicellular living being(s) or viruses, that is to say 100$ inhibition or destruction under the practical conditions of use. However, this is not always the case if the exacting use precautions are not taken or if it is necessary to limit the doses of active principle (in the case of cosmetics, for example).

Moreover, it is generally desirable to have an action on one or more given unicellular living beings or viruses, for example gametes or pathogenic beings, without causing undesirable secondary reactions in the short term and/or in the long term (action on other unicellular living beings, irritations, environmental damage...). However, it is found in practice that the doses needed to solve the first problem mentioned above cause secondary reactions in the long term (generally associated with regular use), and indeed even in the short term (one-off use). In the medical field, teratogenic and/or carcinogenic effects have been found above certain threshold doses and for certain active principles. In the disinfection field? undesirable effects on the materials to be disinfected have also been found.

The object of the invention is to increase the Inhibitory or destructive capacity of a substance or composition containing a given limited concentration of base inhibitory or destructive active principle without increasing this concentration. Another object of the invention is to reduce the concentrations of base active principles without, however, reducing the inhibitory or destructive capacity of the substance or composition, in order to avoid secondary reactions and for better control of the selectivity with respect to the various unicellular living beings and viruses.

In particular, the object of the invention is to propose a pharmaceutical or cosmetic composition, in particular a local contraceptive, and a medicament or product containing such a composition which can he used either in a one-off manner or regularly and continuously in the long term without the risk of a secondary effect, in particular a teratogenic or carcinogenic effect, and of which the efficacy is total, that is to say of which the percentage of failures is statistically aero or negligible, under the usual simple use conditions (without particular precautions).

The invention moreover has the object of providing a local contraceptive pharmaceutical product which is easy to use and totally effective, that is to say gives results comparable to those of oral contraception without having the disadvantages.

The object of the invention is also to propose a obemloal compound which can be used in a local contraceptive method.

Finally, the object of the invention is also to reduce the doses of active principles which inhibit or destroy unicellular living beings or viruses in medicaments, cosmetics or disinfectants, In particular antiseptics, antibiotics, bactericides, antiprotosoics, antifungal agents, spermicides, antiviral agents.

The invention accordingly relates to the use of at least one active principle which inhibits or destroys at least one UEicelluiar living being or virus and of an activating principle in proportions suitable for inhibiting cr destroying at least one enzyme associated with the said unicellular living being cr virus to obtain a product or a medicament for inhibiting or destroying this unicellular living being or virus, with the exception of the case of the combination of benzoic acid, phenol and an alkali metal fluoride, in aqueous solution or aqueous-alcoholic solution to obtain a product for inhibiting or destroying the herpes virus (patent applications EP-A-0 22β 187 and WO-A-87 03482, opposable by way of article 54(3)).

The invention accordingly proposes a substance which inhibits or destroys at least one unicellular living being - in particular a protozoan, microbe, bacterium, gamete, fungus and the like and viruses - characterised in that it contains at least one base active principle which inhibits or destroys the said unicellular living being and a principle which inhibits or destroys at least one enzyme associated with the said living being and constitutes and activator - in particular acting by synergism - of the base active principle.

The principle which inhibits or destroys at least one associated enzyme. called Bactivating principle below, is preferably an agent which prevents functioning of the enzyme/substrate pair.

However, it has been found, surprisingly, that such an agent can advantageously consist of the fluoride anion F~ donated from a fluorine compound, either spontaneously or after enzymatic action. It has also been found that such a fluorine compound itself has a capacity to inhibit or destroy unicellular living beings and viruses and that this fluorine compound acts in synergism with the associated base active principle.

The invention proposes in particular a pharmaceutical composition and a cosmetic composition containing, in combination, at least one base active principle and a chemical fluorine compound which donates the fluoride anion F~, the function of which is to increase the efficacy of the action of the base active principle(s).

More precisely, the invention proposes a local contraceptive composition, in particular a spermicidal composition, characterized in that it contains, by way of the active principle which inhibits or destroys gametes directly or by potentiation, at least one chemical compound which donates the fluoride anion F" and an excipient.

The invention also proposes a medicament, an antiprotozoic - in particular local antiprotozoic - and/or bactericidal - in particular local bactericidal - and/or antifungal - ia particular local antifungal - and/or antibiotic - in particular local antibiotic and/or antiviral « (sic? product, a cosmetic product - in particular a local cosmetic product, such as a synthetic soap or lotion - an antiseptic and/or disinfectant - ia particular local antiseptic - product and a contraceptive product applied locally In contact with gametes - in particular a pessary, cream, gel., solution, foam, tablet,, soluble file, taapon or vaginal suppository characterized in that they contain a substance or a composition according to the invention.

The tern local here and below means used In a given place to be treated, for example the vagina or other anatomical regions, such that the action results in the environment close to this place against unicellular living beings which come into contact with the product, in contrast to uses by a general route (for example perorally).

A substance, a composition, a medicament, a product and a cheaical composition according to th® invention relate both to uses by a local route and uses by a general route. For example, a spermicide according to the invention is applied locally. In addition, to overcome the effects of resistance of pathogenic unicellular living beings to customary therapeutics, the invention will preferably be used by a general rest®.

The invention also proposes the use in a cosmetic produot of a composition containing at least one base active principle and a Chemical fluorine compound which donates the fluoride aalos F" as th® activating principle of the base active principle(s); the use ©f a chemical flucrine compound which donates the fluoride anion F to produce a substance containing at least oes base active principle as the activating principle of the base active prineiple(s); the use of a substance or composition according to the invention to obtain a medicament for use in an antibiotic and/or antiprotozoic and/or bactericidal and/or antifungal and/or antiviral manner; and the use of a substance or composition according to the invention to obtain a local contraceptive for the human or animal being, In particular && inhibitor cr destroyer of gametes.

The invention also proposes a process for the preparation of a substance or composition according to the invention which inhibits or destroys at least one unicellular living being - in particular a microbe, bacterium, gamete, fungus or also virus - characterized is that at least one base active principle which inhibits or destroys the said unicellolar C\ δ living being is mixed with a principle which inhibits or destroys an enzymatic system associated with the said living being - in particular a fluorine compound which donates the fluoride anion F~ - constituting an activator of the base active principle.

The invention proposes a chemical compound containing ionisable fluorine for use in a local contraceptive method for the living being, in particular in a local contraceptive product for the human or animal being according to the invention or in a composition according to the invention.

