NL8903186A - PACKED ANTI-PLAQUE ORAL PREPARATIONS. - Google Patents

Description

Packaged anti-plaque oral preparations.

The present invention relates to packaged anti-plaque oral preparations comprising an anti-plaque antibacterial agent such as 21,4,4'-trichloro-2-hydroxydiphenyl ether (THDE) as an effective anti-plaque component, which preparations are packaged in a packaging comprising a polymeric plastic material in contact with the oral composition, which plastic is compatible with the antibacterial agent in the composition. Although various plastics may reduce the anti-plaque activity of said antibacterial agents, certain plastics, such as polyfluoroethylene and polyvinyl chloride, have been found to be compatible with THDE and have been discovered not to have excessive losses of antibacterial and anti-plaque activity. oral preparation contents upon storage, at room temperatures or elevated temperatures. Even if the contacting plastic part or the contacting plastic parts of the plastic packaging is / are not per se fully compatible with the antibacterial agent, compatibility can be improved by incorporating a stabilizing amount in the oral preparation of a stabilizer for the antibacterial agent, such as a terpene, for example 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 sufficient amount that the oral preparation, such as that which is packaged or dispersed, is an effective anti-plaque preparation, the production of which is an object of this invention. The invention also relates to a method of contacting oral surfaces with oral preparations containing effective amounts of an anti-plaque agent. The invention also includes a toothbrush with an effective amount of an anti-plaque dentifrice on its bristles.

Plaque on teeth is considered one of the causative factors of negative periodontal conditions, and dental plaque is a precursor to tartar. Plaque can form on any part of the tooth surface, including the gum line.

As a result, teeth look matte and in addition to promoting the development of tartar, it is involved in the development of gingivitis. Therefore, oral preparations containing anti-plaque agents, which prevent or inhibit the development of plaque on the teeth, are valuable dental care agents.

While it has been known that antimicrobial agents in oral preparations can reduce plaque, sometimes being particularly effective in combination with other materials, several such antibacterial compounds have deleterious properties which reduce their use in such oral preparations. For example, cationic antibacterial compounds such as quaternary ammonium halides tend to discolour the teeth and can be inactivated in the presence of anionic materials in the oral preparations (and often it will be desirable to use anionic surfactants or detergents in oral preparations).

Essential 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 by various plastics, as discovered by applicant. Therefore, an object of this invention was to incorporate antibacterial anti-plaque agents such as halogenated diphenyl ethers, in particular THDE and DDDE, and corresponding anti-plaque agents into oral preparations, and to store and administer such preparations in from packages or reservoirs, in which they do not lose an excessive portion of the activity of such an antibacterial agent during storage, for intended use. In prior art triclosan dentifrices such as this one. delivered from the operator, the triclosan release was not present in an effective amount to significantly reduce plaque when used once or twice daily at 1.5 g / use for one minute of brushing, which is believed to be approximately normal cleaning use. To be effective, such use should result in at least a 25% decrease 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 compound of the present packaged oral preparations is THDE, which is also known as triclosan. This is disclosed in U.S. U.S. Patent 4,022,880 as an antibacterial agent in combination with an anti-tartaric agent (which provides zinc ions) and in German Patent Application (OLS) No. 35 32 860 in combination with a copper compound. It is also disclosed in European Patent Applications Nos. 0 161 898 and 0 161 899, and in European Patent Application 0 220 890, it is disclosed in dentifrices with polyethylene glycol and Dliebased flavoring.

Various oral preparations or dental preparations are known, including paste, gel, powder, liquid, tablet, lozenge, sachet and packaged dentifrices, liquid mouthwashes and mouthwashes in the form of tablets; and professionally used dental treatments (such as dental hardeners, for example, fluoride solutions). Such products were packaged in deformable tubes, pump dosers, pressurized dosers, packages, bottles, cap bottles and other packaging means. Although deformable or collapsible tubes were originally made of metals such as lead and aluminum, and bottles were made of glass, in recent years such packaging materials have often been made of synthetic organic polymeric plastics or made of laminates comprising such plastics. Interactions between oral preparations and the materials of packaging materials in which they were packaged were known, such as reactions between toothpaste and aluminum packaging agents, and to prevent such reactions, packaging agents were specially treated or other packaging materials were used. Applicants do not believe, however, that prior to their invention it was known in the art that some plastic packaging materials have the anti-plaque action of halogenated diphenyl ether antibacterial compounds used in oral preparations and packed in packaging materials in contact with such plastics, nor do they believe that it has been discovered that such plastics could be used for such packaging materials without causing losses of the anti-plaque actions of halogenated diphenyl ethers or that losses of such actions of oral preparations packaged in contact with "reactive" plastics (which react with the oral formulation, absorb or otherwise reduce its anti-plaque activity) could be inhibited or prevented by including terpenes such as limonene, and other flavoring components for oral formulations in the formulations.

In accordance with certain aspects, the present invention relates to an oral preparation containing an effective anti-plaque amount of a substantially water-insoluble non-cationic antibacterial agent when dosed, is packaged in a dosing package comprising a solid polymer material such as a synthetic organic polymer plastic material in contact with the oral preparation, which solid polymer material is compatible with the antibacterial agent in the presence of the oral preparation, and does not cause excessive loss of antibacterial and anti-plaque activity of the oral preparation during storage in the packaging means (such as at temperatures in the range of 20-40 ° C for several weeks, preferably up to a year or more). The packaged oral preparation is usually a toothpaste, gel dentifrice or mouthwash packed in a deformable dispensing tube, pump dispenser or bottle, respectively, without plastic parts that adversely affect the anti-plaque action of the antibacterial agent (which is preferably a halogenated diphenyl ether such as triclosan) or which contain in the oral composition a component which inhibits or inhibits any such adverse "reactions" between the antibacterial agent and any plastic part of the packaging agent which may otherwise adversely affect the anti-plaque action.

