NO178953B - Oral care packaged in a dispenser container - Google Patents

Description

The invention relates to oral care agent with 0.02-1% of a halogenated diphenyl ether as an essentially water-insoluble, non-cationic, antibacterial dental plaque prevention agent, where the oral care agent is packaged in a dispenser container whose walls that are in contact with the oral care agent consist of polyethylene or polyethylene terephthalate material.

Although different plastics can reduce it

anti-plaque action of the aforementioned antibacterial agents, certain plastics, such as polyfluoroethylene and polyvinyl chloride, have been found to be compatible with THDE and have been found not to cause excessive loss of antibacterial

and anti-plaque activities of contained oral preparations after storage at room temperature or elevated temperatures, even when the plastic part(s) of the container in contact is of a plastic not inherently fully compatible with the antibacterial compound, compatibility can be improved by incorporating in the oral preparation a stabilizing portion of a stabilizing agent for the antibacterial compound, such as a terpene, e.g. limonene, or an essential oil (natural or synthetic) which may be present in a flavoring material for the oral preparations. Such stabilizing material is present in a sufficient proportion that the oral preparation, as it is packaged and dispensed, is an effective anti-plaque preparation, the production of which is an object of the invention.

Plaque on teeth is considered to be the causative factor for negative conditions around the tooth roots, and dental plaque is a precursor to calculus. Plaque can form on any part of the tooth surface, including the edge of the tooth. It makes the teeth look dull, and in addition to promoting the development of tartar, it has been implicated in the development of gingivitis. Oral preparations containing anti-plaque ingredients that prevent or inhibit the development of plaque on the teeth are therefore valuable dental care aids.

Although it has been known that antimicrobial agents in oral preparations can reduce plaque, being sometimes particularly effective in combination with other materials, various such antibacterial compounds have disadvantageous properties which detract from their use in such oral preparations. E.g. cationic antibacterial compounds, such as quaternary ammonium halides, tend to discolour the teeth and can be inactivated by the presence of anionic substances in the oral preparations, (and often it will be desirable to use anionic surfactants or detergents in oral preparations).

Essentially water-insoluble halogenated (and often hydroxylated) diphenyl ethers, such as THDE (triclosan) and 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether (DDDE), are effective anti-plaque antibacterial agents, but can be inactivated by non- ionic surfactants and of many plastics, as discovered by applicants. An object of this invention has thus been to incorporate antibacterial anti-plaque agents, such as halogenated diphenyl ethers, especially THDE and DDDE, and similar anti-plaque agents in oral preparations, and to store such preparations in and dispense them from packages or containers where they will not lose too large a proportion of the activity of such an antibacterial agent after storage, before intended use. In prior art triclosan dentifrices, the triclosan delivery as delivered from the dispenser has not been in an effective amount to significantly reduce plaque when applied once or twice daily at 1.5 g/use with one minute brushing, which is considered to be approximately normal polishing practice. To be effective, such applications should result in at least a 25% reduction in plaque after three weeks of use, compared to three weeks of using a control toothpaste in the same way.

The most preferred antibacterial anti-plaque ingredient in the present packaged oral care products is THDE which is also known as triclosan. This is described in US patent document no. 4,022,880 as an antibacterial agent, in combination with an antitartar agent (which gives zinc ions), and in BRD patent application no. 35 32,860 in combination with a copper compound. It is also described in European Patent Applications No. 0 161 898 and 0 161 899, and in European Patent Application No. 0 220 890 it is described in dentifrices with polyethylene glycol and oil-based flavoring.

Various oral preparations or dental preparations are known, including paste, gel, powder, liquid, tablet, lozenge, lozenge and packaged dentifrices, liquid and tableted mouthwashes; and professionally applied dental treatment agents (such as tooth-hardening preparations, e.g. fluoride solutions). Such products have been packaged in deformable tubes, pump dispensers, pressurized dispensers, gaskets, bottles, jugs and other containers. Although the deformable or squeezable tubes were originally made of metals, such as lead and aluminum, and bottles were made of glass, in recent years such containers have often been made of synthetic organic polymeric plastics or made of laminates comprising such plastics. Interactions between oral preparations and the materials in containers in which they were packaged have been known, such as reactions between toothpastes and aluminum containers, and to prevent such reactions containers have been specially treated or other container materials have been used. However, the inventors do not believe that prior to their invention it had been known in the art that some plastic packaging materials could affect the anti-plaque activities of halogenated diphenyl ether antibacterial compounds that had been incorporated into oral preparations and packaged in containers where they came into contact with such plastics, unfavorably, they also do not believe that it had been discovered that certain plastics could be used for such container parts without causing loss of the anti-plaque activities of halogenated diphenyl ethers, or that loss of such activities of oral preparations packaged in contact with "reactive" plastics (which react with, absorb or otherwise reduce the anti-plaque activity of the oral preparation), could be inhibited or prevented by the incorporation into the preparations of terpenes, such as limonene, and other ingredients in flavors for oral preparations.

