Packaged antibacterial antiplaque oral composition

The present invention relates to oral compositions, effective against dental plaque, packaged, which contain an anti-bacterial anti-plaque agent such as 2 ', 4,4'-trichloro5 2-hydroxy (diphenyl ether) (THED) as anti-plaque component. active, which compositions are packaged in a container which comprises a polymeric plastic material which is in contact with the composition for oral use, this plastic material being compatible with the antibacterial agent of the composition. Although various plastics can reduce the anti-plaque activity of the antibacterial agents mentioned, some plastics, such as polyfluoroethylene and polyvinyl chloride, have been found to be compatible with THED and have been found to cause no loss excessive antibacterial and antiplaque activity of compositions for oral use packaged during storage at room temperature or at high temperatures. Even if the part or parts of plastic material in contact with the container consist of plastic materials which are not in themselves fully compatible with the antibacterial compound, the compatibility can be improved by incorporating into the composition for oral use a proportion with stabilizing effect an agent for stabilizing the antibacterial compound, such as a terpene, for example limonene, or an essential oil (natural or synthetic) which may be present in a flavoring component of this stabilizing agent is sufficient so that the as packaged and positions for oral use, present in a proportion composition for oral use, distributed, is an effective antiplaque composition the production of which constitutes an object of the present invention. The invention includes a method of contacting the surfaces of the oral cavity with compositions for oral use containing effective proportions of antiplaque agent. The invention also includes a toothbrush whose bristles carry an effective proportion of an antiplaque toothpaste.

Dental plaque is considered a factor responsible for negative periodontal states, and dental plaque is a precursor to tartar, plaque can form on any part of the surface of the teeth, including the gingival margin. It gives the teeth a dull appearance and, in addition to the fact that it promotes the development of tartar, it has been implicated in the appearance of gingivitis. Therefore, compositions for oral use which contain antiplaque components preventing or inhibiting the development of dental plaque on the teeth are valuable auxiliaries of oral hygiene.

Although it has been recognized that antimicrobial agents contained in compositions for oral use can reduce plaque, sometimes being particularly effective in combination with other substances, some of these antibacterial compounds have disadvantageous properties which militate against their use in such compositions for oral use. For example, cationic antibacterial compounds, such as quaternary ammonium halides, tend to alter the color of the teeth and can be inactivated by the presence of anionic materials in preparations for oral use (and it is often desirable to d '' use anionic surfactants or detergents in compositions for oral use).

Halogenated (and often hydroxylated) diphenyl ethers essentially insoluble in water, such as THEO (Triclosan) and 2,2'-dihydroxy-5,5'-dibromo (diphenyl ether) (DDED), are agents effective anti-plaque antibacterials, but they can be inactivated by nonionic surfactants and by numerous plastics, as has been discovered by the Applicant. Thus, an object of the present invention has been to incorporate anti-bacterial anti-plaque agents, such as halogenated diphenyl ethers, in particular THED and DDED, and similar anti-plaque agents, in compositions for oral use, and to preserve these compositions. in packages or containers, and distribute them from these packages or containers, in which they do not lose an excessive part of the activity of this antibacterial agent during storage, before final use. In the prior art Triclosan toothpastes, as delivered by the distributor, the supply of Triclosan was not carried out in an amount effective to significantly reduce the plaque when they were used once or twice a day for good reason. 1.5 g / application with brushing for one minute, which is considered to correspond substantially to normal brushing practice. To be effective, these applications must result in a decrease of at least 25% in plaque after three weeks of use, compared to three weeks of similar use of a control toothpaste.

The most popular anti-bacterial anti-plaque component of the conditioned oral use compositions of the invention is THED, which is also known by the name of Triclosan. This compound is proposed in US Pat. No. 4,022,880 as an antibacterial agent in combination with a scale inhibitor (which provides zinc ions) and in the FRA patent application DE-OS-3,532,860 in association with a copper compound. It is also proposed in European patent applications No. 0 161 898 and 0 161 899 and, in European patent application No. 0 220 890, it is proposed in toothpastes in combination with polyethylene glycol and a flavoring substance based on essential oil.

Various compositions are known for oral use or dental preparations, including toothpastes in paste, gel, powder, liquid, tablet, pas tille, sachet and packaged, mouthwashes liquid and in tablets; and dental treatment agents applied in professional use (such as tooth hardening compositions, for example fluoride solutions). These products have been packaged in deformable tubes, pump dispensers, pressure dispensers, packages, vials, jars and other containers. Although deformable or compressible tubes were originally made of metals such as lead and aluminum and the vials were made of glass, these containers have often, in recent years, been made of synthetic organic polymer plastics or laminates comprising such plastics. Interactions between compositions for oral use and the materials of the containers in which they are packaged have already been known, for example reactions between toothpastes and aluminum containers and, to prevent such reactions, the containers have been specially treated where different container materials have been used. However, the Applicant does not believe that before the present invention, it was known in the prior art that certain plastic packaging materials could adversely affect the antiplaque activity of antibacterial compounds of the halogenated diphenyl ether type which have been incorporated. in compositions for oral use and packaged in containers in which they come into contact with these plastics, nor does she think that it has been discovered that certain plastics can be used for such parts of containers without causing losses of anti-plate activity of halogenated diphenyl ethers or losses of such activity of the compositions for oral use conditioned in contact with reactive plastics (which react with ·, the composition for oral use by absorbing or otherwise reducing the antiplaque activity of this composition) can be inhibited or avoided by the incorporation into the compositions of terpenes such as limonene, and other flavoring components for preparations for oral use.

