IE871338L - Fluoride emitting substance - 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

'"O "O £. A •O '*ir 9 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 5 context of both pharmacy or cosmetics and disinfection.

In the following, -inhibition- 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. -Destruction" is understood as meaning the act of 10 killing unicellular living beings or viruses.

^Substance- 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 product5 generally in 15 combination with an excipient and possibly other substances. Moreover, the term "product- designates a finished, usable product. In general, a finished product thus constitutes at least one ezeipisnt and several substances,, each substance consisting of one or more chemical compounds having similar or identical functions. This term "substance3 may 2 0 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 25 effectively realised 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 fieldss such as disinfection and the like.

Spermicidal compositions are known, in particular^ from U.S. Patents « 339 Mil and 4 359 Numerous chemical compounds which can be used In local contraception methods on the living being are also known. In particular,, it is known 30 s) that surface-active surfactants (for exaaple quaternary amaoniuas, nonoxynols, derivatives of aaido-ethyIglycinate ©a fatty acids, sodlun salt oxide methyltauride...) and certain other compounds, such as phenylaercury nitrate, paramenthanylphenylpolyoxyethylene ether or the trlsodiua salt of 5 polysaccharide ether-sulphate, have actions which inhibit or destroy unicellular living beings, in particular spermicidal actions.

Substances which act mechanically on speraatozoa, for example by iaaobilizing then, are also known. Aaerican Patent H 368 186 describes such effects, and a ore particularly the combination of "poloxaaer" with 1 o inhibitors of spermatozoa, in order to control gelling and solubilization of the products and thus to increase the efficacy of the Inhibitors mechanically &J addition or synergism.

Local contraceptive compositions, in particular speraicides, which contain such cheaical compounds and can be used locally to inhibit the 15 reproductive capacity of gametes, in particular spermatozoa of the human or animal being, are also known. These known cod positions have a certain concentration of the inhibiting cheaical compound vfaich is greater than the ainlaua inhibitory concentration, or MIC, in solution or suspension in a pharmaceutical excipienty which depends on the galenical form used. In 20 fact, it ia 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 IPPF, International Planned Parenthood Federation, specifications), It is necessary for the concentration of the spermicidal active principle in 1 aillllltre of 25 pharaaceutical composition to be greater than or equal to the alnlaua inhibitory concentration, or MIC, of this active principle. The 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 foras which contain the composition. 30 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 oosaetics containing S'aefe compositions are knows.

Numerous active principles are already known lis the field of 35 antisepsis and disinfection: halogens (derivatives of oSalorlae or iodine...), aldehydes,, alcohols, phenols, acids, metals (salts of silver, copper, sine, mercury...), amidiness blguanidess carbanilides8 oxidising agents (hydrogen peroxide3 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 u'S-ii~3 995 029 describe the use of sodium fluoride with, in a lesser proportion with respect to the fluorides, a wetting agent consisting of an anionic surfactant for the treatment of acne and the mycosis of athlete "s foot.

European Patent Application EP-I-0 226 187 ai?.d PCT Application MO-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 liait 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 w ith regular use)5 and Indeed even in the short tere (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 5 disinfection field, undesirable effects on the materials to fee 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 5 limited concentration of base inhibitory or destructive active principle without increasing this concentration. Another object of the invention ia 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 1 5 which can be 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 effects and of which the efficacy is total, that is to say of which the percentage of failures is statistically zero or negligible, under the usual simple use conditions (without particular 2 0 precautions).

The invention moreover has the object of providing a, local contraceptive pharaaceutlcal 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. 25 The object of the invention is also to propose a obeaioal oompotaad which can be used la 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, la particular 30 antiseptics, antibiotics, bactericides, antiprotosoics8 antifungal agentss spermicides, antiviral agents.

The Invention accordingly relates to the use of at least one active principle which inhibits or destroys at least one saaicsllelar living beisg or virus and of an activating principle in proportions suitable for 35 inhibiting or destroying at least one enzyme associated with the said unicellular living being or virus to obtain a product or a aedicament 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-0 226 187 and. WO-A-87 03"82. 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 ensvme, called "activating" principle below, is preferably an agent which prevents functioning of the ensyme/substrate pair.

However, it has been found, surprisingly, that such an agent can advantageously consist of the fluoride anion P~ 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 compositions in particular a spermicidal composition,, characterised in that it contains, by way of the active principle which inhibits or destroys gametes directly or by potentiations at least one chessaical compound which donates the fluoride anion F~ and an excipient.

The invention also proposes a medicament., an antiprotosoic - in particular local antiprotosoic - and/or bactericidal - in particular local bactericidal - and/or antifungal - in particular local antifungal - and/or antibiotic - in particular local antibiofcle and/or antiviral - (alo) product, a cosmetic product - in particular a local oosaetio product, snob 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 filn, taapon or vaginal suppository -characterized in that they contain a substance or a composition according to the invention.

