Patent Application
20120039822
Dentinal hypersensitivity is defined as acute, localized tooth pain in response to physical stimulation as by thermal (hot or cold), osmotic, tactile, and/or a combination of thermal, osmotic and tactile stimulation of the exposed dentin.
It is known to the art that potassium salts are effective in the treatment of dentinal hypersensitivity. For example, the prior art discloses that toothpastes containing potassium salts, such as potassium nitrate, potassium chloride or potassium phosphates, desensitize the teeth after tooth brushing for several weeks. It is reported that an elevation in the extracellular potassium concentration in the vicinity of pulpal nerves underlying sensitive dentin is responsible for the therapeutic desensitizing effect of topically applied oral products which contain potassium salts. Due to passive diffusion of potassium ion into and out of the open dentine tubules, repeated application of the active ingredient is necessary to build up the necessary concentration in the vicinity of the pulpal nerves.
In addition to treating dental hypersensitivity, it is desirable to provide dentifrice to control dental plaque. Plaque adheres tenaciously at the points of irregularity or discontinuity, e.g., on rough calculus surfaces, at the gum line and the like. Besides being unsightly, plaque is implicated in the occurrence of gingivitis and other forms of periodontal disease.
A wide variety of antibacterial agents have been suggested in the art to retard plaque formation and the oral infections and dental disease associated with plaque formation. For example, halogenated hydroxydiphenyl ether compounds such as triclosan are well known to the art for their antibacterial activity and have been used in oral compositions to counter plaque formation by bacterial accumulation in the oral cavity. The effectiveness of the antibacterial agent is dependent upon its delivery to and uptake by teeth and soft tissue areas of the gums.
In some current commercial dentifrice formulations, triclosan is solubilized in the presence of sodium lauryl sulfate (SLS), which is a surfactant to provide foaming and cleaning benefits, in order for the triclosan to be able effectively to deliver the benefits of antiplaque efficacy and protection against gingivitis.
However, potassium salts, such as potassium chloride or potassium phosphates, are incompatible with sodium lauryl sulfate due to the formation of potassium lauryl sulfate, a molecule which is insoluble in water. In addition, this combination results in a dentifrice which exhibits very little foaming.
Hydroxypropyl-beta-cyclodextrin (HPβCD) is a molecule known for its ability to increase the solubility of hydrophobic ingredients, including triclosan, in water. However, it has been reported that the combined use of two solubilizing agents, a surfactant (such as sodium lauryl sulfate) and cyclodextrin, results in a much lower solubility of hydrophobic ingredients than when either one is used along at the same concentration.
There is therefore a need in the art to provide means whereby the delivery to and uptake by dental tissue of antibacterial compounds contained in oral compositions containing potassium ions to provide therapeutic efficacy of the antibacterial agent with a desensitizing dentifrice.
There is also a need in the art for a dentifrice composition which can provide both therapeutic and desensitizing benefits.
There is furthermore a need in the art for a dentifrice composition which can provide both therapeutic benefits, from triclosan, and desensitizing benefits, from a potassium salt, and yet provide good triclosan solubility and an acceptable level of foaming.
The present invention relates to a desensitizing dentifrice, and in particular to such a dentifrice additionally having an anti-bacterial efficacy.
In a first aspect, this invention provides an oral composition comprising an orally acceptable vehicle for such composition, an effective therapeutic amount of an antibacterial compound, an effective therapeutic amount of a source of potassium cations, an anionic surfactant and a cyclodextrin.
The antibacterial compound may comprise a halogenated diphenyl ether, typically 2,4,4′-trichloro-2′-hydroxy-diphenyl ether. The 2,4,4′-trichloro-2′-hydroxy-diphenyl ether may be present in the composition at a concentration of 0.05 wt. % to 2 wt. % based on the weight of the composition.
The source of potassium cations may be a water soluble potassium salt, such as potassium chloride. The potassium salt may be present in the composition at a concentration of 3 wt. % to 15 wt. % based on the weight of the composition.
The anionic surfactant is typically sodium lauryl sulfate. The sodium lauryl sulfate may be present in the composition at a concentration of 0.5 wt. % to 2 wt. % based on the weight of the composition.
The cyclodextrin is typically hydroxypropyl-beta-cyclodextrin. The cyclodextrin may be present in the composition at a concentration of 1 wt. % to 15 wt. % based on the weight of the composition.
The oral composition is typically a dentifrice.
