LU84282A1 - VIRULICIDAL PROCESS, COMPOSITION AND PRODUCT - Google Patents

Description

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The present invention relates to a class of virulicidal compositions highly effective against common respiratory viruses such as rhinoviruses, influenza viruses and adenoviruses. The invention also relates to the methods and products using these compositions. In particular, the invention relates to a new type of virulent composition which can be applied to various substrates such as cellulosic webs, nonwoven structures and textile-based materials. In addition, the virulicidal compositions of the class which is the subject of the invention can also be incorporated into nasal sprays, facial creams, hand lotions, lip pencils and similar cosmetic preparations. These compositions can also be used as ingredients in cleaning products for kitchens and bathrooms, polishes for furniture and floors and similar household preparations. Virologists specializing in the field of respiratory viruses generally agree that that rhinoviruses, influenza viruses * and adenoviruses are part of the most important group of pathogens causing respiratory disease. The rhinoviruses, in particular, are believed to be the main causative agent of what is commonly known as "common cold", The term "rhinovirus" implies the appearance of copious nasal discharge when infec-30 tions are caused by this group of viruses. Rhinoviruses belong to the family of pico-RNA viruses which, being deprived of an external envelope, are often called "naked viruses". Although more than 100 different types of rhinovirus antigens are known, they share some important <4 "3" characteristics. For example, they all have ether-resistant capsids and all contain single-stranded RNA (RNA = ribonucleic acid) (about 2.6-x 10 ^ daltons). It is also difficult to make them inactive by common germicides, such as quaternary ammonium compounds,

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Adenoviruses include more than 30 antigenic types. When they invade the respiratory tracts 5 "ratoires, they cause tissue inflammation, 10 leading to symptoms of pharyngitis, bronchitis, etc. Although most adenovirus infections occur in childhood, it is not uncommon for infections to appear in adults as well. Like the rhino-15 viruses, the adenoviruses do not have an envelope but, unlike the rhino-nucleus, the adeno-nucleus contains double-stranded DNA (DNA = deoxyribonucleic acid), Adenoviruses are rarely resistant to inactivation.

20 Influenza viruses belong to the paramyxovirus family. They play an important role in the development of diseases of the lower respiratory tract in children and diseases of the upper respiratory tract in adults.

25 Influenza viruses are RNA-containing viruses and have an ether-sensitive lipoprotein envelope surrounding the nucleocapsid.

These viruses resist inactivation by carboxylic acids in low concentrations, 30 The recent work of Dick et al. [Dick, E, C. and Chesney, P.J ,, "Textbook of Pediatrics Diseases", Feigin, R.D. and Cherry, J.D. ed., Volume II, page II67 (I98I) W.B. Saunders Pub. Co ,, Phila, PA] have considerably clarified the mode of transmission of respiratory diseases caused by rhinoviruses. Although the exact mode of transmission of respiratory tract diseases is not fully understood, practical studies by the above-mentioned researchers have clearly demonstrated that the effective transmission of diseases such as the common cold requires usual-

Furthermore, an intimate association or contact (direct or indirect) between the infected subject and the virtual victim. (Indirect contact can be considered as contact taking place via an intermediate surface, for example, a table top, a door knob, etc.). Therefore, the chain of infection can be interrupted and its spreading power reduced if the virus can be neutralized as soon as it leaves the nose or mouth of the infected person, by immediate exposure to a virulicidal agent. In addition, after their exit, the viruses which can nestle on the face or the hands of the infected person, can also be “killed” if an appropriate virulicide agent 20 · is brought quickly in contact with the appropriate anatomical surface, it i.e., face, hands, etc. A facial tissue containing an effective fast-acting virulicidal composition would be a simple means for performing the above-mentioned procedures.

For a long time, there has been a need to find a safe and inexpensive virulicidal agent in order to effectively combat common respiratory viruses. Simple household germicides are not effective against rhinoviruses and adenoviruses.

U.S. Patent No. 4,045,364 to Richter describes a disposable paper impregnated with an iodophore (i.e., iodine and a carrier) with germicidal properties * 5 and useful as a prewash agent according to a surgical purification routine. In this patent, it is stated that the stability of the iodophor is improved at a lower pH and that, to adjust the pH, small amounts of weak organic acids such as citric acid or acid can be added. acetic.

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In U.S. Patent No. 3,881,210, to the names of Drach et al., There is described a handkerchief pre-moistened for hygienic purposes and which may contain a bactericide. U.S. Patent No. 3,654,665, to the names of Bryant et al., Describes a hygienic scrubbing agent containing iodine having a bactericidal action. In U.S. Patent No. 3 * 567 * 118 to the names of Shepherd et al, a fibrous material for cleaning purposes is described comprising a coating of a hydrophilic acrylate or methacrylate containing, among other things, a bactericide.