The tera "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 ia the environment close to this place against unicellular living beings which come into contact with the product, in contrast to uses by a general routs (for example perorally).

A substance, a composition, a medicament, a product and a chemical composition according to the 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 livisg beings to customary therapeutics, the invention will preferably be used by a general remfce.

The Invention also proposes the use in a eosmetie product of a composition containing at least one base active principle aad a chemical fluorine eo^pousd which doaates the fluoride anion F~ as the activating principle of the base active principle(s); the use of a oheaioal fjUacrioe compound which donates the fluoride anion F~ to produce a substance containing at least one base active principle as the activating principle of the base active principle(s); the msie 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 acoesriisg to the invention to obtain a local contraceptive for the human or animal beings in particular an inhibitor or destroyer of gaaetes.

The Invention also proposes a process for the preparation of a substance or oosposition according to the invention wi&ieh inhibits or destroys at least one unicellular living being - la particular a microbe, bacterium, gamete, fungus or also virus - characterized ia that at least one teas active principle which inhibits or destroys t&s ®nid ualoellolar 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 ensyme 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 (lactaaase-destroying penicillins), so-called "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 abovementioned 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 enzymes8' below designates the vital and/or protective ensymes 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 the usual minimum concentrations. It will be noted, advantageously, that ionised 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 at 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 ia 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 may or may not be pathogenic, and viruses. The invention essentially has two distinct types of use: either uses ia the cosmetic or pharmaceutical field (in the case of the following examples of spermicides or bactericides', acting against pathogenic agents), esr uses la aor® eosiaoa fields, such as agriculture, disinfection (example below) asd the like. In all oases, a substance according to the invention is characterised ia 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 sali living being or virus, constituting aa activator - in particular by synergism if it also itself inhibits or destroys the said living beisg - of the base active principle.

The function of the activating principle is therefor© 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 aaieo F~ donated from 3 fluorine compound, for example a aetal derivative of fluorine. Very positive results were found with sodiua fluoride, calciwm fluwid#, potassium fluoride, aluminium fluoride, tin fluoride, amaooiua fluoride and sodium monoflucr ©phosphate.

The invention can affect, for example, the foHoving asioelialar 10 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 s in particular Colibacilli or Escherichia coli bacilli which are resistant to acids and alcohols, ia 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 virus1"), 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): il TABLE 1 enzyme; SUBSTRATE 10 15 20 25 Alkaline phosphatase Esterase (C ?4) Esterase lipase (C 8) Lipase (C 14) Leucine arylamidase Valine arylamidase Cystine arylamidase Trypsin c<-Chymotr ypsin Acid phosphatase Nephthol AS-B1-phospiiohydrolase tt-Galactosidase ^-Galaotoaidase ^-Glucuronidase 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 thats 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 sua 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 HIC, which corresponds to the concentration of active principle which causes the inhibition or death of all the unicellular living beings or viruses vithin a given time.

In a substance according to the inventions, 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 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 additions the base active principle can itself also be the donor of the activating principle, in particular the fluoride anion F~. & substance or composition according to the invention can contain several base active I principles, the functions of which can be identical or different,, and/or several activating principles acting on at least Okie enzyme associated with one or sore 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 use3 of the products according to the invention there may be mentioned the 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 nonpathogenic 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 h® classified in the pharmaceutical field.

In fact, for example, the effective concentrations of ehenical fluorine compounds, and even of base active principles, can be reduced in proportions such that they become less than the threshold valsss of the concentrations separating the pharmaceutical and cosaetlo fi«ld», but without reducing the efficacy of the product. a substanoe or composition according to the can also advantageously be used in products which are aeltber cosoetles aor pharmaceuticals, for example ir. the field of agriculture, as an antifungal, antiprotozoic, antiseptic, antibiotic or other type of agent, op also ia 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 sale and/or fesale saamals as spermicides and/or bactericides .to combat sexually transait&ed diseases (STD)- The active principles preferably used are benasalkoaitam ohloride sad nonoxynol 9- The activating principle preferably Is asy natal derivative of fluorine, for example sodium fluoride. Ill th«> known u galenical forms can be used, that is to say, in particulars, 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 bensalkonius chloride isj 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 FOE LOCAL CONTRACEPTION The invention advantageously relates to a spermicidal pharmaceutical product applied locally sueh that it oomes 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 P~" K chemical compound according to the invention is a donor of the fluoride anion F~ when it is solvated, in particular in aqueous solution.

