HU206971B - Receptacle containing dentifrice - Google Patents

Description

The present invention relates to containers containing oral anti-plaque agents.

The compositions of the present invention contain an anti-plaque antimicrobial agent, such as 2 ', 4,4'-trichloro-2-hydroxy diphenyl ether (THDE), as an effective anti-plaque component. These formulations are packaged in containers or vials which are polymeric plastics which are in contact with the oral formulation and are compatible with the antibacterial agent in the formulation. Although various plastics reduce the anti-plaque effect of said antimicrobial agents, it has been found that certain plastics such as polyfluoroethylene and polyvinyl chloride are compatible with THDE and do not cause excessive loss of anti-bacterial and anti-plaque effects of oral formulations at room temperature or when stored at elevated temperature. The plastic parts of the container do not cause any loss even if they are not completely metals with the antimicrobial compound, but compatibility can be increased by increasing the proportion of stabilizing agents in the oral compositions relative to the antimicrobial compound. Such stabilizers are terpenes, such as limonene, or natural or synthetic essential oils, which are flavoring or flavoring agents in oral formulations. Such a stabilizer is present in an appropriate amount.

Plaque on the teeth is considered to be caused by negative conditions around the tooth and tooth plaque is a precursor to tartar. Plaque can form on any part of the tooth, including the gingival margin. This makes the teeth dull (non-resonating), and increases the chance of tartar formation and promotes gingivitis. Therefore, oral formulations containing anti-plaque components prevent or inhibit plaque formation on the teeth and are therefore valuable guardians of the tooth.

Although it is known that antimicrobial agents may reduce plaque formation in oral formulations, they are sometimes effective in combination with other substances, but various such compounds also have unfavorable properties, so care should be taken in their use in oral formulations. For example, cationic antibacterial compounds, namely quaternary ammonium halides, tend to discolour teeth, but may be deactivated by the presence of anionic agents in oral formulations (and the use of anionic surfactants or detergents in oral formulations is often desirable).

Essentially water-insoluble, halogenated (and often hydroxylated) diphenyl ethers, such as THDE (triclosan) and 2'2'-dihydroxy-5,5'-dibromodiphenyl ether (DDDE), are effective anti-plaque antibacterials, but they can be deactivated by nonionic surfactants and many plastics, as we have discovered in our work. The present invention encompasses the introduction of an antibacterial anti-plaque agent, such as halogenated diphenyl ethers, in particular THDE and DDDE, and similar anti-plaque agents, into an oral preparation, and the storage and administration of such compositions from containers in which the anti-bacterial agents are retained for use. during. Prior art triclosan dentifrices, as withdrawn from the dispenser, were not effective enough to significantly reduce plaque by brushing once or twice with a daily brushing of 1.5 g, which is approximately standard practice. Such an application is considered effective if it reduces plaque by at least 25% after three weeks of application, compared to the result obtained with a similar use of a control toothpaste for three weeks.

The most important antimicrobial component of the packaged oral formulations of the present invention is THDE, also known as triclosan. The antimicrobial agent disclosed in U.S. Patent 4,022,880 is disclosed in combination with an anti-tartar agent (which provides zinc ions) and in combination with a copper compound as disclosed in US-A-3 532 860. European Patent Nos. 0161898, 0161899 and 0 220 890 describe dentifrices comprising polyethylene glycol and an oil-based flavoring.

Various oral preparations and dentifrices are known, including pastes, gels, lotions, tablets, lozenges, sachets and packaged dentifrices, liquid and tableted mouthwashes and dentifrices used by doctors (professionally used preparations such as fluxes, Such products are marketed in formable tubes, pump dispensers, pressure-operated dispensers, small packages, bottles, flasks and other containers. Although formable or compressible tubes were initially made of metals such as lead and aluminum, however, in recent years, such containers are often made of synthetic organic polymeric plastics or laminated (laminated) materials which contain such plastics. and the container materials into which these formulations are packaged, resulting in reactions between toothpastes and aluminum containers. In order to prevent such reactions, the containers have been specially treated or various container materials have been used. Prior to the present invention, it was not known in the art that many plastic packaging materials may adversely affect the anti-plaque effect of halogenated diphenylether antibacterial compounds when incorporated into the composition of oral formulations and containers. Also, it was known

It is contemplated that certain plastics may be used as part of such containers without eliminating the anti-plaque effects of halogenated diphenyl ethers or reducing the effects of oral formulations, or that such effects may be prevented or prevented by mixing terpenes such as limonene or other flavoring agents in oral formulations. .

The present invention relates to a container comprising a composition containing an effective anti-plaque amount of a substantially water-insoluble non-cationic antibacterial agent and packaged in a delivery container containing a solid polymeric material, such as synthetic organic polymeric material, which is in contact with the oral composition. the solid polymer material is compatible with the antimicrobial agent in the oral preparation and does not cause excessive loss of the anti-bacterial anti-bacterial effect of the oral preparation during storage in the container (e.g., storage at 20-40 ° C for several weeks, preferably at least one year or longer) ). The packaged oral preparation is usually a toothpaste, gel dentifrice or mouthwash, which is marketed in a flexible dispensing tube, pump dispenser or vial where they do not contain any plastic ingredients which adversely affect the antibacterial agent (preferably halogenated diphenyl ether) such as triclosan anti-plaque, or the oral preparation contains a component that prevents or prevents any adverse "reaction" between the antibacterial agent and the plastic component of the container which would adversely affect the anti-plaque formulation.