In certain aspects, the present invention relates to a composition for oral use containing an effective proportion against dental plaque of a non-cationic antibacterial agent substantially insoluble in water when it is dispensed, which is packaged in a dispensing container comprising a solid polymer material such as a synthetic organic polymer plastic, in contact with the composition for oral use, which solid polymeric material is compatible with the antibacterial agent in the presence of the composition for oral use and does not cause excessive loss of the antibacterial and antiplaque activities of the composition for oral use during storage in the container (for example at temperatures of 20 to 40 ° C for several weeks, preferably up to a year or more). The composition for packaged oral use is usually a toothpaste, a toothpaste gel or a mouthwash, respectively contained in a deformable dispensing tube, a pump dispenser or a bottle, not comprising plastic parts which adversely affect the the antiplaque action of the antibacterial agent (which is preferably a halogenated diphenyl ether, such as Triclosan), or else the composition for oral use contains a component which inhibits or prevents such a harmful reaction between the antibacterial agent and any plastic element of the container which could, otherwise, adversely affect the antiplaque action of the composition.

The invention will be better understood with reference to the appended drawings in which:

Figure 1 is a perspective view of a tube of toothpaste and its cap removed, the toothpaste having been delivered on a brush by compression of the tube;

Figure 2 is a partial section on an enlarged scale of a laminated wall of a compressible tube similar to that of Figure 1:

Figure 3 is a vertical section of a pump dispenser used to contain and deliver toothpaste or toothpaste gel, as desired;

Figure 4 is a side elevational view of a heat sealed sachet or pouch containing a single use dose of a toothpaste; and Figure 5 is an elevational view of a mouthwash bottle capped with a cap.

In FIG. 1, an article 11 of conditioned antiplaque toothpaste comprises a deformable tube 13 of toothpaste which contains an antiplaque toothpaste 15, shown delivered in a unit quantity, for example about 0.8 to 2 grams, by compression of the tube on a brush 17. The tube 13 is opaque and made of a synthetic organic polymer plastic material, for example polyfluoroethylene, or it is coated internally, as in a laminate, with such a material which does not adversely affect the antiplaque activity of the dough toothpaste during storage. Alternatively, the tube 13 may be made of or coated internally with a plastic material which has been found to adversely affect the antiplaque activity of the toothpaste (by reducing the antiplaque action of the halogenated diphenyl ether which is a component antibacterial and antiplaque of toothpaste), but, in this case, the harmful effect on the antiplaque activity is prevented or inhibited by the presence, in the toothpaste, of a stabilizing agent which can be a terpene, for example limonene, or other flavor components. Preferably, neither the toothpaste tube, nor its cap 19, nor any other part of the tube which may come into contact with the toothpaste (for example an inner coating of the cap) should consist of a co-polyester / polyether elastomer or other plastic material which significantly reduces the antiplaque activity of the preparation for oral use, even in the presence of a stabilizer of the antiplaque component. It is also considered advantageous to avoid the presence of other elastomers such as isobutadienes, polychloroprenes, butadiene rubbers and nitrile rubbers, which could react with or absorb THED. Advantageously, these parts are made of plastics which do not adversely affect the antiplaque activity, even in the absence of terpenes or other stabilizing agents contained in the toothpaste, but these other destabilizing plastics can be used if such a stabilizer is present in the toothpaste to counteract the inactivation effect of the plastic (but it is however preferable to avoid the copolyester / polyether elastomers and other harmful elastomers) .

Figure 2 shows a laminate consisting of a polyfluoroethylene film 21, an aluminum foil 23 and a polyethylene film 25, the polyfluoroethylene being placed on the inside of the wall of the tube where it comes into contact with toothpaste. The inner lining, not shown, of the cap 19 of FIG. 1 can also consist of polyfluoroethylene, so that all the surfaces which are in contact with the toothpaste during storage are compatible with the halogenated diphenyl ether which is the antibacterial component. of toothpaste and do not cause excessive loss of its antiplaque activity during storage. The inner wall 21 of the laminate, instead of being made of polyfluoroethylene, can be made of polyethylene and the wall 25 can be made of polyethylene or other suitable polymer.

In Figure 3 / the pump dispenser for toothpaste is of a type marketed by Guala SpA, Italy, which is the subject of US Patent No. 4,776,496. The pump dispenser 27, when it is ready to use, contains a toothpaste in a compartment 29 which is defined by a bottom wall 31 and a membrane 33. The lowering of the actuating lever 35 causes a downward movement of the membrane 33, by pushing the toothpaste through a conduit 37 and ejecting it by a spout 39. When the pressure exerted on the actuating lever 35 is released , the membrane 33, which is elastic, returns to its original configuration and returns the conduit 37 and the lever 35 to their initial positions. At the same time, the bottom 31 is pushed upward by atmospheric pressure. The various internal parts of the pump dispenser, which come into contact with the toothpaste, are preferably made of one or more plastics which do not inactivate the halogenated diphenyl ether used as an antibacterial and antiplaque agent. However, if it is not possible to use plastics which have the physical properties necessary to constitute the various parts in contact and which are however compatible with the antiplaque agent, other plastics may be used, as long as the toothpaste (or tooth gel) composition contains a stabilizing substance such as limonene or other terpene or flavor component effective for this purpose. However, it is considered that the best is to avoid the use of all co-polyester / polyether elastomers, in particular to form the pumping membrane (33), since these plastics prove to be particularly active against THED in the compositions for use. buccal of the types described.

FIG. 4 represents a sachet, pocket or package 41 in the form of a heat-sealed element on three of its sides, represented by the reference numbers 43 and 45. The fourth side 47 is simply folded back on itself and does not does not need to be heat sealed. Inside the sealed package is a composition for oral use such as a toothpaste (not shown), and the inner surface of this sachet is made of a plastic material which does not cause excessive loss of antiplaque activity of the antibacterial compound of the composition for oral use contained. As with the other containers for anti-plaque compositions for oral use, laminates can be used, the interior of which is formed by a layer of plastic material which does not adversely affect the antibacterial agent, or, when the plastic material exerts such a harmful effect, it can be counteracted by the presence, in the composition for oral use, of a suitable stabilizer, which is preferably also useful as a flavoring agent for this composition.