It consists of, for example, a metal derivative of fluorine, such as sodiun fluoride, calcium fluoride, potassium fluoride, aluminium fluoride, tin fluoride, ammoniuB flucride, 3odium monof luorophosphate..., or as organic fluorine compound, such as. a fluorinated amine.

The speraioidal activity of a chemical compound cas, be measured, for example, by using the total spermicide test according to the IPPF specifications, which consists of determining the minimum inhibitory concentration or KIC (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 t© the fallowing minimum conditions according to the I??F: - ags of the sample: two hours 5 - density ia gg, c&nion spermatozoa; - mobility: 50$ of the spermatozoa should move forwards with speed when they ares examined at 35° - 37°C ia a fresh sample; - viscosity: suitably liquefied ejaeulate, non-ropey and with a homogeneous appearance tc the naked eye; - collected £e 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 1001 according to the IPPF test.

A spermicidal pharmaceutical composition according to a 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 7 00$ inhibitory composition is required.

The inventors have moreover found that the fluoride anion F~, is addition to having a direct spermicidal activity, has a spermicidal activity by potentiation of known spermicidal compounds. A composition according to the invention consequently advantageously consists of, firstly, at least one base spermicidal active principle such as an anionic, catlonlc, amphoteric or noniorric surface -active surfactant, or para-menthanylphenylpolyoxyethylene ether or a trisodium salt of a 16 polysaccharide ether-sulphate and the like, secondly at least one fluorine compound according to the lamention which donates the fluoride anion F~, and finally a pharmaceutical excipient and various usual additives (antioxidant,...) 5 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 1PPF. A composition according to the invention can. contain a mixture of 10 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; 15 PESSARIES Benzalkonium chloride 1.20% Anion F~ 0.50$ (for example sodium fluoride) Excipient: Semi-synthetic glycerid©3 or cacao butter or gelatine, glycerol 20 and purified water, antioxidants, antiseptics.

CREAMS AMD L0TI0WS; Benzalkonium chloride 1.20$ Anion F~ 0.50? (e.g. : sodium fluoride) 25 Exclpients: Distilled or purified water, humectants, emulsifierf stabiliser, antioxidant, antiseptic. (To be distributed in varying proportions according to the viscosity and the pH to be obtained).

PHGPEHTS and OIHIHEHTS; Beaz&lkonium chloride 1.20? Anion P~ 0.50$ (e.g.: sodiua fluoride) Excipient3: Distilled or purified water, emulsifies, esccipieufcs of the fatty substance type (vaseline, lanolin, lanovaseline, stearovaseline), stabilisers antioxidants antiseptic. (To be distributed ia varying proportions according to the viscosity and pH to be obtained), GEL; Benzalkonium chloride 1.20? Anlo® F" 0.50? (for example 30dium fluoride) Excipients: Soluble derivatives cf cellulose compatible with cationic surface-active surfactants, distilled or purified water, glycerol, sorbitol, antioxidant, antiseptic. (To be distributed is varying proportions according to the viscosity and pH to be obtained), SQLOBLB FXUis Beasalkcaniuia chloride "i.. 20% Isles F~ 0 . 50$ (for example sodium fluoride) Excipients: Polyvinyl alcohol, glycerol, sorbitol, propylene glycol, distilled or purified water, antioxidant.

TABLETS. 3enzal*:oniun chloride Anion F~ Cfop example sodium fluoride) 25 iag per tablet 10 eg per tablet 18 Excipients: Lactose, magnesium stearate, cellulose, starch, citric acid, sodium bicarbonate.

SYNTHETIC SOAPS; Benzalkonium chloride 2% 5 Anion F~ 1? (for example sodium fluoride) Excipients; Foaming and wetting products compatible with quaternary ammoniums (fo? example an amphoteric surfactant of the betaine or amino-betaine type), emollients., stabiliser, antioxidants antiseptic. 10 SOLUTIONS: Benzalkonium chloride 0.50? Anion F~ 0.25? (for example sodius 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 HO. jl The MIC of various known spermicidal compounds was determined by the IPPF test. The following results ware obtained by reacting 1 millilitre of 20 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-Menthanylphenylpolyoxye thylene ether 0.006 Trisodium salt of polysaccharide ether-sulphate 0.007 Anionic surface-active surfactant (sodium salt oxide methyltauride) 1 Cationio surface-active surfactant (benzalkonium chloride) 0.006 Honionic surface-active surfactant (norsoxynol 9) 0.006 Amphoteric surface-active surfactant (derivatives of emidoethylglycinate on fatty acids) Q.001 TEST 10. 2 lb© sane IFPF total spermicide test was carried out with 1 nlHilitfe of composition already containing 0.0001$ (by veigiit) of Sue fleorldt anion F™ reacting as 0.2 aillilitre 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. 9 n h? b Spermicidal compound MIC (15 by weight) p-Menthanylphe nylpolyoxye thylena ether 0.003 Trisodium salt of polysaccharide ether- sulphate 0.0025 5 Anionic surface-active surfactant (sodium salt oxide methyltauride) 0-50 Cationic surface-active surfactant (benzalkonium chloride) 0.002 Honionic surface-active surfactant 10 (nonoxynol 9) 0.003 Amphoteric surface-active surfactant (derivatives of araicloethyiglyeinafca on fatty acids) 0.0005 It is thus found that the inhibitory capacity of known spermicidal 15 principles is greatly increased by addition of ioaisable 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~. 20 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~ ®a°b n°t bave 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~ 21 satisfies the IP?F test. 1 synergisa effect ia thus found.