The present invention relates to an oral care agent with 0.02-1% of a halogenated diphenyl ether as an essentially water-insoluble, non-cationic, antibacterial dental plaque prevention agent, where the oral care agent is packaged in a dispenser container whose walls that are in contact with the oral care agent consist of polyethylene or polyethylene terephthalate material, characterized in that it contains 0.01-2% of a stabilizing terpene and/or an aroma agent, which makes the polymeric material compatible with the antibacterial agent. The solid polymeric material is thus compatible with the antibacterial agent in the oral care agent and does not cause excessive loss of antibacterial and anti-plaque activities of the oral care agent after storage in the container (such as at temperatures in the range of 20-40 °C for several weeks, preferably up to a year or more). The packaged mouth care product is usually a toothpaste, gel tooth care product or mouthwash that is contained in the respective a deformable dispenser tube, pump dispenser or bottle, without any plastic parts which adversely affect the anti-plaque action of the antibacterial agent (which is preferably triclosan), and thus containing an ingredient which inhibits or prevents any such harmful "reaction" between the antibacterial agent and a plastic part in the container which could otherwise adversely affect the anti-plaque effect of the preparation.

The invention will be easily understood from the description seen in conjunction with the drawings where: figure 1 is a perspective view of a toothpaste tube and its removed cap, the toothpaste having been squeezed out of the tube and onto a toothbrush,

Figure 2 is an enlarged, partial cross-section of a laminated wall in a collapsible tube such as that of Figure 1,

figure 3 is a vertical section of a pump dispenser for the content and dispensing of toothpaste or toothpaste gel as desired,

Figure 4 is a side section of a heat-sealed pad or pouch containing a single-use amount of a toothpaste, and

figure 5 is a vertical projection view of a mouth-water bottle with a cap.

In Figure 1, packaged anti-plaque toothpaste article 11 comprises deformable toothpaste tube 13 containing anti-plaque toothpaste 15, shown dispensed in a uniform amount such as 0.8 - 2 g, by squeezing onto toothbrush 17. Tube 13 is opaque and made of a synthetic organic polymeric plastic material, such as polyfluoroethylene, or is lined with such a material, such as in a laminate, which does not adversely affect the anti-plaque activity of the toothpaste after storage. Alternatively, the tube 13 may be made of or lined with a plastic which has been found to adversely affect the anti-plaque effect of the toothpaste (by reducing the anti-plaque effect of the antibacterial or anti-plaque halogenated diphenyl ether component in the toothpaste), but in such a case the harmful effect on the anti-plaque effect is prevented or inhibited by the presence in the dentifrice of a stabilizing agent which may be a terpene, e.g. limonene, or other effective flavoring ingredients. Preferably, neither the toothpaste tube nor the cap 19, nor any other part of the tube that can come into contact with the toothpaste (such as a lining for the cap) should be made of co-polyester/polyether elastomers or of other plastic material that significantly reduces the anti-plaque effect of the oral preparation, even in the presence of a stabilizer for the anti-plaque component. It is also considered desirable to avoid the presence of other elastomers, such as iso-butadienes, polychloroprenes, butadiene rubbers and nitrile rubbers, which may react with or absorb THDE. It is desirable that such parts are made of plastics which do not adversely affect the anti-plaque activity, even in the absence of terpenes or other stabilizing agents in the dentifrice, but such other destabilizing plastics may be used when such stabilizing agents are present in the toothpaste to counteract the inactivating effect of the plastic material (except that elastomer co-polyester/poly-ether and other harmful elastomers will preferably be avoided).

Figure 2 shows a laminate of polyfluoroethylene film 21, aluminum sheet 23 and polyethylene film 25, the polyfluoroethylene being on the inside of the tube wall where it will be in contact with the toothpaste. The lining in the cap 19, which is not shown in figure 1, can also be of polyfluoroethylene so that all surfaces in contact with the toothpaste during storage are compatible with the antibacterial, halogenated diphenyl ether component of the toothpaste and do not promote excessive loss of its anti-plaque activity during storage . Instead of the inner wall 21 in the laminate being made of polyfluoroethylene, it can be made of polyethylene, and wall 21 can be made of polyethylene or another suitable polymer.

In Figure 3, the pump dispenser for toothpaste is of a marketed type which is the subject of US Patent No. 4,776,496. When ready for use, pump dispenser 27 contains toothpaste in compartment 29 which is bounded by bottom wall 31 and membrane 33. Depressing operating rod 35 causes a downward movement of membrane 33 which forces toothpaste through line 37 and out of opening 39. When the pressure on operating rod 35 is lifted, diaphragm 33, which is elastic, returns to its original shape and moves wire 37 and rod 35 back to their original positions. At the same time, bottom 31 is pushed upwards by atmospheric pressure. The various internal parts in the pump dispenser that come into contact with the toothpaste are preferably made of plastic

substance(s) that do not inactivate the antibacterial and anti-plaque agent of halogenated diphenyl ether. In the event that it is not possible to utilize plastics which have the necessary physical properties for the various contact parts, and which are still compatible with the anti-plaque agent, other plastics can however be used provided that the toothpaste preparation (or gel toothpaste) comprises a stabilizing substance, such as limonene or other active terpene or flavor ingredient. However, it is considered best to avoid the use of the co-polyester/poly-ether elastomers, especially for the pump membrane (33), as this plastic appears to be particularly active against THDE in oral preparations of the types described.

