DK173716B1 - Non-pharmaceutical composition containing a surfactant and a fluorine compound - 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

DK 173716 Bl

Non-pharmaceutical composition containing a surfactant and a fluorine compound

The invention relates to a non-pharmaceutical composition for inhibiting or destroying 5 single-celled living beings, such as protozoa, microbes, bacteria, gametes, fungi and other single-celled living beings, and viruses. Accordingly, it is particularly aimed at the technical areas that are constituted by contraception, cosmetics, or disinfection.

Below, the word "inhibition" of a single-celled creature or of a virus 10 either means that its reproduction is inhibited or hindered, respectively prevented, or that it is rendered unable to perform some of the functions that it usually performs. The word destruction means that the single-celled living creatures or viruses are destroyed.

Substances that inhibit or destroy single-celled living creatures, whether in the biological, pharmaceutical, cosmetic or even further fields, such as disinfection and other areas, are already known.

In particular, spermicidal compositions are known from the disclosures of US 20 patents Nos. 4,339,441 and 4,359,475.

Numerous chemical compounds are known which are useful in methods of local contraception in living creatures. In particular, it is known that surfactants that lower the interfacial tension (e.g., quaternary 25 ammonium compounds, nonoxynols, derivatives of fatty acids amidoethyl glycinate, methyltaurine sodium oxysalt (also called sodium N-methyltaurate) ...) and some other compounds such as phenylmercurin nitrate, p-menthanylphenyl-polyoxyethylene ether or the trisodium salt of polysaccharide sulfuric acid ether, have inhibitory or destructive effects on unicellular living creatures and in particular have spermicidal effects.

2 DK17 £! 716B1

Substances that act mechanically on spermatozoa, e.g. by immobilizing them is also known. In the specification of US Patent No. 4,386,186, such effects are described and more specifically, the association of "poloaxms" with agents that inhibit spermatozoa, in view of controlling gelling;> <5 solubilization of the products and thus a mechanical increase in efficiency. a: the inhibitory agents accompanied by an additive or synegistic effect.

Local contraceptive compositions are also known, especially spermicidal compositions, including such chemical compounds, and are useful in local inhibition of the fertility of gametes, especially in human or animal spermatozoa.

These known compositions include a concentration of an inhibitor d 3 chemical compound, which concentration is greater than the minimum inhibitor d 3 concentration, called MIC, in solution each r suspended in a pharmaceutically acceptable excipient which depends on the galenic form used. It is known that in order to have all spermatozoa i <r contained in 0.2 milliliters of sperm, killed in less than 5 seconds (conditions for total spermicide testing according to standards derived from IPPF, Ime. 20 national Planned Parenthood Federation), the concentration of the spermicidal active ingredient in 1 milliliter of pharmaceutical composition must be greater than or equal to the minimum inhibitory concentration, called MIC, for this active ingredient. The MIC of a chemical compound is dependent on the deure compound, but also on the conditions under which it is used, ie. the n 25 galenic form in which the composition is included.

More generally, pharmaceutical or cosmetic compositions containing at least one basic active ingredient that inhibit or destroy at least one living cell and drugs or cosmetic products containing such products are known.

DK 173716 B1 3 In the field of antiseptics and disinfection, numerous active ingredients are known: halogens (chlorinated or iodinated derivatives ...), aldehydes, alcohols, phenols, acids, metals (silver, copper, mercury, zinc salts ... ) amidines, biguanides, diphenylureas, oxidizing agents (hydrogen peroxide, potassium permanganate ...) 5 dyes, interface lowering agents, and wetting agents (cationic, anionic, amphoteric or organic ones).

Antiseptic and / or disinfectant and / or antiprotozoal and / or antifungal and / or antibiotic and / or antiviral products, which include such inhibitory or destructive agents, and methods of preparation for these substances or compositions are also known.

These known substances or compositions are generally satisfactory, but present some problems with their use in practice.

15

These problems are essentially the following: First of all, it is generally desirable to achieve a total inhibitory or destruction efficacy against the living cell (s) or to the virus or viruses, i.e. an inhibition or destruction rate of 100% in the circumstances of the practical application. However, this is not always the case when strict precautions are not taken or when a dose of the active ingredient is required (eg in the case of the cosmetic agent).