The invention will be readily understood from the description thereof and from the accompanying drawings. The

Figure 1 is a perspective view of a toothpaste tube and a removable cap when the toothpaste is pressed from the tube onto the toothbrush; the

Fig. 2 is an enlarged, partial cross-sectional view of the laminated wall of a deformable tube of Fig. 1; the

Figure 3 is a vertical cross-sectional side view of a pump dispenser for receiving and dispensing toothpaste or toothpaste gel; the

Figure 4 is a side elevational view of a heat sealed pouch or bag containing a sufficient amount of toothpaste for single use; and that

Figure 5 is a side view of a bottle with a cap for receiving mouthwash.

Fig. 1 is a commercially available packaged anti-plaque toothpaste product (11) which comprises a convertible (compressible) toothpaste tube (13) containing anti-plaque toothpaste (15) at a time when a unit amount of about 0.8 -2 grams, press on the toothbrush (17). The tube (13) is an opaque and synthetic organic polymeric material, such as polyfluoroethylene, or coated with a material that does not adversely affect toothpaste activity during storage. Alternatively, the tube (13) may be made of a plastics or plastic-coated material which adversely affects the anti-plaque activity of the toothpaste (i.e., reduces the anti-plaque activity of the anti-bacterial component of the toothpaste e.g. halogenated diphenylether). by introducing into the dentifrice a stabilizer which may be a terpene such as limonene or other effective flavoring. Preferably, neither the toothpaste tube nor the cap or other portion of the tube which comes into contact with the toothpaste (such as the cap coating) should be made of polyester / polyether coelastomer or other plastic material which significantly reduces the anti-plaque effect of the oral preparation; even if a stabilizer is present for the anti-plaque component. It is also undesirable to use other elastomers, such as isobutadienes, polychloroprenes, butadiene rubbers and nitrile rubbers, which may react with or absorb THDE. Preferably, such portions may be made from plastics that do not adversely affect anti-plaque activity, even when terpenes or other stabilizing agents are not present in the dentifrice, although such other destabilizing plastics may be used if stabilizing agents are present in the toothpaste. they act against the inactivating effect of the plastic. However, polyester / polyether coelastomers or other unfavorable elastomers should preferably be avoided.

Figure 2 shows a laminate consisting of a poly (fluoroethylene) film (21), an aluminum sheet (23) and a polyethylene film (25), wherein the polyfluoroethylene film is located inside the tube wall, where it comes into contact with toothpaste. The coating layer of the cap of Figure 1 (19) is not shown and may also be polyfluoroethylene so that the entire surface in contact with the toothpaste during storage is compatible with the antimicrobial component of the halogenated diphenyl ether in the toothpaste and prevents excessive reduction of anti-plaque effect. Instead of the inner wall of the polyfluoroethylene laminate 21, the polyethylene may be used and the wall 21 may be polyethylene or other suitable polymer.

Figure 3 illustrates a pump toothpaste dispenser which is a Guala S.p.A. (Italy), which is the subject of U.S. Patent No. 4,776,496. The metering pump (27), when ready for use, holds the toothpaste in the compartment (29), which is bounded by the bottom wall (31) and the membrane (33). The pressure drop of the actuator 35 causes the diaphragm 33 to move downwardly and expels the toothpaste through the conduit 37 and the spout neck 39. When the actuator 35 is pressurized, the diaphragm 33 is actuated, which is resilient and returns to its original shape, while returning the conductor 37 and the lever 35 to its original position. At the same time, the bottom wall (31) is pressed up by the atmospheric pressure. The various internal parts of the metering pump that come into contact with the toothpaste are preferably made of plastic material (s) which does not deactivate the anti-bacterial and anti-plaque agent of the halogenated diphenyl ether. However, in the event that it is not possible to use plastics such as ame3

While the physical properties required for the various contact portions and still being compatible with the anti-plaque agent, other plastics may be used provided that the toothpaste composition (or gel dentifrice) is a stabilizing agent such as limonene or other effective terpene or includes a flavoring component. However, it is best to avoid using any polyester / polyether coelastomers, namely, for the pump membrane (33), which act against THDE in oral compositions of the type described.

The bag, pouch or package 41 of Fig. 4 is preferably heat sealed and is preferably soldered on three sides. The soldering is indicated by reference numerals (43 and 45). The fourth side (47) is simply folded back on itself and does not require soldering. Inside the sealed package is an oral formulation, such as toothpaste, which is not shown, and the inner surface of such a bag is made of a plastic material that reduces the anti-plaque effect of the antibacterial compound in the oral formulation. As with other containers for anti-plaque oral formulations, laminates with a layer of plastic on their inner surface that does not adversely affect the antimicrobial agent, or where the plastic exhibits such a negative effect, can be prevented by with a stabilizing agent, which may advantageously also be used as a flavoring agent.

Fig. 5 shows an opaque bottle (49) provided with a stopper (51). Both the vial and the closure of the cap (not shown) are made of plastics which are compatible with THDE, the mouthwash (53) in the vial. As stated in another example, when a so-called "reactive" plastic material is used as the material for the bottle or inner cap, appropriate stabilizing agents must be present in the mouthwash to prevent excessive reduction of the anti-plaque effect of THDE or other halogenated diphenyl ether.