In a second aspect, this invention provides a dentifrice composition comprising an orally acceptable vehicle for such composition, 0.05 wt. % to 2 wt. % of an antibacterial compound comprising 2,4,4′-trichloro-2′-hydroxy-diphenyl ether, 0.5 wt. % to 20 wt. % of a source of potassium cations, 0.5 wt. % to 2 wt. % of an anionic surfactant comprising sodium lauryl sulfate and 1 wt. % to 15 wt. % hydroxypropyl-beta-cyclodextrin, all weights being based on the weight of the composition.
In a third aspect, this invention provides a solubilizing agent for 2,4,4′-trichloro-2′-hydroxy-diphenyl ether in an oral care composition, the solubilizing agent comprising, in combination, sodium lauryl sulfate and hydroxypropyl-beta-cyclodextrin.
In a fourth aspect, this invention provides a method of solubilizing a halogenated diphenyl ether in a dentifrice composition comprising a source of potassium ions and sodium lauryl sulfate, the method comprising adding a cyclodextrin to the composition. The halogenated diphenyl ether may comprise 2,4,4′-trichloro-2′-hydroxy-diphenyl ether. The cyclodextrin may comprise hydroxypropyl-beta-cyclodextrin.
In a fifth aspect, this invention provides an oral composition comprising an orally acceptable vehicle for such composition, an effective therapeutic amount of an antibacterial compound comprising a halogenated diphenyl ether, an effective therapeutic amount of an anti-hypersensitivity agent comprising a potassium salt, and a solubilizing agent for the antibacterial compound, the solubilizing agent comprising, in combination, sodium lauryl sulfate and a cyclodextrin.
The halogenated diphenyl ether may comprise 2,4,4′-trichloro-2′-hydroxy-diphenyl ether. The 2,4,4′-trichloro-2′-hydroxy-diphenyl ether may be present in the composition at a concentration of 0.05 wt. % to 2 wt. % based on the weight of the composition.
The potassium salt may be water soluble. The potassium salt may be at least one of potassium chloride and potassium nitrate.
The solubilizing agent may comprise 0.5 wt. % to 2 wt. % of sodium lauryl sulfate and 1 wt. % to 15 wt. % hydroxypropyl-beta-cyclodextrin, based on the weight of the composition.
The present invention also provides a method for the treatment and prevention of bacterial plaque accumulation with reduced discomfort and pain associated with dentinal hypersensitivity comprising administering to the oral cavity an oral composition according to the present invention.
The present invention is predicated on the finding by the present inventors that the incorporation of a cyclodextrin, in particular a substituted cyclodextrin, more particularly a hydroxyalkyl-beta-cyclodextrin, most particularly hydroxypropyl-beta-cyclodextrin, into aqueous solutions containing an anionic surfactant, in particular sodium lauryl sulfate, a potassium salt and a halogenated diphenyl ether, such as 2,4,4′-trichloro-2′-hydroxy-diphenyl ether (“Triclosan”) unexpectedly reduced the formation of precipitates and exhibited increased triclosan solubility and increased overall foaming. These technical effects are also exhibited in a dentifrice composition comprising these components. The increased triclosan solubility can result in a corresponding increase in the efficacy of triclosan in a dentifrice composition.
The present invention provides an oral composition, such as a dentifrice, comprising an orally acceptable vehicle for such composition, an effective therapeutic amount of an antibacterial compound, an effective therapeutic amount of a source of potassium cations, an anionic surfactant and a cyclodextrin. The composition can exhibit increased uptake by dental tissue of antibacterial compounds contained therein and eliminates or substantially reduces the discomfort and pain associated with dentinal hypersensitivity.
The present inventors have found that a combination of an anionic surfactant, which is normally incompatible with potassium salts because a precipitate would tend to form, with a cyclodextrin can act as a solubilizing agent for the anti-bacterial compound even in the presence of the potassium salt. The combination of the anionic surfactant and the cyclodextrin can be employed in dentifrice compositions containing an anti-bacterial compound and, as an anti-hypersensitivity agent, a potassium salt. By retaining the anti-bacterial compound in solution, so that it is not precipitated in the composition, the delivery and uptake of the anti-bacterial compound by teeth has been found by the inventors to be greatly enhanced.
The oral composition contains a mixture of an anionic surfactant and a cyclodextrin. Useful cyclodextrins include alpha-CD, beta-CD, gamma-CD, hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD), HP-beta-CD, HP-gamma-CD and trimethyl-beta-CD (TM-beta-CD), particularly hydroxypropyl-beta-cyclodextrin.