TEST HO. 2.: This test consists of carrying out a test identical to tests no. 1 and 2 mentioned above, bat in the presence of sodium borate in order to complex the ion F"; the spermicidal effect of the ion P~ disappeared totally, thus demonstrating that it is solely the ion F~ which is active or potentiates the spermicidal effect..

TEST HO. jf: Various perfluorinated bensalkonium 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 bensalkonlum chloride. Moreover, this activity remains identical under the conditions of test no. 3 In the presence of sodium borate, which demonstrates that the flnwlne bonded to the henselae nucleus has not been ionized.

Test no. 2 was also carried out on perfluorinated bensalkooiua chlorides mixed with another chemical compound which donates the loo F"\ Potentiation of the spermicidal activity of perfluorinated beaxalkonluB chlorides was also found. This same test carried out in the presence of sodium borate (In accordance with test no, 3) resulted Is a spermicidal activity which is tbat of perfluorinated benzalkonium chlorides. these two tests so. 3 and & demonstrate that CSt® 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 tb* base active principle is prepared and is Integrated Into the exelpient chosen according to the galenical form which is te b© produced. In the case of the tablet, the base active principle and the chemical ooapoeitd which donates the ion F~ Integrated 1st® the excipient Is the form of crude products.

COMPARATIVE TEST MO. 5: This in vitro test was carried out on galenical preparations containing benzalkonium chloride as the base active principle by determining the MIC of bensalkoniu® 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 bensalkonium 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 tast according to the IPPF, obtained after simulation and measured by titration on a sample taken from this solution. 20 TEST N0„ 6_: 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: 23 G4LEMICM. FOBS MIC (% by weight) of benzalkonium chloride Pos3ary 0.0023 Cream 0.0030 Tsmpon 0.0025 tablet 0.0025 Soluble fila 0.0017 Gel 0.0033 II) USE OF THE INYBHTIOH J$ THE FIELD OF ANTISEPSIS, AHIJBJOXIC THHHIPI AND 1 0 II PARTICULAR II CQHBATBiG STDs: Preferred embodiments of this invention in the ex&aple of its us© la dermatology as as antiseptic are the following: chksm3 asd lotiobs: Bensalkoai^Ea chloride 1.20$ 15 !aion r* 0.50$ (for exazaple sodium fluoride) Excipients: Distilled or purified water, hanectants, ewBlsiffier, stabiliser, antioxidant, antiseptic. (To be distributed ia varying proportions according to the viscosity and pH fco be obtained). 20 PHGPENTS and OIIIMEMTS; Benzalkoniue oblsride 1- 20? Anion F~ 0.50$ (tor example sodium fluoride) Excipients: Distilled or purified water, emwlslfler, exoiplents of the 25 fatty substance type (vaseline, lanolin, laaovaseline, stearovasellne). 24 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 amino-betaine type), emollients., stabilisers, antioxidant,, antiseptic.

SOLUTIONS: Bensalkoniuss chloride 0.50$ Anion F~ 0.25% (for example sodiua fluoride) Excipients: Distilled or purified water,, ethanol, antioxidant, glycerols serbitol (sic)2 antiseptic- (To be distributed i:a 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: Efthyl alcohol, propylene glycol, distilled water. 25 GELS; Erythromycin base U% Anion F~ 0.5% Excipients; Ethyl alcohols hydroxypropvlcellulose, distilled water, glycerol.

OINTMENTS: Neomycin base 0.35* Anion F~ 0.50? or Bacitracin 50,000 IUJ5 Anion F~ 0.50% or Oxytstracyclins hydrochloride 3% Anion F™ 0.50$ or Aureoraycin hydrochloride 3% Anion F~ 0.50$ Excipients: Vaseline, vaseline oilp 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: Aureoaycin Anion F~ 0.50$ or Oxytetracycline 0.50$ Anion F~ 0.25?^ 26 Excipients: Vaseline, vaseline oil8 lanolin NASAL SOLUTIONS: Soframycin sulphate Anion F" 1.25S 0.50$ 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 use in gynaecology and more particularly for combating SWs? are those described above under the heading "Use for local contraception® and under the subheadings "Pessaries*', "Creams", '"Unguents and ointments", "Gels", "Tablets", "Synthetic soaps- and "Solutions".