The invention will be readily understood from the description thereof in this description in connection with the drawing in which: Fig. 1 is a perspective view of a toothpaste tube and its removed cap, with toothpaste squeezed from the tube onto a brush; FIG. 2 is an enlarged partial cross-sectional view of a laminated wall of a squeezable tube, such as that of FIG. 1; Fig. 3 is a vertical upright cross-section of a pump doser for containing and dosing toothpaste or dentifrice, as desired; Fig. 4 is an upright side view of a heat-sealed sachet or pouch containing an amount of disposable toothpaste? and FIG. 5 is an upright view of a sealed mouthwash bottle.

In Figure 1, the packaged anti-plaque toothpaste article 11 comprises a deformable toothpaste tube 13 containing anti-plaque toothpaste 15, shown as being dosed in a unit dose of about 0.8-2 g by squeezing brush 17. Tube 13 is opaque and made of a synthetic organic polymer plastic material, such as polyfluoroethylene, or is, like a laminate lined with such a material, which does not adversely affect the anti-plaque action of the toothpaste during storage. Alternatively, tube 13 may be made of or lined with a plastic which has been found to adversely affect the anti-plaque activity of the toothpaste (by decreasing the anti-plaque activity of the antibacterial and anti-plaque halogenated diphenyl ether component of toothpaste) but in such a case the adverse effect of the anti-plaque action 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 components. Preferably, neither the toothpaste tube nor its cap 19 nor any other part of the tube that may come into contact with the toothpaste (such as a cap liner) should be made of co-polyester / polyether elastomer or other plastic, which essentially reduces the anti-plaque activity 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 isobutadienes, polychloroprene, butadiene rubbers and nitrile rubbers, which may absorb react with THDE or THDE. Such parts will preferably be made of plastics which do not adversely affect the anti-plaque action even in the absence of terpenes or other stabilizers in the dentifrice, but other destabilizing plastics may be used when such a stabilizer is present in the dentifrice counteract the inactivating effect of the plastic (except that elastomeric co-polyester / polyether and other adverse elastomers will preferably be avoided).

In Fig. 2, a laminate of polyfluoroethylene film 21, aluminum layer 23 and polyethylene film 25 is shown, with the polyfluoroethylene on the inside of the tube wall, where it will be in contact with the toothpaste.

The liner, not shown, for the cap 19 of Fig. 1 may also be polyfluoroethylene, so that all surfaces in contact with the toothpaste during storage are compatible with the halogenated diphenyl ether antibacterial component of the toothpaste and not the excessive losses of promote its anti-plaque effect during storage. Rather than having an inner wall 21 of polyfluoroethylene, the laminate may be made of polyethylene and wall 21 may be a polyethylene or other suitable polymer.

In Fig. 3, the toothpaste pump dispenser is of a type marketed by Guala S.p.A. from Italy, which is the subject of U.S. Patent 4,776,496. Pump doser 27, when ready for use, contains toothpaste in compartment 29, which is defined by bottom wall 31 and membrane 33. Depressing operating handle 35 causes a downward movement of membrane 33, pushing toothpaste through tube 37 and out of nozzle 39 . When the pressure on the operating handle 35 is released, membrane 33, which is elastic, returns to its original configuration and tube 37 and handle 35 return to their original positions. At the same time, bottom 31 is pushed upwards by atmospheric pressure. The various interior parts of the pump doser that come into contact with toothpaste are preferably of a plastic (s) that do not inactivate or inactivate the halogenated diphenyl ether antibacterial and anti-plaque agent. However, in the event that it is not possible to use plastics that have the necessary physical properties for the different contacting parts and are still compatible with the anti-plaque agent, other plastics can be used provided that the toothpaste composition (or gel dentifrice} includes a stabilizing agent, such as limonene or other active terpenes or flavoring components. It is considered best to avoid using any co-polyester / polyether elastomer, especially for the pump membrane (33), which plastic in the appears to be particularly active against THDE in oral preparations of the described types.

In Fig. 4, a sachet, pouch or package 41 is shown as a heat-sealed unit, with heat-seal on three sides thereof, represented by numbers 43 and 45. The fourth side 47 is simply folded back and does not need to be heat-sealed. turn into.

Within the sealed package is an oral preparation, such as toothpaste, which is not shown, and the inner surface of such a sachet is of a plastic material that does not exhibit excessive loss of anti-plaque activity of the antibacterial agent of the oral preparation contained promotes. As with the other packaging materials for the anti-plaque oral preparations, laminates can be used, with a plastic layer on the inside thereof, which does not adversely affect the antibacterial agent, or if the plastic nevertheless has such a negative effect, this can be counteracted by the presence in the oral preparation of a suitable stabilizer, which is preferably also useful as a flavoring agent thereof.

In Fig. 5, an opaque bottle 49 is shown with sealing cap 51 thereon. Both the bottle and the sealing insert (not shown) in the cap are of plastic materials compatible with the THDE, which is the anti-plaque component of the mouthwash detergent 53 contained in the bottle. As in the other examples given, in which a reactive plastic is used as the material of 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 activity of the THDE or other halogenated prevent diphenyl ethers.

In addition to the compositions described as being in the illustrated packages, which include gel dentifrices and thick liquids in place of toothpastes, such packages may also include dental treatment compositions suitable for professional use, such as dental hardeners, which include fluorides and phosphates, antibacterial agents, plaque-detecting dye solutions and other suitable oral preparations.

Also pressurized or aerosol formulations containing said anti-plaque agents may be packaged in pressurized packagings (usually pressurized with nitrogen gas) provided that the plastic contacting parts of such packagings are of materials that do not exhibit excessive loss of anti-plaque agents. cause plaque properties of the anti-plaque agents in the toothpastes or other oral compounds contained therein.