Although in the prior art it has been stated that iodized compositions and products exert a broad spectrum virulicidal effect, an inexpensive product has not yet been developed on an industrial scale for discontinuing effectively spreading viruses such as rhi-novirus or influenza virus. The problems with iodine arise, for example, from its toxicity and the fact that it is an irritant to animal tissue. The action of iodine is non-selective, for example, between bacterial proteins and mammalian proteins, while its uncontrolled use on the skin can cause severe irritation. In addition, its activity can be reduced or neutralized by the action of biological fluids such as blood serum. - The efforts made to modify the iodine to avoid these difficulties have not been fully successful.

There are references in the literature relating to the bactericidal action of acids such as citric acid [eg Reid, James D ", 5" The Disinfectant Action of Certain Organic Acids ",

American Journal of Hygiene, 163 540-556 (1932)] · However, the virulicidal action is fundamentally different from the bactericidal action in the sense that viruses and bacteria represent different microorganisms with different characteristics different. For example, unlike bacteria, viruses do not reproduce host cells from the outside.

Quaternary ammonium compounds such as benzalkonium chloride are often effective against bacteria, but not against viruses such as the various rhinoviruses.

Although, as is known, rhinoviruses are labile towards aqueous solutions of acids under conditions of low pH [eg, Davis, BD et al. "Microbiology" page 1303, Harper E, Row (Publishers) New York, 1973 and Rueckert, R, R., "Picornaviràl Architecture" Comparative Virology - Academie Press, New York (1971)> pages 194-306], known references do not 25 mention of the use of this concept in epidemiological contexts such as the interruption of the chain of infection caused by rhinoviruses. To the best of the Applicant's current knowledge, the only systematic study of the virulicidal action of organic acids (citric acid, malic acid, etc.) which exists in the generally available literature has been carried out by Poli, Blondi, Uberti , Ponti, Balsari and Cantoni [Poli, G, et al,: "Viruci-dal Activity of Organic Acids" Food Chem, (Great Britain 35) 4 (4) 251-8 (1979)] · These researchers have 7 discovered that citric acid, malic acid, pyruvic acid and succinic acid, among others, were effective against the herpes virus, gold-thomyxovirus- and rhabdovirus (rabies virus) Their 5 experiments were carried out at room temperature with aqueous solutions of pure acids "

No substrate or support was used. The three viruses chosen for the studies carried out by these researchers were all "enveloped" viruses resembling, in this regard, the influenza virus 3 · Poli et al. also observed that these acids were not effective against the adenovirus which, it should be remembered, is a "naked" virus. Based on these observations, these researchers concluded that these acids were effective against "enveloped" viruses, but not against "naked" viruses.

Those skilled in the art know that adenoviruses are resistant to acids.

The present invention provides a virulicidal product, composition and method which are highly effective against a broad spectrum of viruses, which product and composition can be safely prepared and used. The invention results from the discovery that carboxylic acids such as citric acid, malic acid and succinic acid, when deployed in an appropriate and physiologically acceptable carrier, were effective not only against certain "enveloped" viruses. respiratory tract, but also against rhinovirus which is a "naked virus". In addition, in the presence of a surfactant such as sodium dodecyl sulfate, i3s are also effective against adenovirus · In addition, the products of the present invention may include a substrate such as - ** 35 facial tissue or nonwoven tablecloth containing

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* 8 compositions see this type. In the process of the invention, an effective amount of this composition is brought into contact with the affected area using these products ·, .. As a rule, these compositions · 5 can be handled without difficulty and it is believed that they have no harmful effect when they are used in accordance with the invention. In addition, when applied to a substrate such as a facial tissue, these compositions have little or no detrimental effect on color, odor, strength and other important properties. The products can be used as a dry handkerchief or kept wet, and they can be used, for example, as an impregnated handkerchief.

The invention will be described with reference to some of its preferred embodiments, but it is understood that it is in no way limited thereto.

On the contrary, it is understood that it encompasses all variants, modifications and equivalent embodiments which may fall within the spirit and the scope of the invention as defined in the claims below.