25

In addition, it is generally desirable to exhibit an activity against one or more given living creatures or viruses, e.g. gametes or pathogens, without giving rise to undesirable side effects in the short or long term (activity against other single-celled living beings, irritations, environmental damage ...). But in practice 30 it has been found that the dose required to solve the first of the above problems causes long-term side effects (in regular use with regular use) and even in side effects on cards (used in "jerk"). In the medical field, some tetratogenic and / or carcinogenic effects resulting from certain threshold doses and with some active ingredients have been noted. In the area of disinfection, some desirable effects on the materials to be disinfected can be observed.

An object of the invention is to increase the inhibitory or destructive ability 3 of a composition which includes a given limited concentration cf basal inhibitory or destructive component, without increasing them. Yet another object of the invention is the reduction in the concentrations of the basic active ingredients without decreasing the inhibitory or destructive ability of the composition against all of the above and to avoid the side effects and to better control the selectivity towards various single celled living creatures or viruses.

15

The purpose of the invention is in particular to provide a novel milk milk composition, in particular a means for local contraception and IT product, which includes such a composition, which composition and which agent, drug or product can be used in "jerk" or regular. 20 and continuously for a long period without risking side effects, such as teratogor e or carcinogenic ones, and which composition and which agent, drug or product is total, ie. that the percentage of unfortunate events is statistically zero or insignificant, and that this is the case in very regular applications as such (without special xr-25 precautionary measures).

Furthermore, the object of the invention is to provide a product for local contraception that is easy to use and totally effective, ie. a product that gives years of results similar to those obtained by oral contraception without having the associated 30 drawbacks.

DK 173716 B1 5

Thus, the invention relates to a non-pharmaceutical composition comprising an effective amount of surfactant suitable for inhibiting or destroying a single cell creature or virus, and an anti-enzymatic amount of a fluorine compound capable of delivering fluoride ions and capable of inhibiting or destroying a enzyme associated with said unicellular creature or virus, wherein the amount of fluoride ions which can be released is 0.025 - 0.5% by weight and is used as a contraceptive, disinfectant or antiprotozoic agent or in a cosmetic product.

The fluorine compound, i.e. the fluorinated compound is an activator of the surfactant compound, preferably with a synergy effect. This activator or activating compound prevents or inhibits, respectively, inhibiting the paired enzyme / substrate in its action.

It has now surprisingly been found according to the invention that such an activator can be constituted by fluoride anion F 'delivered from a fluorinated compound, either spontaneously or after enzymatic action. It has also been found that when the surfactant compound acts as the basic active ingredient, it is sometimes capable of delivering an activating compound itself and / or that the activating compound itself is an active ingredient that inhibits or destroys at least one living cell or virus.

More specifically, it has been noted that such a fluorinated compound itself has the ability to inhibit or destroy single-celled living creatures or viruses, and that such a fluorinated compound has a synergistic effect with the accompanying basal component (s).

In particular, the cosmetic product is a local cosmetic such as a synthetic soap or milky composition. The product for contraception applied locally in contact with gametes - more specifically a suppository, preferably a cream, a gel, a solution, a foam, a tablet, a soluble whey, a tampon or a vaginal suppository .

Here and hereinafter, the word "local" and its derivatives means that the product is '' applied to a predetermined site to be treated, e.g. vagina or other anatomical parts, so that the effect is produced in the environment near this place, namely the effect against unicellular living creatures or viruses, in contact with the product, and this in contrast to general administration (e.g., oral administration or parenteral administration).

10

The composition, substance or product of the invention is directed to local administration as general administration. Eg. can a spermicide according to the invention! ά n is applied locally. Furthermore, when one wishes to overcome resistance effects in pathogenic single-celled living creatures to the commonly used therapies, n.in 15 will rather use general administration according to the invention.

According to the invention, an activating fluorine compound that inhibits or destroys at least one enzyme associated with said single-celled creature or virus causes a considerable sensitization of said single-celled creature to 20 viruses against external attacks, especially against the effect of a basic active ingredient that inhibits or destroys said unicellular creature or vim by "blocking" the paired enzyme / substrate. It is safe to say that every single cell, living creature or vims possesses a vital enzymatic system. In addition, unicellular living creatures or viruses can deliver 25 viruses when exposed to certain circumstances (eg resistance to ovei or antibiotic), some special enzymes that cause the destruction of an invasive agent (e.g. lactamase that destroys penicillins ), these enzymes being called "protective enzymes." The invention lies in the non-functional function of these enzymes, thereby making the single cell live spring jn 30 fragile by creating the optimum conditions for the active stocks' activity against it. numerous advantages in comparison with the prior art DK 173716 B1 7 which, on the one hand, is to fulfill the above stated intentions (eg. aims and intentions) and on the other hand is able to selectively influence a given single-celled living creature or on a given family of single-celled living creatures by effect on a given enzyme or on a given family of enzymes. with the invention to inhibit the enzymes necessary for their formation or their replication.