The methodology used in the testa carried out cm these usea of the invention was as follows: For Neisseria gonorrhoeae: The germs used originate from hospital isolations.

- Dilution range of the substances to be tested: solvent:sterile doubly distilled H,0 Range of geometric ratio 2 Doses: from 2.000 to 1.56 (and less) jag/ml 2 sal of each of the dilutions are mixed with 18 ml of solid culture medium, preferably Gonococci agar-agar isolation medium (Pasteur Institute) enriched with supplement G: Formula: Colt serum 165 m1 least extract 100 ml Corpuscle extract 235 ml Glucose 0.65 ml Distilled B90 q.s.p. 500 ml - Gonococci culture medium: 2*000 sal of Pasteur medium +• 500 ml of /. 51 supplement G.

These culture media combined with dilutions of the active substanoos are the means for investigating the bactericidal activity. Turn final concentrations of substances will be of the order of 800 to 0-156 jig/nl la the Petri dishes. The suspensions used (dilution In physiological water of a 21-hour culture in a liquid nutrient broth medium) are placed in bollow wells in a synthetic base under a laminar flow hood. One strain (multiple culture) was studied in each of the prepared wells. Bach dish studied is examined after 2H and ^8 hours of culture (oven afc 37°C)- - Determination of the HIC: 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 be tested. 5 pi of 10 oolony~forming units/ml deposited on the agar-agar plates, either with or without the substances to be tested (culture of Gonoooool for 18 hours in suspension ia a Sorensen solution).

Incubation was carried out for 18 h at 36°C end the growth or absence thereof of Gonococci found on the plates is recorded.

For Candida aifalosuass; The methodology is largely the same as that for Neisseria gonorrhoeae, but with the following differences: - Dilution range In sterile doubly distilled water from 2,000 to 1-56 pg/nl 1.5 ml of loiros liquid medium are added to 0.5 *1 of eaofa dilution.

- The tubes are seeded with cultures of Candida (21 hoara/Boiron medium) or with the control (Roiron medium). The tubes are indicated in an oven at 37°C for 21 and 18 hours. At t a 2ft feonrs and t = 18 hours, a drop is examined between a slide asd slide cover under a microscope.

- The results are expressed by counting the yeasts and a fungicidal MIC is determined. Determination of the percentage of resistant species on the control tubes. 28 For Trichomonas vaginalis: The same methodology as for Candida albicans.

For Chlamydias - Inoculum: This is Chlamydia host cells or MacCoy cells. They are 5 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 10 - The method used is that of Professor F. CATALAN, P. SEDNAOUJI, A.

MILOVANOVIC et al., Institute A. FOURNIER, PARIS. 1 ml of the dilution of substances to be 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 nil of this mixture is then 15 placed in the plates of the wells™ The plates are cenirifuged (1 hour at 2,000 revolutions/min) and incubated for 1 hour at 37°C. The culture medium is then replaced by 0.2 ml of new medium containing 0.5 rag/I of cyclohexiiaide and the plates are then incubated for 48 hours at 37°C» The cell layer is subsequently fixed with methanol and in particular stained 20 with a monoclonal antibody and conjugated with FITC (fluorescein isothiocyanate). From this., the inclusions present in the MacCoy cells are examined under an inverted eplfluorescence microscope.

The tonicity of the substances to be tasted was thus initially studied and taken into account in considering the total integrity of the host cell. 25 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 30 (loop of 1 pi) using successive dilutions of the dense starting suspension (geometric ratio 10). Incubation for 18 h at 37°C.

- Preparation of dilutions of the substances to be tested ia solution in sterile doubly distilled water- Dilution range ©f geometric ratio 2 (from 2,000 to 0.015 jsg/ml, for example).

- Mixing of the bacterial suspension of Pseudoraonas aeruginosa (of the same origin as the IFMOE standards) witfa a constant concentration (a x 107 bacteria/nl) and of the dilution of the substances in a decreasing order (2,000 to 0.015 fsg/nl).

- Incubation or contact time: 1 hoar,,, 24 hours asad 48 in aa oven at 37°C.

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 is the same time as in the tests.

- Observation after 1 hour, 24 hours and *8 hours.

For Treponema^, Gardnerella, Ducrey bacillus. Streptococci and Staahylococcus aureus: „ ,1,, "• ,— The methodology used is that described by Professor F. ClTILAi. ?. SEDNA00I, A. KIL0¥J!MiG¥2G et al., Institute jL FPuBiJEH.

