NL8301052A - STABILIZED TOOTHPASTE. - Google Patents

Description

τ.

. VO 4683

Stabilized toothpaste.

The invention relates to stabilized toothpaste mixtures and in particular to such mixtures containing a peroxydisphosphate salt (PDP), preferably the tetrapotassium salt (KPDP), and optionally a fluorine-providing anti-caries agent, essentially the only oral chemically active agents.

It is known in the art that hydrogen peroxide and other peroxygen-containing agents are effective against dental caries, plaque, gingivitis, periodontitis, mouth odor and dental stains. Namely, the essential active ingredient PDP used therein has been previously disclosed as an effective anti-odor in a mouth mixture. For example, U.S. Patent 4,041,149 discloses the effectiveness of such oral mixtures, wherein the PDP is activated by the saliva phosphatases to form hydrogen peroxide and / or active or oxygen in statu nascendi, which deodorizes the oral cavity.

Other oral mixtures have been prepared in which a PDP salt is used as an additive for preventing stains normally caused by the essential oral chemically active ingredient in the mixtures. More particularly, US Patent 4,273,759 discloses oral mixtures containing PDP salts to prevent staining normally occurring by cationic nitrogen-containing antibacterial anti-tackifiers and U.S. Patent Application Serial No. 117,410 discloses oral mixtures containing PDP salts to prevent stains normally caused by a tranexamic acid antigivitis agent.

However, it is also known that most peroxygen compounds such as hydrogen peroxide and metal peroxides such as magnesium peroxide are not stable in storage, continuously the ability to release active ___ ...

or lose oxygen in statu nascendi over relatively short periods of time, particularly in the presence of various incompatible inorganic and organic materials such as many of the usual excipients in oral mixtures, especially toothpaste (including dental cream) mixtures. Thus, in French Patent 2325304, this problem is recognized and solved by a relatively difficult and expensive means of preventing the peroxidized component such as magnesium peroxide from contact with acidic material reactive with it such as 8301052 i Λ -2- by coating. of said component and acidic material with suitable excipients, before and until the time of use in the oral cavity.

PDP salts are considered to be much more stable than hydrogen peroxide and magnesium peroxide. In said U.S. Patent 5 4,041,149, it is disclosed that a 10% aqueous solution of the preferred KPDP shows no oxygen loss after four months at 25 ° C and a 3% loss after six months at 50 ° C. Accordingly, it was concluded and thus stated in the patent that this stability imparts a long storage stability to oral mixtures containing said peroxydiphosphate compound.

However, it has been found that the above conclusion is largely unjustified. Extensive tests with oral mixtures containing KPDP in combination with a variety of common excipients such as polishing material (dental abrasives), wetting agents, thickeners, fragrances and the like have revealed hitherto unknown incompatibilities resulting in unsuitably short storage stability or shelf life, premature loss of active oxygen, damage to the desired functions of the various components of the mixtures and / or unacceptable chemical and / or physical and / or cosmetic properties of the mixtures and the like.

It is an object of the invention to provide oral mixtures that are not subject to one or more of the above-mentioned drawbacks and shortcomings. Another object of the invention is to provide stable oral mixtures containing a PDP salt and optionally a fluorine-providing anti-caries agent, as substantially the only oral chemically active agents. Yet another object of the invention is to provide methods of promoting oral hygiene using such mixtures.

In accordance with certain aspects thereof, the invention includes the provision of a toothpaste mixture comprising: I an oral carrier, II as substantially the only oral chemically active agents, A. 0 to about 2% by weight of a fluorine-providing anti- caries compound and B. about 1 to about 7 wt% of a peroxydiphosphate salt 8301052-1-3-III about 10 to about 75 wt% of at least one polishing material selected from the group consisting of silica and hydrated alumina, IV about 0.5 to about 10% by weight of at least one thickener selected from the group consisting of colloxal silica, synthetic hectorite, poly (methyl vinyl ether / maleic anhydride), carboxyvinyl polymer, carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, and hydroxyethyl cellulose V about 5 to about 75 wt% polyethylene glycol as a humectant.