In the following, "affiliated enzymes" means essential and / or protective enzymes in single-celled living creatures and / or viruses.

The inventors have determined that fluorine in the ionized state P has a particularly effective and beneficial effect as an activating ingredient against the associated enzymes and this at negligible regular concentrations. In addition, ionized fluorine P is very common, economical and relatively easy to use. Its handling and utilization is well controlled as well as the side effects that it can provide in accordance with the doses used.

The invention mainly has two types of use: either applications in the cosmetic or contraceptive field (in the case of the following examples of spermicides) or in more common areas such as agriculture, disinfection (the following example) and other areas.

The function of the activating fluorine compound consists in destroying the action of the enzymatic system associated with said living creature or creatures or viruses or viruses. In this way, the inventors have found that such activating compound inhibits or inhibits, respectively, inhibits the action of paired enzyme / substrate. The fluorine compound may e.g. be a metallic derivative of fluorine which gives off fluoride anion P Some very good results have been observed with sodium fluoride, calcium fluoride, potassium fluoride, aluminum fluoride, tin fluoride, ammonium fluoride or sodium monofluorophosphate and others. Eg. the following 30 single-celled living creatures or viruses may be of interest in connection with the invention: • gametes (spermatozoa, ova) • gram-positive chefs such as staphylococci and streptococci • gram-negative cooks such as gonococci 5 · gram-positive bacilli • gram-negative bacilli, such as colibacilli or Escherichia coli acid-alcohol solid bacteria such as mycobacteria, e.g. mycobacterium smegmatis • virus bacteria such as spirochetes, e.g. treponema 10 · various bacteria such as chlamydia • flagella-equipped protozoa such as tricomonas • various yeast species such as Candida albicans • viruses or retroviruses such as HIV (human immunodeficiency virus) and herpes.

15

For example, the following enzymes are linked to at least one such cell; living creature or such virus of interest in connection with the invention (Table 1, Part A and Part E3).

DK 173716 B1 g

Table A, Part A

ENZYM. SUBSTRATE

alkaline phosphatase 2-naphthylphosphate esterase (C4) 2-naphthylbutyrate esterase ellipase (C8) 2-naphthylcaprylate lipase (C14) 2-naphthylmyristate leucinarylamidase L-leucyl-2-naphthylamide validylamidase L-valyl L-cystyl-2-naphthylamide trypsin N-benzoyl-DL-arginine-2-naphthylamide α-chymoptrypsin N-glytarylphenylalanine-2-naphthylamide acid phosphatase 2-naphthyl phosphate DK 173716 B1 10

Table 1, Part B

ENZYM SUBSTRAT

naphthol-AS-B1-naphthol-AS-B1-phosphate phosphohydrolase α-galactosidase 6-Br-2-naphthyl-αD-galactopyranoside β-galactosidase 2-naphthyl-1β-galactoside β-glucoronidase naphthol-AS-B1 -BD -glucoronide α-glucosidgse 2-naphthyl-αD-glucopyranoside β-glucosidase 6-Br-2-naphthyl-β-D-glucopyranoside N-acetyl β-glucosaminidase 1-naphthyl-N-acetyl-βD-glucosaminide α-mannosidase 6- Br-naphthyl-α-D-mannopyranoside α-fucosidase 2-naphthyl-α-L-fucopyranoside DK 173716 B1 11

For example, the basic surfactant used in the composition of the invention is a cationic or anionic or amphoteric or nonionic surfactant which lowers the interface voltage, preferably a quaternary ammonium compound. Benzalkonium chloride and other "benzalkonium urns" are an example of a cationic surfactant. A methyltaurine sodium oxy salt, i.e. the sodium salt of N-methyltaurine, one example of an anionic surfactant. A fatty acid amidoethyl glycinate derivative is an example of an amphoteric surfactant. A nonoxyno! is an example of a nonionic surfactant. The surfactant may also advantageously be phenylmercurine nitrate or a p-menthanylphenyl polyoxyethylene or a trisodium salt of a polysaccharide sulfuric acid ether or others (halogen, aldehyde, alcohol, phenol, acid, metal, amidine, biguanide, diphenylurea, oxidant, dye ... ).