In one embodiment, the composition contains an anionic surfactant having a concentration ranging 0.5 wt. % to 2 wt. % based on the weight of the composition and a cyclodextrin having a concentration ranging 1 wt. % to 15 wt. % based on the weight of the composition. In another embodiment, the composition contains an anionic surfactant having a concentration ranging from 1.25 wt. % to 1.75 wt. % based on the weight of the composition and a cyclodextrin having a concentration ranging 3 wt. % to 10 wt. % based on the weight of the composition. In one embodiment, the anionic surfactant is sodium lauryl sulfate (“SLS”) and the cyclodextrin is hydroxypropyl-beta-cyclodextrin.
In the presence of potassium ions, the SLS anionic surfactant/hydroxypropyl-beta-cyclodextrin mixture of one embodiment acts as a solubilizing agent for the antibacterial compound, in particular when the antibacterial compound comprises a halogenated diphenyl ether, such as 2,4,4′-trichloro-2′-hydroxy-diphenyl ether, so that the antibacterial compound remains in solution, which is essential for the effective delivery of the antibacterial compound. This is unlike certain oral compositions containing sodium lauryl sulfate which causes the antibacterial compound to precipitate from solutions containing potassium ions.
Anti-bacterial agents useful in this invention include water insoluble noncationic compounds, particularly halogenated diphenyl ethers, phenol and homologs, mono- and poly-alkyl and aromatic halophenols, bisphonolic compounds, and resorcinol and its derivatives. More particularly, halogenated diphenyl ethers that are useful for the preparation of the oral care compositions of the present invention, based on considerations of antiplaque effectiveness and safety, include 2,4,4′-trichloro-2′-hydroxy-diphenyl ether (triclosan) and 2,2′-dihydroxy-5,5′-dibromo-diphenyl ether. In one embodiment, the antibacterial compound is 2,4,4′-trichloro-2′-hydroxy-diphenyl ether (“Triclosan”).
Antibacterial compounds including phenol and its homologs, mono and polyalkyl and aromatic halophenols, resorcinol and its derivatives and bisphenolic compounds are fully disclosed in U.S. Pat. No. 5,368,844, the disclosure of which is incorporated herein by reference in its entirety. Phenolic compounds include n-hexyl resorcinol and 2,2′-methylene bis (4-chloro-6-bromophenol).
The halogenated diphenyl ether or phenolic antibacterial compound is present in the oral composition of the present invention in an effective therapeutic amount. In one embodiment, the effective therapeutic amount ranges of 0.05 wt. % to 2 wt. % based on the weight of the composition. In another embodiment, the effective therapeutic amount ranges of 0.1 wt. % to 1% wt. % based on the weight of the oral composition.
The source of desensitizing potassium ion is generally a water soluble potassium salt including potassium nitrate, potassium citrate, potassium chloride, potassium bicarbonate and potassium oxalate. In one embodiment, the water soluble potassium salt is potassium nitrate. In another embodiment, the water soluble potassium salt is potassium chloride. In such embodiment, the potassium salt is generally incorporated in one or more of the dentifrice components at a concentration ranging of 0.5 wt. % to 20 wt. % based on the weight of the composition. In another such embodiment, the potassium salt is generally incorporated in one or more of the dentifrice components at a concentration ranging of 3 wt. % to 15 wt. % based on the weight of the composition.
In the preparation of an oral composition in accordance with the practice of the present invention, an orally acceptable vehicle including a water-phase with humectant is present. The humectant includes one or more of glycerin, sorbitol, propylene glycol and mixtures thereof. In one embodiment, water is present in amount of at least 10 wt. % based on the weight of the composition. In another embodiment, water is present in an amount of at least 30 wt. % to 60 wt. % based on the weight of the composition. In yet another embodiment, the humectant concentration typically totals 40-60 wt. % of the oral composition.
Dentifrice compositions such as toothpastes and gels also typically contain polishing materials. In one embodiment, the polishing material includes crystalline silica, having a particle size of up to 20 microns, such as commercially available Zeodent 115, or Zeodent 165, silica gel or colloidal silica. In another embodiment, the polishing material includes compositions such as complex amorphous alkali metal aluminosilicates, hydrated alumina, sodium metaphosphate, sodium bicarbonate, calcium carbonate, calcium pyrophosphate, dicalcium phosphate and dicalcium phosphate dihydrate. In one embodiment, the polishing material is included in semi-solid or pasty dentifrice compositions, of the present invention, in an amount of 15 wt. % to 60 wt. %. In another embodiment, the composition of the present invention includes polishing material having concentrations ranging of 20 wt. % to 55 wt. % based on the weight of the composition.
Dentifrices prepared in accordance with the present invention typically contain a natural or synthetic thickener. Suitable thickeners include Irish moss, i-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethypropyl cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose (sodium CMC) and colloidal silica. In one embodiment, the thickener concentration ranges of 0.1 wt. % to 5 wt. % based on the weight of the composition. In another embodiment, the thickener concentration ranges of 0.5 wt. % to 2 wt. % based on the weight of the composition.