FIG. 5 represents an opaque bottle 49 comprising a tight closure cap 51. The bottle and the inner seal (not shown) of the cap are both made of plastics which are compatible with THED which is the antiplaque component of mouthwash 53 contained in the bottle. As in the other examples given, when a reactive plastic material is used as material for the internal part of the bottle or the cap seal, the mouthwash contains an appropriate stabilizer to prevent excessive loss of antiplaque activity of THED or other halogenated diphenyl ether.

In addition to the compositions the presence of which has been indicated in the packages shown, which include tooth gels and thick liquids in place of toothpastes, it is also possible to incorporate in these packages dental treatment compositions suitable for professional use, such as dental hardeners, which may contain fluorides and phosphates, compositions of antibacterial agents, plaque indicator dye solutions and other suitable oral compositions. Likewise, compositions under pressure or for aerosol, containing the mentioned antiplaque compounds can be packaged in containers under pressure (generally pressurized with nitrogen gas) provided that the plastic parts, in contact with the composition, of these containers consist of materials which do not cause excessive loss of the antiplaque properties of the antiplaque agent of toothpastes or other compositions for oral use.

In addition to the various containers shown in the drawings and mentioned above, it is also possible to use collapsible bottles, capsules, jars, spongy media and various types of mechanical dispensing containers. Since certain antibacterial compounds of the halogenated diphenyl ether type are photosensitive, it is sometimes advantageous for these containers to be made, coated or laminated with a chemical or physical light-filtering material, many of which are known, in order to prevent transmission. the composition for oral use and the antiplaque compound of any inactivating radiation, for example ultraviolet light. Likewise, these containers are often advantageously opaque in order to prevent the inactivation by such actinic radiation of the antiplaque component of the preparation for oral use which they contain, for example a toothpaste.

The cause or causes of the inactivation by plastics of THED and other substantially non-cationic antibacterial agents endowed with antiplaque properties in compositions for oral use have not yet been established. Research to date has not yet pinpointed the mechanism responsible for the loss of this beneficial activity, and results to date have not conclusively identified chemical reactions or physical absorption. Tests carried out on basic mouthwash formulations containing THED show that when such a mouthwash is aged in dispensing containers at room temperature, at 38 ° C and 49 ° C, for a period up to twelve weeks, excessive losses occur (more than 25% of the initial concentration of THED) when the mouthwash has been brought into contact with walls and container parts made of low density polyethylenes, high density polyethylenes, polyethylene terephthalates, polypropylenes, nylon polyamides, polyallomers and polymethylpentenes. Similarly, high losses occur when this preservation takes place in containers whose walls or internal parts are formed from co-polyester / polyether elastomers, such as those which were previously used in Guala pump membranes. . It has been found that polyfluoroethylenes such as polytetrafluoroethylenes, polyvinyl chlorides, polycarbonates and polysulfones do not absorb, or react with, excessive amounts of THED. However, polycarbonates and polysulfones are fragile, and are therefore often unsuitable for use as elements of dispensing containers. Polyvinyl chlorides sometimes impart a taste foreign to compositions for oral use, such as toothpaste, and therefore they must often be avoided as a container material, except in certain cases where this taste is compatible with that of the flavoring. used in toothpaste. Thus, among all the polymeric plastic materials available, polyfluoroethylene is especially identified as a material usable in the present containers or packaging, which does not severely reduce the antiplaque activity of the antiplaque agents. However, as indicated previously, by incorporating in the compositions for oral use stabilizing compounds for antiplaque agents, such as terpenes, of which limonene is a representative example, essential oils (which often contain terpenes), and other flavoring components with similar stabilizing properties, it is able to reduce the losses of activity of the antiplaque agents when they are brought into contact with containers or parts of receptacles made up of the various polymeric plastics mentioned with which excessive losses of antiplaque activity occur. Consequently, polyfluoroethylene is not limited as a dispensing container material, provided that the composition for oral use also contains a stabilizing proportion of terpene or other suitable stabilizer. When such a stabilizer is present in compositions for oral use or when polyfluoroethylene (or polyvinyl chloride, a polycarbonate or a polysulfone) is the only polymer plastic material in contact with the composition for oral use, the activity losses anti-plate on storage are less than 25%, and preferably less than 10%, even after storage between room temperature and a relatively high temperature, for example from 20 to 40 ° C, for periods of time of several weeks up to a year or more. It is considered that the most stable compositions for oral use are those which contain a proportion with stabilizing effect of terpene or other suitable stabilizer and which are only brought into contact with container parts made of polyfluoroethylene (or any one other non-reactive plastics). Although terpenes and essential oils are the main stabilizers according to the present invention, other flavoring components can also contribute to the stabilization of the antiplaque agent, either by hindering any destabilizing reaction, or by inhibiting the absorption of the diphenyl ether halogenated by plastic (or some other unknown mechanism). Thus, a theory has been advanced according to which certain components of the compositions for oral use, which tend to dissolve THED, can act so as to maintain it in the composition and to inhibit or prevent its migration into the plastic material. On the other hand, a theory has also been advanced according to which such a solubilizing action could favor the migration of THED solubilized in the plastic material. Since the question has not yet been resolved, the Applicant does not stick to any theory. Likewise, although it is advantageous that the terpenes and other stabilizers are flavoring components, this is not essential, and the stabilizers may be useful only for stabilization purposes.