The present invention results from the following unexpected discovery: certain acids such as citric acid, malic acid, succinic acid and benzoic acid, used in appropriate concentrations and as described in more detail below, are highly effective against rhinoviruses Ιό, IA and 86. When used in the presence of a surfactant such as sodium dodecyl sulfate (SDS), these acids have been found to be also effective against the virus para-influenza 3 after adenovirus 5 · (The particular viruses chosen for the studies carried out, that is to say RV-16, RV-IA, 35 RV-86, para-3 and adeno-5 are representative viruses

There 9 * of their classes). In general, the water-soluble carboxylic acids useful according to the present invention have the following structure:

R-COOH

5 where R can represent a lower alkyl group (1 to 6 carbon atoms), a lower alkyl group substituted— [·, for example a hydroxy-lower alkyl group (for example, HOCH ^ -), a carboxy- lower alkyl (for example, HOOC-CH2-CH2—), a carboxy-hydroxy-lower alkyl group (for example; H00CCH2CH0H-) J a carboxy-halo-lower alkyl group (for example, HOOCCILjCHBr-) $ a carboxy-dihydroxy-lower alkyl group (for example, H00C-CHOH-CHOH-) i a dicarboxy -hydroxy-lower alkyl group (for example: OH - hooc-ch2c-ch2-), C00H __ a lower alkenyl group, a lower carboxy-alkenyl group (for example, H00CCH = CH-), a lower dicarboxy-alkenyl group (for example,

CO OH

H00C-CH2C = CH-), a phenyl group (for example, C ^ H ^ -), a substituted phenyl group (for example, a hydroxyphenyl group HO-C ^ H ^ -) · Among other acids, it there are, for example: 1 * lactic acid (hydroxy-lower alkyl acid); 1 2-methyl-malic acid (carboxy-hydroxy-lower alkyl acid); 2-chloro-3-methyl ~ succinic acid (carboxy-30 halo-lower alkyl acid); 2-methyl-tartaric acid (carboxy-dihydroxy-lower alkyl acid) to 2-methyl-citric acid (dicarboxy-hydroxy-lower alkyl acid) and fumaric acid (carboxy-lower alkenyl acid). The above definitions are used by way of illustration, but * 10 without any limiting character, the expression "substituted ^)" indicates that one or more hydrogen atoms is or are substituted by a or more halogen atoms (F, Cl, Br, I), hydroxy groups, -5 amino groups, thiol groups, nitro groups, cyano groups, etc.

The surfactant can be non-ionic (for example, polyoxyethylenated alkylphenols such as "TRITON X-100" (registered trademark), fa-10 shortened by "Rhom and Haas" $ polyoxyethylenated sorbitol esters such as " TWEEN 40 "(registered trademark), manufactured by" ICI United States, Inc · "), cationic (for example, cetylpyridium chloride (CcH_N + (CH9) 1 rCH-Cl" "),. Methyl chloride -0 ο z * 0 o 15 benzethonium

Me (Me3CCH2C (Me) 2-C6H3 (Me) -OCH2CH2OCH2-CH2NÎCH2C6H5 Cl “)

Me or anionic (e.g. sodium dodecyl sulfate (CH3 (CH2) 10-CH20S037-Na), ester 1,4-bis- (2-ethylhexylic), sodium salt of sulfo acid succinic, for example, that manufactured by "American Cyanamid Company" under the trade name "AEROSOL 0T". The preferred anionic surfactants can be represented by the following structures: 1. (roso3) xm + or (rso3) xm + where M + represents a cation of a monovalent, bivalent or trivalent metal or an ammonium or substituted ammonium ion; x is an integer 5 and R represents an alkyl group.

/ CH „C0„ R1 \, M + (I2 21) \ -03S-CHC02R2 / x where M + and x have the meanings defined above ^ 35 while R ^ and R2 can be identical or different and can * 11 represent straight or branched chain aliphatic groups. The above anionic surfactants are given by way of illustration rather than in a limiting sense. Generally, the surfactants alone are not virulicidal against naked viruses such as rhinovirus.

Although the invention is in no way limited to the use of a cellulosic web (for example, a facial tissue, a bathroom tissue, hand towels for toilets and other uses and the like) as a substrate or support for virulicidal agents, a facial tissue impregnated with these new virulicidal agents sufficiently illustrates the principle underlying the invention, of which it represents a simple and useful application.

For this reason, the experiments described below were carried out using facial tissue as a substrate. Examples of suitable nonwoven substrates are impregnated cleaning materials such as wet-crimped hand towels, as well as extrusion-bonded and melt-blown polymeric webs. There are usually used in the manufacture of disposable articles for hospitals such as surgical clothing, surgical gowns, bed sheets, pillows and the like * Textiles of all types, including laminates of different materials, may constitute suitable substrates. For example, hygienic face masks used by people suffering from respiratory diseases constitute an excellent means of implementing the present invention. Other physiologically acceptable and essentially inert carriers, ie those which are essentially "non-toxic and non-irritating to human or animal tissue under normal use conditions will be obvious to the skilled artisan. view of applications such as lotions, sprays, creams, varnishes and the like.

