JP2559735B2 - Anti-microbial composition - 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

BACKGROUND OF THE INVENTION The present invention relates to the inhibition or destruction of protozoa, microorganisms, bacteria, germs, fungi and other unicellular organisms and viruses. As a result, the present invention is particularly directed to the fields of topical contraception, antibiotic therapy as part of pharmacy or cosmetology, antiseptic and consumption.

In the following, "suppression" of unicellular organisms or viruses
The term means to inhibit its growth or to make it impossible to achieve any function it normally achieves. The term "destroying" means killing a unicellular organism or virus.

In the context of the present invention, the term "substance" in the following refers to any compound or group of compounds having at least one given function or one function in common with the compound, usually more than one in the composition of the final product. Means that can be included with the excipients and other substances. Similarly, the term "product" means a usable final product. That is, the final product is generally composed of at least one excipient and several substances, each substance being composed of several compounds having similar or identical functions. The term “substance” may correspond to the actual facts, but it is purely theoretically functional in the case of complex mixtures where the compounds have multiple effects or the effects interfere with each other. You can The mechanical classification of compounds, substances and products does not necessarily correspond to the mixtures actually obtained in the manufacturing process and practice of the products. Usually, the term "composition" is used in mushrooms and in all texts below intended to refer to pharmaceutical or cosmetic substances.

(Description of the Prior Art) Substances which inhibit or destroy unicellular organisms in the fields of biology, medicine, cosmetology, and disinfection and other broader fields are already known.

In particular, spermicidal compositions are disclosed in U.S. Pat. Nos. 4,339,441 and 4,359,4.
Known from specification No. 75.

Numerous compounds are also known which can be used in topical contraceptive methods for organisms. In particular, surfactants that lower the interfacial tension (eg, quaternary ammonium, nonoxynol,
Some other compounds such as derivatives of amidoethyl glycinate on fatty acids, methyl tauride sodium oxysalt ...) and trisodium salt of phenylmercuric nitrate, para-menthanyl phenyl polyoxyethylene ether or polysaccharide sulfate ether are It has an inhibitory or destructive effect on unicellular organisms, especially a spermicidal effect.

Substances which act mechanically on sperm, for example by immobilizing them, are also known. US Patent 4
No. 368 186 describes such an effect and more particularly describes the cooperation of "poloxamers" with sperm inhibitors in the light of inhibiting gelation and solubilization of products. In this way, the efficiency of the inhibitor is mechanically increased by the additive, that is, a synergistic effect is obtained.

Topical contraceptive compositions, especially spermicidal compositions, containing such compounds are also known, and they can be used topically to suppress the fertilizing capacity of the reproductive body, especially human or animal sperm.

These known compositions contain a concentration of the inhibitory compound above the minimum inhibitory concentration, called MIC, as a solution or suspension in a pharmaceutically acceptable excipient which depends on the galenical form used. 5% of all sperm contained in 0.2 ml of semen
To be killed within minutes (conditions for a total sperm test according to IPPF, International Planned Parenthood Federadion standard), 1 ml of the pharmaceutical composition
The spermicidal active ingredient therein must be above or equal to the minimum inhibitory concentration called the MIC of this active ingredient.
The MIC of a chemical compound depends on the compound, but also on the condition in which it is used or the galenical form containing the composition.

More generally, pharmaceutical or cosmetic compositions containing at least one basic active ingredient which inhibits or destroys at least one unicellular organism and pharmaceuticals or cosmetics containing such compositions are known.

Many active ingredients are known in the field of antiseptic and disinfection: halogens (chlorinated or iodinated derivatives ...), aldehydes, alcohols, phenols, acids, metals (silver, copper, mercury, zinc). Salt ...), amidines,
Biguanides, diphenylureas, oxidants (hydrogen peroxide, potassium permanganate ...), Colorants, interfacial tension reducing agents and wetting agents (cationic, anionic, amphoteric or organic).

Antiseptic and / or disinfecting and / or antigenic animals and / or antifungal and / or antibiotic and / or antiviral products containing such suppressive or destructive substances and processes for the preparation of these substances or compositions are also known. .

These known substances or compositions are generally satisfactory, but there are some problems with their practical use.

These problems are essentially as follows: First of all, it is generally desirable to obtain a total inhibition or destruction of unicellular organisms or viruses, i.e. 100% inhibition or destruction rate in practical application situations. However, if strict precautions for use are not needed or if a limited volume of active ingredient is required (eg for cosmetics)
In, this is not always the case.

In addition, causing short-term and / or long-term undesired side effects (activity against other unicellular organisms, inflammation, harm to the environment ...) to one or more given unicellular organisms or viruses, such as germs or pathogens. It is generally desirable to exhibit activity without. However, in practice there is a long-term side effect (generally associated with regular use) that is needed to solve the above first problem.
And even short-term side effects (paroxysmal use) have been found to occur. In the medical field, host and / or carcinogen effects have been recognized from certain threshold doses and for certain active ingredients. In the field of disinfection, some undesired effects on the substances to be disinfected have been observed.

OBJECT OF THE INVENTION The object of the present invention is to increase, without increasing this concentration, the inhibitory or destructive capacity of a substance or composition containing a given limited concentration of a basic inhibitory or destructive active ingredient. . Yet another object of the present invention is to reduce the inhibitory or destructive ability of a substance or composition for its own purpose and to avoid side effects and to better control its selectivity for various unicellular organisms and viruses. Without reducing the concentration of the basic active ingredient.