In addition to the various packaging means illustrated in the drawings and above, squeeze bottles, capsules, stopper bottles, spongy agents and various types of mechanical dosing packages can also be used. Because some of the halogenated diphenyl ether antibacterial compounds are photosensitive, it will sometimes be desirable for such packages to be composed of, or coated or laminated with a chemical or physical light-shielding material, many of which are known, for transmission to the oral preparation and to prevent the anti-plaque agent from any inactivating radiation, for example ultraviolet light. Also, such packages will often be desirably opaque to retain such actinic radiation to inactivate the anti-plaque agent of the contained oral composition, such as a toothpaste.

The cause (s) of inactivation by plastics of THDE and other substantially non-cationic antibacterial agents, which have anti-plaque properties in oral preparations, have not yet been determined. Studies to demonstrate this have not yet established the mechanism responsible for losses of such desirable activity, but results so far do not point to either chemical reactions or physical absorptions. Tests of basic mouthwash or mouthwash formulations containing THDE show that when such a mouthwash or mouthwash ages in dosage packs at room temperature, 38 ° C and 49 ° C, for up to 12 weeks, there will be excessive losses (above 25% of the original concentration of THDE), when the mouthwash has been in contact with such packaging walls and parts of low-density polyethylenes, high-density polyethylenes, polyethylene terephthalates, polypropylenes, nylons, polyalmers and polymethylpentenes. Similarly, high losses occur when such storage occurs in packaging materials with inner walls or co-polyester / polyether elastomer components such as those previously used in Guala pump membranes. It has been found that polyfluoroethylenes, such as polytetrafluoroethylenes, polyvinyl chlorides, polycarbonates and polysulfones do not absorb and do not react with excessive amounts of the THDE. Polycarbonates and polysulfones, however, are brittle and therefore often unsuitable for the use of dosing packaging parts. Polyvinyl chlorides sometimes give a strange taste to oral preparations, such as toothpastes, and will therefore often be avoided as a packaging material, except in certain cases where such a taste is compatible with the taste of the toothpaste flavoring agent used. Therefore, of all polymeric plastic materials available, polyfluoroethylene is specifically designated as a suitable material for use in the present packaging or packaging, which does not severely reduce the anti-plaque activity of the anti-plaque agents. However, as previously indicated by incorporation in the oral preparation of anti-plaque stabilizing compounds, such as terpenes, of which limonene is representative, essential oils (often containing terpenes), and other flavoring agents with similar stabilizing properties, one is able to reduce the activity losses of the anti-plaque agents when in contact with packaging materials or parts of packaging materials made of the various polymeric materials mentioned, thereby causing significant losses in anti-plaque activity. Therefore, one does not have to depend on polyfluoroethylene as a packaging dosage material, provided that the oral preparation also contains a stabilizing amount of terpene or other suitable stabilizer. When such a stabilizer 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 losses of the anti-plaque action of less than 25 occur. %, and preferably will be less than 10% even after storage at ambient temperature to relatively high temperature, for example, 20-40 ° C, for periods of several weeks up to a year or more.

It is believed that the most stable oral preparations are those which comprise a stabilizing amount of terpene or other suitable stabilizer and also include contacting packaging parts of polyfluoroethylene alone (or any of the other non-reactive plastics). Although the terpenes and essential oils are the primary stabilizers, according to the present invention, other flavors may also contribute to the stabilization of the anti-plaque material, either by acting on any destabilizing reaction or by inhibiting the absorption of the halogenated diphenyl ether by the plastic (or by other unknown mechanisms). Thus, there is a theory that some components of the oral formulations that tend to solubilize THDE may act to maintain it in the oral formulation and inhibit or prevent it from migrating into the plastic. On the other hand, it has also been found that such a solubilizing action can promote migration of the solubilized THDE into the plastic. Since the matter has not yet been resolved, the applicants are not bound by any theory. However, since it is desirable for the terpenes and other stabilizers to be flavors, this is not necessary, and the stabilizers may be useful for a stabilizing purpose only.

While it is preferred that the packages of this invention include internal walls (in contact with the compositions) of or lined with solid synthetic organic polymeric plastic materials, it is within the invention to include other solid (and / or film-forming) polymeric materials, whether or not they are synthetic, organic or even plastic. Thus, polyethylene glycols and methoxy polyethylene glycols, such as those of the CarbowaxR type, e.g., Carbowax 4000 and Carbowax 6000, can be used, often as lining materials in dosage packages of the disclosed compositions. Inorganic silicon polymers, such as siloxanes, and non-synthetic organic film-forming materials, such as gums, for example, carrageenan, tragacanth, karaya, are also useful as dosing liner materials. Additionally, solid polymeric materials, such as cellulose and starch and derivatives thereof, are also useful as packaging materials in contact with the contained antibacterial and anti-plaque preparations of the present packaged oral preparations.

The various oral packaged compositions of this invention that are most commonly made are toothpastes, dentifrice gels, and mouthwashes (sometimes called mouthwashes). The two former will be referred to herein as dentifrice and the latter will usually be referred to as mouthwash. Dentifrices include three main groups of components, the carrier, the polishing agent and the surfactant (or detergent). The antibacterial agent, for example halogenated diphenyl ether, is generally present in the carrier, which carrier usually constitutes about 10-80% (all numbers based on the final product) of the dentifrice. About 3-40% of the carrier will be water, about 7-77% will be wetting agent, such as glycerol, sorbitol, propylene glycol or mixtures thereof, and 0.5-10% will be a gelling agent, such as sodium carboxymethyl cellulose, Irish moss iota carrageenan or hydroxyethyl cellulose or the like, including mixtures thereof. The polishing material of the dentifrice will normally be present between 10-75% in a gel or toothpaste or between 50-99% in a powder, and such a 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, other known materials, or mixtures thereof. The surfactants include anionic, nonionic, cationic and zwitterionic surfactants, but often the use of nonionic surfactant is avoided due to its adverse effect on the antibacterial compounds, e.g. THDE, and the use cationic and zwitterionic surfactants are also often avoided because they tend to stain or darken teeth. Thus, synthetic organic anionic surfactants, which are also detergents, are the preferred cleaning agents in the dentifrices, and of these there is a preference for sodium lauryl sulfate and other sodium higher alkyl sulfates of 10-18 carbon atoms in the alkyl group thereof, although several other well known sulfated and sulfonated detergents may substitute for them, at least in part. Other active ingredients, such as compounds that provide fluoride, such as sodium fluoride or sodium monofluorophosphate, may be present to harden the teeth, generally in amounts giving about 0.001-1% fluoride to the composition, and additives such as flavors and sweeteners , in amounts of 0.1-10%, can be used. In addition, it may be desirable to use a polycarboxylate such as polyvinylmethyl ether maleic anhydride (PVM / MA) copolymer (GantrezR) in an amount corresponding to about 0.5-4% of the dentifrice. Such polycarboxylate material has been found to substantially improve the anti-plaque action of the antibacterial agent. Use of such polycarboxylates in oral preparations is described in U.S. Pat. U.S. Patent 4,627,977, the description of which is hereby incorporated by reference.