The above-described oral chemically active IIA and B components are typical and preferably inorganic. These mixtures containing mutually compatible components afford to achieve one or more unexpected improvements such as an unexpected improved storage stability or shelf life, acceptable chemical and / or physical and / or cosmetic properties, retaining the desired functions of the individual components and of such. As used herein, the term "oral chemically active agent" refers to anti-caries? antiplak7 antigingivitis? antiperiodontitis? anti-odor and bleaching agents and the like that chemically react to, with respect to or in relation to the teeth, bone tissues and / or mouth environment, as opposed to polishing material (dental abrasives) which have a physical effect on the teeth and inert components which Determine properties of the mouth mixture per se such as thickeners, wetting agents, fragrances, surfactants, sweeteners, dyes, whiteners, brighteners, preservatives and other common excipients. The essential PDP salts used herein, in particular KPDP, fall into the category of any of the aforementioned oral chemically active agents. The oral mixtures of the invention are, for similar reasons, mutually exclusive of the antibacterial anti-plaque mixtures of U.S. Patent 4,273,759 and the anti-gingivitis mixtures of United States Patent Application Serial No. 117,410.

8301052 i -S.

-4-

Any of the alkali metal, alkaline earth metal, metal or ammonium peroxy diphosphates or their corresponding water-soluble acid salts to the extent of about 0.001% by weight can be used in the mixtures of the invention. Examples of these are tetra-5 potassium peroxydiphosphate (KP0 O0), tetralithium peroxydiphosphate (Li.Po0Q), tetrasodium peroxydiphosphate (Na4P20g), tripotassium monosodium trioxy peroxy diphosphate (K ^ NaP ^ og220, dipotassium disodium phosphate (dipotassium phosphate) g), monopotassium monosodium dihydrogen peroxydiphosphate (KNaH2P20g), trilithium monopotassium peroxy-10 diphosphate (Lig10 ^ Og), diithium dipotassium diphosphate (Li2K2P20g), monolithium tripotassium potassium peroxydiphosphate NaP ^ g), dilithim disodium peroxy diphosphate (Li2Na2P20g), monolithium trisodium peroxy diphosphate (LiNa ^ PjOg), monolithium monosodium dihydrogen peroxy diphosphate (LiNaH2P20g), and 15 monolithium dihydrogen ammonium peroxydiphosphate dihydrate (NH) P 0.2H.0), and the acid salts of the metals of the group 4 4 2 o 2 2 such as barium dihydrogen peroxydiphosphate (BaH P 0 0o), cal cium diwater 2 2 o dust peroxide diphosphate (CaH2P20g) and the like.

The preferred tetrapotassium peroxydiphosphate (KPDP) is a stable, odorless, finely divided, free-flowing, white, non-hygroscopic crystalline solid with a molecular weight of 346.35 and an active oxygen content of 4.5%. The potassium peroxide diphosphate is 47-51% water-soluble at 0-61 ° C, but insoluble in the usual solvents such as acetonitrile, alcohols, ethers, ketones, dimethylformamide, dimethyl sulfoxide, and the like. A 2% aqueous solution has a pH of about 9.6 and a saturated solution thereof has a pH of about 10.9.

The essential PDP salt (or mixture thereof) is used in an amount effective to achieve the desired therapeutic, anti-odor, bleaching or other function, typically constituting about 1 to about 7 wt%, preferably about 2 to about 5 wt%, most preferably about 3 wt% of the present oral mixtures.

The fluorine-providing anti-caries compounds optionally present in the present oral compositions may be slightly soluble in water or may be completely water-soluble.