In particular, the present invention is free from the risk of side effects such as host substances or carcinogens, is used paroxysmally or regularly and continuously for a long time, and its efficiency is perfect, ie the% failure is statistically zero. Or to provide a new pharmaceutical or cosmetic composition which is insignificant and which is a normal mere use situation (without special care), more particularly a topical contraceptive and a drug or product containing such a composition. It is intended.

It is a further object of the present invention to provide a topical contraceptive drug which is easy and completely efficient to use, i.e. without some of its drawbacks and giving some results similar to those of oral contraceptives. .

The present invention also aims to provide compounds that can be used in methods of topical contraception.

Finally, another object of the present invention is to control or destroy unicellular organisms or viruses in drugs, cosmetics or antiseptic products, especially antiseptic, antibiotic, antibacterial, antiprotozoal, antifungal, spermicidal, antiviral ... products. It is the decrease in the volume of the active ingredient.

(Summary of the Invention) The present invention relates to a substance that suppresses or destroys at least one unicellular organism or virus such as protozoa, microorganisms, bacteria, reproductive bodies, and fungi, which inhibits the unicellular organism or virus. Or at least one basic active ingredient that destroys and at least one ingredient that inhibits or destroys at least one enzyme associated with the organism or virus, the latter component of the former basic active ingredient-preferably Has a synergistic effect-a substance characterized in that it is an activator.

Preferably, a component that suppresses or destroys at least one related enzyme, which is referred to as an "activating component" or "activating agent" below, is a reagent that inhibits the action of the enzyme / substrate couple.

However, it was surprisingly found that such agents can be advantageously formed with the fluorine anion F ⁻ released from the fluorinated compound either spontaneously or after enzymatic action. It has also been found that, in some cases, the basic active ingredient itself can release the activator ingredient, and / or the activator ingredient itself is an active ingredient that suppresses or destroys at least one unicellular organism or virus.

More precisely, such a fluorinated compound may itself have the ability to suppress or destroy unicellular organisms and viruses, and such a fluorinated compound may have a synergistic effect with the associated base active ingredient. Admitted.

A feature of the invention is a topical composition, more particularly a spermicidal composition, which is an active ingredient which inhibits or destroys the reproductive body either directly or by enhancing a compound capable of releasing at least one fluorine anion F ^−. And to provide an activator.

The invention also relates to chemicals, preservatives and / or disinfectants-more particularly topical preservatives-and / or protozoa-more specifically topical protozoa- and / or antibacteria-more particularly topical. Antibacterial and / or antifungal-more specifically topical antifungal- and / or antibiotics-more specifically topical antibiotics- and / or antiviral products, cosmetics-more particularly topical such as synthetic soaps or emulsions Cosmetics-and contraceptive products applied topically in contact with the reproductive body-more particularly eggs, creams, solutions, foams, tablets, soluble waffles, tampons, vaginal suppositories-the substances according to the invention. Alternatively, there is provided a composition comprising a composition.

Mushroom and in the following the term "topical" and its derivatives are used in certain places where the product is treated, for example in the vagina and other anatomical parts, where the effect is on unicellular organisms or viruses which come into contact with the product. It is meant to occur in an environment near this location, as opposed to conventional administration (eg, oral or parenteral).

The substances, compositions, medicaments, products, compounds according to the invention are suitable for topical administration as well as general administration. For example, the spermicide according to the invention is applied topically. Moreover, if it is desired to overcome the resistance effect of pathogenic unicellular organisms to conventional treatments, the general administration of the invention may be used rather.

The present invention also relates to the use of a composition comprising at least one basic active ingredient and at least one fluorinated compound capable of releasing the fluorine anion F ⁻ as an active ingredient of said basic active ingredient in cosmetics, at least one Use of a fluorinated compound capable of releasing a fluorine anion F ⁻ as an activator of said basic active ingredient for producing a substance containing a basic active ingredient, a constituent and / or an antigen of a substance or composition according to the invention Use in the manufacture of a drug used as a sex animal agent and / or antibacterial agent and / or antifungal agent and / or preservative and / or antiviral agent,
And the production of topical contraceptives for humans or animals, in particular the use of the substances or compositions according to the invention in the control or destruction of the reproductive body.

The present invention also relates to a method for producing a substance or composition for inhibiting or destroying at least one unicellular organism, particularly a protozoa, microorganism, bacterium, germ, fungus, virus, etc., which inhibits or destroys the unicellular organism or virus. Characterized in that at least one basic active substance is mixed with at least one component that suppresses or destroys the enzyme system related to the organism or virus, and the latter component is an activator of the former basic active component. Also provides a way to do.

The invention also provides an ionizable fluorine for use in a method of local contraception for an organism, more particularly in a topical contraceptive product for humans or animals of the invention or in a substance or composition according to the invention. Also provided are compounds that include.