In mouthwashes, the oral carrier is preferably aqueous or alcoholic, the alcohol being ethanol or isopropanol. The carrier will normally make up 90-99.9% of the formulation, the alcohol of which is 5-30% and propylene glycol often makes up 2-10% based on the final product. The remainder of the composition, 0.1-10%, may include flavoring, surfactant, sweetener, colorant, anti-plaque agent and other special purpose additives. For dentifrice and mouthwash preparations, the effective amount of antibacterial anti-plaque compound (s) will normally be in the range of 0.02-0.2%, more preferably 0.03-0.1% in mouthwashes, and normally about 0, 25-1%, more preferably 0.25-0.5 or 0.6% in dentifrices, the ranges not exceeding 0.8% THDE in toothpastes and 0.2% THDE in mouthwashes (due to possible mouth numbing effects at higher concentrations), and not lower than indicated for the purpose of avoiding non-ineffectiveness against plaque at low concentrations. Preferably, the dosed compositions will contain amounts of the anti-plaque agent and THDE within the given ranges, but when the original concentration thereof is within the given range, a loss of up to 25% may be acceptable, and such dosed compositions are within the range. field of the invention.

In order to stabilize oral preparations which are packaged in packaging materials having plastic walls or other parts, in which the plastics belong to those reactive with the antibacterial agent, 0.01-2% terpene or stabilizer (s) will desirably be present in the oral preparations, preferably 0.05-1% and even more preferably 0.1-0.5%. Such stabilizers may be present in a suitable flavoring for the dentifrice, if desired (and this is often the case) and will be at least 5% of the flavoring, preferably at least 10%, most preferably at least 25% and most preferably at least 50% of the flavoring agent.

While the above description is primarily of interest to dentifrices and mouthwashes, other oral preparations (eg, including chewing gums) of the invention will contain equal amounts of components depending on the form of the preparation (liquids contain less as in the mouthwashes, and contain thicker components more as in the toothpastes), often with additives of special agents to suit the purposes of such preparations. Thus, dental hardening compositions can include fluorides and phosphates, such as sodium or potassium fluoride and sodium fluorophosphate, in both dentifrice and mouthwash agent bases, often in percentages in the range of 1-5%. Plaque-detecting dye solutions can include a suitable colorant (red is probably the most preferred color for such products) often at a concentration in the range 0.001-0.1% in a mouthwash base. The formulations of the other products will be adapted accordingly, as is known to those skilled in the art.

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

Of the antibacterial agents, the halogenated diphenyl ethers will generally contain bromine and / or chlorine, with chlorine being the preferred halogen. They will preferably be substituted with 1-3 hydroxyl groups and 1-4 halogens. More preferably, they will be substituted with 1 or 2 hydroxyl groups and 2 or 3 halogens, most preferably with four substituents, two on each ring. Among the more preferred of such compounds are 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether and 21,4,41-trichloro-2-hydroxydiphenyl ether, the latter compound (THDE) being the most preferred. Several replacement halogenated phenolic, non-cationic, virtually water-insoluble antibacterial anti-plaque compounds, such as those listed on page 11. 2-8 of application S.N. 07 / 398,566, filed August 25, 1989, which application is to be deemed incorporated herein by reference, will be substituted in whole or in part for the halogenated diphenol ethers, if deemed appropriate.

The terpenes, which term for the purpose of this disclosure includes the terpene hydrocarbons and oxygenated derivatives thereof, include such components as dl-limonene, menthol, diterpenes, polyterpenes and derivatives thereof, many of which are found in various essential oils and other flavoring agents. Also useful as a stabilizer for halogenated diphenyl ethers, they often contribute desirable flavors to the present oral compositions. The terpenes and their derivatives are thought to best balance limonene properties, although other terpenes, including those which are not flavoring, are also useful, as are other emulsifiable, lipophilic essential oils and flavoring agents containing stabilizing components.

The various plastics, which have been previously described, as the components of parts of packages and / or dosers, have only been described briefly, as it is believed that their chemical nature and degree of polymerization are well known, so that details thereof are unnecessary in this description . When further details are desired, we refer to Modern Plastics Encyclopedia, which is published on an annual basis by McGraw-Hill Ine., New York, New York.

As described in the incorporated S.N. 07 / 398,566, the compositions (according to the invention) may contain a source of fluoride ions capable of supplying 25-5000 ppm of fluoride ions in the oral cavity, preferably 300-2000 ppm and most preferably 800-1500 ppm. See the incorporated U.S. U.S. Patent 4,627,977 for further details regarding suitable fluorides, properties and manufacturing details. The fluoride acts primarily as a dental hardener, but also serves to stabilize polyphosphate anti-dental calculi compounds when present. Preferably such polyphosphate is a mixture of sodium and potassium pyrophosphates and it is also stabilized by Gantrez S-97. Quantity ranges are given in U.S.S.N. 07 / 398,605, filed August 25, 1989, which application is hereby incorporated by reference, and in U.S. Pat. U.S. Patent 4,627,977 and U.S. Pat. U.S. Patent 4,806,340, which are incorporated herein by reference.