According to the invention, the activating principle which inhibits or destroys at least one enzyme associated with a unicellular living being enables the said unicellular living being, by "blocking® the enzyme/substrate pair, to be substantially sensitised to external attacks, in particular the action of the said base active principle which inhibits or destroys the said unicellular living being. It is known, in fact, that every unicellular living being has a vital enzymatic system. Furthermore, unicellular living beings can release, depending on the circumstances (for example resistance to an antibiotic), particular enzymes which allow destruction of an aggressive agent (lactamase-destroying penicillins), socalled enzyme protectors". The invention thus comprises inhibiting the role of these enzymes and causing the unicellular living being to become fragile by creating optimum conditions for the efficacy of the active principles opposing It. This provides several advantages with respect to the prior art, that Is to say, on the one hand, the abovementloned aims are fulfilled, and on the other hand, a particular unicellular living being or a particular family of unicellular living beings can be acted upon more selectively by acting on a particular enzyme or a particular family of enzymes. In the case of viruses, the object of the Invention is to inhibit the enzymes needed for their formation and/or their replication. «Associated enzymes" below designates the vital and/or protective enzymes of the unicellular living being and/or of the viruses.

The inventors have found that fluorine in the ionised state F~ acts in a particularly effective and beneficial manner as an activating principle acting against the associated enzymes below th© usual minimum concentrations. It will be noted, advantageously, that ionized fluorine F is very common, economical and relatively easy to use. Its handling and use are readily controlled, as are the secondary reactions which it can cause, depending on the doses used.

Finally, the invention proposes a process for the inhibition or destruction of at least one unicellular living being - is particular a protozoan, microbe, bacterium, gamete, fungus or also virus - characterised in that at least one base active principle which inhibits or destroys the said unicellular living being and a principle which inhibits or destroys afc least one enzyme associated with the said living being, constituting an activator - in particular acting by synergism - of the base active principle, is used, and such a process in which at least one substance or composition according to the invention is used.

Other characteristics and advantages of the invention will be apparent from reading the detailed description and the examples which follow.

The invention relates to the inhibition or destruction of unicellular living beings, such as protozoans, microbes, bacteria, gametes and fungi, which nay or nay not be pathogenic, and viruses. The invention esa&abi&lly has two distinct types of uses either uses in the cosmetic or pharmaceutical field (in th® case of the following examples of spermicides or bactericides acting against pathogenic agents), or uses la more common fields, such as agriculture, disinfection (example below) and the like. In all oases, a substance according to the invention is characterised in that it contains at least one base active principle which inhibits or destroys the said unicellular living being and a principle which inhibits or destroys at least one enzyme associated with the said living being ©r virus, constituting an activator - in particular by synergism if It also itself inhibits or destroys the said living being - ©f the base aotlve principle.

The function of the activating principle is therefore to annihilate the role of the enzymatic system associated with the said living beiagCs) or viruses. The inventors have accordingly found that this activating principle is advantageously an agent which prevents functioning of the enzyme/substrate pair, in particular the fluoride anion donated from a fluorine compound, for example a metal derivative ©f fluorine. Very positive results were found with sodium fluoride, calcium fluoride, potassium fluoride, aluminium fluoride, tin fluoride, ammonium fluoride and sodium monofluorophosphafce.

The Invention can affect, for example, the following unicellular ίΟ living beings or viruses: gametes (spermatozoa, ovules) Gram-positive cocci, in particular Staphylococci and Streptococci Gram-negative cocci, in particular Gonococci Gram-positive bacilli Gram-negative bacilli, in particular Colibacilli or Escherichia coli bacilli which are resistant to acids and alcohols, in particular mycobacteria, such as Mycobacterium smegmatis spiral-shaped bacteria, in particular Spirochaeta, such as Treponema various bacteria, in particular Chlamydia flagellated protozoans, in particular Trichomonas various yeasts, in particular Candida albicans viruses or retroviruses, in particular LAV or HIV (human immunodeficiency virus), and herpes.

The following enzymes associated with at least one of these unicellular living beings or viruses can be affected, for example, by the invention (Table 1): ίί TABLE 1 asziMs SUBSTRATE Alkaline phosphataseΛ 2-Naphthyl phosphate Esterase (C 4) 2-Naphthyl butyrate Esterase lipase (C 8) 2-Naphthyl caprylate Lipase (C 14) 2-Naphthyl myristate Leucine arylamidase L-Leucyl-2-naphthylasaide Valine arylamidase L-Valy1-2-naphthylamide Cystine arylamidase L-Cysty1-2-naphthylamlde Trypsin N-Benzoyl-DL-arginiae 2~naphthylamide cC-Chymo tr yp sin N-Glutaryl-phenylalanine 2-naphthylamide Acid phosphatase 2-Naphthyl phosphate Naphthol 18-31- phosphohydrolase Naphthol AS-B1-phosphats «q-Galactosidase 6-Er-2-naphthyl e*-B- galactopyranoside ^-Galactosidase 2-Naphthyl βΒ-galactopyranoside ^-Glucuronidase Haph th ol AS-91 -fSHglucuroaide eq-Glucosldase 2-Naphthyl ecD-glueopyranoside β-Glaccsidase 6-Br-2-naphthyl f!®- glucopyranosid© N-Acetyl-|3-glucosarainidase 1-Naphthyl H-aeetyl-^Dgiueosamlmnide (sic) ai-Maaaasidase 6-Br-2-naphtiayl «&Β- mannopyranoside ξχ-Fucosidase i-Naphthyl oflt-fucopyranoside A base active principle used in a substance or composition according to the invention is, for example, an anionic* cationic* amphoteric or nonionio surface-active surfactant, t.n particular a quaternary aanoaiw»An example of a cationic surface-act ive surfactant is bensalkoniuai daleridto or another alkylbenzalkoniura chloride. An example of an anionic surfaceactive surfactant is a sodium salt oxide methyltauride. An example of an amphoteric surface-active surfactant is a derivative of afflldoethylglycinate on a fatty acid. An example of a nonionic surface-active surfactant Is a nonoxynol. The base active principle can also advantageously be phenylmercury nitrate or para-menthanylphenylpolyoxyethylene ether or a trisodium salt of a polysaccharide ether-sulphate, or another substance (halogen, aldehyde, alcohol, phenol, acid, metal, amidine, bigua^iide Zshe-;’, carbanilide, oxidising agent, colouring agents),.

In the various uses tested, it was possible to demonstrate the fact that the activating principle alone generally also has an activity directly against the said unicellular living being or virus. It has thus been found that, surprisingly, the combination of the activating principle with the base active principle has a synergistic effect to the extent that the results obtained do not correspond merely to the sum of the results anticipated solely by the presence of the base active principle and of the activating principle, but on the contrary are greater than this sum.

The efficacy of such active or activating principles can be determined from the minimum inhibitory concentration or MIC, which corresponds to the concentration of active principle which causes the inhibition or death of all the unicellular living beings or viruses within a given time.

In a substance according to the invention, the concentration of the fluoride anion F donated by the activating fluorine compound is advantageously less than the minimum inhibitory concentration (MIC) of the fluoride anion F without the base active principle.