In general terms, the experimental procedure adopted for the preparation of the samples mentioned in the examples below was simple and straightforward. By simple immersion, we impregnated facial tissue 10 "KLEENEX" (registered trademark) with three plies (280 x 305 nun $ basic weight: about 12 kg / 268 m2 for the three plies combined) with aqueous solutions of * citric acid, malic acid, succinic acid and benzoic acid. The acids were used either individually or as homogeneous mixtures. Usually, the impregnation solution also contained a small percentage of a surfactant such as "Aerosol-OT" [sodium salt of the 1,4-bis- (2-ethylhexylic) ester of sulfo-20 acid. succinic, manufactured by "American Cyanamid"] or sodium dodecyl sulfate. In some cases, a small amount of glycerol has also been used to improve the flexibility of the tissue. Saturated fabrics were pressed between rollers in order to express the excess saturating agent and to ensure uniformity of saturation. The tissues were weighed, dried and the degree of saturation (i.e. the percentage of absorption of the saturating agent) was calculated. Then, the tissues were ready for the virulicidal efficacy test.

The method adopted for the virulicidal efficacy determination test is in accordance with conventional virological assay techniques (DICT ^ q = dos e ~ infecteuse ~ d-un-culture de fabric à 50%) with - 35 simple variations that requires the presence of the cellulosic substrate. A description of the process will be given below: VIRÜLICIDE I DOSING PROCESS, Materials -: 5 A, Solutions:

1, Neutralizing solution: 6.4 ml of NaoHP04 2M

v ï —2 4 1.2 ml of citric acid IM 92.4 ml of medium 199 IX (nutrient medium 10 'for tissue culture) 2, Hanks-McLean salt solution (HMSS): 2.0 ml d citric acid IM Dilution to 2 liters

18.0 ml of sterile Na2HP04 2M Ha ^ T

15 The pH of this solution is 7 * 3 # Hanks balanced salt solution: g / liter in double distillation water

NaCl 8.0 20 KC1 0.4

MgS04.7H20 0.2

CaCl2 (anhydrous) 0.14

Na „HP0., 2Ho0 0.00 2 · 4" KHoP0. (Anhydrous) 0.06 ^ 4 25 Glucose 1.0

Phenol red 0.005

NaHC03 0.35

Note: the above solutions are not virulicidal, 30 B, Virus and tissue culture cell lines: 1, Rhinovirus type 16, type IA and type 86:

Rhinovirus types 16, IA and 86 (RV 16,

IA and 86 respectively) are grown in HeLa (0-HeLa) tissue culture cells of Ohio state (E.U.A.) and are stored at -51 µl ° C

14 »» up to their use * The virulicidal test in which the rhinoviruses intervene is carried out using tissue culture test tubes 0 — HeLa incubated on a roller drum at 33 ° C * 5 2. Paraffin virus type 3: type 3 influenza virus (para 3) is elevated in rhesus monkey kidney tissue culture cells and is stored at -51.11 ° C until needed, The virulide assay the para 3 virus is ef-10 performed using de-HeLa tissue culture test tubes incubated in a fixed position at 33 ° C.

3 * Adenovirus type 5 ï L * adenovirus type 5 (adeno 5) is elevated in HEp-2 tissue culture cells and is stored at -51jll ° C until used, The virulicidal assay in which intervenes the adeno 5 * virus is carried out using tissue culture test tubes of human epithelium carcinoma - 2 (HEp-2), incubated in a fixed position at 37 ° C. II, Methods 20 A, Virulicidal test

A 1: 1 (volume / volume) mixture of virus and saliva is prepared. A 6.451 cm 2 sample of "KLEENEX" (registered trademark) fabric treated with Kimberly-Clark is cut and placed in a plastic Petri dish. (A treated fabric is a fabric impregnated with the virulicidal agent examined Using a pipette, 0.1 ml of the virus / saliva mixture is directly deposited on this sample and it is left to react for one minute. Note that this is a double dilution After a reaction time of one minute, by means of a pipette, 5 ml of neutralizing solution are deposited on the sample in the Petri dish and the mixture is stirred for three seconds.

35 is then a hundredfold dilution of virus. Using a pipette, the neutralizing solution / virus / saliva mixture is then removed from the Petri plate and added to a tube containing 5 ml of Hanks-Mcllvaine saline solution. add 5 1 * sample to the same tube by tilting the plate and using the tip of a pipette to introduce it into the tube. The tube containing the 10 ml of solutions and 11 sample is swirled for 30 seconds. This tube contains a 10 10 or 1; 200 dilution of virus. From the dilution ΙΟ "- ^ * ^, tenfold dilutions are formed in series (fresh pipette for each dilution) by taking 0.3 ml of the previous dilution. and by adding to 2.7 ml of Hanks-Mclvaine saline, 0.1 ml is inoculated into each tissue culture test tube. As a rule, two samples are inoculated by dilution.