For other details of formulations, components, additives, fabrications and uses, see the patent, descriptions and applications cited herein in this specification, which are hereby incorporated by reference.

Manufacture of the described oral preparations is by any of the various standard techniques for producing such classes of preparations. Referring to specific examples for simplification, THDE is dosed and / or dissolved in the carrier portion of the dentifrice and the terpene is present in the flavoring agent. To prepare a dentifrice, the carrier containing glycerol, sorbiol, and propylene glycol, gelling agents and suitable additives (including GantrezR S-97 and triclosan) is prepared, and the carrier and aqueous anionic detergent (preferably sodium lauryl sulfate or a mixture of sodium lauryl sulfate and sodium methyl cocoyl taurate). solution, followed by mixing in the polishing agent composition with the pre-mix. Finally, flavoring agent comprising terpene dissolved in ethanol is mixed in and the pH is adjusted. To prepare the mouthwash detergent, the various components thereof are merely mixed in the alcohol or aqueous alcoholic medium and stirred until dissolved. A mixture of sodium lauryl sulfate (SLS) and sodium methyl cocoyl taurate (in a ratio in the range 1: 4 to 4: 1) is preferably used as the anionic surfactant component of the mouthwash detergent, which, due to the presence of the taurate, provides a corresponding desired decrease in SLS quantity is allowed, which is desirable. Other oral preparations are prepared according to corresponding relevant procedures.

When packaging the oral compositions in the dosage packages it will be desirable to avoid contact of the compositions with plastic parts of co-polyester / polyether elastomer and it will also be desirable to avoid contact of any composition containing no stabilizing agent (such as terpene or flavors containing it) with plastic parts made from these plastics, which have been previously mentioned in this specification as being reactive with THDE and other such antibacterial and anti-plaque compounds. It will be particularly important to avoid said plastic parts as a container with reservoirs and other packaging means, tubes, pumps or equipment, in which the oral preparation can be held for any desired length of time or held for shorter periods of time at elevated temperatures.

Even when preparing the packaged preparations of this invention and avoiding contacts of the oral preparations containing THDE, or other halogenated diphenyl ether antibacterial preparations with the reactable plastics, it will still be desirable to expose such packaged preparations to heat and to light , both of which have been proven to minimize loss of anti-plaque activity. Thus, the invented compositions are preferably stored and packaged in opaque packages and dispensers at a temperature in the range of 10-38 ° C and are also stored at such a temperature. Incidentally, the packaged preparations can be stored and used in a normal manner and the desired anti-plaque effects thereof will be obtained. Such effects have been verified by laboratory studies and by evaluations of the teeth of volunteers, who were members of human panels, using the different packaged preparations and controls as indicated. Significant improvements in the anti-plaque actions of the packaged compositions of this invention were observed, compared to the control packaged compositions, wherein the package contained plastic parts reactive with the halogenated diphenyl ether antibacterial compound and which did not contain a stabilizing agent in the oral preparation. Such improvements were also found when packages made of reactive plastics (but not copolyester / polyether elastomers) were used with oral preparations containing terpenes, and compared with controls in which the oral preparations did not contain terpenes and no flavors.

The following examples illustrate but do not limit the invention. Unless otherwise indicated, all percentages and ratios in these examples, and the pending claims are based on weight, and all temperatures in ° C.

Example I

Component Percentage

Water, deionized 47.84

Sorbitol (70% aqueous solution) 20.00

Ethanol (95% aqueous solution) 12.50

Glycerol 10.00

Propylene glycol 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 **** (IrgasanR DP 300, manufactured by CIBA-GEIGY) 0.05 100.00 * Polyvinyl methyl ether / maleic anhydride copolymer (GAF Corp.), ** Sodium methyl cocoyl taurate, *** Contains at least 25% terpenes at least 25% limons include, **** HDE {21,4,4 * -trichloro-2-hydroxydiphenyl ether).

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

The resulting mouthwash had excellent cosmetic stability and acceptable taste, and the flavoring and triclosan were sufficiently dissolved, such solution being at least in part due to the presence of the Tauranol WSHP. When only 0.25% SLS was used as the anionic surfactant, the solubilities of the flavoring and triclosan were not sufficient. Although such solubilities could be increased by using more SLS, the maximum acceptable value of such a compound in the mouthwash waters was often about 0.25% and the TauranolR WSHP and SLS were safe and acceptable in the amounts used. The described mouthwash waters were tested in vitro to compare the bioavailability of triclosan compared to comparable mouthwash waters with formulations without the Tauranol WSHP, in one case, and to replace with half as much of a nonionic surfactant (Pluronic F-127) in the other case.

In triclosan uptake assays, where triclosan absorption was measured on hydroxyapatite disks coated with saliva, and protein absorption (inhibition zone) assays found that the presence of the mixed anionic surfactant resulted in comparable bioavailability of triclosan compared to such availability from the SLS-only formulation, and such availability is considerably higher for the formulations containing no nonionic detergents than for those containing the nonionic detergents (PluronicR F-127).

The mouthwash with the formulation of this example was aged at elevated temperature (41 ° C) for three and five weeks, which was considered to be equal to resp. at least about six months and one year of actual aging at room temperature.

Such aging tests were performed in dosing packages (bottles) made of glass, polyvinyl chloride and polyethylene terephthalate (or lined with the plastic materials). Although chemical analysis of the mouthwash waters after such an aging period did not find any losses of triclosan, when the glass packaging is, losses of triclosan from the mouthwash waters were noted, when the packaging was of polyethylene terephthalate or of this sample of polyvinyl chloride, but clearly less than an acceptable 25% (of the original concentration), and could be below 5 or 10%.