According to the present invention, an activator component that suppresses or destroys at least one enzyme associated with the unicellular organism or virus is against an external attack, particularly against the action of the basic active component that suppresses or destroys the unicellular organism or virus. The marked susceptibility of unicellular organisms or viruses is elicited by "inhibiting" the enzyme / substrate couple. It is effectively known that each unicellular organism or virus possesses an important enzyme system. Moreover, unicellular organisms or viruses release certain enzymes that, depending on the circumstances (eg, resistance to antibiotics), give particular enzymes that cause the destruction of certain attacking agents (eg, lactamase that destroys penicillin). The enzyme is called a "protection enzyme". The present invention consists in suppressing the function of these enzymes, thus weakening the unicellular organism by creating optimal conditions for the efficiency of the active ingredients.
This brings a number of advantages over the prior art, which on the one hand fulfills the above-mentioned objectives and, on the other hand, selectively on a given unicellular organism or a given unicellular organism of a given family. It is capable of acting on a given enzyme or a given family of enzymes. In the case of viruses, the present invention aims at inhibiting the enzymes required for their formation and / or their replication. In the following, "related enzyme" means an important and / or protective enzyme of unicellular organisms and / or viruses.

The present inventors have fluorine ionized state F ^- has a particularly efficient and beneficial effects as an activator component for the relevant enzymes,
And it was determined to have this at a slight normal concentration.
Furthermore, ionized fluorine F ^- is quite common, economical and relatively easy to use. Its manipulation and utilization are as well controlled as the side effects given according to the volume used.

The present invention relates to a method for inhibiting or destroying at least one unicellular organism or virus-particularly a protozoan, a microorganism, a bacterium, a germ, a fungus, etc.-at least one basic active ingredient and an organism which inhibits or destroys the unicellular organism or Uses at least one ingredient that inhibits or destroys at least one enzyme associated with the virus, the latter ingredient having-preferably a synergistic effect-of the former active ingredient.
Methods are provided which are characterized by being activators, and such methods include the use of at least one substance or composition according to the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the inhibition or destruction of unicellular organisms such as protozoa, microorganisms, bacteria, germs, fungi and viruses regardless of whether they are pathogenic bacteria or not. In most cases the invention is
It has two different uses. That is, either in the field of cosmetics or pharmaceuticals (in the case of the following specific examples of spermicide or bactericide acting on the following pathogens), or in the more general fields of agriculture, disinfection (specific examples below), etc. Is. In all cases the substance according to the invention comprises one basic active ingredient which inhibits or destroys said unicellular organism or virus and at least one ingredient which inhibits or destroys at least one enzyme associated with said organism or virus. The latter ingredient is preferably an activator having a synergistic effect when the former basic active ingredient, preferably itself, can suppress or destroy the organism or virus.

The function of this activating component is to eliminate the function of the enzyme system related to the organism or virus. In this way, we have found that such activator components are agents which inhibit the action of the enzyme / substrate couple, preferably the anion fluorine F ⁻ released from a fluorine compound such as a metal derivative of fluorine.
I found that. Some good results have been found with sodium fluoride, calcium fluoride, potassium fluoride, aluminum fluoride, tin fluoride, ammonium fluoride or sodium monofluorophosphate. For example, the following unicellular organisms or viruses are relevant to the present invention: • Reproductive bodies (sperms, eggs) • Gram-positive cocci such as staphylococus and streptococus • gonococus, etc. Gram-negative cocci, Gram-positive Bacillus, colibacill, Escherichia coli, and other Gram-negative Bacillus mycobacteria, such as Mycobacterium smegmatis, acid-alcohol-resistant Bacillus・ Spirochetes, for example, spiral bacteria such as Treponema ・ Miscellaneous bacteria such as Chlamydia ・ Filamentous protozoa such as Trichomonas ・ Miscellaneous yeasts such as Candida albicans ・ HIV (human immunodeficiency) virus And herpes (Herpe
Viruses such as s) or retroviruses.

For example, at least one such unicellular or virus-related enzyme below is relevant to the present invention (Table 1): Basic active ingredients used in the substances or compositions according to the invention are, for example, cationic or anionic or amphoteric or nonionic surfactants, which lower the interfacial tension, preferably quaternary ammonium. Benzalkonium chloride or other alkylbenzalkonium is an example of a cationic surfactant, and methyl tauride sodium oxysalt is an example of an anionic surfactant. Derivatives of amidoethyl glycinate on fatty acids are an example of amphoteric surfactants. Nonoxynol is an example of a nonionic surfactant. This basic active ingredient may also be phenyl mercury nitrate or paramenthanyl phenyl polyoxyethylene ether or polysaccharide sulfate ether or others (halogen, aldehyde, alcohol,
Phenols, acids, metals, amidines, biguanides, diphenylureas, oxidants, colorants ...) are advantageous.

In various tested applications, the activating component alone has generally been shown to itself have direct activity against the unicellular organism or virus. Then, surprisingly, not only does the result obtained with the combination of activator and basic active ingredient correspond to the sum of the results expected only from the presence of the basic active ingredient and the active ingredient, but on the contrary this It was found to have a synergistic effect in that it was superior to the sum.

The efficiency of such an active ingredient or activator can be measured by the minimum inhibitory concentration called MIC, which corresponds to the concentration of the active ingredient that induces inhibition or death of a whole unicellular organism or virus within a given time period. .

In the substances according to the invention, the anionic fluorine F ⁻ concentration also released in the activated fluorinated compound is advantageously below the minimum inhibitory concentration (MIC) of the fluorine anion F ⁻ without the basic active ingredient.

Similarly, the concentration of basic active ingredient in the substances according to the invention can be below the minimum inhibitory concentration (MIC) of this basic active ingredient without the active ingredient. Even so, surprisingly, such substances according to the invention have a total efficiency, ie only the fluorine anion F ^{− at a} concentration above or equal to its MIC or only the basic active ingredient above or equal to its MIC. Has an efficiency at least equal to that of a material containing any of the above.