In Figure 4, pad, pocket or gasket 41 is shown as a heat-sealed unit, with approx. three sides heat sealed, represented by the numbers 43 and 45. The fourth side 47 is simply folded back on itself and does not need to be heat sealed. Inside the sealed package is an oral preparation, such as toothpaste, not shown, and the inner surface of such a pad is of a plastic material which does not promote excessive loss of anti-plaque action of the antibacterial compound in the contained oral preparation. As with the other containers for the anti-plaque oral preparations, laminates can be used with a plastic layer on the inside which does not adversely affect the antibacterial agent, or when the plastic has such a negative effect, it can be counteracted by the presence in the oral preparation of a suitable stabilizing agent which is preferably also usable as a flavoring agent for the preparation.

Figure 5 shows an opaque bottle 49 with a sealing cap 51 on it. Both the bottle and the sealing gasket (not shown) in the cap are made of plastic materials which are compatible with THDE which is the anti-plaque component in the mouthwash 53 contained in the bottle. As in the other examples given, when a "reactive" plastic is used as the material in the inner part of the bottle or of the cap seal, a suitable stabilizer will be present in the mouthwash to prevent excessive loss of anti-plaque effect of THDE or other halogenated diphenyl ether.

In addition to the preparations described as being present in the illustrated packages, which include gel dentifrices and thick liquids instead of toothpastes, there may also be incorporated in such packages dental treatment preparations suitable for professional use, such as tooth hardeners which can include fluorides and phosphates, compound antibacterial agents, plaque-indicating dye solutions and other suitable oral preparations. In addition, pressurized or "aerosol" preparations containing the aforementioned anti-plaque compounds may be packaged in pressurized containers (usually pressurized with nitrogen gas), provided that plastic parts of such containers that come into contact are of materials that do not cause too large a loss of anti-plaque properties of the anti-plaque agent in the contained toothpastes or other oral preparations.

In addition to the various containers illustrated in the drawing and mentioned above, squeeze bottles, capsules, jugs, sponge-like media and various types of mechanical dispenser containers can also be used. As some of the antibacterial halogenated diphenyl ether compounds are light sensitive, it will sometimes be desirable for such containers to be composed of, coated or laminated with, a chemical or physical light shielding material, many of which are known, to prevent transfer to the oral preparation and to the anti-plaque compound of any inactivating radiation, e.g. ultraviolet light. It is also often desirable that such containers are opaque to prevent such actinic irradiation from inactivating the anti-plaque component in the contained oral preparation, such as a toothpaste.

The reason(s) for the inactivation of THDE and other predominantly non-cationic antibacterial agents that have anti-plaque properties by plastics in oral preparations has not yet been determined. Research has so far not pointed to the mechanism responsible for the loss of such desirable activity, but so far the results do not conclusively point to either chemical reactions or physical absorptions. Tests of basic mouthwash or mouthwash preparations containing THDE show that when such mouthwash or mouthwash is aged in dispenser containers at room temperature, 38°C and 49°C for up to 12 weeks, there are "exceptionally large" losses (over 25% of the initial concentration of THDE ) when the mouthwash has been in contact with such container walls and parts of low-density polyethylenes, high-density polyethylenes, polyethylene terephthalates, polypropylenes, nylon fabrics, polyallomers and polymethylpentenes. Similarly, there are large losses when such storage is in containers with inner walls or parts of co-polyester/polyether elastomers, such as those that have previously been used in "Guala" pump membranes. It has been found that polyfluoroethylenes, such as polytetrafluoroethylenes, polyvinyl chlorides, polycarbonates and polysulfones, did not absorb or react with unusually large proportions of THDE. However, polycarbonates and polysulfones are fragile and consequently often unsuitable for use as dispenser container parts. Polyvinyl chlorides sometimes impart a foreign taste to oral preparations, such as

toothpastes, and will therefore often be avoided as a container material, except in certain cases where such a taste is compatible with the taste of the toothpaste flavoring used. Thus, among all the polymeric plastic materials available, polyfluoroethylene has been particularly identified as a favorable material for use in the present containers or packs, which does not seriously reduce the anti-plaque activity of the anti-plaque agents. As previously indicated, however, it is possible to reduce the activity losses of the antiplaque agents when they are in contact with containers or container parts made of the various aforementioned polymeric plastics with which unusually large losses in antiplaque activity occur, by incorporating into the the oral preparations stabilizing compounds for the anti-plaque agents, such as terpenes, of which limonene is representative, essential oils (which often contain terpenes) and other flavor components with similar "stabilizing" properties. One therefore need not depend on polyfluoroethylene as a container dispenser material, provided that the oral preparation also contains a stabilizing portion of the terpene or other suitable "stabilizing agent". When such a stabilizing agent is present in the oral preparations, or when polyfluoroethylene (or polyvinyl chloride, polycarbonate or polysulfone) is the only polymeric plastic in contact with the oral preparation, storage loss of anti-plaque activity is less than 25%, and will preferably be less than 10%, even after storage at ambient temperature to a relatively high temperature, e.g. 20 - 40°C, for periods of several weeks and up to a year or more. The oral preparations considered to be the most stable are those which include a stabilizing portion of terpene or other suitable stabilizing agent, and which also include contact with container parts only of polyfluoroethylene (or any of the other non-reactive plastics). Although the terpenes and the essential oils are the most important stabilizing agents according to the present invention, other flavor components can also contribute to the stabilization of the anti-plaque material, either by acting on a possible destabilizing reaction, or by inhibiting absorption of the halogenated diphenyl ether by the plastic material ( or by some other unknown mechanism). It has thus been theorized that some components in the oral preparations which tend to solubilize THDE may act to maintain it in the oral preparation and inhibit or prevent its migration into the plastic. On the other hand, it has also been theorized that such a solubilizing effect could promote migration of the solubilized THDE into the plastic. Due to the fact that the question has not been resolved, the applicants have not been bound to any of the theories. Moreover, although it is desirable that the terpenes and other stabilizers be flavor components, this is not necessary, and the stabilizers may be useful only for a stabilizing purpose.