COMPARATIVE TEST SO- 7" The following results were obtained with benzalleoniua chloride by itself and noncxyaol 9 by itself: 30 SIR AIMS MINIMUM INHIBITORY COM CEMTMTIOM (MIC) BsnsalkorJ.ua cblorid© by itsalf Gonococci 1.15 Big/I Treponemae 70 Mg/1 Trichomonas 1.3 sag/1 Candida albicans 50 tug/1 Chlamydia 100 SJg/1 Gardnerella 50 Eg/1 10 Ducrey bacillus 75 mg/1 Streptococcus 15 mg/1 Pseudosonas aeruginosa 31-25 ag/1 Staphylococcus aureus 1.56 sag/I MINIMUM INHIBITORY COMCENTR ATION (MIC) Nonoxynol 9 by itself Treponemae 75 ntg/1 Pseudomonas aeruginosa 50 sag/I Staphylococcus aureus is mg/1 Streptococcus 20 ©g/1 TEST MO. 8% The same test as above, carried out in the presence of the fluoride STRAINS 15 31 anion F™, led to the following results; STHAINS MINIMUM INHIBITOR* G0HGBHTBATI0N (MIC) Benzalkonium chloride + F~~ 5 1 microgram/mi Gonococous 0.60 mg/1 Trepone&i&e 56 mg/1 Triohononas 0»9 Mg/1 Candida albicans 35 JBg/1 Chlamydia 85 Eg/1 Gardnerella HI mg/1 Ducrey bacillus 62 mg/1 Streptococcus 9 Mg/1 Pseudcaonas aeruginosa 18 mg/1 Staphylococcus aureus 1.1 «ag/l STBAINS MIHIMOH INHXBXTOBI OOHCSNT8ATSOS (MIC) Mo&oxpsoi O * P" 1 aicrogrsm/ssl Treponema© 60 Mg/1 Pseudomonas aeruginosa 35 mg/1 Staphylococcus aureus ,2.5 ag/1 Streptococcus 15 mg/1 32 COMPARATIVE TEST MO. 9s 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 COMCEHTHAT 10'?!S MINIMUM INHIBITORY OF SERUM COM CE MIRAIX0! (MIC) PROTEIHS Bensalkoniusa chloride by itself Streptococcus 10 faecalis 0 15 mg/ml 30 sag/ml 15 mg/ml 60 mg/ml 16 mg/ml 90 mg/ml 68 mg/ml neisseria 15 gonorrhoeae 0 1.5 mg/ml 30 sag/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 M0. 10; This test was carried out in aa identical ©saner to test no. 9» but in the presence of the fluoride anion F~ in the composition. The following results were obtained? 33 STRAINS CONCENTRATIONS OF SEHUM PROTEINS HIIIMOH INHXBITOBT COICEMTMIIOI (HIC) B'stmslko'-aiim chloride * F" 1 microgram/ml Streptococcus faecalis 0 30 mg/ml 60 mg/ml 90 mg/ml 9 21 ag/al sgMl ag/cal Neisseria gonorrhoeae 0 30 mg/ml 80 sag/ml 90 sag/ml 0.6 0*6 0*6 1*2 ag/hl Bg/al sag/al rsg/tal This test shews that the fluoride anion F~ allows a very favourable reduction in the adverse effect of serum proteins.

COMPAMfllE TEST IP.. 11; Ibis test was carried out on the galenical foras ia vitro (is a aaasser similar to tests 5 and 6). starting from products containing benzalkonium ohloride as tb® active principle and without an activating principle. The following results sere obtained: 34 STRAINS GALEMICAL FORM MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride by itself Gonococcus pessary Tablet Trichomonas Pessary Tablet 23-65 mg/1 15-62 mg/1 11.80 mg/1 15-60 mg/1 The concentrations are those present in the liquid obtained after simulation and used for the test. 1 0 TEST MO. J2: This test was carried out under the sane 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 MINIMUM INHIBITORY 15 FORM CONCENTRATION (MIC) Bsns&lkonium chloride * F" in a concentration of 0»5S» Gonococcus Pessary 5 mg/1 Tablet 3 mg/1 20 Trichomonas Pessary Tablet 5 ffig/X 3 mg/1 35 HI) OSB OF THE BIfliTIOI H THE FIELD OF DISINFECTION: This field relates to treatment of soils, surfaces, Instrunents— with contact bactericidal products.