For each experience, two groups of witnesses are used. The first is called "2 ° virus control" and it is intended to control the infectivity of the virus suspension itself without saliva or the tissue substrate. The virus suspension is subjected to a 10-fold serial dilution in Hanks-Mcllvaine saline. 0.1 ml of specific dilutions are inoculated by tissue culture cell test tube. The information obtained with this control gives the number of infectious viral units which are contained in the virus solution stored at -51.11 ° C and they confirm that the aliquot part 30 of the virus solution used during the experiment n * has not lost its infectivity during the freezing, preservation or thawing processes,

The second witness, to know the "fabric" indicator, is to carry out the viral test experiment.

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16 licid using 6.451 cm2 of untreated "KLEENEX" fabric. The information provided by this witness gives the number of infectious viral units which can be recovered from an untreated handkerchief in a 25.4 mm square after the virulicidal test process. inoculations are examined for 7 days to determine viral infection.

10 The end point of a virulicidal test for a given handkerchief is the dilution of virus which actually gives rise to an infection or which is calculated to infect only one of the two test tubes which have been inoculated. This number constitutes the infective dose of tissue culture (DICT ^ -q). The results of the virulicidal activity of a given handkerchief are usually indicated by the "log difference" between the common logarithm of the tissue. result of the DICT ^ q value of the treated sample, subtracted from the common logarithm of the DICT ^ q value of the untreated sample.

The virulicidal efficacy of a sample can be determined from the "log difference" as follows: 25 Virulicidal efficacy = (). $ 100 where X = initial concentration of virus (infectious units - ses / 0.1 ml) of the untreated sample used as a control.

30 Y = final concentration of virus (infectious units / 0.1 ml) of the treated sample.

The following examples explain the calculation method * (In the experiments, the final virus concentration was always less than or equal to 10> ύ infectious units / 0.1 ml). For the

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17 majority of the results, the final virus concentration was less than 10 3 which, with an initial virus concentration of 10 ^ l3, would mean a log difference greater than 4 and a -5 "mortality" greater than $ 99.99 · 1 * Initial concentration: X = 10 3 ° “- 2 3

Final concentration: Y = 10 3 °

Logarithmic difference = (log 10 ^ 3 3 - log 10 ^ 33) = 4 1 () 6.3 _ in2> 3 10 Virulicidal efficacy = (-r — r-) x $ 100 10 °> 3 = (10 * 3 ~ ^) x $ 100 10 ° 33 15 = $ 99.99.

"8 2. Initial concentration: X = 10 ^ 3 2 o

Final concentration: Y = 10 90 m

Logarithmic difference = 2.5 1q4> 8 ^ iq2.3 20 Virulicidal efficacy = (--— π-) x $ 100 104'8 = 99.7 #.

The process described above is in accordance with conventional microbiological assay techniques. It gives reliable and reproducible results within the limits of variability associated with biological experiments.

RESULTS

The results are shown in Tables 30 I, II and III. The data in Table I demonstrate that simple organic carboxylic acids such as 1 * citric acid, 1 * malic acid, 1 * tartaric acid, 1 * succinic acid and their substituted derivatives (e.g., - 1 * acid - 2- bromosuccinic), as well as benzoic acid and its substituted derivatives 9 18 (salicylic acid), used in facial tissue in appropriate concentrations, are highly virulent against rhinovirus 16 and paragrip-pal virus 3 · ' In addition, the data in Table I demonstrate that by using them in conjunction with a surfactant such as "Aerosol OT" or sodium dodecyl sulfate, the concentrations of acids in the facial tissue can be reduced without however alter 10 Virulicidal ineffectiveness.

Table XX gives the results of experiments carried out with mixtures of acids chosen from the group comprising 1 * citric acid, 1 * benzoic acid, 1 * succinic acid and 1 * malic acid. The data in this table demonstrate that the facial tissues treated with the mixtures of acids are virulicidal against rhinovirus 16 and the influenza virus 3 "The data in Table II also demonstrate that a facial tissue impregnated with a system of mixed acids such as 20 that citric acid and malic acid, as well as with a suitable surfactant such as sodium dodecyl sulfate, is effective against rhinovirus 16, IA and 86, as well as against adenqvirus 5 demonstrate these examples, according to the present inven-tion, when * used in conjunction with a suitable surfactant such as sodium dodecyl sulfate, simple organic acids such as 1 * citric acid / malic acid / acid succinics Are highly virulicidal against common respiratory tract viruses including rhinoviruses 16, IA and 86, influenza virus 3 and adenovirus 5 are specific examples * In addition, products in which tissue f acials as a means of deploying the mentioned virulicidal compositions are highly effective *; 19 »» The importance of the invention lies in the fact that it provides the basis for interrupting the chain of infection caused by respiratory tract viruses. # Since the viruses do not reproduce host cells outside, the degree of inactivation demonstrated by those experienced - y 'ces, is a simple and practical way to reduce the concentration of viruses in the vicinity of a person infected with a respiratory tract virus, 10 which, in turn, significantly reduces the potential for spread infection.