The various packaged oral care products according to the invention that are most often made are toothpastes, dental care gels and mouthwashes (sometimes called mouth rinses). The first two will be referred to here as dentifrices, and the latter will usually be called mouthwash. Tooth care products comprise three main groups of ingredients, the carrier, the polishing material and the surface-active agent (or detergent). The antibacterial agent, e.g. halogenated diphenyl ether, is normally present in the carrier which usually comprises 10 - 80% (all figures are based on the final mixture) of the dentifrice. Of the carrier, 3 - 40% will be water, 7 - 77% will be a wetting agent, such as glycerol, sorbitol, propylene glycol or mixtures thereof, and 0.5 - 10% will be a gelling agent, such as sodium carboxymethylcellulose, Irish moss, iotacarrageenan or hydroxyethylcellulose or similar, including mixtures thereof. The polishing material in the dental care agent will normally be from 10 to 75% of it in a gel or toothpaste, or 50 - 99% in a powder, and such polishing material can be colloidal silica, precipitated silica, sodium aluminum silicate, insoluble sodium metaphosphate, hydrated alumina, calcined alumina, dicalcium phosphate -dihydrate, anhydrous dicalcium phosphate or calcium carbonate, or other known materials, or mixtures thereof. The surfactants include anionic, non-ionic, cationic and zwitter-ionic surfactants, but often the use of non-ionic surfactant is avoided due to its deleterious effect on the antibacterial compounds, e.g. THDE, and the use of cationic and zwitterionic surfactants are also often avoided due to their tendency to stain or darken the teeth. Synthetic organic anionic surfactants which are also detergents are thus the preferred cleaning agents in the dentifrices, and among these sodium lauryl sulfate and other sodium (higher alkyl) sulfates with 10 - 18 carbon atoms in the alkyl groups are preferred, although various other well-known sulfated and sulfonated detergents can replace them, at least partially. Other active ingredients, such as fluoride-giving compounds, e.g. sodium fluoride or sodium monofluoro-phosphate, may be present to harden the teeth, usually in proportions giving 0.001 - 1% fluoride to the preparation, and auxiliaries, such as flavorings and sweeteners, in proportions of 0.1-10%, may be used . In addition, it may be desirable to use a polycarboxylate, such as polyvinyl methyl ether maleic anhydride (PVM/MA) copolymer ("Gantrez") in an amount corresponding to 0.5-4% of the dentifrice. Such polycarboxylate material has been found to substantially enhance the anti-plaque activity of the antibacterial compound. Use of such polycarboxylates in oral preparations is described in US Patent No. 4,627,977.

In mouthwash, the oral carrier is preferably aqueous and alcoholic, the alcohol being ethanol or isopropanol. The carrier will normally be 90-99.9% of the preparation, of which the alcohol is 5-30% and the propylene glycol is often 2-10%, on a final product basis. The remainder of the preparation, 0.1-10%, may include flavouring, surface-active agent, sweetener, colourant, anti-plaque agent and other auxiliaries for specific purposes. In dentifrice and mouthwash preparations, the effective amount of antibacterial plaque prevention agent will normally be in the range of 0.02-0.2%, more preferably 0.03-0.1% in mouthwash, and normally 0.25-1%, more preferably 0.25-0.5 or 0.6% in dental care products, with the proportion ranges not exceeding 0.8% for THDE in toothpastes and not exceeding 0.2% THDE in mouthwash (due to possible numbing effects in the mouth at higher concentrations ), and is not less than specified to avoid ineffectiveness against plaque at low concentrations. Preferably, the dispensed preparations will contain proportions of the antiplaque agent and THDE within the specified ranges, but when the initial concentration thereof is within the specified range, a loss of up to 25% may be acceptable, and such dispensed preparations are within the scope of the invention.

In order to stabilize oral care agents that are to be packaged in containers containing plastic walls or other plastic parts where the plastics are those that are "reactive" with the antibacterial compounds, as mentioned, 0.01-2% of the terpene or stabilizer will be present in the oral care agents, preferably 0 .05-1%, and preferably 0.1-0.5%. Such stabilizers may be present in a suitable flavoring agent for the dentifrice, if desired (and often are), and will be at least 5% of the flavoring agent, preferably at least 10%, more preferably at least 25% and most preferably at least 50%.

Although the above description is primarily relevant to dentifrices and mouthwashes, other oral care products (e.g. including chewing gums) according to the invention will contain similar proportions of ingredients, depending on the form of the preparation (liquids contain less, such as in mouthwashes, and thicker preparations contain more , such as in toothpastes), often with additions of specific means for achieving the purposes of such preparations. Tooth-hardening preparations can thus include fluorides and phosphates, such as sodium or potassium fluoride and sodium fluorophosphate, either in toothpaste or mouthwash bases, often in percentages in the range of 1-5%. Plaque-indicating dye solutions may comprise a suitable dye (red is obviously the most favorable color for such products), often at a concentration in the range of 0.001-0.1%, in a mouthwash base. The compositions of the other products will be correspondingly regulated, which will be known to those skilled in the art.