In addition to the compositions described, which are present in the containers described above, and which may be gel dentifrices and dense liquids in place of toothpastes, the containers may also be filled with dental preparations suitable for dental use, such as toothpastes containing fluorides and phosphates; suitable coloring solutions and other suitable oral compositions. Pressurized or "aerosol" formulations containing the said anti-plaque compounds may also be filled into pressurized containers (usually containing pressurized, gaseous nitrogen propellant), provided that the contacting plastic parts of such containers do not cause actual loss of toothpaste or anti-plaque agents in other oral formulations with anti-plaque properties.

In addition to the accompanying drawings and the various containers mentioned above, others such as compression bottles, capsules, jars, foam-like materials, and various types of mechanical delivery containers may be used. Because the halogenated diphenyl ether antimicrobial compounds are photosensitive, it is often necessary to use a chemical or physical light-screened or laminated material that prevents any inactivating radiation, such as ultraviolet light, oral preparation and anti-plaque compound. In such containers, it is often desirable to be opalescent and thus prevent or prevent the formation of such actinic radiation from the inactivating anti-plaque component of an oral preparation such as toothpaste.

The reason (s) for the inactivation of the anti-plaque properties of THDE and other substantially non-cationic antibacterial agents by plastics have not yet been elucidated. Relevant research to date has not established the exact mechanism responsible for such losses, which cannot convincingly be traced back to chemical reactions or physical absorption. Aging in basic mouthwash or mouthwash containers containing THDE at room temperature, 38 ° C, and 49 ° C for up to 12 weeks results in “excessive” losses (25% of initial THDE concentration) when the mouthwash is used. contacted the container walls and their low density polyethylene, high density polyethylene, polyethylene terephthalate, polypropylene and polymethylpentene. Similarly, it has resulted in significant losses when stored in containers having internal walls or portions thereof with polyester / polyether coelastomers, such as those previously used in Guala pump membranes.

Polyfluoroethylenes such as polytetrafluoroethylenes, polyvinyl chlorides, polyvinyl carbonates and polysulfones have been found not to absorb or react with excess THDE. However, polyacrylates and polysulfones are fragile and therefore often unsuitable for use as part of dispensing containers. Polyvinyl chlorides often give a foreign taste to oral formulations such as toothpastes and should therefore be avoided for use as a container material unless such taste (the toothpaste taste) is compatible with the flavoring agent used, so that any of the available polymeric plastics Polyfluoroethylene is particularly suitable for use in such containers or packages as it does not unduly reduce the anti-plaque effect of anti-plaque agents. For example, the inclusion of terpenes in oral formulations containing limonene, essential oils (which often contain terpenes) and other flavoring agents having "stabilizing" properties as anti-plaque agents is one suitable for reducing the loss of activity of anti-plaque agents. resulting from contact with various containers or container parts made of said polymeric plastics. Therefore, it is not necessary to use polyfluoroethylene as the container material if the oral formulation contains a suitable ratio of terpene stabilizer or other suitable "stabilizer".

HU 206 971 Β cake ”. If such a stabilizer is present in oral formulations, or if polyfluoroethylene or polyvinyl chloride (possibly polycarbonate or polysulfone) is the only polymeric material in contact with the oral formulation, the anti-plaque effect is less than 25% when stored, preferably 10% - less when stored at ambient or relatively higher temperatures, such as 20-40 ° C, when stored for a few weeks to a year or more. The most stable oral formulations contain a terpene stabilizer or other suitable stabilizer and only poly (fluoroethylene) (or other non-functional plastic) is present as a contact reservoir. Although terpenes and essential oils are the primary stabilizing agents in the compositions of the present invention, other flavoring agents that inhibit destabilizing reactions or the absorption of halogenated diphenyl foods by the plastic (or by other unknown mecanism) may be used. Certain constituents of oral formulations are expected to solubilize THDE and thus prevent or prevent its migration into plastic. On the other hand, it is also believed that such a solubilizing effect facilitates the migration of solubilized THDE into the plastic. Since there is no clear answer to the question, we are not bound to any theory. Preferably, the terpenes and other stabilizers are the flavoring components themselves, since no other stabilizing agents are required.

Oral compositions filled in the containers of the present invention are most often toothpastes, dentifrices and mouthwashes, often referred to as mouthwashes. The first two are referred to herein as dentifrices and the last two as mouthwashes. Dentifrices are made up of three main ingredients, such as carrier, cleanser, and surfactant. An antibacterial agent, such as halogenated diphenyl ether, is usually embedded in the vehicle. The carrier will generally comprise from 10% to 80% of the dentifrice (each based on the final composition). The carrier comprises 3-40% water, 777% diluents such as glycerol, sorbitol, propylene glycol or a mixture thereof and 0.5-10% gelling agent such as sodium carboxymethylcellulose. Dog milk, carrageenan or hydroxyethyl cellulose or the like may also be included. The dentifrice cleanser typically comprises 10-75% of the dentifrice embedded in a gel or toothpaste, or 50-90% when mixed with powder. Such cleaning agents include colloidal silica, precipitated silica, sodium aluminosilicate, insoluble sodium metaphosphate, hydrated alumina, calcined alumina, dicalcium phosphate dihydrate, anhydrous dicalcium phosphate, or mixtures thereof. Surfactants can be anionic, nonionic, cationic and zwitterionic surfactants, but the use of nonionic surfactants is often avoided because of their detrimental effect on antimicrobial compounds such as THDE and in some cases avoidance of cationic and zwitterionic surfactants. also because they tend to discolour or darken the teeth. Thus, synthetic organic anionic surfactants, which are also detergents, are preferred dentifrices in dentifrice formulations, with sodium lauryl sulfate and other higher alkyl sulfates having from 10 to 18 carbon atoms in their alkyl groups, though other well-known sulfates and sulfonated detergents can at least partially replace them. Other active ingredients, such as fluoride-providing compounds, such as sodium fluoride or sodium monofluorophosphate, may also be present in the composition to strengthen the teeth, usually in a proportion of 0.001 to 1% fluoride by weight of the total composition, and other excipients such as flavoring and sweeteners in an amount of 0.1-10%. In addition, if desired, polycarboxylates such as polyvinylmethyl ether / maleic anhydride (PVM / MA) copolymers (Gantrez) may be used in an amount of 0.5-4% by weight of the dentifrice. It has been found that such polycarboxylate substances significantly enhance the anti-plaque effect of the antibacterial compound. The use of such polycarboxylates in oral formulations is described in U.S. Patent 4,627,977.