Moreover, the concentration of the base active principle in a substance according to the invention can be less than the minimum inhibitory concentration (MIC) of this base active principle in the absence of the activating principle. Nevertheless, such a substance according to the invention surprisingly has a total efficacy, that is to say at least equal to that of substances containing either only the fluoride anion F" in a concentration greater than or equal to its MIC, or solely a base active principle in a concentration greater than or equal to its MIC.

In addition, the base active principle can Itself also be the donor of the activating principle, in particular the fluoride anion F". a substance or composition according to the invention can contain several base active principles, the functions of which can bo identical or different, and/or several activating principles acting on at least one enzyme associated with one or more of these base active principles.

A substance or composition according to the invention can be the subject of multiple uses to obtain products which can be administered locally or by a general route, depending on the uses of the said products.

Amongst the particularly advantageous usee of the products according to the invention there may be mentioned th® various possible therapeutic uses as medicaments. In fact, the problem of inhibition or destruction of unicellular living beings or viruses is encountered in a considerable and constantly increasing number of therapeutic uses. It may be that of combating pathogenic agents, and the products are thus antibiotics and/or antiprotozoics and/or bactericides and/or antifungal agents and/or antiseptics and/or antiviral agents, or even non-pathogenle agents, such as gametes, for example spermatozoa in the context of contraception, in particular local contraception.

A substance or composition according to the invention can also advantageously be used in a cosmetic product, in doses and concentrations which do not allow it to be classified in the pharmaceutical field.

In fact, for example, the effective concentrations of chemical fluorine compounds, and even of base active principles, can be reduced in proportions such that they become less than the threshold values of the concentrations separating the pharmaceutical and oosaetlo fields, but without reducing the efficacy of the product.

A substance or composition according to the invention can also advantageously be used in products which are neither cosnietles nor pharmaceuticals, for example ir. the field of agriculture, as an antifungal, antiprotozoic, antiseptic, antibiotic or other type of agent, or also in the field of disinfection of surfaces.

The preferred embodiment or the invention currently known is that of products used locally on the .genital areas of male and/or female sasmals a® spermicides and/or bactericides .to combat sexually transmitted diseases (STD).

The active principles preferably used are benzalkonium chloride and nonoxynol 9. The activating principle preferably used is any metal derivative of fluorine, for example sodium fluorid®. All the knows galenical forms can be used, that is to say. in particular, a pessary, cream, gel, solution, foam, tablet, soluble film, tampon, vaginal suppository and the like.

The proportions of active principle and activating principle to be used vary from one galenical form to another, since only the effective concentrations which result in vivo are important with respect to the efficacy of the product.

These proportions should vary between the MIC and the maximum concentrations above which secondary effects are caused. In the case of local application, intolerances (irritations) of the treated areas should be avoided. In the case of general administration, toxic concentrations should be avoided.

The in vivo concentration of benzalkonium chloride is thus preferably 1.2$ (by weight), and the in vivo concentration of the fluoride anion F is preferably 0»5$ (by weight).

Several preferred embodiments of the invention will now be described for the various uses tested, with reference to tests carried out in vitro and in vivo on various unicellular living beings. 1) USE OF THE INVENTION FOR LOCAL CONTRACEPTION The invention advantageously relates to a spermicidal pharmaceutical product applied locally sueh that it comes into contact with sperm and kills or inhibits spermatozoa.

A spermicidal pharmaceutical product according to the invention can be In various galenical forms: tablet, pessary, solution, cream, gel, soluble film, tampon, foam or vaginal suppository introduced Into the vagina before the sex act such that the spermatozoa are killed or inhibited before they come into contact with the ovules, to avoid fecundation.

A product according to the invention comprises a composition which contains, as the active principle which is spermicidal directly or by potentiation, at least one chemical compound according to the invention which contains ionisable fluorine, that is to say a donor of the fluoride anion F"· A chemical compound according to the invention is a donor of the fluoride anion F when it is solvated, in particular in aqueous solution. ί5 It consists of, for example, a metal derivative of fluorine, suoh as sodium fluoride, calcium fluoride, potassium fluoride, aluminium fluoride, tin fluoride, ammonium fluoride, sodium monofluorophosphate..., or an organic fluorine compound, such as a fluorinated amine.

The spermicidal activity of a chemical compound can be measured, for example, by using the total spermicide test according to the IP?? specifications, which consists of determining the minimum inhibitory concentration or MIC (expressed as a percentage by weight) of the chemical compound in 1 millilitre of solution which causes the death of all the spermatozoa contained in 0.2 millilitre of sperm within 5 seconds. The test is carried out on at least 6 sperm samples from different donors, corresponding to the following minimum conditions according to the IPPF: - age of the sasaple: two hours; - density is 50 million spermatozoa; - mobility: 50$ of the spermatozoa should move forwards with speed wises they are examined at 35° - 37°C in a fresh sample; - viscosity: suitably liquefied ejaculate, non-ropey and with a homogeneous appearance tc the naked eye; - collected is sterile glass tubes, hermetically sealed, stored at 37°C.

The inventors have found that under these conditions the fluoride anion F" present in an amount of 5 milligrams per litre has a spermicidal activity of 100$ according to the IPPF test.

A spermicidal pharmaceutical composition according to & first possible variant of the invention contains as a single inhibitory or destructive active principle at least one chemical fluorine compound which donates the fluorine anion F~. The F" content in the composition is advantageously greater than 4.5 ppm, in particular of the order of 5 ppm. if a 100$ inhibitory composition is required.

The inventors have moreover found that the fluoride anion F~, in addition to having a direct spermicidal activity, has a spermicidal activity by potentiation of known spermioidal compounds. A composition according to the invention consequently advantageously consists of, firstly, at least ©se base spermicidal active principle suoh as as aaiosio, cationic, amphoteric or nonionic surface -active surfactant, cr paramenthanylphenylpolyoxyethylene ether or a trisodium salt of a ίδ polysaccharide ether-sulphate and the like, secondly at least one fluorine compound according to the invention which donates the fluoride anion F", and finally a pharmaceutical excipient and various usual additives (antioxidant....) In a composition according to the invention, the concentration of the base active principle can be less than the MIC of this active principle in the absence of the ion F", the composition nevertheless being 100% inhibitory, that is to say satisfying the total spermicide test of the IPPF. A composition according to the invention can contain a mixture of several base active principles which inhibit gametes and/or a mixture of several different chemical fluorine compounds.

The percentages given in the following' are percentages by weight. Preferred embodiments of the invention for its uses in local contraception are the following: PESSARIES Benzalkonium chloride 1.20$ Anion F" 0.50$ (for example sodium fluoride) Excipient: Semi-synthetic glycerides or cacao butter or gelatine, glycerol and purified water, antioxidants, antiseptics.

CREAMS AND LOTIONS: Benzalkonium chloride 1.20$ Anion F" 0.50$ (e.g.: sodium fluoride) Excipients: Distilled or purified water, humectants, emulsifier, stabilizer, antioxidant, antiseptic. (To be distributed in varying proportions according to the viscosity and the pH to be obtained).