When, instead of the flavoring mixture, dl of limonene was used in 0.1, 0.2 and 0.4% amounts, even better stabilizations of the triclosan in the packaged dentifrice of the invention described were obtained, and such stabilizations also resulted when other terpenes of each of the different ethical oils, and flavoring agents, were present in sufficient amounts. Such good results were also obtained when the packaging material or the liner thereof was a polymethylpentene, polyalmer, polypropylene, high or low density polyethylene, and nylon, although such materials in the absence of the flavoring mixture (and containing terpenes) were substantial and caused excessive losses of available triclosan from the mouthwash that had been stored, especially in the case of elevated temperatures.

Example II

Component Percentage

Water, deionized 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 of the above formulation was tested for the availability of triclosan after storage for three weeks in dose containers made of or lined with different plastics. The tests were performed at room temperature, 38 ° C and 49 ° C with the elevated temperature storage simulating a longer storage time to one year or more at room temperature. Losses of more than 25% of the triclosan of the stored mouthwash water were noted when the packages were of polymethylpentene, polyallomer, polypropylene, high and low density polyethylene and nylon, with unacceptable results (excessive losses) noted when the packages of polypropylene, polyethylene and nylon (with nylon as worst).

When the packaging material or liner was polyvinyl chloride, polycarbonate, polysulfone or polyfluoroethylene, for example polytetrafluoroethylene or TeflonR, virtually no losses of triclosan occurred. Losses of triclosan from mouthwash waters stored in packages of or lined with said polymers (polymethylpentene, etc.) could be reduced in the same manner as described in Example I by incorporation into the mouthwash water formulation of limonene, other terpenes, or essential oils containing such wherein the amount of terpene was preferably at least 0.1%, more preferably greater, for example 0.2% or 0.4%, on a final product basis. In some cases, even the use of flavorings, which do not contain a clear amount of terpenes, will have a positive effect, although such effect is not expected to be as good as with terpenes in the formulation.

Example III

Component Percentage

Propylene glycol 10.00

Jota carrageenan 0.75

Sodium fluoride 0.33

Sorbitol (70%) 30.00

Sodium saccharin 0.30

Titanium dioxide 0.50

Sodium hydroxide (50% aqueous solution 0.80

Water, deionized 27.71

Luviform ™ * (35% solution) 4.76

Zeodent ™ ** 113 20.00

Sident ™ *** 22S 2.00

Sodium lauryl sulfate (94% active) 1.60

Flavoring 0.95

Triclosan 0.30 100.00 * Polyvinyl methyl ether / maleic anhydride copolymer (BASF Corp.), ** Silica polishing agent (J.M. Huber Corp.), *** Silica thickener (Degussa Co.).

A dentifrice of the above formulation was normally prepared and used as a medium for testing the stability of triclosan when the dentifrice containing it was exposed to various plastics used as packaging materials or as parts of the dosers in which dental products are stored and from which they are dosed. The plastics for the tests are Pibiflex ™ 46, made by Inmont, and Arnitel ™ 460 EM, modified by AKZO, which are plastics used as membranes or bellows of a pump doser, as illustrated in Fig. 3. Six samples of plastics tested three of each of said plastics, each of three being treated with a different mold release agent (to determine whether the nature of the release agent is important to the problem of triclosan stability 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 O Master ™ (5% oleoamide and 95% polypropylene). After two weeks of storing the test samples in contact with the dentifrice at different temperatures (room temperature, 38 ° C, and 49 ° C), the dentifrice was removed from the plastic packaging materials and the plastics were washed with water and dipped in methanol to dissolve all triclosan discharge, which may have been absorbed by these materials during storage. The washing methanol was collected and analyzed by high performance liquid chromatography. It was found that almost the same type of absorption of triclosan occurred with different membrane materials and although there were variations among themselves and therefore somewhat dependent on the release agents used, the results were almost the same in all cases.

The co-polyester / polyether elastomers have been found to absorb significant percentages of triclosan from the dentifrice, which results have been confirmed when the co-polyester / polyether elastomers are used as bellows materials in pump dispensers containing the described dentifrices and other dentifrices within the invention. Accordingly, it is considered undesirable to bring co-polyester / polyether elastomers into contact with the subject dentifrices or mouthwashes, even when the dentifrices and mouthwashes contain flavors comprising terpenes (which are present in the flavors of the dentifrice formulation) in an amount of at least 0.1% of the dentifrice.

When the tests were repeated using topical Guala pump dosers as packaging 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 acceptable plastics for example polyfluoroethylene, the triclosan activity was improved to within acceptable limits. Likewise, other plastic parts of such pump dispensers, such as polypropylene inner walls thereof, have not been found to absorb excessive amount of triclosan and not to seriously reduce the anti-plaque action of the dentifrice, probably due to the presence of terpenes in the flavors of it contained dentifrice.

A panel test was conducted consisting of at least 10 people using the dental powder of this example dosed from polyethylene terephthalate and polyethylene lined tubes, brushing teeth twice daily for one month during which time plaque evaluations of the teeth were made by trained observers. The test results showed that the dental powder composition had a clear anti-plaque effect similar to that observed in tests with the mouthwash water of Examples I and II, and it was also proven that triclosan was not unacceptably inactivated, and was still present in an effective antibacterial and anti-plaque amount in the tooth powder.