In the various tested applications, it has been demonstrated that the activating fluorine compound taken alone generally possesses in itself an activity directly directed to said single celled living creature or virus. It has now surprisingly been found that the compound (eg combination) of the activating fluorine compound with the surfactant acting as the basic ingredient has a synergistic effect in that they do not merely correspond to the sum of the results obtained. is expected from the presence only of the basic active ingredient or of the activating fluorine compound, but on the contrary is greater than this sum.

The effectiveness of such active constituents or activators can be measured with the minimum inhibitory concentration, called MIC, which corresponds to the concentration of the active ingredient that causes inhibition or death of the whole unicellular living creatures or viruses over a given time.

It is an advantage of the composition of the invention that the concentration of fluoride anion F delivered by the activating fluorinated compound is less DK 17: 1716 B1 12 than the minimum inhibitory concentration (MIC) of fluoride anion F 'without base a active ingredient. .

Similarly, the concentration of the basic active ingredient in the * 5 composition of the invention may be lower than the minimum inhibitory concentration (MIC) of this basic active ingredient without activating fluorine compound. Yet and surprisingly, it has been found that a composition according to the invention has a total efficiency, ie. at least equal to the efficacy of substances containing either only fluoride anion F iei 10 concentration greater than or equal to its MIC, or only a basic al ten / component of a concentration greater than or equal to with its MIC.

In addition, the basic active ingredient may also be capable of delivering fluoride anion. The composition of the invention may include several basic ingredients whose functions may be the same or different, and / or further activating compounds affecting at least one enzyme linked to one or more basic active ingredients.

The composition of the invention can be used in a variety of ways to obtain products and, according to the way the products are used, can be used for localization. or general administration.

Among the particularly advantageous uses of compositions of the invention η i may be mentioned the control of certain non-pathogenic agents such as gametes, e.g.

25 spermatozoa within the context of contraception, specifically local contraceptive i.

The composition of the invention can also advantageously be used as A in cosmetic product containing such doses and concentrations which do not allow it to be classified as a pharmaceutical product.

30 DK 173716 B1 13

The composition of the invention may also be used e.g. such as antifungal, antiprotozoal, and in other products in the field of agriculture or also in the field of surface disinfection.

A preferred embodiment of the invention is that consisting of the products used locally on the male or female mammalian genitalia, such as spermicides.

Benzalkonium chloride and nonoxynol 9 are preferably used as the active ingredients, e.g. as surfactant compound. Any metallic derivative of fluorine, e.g. sodium fluoride, preferably used as activating fluorine compound. All of the known galenic forms are useful, such as preferably suppository, cream, gel, solution, foam, tablet, soluble waffle, tampon, vaginal suppository or other forms.

15

The proportion to be used of surfactant and activating fluorine compound is dependent on the galenic form, since only the actual concentration elicited in vivo is important in terms of product efficiency.

These proportions must vary between the MIC and the maximum concentrations at which side effects are induced. In case of local administration, forms of intolerance (irritation) of the treated parts should be avoided. In general, toxic concentrations should be avoided.

Therefore, the in vivo concentration of benzalkonium chloride is preferably 1.2% (by weight) and the in vivo concentration of fluoride anion F is preferably 0.5% (by weight).

Several preferred embodiments of the invention are described below in several tested applications by reference to tests performed on multiple single-celled living creatures.

in 14 DK17; néB1

1) APPLICATION OF THE INVENTION TO LOCAL ANTI-CONCEPTION

The invention advantageously provides a spermicide product applied locally so that it comes into contact with sperm and kills or inhibits spermatozoa.

A spermicide product according to the invention can be presented in a difference? g 3 j galenic forms: Tablet, suppository, soluble (egti. solution), cream, ge, j 10 soluble waffle, tampon, foam, vaginal suppository inserted into the vagina in sexual circulation to prevent fertilization by killing or inhibiting sp e -; matozoeme before coming into contact with ova.

A product according to the invention comprises a composition comprising: 1 <RTI ID = 0.0> at least </RTI> one chemical compound of the invention which includes ionizable fluorine, i.e. a chemical compound capable of delivering fluoride anion P, as active ingredient, and being spermicidal, directly or by potentiation.

A chemical compound of the invention is capable of delivering fluoride anion F, n; it is dissolved, especially in an aqueous solution. Eg. is it a metal; k j derivatives of fluorine, such as sodium fluoride, calcium fluoride, potassium fluoride, j aluminum fluoride, tin fluoride, ammonium fluoride, sodium monofluorophosphate .... chlorine in an organic fluorinated compound such as a fluorinated amine.