The antibacterial agent is a non-cationic material which is water-insoluble or substantially water-insoluble (with a solubility in water at 25°C of less than 10 g/l, and sometimes less than 1 or 0.1 g/l ).Such materials are soluble or dispersible in dental care carriers containing glycerol, sorbitol and/or propylene glycol, and in end products based on such media. They are also soluble or dispersible in the aqueous alcoholic media of mouthwash.

The halogenated diphenyl ethers will normally contain bromine and/or chlorine, chlorine being the preferred halogen. They will preferably be substituted with 1-3 hydroxyl groups and 1-4 halogen atoms. More preferably, they will be substituted with 1 or 2 hydroxyl groups and 2 or 3 halogen atoms, preferably with four substituents, two on each ring. Among the more preferred of such compounds are 2,2'-dihydroxy-5,5'-dibromodiphenyl ether and 2',4,4'-trichloro-2-hydroxy-diphenyl ether, the latter compound (THDE) being most preferred. Various halogenated, phenolic, non-cationic, substantially water-insoluble antibacterial anti-plaque replacement compounds, such as those disclosed on pages 2-8 of US Patent No. 5,032,386, will fully or partially replace the halogenated diphenol ethers when considered to be appropriate.

The terpenes, a term which for the purpose of this description includes the terpene hydrocarbons and oxygenated derivatives thereof, includes such compounds as dl-limonene, menthol, diterpenes, polyterpenes and derivatives thereof, many of which are found in various essential oils and other flavourings. In addition to being useful as stabilizers for halogenated diphenyl ethers, they often contribute desirable taste to the existing oral preparations. Among the terpenes and their derivatives, limonene is considered to best balance these properties, although other terpenes, including non-flavoring ones, are also useful, as are other emulsifiable lipophilic essential oils and flavoring agents containing stabilizing ingredients.

The various plastics that were previously described as constituents of container and/or dispenser parts have only been briefly described because their chemical properties and degrees of polymerization are considered to be well known, so that further description of this is unnecessary in this description. If further details are desired, reference is made to the Modern Plastics Encyclopedia, published annually by McGraw-Hill

Inc., New York, New York.

As was described in US Patent No. 5,032,386, the agents (according to the invention) may contain a source of fluoride ions capable of delivering 25-5,000 ppm fluoride ion into the oral cavity, preferably 300-2,000 ppm, and preferably

800-1,500 ppm. Reference is made to US Patent No. 4,627,977 for further details regarding suitable fluorides, proportions and manufacturing details. The fluoride acts primarily as a tooth hardener, but also serves to stabilize the polyphosphate-antitartar bond when present. Such polyphosphate is preferably a mixture of sodium and potassium pyrophosphates, and it is also stabilized by "Gantrez S-97". Share areas are indicated in US patent documents no. 4,627,977 and 4,806,340.

For other details regarding compositions, components, excipients, preparations and applications, reference is made to the previously mentioned patent documents and applications.

Production of the described oral care agents takes place by means of any of various standard techniques for the production of such preparation classes. Referring to specific examples for convenience, the THDE is dispersed and/or dissolved in the carrier portion of the dentifrice, and the terpene is present in the flavoring agent. To make a dentifrice, the carrier containing glycerol, sorbitol and propylene glycol, gelling agents and suitable excipients (including "Gantrez S-97" and triclosan) is prepared, and the carrier and the aqueous anionic detergent solution (preferably sodium lauryl sulfate or a mixture of sodium lauryl sulfate and sodium methylcocoyl taurate) are mixed, followed by mixing the polishing agent component into the premix. Finally, a flavoring agent, including the terpene, dissolved in ethanol, is added, and the pH is adjusted. To make the mouthwash, the various ingredients are simply mixed in alcohol or the aqueous alcoholic medium and stirred until dissolved. A mixture of sodium lauryl sulfate (SLS) and sodium methylcocoyltaurate (in a ratio in the range 1:4-4:1) is preferably used as the anionic surfactant component in the mouthwash, the presence of the taurate enabling a correspondingly desirable reduction in the SLS content. Other oral preparations are prepared according to similar relevant methods.

When packaging the oral care agent in the dispenser containers, it will be desirable to avoid bringing the preparations into contact with plastic parts of co-polyester/polyether elastomers, and it will also be desirable to avoid bringing all preparations that do not contain stabilizers (such as terpene or flavoring agent containing it) in contact with plastic parts made of the plastics previously indicated in the description as reactive with THDE, and other such antibacterial and anti-plaque compounds. It will be particularly important to avoid the aforementioned plastic parts in storage containers or all other containers, pipes, pumps or equipment where the oral preparation can be stored for any significant period of time, or stored for a shorter period of time at elevated temperatures.