Example IV

Component Percentage

Glycerol 7.00

Propylene glycol 3.00

Jota carrageenan 0.75

Sorbitol (70%) 30.00

Sodium saccharin 0.30

Sodium fluoride 0.33

Titanium dioxide 0.50

GantrezR S-97 (13% solution) 15.00

Deionized water 16.07

Sodium hydroxide (50% aqueous solution) 0.80

ZeodentR 113 (J.M. Huber Corp.) 20.00

SylodentR 15 (a silica thickener; W.R. Grace Corp.) 3.00

Flavor 1 0.95

Sodium lauryl sulfate 2.00

Triclosan 0.30 100.00

A toothpaste of the above formulation was prepared and stored in Guala ™ pump dispensers with bellows membranes of the Arnitel type. The dentifrice was also filled in laminated tubes with polyethylene terephthalate on the inside of the laminate, in contact with the dentifrice. The dentifrices are aged at 5 ° C, 25 ° C, and 39 ° C for two, four, and six weeks. After such aging periods, the dentifrices were dosed at about 1.5 g per day and after weekly intervals, the triclosan amounts of the dosed dentifrices were determined by analysis. In the case of the Guala pump doser, the dosed dentifrice lost about 27% of the triclosan, which is excessive and rejectable. The loss was approximately constant, regardless of the storage temperature or the time of storage, which can be explained by absorption of the triclosan to the pump membrane with which it was contacted for dosing. Such a membrane is of a co-polyester / polyether elastomer, which class of plastics should be avoided as a packaging material or as a part in a package or doser for dentifrice containing triclosan. However, when the elastomeric co-polyester / polyether membrane was replaced with one made of any of the aforementioned acceptable plastics, such as polyethylene terephthalate, which may serve as membrane material in modified pump metering units (modified to compensate for the different properties of such plastics) the triclosan stability is increased and the dosed preparation is sufficient and effective as an anti-plague toothpaste.

Gel toothpaste formulations in such packages behaved similarly to triclosan stability after storage and upon dosing.

In similar tests using polyethylene terephthalate-lined tubes, a slight loss (less than 5%) of triclosan was noted, indicating that the presence of the terpenes (0.1% or more of the preparation), including limonene , in the flavoring agent (or the flavoring agent itself) prevents loss of the triclosan or inactivation thereof. When polyfluoroethylene-lined tubes have been used, there will even be little loss of triclosan if the flavoring agent is omitted from the dentifrice and this will also be the case when polyvinyl chloride is used as the feed material in contact with the dentifrice or when polysulfone or polycarbonate packaging parts are in contact with such dentifrice. However, as previously indicated, such three of the latter plastics will normally not be used.

In the said test in which the dentifrice was dosed from a Guala doser, when the Gantrez S-97 was replaced by 4.76 parts of Luviform (35%) with the difference that it was made in deionized water, no desired difference in triclosan stability was noted between the formulations.

In the above formulations, the polishing system was a siliceous system, preferred over one based on alumina. When the polishing agent was replaced with an alumina agent, the aforementioned problems noted with some plastics were alleviated but persisted. Also, the presence of terpenes in the dentifrices promoted triclosan stability as such presence in corresponding dentifrice compositions based on siliceous polishes.

Example V

The mouthwash waters and the dentifrices of the previous examples can be varied in composition + 10% and + 25% for the various components thereof provided that such percentages are not outside the ranges given elsewhere in this description, and effective and effective antibacterial and anti-plaque products are available, which can be dosed in effective anti-plaque condition from the said dosing packages, which are made of compatible plastics. The products can also be modified by being converted into dental gels, oral gels, pastes, liquids, lozenges, capsules, tablets and sachets of the types mentioned above in the description. Such products will also behave similarly, with the triclosan or other halogenated diphenyl ether or antibacterial anti-plaque agent being sufficiently stable in the presence of polyfluoroethylene, polyvinyl chloride, polycarbonate and polysulfone packaging or packaging component materials even when no flavoring agent and no terpenes are present in the oral preparations, and while stable in the presence of polyethylenes, polypropenes, polyethylene terephthalates, polyallomers, nylons and polymethyl pentenes as packaging or component materials, provided that terpene, such as limonene, or a stabilizing flavoring component is present in the oral preparation. As with the other dentifrices and mouthwashes, commented above due to excessive absorption or other adverse effect with respect to triclosan by co-polyester / polyether and other elastomers, use of such materials will preferably be avoided.

Example VI

Dentifrices of the formulations of Examples III and IV were made and dosed after one month of storage at 30 ° C in squeezable toothpaste tubes, lined with polyethylene in one case, and polyethylene terephthalate in another, on bristled toothbrushes as illustrated in FIG. 1. The amounts of toothpaste on the toothbrush were in the range of 0.8-2 g with 1-1.5 g as being preferred. When dosing 1.5 g, the amount of active triclosan in the dentifrice on the brush was about 4 mg (inactivated with only 10% of the triclosan). When stored for a long time or at a high temperature or with a more destabilizing plastic, in contact with the dentifrice during storage, the packaged preparations may contain about 3 mg of triclosan in the 1.5 g on the brush. Thus, with 1 g of dentifrice on the brush, the amounts of triclosan will be about 2.7 and 2 mg, respectively. For dentifrices containing 0.25-0.6% triclosan, the toothbrush may contain 2.2-8mg triclosan when the triclosanin activation is in the range of 10-25% or up to about 9mg when no triclosan is inactivated.

The described packaged dentifrices were used to brush teeth with typically about 0.8-2 g dosed on toothbrushes for each brushing. Brushing is done twice daily, in the morning and evening, for one minute each for four weeks, after which there has been a marked improvement in anti-plaque activity compared to a control dental product containing no triclosan. Improvement in anti-plaque activity was also seen compared to a flavorless control (containing no terpene) containing triclosan in a dentifrice package in polyethylene and polyethylene terephthalate lined tubes.

The present invention has been described with respect to illustrative examples and embodiments thereof, but is not limited to them, as it is understood that anyone skilled in the art with the present disclosure will be able to substitute for him or her and equivalents without departing from the invention.