For example. one can measure the spermicidal activity of a chemical compound using the total spermicide test according to the standards derived from the IPPF, which consists of finding the minimum inhibitory concentration called MIC in (expressed by a weight percentage) of the chemical compound in a millimeter-south solution causing the death of all the spermatozoa contained in 0.2 µm 30 milliliters of sperm in less than 5 seconds. The test is carried out on the sperm of 6 in ί DK 173716 B1 15 sperm from different donors who meet the following minimum conditions from the IPPF: • age of the sample: two hours • density per day. mm3: 50 million spematozoa 5 · mobility: 50% must move fast when examined at 35-37 ° C in a recent sample.

• Viscosity: ejaculum brought in suitable liquid form, not consisting of thread-like parts and homogeneous appearance seen with the naked eye 10 · Collected in sterile glass tubes hermetically sealed and stored at

37 ° C

f

The inventors have found that in these circumstances fluoride anion F has spermicidal activity of 100% according to the IPPF test when present with a titer of 15 5 ppm (ie 5 milligrams per liter).

In addition, the inventors have found that in addition to this direct spermicidal activity, fluoride anion F possesses a spermicidal activity by potentiating known spermicidal compounds. Therefore, a composition of the invention 20 is constructed on one side of at least one basic active spermicidal component comprising a surfactant such as a cationic or anionic or amphoteric or nonionic surfactant lowering the interfacial tension, or even p-menthanylphenylpolyoxyethylene or a trisodium salt of a polysaccharide sulfuric acid ether or other similar constituents, and on the other hand at least one fluorinated compound of the invention capable of delivering fluoride anion F, and finally of an excipient and various usual additives (antioxidant ... ).

In a composition according to the invention, the concentration of the basic active ingredient may be lower than the MIC of the relevant basic active ingredient without fluoride anion F, since the composition is nonetheless 100% inhibitory, ie. satisfies the total spermicidity test according to IPPF. ! on | composition of the invention may include a mixture of basic active ingredients which inhibit or hinder, respectively prevent gametes, and / or on I mixture of several different fluorinated compounds.

5

Below are the percentages by weight.

The preferred embodiments of the invention for its use at premises in contraception are as follows: 10

suppositories:

Benzalkonium chloride 1.20% F anion 0.50% (eg sodium fluoride) 15

Excipients: Semisynthetic glycerides or cocoa butter or gelatin or glycei and the like in and purified water, antioxidants, antiseptics.

Creams and milk formulas: 20 Benzalkonium chloride 1.20% F anion 0.50% (eg sodium fluoride)

Excipients: Distilled or purified water, wetting agents, emulsifiers, stabilizers, antioxidants, antiseptics (to be included in variable proportions all of the viscosity and pH to be achieved).

Ointments and pomades:

Benzalkonium chloride 1.20% F anion 0.50% (eg sodium fluoride) DK 173716 B1 17

The excipient Distilled or purified water, emulsifier, excipients of the type constituted by fatty compositions (vaseline, lanolin, lanovaseline, stearovaseline), stabilizers, antioxidants, antiseptics (to be included in variable proportions according to the viscosity and pH, to be achieved).

gel:

Benzalkonium chloride 1.20% F * anion 0.50% 10 (eg sodium fluoride)

The excipient Soluble derivatives of cellulose compatible with the cationic surfactants, distilled or purified water, glycerol, sorbitol, antioxidants, antiseptics (to be included in variable proportions according to the viscosity and pH to be achieved).

Soluble waffle:

Benzalkonium chloride 1.20% F anion 0.50% 20 (eg sodium fluoride)

The excipient Polyvinyl alcohol, glycerol, sorbitol, propylene glycol, distilled or purified water, antioxidants.

25 tablets

Benzalkonium chloride 25 mg per tablet F anion 10 mg per tablet (e.g., sodium fluoride) The Excipient Lactose, magnesium stearate, cellulose, amylum, citric acid, sodium bicarbonate.

DK 173710 B1 18

Synthetic soaps:

Benzalkonium chloride 2% F anion 1% 5 (eg sodium fluoride)

Excipients: Foaming and wetting products compatible with materials j containing quaternary ammonium groups {e.g. amphoteric surfactants (such as betaine or aminobetaine), plasticizers, stabilizers, antioxidants, antiseptics.

solutions:

Benzalkonium chloride 0.50% F * anion 0.25% (e.g. sodium fluoride)

Excipients: Distilled or purified water, ethanol, antioxidants, glycerol, sorbito, antiseptics (to be included in variable proportions according to the viscosity and pH, tie r; must be obtained).