Although it is preferable that the packages of the present invention have internal walls (in contact with the compositions) made of or coated with a solid synthetic organic polymeric plastic material, the invention includes the use of other solid polymeric materials (and / or film-forming), whether or not synthetic, organic or even plastic. Thus, one can use polyethylene glycols and methoxypolyethylene glycols, such as those of mouth toothpaste. Toothpaste a mouthwash. The main groups of polishing material and (R) type Carbowax, for example Carbowax 4000 and Carbowax 6000 / often as materials for the internal coating of dispensing containers of the compositions described. Inorganic silicon polymers, such as silo xanes, and non-synthetic organic film-forming materials such as gums, for example carrageenan, gum tragacanth, karaya gum, are also useful as interior coatings for dispensers. In addition, solid polymeric materials such as cellulose and starch, and their derivatives, are also useful as container materials in contact with the antibacterial and antiplaque components contained in the present packaged oral compositions.

The various most often prepared forms of the packaged compositions for oral use of the present invention are toothpastes, gels and washing or rinsing baths of the first two will be called dentifrices here and the last will generally be called dentifrices contain three components, the vehicle, the surfactant (or detergent). The antibacterial agent, for example halogenated diphenyl ether, is normally present in the vehicle, which vehicle generally constitutes about 10 to 80% (all numerical values ​​are expressed on the basis of the final composition) of the toothpaste. The vehicle consists of approximately 3 to 40% water, approximately

7 77% of a humectant, such as glycerol, sorbitol, propylene glycol or mixtures thereof, and 0.5 to 10% of a gelling agent such as sodium carboxymethylcellulose, Irish moss, iota carrageenan or hydroxyethylcellulose, etc., including their mixtures. The toothpaste polishing material normally constitutes about 10 to 75% in a gel or toothpaste or about 50 to 99% in a powder and this polishing material can consist of colloidal silica, precipitated silica, sodium aluminosilicate, sodium metaphosphate. insoluble sodium, hydrated alumina, calcined alumina, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate or calcium carbonate, other known materials, or mixtures thereof. Surfactants include anionic, nonionic, cationic and zwitterionic surfactants, but the use of a nonionic surfactant is often avoided due to its detrimental effect on antibacterial compounds, eg THED, and is often also avoided. use of cationic and zwitterionic surfactants because they tend to stain or blacken teeth. Thus, synthetic organic anionic surfactants, which are also detergents, are the preferred cleaning agents in toothpaste, and among them, sodium lauryl sulfate or other (higher alkyl) sodium sulfates of which the alkyl group has 10 to 18 are preferred. carbon atoms, although they can be replaced, at least in part, by other well known sulfated and sulfonated detergents. Other active ingredients, such as compounds providing fluorine, for example sodium fluoride or sodium monofluorophosphate, may be present to harden the teeth, usually in proportions providing approximately 0.001 to 1% of fluoride in the composition, and adjuvants, such as flavoring and sweetening agents, can be used in amounts of 0.1 to 10%. In addition, it may be advantageous to use a polycarboxylate such as a poly (vinyl ether / methyl ether / maleic anhydride) (PVM / AM) (Gantrez) type copolymer in an amount corresponding to about 0.5 to 4 % toothpaste. It has been found that such a polycarboxylate significantly improves the antiplaque action of the antibacterial compound. The use of such carboxylates in compositions for oral use is described in the patent of the E.ü.A. No. 4,627,977, the description of which is incorporated herein by this reference.

In mouthwashes, the vehicle for oral use is preferably aqueous and alcoholic, the alcohol being ethanol or isopropanol. The vehicle normally represents 90 to 99.9% of the composition, alcohol representing 5 to 30% and propylene glycol often 2 to 10%, based on the final product. The rest of the composition, namely 0.1 to 10%, may include a flavoring agent, a surfactant, a sweetener, a coloring agent, an antiplaque agent and other adjuvants used for specific purposes. In toothpaste and mouthwash compositions, the effective amount of the antibacterial anti-plaque compound (s) is normally in the range of 0.02 to 0.2%, preferably 0.03 to 0.1% in baths mouth, and normally about 0.25 to 1%, preferably 0.25 to 0.5 or 0.6% in toothpaste, proportion intervals not exceeding 0.8% THED in toothpaste and not exceeding 0.2% THED in mouthwashes (due to possible numbing effects of the mouth at higher concentrations ) and not less than the values ​​indicated in order to avoid ineffectiveness against dental plaque at low concentrations. Preferably, the compositions delivered contain proportions of the antiplaque agent or of THED lying within the ranges indicated, but when its initial concentration is within the range mentioned, a loss of 25% at most may be acceptable and these compositions issued are within the scope of the invention.

In order to stabilize the compositions for buccal use which must be packaged in containers comprising walls or other parts made of plastics which are among the plastics known as reactive with antibacterial compounds, the compositions for buccal use advantageously contain 0.01 to 2% one or more terpenes or stabilizers, preferably 0.05 to 1%, and more preferably 0.1 to 0.5%. These stabilizers can be present, if desired (and this is often the case), in a flavoring agent suitable for toothpaste and they represent at least 5% of the flavoring, preferably at least 10%, better still at minus 25%, and most preferably at least 50%.

Although the above description is primarily focused on toothpaste and mouthwashes, other oral compositions of the invention (including, for example, chewing gum) contain similar proportions of components, depending on the form of the composition (liquids such as mouthwashes containing less, and thicker compositions such as toothpaste containing more), often with additions of specific agents to achieve the desired functions of such compositions. Thus, tooth hardening compositions can contain fluorides and phosphates, such as sodium or potassium fluoride and sodium fluorophosphate, in toothpaste or mouthwash bases, often in percentages of 1 to 5%. . Solutions of plaque indicator dyes may contain an appropriate dye (red is clearly the most preferred color for such products), often at a concentration of 0.001 to 0.1%, in a mouthwash base. The compositions of the other products are adjusted accordingly, as is well known to those skilled in the art.