The oral composition may also contain a source of fluoride ions, or fluoride-providing compound, as an anti-caries agent. In one embodiment, the fluoride ion composition is provided in an amount sufficient to supply fluoride ions ranging from 25 ppm to 5,000 ppm of the oral composition In another embodiment, the fluoride ion composition is provided in an amount sufficient to supply fluoride ions ranging from 500 to 1500 ppm of the oral composition. Representative fluoride ion providing compounds include inorganic fluoride salts, such as soluble alkali metal salts, for example, sodium fluoride, potassium fluoride, sodium fluorosilicate, ammonium fluorosilicate and sodium monofluorophosphate, as well as tin fluorides, such as stannous fluoride and stannous chloride.
An antibacterial enhancing agent may also be included in the oral composition. In one embodiment, the antibacterial enhancing agent is incorporated in the compositions of the present invention in weight amounts ranging of 0.05 wt. % to 3 wt. % based on the weight of the composition. In another embodiment, the antibacterial enhancing agent is incorporated in the compositions of the present invention in weight amounts ranging of 0.1 wt. % to 2 wt. % based on the weight of the composition.
The use of antibacterial enhancing agents in combination with antibacterial agents such as triclosan is known to the art, as for example U.S. Pat. No. 5,188,821 and U.S. Pat. No. 5,192,531, each of which are incorporated by reference herein it its entirety. In one embodiment, the antibacterial enhancing agent is an anionic polymeric polycarboxylate having a molecular weight ranging from 1,000 to 5,000,000 g/mole. In another embodiment, the antibacterial enhancing agent is an anionic polymeric polycarboxylate having a molecular weight ranging from 30,000 to 2,500,000 g/mole. In one embodiment, the anionic polymeric polycarboxylates are generally employed in the form of their free acids. In another embodiment, the anionic polymer polycarboxylates are employed in the form of a partially or fully neutralized water soluble alkali metal salt, e.g., sodium, potassium or ammonium salts. In one embodiment, the antibacterial enhancing agents include 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer. In one such embodiment, the maleic anhydride copolymer includes a methyl vinyl ether/maleic anhydride copolymer having a molecular weight (“M.W.”) ranging from 30,000 to abut 2,500,000 g/mole. These copolymers are commercially available, for example, under the trademark Gantrez, including Gantrez® AN 139 (M.W. 1,000,000 g/mole), Gantrez® AN 119 (M.W. 200,000 g/mole), Gantrez® ES-225 (M.W. 100,000 to 150,000 g/mole) and Gantrez® S-97 Pharmaceutical Grade (M.W. 2,000,000 g/mole), of ISP Corporation.
Any suitable flavoring or sweetening material may also be employed in the preparation of the oral compositions of the present invention. Examples of suitable flavoring constituents include flavoring oils, e.g. oil of spearmint, peppermint, wintergreen, clove, sage, eucalyptus, marjoram, cinnamon, lemon, orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, xylitol, sodium cyclamate, aspartyl phenyl alanine methyl ester, saccharine and the like. Suitably, flavor and sweetening agents may each or together constitute 0.1 wt. % to 5 wt. % of the oral composition.
Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, including urea peroxide, calcium peroxide, and hydrogen peroxide, preservatives, vitamins such as vitamin B6, B12, E and K, silicones, chlorophyll compounds and potassium salts for the treatment of dental hypersensitivity such as potassium nitrate and potassium citrate. These agents, when present, are incorporated in the compositions of the present invention in amounts which do not substantially adversely affect the properties and characteristics desired.
The present invention also provides for a method for the treatment and prevention of bacterial plaque accumulation with reduces discomfort and pain associated with dentinal hypersensitivity by administering to the oral cavity the oral composition discussed herein.
The manufacture of the oral composition of the present invention is accomplished by any of the various standard techniques for producing such compositions. To make a dentifrice, a vehicle is prepared containing humectant, for example, one or more of glycerin, glycerol, sorbitol, and propylene glycol, thickener agents and antibacterial agent such as triclosan, and the vehicle and the anionic surfactant, such as SLS, and the cyclodextrin are added, followed by blending in of a polishing agent, as well as fluoride salts, with the pre-mix. Finally, flavoring agent, is admixed and the pH is adjusted to between 6.8 to 7.
The following examples are further illustrative of the present invention, but it is understood that the invention is not limited thereto. All amounts and proportions referred to herein and in the appended claims are by weight, unless otherwise indicated.