8301052 -5- ir .: *>

They are characterized by their ability to release fluorine ions in water and a substantial freedom of reaction with other compounds of the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal, and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as copper (I) fluoride, zinc fluoride, and tin fluoride such as tin fluoride. IV) Fluoride or Tin (II) Chlorofluoride, Barium Fluoride, Sodium Fluorosilicate, Ammonium Fluorosilicate, Sodium Fluorozirconate, Sodium 10 Monofluorophosphate, Aluminum Mono- and Di-Fluorophosphate, and Fluorinated Sodium Calcium Pyrophosphate. Alkali metal and tin fluorides, such as sodium and tin (ill) fluorides, sodium monofluorophosphate (MFP) and mixtures thereof are preferred.

* The amount of the fluorine-providing compound depends to some extent on the type of compound, its solubility and the type of oral preparation, but it must be a non-toxic amount.

An amount of such a compound which releases a maximum amount of about 1% fluoride by weight of the composition is considered satisfactory. Any suitable minimum amount of such a compound may be used, but it is recommended to use a sufficient compound to release about 0.005 to 1%, preferably about 0.1% fluoride ion. Typically particularly in the cases of MFP alkali metal fluorides and tin (II) fluoride, this component is present in an amount of from about 0.01 to about 2% by weight based on the weight of the composition and preferably in the range from about 0.05 to about 1 wt%, especially about 0.76 wt%.

To obtain the desired results, component Iir * polishing material should be selected from silica, preferably hydrated alumina (alpha-alumina trihydrate), both of which are conventional dental polishing materials in themselves with average particle sizes ranging from about 0.1 to about 30 µm, preferably about 1.0 to about 15 µm. The following are examples of such preferred polishing materials.

The silica polishing material may be in the form of crystalline silica having a particle size of up to 5 µm an average particle size. 8301052 2-6 size up to about 1.1 ^ un and a surface area up to 50,000 m / g, silica gels, Zeodent (e.g. Zeodent 49, 119) precipitated silica products from J.M. Huber Corp., complex amorphous alkali metal alumino silicates, and the like. The types of silica dental abrasives disclosed in US Patent 3,862,307 can be used.

When using visually clear gels, a silica xerogel or colloldale polishing agent such as that sold under the trade name SYLOID (WR Grave & Co. e.g. Syloid 63, 64, 72 or 74) or under the trade name SANTOCEL as Santocel-100 and alkali metal aluminosilicate complexes are particularly suitable since they have refractive indices close to the refractive indices of gelling agent / liquid (including water and / or humectant) systems commonly used in dental treatments.

Hydrated alumina, in particular the hydrated alumina of the trade name Alcoa as C333, which has an alumina content of 64.9% by weight, a silica content of 0.008%, an iron (III) oxide content of 0.003% and a moisture content of 0.37% at 110 ° C, and having a specific gravity of 2.42 and a particle size such that 100% of the particles are less than 50 µm and 84% of the particles are less than 20 It is particularly suitable. Hydrated alumina has been found to be the most compatible polishing material herein.

The polishing material is generally present in amounts ranging from about 10% to about 75% by weight, preferably about 35% to 65% by weight, most preferably about 45% to about 55% by weight, in these toothpaste compositions.

The thickening component IV used in amounts from about 0.5 to about 10, preferably about 1 to about 5% by weight of the mixture, should be one or a mixture of the above group members. A preferred thickener is synthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex clay, available, for example, as Laponite (eg, XLG, XLS, D) sold by Laporte Industries Limited.

Laponite D analysis shows approximately by weight 58.00% SiC 2 / 25.40% MgO, 3.05% Na 2 O, 0.98% Li 2 O and some water and trace metals. Its true density is 2.53 and it has an apparent bulk density (g / cm at 8% moisture) of 1.0.

8301052 ir -7-

Other thickeners include carboxymethyl cellulose, hydroxybutylmethyl cellulose, hydroxypropylmethyl cellulose, and preferably hydroxyethyl cellulose (e.g. available as Natrosol).

For example, the poly (methyl vinyl ether / maleic anhydride) thickener is available as Cantrez AN 139 (GAF Corp.) and the colloidal silica thickener as a more finely ground Syloid (e.g., 244).