Preferred embodiments of the invention for this use are the following: OSES 9BNZAL.K0NIUM CHLORIDE Anion r~ ESCIFISIfS Hands Epidersds 0.1# 0,25% Purified waiter or alcohol q„s„P» 100$ 10 Instruments to be sterilised fco be disinfected 1.0# o.so# Purified wat®? j.s.p. 100# 15 Textiles 0.05$ lastruaents thermometer fcjpe 1.0# 0.025# 0- Furified water q.s.p. 100# Btfaanol 10# purified water q.s.p. 100# 20 Washing of surfaces (rooos, floors,, 0.1# soils) 0-25# Purified water (J» s. p.

Ike tests were carried out in accordance with ftPSd standard SFX "2-150 March 81 with benzalkonium chloride and then with aoooxjnoJ. 9 as the active prlaclple. lite neutralizing agant used was fee following: 3# of SwasP 80 25 (V/Y) assi Cl,3# of leoithia (W/V1. The pi of the issdiwas was 7»2« I C'f d'c COMPARATIVE TEST MO. 13: This test was carried out without sis activating principle.

STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Bensalkonium chloride by itself 10 15 Pseudomonas aeruginosa CM CM A 22 Escherichia coll CMCM 54 127 Staphylococcus aureus Oxford strain CMCH 53 15'' Streptococcus faecalis CMCH 5 855 Mycobacterium sraegjnatis CMCH 7 325 31.25 sag/litre 6,57 mg/1 1.56 sag/1 H mg/1 30 mg/1 37 STRAINS MINIMUM INHIBITORY COICEMTR&TXOM (MIC) Nonoxyisol 9 by itself Pseudomonas aeruginosa CMCM A 22 50 mg/litre Escherichia coli CMCM 54 127 8 mg/1 Staphylococcus aureus Oxford strain CMCM 53 154 4 Mg/1 Streptococcus faecalis CMCM 5 855 7 mg/1 Mycobacterium smegpsatis CMCM 7 326 65 mg/1 TEST MO. J4: 15 This test is identical to the above, but ia the presence of the fluoride anion F~ as an activating principle. 0 Q STRAINS 10 Pseudomonas aeruginosa CMCM A 22 Escherichia coli CMCM 54 127 Staphylococcus aureus Oxford strain CMCM 53 154 Streptococcus faecalis CMCM 5 855 Mycobacterium smegmatis CMCM 7 326 MINIMUM INHIBITORY CONCENTRATION (MIC) Benzalkonium chloride * F~ 1 microgram/®! 18 lag/I it re 3 mg/1 1.1 mg/1 3»6 mg/1 26 mg/1 15 STRAINS MINIMUM INHIBITORY CONCENTRATION (MIC) Nonoxynol 9 by itself (sic) + F" 1 microgram/®! 20 25 Pseudomonas aeruginosa CNCM A 22 Escherichia coli CNCM 54 127 Staphylococcus aureus Oxford strain CMCM 53 15^ Streptococcus faecalis CNCM 5 855 Mycobacterium smegmatis CMCM 7 326 35 mg/litre 6.5 mg/1 2„5 mg/1 5 - 5 mg/1 50 mg/1 39 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: 5 creams, lotions, ointments, solutions, bubble baths, synthetic soaps, shampoos,, intimate lotion, disinfectant lotion.

The formulations of excipients are the same as for the phariaaceutical presentations., but the concentrations of benzalkonium chloride and anion F" will be different. 10 These concentrations will thus be the following for all the products: benzalkonium chloride." 0.2%, anion F"s 0»,1?L Chemical active principles or those of a natural origin can also be included in these formulations in concentrations and doses approved in cosmetology. 1 5 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: 20 Husectants: glycerol, propylene glycol, diethylene glycol, sorbitol, polyoxyethylene glycol.

Emulsifiers: sodium stearate, beeswax, sorbitol ester, polyoxyethylene glycol ester, fatty alcohol, triethanolasaine-lanolin, Tween, glycol stearate and polyglycols. 25 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, parabensoic acid and their methyl or propyl esters, free or in the sodium form. 30 pH: all 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 (2)