Moreover, the basic active ingredient itself is also a fluorine anion.
It is also possible to release activating components such as F ⁻ . A substance or composition according to the invention may have several activators acting on several basic active ingredients whose function is the same or different and / or at least one enzyme related to one or several of the basic active ingredients. May include ingredients.

The substances or compositions according to the invention can be used in several ways to obtain a product and, depending on the method of use of the product, can be used topically or in general administration.

Among the particularly advantageous uses of the products according to the invention, mention may be made of their possible therapeutic uses as various drugs. Indeed, the problem of inhibition or destruction of unicellular organisms or viruses is encountered in an ever increasing number of therapeutic applications. This is any battle against several pathogens, where these products are antibiotics and / or antigenic animal agents and / or fungicides and / or antifungal agents and / or antiseptics and / or antiseptics. It is a viral agent, or a fight against some non-pathogens such as the reproductive body eg sperm within the framework of contraception, especially local contraception.

The substances or compositions according to the invention can also be used advantageously in cosmetics in such a way and in a concentration that the classification is not pharmaceutical products.

In fact, for example, the effective concentrations of fluorinated compounds and basic active ingredients can be reduced to the extent that they are below the threshold separating the pharmaceutical and cosmetic fields, and this should be done without reducing the efficiency of the product. You can

The substances or compositions according to the invention can also be used in products which are neither cosmetic nor pharmaceutical products, such as antifungal agents, antiprotozoal agents, preservatives, antibiotics or other agricultural fields or also in the field of surface disinfection. can do.

Preferred Embodiments of the Invention Presently known preferred embodiments of the invention include male and / or female mammals as spermicidal and / or fungicides to combat sexually transmitted diseases (STDs). It is one of the products that is used locally in the reproductive organs of.

Benzalkonium chloride and nonoxynol 9 are preferably used as active ingredients. Any metal derivative of fluorine, such as sodium fluoride, is preferably used as the activating component. All known galenical forms preferably eggs, creams, gels, solutions, foams, tablets, soluble waffles,
Tampons, vaginal suppositories and others can be used.

The proportions of active ingredient and activating ingredient used depend on the galenical form, since only the actual concentrations induced in vivo are important for the efficiency of the product.

These rates must be varied between the MIC and the maximum concentration at which side effects are elicited. For topical administration,
Intolerance (inflammation) of the treated part must be avoided. Toxic concentrations should be avoided in general administration.

That is, the concentration of benzalkonium chloride in vivo is preferably 1.2% (by weight), and
F ^- is preferably 0.5% (by weight).

Some preferred embodiments of the invention are described below by tests carried out on some unicellular organisms in some test applications.

I) Uses of the invention for local contraception: The invention advantageously provides a spermicidal medicament which is topically applied so that it comes into contact with semen to kill or suppress sperm.

The spermicidal drug according to the present invention is inserted into the vagina before sexual intercourse to prevent fertilization by killing or suppressing sperm before they contact the egg, various herbal medicine forms, tablets, eggs, It is provided in the form of creams, gels, soluble waffles, tampons, foams, vaginal suppositories and the like.

The products according to the invention consist of a composition which comprises, directly or as an active ingredient spermicide, at least one compound according to the invention capable of releasing ionizable fluorine, ie the fluorine anion F ⁻ .

The compounds according to the invention are capable of releasing the fluorine anion F ⁻ when dissolved, especially in aqueous solution. For example, it is composed of a metal derivative of fluorine such as sodium fluoride, calcium fluoride, potassium fluoride, aluminum fluoride, tin fluoride, ammonium fluoride, sodium monofluorophosphate or an organic fluorinated compound such as fluorinated amine. .

For example, to measure the spermicidal activity of a compound 0.2 ml
Induces the death of all sperm contained in the semen of the cat in less than 5 seconds
A total spermicidal test according to the IPPF standard is used to find the minimum inhibitory concentration (expressed in% by weight) of a compound called MIC in 1 ml of solution. This test is carried out for at least six semen from various administration who satisfies the minimum condition from the next IPPF: - Sample age: 2 hours; - mm ³ per Density: 50,000,000 spermatozoa; - mobility : 50 when examined at 35 ° to 37 ° C in recent samples
% Sperm should move fast forward; viscosity: appropriately liquefied ejaculate, not macroscopically filamentous and uniform in appearance; collected in a sealed sterile glass tube and stored at 37 ° C.

The present inventors have found that under these conditions, the fluorine anion
IPPF when F ^- is present at a titer of 5 ppm (eg, 5 ml per)
It was found to have 100% spermicidal activity by the test.

The first pharmaceutical spermicidal composition according to variations like the present invention is a fluorine anion F as unique active suppression or destruction component ^- are those containing at least one fluorinated compound capable of releasing. Advantageously, the F ⁻ titer in the composition is above 4.5 ppm, preferably about 5 ppm if 100% inhibitory composition is desired.

Further, the present inventors have found that the fluorine anion F ⁻ has spermicidal activity due to enhancement of known spermicidal compounds in addition to these direct spermicidal activities. Thus, the composition according to the invention comprises on the one hand at least one basic active spermicidal component such as a cationic, anionic, amphoteric or nonionic surfactant which lowers the interfacial tension or also paramenthanylfel polyoxyethylene ether or while being configured of a trisodium salt of polysaccharide sulfuric ether it is advantageous, in the second fluorine anion F according to the invention ^- at least one fluorinated compound capable of releasing, and finally pharmaceutical vehicles It is advantageous to be composed of a shaping agent and various usual additives (antioxidant ...).