The antibacterial agent is a non-cationic substance which is insoluble in water or essentially insoluble in water (whose solubility in water at 25 ° C is less than 10 g / 1, and sometimes less than 1 or 0 , 1 g / 1). These substances are soluble or dispersible in toothpaste vehicles which contain glycerol, sorbitol and / or propylene glycol, and in the final products based on such media. They are also soluble or dispersible in aqueous alcoholic media in mouthwashes.

Among the antibacterial agents, halogenated diphenyl ethers normally contain bromine and / or chlorine, chlorine being the preferred halogen. They are preferably substituted by 1 to 3 hydroxyl groups and 1 to 4 halogen atoms. More preferably, they are substituted with 1 or 2 hydroxyl groups and 2 or 3 halogen atoms, preferably with four substituents, two of which are on each nucleus. Among these compounds, those which are preferred are 2,2'-dihydroxy5,5'-dibromo (diphenyl ether) and 2 ', 4,4'-trichloro-2-hydroxy (diphenyl ether), last compound (THED) being the most appreciated. Various other non-cationic, phenolic, halogenated antibacterial anti-plaque compounds, substantially insoluble in water, such as those listed on pages 2 to 8 of the US patent application 07/398 566 deposited on August 25, 1989, can replace all or part of the halogenated diphenyl ethers, when this is considered appropriate.

Terpenes (this term, for the purposes of this description, including terpene hydrocarbons and their oxygen derivatives) include compounds such as dl-limonene, menthol, diterpenes, polyterpenes and their derivatives, many of which exist in various oils essential and other flavoring substances. Besides being useful as stabilizers for halogenated diphenyl ethers, they often contribute to imparting pleasant aromas to the compositions for buccal use of the present invention. Among terpenes and their derivatives, limonene is considered to have the best balance of these properties, although other terpenes, including those which are not flavorings, are also useful, as are other essential oils as well. and emulsifiable lipophilic flavoring substances which contain stabilizing components.

The various plastics which have previously been described as constituents of elements or parts of containers and / or dispensers have only been described succinctly, since it is considered that their chemical natures and their degrees of polymerization are well known, their detailed description therefore being unnecessary in this memo. If further details are desired, reference may be made to Modem Plastics Encyclopedia, published annually by McGraw-Hill Inc., New York, New York.

As described in the aforementioned application No. 07/398 566, the compositions (of the invention) may contain a source of fluoride ions, capable of supplying -4 to 5000 x 10% of fluoride ions in the oral cavity, preferably 300 to 2000 x 10%, and better still 800 to 1500 x 10%. See the USA patent

No. 4,627,977 cited above for further details regarding fluorides, proportions and suitable manufacturing details. Fluoride mainly acts as a hardener for teeth, but it also serves to stabilize a polyphosphate possibly present as an anti-scale agent. This polyphosphate is preferably a mixture of sodium and potassium pyrophosphates and it is also stabilized by Gantrez S-97. The proportion ranges are given in the US patent application 07/398 605 filed August 25, 1989, as well as in the above-mentioned US patent No. 4,627,977 and the US patent No. 4,806,340 which is incorporated herein. by this reference.

For further details concerning the formulations, components, adjuvants, methods of manufacture and use, see the patents, descriptions and applications previously mentioned in this memo.

The oral compositions described are made by any of a variety of conventional techniques for producing these types of compositions. Considering particular examples for simplicity, THED is dispersed and / or dissolved in the vehicle of the toothpaste and the terpene is present in the flavoring agent. To make a toothpaste, a vehicle is prepared containing glycerol, sorbitol, and propylene glycol, gelling agents and suitable (R) adjuvants (including Gantrez S-97 and Triclosan), and the mixture is mixed. vehicle and an anionic detergent in aqueous solution (preferably sodium lauryl sulfate or a mixture of sodium lauryl sulfate and sodium methyl cocoyl taurate), then the polishing agent is incorporated into the premix. Finally, a flavoring agent, comprising a terpene, dissolved in ethanol, is added and mixed, and the pH is adjusted. To make a mouthwash, simply mix its various components in alcohol or the aqueous alcoholic medium and stir them until dissolved. Sodium lauryl sulfate (LSS) and sodium methyl cocoyltaurate (in a ratio between 1: 4 and 4: 1) are preferably used as the anionic surfactant component of the mouthwash, the presence of taurate allowing a reduction corresponding to the LSS content, which is advantageous. Other compositions for oral use are prepared according to suitable analogous procedures.

To condition the composition for oral use in dispensing containers, it is desirable to avoid contact of the compositions with parts or elements of plastic material constituted by a co-polyester / polyether elastomer and it is also desirable to avoid contact with any compositions not containing a stabilizing agent (such as a terpene or flavoring container) with parts or elements made of plastics previously cited in this specification as reacting with THED and other antibacterial compounds and antiplaque of this type. It is particularly important to avoid the plastics mentioned for storage containers or any other containers, pipes, pumps or equipment in which the composition for oral use can be contained for any appreciable duration or maintained for shorter durations at temperatures. high.

Even if the conditioned compositions of the present invention are prepared and stored avoiding contact of the compositions containing THED or other halogenated diphenyl ether type antibacterial compound with reactive plastics, it is still desirable to minimize the exposure of such compositions conditioned by heat and light, which have both been shown to accelerate the loss of antiplaque activity. Thus, the compositions of the invention are preferably stored and packaged in opaque containers and dispensers at temperatures of 10 to 38 ° C and are also stored at these temperatures. For the rest, the conditioned compositions can be stored and used normally and their advantageous antiplaque effects are obtained. These effects were verified by laboratory tests and by evaluations on the teeth of volunteers comprising a human experimental group, who used the various conditioned and control compositions as prescribed. Significant improvements are observed in the antiplaque activity of the conditioned compositions of the present invention, compared with the control conditioned compositions in which the packaging comprises plastic parts which were reactive with the antibacterial compound (halogenated diphenyl ether), and which do not contain a stabilizing agent. These improvements are also observed when packages made with reactive plastics (but not copolyester / polyether elastomers) are used with compositions for oral use containing terpenes and are compared with controls in which the compositions for oral use do not contain no terpenes or flavoring agents.