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In order to more specifically illustrate the best effects obtained in accordance with the invention, additional examples were carried out by varying the concentration of the chosen acid compositions and by measuring the virulicidal activity after one and five minutes. The results are shown in Table IV. As a general rule, the acid compositions within the scope of the invention exert a virulicidal effect to a high degree; for example, in the case of rhinoviruses or influenza viruses, they produce an inactivation corresponding to a log difference of 2 or more, in one minute or less. For adenoviruses, this inactivation time will be 5 minutes or less. As a general rule, the degree of inactivation is greater after 5 minutes than after 1 minute as might be expected. Some minor contradictions appear in the results mentioned due to the margin of error and the nature of the test procedure. Those skilled in the art will understand that the effectiveness is also influenced by the amount of the composition available for contact with the virus, this amount depending, in turn, on the nature of the support.

For example, as shown in Table IV below, a relatively thick support with large voids, for example wool, may be ineffective if it is not treated with large amounts of the composition * Other on the other hand, a light and relatively closed structure such as a fabric or nonwoven material will require a smaller amount of the composition. However, on the basis of the tests described, the effectiveness of a given combination of the composition and the support can be determined.

For example, as shown in Table IV, citric acid is effective at concentrations of S at 10% 24 (in addition). The process adopted is described below.

For these examples, the results relating to the DXCT ^ q value were obtained using WÎ-38 cells with low passage from the laboratories 5 "Flow Laboratories, Inc." which were initially passed at least once to ensure growth potential. The flasks were divided in a 1: 2 ratio and seeded into 96 tissue culture plates grouped into 10 shaped housings wells having a flat base growth area of 0.32 cm2, these plates being supplied by "MA Bioproducts ". The cells were incubated at 37 ° C under a 5% CO2 atmosphere and, after 24 hours, they were placed in a carpet at 80-90 $ in the usual way, their appearance being normal before 1 * use during the assay. The medium (2% MM), used for the two dilutions and the maintenance of the cells was the "MEM EaglesM with" Earles BSS "medium (with the addition of glutamine, gentamycin and 20. fetal serum from 2% calf). Rhinovirus IA was supplied by the National Institute of Allergy · and Infectious Diseases, Bethesda, Maryland, E.U.A. A vial was grown in "WI-38" cells and harvested after observing a cytopathic effect of 4 days 2 after inoculation. The virus was harvested and formed into aliquots which were then frozen at -70 ° C for subsequent titration in WI-38 cells in 96 plates grouped into housings.

For the assay, the medium was removed from the plates by placing a sterile gauze between each plate and the cover and inverting the plate. All the six housings used received 0.1 ml of 35 mm 2%. To the housings to be used as cell controls, another fraction of was added. 0.1 ml of 2% MM% To cells that should have. to receive the compounds, 0.1 ml was added to each of the six housings. .the appropriate dilution of material *.

For the initial dilution, the strain virus was mixed in the ratio of 1: 2 with MM at 2% m. 100 micromiliter of this virus dilution was then added to a treated disc in a Petri dish. The virus was uniformly applied to a tissue disc using a microliter syringe. The virus was left on the disc for one or five minutes, then 5 ml of 2% MM was added to the disc. found in the Petri dish and this disc was subjected to slight agitation. The disc and the solution were removed, they were placed in a sterile tube and they were agitated by giving them a vortex movement for 30 seconds, which represents m the first dilution * From the initial tube, three tenfold dilutions were formed and 0.1 ml of the four dilutions were added to nWI-38n cells arranged in a single layer. Six ‘slots were used for each dilution. Untreated controls were tested at one and five minutes, with and without virus, and virus titration was also performed with each assay. Plates were reincubated at 37 ° C in a CO2 atmosphere. at 5% for the duration of the test.

Acids such as sulfamic acid and phosphoric acid have also been found to be virulicidal. However, it has been found that these acids degrade supports such as tissue.

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Since these acids are soluble in water, they can be applied very easily in aqueous solutions on many substrates by immersion coating or other conventional means 5 such as spraying or gravure printing. When the composition is applied to the substrates, it must be used in an amount sufficient to exert the virulicidal activity defined in this specification * Specification # Although the lower effective limit of acids has not been precisely determined , as a general rule, for a substance such as a facial tissue having a basis weight in the range of 10.41 to 14.04 kg / 268 m2 (three plies), one must have an absorption of at least minus about 2% and preferably about 5% of acids such as citric acid, calculated on a dry basis # Other substrates such as non-woven materials can also be used #