In the composition according to the invention, the basic active ingredient concentration is below the MIC of this basic active ingredient without ion F ⁻ .
The composition is nevertheless 100% inhibitory, that is to say that it satisfies the IPPF total spermicidal test. The composition according to the invention may comprise a mixture of some basic active ingredients and / or several different fluorinated compounds.

 In the following,% is given by weight.

A preferred embodiment for use of the local contraceptive of the present invention are as follows: egg: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: semi-synthetic Guriserudo acids Alternatively, cocoa butter, gelatin or glycerin purified water, anti-oxygen agent, preservative.

Cream and milk: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: distilled or purified water, wetting agents, emulsifiers, stabilizers,
Antioxidant, antiseptic (included in various proportions depending on the viscosity and pH obtained).

- Ointments and pomade: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: distilled or purified water, emulsifier, the type of excipient fatty compounds (petrolatum, Ranorein, Ranowaserin, steer Looserine), stabilizers, anti-oxygen agents, preservatives (included in various proportions depending on the viscosity and pH obtained).

Gel: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: soluble derivatives of cellulose cationic surfactant compatible, distilled or purified water, glycerin, sorbitol, anti-oxygen Agents, preservatives (included in various proportions depending on the viscosity and pH obtained).

- soluble waffle: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: polyvinyl alcohol, glycerin, sorbitol, propylene glycol, distilled or purified water, anti-oxygen agent.

- Tablets: benzalkonium chloride per tablet 25mg anion F ^- (eg, sodium fluoride) per tablet 10mg excipients: lactose, magnesium stearate, cellulose, Amiramu, citric acid, sodium bicarbonate.

Synthetic soap: benzalkonium chloride 2% anion F ^- (eg, sodium fluoride) 1% Excipients: quaternary ammonium compatible foaming and wetting products (e.g., betaine or amino - amphoteric surfactants such as betaine Agents), emollients, stabilizers, anti-oxygen agents, preservatives.

- solution: benzalkonium chloride 0.50% anion F ^- (eg, sodium fluoride) 025% excipient: distilled or purified water, ethanol, anti-oxygen agent, glycerin, sorbitol, depending on the preservative (obtained pH guests Included in species ratio).

Comparative test No. 1: The MIC of various known spermicidal compounds was determined by the IPPF test. The following results are obtained by determining the minimum concentration of spermicidal compounds that induces death of all sperms within 5 seconds with 1 ml of composition that reacts with 0.2 ml of semen, and for 6 sperms of various donors. Obtained by doing.

Test No. 2: Same spermicidal test of IPPF reacted with 0.2 ml of semen 1 m containing already 0.0001% (by weight) of fluorine anion F ⁻
The composition of 1 was used to determine the minimum concentration of spermicidal compound that induces death of all sperm within 5 seconds and by doing this for 6 semen from various donors.

Thus, it can be seen that the known ability to suppress spermicidal components is greatly improved by the addition of ionizable fluorine. Therefore, the composition according to the invention may contain very small amounts of the basal active spermicidal component, in particular below the minimum inhibitory concentration of this active component without ionic F ⁻ .

Furthermore, the concentration of ions F ⁻ associated with the basic active ingredient may also be very low, especially below the minimum inhibitory concentration of the fluorine anion F ⁻ .

As an example, we have found that a solution containing 0.003% benzialkonium chloride and 0.0001% fluorine anion.
F ^- if no total sperm activity by IPPF test each solution containing 0.003% of the benzalkonium chloride and
It was found that the solution containing both 0.001% of fluorine anion F ⁻ actually satisfied the IPPF test. Therefore a synergistic effect is observed.

Test No. 3: This test is the same as Test No. 1 and 2 above, except for ions
F ^- a is to realize in the presence of sodium borate in order to complexing. As a result, ions F ^- spermicidal effect at all disappeared, the ion F ^- is only active, indicated that i.e. potentiators of spermicidal effect.

Test No. 4: Various perfluorinated benzalkonium chlorides were used as basic spermicidal compounds under the same conditions as above (Test Nos. 1 to 3). Thus, it was shown that perfluorinated benzalkonium chloride has spermicidal activity similar to just one of the alkonium chlorides. Moreover, this activity remained identical to itself under the conditions of Test No. 3 in the presence of sodium borate, indicating that the fluorine fixed on the benzine nucleus was not ionized.

Test No. 2 was also realized with perfluorinated benzalkonium chloride mixed with another chemical compound capable of releasing the ion F ⁻ . Enhanced spermicidal activity of perfluorinated benzalkonium chloride was also observed. This same test, carried out in the presence of sodium borate (according to test No. 3), induced spermicidal activity which is that of perfluorinated benzalkonium chloride.

These two tests No. 3 and 4 show that the enhancement of the basic active ingredient occurs only in the presence of the fluorine anion F ⁻ .

In order to produce a spermicidal drug according to the invention, a solution with a predetermined concentration of fluorine anion F ⁻ and eventually the basic active ingredient is realized and incorporated into an excipient chosen according to the galenical form to be produced. In the case of tablets, the basic active ingredient and the compound capable of releasing ionic F ^- are incorporated into the excipient in the form of a primary product.