For oral use, the oral carrier is preferably an aqueous or alcoholic substance, the alcohol preferably being ethanol or isopropanol. The carrier will usually be 99-99.9% of the formulation, of which alcohol will be 530% and propylene glycol will generally be 2-10% based on the final product. The remainder of the composition comprises 0.1-10% of a flavoring agent, surfactant, sweetener, coloring agent, anti-plaque agent or other excipient for a specific purpose. The effective amount of anti-bacterial anti-bacterial compounds in dentifrice and mouthwash formulations is usually 0.02-0.2%, preferably 0.03-0.1% in mouthwash, and usually 0.25-1%, preferably 0.250.5% or 0.6% in dentifrices with the proviso that the proportions should not exceed 0.8% THDE in toothpastes and may not exceed 0.2% THDE in mouthwashes as they may cause numbness at higher concentrations, in addition, there should be no less anti-bacterial anti-plaque agent than those mentioned above, since at lower concentrations it is inactive against plaque. Preferably, the dosage formulations should contain the anti-plaque agent and THDE in the range given above, but if they are present at an initial concentration in the range specified, a loss of up to 25% is acceptable within the scope of the invention.

Containers having plastic walls or other parts in which the plastics "react" with the antibacterial compounds require the presence of 0.01 to 2% of terpene (s) or stabilizer (s) in the oral formulations. Preferred amounts are in the range of 0.05% to 1%, in particular in the range of 0.5% to 5%. Such stabilizers may be present as suitable flavoring agents for use in dentifrices, and if desired

The amount of flavoring agent is at least 5%, preferably at least 10%, in particular at least 25% and in particular at least 50%.

Although the description is primarily directed to dentifrices and mouthwashes, other oral formulations, such as chewing gum, may also be stored in containers within the scope of the invention containing a similar proportion of ingredients depending on the form of the formulation, so that liquids contain less, e.g. include more so toothpastes. These formulations also contain specific agents, depending on the intended use of the formulations. Thus, dentifrice compositions may contain fluorides and phosphates, namely sodium or potassium fluoride and sodium fluorophosphate, either in the form of a dentifrice or a mouthwash, often in amounts of 1-5%. Plaque detection dye solutions generally contain appropriate dyes (red is the most preferred color for detecting such spots) in a concentration of 0.001-0.1% based on the mouthwash. These other products may be packaged in the manner customary in the art.

The antimicrobial agent is a non-cationic substance which is water insoluble or substantially water insoluble so that its solubility in water at 25 ° C is less than 10 g / l and often less than 1 g or 0.1 g per liter. Such materials may be soluble or dispersible in dentifrice carriers containing glycerol, sorbitol and / or propylene glycol. They may also be soluble or dispersible in aqueous, alcoholic media of the mouthwash.

Of the other antibacterial compounds, the halogenated diphenyl ethers contain bromine and / or chlorine, but the chlorine atom is preferred. These compounds are preferably 1-3 hydroxy groups and

They are substituted with 1 to 4 halogens. The compounds are primarily substituted with 1 or 2 hydroxy groups and 2 or 3 halogen atoms, preferably having four substituents, two on each ring. Of these compounds, 2,2-dihydroxy-5,5'-dibromo-diphenyl ether and 2 ', 4,4'-trichloro-2-hydroxy-diphenyl ether are preferred. The latter compound, also designated as THDE, is particularly preferred. Various halogenated phenolic, non-cationic, substantially water-insoluble anti-bacterial anti-plaque compounds may be used, in whole or in part, instead of the halogenated diphenyl ethers, if appropriate.

Compositions filled into the container of the present invention include terpenes, terpene hydrocarbons and oxidized derivatives thereof, such as dl-limonene, menthol, diterpenes, polytherpenes and derivatives thereof, some of which are found in various essential oils and other flavorings. In addition to being useful as stabilizers for halogenated diphenyl ethers, they are often suitable for flavoring the oral compositions of the invention. Of terpenes and their derivatives, limonene has the most of these properties, although other terpenes, such as non-flavoring agents, can also be used. Other emulsifiable lipophilic essential oils and flavoring agents containing stabilizing components are also suitable for this purpose.

The various plastics described above as components or parts of containers and / or dispensers do not need to be described in more detail than their brief description, since their chemical behavior and degree of polymerization are well known in the art. For more information, see Modem Plastics Encyclopedia, published by McGraw-Hill, Inc., New York.