1. Claims 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 corn pound which donates ionic fluorine. 3« Use according to Claim 2. in which the fluorine compound is a metal derivative of fluorine. 15*4. Use according to Claim 3? in which the fluorine compound is selected from the group comprising sodium fluoride., calcium fluoride9 potassium fluoride., aluminium fluoride, tin fluoride, ammonium fluoride and sodium monofluorophosphate. 5- Use according to Claim 1, in which the activating principle is the 20 fluoride anion F~. 6. Use according to any one of Claims 1 to 5S in which one active principle is a surfactant surface-active compound. 7. Use according to Claim 6S in which the active principle is cationic. 8. Use according to Claim 7, in which the active principle is a 25 quaternary ammonium. 9„ Use according to any one of Claims 6 to 8„ in which the active principle is benzalkonium chloride. k I 10. use according to Claim 6. in which one active principle is an anionic surfactant surface-active compound. 11. Use according to Claim 6. in which one active principle is an amphoteric surfactant surface-active compound, 5 12. Use according to Claim 59 in which one active principle is a nonionic surfactant surface-active compound™ 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 o^ide methyltauride. a derivative of aminoethylglycinate on a fatty acid, a 1 o nonoxynol, phenylmercury nitrate, para-menthanylphenylpolyoxyethylene ether, or a trisodiua salt of a polysaccharide ether-sulphate. 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 gasaete, or a fungus, or a virus. 15 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. Gram-negative bacilli, bacilli resistant to acid alcohols, bacteria, 20 flagellated protozoans, yeasts, viruses or retroviruses. 16. 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. 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, ore am, lotion, unguent, ointment, gel or soluble film containing 1.20? by weight of 42 benzalkoniua chloride and 0.50? by weight ©f the aaioo P", or a product ia the fora of a tablet containing 25 :*g per tablet of benzalkoniua chloride., and 10 ag per tablet of the anion F~» or a product in the fora of a synthetic soap confiaitniag 2? by weight of 5 benzalkoniua chloride and 1? by weight of the anion r, or a produot ia the form of a solution containing 0-50$ by weight of benzalkoniua chloride and 0-25? by -eight of the aaios, F~„ 18. Use according to Claim 16, in which one active principle Is a fluorine compound capable of donating ionic fluorine. 10 19- Use according to any one of Claims 1 to 15 of at least one active principle which inhibits or destroys at least one unicellular living being responsible for sexually transmitted diseases and of as activating principle in proportions suitable for Inhibiting or destroying at least one enzyae associated with the said osioeUnlar 15 living being to obtain a medicament intended to ooobat sexually tr&nsaitted diseases. 20. Use according fc© Claim 19 of benzalkoniua chloride and of a fluorins ooapound which donates ionic fluorine in proportions suitable for obtaining a product in the fora of a pessary, oream, lotion, unguent, 20 ' ointment, gel or soluble film, containing; 1.20$ by weight of benzalkoniua chloride and 0~50? by weight of the anion F"", or a produot in the fora of a tablet containing 25 *& per tablet of benzalkoniua chloride and 10 ag per tablet of the anion F"% or a produot in the fora of a synthetic soap containing 2% by weight of 25 benzalkoniua chloride and 1? by weight of the anion P", or a produot in the fora of a solution containing 0.50$ by weigjat of bensalSeeeo&ms chloride and 0.25$ by weight of the anion F~. 21. Ua« according to Claim 19» in which ose active principle is a fluorine ooapound capable of donating ionic fluorine. 30 22. Use according to any one of Claims 1 to 15 of at least one active principle having an antibiotic action towards at least, one oaioelltalar 43 living being and of as activating principle in proportions suitable for inhibiting or destroying at least one enzyme associated with the said unicellular lining being to obtain a medicament to combat by antibiotic therapy the diseases for which the said unicellular living being is responsible. Use according to Claim 22 of benzalkonium chloride or erythromycin base or neomycin base or bacitracin or oxytetracycline hydrochloride or aureomycin hydrochloride or soframycin sulphate or aureomycin or oxytetracycline and of a fluorine compound capable of donating ionic 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)1 by weight of the anion or a medicament in the fora of a synthetic soap containing 2% by weight of benzalkonium chloride and V% by weight of the anion F~, or a medicament in the form 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 for® 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 0.35/5 by weight of neomycin base and 0-50$ by weight of the anion F™, or 50,000 lu % and 0.50% of the anion F"% or 3?o 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 and 0-50$ by weight of the anion F", or a medicament in the form of an ophthalmic ointment containing 1)5 by weight of aureomycin and 0.50)5 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)5 by weight of soframycin sulphate and 0.50? by weight of the anion f~- Use according to Claim 22 of benzalkonium chloride or erythromycin base or neomycin base or bacitracin or oxy tetracycline hydrochloride or aureomycin hydrochloride or soframycin sulphate or aureomycin or oxytetracycline and of a fluorine compound capable of donating ionic 44 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 neosaycin base. 0*50/1 5 of the anion F~ and 0.10? of benzalkonium chloride^ or 50-000 IU %, 0.50$ of the anion F" and 0.10$ of benzalkoniua 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 Height of aureomycin hydrochloridej, 0.50$ by weight of the anion F~ and 0.10$ of 10 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 o::ytetracycline, 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. 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. 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-protozoie product. 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. 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."/$ of benzalkonium chloride aad 0.25$ of the aril on F", or V% of benzalkonium chloride asd 0.50$ of the anion F~, or 0.05$ of benzalkoniua chloride and 0.025$ of the anion F". 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 retrovirus to obtain an antiviral medicament or produot. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.