Comparative test No. 5: This in vitro test was carried out on a crude drug formulation containing benzalkonium chloride as a basic active ingredient after in vitro simulation (extraction, solubilization…) of actual conditions in vivo. This was done by asking for the MIC of.

This test, carried out without the activator, gave the following results:

These percentages are for IPPF spermicidal testing
It was used in vitro and corresponds to the proportions (weight) of benzalkonium chloride in the solution obtained after the simulation, these proportions were determined by titrating with samples taken from the solution.

Test No. 6: The same conditions were used as in comparative test No. 5, but the galenical forms each initially contained 0.45% (by weight) of fluorine anion F ⁻ .

 The following results were obtained.

II) Use of the invention for combating preservatives, antibiotics, ... and especially STD. Preferred embodiments of the use of the invention as a preservative, for example in dermatology, are as follows.

Cream and milk: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: distilled or purified water, wetting agents, emulsifiers, stabilizers,
Antioxidant, antiseptic (included in various proportions depending on the viscosity and pH obtained).

- Ointments and Bomado: benzalkonium chloride 1.20% anion F ^- (eg, sodium fluoride) 0.50% Excipients: distilled or purified water, emulsifier, the type of excipient fatty compounds (petrolatum, Ranorein, Ranowaserin, steer Loiserine), stabilizers, anti-oxygen agents, preservatives (various proportions depending on the viscosity and pH obtained).

Synthetic soap: benzalkonium chloride 2% anion F ^- (eg, sodium fluoride) 1% Excipients: quaternary ammonium compatible foaming and wetting products (e.g., betaine or amino - amphoteric surfactants such as betaine Agents), emollients, stabilizers, anti-oxygen agents, preservatives.

- solution: benzalkonium chloride 0.50% anion F ^- (eg, sodium fluoride) 0.25% Excipients: distilled or purified water, ethanol, anti-oxygen agent, glycerin, sorbitol, various depending on preservative (obtained pH Included as a percentage).

Preferred embodiments of the invention for its use in dermatology, eg as topical antibiotics, are:

- solution: Erythromycin base 4% anion F ^- 0.5% Excipients: ethyl alcohol, propylene glycol, distilled water.

Gel: Erythromycin base 4% anion F ^- 0.5% Excipients: ethyl alcohol. Hydroxypropyl cellulose, distilled water, glycerin, pomade: Neomycin base 0.35% anion F ^- 0.50% or bacitracin 50.000 IU% anion F ^- 0.50% or oxytetracycline clorrole hydrate 3% anion F ^- 0.50% or aureomycin chlorhydrate blade 3% anion F ^- 0.50% excipients: vaseline, vaseline oil, lanoline.

Cream: Sofura mycin sulfate 2.5% anion F ^- 0.50% Excipients: propylene glycol, polyoxyethylene glycol, distilled water.

A preferred embodiment of the invention for its use as a topical antibiotic in, for example, otolaryngology is as follows.

- ophthalmic pomade: aureomycin 1% anion F ^- 0.50% or oxytetracycline 0.50% anion F ^- 0.25 Excipients: vaseline, vaseline oil, lanoline.

Nasal Solution: Soframycin Sulfate 1.25% Anion F ^- 0.50% Excipients: Distilled water, citric acid, sodium chloride.

0.10 to increase the activity of topical antibiotic treatments
It is advantageous to add% benzalkonium chloride.

More specifically, for example, gynecology of the present invention, sexually transmitted disease STD
A preferred embodiment of the use for combating against the items "use of the invention for topical contraception" and the names "eggs", "creams", "ointments and pomades", "gels", "tablets",
They are described under "Synthetic soap" and "Solutions".

The methods used in the tests conducted for their use according to the invention are as follows.

・ Neisseria Gonorrhoea
For e): The microorganism used is from a hospital isolate.

-Dilution range of test substance: solvent: double-distilled sterile H ₂ O common ratio range of 2 Dose: 2000-1.56 (and below) μg / ml 2 ml of each dilution was mixed with 18 ml of solid preferred culture medium : G-rose medium for isolation of Gonokkochi rich in G replenisher (Pasteur Institute): Formulation: -Poulain serum 165ml-Yeast extract 100ml-Globular extract 235ml-Glucose 0.65ml-Distilled H ₂ O Set to 500 ml.

-Gonocchi's culture medium: 2000 ml Pasteur medium + 500
ml G replenisher.

The culture media associated with the dilutions of these active substances form the basis for studying bactericidal activity. The final concentration of these substances is about 800-0.156 μg / ml in Petri dishes. The suspension used (nutrient liquid-dilution of 24 hours culture in physiological water in broth medium) was placed in wells drilled in synthetic substrate under laminar flow hood. In each of the adjusted wells,
Strains (multiple inoculum) were studied. Each studied dish was incubated (37 ° C stove) and examined after 24 and 48 hours.

-Determination of MIC: Gonococchi strains were spread on plates (dilution on plates) and some of them were prepared as comparative and control strains without test substance.

5μ of 10 forming colonies / ml were deposited on gelose plates with or without test substance (Sorens
18-hour broth of Gonococchi suspended in en solution).

Incubation is carried out at 36 ° C. for 48 hours, and then the growth or lack of growth of Ganococchi is observed on the plate.

・ About Candida Albicans: The method is Neisseria Gono
rrhoeae) but with the following differences: Dilution range of double distilled sterile water column 2000-1.56 μg / ml.