The compositions may also contain fluoride ion sources capable of delivering 25-5000 ppm fluoride ion to the oral cavity. Preferred amounts of fluorine are 300-2000 ppm, especially 800-1500 ppm. U.S. Pat. No. 4,627,977 discloses suitable fluorides and ratios and details of their preparation. Fluoride acts primarily as a curing agent, but may also serve to stabilize polyphosphate, which is an inhibitor of stone formation, if present. Such polyphosphate is preferably a mixture of sodium and potassium polyphosphates, which is also stabilized with Gantrez S-97. Proportional ranges are described, for example, in U.S. Patent Nos. 4,627,977 and 4,863,640.

Formulation details, components, excipients, methods of preparation and uses are also described in the foregoing patents.

The oral compositions described are prepared by standard procedures commonly used to prepare such compositions. For the sake of simplicity, specific examples are cited and the THDE is dispersed and / or dissolved in the dentifrice and the terpene carrier in the flavoring agent. For the preparation of a dentifrice, a carrier comprising glycerol, sorbitol and propylene glycol, gelling agents and suitable excipients (including Gantrez S-97 and triclosan), and a carrier as well as an aqueous anionic detergent (preferably sodium) is prepared. lauryl sulphate or a mixture of sodium lauryl sulphate and sodium methyl cocooctylurate) is mixed with each other and subsequently the cleaning agent component is added to this premix. Finally, a flavoring agent such as terpene dissolved in ethanol is added to the mixture and the pH is adjusted. To make mouthwash, its various components are simply mixed with alcohol or aqueous-alcoholic media and mixed until a solution is obtained. A 1: 4 to 4: 1 mixture of sodium lauryl sulfate (SLS) and sodium methyl cocooctylurate is preferably used as the anionic surfactant component of the mouthwash with the desired amount of taurate charged to the SLS. Other oral formulations may be prepared by similar methods.

When filling the oral formulation into the dosing container, care must be taken to avoid contact of the formulations with the plastic parts of the polyester / polyether coelastomer and to ensure that formulations do not contain a stabilizer such as terpene or terpene.

EN 206 971 B flavoring agent, do not come into contact with any plastic moiety which is reactive with THDE and other such antibacterial and anti-plaque agents. It is very important not to use said plastic parts as part of containers or tanks, pipelines, pumps or devices in which the oral preparation is kept at a higher temperature for shorter or longer periods.

When containers and formulations of the present invention are prepared and oral formulations containing THDE or other halogenated diphenyl ether antimicrobial agents have been avoided to contact reactive plastics, care must be taken to minimize exposure to such packaged formulations. heat and light, which accelerate the reduction in anti-plaque effect. Thus, the compositions of the invention are preferably filled into opaque containers at a temperature between 10 ° C and 38 ° C. Otherwise, the filled formulations may be stored and used under normal conditions to obtain the desired anti-plaque effect. In laboratory studies, the teeth of human volunteers were treated using formulations and controls in different containers. It has been found that the reduction in anti-plaque effect of the compositions packaged in the container of the present invention is significantly less when compared to control, packaged compositions containing the plastic parts that were "reactive" to halogenated diphenyl ether antimicrobial compounds and no stabilizer. in the oral preparation. These improvements were also observed when the container was made from "reactive" plastics (but not polyester / polyether coelastomers), but the oral formulations contained terpenes as opposed to the oral formulations which contained neither terpenes nor flavorings.

The following examples are intended to further illustrate the invention, but the scope thereof is not limited to these examples. Unless otherwise stated, percentages and ratios in the examples, throughout the specification, and in the claims are weight percentages and weight percentages, and temperatures are in ° C.

Example 1 Artist materials 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 laureth sulfate 0.25 tauranol WSHP 0.20 ⁺⁺⁺ Flavor Mixture 0.12 ⁴⁴⁴⁴ Triclosan (Irgasan DP 300, Ciha- Geigy) 0.05

100.00 ⁺ polyvinylmethyl ether / maleic anhydride copolymer (GAF Corp.), containing at least 25% terpene, including 25% limonene + ^444- THDE (2 ', 4,4'-trichloro-2-hydroxy) diphenyl ether)

The exemplary mouthwash (mouthwash) is prepared by mixing the various ingredients listed in any suitable order according to standard methods but first dissolving the triclosan in a mixture of propylene glycol and ethanol and then mixing the sorbitol, glycerol and anionic surfactants and finally the flavoring mixture is added. The sodium hydroxide solution is used to neutralize the resulting acidic mixture to adjust the pH to 6.84 (preferably the pH of the product thus obtained is at or near the neutral value).

The resulting mouthwash has excellent stability and acceptable taste, the flavoring and the triclosan are sufficiently soluble and this solubility is due at least in part to Tauranol WSHP. If only 0.25% SLS is used as anionic surfactant, the solubility of the flavor and triclosan is not satisfactory. Although such solubilizations may be enhanced by the use of multiple SLSs, the maximum acceptable concentration of the compound in such mouthwashes is 0.25%, while Tauronol WSHP and SLS are safe and acceptable in the proportions used. The mouthwash described was tested for bioavailability of triclosan compared to mouthwash formulations that omitted Tauranol WSHP in one case and replaced half of it with a nonionic surfactant (Pluronic F-127) in the other. In triclosan uptake, triclosan absorption was measured with hydroxyapatite discs coated with saliva and protein absorption "zone inhibition" assays, and found to have a much higher degree of non-ionic detergent (Pluronic) non-ionic detergent (Pluronic 127). it is.