With regard to other substrates, preference is given to those having a high impregnation ability. As indicated, it is believed that the weak virulicidal effect obtained with substrates such as wool is due to The inability of the virulicidal composition to penetrate into the substrate # 25 When mixtures of acids are used, these can be in any proportion but, preferably, the mixtures contain at least about 0.2 to $ 10 of each acid, calculated on the weight of the substrate after drying # 30 When surfactants are used, these are preferably chosen from the group of anionic surfactants and their quantity is between about 0.05 and 5 $ * calculated on the weight of the substrate after drying # »31 r

When applying the organic acids with virulicidal activity defined in this specification in other substrates or carriers such as lotions, mouthwashes, creams, sprays, varnishes and the like, the effective amount of the point of Virulicidal view can be readily determined by applying the methods described in this specification. For example, a log difference of 2 or more would mean that 99% or more of the host viruses are made inactive on contact with the antiviral acid compositions. described and claimed in this specification * It is therefore evident that the present invention provides a virulicidal product which, under conditions of normal use, fully achieves the objects and advantages set out above *

Although the invention has been described with reference to some of its specific embodiments, it is evident that many variations, modifications and variations will become apparent to the skilled person upon reading the description below. above * Consequently, it is understood that the invention encompasses these variants, modifications and variations coming within the spirit and the scope of the claims 25 below *

Claims (21)