Add 0.5 ml of each dilution to 4.5 ml of liquid Roiron medium.

-Inoculate the tubes with Candida (24 hours / Roiron medium) culture or the comparative strain (Roiron medium). Incubate the tubes in a stove at 37 ° C for 24 and 48 hours. Observe droplets between slide and cover glass under microscope at t = 24 hours and t = 48 hours.

-Expression of results by counting yeast and determination of fungicidal MIC. Determination of percent resistant bacteria for comparison tubes.

・ Trichomonas Vaginali
s): The same method as for Candida Albicans.

・ About Chlamydia ・ Inoculum: Consists of host cells of Chlamydia or Mac Coy cells. They are stored at -80 ° C. The cell concentration is 2-2.5 x 10 cells / ml for the test. The cell layer is prepared in complete culture medium.

Dilute the test substance in double-distilled sterile water in an increasing range with a common ratio of 2.

・ The method used is A.FOURNIER INS
F.Catalan (P.SEDNAOUI), A.MILOVANO (A.MILOVANO) of TITUTE, Paris)
VIC) Professor and others.

Mix 1 ml of the test substance dilution with 1 ml of cell suspension (Mac Coy cells) and then in the stove at 37 ° C for 1 hour and
Incubate for 24 hours. 0.2 ml of this mixture is then placed in the well plate. The plates are centrifuged (2000 rpm for 1 hour) and incubated at 37 ° C for 1 hour. The culture medium was then replaced with 0.2 ml of fresh medium containing 0.5 mg / cycloheximide and the plate was then replaced with 3 ml.
Incubate at 7 ° C for 48 hours. The cell layer is then fixed with methanol and the whole is stained with a complex with a monoclonal antibody and FITC (fluorescein isothiocyanate). The contents present in Mac Coy cells are then observed under an inverted epifluorescein microscope.

Therefore, the toxicity of the test substance was first tested and taken into account for a comprehensive consideration of the integrity of the host cell.

・ Pseudomonas Aerugi
nosa) -preparation of a concentrated solution using the two strains.

Suspension in NaCl isotonic solution (0.85% by weight).

-Check that the suspension contains the same number of bacteria: grooved inoculation (1 µ trap) of the serial dilution of the original concentrated solution (common ratio 10)
Standard technique in gelose medium according to. Incubation for 18 hours at 37 ° C.

-Preparation of a dilute solution of the test substance in double-distilled sterile water. Dilution range of common ratio 2 (eg, 2000-0.015 μg / ml).

-Pseudomonas at a fixed concentration (= 4 x 10 ⁷ bacteria / ml)
A mixture of Pseudomonas Aeruginosa bacterial suspension (of the same origin as the AFNOR standard) and a dilution of the substances in phenomenological order (2000-0.015 μg / ml).

-Incubation or contact time: 1 hour, 24 hours and 48 hours in the stove at 37 ° C.

 The test was performed in duplicate for each substance dilution.

-Observation of the number of survivors recorded with respect to the average number of comparative strains cultured at the same time as the test.

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

・ Treponema, Gardnerella
ella), Ducrey's Bacilla
s), Streptococci and Staphylococcus Aureus, the method used is A. FOURNIER INS.
TITUTE) F. CATALAN, P. SEDANAOUI, A. MILOVANOVI
C) It was explained by a professor.

Comparative Experiment No. 7: Using benzalkonium chloride alone and nonoxynol 9 alone, the following results were obtained.

Test No. 8 A test carried out in the presence of the fluorine anion F ^{− in} the same manner as described above gave the following results.

Comparative test No. 9: This test was carried out with substances containing benzalkonium chloride in the presence of serum proteins without activating components. It gave the following results.

This test shows the known unfavorable effect of serum proteins on the efficiency of benzalkonium chloride.

Test No. 10: This test was carried out as for Test No. 9 except that the fluorine anion F ⁻ was present in the composition. The following results were obtained.

This test fluoride anion F ^- indicates that reducing advantageously the undesirable effect of serum proteins.

Comparative test No. 11: This test was carried out in in vitro galenical form using a product containing benzalkonium chloride as active ingredient and no activating component (similar to Test Nos. 5 and 6).

 The following results were obtained.

The concentrations are those present in the liquid obtained after the simulation used in the test.

Test No. 12: This test was carried out under the same conditions as comparative test No. 11 from a product containing 0.5% (by weight) of fluorine anion F ⁻ .

 The following results were obtained.

III) Use of the invention in the field of disinfection: This field relates to the treatment of floors, surfaces, equipment ... With contact sterilization products.

Preferred embodiments of the invention for this application are as follows.

These tests were performed using benzalkonium chloride followed by nonoxynol 9 as the active ingredient in standard AFNOR NFT 72.
-150, March 81.

The neutralizing agents used were: 3% Tween 80 (V /
V) and 0.3% lecithin (M / V). The pH of the medium was 7.2.

Comparative test No. 13: This test was carried out without activating components.

Test No. 14: This test is the same as the above test except that the fluorine anion F ⁻ was present as an activating component.

IV) Use of the present invention in cosmetic surgery: Preferred embodiments of the present invention in cosmetic surgery will be described below.

The following galenical forms are provided in cosmetology: creams, emulsions, pomades, solutions, foam baths, synthetic soaps, shampoos, foundation lotions, antiseptic lotions.