The mouthwash composition of this example was effective at elevated temperature (41 ° C) for three to five weeks, which is considered to be effective for at least about six months and one year at room temperature. Efficacy studies are conducted in containers (bottles) made of glass, polyvinyl chloride and polyethylene terephthalate (or plastic-coated). Chemical analysis of mouthwash formulations showed no loss of triclosan during these potency periods when the containers were made of glass, but the triclosan content of the mouthwashes was reduced when containers made of polyethylene terephthalate were used. For tanks made of polyvinyl chloride, the decrease was well below the allowable loss of 25% and remained below 5 or 10% (based on the original concentration).

If dl-limonene is used in amounts of 0.1,0.2 and 0.4% instead of flavoring mixture,

This results in better stabilization of triclosan, and such stabilization results are obtained when terpenes and flavorings from different essential oils are present in similar amounts. Such good results are obtained even if the container material or coating is polymethylpentene, polyallomer, polypropylene, high or low density polyethylene and nylon, although these substances, without the flavoring mixtures (containing terpenes), cause great losses in the oral rinse aids. especially when stored at elevated temperatures.

Example 2 Artist materials Percentage water, deionized 84.42 ethanol (95%) 10.00 propylene glycol 5.00 sodium laureth sulfate 0.50 triclosan 0.06 Sodium saccharin 0.02

100.00

The triclosan content of the mouthwash composition and the amount of triclosan that can be utilized after three weeks of storage were tested in dosing containers made of or coated with different plastics. The tests were performed at room temperature, 38 ° C and 49 ° C. At elevated temperature storage we simulated longer storage at room temperature for a year or more. Triclosan losses of the stored mouthwash were observed when stored in containers made of polymethylpentene, polyallomer, polypropylene, high or low density polyethylene and nylon. Unacceptable results (excessive losses) have been encountered with containers made of polypropylene, polyethylene and nylon (worst for nylon).

If the material or coating was polyvinyl chloride, polycarbonate, polysulfone or polyfluoroethylene, such as polytetrafluoroethylene or teflon, there was essentially no loss of triclosan. When stored in containers made of or coated with the aforementioned polymers (polymethylpentene and the like), triclosan losses could be reduced as described in Example 1 by the addition of limonene, other terpenes or essential oils containing terpene to the mouthwash. in a proportion, preferably at least 0.1%, or preferably higher, e.g. 0.2% or 0.4%, based on the total amount of the composition. In some cases, the use of flavoring agents which do not contain a significant amount of terpenes may also have a beneficial effect, although not as good as those containing terpenes.

Example 3 Artist materials Percentage propylene glycol 10.00 iota 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 ⁺⁺⁺ Sident22S 2.00 sodium lauryl sulfate (94% active- material) 1.60 flavoring 0.95 triclosan 0.30 100.00

⁺ polyvinylmethyl ether / maleic anhydride copolymer (BASF) 'silica cleaner (JM Huber Corp.) ⁺⁺⁺ silica thickener (Degussa Co)

The above dentifrice composition is prepared in a conventional manner and a medium containing a dentifrice composition is used for the stability testing of triclosan. This composition is exposed to various plastics which are used as materials for the containers or as part of the dispensers in which these dentifrice compositions are stored or dispensed. Examples of such plastics for testing are Pibiflex 46 (Inmont) and Amitel 460 EM (AKZO) (polyester / polyether coelastomers). These plastics are used as diaphragms or nozzles for the pump dispenser shown in Figure 3. Six plastic samples, three of which are from the aforementioned plastics, were analyzed, each of these three being treated with different release agents to determine whether the release agent is responsible for the triclosan stability problem during storage. Mold release agents are Silicone Master (5% Silicone Oil and 95% Polypropylene), Silicone Master and Silicone Oil (Special Silicone Oil) and Armid O Master (5% Oleoamide and 95% Polypropylene). The specimens to be tested are exposed to the dentifrice during storage for two weeks at various temperatures, such as room temperature, 38 ° C and 49 ° C, then the dentifrice is removed from the plastic containers, the materials and plastics are washed with water and to dissolve the triclosan taken up during storage.

The methanolic wash was analyzed using a high performance liquid chromatography method. It was found that substantially the same type of triclosan absorption was achieved for the different membrane materials and although there were differences between them and thus somewhat dependent on the form release agents used, the results were essentially the same in each case.

HU 206971 Β

It has been found that the polyester / polyether coelastomers absorb significantly triclosan from the dentifrice, and these results are confirmed by the results obtained when the polyester / polyether coelastomers were used as an internal part of the pump dispensers when the same or other dentifrices. In view of these, it can be said that the use of polyester / polyether coelastomers for storing the dentifrices and mouthwashes of the present invention is undesirable even if the dentifrices and mouthwashes contain flavoring agents such as terpenes which are present in the dentifrice flavoring agent. 0.1%.

If the tests are repeated using the current Guala pump dispensers for receiving dentifrices containing polyester / polyether coelastomer Amitel membranes, triclosan losses are also unacceptable, but if the polyester / polyether coelastomer with other , the triclosan activity is increased within acceptable limits.

If the other plastic parts of such pump dispensers, such as their inner walls of polypropylene, show that they do not absorb excess or excess triclosan and do not significantly reduce the anti-plaque effect of the dentifrice, it is obviously in the dentifrices they contain. thanks to terpenes.