OHGOENTS and OISIMSHTS: Benzalkonium chloride 1.20# Arion F 0.50# (e.g.: sodium fluoride) Excipients: Distilled or purified water, emulsifier, excipients of the fatty substance type (vaseline, lanolin, lanovaseline, stearovaseline), stabilizer, antioxidant, antiseptic. (To be distributed ia varying proportions according to the viscosity and pH to be obtained).

GEL: Benzalkonium chloride 1.20# Anion F~ 0.50# (for example sodium fluoride) Excipients: Soluble derivatives of cellulose compatible with cationic surface-active surfactants, distilled or purified water, glycerol, sorbitol, antioxidant, antiseptic. (To be distributed in varying proportions according to th® viscosity and pE to fee obtained).

SOLPBLB FILM: Benzalkonium chloride 1.20# laisa F" 0.50# (for example sodium fluoride) Excipients: Polyvinyl alcohol, glycerol, sorbitol, propylene glycol, distilled or purified water, anti oxi dant.

TABLETS: Benzalkonium chloride 25 mg per tablet Andon F" 'θ mg P®r tablet (fee* example sodium fluoride) is Excipients: Lactose, magnesium stearate, cellulose, starch, citric acid, sodium bicarbonate.

SYNTHETIC SOAPS: Benzalkonium chloride 2$ 3 Anion F 1$ (for example sodium fluoride) Excipients; Foaming and wetting products compatible with quaternary ammoniums (for example an amphoteric surfactant of the betaine or aminobetaine type), emollients, stabiliser, antioxidant, antiseptic.

SOLUTIONS: Benzalkonium chloride 0.50$ Anion F 0.25$ (for example sodium fluoride) Excipients: Distilled or purified water, ethanol, antioxidant, 15 glycerol, sorbitol, antiseptic. (To be distributed in varying proportions according to the pH to be obtained).

COMPARATIVE TEST NO. 2 The MIC of various known spermicidal compounds was determined by the IPPF test. The following results were obtained by reacting 1 millilitre of composition with 0.2 millilitre of sperm and determining the minimum concentration which causes the death of all the spermatozoa within 5 seconds, on 6 sperm specimens from different donors.

Spermicidal compound KEC ($ by weight) p-Menthaayl phenyl polyoxyethylene ether 0.006 Trisodiusa salt of polysaccharide ether- sulphate 0.007 Anionic surface-active surfactant (sodium salt oxide methyltauride) 1 Cationic surface-active surfactant (benzalkonium chloride) 0.006 Konionie surface-active surfactant (nonoxynol 9) 0.006 Amphoteric surface-active surfactant (derivatives e* amidoethylglycinate on fatty acids) ©.001 TEST 80. 2 The same IPPF total spermicide test was carried out with 1 millilitre of composition already containing 0.0001$ (by weight) of the fluoride anion F~ reacting on 0.2 millilitre of sperm, by determining the minimum concentration of the spermicidal compounds which causes the death of all the spermatozoa within 5 seconds, on 6 sperm samples from different donors. 2δ Spermicidal compound MIC ($ by weight) p-Menthanylphenylpolyoxye thylene e then 0.003 Trisodium salt of polysaccharide ether- sulphate 0.0025 Anionic surface-active surfactant (sodium salt oxide methyltauride) 0.50 Cationic surface-active surfactant (benzalkonium chloride) 0.002 Nonionic surface-active surfactant (nonoxynol 9) 0.003 Amphoteric surface-active surfactant (derivatives of amidoethylglycinate on fatty acids) 0.0005 It is thus found that the inhibitory capacity of known spermicidal principles is greatly increased by addition of ionisable fluorine to the composition. A composition according to the invention could thus contain very little base spermicidal active principle, In particular in a concentration less than the minimum inhibitory concentration of this active principle In the absence of the ion F.

Moreover, the concentration of the ion F~ combined with a base active principle could also be very low, in particular lower than the minimum inhibitory concentration of the fluoride anion F.

By way of example, the inventors found that although a solution of benzalkonium chloride in a concentration of 0.003$ and a solution containing 0.0001$ of the fluoride anion F" eac^ do not have a total spermicidal activity according to the IPPF test, a solution containing both 0.003$ of benzalkonium chloride and 0.0001$ of the fluoride anion F" satisfies the IPPF test. A synergism effect is thus round.

TEST NOThis test consists of carrying out a test identical to tests no. 1 and mentioned above, but in the presence of sodium borate in order to complex the ion F"; the spermicidal effect of the ion F disappeared totally, thus demonstrating that it is solely the ion F" which is active or potentiates the spermicidal effectTEST NO. 4: Various perfluorinated benzalkonium chlorides were used as the base spermicidal compounds under the same conditions as described above (tests no. 1 to 3)- It was thus found that perfluorinated benzalkonium chlorides have a spermicidal activity similar to that of benzalkonium chloride. Moreover, this activity remains identical under the conditions of test no. in the presence of sodium borate, which demonstrates that the fluorine bonded to the benzene nucleus has not been ionized.

Test no- 2 was also carried out on perfluorinated benzalkonium chlorides mixed with another chemical compound which donates the ion F. Potentiation of the spermicidal activity of perfluorinated benzalkonium chlorides was also found. This same test carried out in the presence of sodium borate (la accordance with test no. 3) resulted in a spermicidal' activity which Is that of perfluorinated benzalkonium ohlorldesThese two tests no. 3 and 4 demonstrate that the potentiation of the base active principle takes place only in the presence of the fluoride anion F".

To produce a spermicidal pharmaceutical product according to the invention, a solution of a given concentration . of fluoride anion F" and, if appropriate, of the base active principle is prepared and is integrated Into the excipient chosen according to the galenical form which is to be produced. la the case of the tablet, the base active principle aad the chemical eoapous-d which donates the ion F" ;a,r's Integrated 1st© the excipient Is the form of crude products.

Ai COMPARATIVE TEST NO. 5: This in vitro test was carried out on galenical preparations containing benzalkonium chloride as the base active principle by determining the MIC of benzalkonium chloride after in vitro simulation of actual conditions in vivo (extraction, solubilization—.).

This test carried out without an activating principle led to the following results: GALENICAL FORM MIC ($ by weight) of benzalkonium chloride Pessary 0.0063 Cream 0,0033 Tampon 0.0075 Tablet 0.0095 Soluble film 0.0080 Gel 0.0080 The percentages correspond to the proportions (by weight) of benzalkonium chloride in the in vitro solution used for the spermicide test according to the IPPF,, obtained after simulation and measured by titration on a sample taken from this solution.

TEST NO. j>: The same conditions as in comparative test no» 5 were used, but on galenical forms each containing 0.45$ (by weight) of the fluoride anion F" at the start.