While blending the excipients are the same as for the pharmaceutical formulation, however, benzalkonium chloride and an anion F ^- concentrations yl. Their concentrations are preferably as follows for all products: 0.2% benzalkonium chloride and 0.
1% of fluoride anion F ^-.

Chemically or naturally active ingredients may also be incorporated into these formulations in cosmetically acceptable concentrations and volumes.

Creams and emulsions may be in the continuous aqueous phase (oil / water or water / oil emulsion) or pastes when warm and may be self-diluting in water.

The various excipients given as specific examples correspond to the following products as non-limiting illustrations.

Wetting agent: glycerol, propylene glycol, diethylene glycol, glycol, sorbitol, polyoxyethylene glycol.

・ Emulsifier: sodium stearate, beeswax, sorbitol ester, polyoxyethylene glycol ester,
Fatty alcohol, triethanolamine lanolin, Twee
n, glycol stearates and polyglycols.

Stabilizer: glycol stearate, cetyl alginate alcohol, pectin, gum, fatty ester of polyol, soluble cellulose ester.

• Anti-oxygen agents: tartaric acid, citric acid, and ascorbic acid.

-Preservatives: boric acid, benzoic acid, parabenzoic acid and their methyl or propyl esters.

-PH: All these formulations are particularly efficient for a pH of 4.5-6.5. To obtain such a range, citric acid is mainly used.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 7/00 A61K 7/00 C 9/02 9/02 N 9/06 9/06 K 9 / 08 9/08 EM 9/20 9/20 B 31/085 31/085 31/14 AEB 31/14 AEB 31/185 31/185 31/195 31/195 31/31 31/31 31/725 31 / 725 31/765 31/765 33/24 ACZ 33/24 ACZ 33/42 ADB 33/42 ADB (72) Inventor Pierre Viro France, 92200 Nuilly Sur Seine, Boulevard de la Sosei, 20

Claims (25)

(57) [Claims] 1. A composition for inhibiting or destroying at least one microorganism, comprising at least one basic active ingredient for inhibiting or destroying said microorganism, and a fluorine compound capable of releasing a fluorine anion F ^−. A composition consisting of. 2. The fluorine compound is a metal derivative of fluorine selected from sodium fluoride, calcium fluoride, potassium fluoride, aluminum fluoride, tin fluoride, ammonium fluoride or sodium monofluorophosphate. The composition according to claim 1. 3. The fluorine anion F ⁻ concentration released by the fluorine compound is such that the fluorine anion F ⁻ without the basic active ingredient.
A composition according to claim 1 or 2 which is below the minimum inhibitory concentration (MIC). 4. A composition according to claim 1, wherein the basic active ingredient concentration is below the minimum inhibitory concentration (MIC) of the basic active ingredient without a fluorine compound. . 5. In addition to the fluorine compound capable of releasing the fluorine anion F ⁻ , the basic active ingredient itself can also release the fluorine anion F ⁻ .
Item 5. A composition according to any one of items 4 to 4. 6. A fluorine compound capable of releasing the fluorine anion F ⁻ in addition to the basic active ingredient for inhibiting or destroying the microorganism can inhibit or destroy at least one microorganism. The composition according to any one of items 1 to 5. 7. The titer of F in the composition is higher than 4.5 ppm in order to obtain 100% spermicidal activity by the IPPF total spermicidal test. The composition according to item 1. 8. A composition comprising at least one compound as a basic active ingredient for suppressing or destroying a reproductive body, and its suppressing or destroying ability is enhanced by the presence of the fluorine anion F ^−. The composition according to any one of item 7. 9. A composition according to claim 1, wherein the basic active ingredient is quaternary ammonium. 10. A method according to any one of claims 1 to 9 which comprises a cationic surfactant, an anionic surfactant, an amphoteric surfactant, or a nonionic surfactant.
The composition according to Item. 11. The cationic surfactant is benzalkonium chloride, the anionic surfactant is sodium methyl taurate oxysalt, and the amphoteric surfactant is an amidoethylglycinate derivative of a fatty acid. Alternatively, the composition according to claim 10, wherein the nonionic surfactant is nonoxynol. 12. The basic active ingredient according to claim 1, which comprises trisodium salt of phenylmercuric nitrate, para-menthanylphenyl polyoxyethylene ether or polysaccharide sulfate ether. The composition according to item 1. 13. A pharmaceutical as claimed in any one of claims 1 to 12.
The composition according to any one of paragraphs. 14. A composition according to claim 13 for sexually transmitted diseases. 15. The composition according to any one of claims 1 to 12, which is a preservative and / or a disinfectant. 16. A composition according to any one of claims 1 to 12 which is an anti-protozoan product. 17. A composition according to claim 16 wherein the anti-protozoan product is a topical anti-protozoan product. 18. The composition according to any one of claims 1 to 15, which is a bactericide. 19. A composition according to claim 18, wherein the bactericide is a topical fungicide. 20. The composition according to any one of claims 1 to 15, which is an antifungal agent. 21. The antifungal agent is a topical antifungal agent,
The composition according to claim 20. 22. The composition according to claims 1 to 15 which is an antibiotic product. 23. The composition of claim 22 wherein said antibiotic product is a topical antibiotic product. [Claim 24] A claim, which is a cosmetic product.
The composition according to paragraph 15. 25. An ovule, cream, gel, solution, foam, tablet, soluble waffle, tampon or vaginal suppository according to any one of claims 1 to 24.
The composition according to Item.