Even when the packaged oral care products according to this invention are produced and contact between the oral care products containing THDE or other halogenated diphenyl ether-containing antibacterial preparation and the reactive plastics is avoided, it will still be desirable to minimize exposures of such packaged preparations to heat and light, both of which have been found to accelerate loss of anti-plaque activity. The invented agents are thus preferably stored and packaged in opaque containers and dispensers at a temperature in the range of 10-38 °C, and are also stored at such a temperature. Otherwise, the packaged agents can be stored and used in the normal way, and the desirable anti-plaque effects thereof will be achieved. Such effects have been verified by laboratory testing and by evaluation of the teeth of volunteers in human panels, as used in the various packaged agents and the controls as directed. Significant improvements in anti-plaque activities of the packaged oral care products according to the invention are observed, compared to packaged preparations for control where the packaging included plastic parts which were "reactive" with the antibacterial halogenated diphenyl ether compound and which did not contain a stabilizer in the oral preparation. Such improvements have also been found when gaskets made of "reactive" plastics (but not co-polyester/polyether elastomers) are used together with oral preparations containing terpenes, and are compared with controls where the oral preparations do not contain terpenes

and does not contain flavoring agents.

The following examples illustrate the invention. Unless otherwise indicated, all percentages and proportions in these examples, description and claims are by weight and all temperatures are in °C.

<*> Polyvinyl methyl ether/maleic anhydride copolymer

<**> Sodium methylcocoyltaurate

Contains at least 25% terpenes, including at least 25%

the limon

<****>THDE (2',4,41-trichloro-2-hydroxy-diphenylethene)

The mouthwash (or mouthwash) of this example is made by mixing together the various indicated ingredients in any suitable order according to standard procedures, but preferably the triclosan is first dissolved in the propylene glycol and ethanol mixture, after which it is mixed with an aqueous solution of sorbitol , glycerol and the anionic surfactants, the flavor mixture being added last. The sodium hydroxide solution is used to neutralize the resulting acidic mixture, with the neutralization taking place to a pH of 6.84 (it is desirable to have the product at or close to a neutral pH).

The resulting mouthwash is of excellent cosmetic stability and has an acceptable taste, and the flavoring and triclosan are satisfactorily dissolved, this dissolution being at least partially attributable to the presence of "Tauranol WSHP". When only 0.25% SLS is used as the anionic surfactant, solubilizations of the flavoring agent and triclosan are not as satisfactory. Although such solubilizations can be increased by using more SLS, the maximum acceptable limit for such a compound in mouthwashes is often approx. 0.25%, and "Tauranol WSHP" and SLS are safe and acceptable in the proportions used. The described mouthwash is tested in vitro with regard to the bioavailability of triclosan against comparable mouthwashes with compositions where "Tauranol WSHP" is omitted,

in one case, and by replacing it with half as much of a nonionic surfactant ("Pluronic F-127")

in another case. Using triclosan uptake tests where triclosan absorption is measured using saliva-coated hydroxyapatite discs, and protein absorption "zone of inhibition" tests, it is found that the presence of the mixed anionic surfactant results in comparable bioavailability of triclosan , compared to such availability from the composition with only SLS, and such availability is significantly higher for the compositions containing no nonionic detergent than for the one where the nonionic detergent ("Pluronic F-127") is present.

The mouthwash with the composition according to this example is aged at elevated temperature (41°C) for 3 and 5 weeks, which is considered to be equivalent to at least approx. 6 months and 1 year of real aging at room temperature. Such aging tests are carried out in dispenser containers (bottles) made of glass, polyvinyl chloride and polyethylene terephthalate (or lined with the plastic materials). Although chemical analyzes of the mouthwashes after aging periods find no loss of triclosan when the container is glass, losses of triclosan from the mouthwashes are noticed when the containers are polyethylene terephthalate or, in this example, polyvinyl chloride, but they are significantly less than a tolerable 25 % (of the original concentration), and may be below 5 or 10%.

When dl-limone is used instead of the flavoring mixture in amounts of 0.1, 0.2 and 0.4%, even better stabilizations of the triclosan in the described packaged dental care products according to the invention can be achieved, and such stabilizations are obtained also when other terpenes from any of the various essential oils and flavoring agents are present in similar proportions. Such good results can also be achieved when the container material or liner is of polymethylpentene, polyalloms, polypropylene, high and low density polyethylenes, and nylon, although such materials in the absence of the flavor mixture (and contained terpenes) cause significant and excessive losses of available triclosan from the mouthwash during storage, especially at elevated temperatures.

A mouthwash with the above-mentioned composition was tested for triclosan available after storage for 3 weeks in dispenser containers made of, or mixed with, various plastics. The tests took place at room temperature, 38°C and 49°C, the storages at elevated temperature simulating long-term storage times of up to a year or more at room temperature. There was a loss of over 25% of the triclosan from the stored mouthwash when the containers are made of polymethylpentene, polyallomers, polypropylene, polyethylenes with high and low density, and nylon, while unacceptable results (too large losses) were obtained when the containers are made of polypropylene, polyethylene and nylon (as nylon is the worst).

When the container material or liner is polyvinyl chloride, polycarbonate, polysulfone or polyfluoroethylene, e.g. polytetrafluoroethylene or "Teflon", essentially no loss of triclosan occurred. Loss of triclosan from the mouthwash stored in containers of, or lined with, the aforementioned polymers (polymethylpentene, etc), can be reduced in the same way as described in example 1 by incorporating into the mouthwash composition limonene, other terpenes or essential oils where such may be present present, the proportion of the terpene being preferably at least 0.1%, and preferably greater, e.g. 0.2% or 0.4%, on a final mix basis. In some cases, even the use of the flavoring material which does not contain any significant proportion of terpenes will have a positive effect, although such an effect is not expected to be as good as with terpenes in the mixture.