The long-term observation (panel test) required at least ten human patients to use the dentifrice of this example administered for one month through polyethylene terephthalate and polyethylene-coated tubes, twice daily for a period of plaque (patch) development is monitored. The test results show that the dentifrice formulations have a specific anti-plaque effect similar to that observed with the mouthwash tests of Examples 1 and 2. This shows and proves that triclosan has not been inactivated to an unacceptable extent and that an effective amount of antibacterial and anti-plaque agents are still present in the dentifrice.

Example 4 Artist materials 7.00 glycerol 3.00 propylene glycol iota carrageenan 0.75 sorbitol (70%) 30.00 Sodium saccharide 0.30 Sodium fluoride 0.33 titanium dioxide 0.50 Gantez S-97 (13% solution) 15.00 deionized water 16.07 sodium hydroxide (50% aqueous solution) 0.80 Zeodent 113 (J.M. Huber corp.) 20.00

Sylodent 15 (silica thickener; (W. R. Grace Corp.) 3.00 flavoring 0.95 sodium laureth sulfate 2.00 triclosan 0.30 100.00

The toothpaste of the above formula is stored in a Guala pump dispenser equipped with an Amitel type drive diaphragm. The dentifrice is filled into a laminated tube containing polyethylene terephthalate on the inner portion of the laminate that is 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 are added at a rate of about 1.5 g / day and the triclosan content of the dentifrices is determined by analysis at weekly intervals. With the Guala Pump Dispenser, the dentifrice dispensed loses about 27% of triclosan, which is excessive and unacceptable. The loss is essentially constant, regardless of storage temperature and storage time. This can be explained by the absorption of triclosan by the pump membrane that it was in contact with before dosing. Thus, the use of a polyester / polyether coelastomer membrane as a container material and as part of a container or dispenser that comes into contact with triclosan containing dentifrices should be avoided. However, when the polyester / popether coelastomer membrane is replaced by a membrane made from one of the aforementioned acceptable plastics such as polyethylene terephthalate as a pump diaphragm for the modified dispensers (modified to offset the various properties of such plastics), the triclosan stability and effective as an anti-plaque toothpaste.

Gel toothpaste formulations behave similarly in similar containers with respect to triclosan stability after storage and administration.

In similar studies using polyethylene terephthalate coated tubes, very small losses (less than 5%) of triclosan are observed, indicating that the presence of terpenes, including limonene, in 0.1% or more prevents loss or inactivation of triclosan in the flavorings (or the flavoring itself). When polyfluoroethylene coated tubes are used, there is a small loss of triclosan, even if the flavoring agent is omitted from the dentifrice composition, and the same is true when polyvinyl chloride is used as a coating material in contact with the dentifrice or polysulfone or polycarbonate. parts come into contact with such a dentifrice.

In the above assay, where the dentifrice is administered from a Guala dispenser, Gantrez S-97 is replaced with 4.76 parts Luviform (35%) (the solution is made with deionized water).

There is no appreciable difference in the stability of triclosan between the two formulations.

In the above formulations, the polishing system is generally a silicon system and not a system based on alumina. In the event that the polishing agent is converted to alumina, the above-mentioned problems with respect to some of the aforesaid materials are reduced, but persist. The presence of terpenes in such dentifrices also increases the stability of triclosan, and thus their presence provides dental formulations similar to those containing silicon based polishes.

Example 5

In the mouthwash formulations of the preceding Examples, the ingredients may vary from ± 10% to ± 25%, provided such percentages do not exceed the limits stated elsewhere herein, and may be administered in functional and effective anti-bacterial and anti-plaque form from said dispensing containers which are compatible made of plastics. The products may also be modified by converting them into dentifrice gels, oral gels, pastes, lotions, lozenges, capsules, tablets, and the various types of sachets mentioned herein. Such products also behave similarly to triclosan or other halogenated diphenyl ether or anti-bacterial anti-plaque agents which are sufficiently stable in the presence of poly (fluoroethylene, polyvinyl chloride, polycarbonate and polysulfone packaging component or packaging materials, even if they are not flavorings, they are not present in oral formulations and are stable in the presence of polyethylenes, polypropylenes, polyethylene terephthalates, polyallomers, nylons and polymethylpentenes when terpenes such as limonene or stabilizing flavoring components are present. As mentioned above for other dentifrices and mouthwashes, polyester / polyether coelastomers and other elastomers containing them will excessively absorb or otherwise weaken the action of triclosan and should be avoided.

Example 6

The dentifrice compositions of Examples 3 and 4 are, after storage for one month at 30 ° C, filled into foldable toothpaste tubes coated with polyethylene in one case and polyethylene terephthalate in the other, as shown in Figure 1. The amount of toothpaste applied to the toothbrush is between 0.8 g and 2.0 g, preferably between 1 and 1.5 g. When 1.5g of toothpaste is applied to the toothbrush, the effective amount of triclosan in the toothpaste applied to the toothbrush is about four milligrams (only 10% of the triclosan is inactivated). In the event that the dentifrice has been in contact with a longer-lasting or elevated temperature or a more destabilizing plastic during storage, the packaged compositions contain about 3 mg of triclosan in 1.5 g of toothbrush. Thus, about 2.7 and 2 mg of triclosan was applied with a dentifrice to 1 g of toothbrush. For dental care products containing from 0.25 to 0.6% triclosan, the toothpaste on the toothbrush may contain from 2.2 to 8 mg of triclosan when the inactivation of triclosan is in the range of 10-25%, or about 9 mg if not inactivated. triclosan.