The following nonlimiting examples illustrate the invention. Unless otherwise specified, the percentages and proportions referred to in these examples are all expressed by weight.

EXAMPLE 1

Water component, deionized

Sorbitol (70% aqueous solution) Ethanol (95% aqueous solution) Glycerol

Propylene glycol

Percentage

47,84

20/00

12,50

10,00

7.00 * Gantrez S-97 (13% solution) 1.92

Sodium hydroxide (50% aqueous solution) 0.12

Sodium lauryl sulfate 0.25 ** Tauranol WSHP 0.20 *** Flavor mixture 0.12 **** Triclosan (Irgasan ^ 'DP 300 manufactured by CIBA-GEIGY) * 0.05

100.00 * Methyl vinyl ether / maleic anhydride copolymer (GAF Corp.) ** Sodium methyl cocoyl taurate *** Contains at least 25% terpenes, of which at least 25% limonene **** THED (2 ', 4,4'-trichloro-2-hydroxy (diphenyl ether))

The mouthwash of this example is prepared by mixing together the various components listed in any suitable order, according to conventional procedures, but preferably, Triclosan is first dissolved in the mixture of propylene glycol and ethanol, after which it is mixed with an aqueous solution of sorbitol, glycerol and anionic surfactants, the flavoring mixture being added last. The sodium hydroxide solution is used to neutralize the resulting acid mixture, the neutralization being carried out up to a pH of 6.84 (it is advantageous for the product to have a pH equal to or close to neutral).

The resulting mouthwash has excellent cosmetic stability and an acceptable aroma, and the flavoring agent and Triclosan are adequately dissolved, this dissolution being at least partly attributable to the presence of Tauranol WSHP. When only 0.25% LSS is used as an anionic surfactant, the solubilization of the flavoring agent and Triclosan is not as satisfactory. Although these solubilizations can be increased by using more LSS, the maximum acceptable limit for this compound in mouthwashes is often about 0.25%, (R) and Tauranol WSHP and LSS are harmless and acceptable in proportions used. The described mouthwash is subjected to in vitro tests to determine the bioavailability of Triclosan compared to comparable mouthwashes whose formulas omit Tauranol WSHP in one case, and replace half of it with a nonionic surfactant (Pluronic F- 127) in the other case. By tests of fixation of Triclosan, measuring the absorption of Triclosan by hydroxyapatite discs having been coated with saliva, and by tests of zone of inhibition of protein absorption, it is found that the presence of the anionic surfactant mixed ensures comparable bioavailability of Triclosan, compared to this bioavailability from the formula containing only LSS, and this availability is much greater for formulas containing no non-ionic detergent than for that where, the non-ionic detergent (R) (Pluronic ^v 'F-127) is present.

The mouthwash of the formula in this example is aged at high temperature (41 ° C) for three and five weeks, which is considered to be equivalent to at least six months and about a year of actual aging at room temperature. . These aging tests are carried out in receptacles (vials) dispensers consisting of glass, polyvinyl chloride and polyethylene terephthalate (or coated internally with these plastics). While chemical analyzes of mouthwashes after these aging periods do not reveal losses of Triclosan when the container is made of glass, there are losses of Triclosan in mouthwashes when the containers are made of polyethylene terephthalate or of this same sample of polyvinyl chloride, but these losses are much less than a tolerable percentage of 25% (of the initial concentration) and can be less than 5 or 10%.

If, instead of the flavoring mixture, dl-limonene is used in amounts of 0.1, 0.2 and 0.4%, even better stabilizations of Triclosan can be obtained in the conditioned toothpastes described in invention, and these stabilizations also take place if other terpenes from various essential oils and flavoring agents are present in similar proportions. These good results can also be obtained when the material of the container or of its internal coating consists of polymethylpentene, polyallomer, polypropylene, high and low density polyethylenes, and nylon, whereas these materials, in the absence of the flavoring mixture (and terpenes), cause significant and excessive loss of active Triclosan in mouthwashes during storage, especially at high temperatures.

EXAMPLE 2

Component Percent

Deionized water 84.42

Ethanol (95%) 10.0

Propylene glycol 5.0

Sodium lauryl sulfate 0.50

Triclosan 0.06

Sodium saccharin 0.02

100,00

A mouthwash having the above formula is tested to determine the bioavailability of Triclosan after storage for three weeks in dispenser containers made of or internally coated with various plastics. The tests take place at room temperature, at 38 ° C and at 49 ° C, the high temperature storage simulating longer storage periods, up to a year or more at room temperature. We notice losses greater than 25% of Triclosan in the mouthwash stored when the containers are made of polymethylpentene, polyallomer, polypropylene, high and low density polyethylenes and Nylon, unacceptable results (excessive losses) being observed when the containers are polypropylene, polyethylene and Nylon (Nylon being the worst).

When the constituent material or the internal coating of the container consists of polyvinyl chloride, polycarbonate, polysulfone or polyfluoroethylene, for example polytetrafluoroethylene or (R)

Teflon, there is practically no loss of Triclosan. Losses of Triclosan in mouthwashes stored in containers made or internally coated with the polymers mentioned (polymethylpentene, etc.) can be reduced in the same way as described in Example 1 by incorporating into the mouthwash formula the limonene, other terpenes, or essential oils in which these may be present, the proportion of terpene being preferably at least 0.1%, and better still higher, for example 0.2% or 0.4%, based on the final composition. In some cases, even the use of a flavoring substance which does not contain terpenes in significant proportion exerts a positive effect, although this effect is not expected to be as good as with terpenes in the formulation .