The following results were obtained: GALENICAL FORM MIC (# by weight) of benzalkonium chloride Pessary 0.0023 Cream 0.0030 Tampon 0.0025 Tablet 0.0025 Soluble film 0.0017 Gel 0.0033 II) USE OF THE ΙΗΪΒΗΠΟΗ Bs THE FIELD OF ANTISEPSIS, ANTIBIOTIC ΤΗΕΒΑΡΪ AND IK PARTICULAR IK COMBATIHG STDs: Preferred embodiments of this invention in the example of its use ln dermatology as an antiseptic are the following: CHASMS and LOTZQSS; Benzalkonium chloride 1-20# Anion F" 0-50# (for example sodium fluoride) Excipients: Distilled or purified water, humectants, emulsifier, stabiliser,,, antioxidant, antiseptic. (To he districted la varying proportions according to the viscosity and pH to be obtained).

UNGUENTS and OBiTMEHTS: Benzalkonium chloride I - 20# Asioa r~ 0.50# (for example sodium fluoride) Excipients: Distilled or purified water, emulsifier,,, excipients of the fatty substance type (vaseline, lanolin, lanovaseline, stearovaseline), stabiliser, antioxidant, antiseptic. (To be distributed in varying proportions according to the viscosity and pH to be obtained).

SYNTHETIC SOAPS: Benzalkonium chloride 2$ Anion F~ 1$ (for example sodium fluoride) Excipients: Foaming and wetting products compatible with quaternary ammoniums (for example amphoteric surfactants of the betaine or aminobetaine type), emollients, stabiliser, antioxidant, antiseptic.

SOLUTIONS: Benzalkonium chloride 0.50$ Anion F 0.25$ (for example sodium fluoride) Excipients: Distilled or purified water, ethanol, antioxidant, glycerol, serbitol (sic), antiseptic. (To be distributed in varying proportions according to the pH to be obtained).

Preferred embodiments of the invention in the example of its use in dermatology as a local antibiotic are the following: SOLUTIONS: Erythromycin base 4$ Anion F" 0.5$ Excipients: Ethyl alcohol, propylene glycol, distilled water.

GELS: Erythromycin base 4% Anion F" 0.5% Excipients: Ethyl alcohol, hydroxypropylcellulose. distilled water, glycerol.

OINTMENTS: Neomycin base 0.35$ Anion F~ 0.50$ or Bacitracin 50,000 IU$ Anion F" 0.50$ or Oxytetracycline hydrochloride 3% Anion F 0.50$ or Aureomycin hydrochloride 3$ Anion F" 0.50$ Excipients: Vaseline, vaseline oil, lanolin CREAMS: Soframycin sulphate 2.5$ Anion F 0.50$ Excipients: Propylene glycol, polyoxyethylene glycol, distilled water. Preferred embodiments of the invention in the example of its use in oto-rhino-laryngology as a local antibiotic are the following: OPHTHALMIC OINTMENTS: Aureomycin 1$ Anion F" 0.50$ Oxytetracycline 0.50$ Anion F" 0.25$ Excipients: Vaseline, vaseline oil, lanolin NASAL SOLUTIONS: Soframycin sulphate Anion F Excipients: Distilled water, citric acid, sodium chloride. 0.10$ of benzalkonium chloride can advantageously be added to increase the activity of preparations for local antibiotic therapy.

Preferred embodiments of the invention in the example of its us© in gynaecology snd more particularly for combating STDs? are those described above under the heading Use for local contraception* and under the subheadings Pessaries, Creams, Unguents and ointments, Gels, "Tablets-s Synthetic soaps and Solutions.

The methodology used in the tests carried out on these uses of the Invention was as follows: For Neisseria gonorrhoea©: The germs used originate from hospital isolations.

- Dilution range of the substances to be tested: solvent:sterile doubly distilled H9O Range of geometric ratio 2 Doses: from 2.000 to 1.56 (and less) pg/ml ml of each of the dilutions are mixed with 18 ral of solid culture medium, preferably Gonococci agar-agar isolation medium (Pasteur Institute) enriched with supplement G: Formula: Colt serum 165 ml Yeast extract 100 ml Corpuscle extract 235 ml Glucose 0.65 ml Distilled H^O q.s.p. 500 ml - Gonococci culture medium: 2,000 ml of Pasteur medium * 500 ml of supplement GThese culture media combined with dilutions of the active substances are the means for investigating the bactericidal activity. The final concentrations of substances will be of the order of 800 to 0-156 jsg/ol in the Petri dishes» The suspensions used (dilution in physiological water of a 24-hour culture In a liquid nutrient broth medium) are placed in hollow wells in a synthetic base under a laminar flew hood» On© strain (multiple culture) was studied in each of the prepared wells. Bach dish studied is examined after 24 and 48 hours of culture (oven at 37°O- Determination of the MIC: The Gonococci strains were spread over the plates (dilution on the plate), some of which were prepared as references and a control, without a substance to he tested. pi of 10 colony-forming units/ml deposited on the agar-agar plates, either with or without the substances to be tested (culture of Gonoeooei for 18 hours in suspension in a Sorensen solution).

Incubation was carried out for 48 h at 36°C and the growth or absence thereof of Gonococci found on the plates is recorded.

For Candida alhioanss The methodology is largely the same as that for Neisseria gonorrhoeae, but with the following differences: - Dilution rang® ip sterile doubly distilled water from 2,000 t® TLSS jxg/sal 4-5 al of Boirca liquid medium are added to 0.5 ml of each diluticra- Th© tubes are seeded with cultures of Candida (24 hours/Roiron medium) or with the control (Roiron medium). The tubes are indicated in an oven at 37°C for 24 and 48 hours. At t = 24 hours and t = 48 hours, a drop is examined between a slid© aad slide cmr under a microscope.

- The results are expressed by counting the yeasts and a fuagioidal MIC is d@terBis.ed» Determination of the percentage ©f resistant species ©a the control tubes.

For Trichomonas vaginalis: The same methodology as for Candida albicans.

For Chlamydia: - Inoculum: This is Chlamydia host cells or MacCoy cells. They are kept at -80°. The cell concentration will be 2 to 2.5 x 10 cells/ml for the tests. The cell layer is prepared in a complete culture medium.

- The substances to be tested are diluted in an increasing range of geometric ratio 2 in sterile doubly distilled water.

- The method used is that of Professor F. CATALAN. P. SEDNAOUI, A. MILOVANOVIC et al.. Institute A. FOURNIER, PARIS. ml of the dilution of substances to bs tested is mixed with 1 ml of the cell suspension (MacCoy cell) and the mixture is then incubated for 1 hour and 24 hours at 37°C in an oven. 0.2 ml of this mixture Is then placed in the plates of the wells. The plates are centrifuged (1 hour at 2,000 revolutions/min) and incubated for 1 hour at 37°0. The culture medium is then replaced by 0.2 ml of new medium containing 0.5 mg/1 of cycloheximide and the plates are then incubated for 48 hours at 37°C. The cell layer is subsequently fixed with methanol and in particular stained with a monoclonal antibody and conjugated with FITC (fluorescein Isothiocyanate). From this, the inclusions present in the MacCoy cells are examined under an inverted epifluorescence microscope.