When packaged dentifrices are applied to a toothbrush, an amount of usually 0.8 to 2 g is applied to each toothbrush. If you brush your teeth twice a day, in the morning and in the evening for one minute for four weeks, the anti-plaque effect is clearly visible, in contrast to the effects of control dental products that do not contain triclosan. An increased anti-plaque effect is observed when the effects of the compositions of the present invention are compared with those of non-flavored (terpene-free) formulations containing triclosan and filled in polyethylene and polyethylene terephthalate coated tubes.

Claims (23)

PATENT CLAIMS CLAIMS 1. A container containing a non-cationic, water-insoluble antimicrobial dentifrice composition, wherein the container has an inner surface directly in contact with the composition. (i) the composition is compatible with polyfluoroethylene or polyvinyl chloride compatible with the composition; terpene stabilizer and / or flavoring agent as additional components. Container according to claim 1, characterized in that the toothpaste, gel or liquid dentifrice, liquid mouthwash or paste, gel or liquid dentifrice, wherein the antimicrobial agent is a halogenated diphenyl ether, and the container is a flexible dosing tube. , a pump dispenser, a pressurized dispenser or a bag of toothpaste, gel toothpaste or paste or gel toothpaste, or a bottle or other container for receiving a dentifrice, mouthwash or dentifrice. Container according to claim 2, characterized in that the antimicrobial agent is a halogenated diphenyl ether substituted with 1-3 hydroxy groups and 1-4 halogen atoms, preferably chlorine or bromine. Container according to claim 3, characterized in that the toothpaste comprises a gel-like dentifrice or liquid mouthwash, wherein the halogenated diphenyl ether antimicrobial agent is diphenyl ether having 1 or 2 hydroxy groups and 2 or 3 chlorine. The container is a flexible dosing tube, a pump dosing bag for toothpaste or gel dentifrice, or a bottle dosing container for liquid mouthwash. Container according to claim 4, characterized in that the halogenated diphenyl ether is 2 ', 4,4'-trichloro-2-hydroxydiphenyl ether (THDE), which is present in an amount of 0.02 to 1% by weight. composition. 6. A container according to claim 5, wherein the liquid mouthwash contains 0.03-0.1% by weight of THDE and the inner wall of the container which is in direct contact with the oral composition of the container comprises polyfluoroethylene or polyvinyl chloride. 7. A container according to claim 5, wherein the toothpaste or gel dentifrice composition comprises 0.250.5% by weight of THDE in a flexible dispensing tube, pump dispenser or bag, and the inner wall directly in contact with the composition is polyfluoroethylene or polyvinyl. contains chloride. A container according to claim 5, wherein the toothpaste or gel dentifrice composition comprises 0.3% by weight THDE, and the container is a flexible dispensing tube or pump dispenser. 9. A container according to claim 7, characterized in that it is a flexible dosing tube having a polyfluoroethylene inner surface directly in contact with the oral composition. 10. The container of claim 1, wherein the antimicrobial agent comprises a terpene stabilizer or a flavoring stabilizer in the presence of a polymeric material. Container according to claim 6, characterized in that it comprises a liquid mouthwash containing a terpene or a flavor stabilizing agent in the presence of a polymer directly contacting the THDE with the oral preparation. A container according to claim 7, characterized in that the toothpaste comprising a terpene stabilizing agent or a stabilizing moiety of THDE in the presence of a polymer in direct contact with the oral composition. Container according to Claim 12, characterized in that it is filled with 0.01 to 2% by weight of a stabilizing toothpaste containing terpene and / or flavoring agents and has an inner wall made of polyethylene, polypropylene, polymethylpentene, polyallomer, nylon, polyfluoroethylene or consists of polyvinyl chloride. Container according to claim 11, characterized in that it is filled with mouthwash containing 0.01 to 2% by weight of stabilizing terpene and / or flavorings and has an inner wall made of polyethylene, polypropylene, polymethylpentene, polyallomer, nylon, polyfluoroethylene or consists of polyvinyl chloride. 15. A container according to claim 14, characterized in that it is filled with a terpene-containing composition containing limonene. Container according to claim 10, characterized in that it is filled with a composition containing from 0.5 to 4% by weight of a polyvinylmethyl ether / maleic anhydride copolymer. Container according to claim 1, characterized in that it is filled with a composition containing 0.5 to 4% by weight of a polyvinylmethyl ether / maleic anhydride copolymer. 18. A container according to claim 1, characterized in that it is an opaque dispensing container. 19. A 2-17. A container according to any one of claims 1 to 3, characterized in that it is filled with a composition containing a fluorine-providing compound. 20. A 2-17. Container according to any one of claims 1 to 3, characterized in that it is filled with a composition containing a polyphosphate compound which inhibits tartar formation. A packaged container according to claim 20, characterized in that it is filled with a composition comprising sodium pyrophosphate and potassium pyrophosphate as an anti-tartar polyphosphate. 22. A 2-17. Container according to any one of claims 1 to 3, characterized in that it is filled with a composition comprising a fluorine-providing compound and a polyphosphate compound that inhibits tartar formation. A container according to claim 22, characterized in that it is filled with a composition comprising sodium pyrophosphate and potassium pyrophosphate as an anti-tartar polyphosphate.