20 COMPARISON TEST NO. 1: The MIC for various known spermicidal compounds was determined by the IP3: j test. The following results have been obtained by reacting 1 milliliter wound - 0.2 ml sperm loading and by determining the minimum concentration of spermicidal compound that causes death for all 3! spermatozoa in 5 seconds and this is done with 6 samples of sperm Free j different donors 30! DK 173716 B1 19

Spermicide compound MIC (% by weight) p-menthanyl ph enylpolyoxyethylene ether 0.006

Poly saccharide sulfuric acid ether sodium salt 0.007

Anionic Surfactant (Methytaurine Sodium Salt) 1

Cationic surfactant (benzalkonium chloride) 0.006

Nonionic Surfactant {Nonoxynol 9) 0.006

Amphoteric surfactant (fatty acid amidoethyl glycinate derivative) 0.001 TEST NO. 2: 5

The same total spermicide test according to IPPF was performed with 1 milliliter composition already containing 0.0001% (by weight) of fluoride anion F, which was reacted with 0.2 milliliter of sperm, by determining the minimum concentration of the spermicidal compound which causes death for 10 all spermatozoa in 5 seconds, and this is done with 6 samples of sperm from different donors.

DK 173716 B1 20

Spermicide compound MIC (% by weight) p-menthanylphenyl polyoxyethylene ether 0.003

Trisodium salt of polysaccharide sulfuric acid ether 0.0025

Anionic surfactant (methyltaurine sodium salt) 0.5

Cationic. surfactant (benzalkonium chloride) 0.002

Nonionic Surfactant (Nonoxynol 9) 0.003

Amphoteric surfactant (fatty acid amidoethyl glycinate derivative) 0.005 in

Thus, it is notable that the inhibitory ability of the known spermicidal components is greatly enhanced by the addition of ionizable flies to the composition. Therefore, a composition according to the invention may contain very little of the basic active spermicidal component, especially at a concentration which is lower than the minimum inhibitory concentration of that particular active ingredient without F * ion.

In addition, the concentration of F 'ion attached to a basal active ingredient can also be I

be very low, especially lower than the minimum inhibitory concentration I or | fluoride anion F \ | 21 DK 173716 B1

For example, the inventors have found that when a solution containing 0.003% benzalkonium chloride and a solution containing 0.0001% fluoride anion do not individually total spermicidal activity according to the IPPF test, then a solution containing both 0.003% benzalkonium chloride and 0.0001% fluoride anion F "5 together, the IPPF test. A synergistic is therefore observed.

TEST NO. 3:10

This test consists of performing a test identical to Tests Nos. 1 and 2 above, but in the presence of sodium borate to complex the ion F ': The spermicidal effect has disappeared altogether and demonstrates that it is exclusively the ion F , which is active or is a potentiator of the spermicidal action.

15 TEST NO. 4:

Under the same circumstances described previously (Tests 1-3), 20 different perfluorinated benzalkonium chlorides were used as the basic spermicidal compounds. Thus, it was shown that perfluorinated benzalkonium chlorides have a spermicidal effect similar to the spermicidal activity of the benzalkonium chloride as such. In addition, this activity remains identical to itself under the conditions of test # 3 in the presence of sodium borate, which shows that fluorine 25 attached to the benzene core was not ionized.

Test # 2 was also performed on perfluorinated benzalkonium chloride mixed with another chemical compound capable of delivering F ion. The potentiation of the spermicidal activity of the perfluorinated benzalkonium chloride was also observed.

This same test, when carried out in the presence of sodium borate 22, elicited a spermicidal activity which is the spermicidal activity of perfluorinated benzalkonium chloride.

The two tests # 3 and # 4 show that the potency of the basic active ingredient # 5 takes place only in the presence of fluoride anion F.

To prepare a spermicidal product according to the invention, a solution is prepared having a given concentration of fluoride anion F and optionally of the basic | active ingredient and this solution is integrated into the excipient, which is selected according to the galenic form it is intended to prepare. In the case of π in the € d j tablet, the basic active ingredient and the chemical compound that e; i | capable of delivering F ion, integrated into the excipient in the form of the primary products.