EXAMPLE 3

<td>Component</td><td>Percent</td>

<td>Propylene glycol</td><td> 10,00</td>

<td>Iota-carrageenan</td><td> 0,75</td>

<td>Sodium fluoride</td><td> 0,33</td>

<td>Sorbitol (70%)</td><td> 30,00</td>

<td>Sodium saccharinate</td><td> 0,30</td>

<td>Titanium dioxide</td><td> 0,50</td>

<td>Sodium hydroxide (50% aqueous solution)</td><td> 0,80</td>

<td>Water, deionized</td><td> 27,71</td>

<td>+ TM Luviform (35% solution)</td><td> 4,76</td>

<td>⁺⁺Zeodent ™ 113</td><td> 20,00</td>

<td>⁺⁺⁺Sident ™ 22S</td><td> 2,00</td>

<td>Sodium lauryl sulfate (94% active ingredient)</td><td> 1,60</td>

<td>Aroma</td><td> 0,95</td>

<td>triclosan</td><td> 0,30</td>

100,00 ⁺ Vinyl ether-methyl / maleic anhydride copolymer (BASF Corp.) ⁺⁺ Polishing agent (silica) (JM Huber Corp.) ⁺⁺⁺ Thickening agent (silica) (Degussa Co.)

A toothpaste having the above composition is normally prepared and used as a medium for testing the stability of Triclosan when the toothpaste containing it is exposed to different plastics which are used as materials for containers or components. dispensers where toothpaste is kept and from which it is delivered. The plastics used for the tests are Pibiflex 46, manufactured by TM by Inmont, and Arnitel 460 EM, manufactured by AKZO, which are plastics used to form membranes or bellows of a pump dispenser, as shown in Figure 3 . Six plastics samples are tested, three of each of the plastics mentioned, each of the three being treated with a different release agent (to determine if the nature of the release agent is involved in the problem the stability of Triclosan in contact with plastics during storage). The release agents are respectively Silicone Master (5% silicone oil and

95 % polypropylene), Silicone Master plus silicone oil (with a supplement of silicone oil) and Armid O Master (5% oleamide and 95% polypropylene). After having kept the test samples in contact with the toothpaste for two weeks at different temperatures (room temperature, 38 ° C and 49 ° C), the toothpaste is removed from the plastic containers and the plastic materials are washed with water and immerse them in methanol to dissolve any Triclosan they may have absorbed during storage. The methanolic wash liquors are collected and analyzed by high performance liquid chromatography. It is found that essentially the same types of absorption of Triclosan take place with the different membrane materials and, although there are variations between them and that these depend to a certain extent on the release agents used, the results are essentially the same in all cases. It can be seen that the co-polyester / polyether elastomers absorb large percentages of Triclosan from the toothpaste, these results being able to be confirmed when the co-polyester / polyether elastomers are used as bellows materials in pump dispensers containing the toothpaste described and other toothpastes according to the invention. Therefore, it is considered to be disadvantageous to use co-polyester / polyether elastomers in contact with the present dentifrices or mouthwashes, even if the dentifrices and mouthwashes contain healthy flavoring substances including terpenes (which are present in the formulation of the toothpaste), in a proportion of at least 0.1% of the toothpaste.

When repeating the tests using Guala pump dispensers as receptacles for toothpaste with membranes made of Arnitel co-polyester / polyether elastomer, the losses of Triclosan are also unacceptable, but when the co-elastomer is replaced polyester / polyether by other acceptable plastics, for example polyfluoroethylene, the activity of Triclosan is improved by returning to acceptable limits. In addition, it is not found that other plastic parts of these pump dispensers, such as their internal polypropylene walls, absorb excessive amounts of Triclosan or significantly reduce the antiplaque activity of the toothpaste, which is clearly due to the presence of terpenes in the flavoring agent of the conditioned toothpaste.

A trial is carried out with an experimental group comprising at least ten people who use the toothpaste of this example, distributed by tubes internally coated with polyethylene terephthalate and polyethylene, by brushing twice a day for a month, during which time observers trained perform dental plaque assessments on the subjects' teeth. The results of the tests establish that the toothpaste composition exerts a marked antiplaque activity, analogous to that which is also observable in tests with the mouthwashes of Examples 1 and 2, and also prove that Triclosan was not inactivated in a unacceptable measure and that it is still present in an effective antibacterial and antiplaque proportion in the toothpaste.