1 · A method for interrupting or preventing the spread of respiratory tract viruses, characterized in that it consists in bringing a · 5 area containing viruses in contact with a composition with virulicidal activity in an effective amount of the point of virulicidal view, this composition comprising one or more virulicidal acids which are essentially non-toxic and non-irritant for human or animal tissues, each of these acids having the following structure: R-CO OH where. R is selected from the group comprising a lower alkyl group; a substituted sub-15 · alkyl group; a carboxy-lower alkyl group; a carboxy-hydroxy-lower alkyl group; a carboxy-halo-lower alkyl group; a carboxy-dihydroxy-lower alkyl group; a dicarboxy-hydroxy-lower alkyl group; a lower alkenyl group; a carboxy-lower alkenyl group; a dicarboxy-lower alkenyl group; a phenyl group and a substituted phenyl group, 2, Process according to claim 1, characterized in that these compositions also include a surfactant chosen from the group comprising nonionic, cationic and anionic surfactants, 3 * Process according to any one of the Claims 1 and 2, characterized in that the acid 30 is chosen from the group comprising citric acid, malic acid, succinic acid, benzoic acid and their substituted derivatives, as well as mixtures of two of these or more acids, 4 · Process -depending on claim._3, charac- terized in that the surfactant is chosen "" from the group comprising polyoxyethylenated alkyl phenols, esters of polyoxyethylenated sorbitol, quaternary ammonium salts or the ester salts of 1 * sulfuric acid and the ester salts of 1 * sul-fo-5 succinic acid having the following structure: / CHC09R1V · h / j λ (RS03) M + or (R0S03) xM +, or \; - 03S-CHC02R2yχ 1 ° where. M * represents a cation of a monovalent, bivalent or trivalent metal, or an ammonium or substituted ammonium ion, x is an integer; and R represents an alkyl group, while R ^ and R2 represent aliphatic groups with a straight or branched chain, identical or different · 5 · Process according to claim 3? characterized in that the surfactant is selected from the group comprising the sodium salt of the 1,4-bis- (2 ~ ethylhexylic) ester of sulfosuccinic acid 20 and sodium dodecyl sulfate. 6. Method according to claim 3, characterized in that the acid is a mixture of citric acid and malic acid. . 7 "Process according to claim 3? ca-25 characterized in that the acid is a mixture of citric acid and benzoic acid, 8. Method according to claim 3 * characterized in that the acid is a mixture of citric acid and succinic acid. 9. The process as claimed in claim 3, 3 ca characterized in that the acid is a mixture of malic acid and benzoic acid. 10, A method according to claim 33 characterized in that the acid is a mixture of malic acid and succinic acid. 11 · Process according to claim 3, characterized in that 1 * acid is a mixture of succinic acid and 1 * benzoic acid. 12, ... A virulicidal composition comprising a physiologically acceptable carrier containing, in a virulicidally effective amount, one or more acids which are non-toxic and non-irritant to human or animal tissue in quantity; 'tity used, each of these acids having the following structure: R-C00H where. R is selected from the group comprising a lower alkyl group 3 a lower alkyl group substituted by a carboxy-lower alkyl group 3 a carboxy-hydroxy-lower alkyl group; a carboxy-halo-lower alkyl group a carboxy-dihydroxy-lower alkyl group; a dicarboxy-hydroxy-lower alkyl * group; a lower alkenyl group 3 a carboxy-lower alkenyl group 3 a dicarboxy-lower alkenyl group 3 as well as a phenyl group and substituted phenyl group. 13. Composition according to claim 12, characterized in that it also contains wine surfactant chosen from the group comprising nonionic, cationic and anionic surfactants, 14. Composition according to claim 12, characterized in that the acid is chosen from the group comprising citric acid, malic acid, succinic acid, benzoic acid and their substituted derivatives, as well as mixtures of any of these acids. 15. Composition according to any one of claims 12 and 13, characterized in that - the surfactant is chosen from the group consisting of polyoxyethylenated alkyl phenols, polyoxyethylenated sorbitol esters, salts of quaternary ammonium, the ester salts of sulfuric acid, the salts of alkyl sulfonic acids and the ester salts of sulfo-succinic acid having the following structures: *. ', ch9co9riX M + r I) (RS03) M +, .or (R0S03) x M +, or \ -O ^ -CHCO ^ / χ 10 where M represents a cation of a monovalent metal, bivalent or trivalent, an ammonium ion or a substituted ammonium ion ix is an integer 5 and R is an alkyl group, while R ^ and R2 represent aliphatic groups, straight or branched, identical or different · 16 ·. Composition according to Claim 159, characterized in that the surfactant is chosen from the group comprising the sodium salt of the 1,4-bis- (2-ethylhexylic) ester of sulfosuccinic acid and the dodecyl- sodium sulfate, r 17 · Composition according to Claim 14, characterized in that the acid is a mixture of citric acid and malic acid · 25 '18. Composition according to Claim 14, characterized in that l acid is a mixture of citric acid and benzoic acid, 19 * Composition according to claim H, characterized in that the acid is a mixture of citric acid and succinic acid, 20 · Composition according to Claim 14, characterized in that the acid is a mixture of malic acid and benzoic acid, 21. JComposition according to claim 35 14, characterized in that the acid is a mixture of »P 1 * malic acid and 1 * succinic acid · 22. Composition according to Claim 14, characterized in that 1 * acid is a mixture of 1 * succinic acid and 1 * benzoi * acid. 5 23, Virulicidal product comprising a web substrate containing, in a virulicidally effective amount, a composition comprising one or more acids which are non-toxic and non-irritant to human or animal tissue in the amount used, each of these acids having the following structure: R-C00H where R is chosen from the group comprising a lower alkyl group; a lower alkyl group substituted by a carboxy-lower alkyl group 5 a carboxy-hydroxy-lower alkyl group 5 a carboxy-halo-lower alkyl group; carboxy-dihydroxy- * lower alkyl; a dicarboxy-hydroxy-lower alkyl group; a lower alkenyl group; a carboxy-lower alkenyl group; 5 a dicarboxy-, lower alkenyl group; as well as a phenyl group and a substituted phenyl group * 24. Product according to claim 23, characterized in that this composition also includes a surfactant chosen from the group comprising nonionic, cationic and anionic surfactants. 25. Product according to any one of claims 23 and 24, characterized in that the substrate is chosen from the group comprising cellulosic fabrics, non-woven fabrics and textile materials. 26. Product according to claim 25, characterized in that the acid is chosen from the group comprising citric acid, succinic acid, benzene and their substituted derivatives, same as mixtures of any of these acids, this acid being present in an amount of about 2% or more, calculated on the weight of the substrate. ’5 27 · Product according to claim 25, characterized in that the substrate is a facial tissue * 4 * - cellulosic. - 28. Product according to claim 25,; characterized in that the surfactant is selected from the group consisting of polyoxyethylenated alkyl phenols, polyoxyethene sorbitol esters, quaternary ammonium salts, ester salts of sulfuric acid, salts of * alkyl sulfonic acids, the ester salts of sulfosuceinic acid having the following structures: f2C02Rl \ (RS03) M, or (R0S03) x M, or (j V- ° 3S-CHC02R2 A 20 '· O- ^ j · where M represents a cation of a monovalent metal, ivalent bivalent or trivalent ·, an ammonium ion or a substituted ammonium ion $ x is an integer $ and R is an alkyl group, while R ^ and R2 25 represent aliphatic groups with straight or branched chain, identical or different. 29. Product according to claim 25, characterized in that the surfactant is chosen from the group comprising the sodium salt of ester 1,4-bis- (2-ethylhexyl) of 1 *. sulfosuccinic acid and sodium dodecyl sulfate. 30. Product according to claim 25, characterized in that the acid is a mixture of citric lucid and maleic acid. i 31 · Product according to claim 25, characterized in that 11 acid is a mixture of 11 citric acid and 11 benzoic acid · 32 ».. Product according to claim 25, 5 characterized in that 11 acid is a mixture of 11 citric acid and 11 succinic acid1 - 33 · Product according to claim 25, j; characterized in that 11acid is a mixture of 11ac from malic and 11benzoic acid. 10 · 34. Product according to claim 25, characterized in that the acid is a mixture of malic acid and succinic acid. 35. Product according to claim 25, characterized in that the acid is a mixture of succinic acid and benzoic acid.