+ Polyvinyl methyl ether/maleic anhydride copolymer ++ Silica as a polishing agent

+++Silica as thickener

A dental pieiemiaaei with the composition stated above is made pl. normal way and is used as a medium for testing the stability of triclosan when the dentifrice containing it is exposed to various plastics that are used as materials in containers or in parts of the dispensers where dentifrices are stored and from which they are dispensed. The plastics for the tests are "Pibiflex 46" and "Arnitel 460 EM", which are plastics used as the membranes or bellows in a pump dispenser as illustrated in Figure 3. Six samples of plastics are tested, three of each of the aforementioned plastics, each of the three are treated with a mold release agent (to determine whether the properties of the release agent are relevant to the problem of triclosan instability in contact with plastics during storage). The release agents are "Silicone Master" (5% silicone oil and 95% polypropylene), "Silicone Master plus Silicone Oil" (with additional silicone oil) and "Armid 0 Master" (5% oleoamide and 95% polypropylene). After two weeks of storage of the test samples in contact with the toothpaste at different temperatures (room temperature, 38°C and 49°C), the toothpaste is removed from the plastic container materials, and the plastics are washed with water and immersed in methanol to dissolve any triclosan that may have been recorded by them during storage. The methanol washes are collected and analyzed using high performance liquid chromatography. It is found that essentially the same types of absorptions of triclosan take place with the different membrane materials, and although there are variations between them and such are somewhat dependent on the release agents used, the results are essentially the same in all cases. The co-polyester/polyether elastomers are found to absorb significant percentages of triclosan from the dentifrice, results which can be confirmed when the co-polyester/polyether elastomers are used as bellows materials in pump dispensers containing the described dentifrice and other dentifrices according to the invention. Accordingly, it is considered undesirable to use co-polyester/polyether elastomers in contact with the present dentifrices or mouthwashes, even when the dentifrices and mouthwashes contain flavoring materials comprising terpenes (which are present in the flavoring of the dentifrice composition) to an extent of at least 0.1% of the toothpaste.

When the tests are repeated using "Guala" pump dispensers as containers for the dentifrices, with "Arnitel" co-polyester/polyether elastomer membranes, the losses of triclosan are also unacceptable, but when the co-polyester/polyether elastomer is replaced by other the acceptable plastics, e.g. polyfluoroethylene, the triclosan activity is improved so that it comes within acceptable limits. Furthermore, other plastic parts of such pump dispensers, such as polypropylene inner walls, have not been found to absorb excessive amounts of triclosan and do not seriously reduce the anti-plaque activity of the dentifrice, apparently due to the percentage of terpenes in the flavoring agent in the dentifrice contained.

A panel test is carried out comprising at least ten human subjects using the dental care agent according to this example dispensed from polyethylene terephthalate and polyethylene-lined tubes, in brushings twice a week. day for one month, during which plaque evaluations of the individuals' teeth are made by trained observers. The test results establish that the dentifrice composition has a decided anti-plaque activity which is similar to the activity also observable in tests with the mouthwashes of Examples 1 and 2, and also proves that the triclosan has not been unacceptably inactivated and is still present in an effective antibacterial and anti-plaque component in the dental care product.

A toothpaste of the above composition is prepared and stored in "Guala" pump dispensers with bellows membranes of the "Arnitel" type. The dentifrice is also filled on laminated tubes with polyethylene terephthalate on the inside of the laminate in contact with the dentifrice. The toothpastes are aged at 5, 25 and 39°C for two, four and six weeks. After such aging periods, the dental care products are dispensed at a rate of approx. 1.5 g per day, and at weekly intervals, the triclosan contents in the dispensed dental care products are determined using analyses. In the case of the "Guala" pump dispenser, the dispensed toothpaste loses approx. 27% of triclosan, which is too much and unfortunate. The loss is approximately constant regardless of storage temperature or storage time, which can be explained by absorption of the triclosan in the pump membrane with which it is brought into contact before dispensing. Such membrane is of a co-polyester/polyether elastomer which should be avoided as a container material or as part of a container or dispenser for dentifrices containing triclosan. When the elastomeric co-polyester/polyether membrane is replaced with one made of any of the aforementioned acceptable plastics, such as polyethylene terephthalate, which can serve as membrane materials in modified pump dispensers (modified to compensate for different properties of such plastics), however, triclosan stability is increased, and the dispensed mixture is satisfactory and effective as an anti-plaque toothpaste.

Gel toothpaste mixes in such packages behave similarly in terms of triclosan stability after storage and dispensing.

In similar tests, small losses (less than 5%) of triclosan are obtained when polyethylene terephthalate-lined tubes are used, indicating that the presence of the terpenes (0.1% or more of the mixture), including limonene, in the flavoring (or the flavoring itself ) prevents the loss of the triclosan or its inactivation. When polyfluoroethylene-lined tubes are used, there will be little loss of triclosan even when the flavoring agent is omitted from the dentifrice mixture, and this will also be the case when polyvinyl chloride is used as the liner in contact with the dentifrice, or when polysulfone or polycarbonate packaging parts are in contact with the dentifrice . As previously indicated, however, one will not usually use such as the three last-mentioned plastics.