The toxicity of the substances to be tested was thus initially studied and taken into account in considering the total integrity of the host cell.

For Pseudomonas aeruginosa: = Preparation of a dense solution of two strains.

- Suspension in isotonic NaCl solution (0.85$ by weight).

- Verification that the suspensions contain the same number of bacteria: usual techniques in agar-agar medium by culture in streaks (loop of 1 pi) using successive dilutions of the dense starting suspension (geometric ratio 10). Incubation for 18 h at 37°C.

- Preparation ©* dilutions of the substances to be tested ia solution In sterile doubly distilled water- Dilution range of* geometric ratio 2 (from 2,000 to 0.015 μβ/®1„ for example).

- Mixing of the bacterial suspension of Pseudomonas aeruginosa (of the same origin as the AFNOR standards) with a constant concentration (a χ 1O7 bacteria/ml) and of the dilution of the substances in a decreasing order (2.000 to 0.015 pg/ml).

- Incubation or contact tise: 1 hour, 24 hours and 48 hours, in an oven at 37°C. 0 The tests were duplicated for each dilution of substance.

- Observation of the number of survivors recorded with respect to the average number of control strains cultured in the same time as in the tests.

- Observation after 1 hour, 24 hours and 48 hours.

For Trepoasaae, Gardnerella, Ducrey bacillus. Streptococci gad Staphylpooccu3 aureus: The methodology used is that described by Professor F. CATALAS, ?. SEDNAOUI, A. MILGVASOVXC at al- Institute A. FWRNIER.

COMPARATIVE TEST SO- 7: The following results were obtained with benzalkonium ehloride by itself and nonoxyaol 9 by Itself: STRAINS 3δ MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride by itself Gonococci 1-15 mg/1 Treponemae 70 mg/1 Trichomonas 1.3 mg/1 Candida albicans 50 mg/1 Chlamydia 100 mg/1 Gardnerella 50 mg/1 Ducrey bacillus 75 mg/1 Streptococcus 15 mg/1 Pseudomonas aeruginosa 31-25 mg/1 Staphylococcus aureus 1.56 mg/1 STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Nonoxynol 9 by itself Tre ponemae 75 mg/1 Pseudomonas aeruginosa 50 mg/1 Staphylococcus aureus 4 mg/1 Streptococcus 20 ©g/1 TEST HO, 8: The same test as above, carried out in the presence of the fluoride anion F, led to the following 'results; STRAINS MINIMUM INHIBITOR! COHCBNTSITIOSi (MIC) Benzalkonium chloride * F" 1 micrograa/al Gonococcus 0.50 mg/1 Treponasae 55 fflg/I Tbiehosonas 0.9 Bg/1 Candida albicans 35 mg/1 Chlamydia 85 mg/1 Gardnerella ti mg/1 Ducrey bacillus 62 mg/1 Streptococcus 9 mg/1 Pseudceonas aeruginosa J8 ®g/l Staphylococcus aureus 1.1 mg/1 STRAINS MINIMUM IHHIBITOBT OTHCSHTSATIOS (MIC) Nonoxynol o * F sicrogram/ml TTeponeaae 60 mg/1 Pseudomonas aeruginosa 35 mg/1 Staphylococcus aureus 2.5 mg/1 Streptococcus 15 mg/1 Λ ΖΎ· COMPARATIVE TEST NO. 9: This test was carried out with a substance containing benzalkonium chloride without an activating principle but in the presence of serum proteins. It led to the following results: STRAINS CONCENTRATIONS OF SERUM PROTEINS MINIMUM INHIBITOR! CONCENTRATION (MIC) Benzalkonium chloride by Itself Streptococcus faecalis 0 15 mg/ml 30 mg/ml 15 mg/ml 60 sag/ml 16 mg/ml 90 mg/ml 68 mg/ml Neisseria gonorrhoeas 0 1.5 mg/ml 30 mg/ml 1.5 mg/ml 60 mg/ml 1.5 mg/ml 90 mg/ml 9 mg/ml This test shows the well-known adverse effect of serum proteins on the 20 efficacy of benzalkonium chloride.

TEST NO. 10: This test was carried out in an identical manner to test no. 9» hut in the presence of the fluoride anion F" in the composition. The following results were obtained: STRAINS CONCENTRATIONS OF SERUM PROTEINS MINIMUM INBISITOST CONCENTRATION (MIC) Benzalkonium chloride * F 1 microgrem/al Streptococcus faeealis 0 9 mg/ml 30 mg/ml 9 mg/ml 60 mg/ml 9 og/tel 90 mg/ml 21 mg/ml Neisseria gonorrhoeas 0 0.6 mg/ml 30 mg/ml 0.6 mg/ml 60 mg/ml 0.6 sag/al 90 mg/ml 1.2 Hg/al This test shows that the fluoride anion F allows a very favourable reduction in the adverse effect of serum proteins.

COHPA^TIYS TEST SO.. JH: This test was carried out on the galenical fores in vitro (in a aaamer similar to tests 5 and 6), starting from products containing benzalkonium chloride as the active principle and without an activating principle. The following results were obtained: 4 STRAINS GALENICAL FORM MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride by itself Gonococcus pessary Tablet 23.65 mg/1 15-62 mg/1 Trichomonas pessary 11.80 mg/1 Tablet 15-60 ag/1 The concentrations are those present in the liquid obtained after simulation and used for the test. θ TSST NO. J_2: This test was carried out under the same conditions as comparative test no. 11, starting from products containing 0.5$ (by weight) of the fluoride anion F". The following results were obtained: STRAINS GALENICAL FORM MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride + F in a concentration of 0.5$ Gonococcus Pessary Tablet 5 mg/1 3 mg/1 Trichomonas Pessary Tablet 5 rng/I 3 mg/1 III) USB OF TSE INVENTION IN THE FIELD OF DISINFECTION: This field relates to treatment of soils, surfaces, instruments... with contact bactericidal products.

Preferred embodiments of the invention for this use are the following: USES BENZALKONIUM CHLORIDE Anion F BXGIPISITS Hands Purified water (3.1$ 0.25$ or alcohol Epidermis q.s.p. 100$ Instruments Purified water to be sterilized 1.0$ 0.50$ to be disinfected q.s.p. 100$ Purified water Textiles 0.05$ 0.025$ q.e.p. W0$ Instruments Ethanol 10$ 1.0% 0.50$ purified water thermometer type q.s.p. W$ Washing of surfaces Purified water (rooms, floors. 0.1$ 0.25$ soils) q.s.p. W0$ The tests were carried out in accordance with A.FSOB standard SFT 72-150 March 31 with benzalkonium chloride and then with noaoxyaol 3 as the active principle. Tfe® neutralizing agent used was the following: 3$ of Tween^ 80 (V/V) and ®„3$ of lecithin (W/Vk Th® pH of th© medium was I'.Z, COMPARATIVE TEST NO. J3,This test was carried out without an activating principle.

STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride by itself Pseudomonas aeruginosa CNCM A 22 31.25 ag/litre Escherichia coll CNCM 54 127 6.57 mg/1 Staphylococcus aureus Oxford strain CNCM 53 154 1.56 sg/1 Streptococcus faecalis CNCM 5 855 4 ©g/1 Mycobacterium smegmatia CNCM 7 326 30 mg/1 STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Nonoxynol 9 by itself Pseudomonas aeruginosa CNCM A 22 Escherichia coli 50 mg/litre CNCM 54 127 Staphylococcus aureus 8 ag/1 10 Oxford strain CNCM 53 154 Streptococcus faecalis 4 mg/1 CNCM 5 855 Mycobacterium sme^satis 7 mg/1 CNCM 7 326 65 sng/1 TEST NO. Jjl: This test is identical to the above, but in the presence of the fluoride anion F as an activating principle.

Q Ta Λ.

STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride ·*· F' 1 microgrsm/ml Pseudomonas aeruginosa CNCM A 22 18 mg/litre Escherichia coli CNCM 54 127 3 mg/1 Staphylococcus : aureus Oxford strain CNCM 53 154 1.1 mg/1 Streptococcus faecalis CNCM 5 855 3.6 mg/1 Mycobacterium smegjnatis CNCM 7 326 26 mg/1 STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Nonoxynol 9 by itself (sic) F" 1 microgram/ml Pseudomonas aeruginosa CNCM A 22 35 mg/litre Escherichia coli CNCM 54 127 6.5 mg/1 Staphylococcus aureus Oxford strain CNCM 53 15u 2.5 ag/1 Streptococcus faecalis CNCM 5 855 5-5 mg/1 Mycobacterium saegmatis CNCM 7 326 50 mg/1 IV) USE OF THE INVENTION IH COSMETOLOGY: Preferred embodiments of the invention in cosmetology are described below.

The following galenical forms can be made available in cosmetology: creams, lotions, ointments, solutions, bubble baths, synthetic soaps, shampoos, intimate lotion, disinfectant lotion.

The formulations of excipients are the same as for the pharmaceutical presentations, but the concentrations of benzalkonium chloride and anion F will be different.

These concentrations will thus be the following for all the products: benzalkonium chloride: 0.2#, anion F: 0.1#.

Chemical active principles or those of a natural origin can also be included in these formulations in concentrations and doses approved in cosmetology.

The creams and lotions can be in a continuous aqueous phase (oil/water emulsion or water/oil emulsion) or in a pasty base which is diluted in water when hot.

The various excipients mentioned by way of example correspond by way of non-limiting indication to the following products: Humectants: glycerol, propylene glycol, diethylene glycol, sorbitol, polyoxyethylene glycol.

Emulsifiers: sodium stearate, beeswax, sorbitol ester, polyoxyethylene glycol ester, fatty alcohol, triethanolaminelanolin- Tween, glycol stearate and polyglycols.

Stabilizers; glycol stearate, cetyl alcohol alginate, pectin, gum, fatty esters of polyols, soluble cellulose esters.

Antioxidant: tartaric, citric and ascorbic acid.

Antiseptic: boric acid, benzoic acid, parabenzoic acid and their methyl or propyl esters, free or in the sodium form. pH: ail these formulations are particularly effective at a pH of between 4.5 and 6-5. Citric acid Is mainly used to obtain this range.

Claims (27)

1. , Use of at least one active principle which inhibits or destroys at least one unicellular living being or virus and of an activating principle in proportions suitable for inhibiting or destroying at 5 least one enzyme associated with the said unicellular living being or virus, to obtain a product or a medicament for inhibiting or destroying this unicellular living being or virus, with the exception of the case of the combination of benzoic acid, phenol and an alkali metal fluoride in aqueous solution or aqueous-alcoholic solution to 10 obtain a product for inhibiting or destroying the herpes virus.

2. » Use according to Claim 1, in which the activating principle is a fluorine compound which donates ionic fluorine.

3. - Use according to Claim 2. in which the fluorine compound is a metal derivative of fluorine. 154. Use according to Claim 3 S in which the fluorine compound is selected from the group comprising sodium fluoride, calcium fluoride, potassium fluoride, aluminium fluoride, tin fluoride, ammonium fluoride and sodium monofluorophosphate.

4. 5. use according to Claim 1, in which the activating principle is the 20 fluoride anion F~.

5. 6. Use according to any one of Claims 1 to 5, in which one active principle is a surfactant surface-active compound.

6. 7. Use according to Claim 6, in which the active principle is cationic.

7. 8. Use according to Claim 7, in which the active principle is a 25 quaternary ammonium.

8. 9. use according to any one of Claims 6 to 8, in which the active principle is benzalkonium chloride.

9. 10. use according to Claim 6, In which one active principle is an anionic surfactant surface-active compound.

10. 11. Use according to Claim 6, in which one active principle is an amphoteric surfactant surface-active compound.

11. 12. Use according to Claim 6, In which one active principle is a nonionic surfactant surface-active compound.

12. 13. Use according to any one of Claims 6 to 12. in which one active principle Is selected from the group comprising a sodium salt oxide methyltauride, a derivative of aminoethylglycinate on a fatty acid, a 10 nonoxynol, phenylmercury nitrate, para-menthanylphenylpolyoxyethylene ether, or a trisodium salt of a polysaccharide ether-sulphate.

13. 14. Use according to any one of Claims 1 to 13, to obtain a product or a medicament for inhibiting or destroying a protozoan, or a microbe, or a bacterium, or a gamete, or a fungus, or a virus.

14. 15. Use according to any one of Claims 1 to 14, to obtain a product or a medicament for inhibiting or destroying at least one unicellular living being or a virus selected from the group comprising gametes. Gram-positive cocci. Gram-negative cocci. Gram-positive bacilli, Gramnegative bacilli,, bacilli resistant to acid alcohols, bacteria, flagellated protozoans, yeasts, viruses or retroviruses. Ιό. Use according to any one of Claims 1 to 15 of at least one active principle which inhibits or destroys gametes and of an activating principle in proportions suitable for inhibiting or destroying at least one enzyme associated with the said gamete to obtain a local 25 contraceptive product.