Four aqueous solutions containing sodium lauryl sulfate (SLS), potassium chloride and hydroxypropyl-beta-cyclodextrin, were prepared. Their composition with respect to these ingredients (all amounts are in wt %) together with their appearance and foaming characteristics, are shown in Table 1 below.
Formula No. 1, containing 1% SLS and 1% KCl, showed the formation of a thick precipitate with little foaming. To demonstrate the impact of the cyclodextrin on precipitate formation and foaming, formula nos. 2, 3 and 4 were tested. These formulas contained increasing levels of KCl (from 1% to 1.5% KCl) along with 1% SLS and 10% Hydroxypropyl-beta-cyclodextrin. The solutions remained clear up to a KCl concentration of 1.25%. Beyond that, at 1.5% KCl, the solution became slightly turbid; however, the turbidity was significantly reduced compared to Formula no. 1 without any cyclodextrin. Additionally, the solutions containing cyclodextrin exhibited higher amounts of foam compared to Formula no. 1 without any cyclodextrin.
A further aqueous solution, Formula no. 5, containing 1.5% SLS and 3.75% KCl (representing typical concentrations of these components in dentifrices), is shown in Table 2. When these agents are present in water, the solution appeared turbid with precipitate formation, and exhibited no foaming. A similar solution with the addition of 10% Hydroxypropyl-beta-cyclodextrin (formula no. 6, Table 2), however, appeared less turbid, with a lower amount of precipitate, and exhibited increased foaming.
The reduced formation of precipitate and increased foaming with hydroxypropyl-beta-cyclodextrin was attributed by the present inventors to the ability of hydroxypropyl-beta-cyclodextrin to interfere with precipitation, leading to more free SLS. If this attribution was true, since the solubility of triclosan is dependent on the availability of SLS in solution, the addition of hydroxypropyl-beta-cyclodextrin was postulated by the present inventors to be likely to increase the solubility of triclosan.
Results from the following experiments confirmed the increased solubility of triclosan in the presence and absence of KCl due to the addition of hydroxypropyl-beta-cyclodextrin.
In the first set of experiments, the solubility of triclosan in the presence/ absence of KCl was measured using a filtration methodology in which the filtrate was analyzed for triclosan. Solubility results, shown in Table 3, suggest that addition of SLS increased the solubility of triclosan (compared to the control with no SLS). Addition of KCl showed precipitation and the analysis of the filtrate showed decreased solubility of triclosan (compared with 1.5% SLS alone). These results were as predicted based on the prior results of Experiment 1.
0% SLS - 0%
In the following experiments, triclosan solubility was measured with increasing concentrations of hydroxypropyl-beta-cyclodextrin (no SLS, no KCl). The results are shown in Table 4, and clearly showed that triclosan solubility increased in a dose-dependent manner.
In the next experiments, triclosan solubility was measured in the presence of hydroxypropyl-beta-cyclodextrin along with SLS and KCl. The results shown in Table 5 clearly showed increased solubility of triclosan in the presence of cyclodextrin; the dissolved amount also increased in the dose-dependent manner.
0% SLS
These results of these experiments suggest that by incorporating hydroxypropyl-beta-cyclodextrin, the solubility of triclosan in formulations can be improved.
Dentifrice formulations were prepared containing typical active constituents and orally acceptable vehicles.
In accordance with Example 1, a dentifrice composition had the formulation shown in Table 6, and included, inter alia, triclosan, SLS, KCl, and hydroxypropyl-beta-cyclodextrin in the amounts shown. A comparative dentifrice composition had the formulation shown in Table 6 for Comparative Example 1, and included, inter alia, triclosan, SLS, and KCl in the amounts shown, but did not include hydroxypropyl-beta-cyclodextrin.
The compositions were tested to determine the solubility of triclosan in the respective compositions and the results are shown in Table 7.
From Table 7 it may be clearly seen that the solubility of triclosan increased with the addition of the hydroxypropyl-beta-cyclodextrin to the dentifrice composition. The solubilized amount of triclosan from the dentifrice composition of Example 1 was measurable even after three-fold dilution with water, as shown in Table 7.
Taken together, these results clearly demonstrate the unexpected benefit of hydroxypropyl-beta-cyclodextrin towards increasing the solubility of triclosan in the presence of KCl and SLS. While the potassium salt could deliver the desensitizing benefit, triclosan, now readily available in dissolved form, could potentially provide the other therapeutic benefits.
The invention is not to be limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrations of a few aspects of the invention, and any embodiments, which are functionally equivalent, are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the appended claims.
For all references that have been cited herein, the entire disclosures of each are incorporated herein by reference in their entirety.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2009/039201 | 4/1/2009 | WO | 00 | 9/28/2011 |