Claims (23)

An oral composition containing an effective anti-plaque amount of a substantially water-insoluble non-cationic antibacterial agent when dosed, which composition is packaged in a dosage package comprising a solid polymer material in contact with the oral composition, which solid polymer material is compatible with the antibacterial agent in the presence of the oral composition and does not cause excessive loss of antibacterial and anti-plaque activity of the oral composition upon storage in the package. The packaged oral preparation according to claim 1, wherein the solid polymeric material in contact with the oral preparation comprises a solid synthetic organic polymeric plastic material. A packaged oral preparation according to claim 2, which is a toothpaste, gel or liquid dentifrice, a liquid mouthwash, or a paste, gel or liquid dentifrice, the antibacterial agent comprising a halogenated diphenyl ether, and the package being a deformable dosing tube, a pump - sealer, a pressurized doser, or a sachet for toothpaste, gel dentifrice, or paste or gel dentifrice, or a bottle or other packaging means for a liquid dentifrice, mouthwash or dentifrice. A packaged oral preparation according to claim 3, wherein the antibacterial agent consists of a halogenated diphenyl ether substituted with 1-3 hydroxyl groups and 1-4 halogens selected from the group consisting of chlorine and bromine. A packaged oral preparation according to claim 4, which is a toothpaste, gel dentifrice or liquid mouthwash, and wherein the halogenated diphenyl ether antibacterial agent comprises a diphenyl ether substituted with 1 or 2 hydroxyl groups and 2 or 3 halogens selected from the group consisting of chlorine and bromine and the packaging means is a deformable dispensing tube, a pump dispenser or a sachet for toothpaste or gel-toothpaste or a bottle or dispenser for liquid mouthwash. The packaged oral preparation of claim 5, wherein the halogenated diphenyl ether antibacterial agent is 2 ', 4,4'-trichloro-2-hydroxydiphenyl ether (THDE) in an amount of about 0.02-1% by weight. A packaged oral preparation according to claim 6 which is a liquid mouthwash containing 0.03-0.1% THDE wherein the solid polymeric material in contact with the oral preparation in the package comprises polyfluoroethylene or polyvinyl chloride. Packaged oral preparation according to claim 6, which is a toothpaste or gel-toothed agent containing 0.25-0.5% THDE in a deformable dosing tube, a pump doser or a sachet and the solid polymeric material in contact with the oral preparation in the packaging polyfluoroethylene or polyvinyl chloride. The packaged oral preparation according to claim 6, which is a toothpaste or gel-toothpaste containing about 0.3% THDE and wherein the packaging means is a deformable dosing tube or a pump doser. The packaged oral preparation according to claim 8, wherein the packaging means is a deformable metering tube, the inner surface of which contacts the oral preparation comprises polyfluoroethylene. A packaged oral preparation according to claim 6, wherein the solid polymeric material in contact with the oral preparation comprises a synthetic organic non-elastomeric plastic material. A packaged oral preparation according to claim 1, containing a stabilizing amount of a terpene or flavoring agent which stabilizes the antibacterial agent in the presence of said solid polymeric material. A packaged oral preparation according to claim 7, which is a liquid mouthwash containing a stabilizing amount of a terpene or a flavoring agent that stabilizes the THDE in the presence of synthetic organic non-elastomeric polymeric plastic material in contact with the oral preparation. A packaged oral preparation according to claim 8, which is a toothpaste containing a stabilizing amount of a terpene or a flavoring agent that stabilizes the THDE in the presence of synthetic organic non-elastomeric polymer plastic material in contact with the oral preparation. The toothpaste according to claim 14, wherein the amount of stabilizing terpene (s) and / or flavoring (s) in the toothpaste is in the range of 0.01-2% and said plastic material is selected from the group consisting of polyethylenes, polypropenes , polymethylpenes, polyallomers, nylons, polyfluoroethylenes, polyvinyl chlorides, polycarbonates and polysulfones. Packaged liquid mouthwash according to claim 13, wherein the amount of stabilizing terpene (s) and / or flavoring agent (s) in the mouthwash is in the range of 0.01-2% and said plastic material is selected from the group consisting of polyethylenes , polypropenes, polymethyl pentenes, polyallomers, nylons, polyfluoroethylenes, polyvinyl chlorides, polycarbonates and polysulfones. Packaged oral preparation according to claim 12, wherein the terpene content of the preparation stabilizer is a flavoring component and is in the range 0.01-2%. A packaged oral preparation according to claim 17, wherein the terpene is limonene. A packaged oral preparation according to claim 11, which comprises 0.5-4% polyvinyl methyl ether maleic anhydride copolymer. The packaged oral preparation of claim 1, which comprises 0.5-4% polyvinyl methyl ether-maleic anhydride copolymer. A toothbrush containing, on the bristles thereof, a toothbrush amount in the range of 0.8-2g, of a toothpaste or gel toothpaste according to claim 2, which is dosed from a packaging agent containing amount of toothpaste or gel toothpaste containing an effective anti-plaque amount of THDE. A method of inhibiting plaque development on teeth in which said oral preparation is a toothpaste or gel-toothpaste and comprising use on teeth of said toothpaste or gel-toothpaste according to claim 2, which is dosed from a packaging agent according to that claim and which is an effective anti-plaque amount of such a composition. The method of claim 22, wherein the composition is a toothpaste or gel toothpaste which is brushed on the teeth at least daily in an amount in the range of 0.8-2 g at a time and which contains THDE as its antibacterial component. 24. Oral formulation containing an effective anti-plaque amount of a substantially water-insoluble non-cationic antibacterial agent, which formulation is packaged in a opaque dosing packaging agent comprising a solid synthetic organic polymer plastic material in contact with the oral formulation, which organic polymer plastic material in the presence of the oral composition does not cause loss of effective antibacterial and anti-plaque actions of the oral composition upon storage in the packaging. A packaged oral preparation according to any of claims 2 to 20, wherein the oral preparation contains a fluorine-providing compound. A packaged oral preparation according to any of claims 2 to 20, wherein the oral preparation contains an anti-tartar polyphosphate compound. The packaged oral preparation of claim 26, wherein the anti-tartar polyphosphate compound is a mixture of sodium and potassium pyrphosphates. A packaged oral preparation according to any of claims 2 to 20, wherein the oral preparation contains a fluorine-providing compound and an anti-tartar polyphosphate compound. The packaged oral preparation of claim 28, wherein the anti-tartar polyphosphate compound is a mixture of sodium and potassium pyrophosphates.