15 COMPARISON TEST NO. 5:

This in vitro test was performed on galenic preparations containing benzalkonium chloride as the basic active ingredient, as determined by the MIC of this benzalkonium chloride after simulating the actual conditions in vivo 20 (extraction, solubilization

This test, performed without an activating component, resulted in the following «e | results! 25 i in DK 173716 B1 23

Galenic form MIC (% by weight) for

benzalkonium chloride

Suppository 0.0063

Cream 0.0083

Tampon 0.0075

Tablet 0.0095

Soluble waffle 0.0080

Gel 0.0080

The percentages indicated correspond to the proportions (by weight) of benzalkonium chloride in the solution used in vitro for the IPPF spermicide test, obtained 5 after simulation, the proportions measured by titration using a sample taken from the solution.

TEST NO. 6:10

The same conditions as in Comparison Test No. 5 were used, but from galenic forms, each containing initially 0.45% (by weight) of fluoride anion F.

The following results were obtained: DK 17571 $ B1 24

Galenic form MIC (% by weight) for!

Benzalkonium chloride - '' | > Suppository 0.0023

Cream 0.0030

Tampon 0.0025

Tablet 0.0025

Soluble waffle 0.0017

Gel 0.0033

• I

II) APPLICATION OF THE INVENTION IN THE FIELD OF DISINFECTION

|

This area concerns the treatment of floors, surfaces, instruments down

bactericidal products upon contact. j 10 i!

The preferred embodiments of the invention for this application are as follows

Used ten [Benzalkonium chloride in F anion Excipiens Hands Purified water or 0.1% 0.25% alcohol by 100%

Epidermis Instruments to be sterilized, 1.0% 0.50% Purified water respectively. 100% disinfected

Textiles 0.05% 0.025% Purified water by 100%

Instruments Ethanol 10% purified (eg 1.0% 0.50% water by 100% thermometers)

Cleaning of Purified Water Surface 0.1% 0.25% 100% (Rooms, Floors ....) DK 173'rlé B1 26

The test was performed according to the standard AFNOR NFT 72-150, March 81 with 1 µl of benzalkonium chloride, then with nonoxynol 9 as the active ingredient.

The neutralizer used was as follows: 3% Tween 80 (volume / volume) and 0.3% lecithin. The pH of the medium was 7.2.

COMPARATIVE TEST NO. 7:10

This test was performed without activating component :; i in DK 173716 B1 27 STAMMER Minimum inhibitory concentration (MIC)

Benzalkonium fluoride alone

Pseudomonas aeruginosa, CNCMA22 31.25 mg / l

Escherichia coii CNCM 54 127 6.57 mg / l

Staphylococcus aureus Oxford origin CNCM54 154 1.56 mg / l

Streptococcus faecalis CNCM 5 855 4 mg / l

Mycobacterium smegmatis CNCM 7 326 30 mg / l DK 1737lé B1 28 STAMMER Minimum inhibitory concentration (MIC)

Nonoxynol 9 alone

Pseudomonas aeruginosa, CNCM A 22 50 mg / l i

Escherichia coli CNCM 54 127 8 mg / l |

Staphylococcus aureus

Oxford origin S

CNCM 54 154 4 mg / l] i

Streptococcus faecalis j CNCM 5 855 7 mg / l! i i i j

Mycobacterium smegmaiis CNCM 7 326 65 mg / l | TEST NO. 8:

5 I

in

This test is identical to the previous test, but performed in the presence of fluoride anion F as the activating component.

i i i | i j i DK 173716 B1 29 STAMMER Minimum inhibitory concentration (MIC) _._._ *

Benzalkonium fluoride + F * (1 pg / ml)

Pseudomonas aeruginosa, CNCMA22 18 mg / l

Escherichia coli CNCM 54 127 3 mg / l

Staphylococcus aureus Oxford origin CNCM 54 154 1.1 mg / l

Streptococcus faecalis CNCM 5 855 3.6 mg / l

Mycobacterium smegmatis CNCM 7 326 26 mg / l DK 17 (: 716 B1 30 STAMMER Minimum inhibitory concentrator (MIC)

Nonoxynol 9 + F '(1 pg / ml) | '|

Pseudomonas aeruginosa, CNCM A 22 35 mg / l

Escherichia coli CNCM 54 127 6.5 mg / l

Staphylococcus aureus Oxford origin CNCM 54154 2.5 mg / l i

Streptococcus faecalis {CNCM 5 855 5.5 mg / l i

Mycobacterium smegmatis CNCM 7 326 50 mg / l i i i i j DK 173716 B1 31

III) APPLICATION OF THE INVENTION IN COSMETOLOGY

The preferred embodiments of the invention in cosmetology are described below: 5

The following galenic forms can be presented in cosmetology: Creams, milky preparations, pomades, solutions, foaming baths, synthetic soaps, shampoos, intimate lotions, disinfectant lotions.