15. 17. Use according to Claim 16 of benzalkonium chloride and of a fluorine compound which donates Ionic fluorine, in proportions suitable for obtaining a product in the form of a pessary, cream, lotion, unguent, ointment, gel or soluble film containing 1.20$ by weight of benzalkoniua chloride and 0.50$ by weight of the anion F, or a product ia the fora of a tablet containing 25 »g per tablet of benzalkonium chloride., and 10 ng per tablet of the anion F, or a product ia the fora of a synthetic soap containing 2$ by weight of benzalkonium chloride and 1$ by weight cf the anion F~, or a product la the fora of a solution containing 0.50$ by weight ©f benzalkonium chloride and 0.25$ by weight of the asaioa F“.

16. 18. Ose according to Claim 16, in which one active principle is a fluorine compound capable of donating ionic fluorine.

17. 19. Ose according to any one of Claims 1 to 15 of at least one motive principle which inhibits or destroys at least one unicellular living being responsible for sexually transmitted diseases and of aa activating principle is proportions suitable for inhibiting or destroying at least one enzyme associated with the said unicellular living being to obtain a medicament intended to combat sexually transmitted diseases,

18. 20. Ose aeccrdiag to Claim 19 of benzalkonium chloride and of a flusrize compound which donates ionic fluorine in proportions suitable for obtaining a product ia the fora of a pessary, eream,, uagaent, ointaent, gel or soluble film, containing 1.20$ by weight of benzalkonium chloride and 0.50$ by weighfc of the aaioa F“ s or a product is tbe fora ©f a tablet containing 25 mg per tablet of benzalkoniua chloride and 10 ag per tablet of the anion F~, or a product in the form of a synthetic soap containing 2$ by weight of benzalkonium chloride and 1$ by weight of the aaioa F“, or a product in the form of a solution containing 0.50$ by weight of benzalkonium chloride and 0.25$ by weight of the anion F“„

19. 21. Use according to Claim 19, in which one active principle is a fluorine compound capable of donating ionie fluorine.

20. 22. Ose according to any one of Claims 1 to 15 of at least one active principle having as, antibiotic actios towards at least, ooe unicellular living being and of an activating principle in proportions suitable for inhibiting or destroying at least one enzyme associated with the said unicellular living being to obtain a medicament to combat by antibiotic therapy the diseases for which the said unicellular living 5 being is responsible.

21. 23. use according to Claim 22 of benzalkonium chloride or erythromycin base or neomycin base or bacitracin or oxytetraeycline hydrochloride or aureomycin hydrochloride or soframycin sulphate or aureomycin or oxytetracycline and of a fluorine compound capable of donating ionic 10 fluorine to obtain a medicament in the form of cream or lotion, or unguent or ointment containing 1.20$ by weight of benzalkonium chloride and 0-50$ by weight of the anion F”» or a medicament in the fora of a synthetic soap containing 2$ by weight of benzalkonium chloride and 1$ by weight of the anion F“. or a medicament in the form 15 of a solution containing 0-50$ by weight of benzalkonium chloride and 0.25$ by weight of the anion F~, or a medicament in the form of a solution or a gel containing 4$ by weight of erythromycin base and 0-5$ by weight of the anion F“, or a medicament in the form of an ointment containing 0-35$ by weight of neomycin base and 0-50$ by 2 θ weight of the anion F“„ or 50-000 IU $ and 0-50$ of the anion F”, or 3$ by weight of oxytetracycline hydrochloride and 0.50$ by weight of the anion F, or 3$ by weight of aureomycin hydrochloride and 0.50$ by weight of the anion F, or a medicament in the form of a cream containing 2-5$ by weight of soframycin sulphate aad 0-50$ by weight 2 c of the anion F”, or a medicament in the form of an ophthalmic ointment containing 1$ by weight of aureomycin and 0.50$ by weight of the anion F~, or 0.50$ by weight of oxytetracycline and 0.25$ by weight of the anion F, or a medicament in the form of a nasal solution containing 1.25$ by weight of soframycin sulphate and 0.50$ by weight of the 30 . anxon F ,.

22. 24. Use according to Claim 22 of benzalkonium chloride or erythromycin base or neomycin base or bacitracin or oxytetracyellne hydrochloride or aureomycin hydrochloride or soframycin sulphate or aureomycin or oxytetracycline and of a fluorine compound capable of donating ionic ¢4 fluorine to obtain a medicament in the form of a solution or a gel containing 4$ by weight of erythromycin base. 0.5$ by weight of the anion F” and 0.10$ of benzalkonium chloride, or a medicament in the form of an ointment containing 0.35$ by weight of neomycin base. 0.50$ of the anion F and 0.10$ of benzalkonium chloride, or 50,000 IU %, 0.50$ of the anion F and 0.10$ of benzalkonium chloride or 3$ by weight of oxytetracycline hydrochloride, 0.50$ by weight of the anion F and 0.10$ of benzalkonium chloride, or 3$ by weight of aureomycin hydrochloride, 0.50$ by weight of the anion F and 0.10$ of benzalkonium chloride, or a medicament in the form of cream containing 2.5$ by weight of soframycin sulphate, 0.50$ by weight of the anion F and 0.10$ of benzalkonium chloride, or a medicament in the form of an ophthalmic ointment containing 1$ by weight of aureomycin, 0.50$ by weight of the anion F“ and 0.10$ of benzalkonium chloride, or 0-50$ by weight of oxytetracycline, 0.25$ by weight of the anion F and 0.10$ of benzalkonium chloride, or a medicament in the form of a nasal solution containing 1.25$ by weight of soframycin sulphate, 0.50$ by weight of the anion F* and 0.10$ of benzalkonium chloride.

23. 25. Use according to any one of Claims 1 to 15, of at least one active 20 principle which inhibits or destroys at least one fungus and of an active principle in proportions suitable for inhibiting or destroying at least one enzyme associated with the said fungus to obtain an antifungal product.

24. 26. Use of at least one active principle which inhibits or destroys at 25 least one protozoan and of an activating principle in proportions suitable for inhibiting or destroying at least one enzyme associated with the said protozoan to obtain an anti-protozoic product.

25. 27. Use of at least one active principle which inhibits or destroys at least one bacterium and of an activating principle in proportions 30 suitable for inhibiting or destroying at least one enzyme associated with the said bacterium to obtain a bactericidal product or medicament.

26. 28. Use according to Claim 27, of benzalkonium chloride and of a fluorine compound which donates ionic fluorine to obtain a bactericidal contact product containing 0.1# of benzalkonium chloride and 0.25# of the anion F~, or 1# of benzalkonium chloride and 0.50# of the anion F“, or 5 0.05# of benzalkonium chloride and 0.025# of the anion F.

27. 29» Use according to any one of Claims 1 to 15» of at least one active principle which inhibits or destroys at least one virus or retrovirus and of an activating principle in proportions suitable for Inhibiting or destroying at least one enzyme associated with the said virus or • 30 retrovirus to obtain an antiviral medicament or product.