EXAMPLE 4

<td>Component</td><td>Percent</td>

<td>Glycerol</td><td> 7,00</td>

<td>Propylene glycol</td><td> 3,00</td>

<td>Iota-carrageenan</td><td> 0,75</td>

<td>Sorbitol (70%)</td><td> 30,00</td>

<td>Sodium saccharinate</td><td> 0,30</td>

<td>Sodium fluoride</td><td> 0,33</td>

<td>Titanium dioxide</td><td> 0,50</td>

<td>Gantrez ^) S-97 (13% solution)</td><td> 15,00</td>

<td>Deionized water</td><td> 16,07</td>

<td>Sodium hydroxide (50% aqueous solution)</td><td> 0,80</td>

<td>Zeodent 113 (JM Huber Corp.)</td><td> 20,00</td>

<td>(R) Sylodent^v 15 (a thickener siliceous: WR Grace Corp.)</td><td> 3,00</td>

<td>Flavoring agent</td><td> 0,95</td>

<td>Sodium lauryl sulfate</td><td> 2,00</td>

<td>triclosan</td><td> 0,30</td>

100,00

A toothpaste of the above formula is prepared and stored in pump dispensers TM from Guala comprising bellows membranes of the Arnitel type. The toothpaste is also introduced into laminated tubes, where the inner face of the laminate is made of polyethylene terephthalate, in contact with the toothpaste. The toothpastes are aged at 5 ° C, 25 ° C and 39 ° C, for two, four and six weeks. After these periods of aging, the toothpastes are delivered at the rate of approximately 1.5 grams per day and, at intervals of one week, the content of toothpastes in Triclosan is determined by analysis. In the case of the Guala pump dispenser, the toothpaste delivered loses approximately 27% of the Triclosan, which is excessive and harmful. The loss is more or less constant, whatever the temperature or the storage time, which can be explained by the absorption of Triclosan by the membrane of the pump with which it comes into contact before being delivered. This membrane is formed from a co-polyester / polyether elastomer, this class of plastics being to be avoided as container material or as part of container or dispenser of toothpaste containing Triclosan. However, when the co-polyester / polyether elastomer membrane is replaced by a membrane made of any of the previously mentioned acceptable plastics, such as polyethylene terephthalate, which can serve as membrane materials in pump dispensers modified (modified to take into account the different properties of these plastics), the stability of Triclosan is increased and the composition delivered is satisfactory and effective as an antiplaque toothpaste.

The tooth gel compositions contained in these packages behave similarly with respect to the stability of Triclosan after storage and distribution.

In similar tests, using tubes coated internally with polyethylene terephthalate, little loss (less than 5%) of Triclosan is noted, which shows that the presence of terpenes (0.1% or more of the composition), including limonene, in the flavoring agent (or forming the flavoring agent itself), prevents loss of Triclosan or its inactivation. When using tubes coated internally with polyotetrafluoroethylene, there is little loss of Triclosan even if the flavoring agent is not included the composition of toothpaste, and this is also the case when using chloride of polyvinyl as an interior coating material in contact with the toothpaste or when packaging parts made of polysulfone or polycarbonate are in contact with such a toothpaste. However, as indicated above, these last three plastics are not usually used.

When Gantrez S-97 is replaced by 4.76 parts of Luviform (35%) in the test described in which the toothpaste is supplied from the Guala dispenser, the difference being compensated by deionized water, we do not note no appreciable difference in the stability of Triclosan between the formulas.

In the above formulas, the polishing system is a siliceous system rather than an alumina-based system. When the polishing agent is an alumina, the problems previously observed with certain plastics diminish but nevertheless exist. Again, the presence of terpenes in toothpaste promotes the stability of Triclosan, as well as in similar toothpaste compositions based on siliceous polishing agents.

EXAMPLE 5

The proportion of the various components of the mouthwash and toothpaste compositions of the preceding examples can be varied by 10% and 25%, provided that these percentages do not depart from the ranges given elsewhere in this specification, and can obtain useful and effective antibacterial and antiplaque products which can be delivered, in an effective state against dental plaque, from dispensing containers made of compatible plastics. The products can also be modified by transforming them into toothpaste gels, gels for oral use, pastes, liquids, lozenges, capsules, tablets and sachets of the types previously mentioned in this memo. These products also behave in an analogous manner, Triclosan or other anti-bacterial anti-plaque agent of the halogenated diphenyl ether type being sufficiently stable in the presence of packaging or of packaging constituent materials of the polyfluoroethylene, polyvinyl chloride, polycarbonate and polysulfone types, even if the compositions for oral use do not contain any flavoring agent or terpenes, and also stable in the presence of polyethylenes, polypropylenes, polyethylene terephthalates, polyallomers, nylon and polymethylpentenes used as packaging or packaging materials, provided that the composition for oral use contains a terpene, such as limonene, or a flavoring component with stabilizing effect. As in the case of the other toothpastes and mouthwashes previously examined, due to the excessive absorption or other harmful action towards Triclosan which is exerted by the co-polyester / polyether and other elastomers, it is preferable to avoid the use such matters.

EXAMPLE 6

The dentifrices of the formulas of Examples 3 and 4 are prepared and, after one month of storage at 30 ° C. in tubes of compressible toothpaste internally coated with polyethylene, in one case, and polyethylene terephthalate, in another case, they are delivered on toothbrushes with bristles, as shown in Figure 1. The amounts of toothpaste on the toothbrush are in the range of 0.8 to 2.0 grams, an amount of 1 to

1.5 g being preferred. When a quantity of

1.5 g, the amount of active Triclosan contained in the toothpaste on the brush is approximately 4 mg (only 10% of Triclosan being inactivated). When the storage lasts longer or takes place at a higher temperature or with more destabilizing plastic material in contact with the toothpaste during storage, the packaged compositions may contain approximately 3 mg of Triclosan in the amount of

1.5 g delivered on the brush. Thus, with 1 g of toothpaste on the brush, the amounts of Triclosan are approximately 2.7 mg and 2 mg respectively. For toothpaste containing 0.25 to 0.6% Triclosan, the toothbrush can carry 2.2 to 8 mg of Triclosan if the inactivation of Triclosan is 10 to 25%, or up to about 9 mg when 'there is no inactivation of Triclosan.

The conditioned toothpastes described are used for brushing the teeth, typically delivering 0.8 to 2 g of toothpaste on the toothbrushes during each brushing. Brushing is carried out twice a day, morning and evening, one minute each time, for four weeks, after which a marked improvement in the antiplaque action is apparent, compared to a control toothpaste not containing Triclosan. The improvement in the antiplaque action is also visible, compared to a non-flavored control (not containing terpene) which contains Triclosan in a package of toothpaste consisting of tubes internally coated with polyethylene and polyethylene terephthalate.

It goes without saying that the invention is not limited to the embodiments described and that it is possible to make various variants and modifications without departing from its scope.