The cosmetic products preferably contain 0.2% benzalkonium chloride and 0.1% fluoride anion F '(e.g. sodium fluoride).

In creams and milky preparations, the excipients are preferably distilled or purified water, wetting agents, emulsifiers, stabilizers, antioxidants, antiseptics (to be included in variable proportions according to the viscosity and pH to be achieved).

In pomades, the excipients are preferably distilled or purified water, emulsifier, excipients of the form constituted by fatty compositions (vaseline, lanolin, 20 lanovaseline, stearovaseline), stabilizers, antioxidants, antiseptics (to be included in variable proportions according to the viscosity and the pH to be achieved).

In solutions, the excipients are preferably distilled or purified water, ethanol, antioxidants, glycerol, sorbitol, antiseptics (to be included in variable proportions according to the viscosity and pH to be achieved).

In soaps, the excipients are preferably foaming and wetting products compatible with materials containing quaternary ammonium groups (e.g., amphoteric surfactants such as betaine or aminobetaine), plasticizers, stabilizers, antioxidants, antiseptics.

DK 1737113 B1 32

Chemically active ingredients or active ingredients of natural origin can also enter these prescriptions with concentrations and dosages allowed in cosmetology.

Creams and milky preparations can be in a continuous aqueous phase (oil / water or water / oil emulsion) or paste-like - and when hot * self-diluting in water.

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The various excipients referred to as examples correspond to e in 10 non-limiting and indicative ways to the following products:. Wetting agents: Glycerol, propylene glycol, diethylene glycol: o, glycol, sorbitol, polyoxyethylene glycol.

15 ·. Emulsifiers: Sodium stearate, beeswax, sorbitol esters, polyoxyethylene glycol ester, fatty alcohol, triethanolamine lanoil in, in tween, glycol stearate and polyglycols.

• Stabilizers. Glycol stearate, cetyl alginate alcohol, peclir, 20 polysaccharide rubbers, fatty esters of polyols, soluble 3 cellulose esters. | i • Antioxidants: Tartaric, citric and ascorbic acids.

· Antiseptics: Boric acid, benzoic acid, p-benzoic acid and their methyl or propyl esters, such as sodium salt or not. jj j • pH: All of these recipes are particularly effective with pH ranges between 4.5 and 6.5 To achieve such an area, 30 mainly citric acid is used.

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Claims (11)

A non-pharmaceutical composition, characterized in that it contains an effective amount of a surfactant suitable for inhibiting or destroying a single cell creature or virus, and an anti-enzymatic amount of a fluorine compound capable of delivering fluorine ions and which is suitable for inhibiting or destroying an enzyme associated with said unicellular creature or virus, whereby the amount of fluorine ions which can be released is 0.025-0.5% by weight and is used as a contraceptive, disinfectant or antiprotozoal agent. or in a cosmetic product. Composition according to claim 1, characterized in that the fluorine compound is a metal derivative of fluorine. 15 Composition according to claim 1 or 2, characterized in that the fluorine compound is sodium fluoride, calcium fluoride, potassium fluoride, aluminum fluoride, tin fluoride, ammonium fluoride or sodium monofluorophosphate. 20 Composition according to any one of the preceding claims, characterized in that the surfactant is a cationic surfactant. Composition according to any one of the preceding claims, characterized in that the surfactant is a quaternary ammonium. Composition according to any one of the preceding claims, characterized in that the surfactant is benzalkonium chloride. 30 Composition according to any one of claims 1-3, characterized in that the surfactant is an anionic surfactant. Composition according to any one of claims 1-3, characterized in that said surfactant is an amphoteric surfactant. * 5 Composition according to any one of claims 1-3, characterized in that in surfactant it is a nonionic surfactant. A composition according to any one of the preceding claims, characterized in that the surfactant is a sodium oxide salt of methyl tauride, an aimidoethyl glycinate derivative of a fatty acid, nonoxyno, phenylmercurin nitrate, para-methanylphenylpolyoxyethylene ether or a trisodium acid sulfuric acid salt of polysaccharide salt of polysaccharide salt. Composition according to any one of the preceding claims, characterized in that it contains 0.05-1% by weight of the surfactant compound. 20 i <i j i j