When in the reported test where the dentifrice is dispensed from the Guala dispenser, "Gantrez S-97" is replaced with 4.76 parts of "Luviform" (35%), the difference being made up by deionized water, no appreciable difference in triclosan stability is obtained between the mixtures.

In the above-mentioned mixtures, the polishing system is

a siliceous system and not one based on alumina. When the polishing agent is changed to an alumina, the problems which have previously been mentioned are reduced

some plastics, but still available. The presence of terpenes in the dentifrices also promotes triclosan instability, as such presence does in similar dentifrice compositions based on silicon-containing polishes.

Example 5

The mouthwashes and dentifrices according to the above examples can be varied in composition -10% and -25% for the various ingredients, provided that such percentages are not outside the ranges indicated elsewhere in the description, and it is possible to obtain operative and effective antibacterial and anti-plaque products which can be dispensed in an effective anti-plaque state from the aforementioned dispenser containers which are made of compatible plastics. The products can also be modified by being converted into dental care gels, oral gels, pastes, liquids, lozenges, capsules, tablets and pads of the types previously mentioned in the description. Such products will also behave in similar ways, in that the triclosan or other halogenated diphenyl ether-containing or antibacterial anti-plaque agent is sufficiently stable in the presence of polyfluoroethylene, polyvinyl chloride, polycarbonate and polysulfone as packaging or packing component materials, even when no flavoring agent and no terpenes are present in oral preparations, and are stable in the presence of polyethylenes, polypropylenes, polyethylene terephthalates, polyallomers, nylons and polymethylpentenes, as packing or component materials, provided that a terpene, such as limonene, or a stabilizing flavor component is present in the oral preparation . Like the other dentifrices and mouthwashes previously discussed, applications of such materials will preferably be avoided due to excessive absorption or other adverse effects with respect to triclosan by co-polyester/polyether and other elastomers.

Example 6

Tooth care agents with the compositions according to examples 3 and 4 are made and dispensed after one month of storage at 30°C in squeezable toothpaste tubes lined with polyethylene in one case, and polyethylene terephthalate in another, on the bristles of toothbrushes, as shown in Figure 1. The amounts of toothpaste on the toothbrush is in the range 0.8 - 2.0 g, with 1 - 1.5 g being preferred. When 1.5 g is dispensed, the active triclosan in the toothpaste is on the brush, approx. 4 mg (since only 10% of the triclosan is inactivated). When storage is for a longer period of time or at a higher temperature or with a more destabilizing plastic substance in contact with the dental care agent during storage, the packaged preparations may contain approx. 3 mg of triclosan in the 1.5 g on the brush. With 1 g of toothpaste on the brush, the amounts of triclosan will be respectively about. 2.7 mg and approx. 2 mg. For dental care products containing from 0.25 to 0.6% triclosan, the toothbrush can contain from 2.2 to 8 mg of triclosan if the triclosan inactivation is in the range of 10 - 25%, or up to approx. 9 mg when no triclosan is inactivated .

The described packaged dental care agents are used to brush the teeth with, as usually approx. 0.8 - 2 g is dispensed on toothbrushes for each brushing. Brushing takes place twice a year. day, morning and evening, one minute each time for four weeks, after which a clear improvement in anti-plaque effect is obvious compared to a control toothpaste that does not contain triclosan. Improvement in anti-plaque action is also visible compared to a control unflavored (non-terpene containing) containing triclosan in a dentifrice package in polyethylene and polyethylene terephthalate-lined tubes.

Claims (11)

1. Oral care agent with 0.02-1% of a halogenated diphenyl ether as a substantially water-insoluble, non-cationic, antibacterial anti-plaque agent, wherein the oral care agent is packaged in a dispenser container whose walls in contact with the oral care agent consist of polyethylene- or polyethylene terephthalate material, characterized in that it contains 0.01-2% of a stabilizing terpene and/or an aroma agent, which makes the polymeric material compatible with the antibacterial agent. 2. Oral care agent according to claim 1, characterized in that the halogenated diphenyl ether is triclosan. 3. Oral care product according to claim 1 or 2, characterized in that the stabilizer is a terpene. 4. Oral care product according to one of claims 1-3, characterized in that the stabilizer is a limonene. 5. Oral care agent according to one of claims 1-4, characterized in that it also contains polyphosphate as a calculus-preventing agent. 6. Oral care product according to claim 5, characterized in that the polyphosphate is tetrasodium or tetrapotassium pyrophosphate or a mixture thereof. 7. Oral care product according to one of claims 1-6, characterized in that it contains a source of fluoride ions which provides 25-5,000 ppm fluoride ions. 8. Oral care product according to one of claims 1-7, characterized in that it also contains 0.5-4% of a polycarboxylate. 9. Oral care agent according to claim 8, characterized in that the polycarboxylate is a polyvinyl methyl ether/maleic acid or maleic anhydride copolymer. 10. Oral care product according to one of the preceding claims, characterized in that the dispenser container is opaque. 11. Oral care agent according to one of the preceding claims, characterized in that it contains a stabilizing terpene which is not a component of an aroma agent.