The carboxyvinyl polymer suitable as a thickening agent is available, for example, as Carbopol (e.g. 934, 940, 941). These 10 products from B.F. Goodrich Co. are disclosed in U.S. Pat. Nos. 2,798,053, 2,923,692, and 2,980,655, and substantially colloldal water-soluble acrylic acid carboxylic polymers are cross-linked with about 0.75 to about 2.0% of a cross-linking agent of polyallyl saccharose or polyallyl pentaerythritol.

The humectant component V used in amounts of from about 5-75, preferably from about 10-45, most preferably from about 15-35% by weight of the toothpaste blends of the invention is polyethylene glycol (eg 400, 600) . This relatively low molecular weight component (e.g., about 300 to about 1000) also often functions as the liquid carrier, alone or in combination with water and / or ethanol.

Any flavoring optionally but most preferably used in the PDP-containing toothpaste preparations according to the invention should, of course, also be compatible with the PDP.

Flavoring is typically included in the oral compositions of the invention in weights of about 0.01 to 3.0%, preferably 0.5 to 2.0%, most preferably 0.75 to 1.0%. Some illustrative examples of compatible flavors include pulegol, anethole, isoeugenol, guaiacol, creosol, thymol, menthol, cineol, eugenol, clove oil, peppermint and cardiac extracts, carvone, methyl paracresol, eucalyptol, safrole, anisole and the like.

The solid and liquid components of the mixtures according to the invention are used in mutual proportions in the usual manner to form a paste, creamy or gelled mass which can be dispensed or extruded from a pressure vessel or from a flexible or compressible container or tube, for example alumina, lined lead or plastic or the like. The mixtures may be substantially anhydrous, but generally contain up to about 25, typically about 5 to about 20, weight percent water. These mixtures preferably have a pH determined as a 20% aqueous suspension from 7.8 to about 10.5, most preferably about 8.5 to about 10.5, especially about 9.5 to 10.5, since the PDP, in particular the KPDP, has been found to be more stable, i.e., with better retention of active oxygen activity in these strong alkaline regions in the presence of the other components of the mixtures. The pH can be controlled by including the required amounts of acidic components such as citric acid or benzoic acid, basic components such as sodium hydroxide, and / or buffer agents such as sodium citrate, benzoate, bicarbonate or carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, or mixtures thereof. It should be noted that selection of the appropriate dental polishing agent is important in maintaining the above alkaline pH ranges, since the most common polishing agents cannot be used in the present mixtures at such pH ranges. For example, when insoluble sodium meta-phosphate (IMP) polishing agent is used with the other above-mentioned components of these mixtures and the pH is adjusted to 9.7, the mixture loses significant amounts of its available oxygen when aged at 120 ° F and the pH shifts down to about 7.2. In contrast, although mixtures of the invention with silica as the polishing material exhibit poor stability at an "as is" pH of 7.7, the mixture is stabilized when the pH is adjusted upward as above, for example to 9.7 and the pH does not shift significantly with age. Hydrated alumina works excellently in this regard as its normal pH falls within the above ranges.

The toothpaste compositions of the invention may contain a non-soap synthetic sufficiently water-soluble organic anionic or non-ionic surfactant in concentrations generally ranging from about 0.05 to about 10, preferably about 0.5 to about 5, weight .% to promote moisturizing, detergency and foaming properties.

U.S. 8301052 + U.S. Patent 4,041,149 discloses such suitable anionic surfactants in column 4, lines 31-68 and in column 9, lines 1-12, which are considered to be incorporated herein. Pluronic-5 type nonionic surfactants (polyoxyethylene polyoxypropylene block polymers) such as Pluronic PI08 and PI27 can also be used.

Various other common toothpaste additives or excipients can also be included such as whitening or coloring agents, preservatives, silicones, ammonia such as urea and diimnonium phosphate, and sweeteners in amounts ranging from about 0.01 to about 5 wt% or more. Suitable sweetening agents include, for example, sorbitol, xylitol, sodium cyclamate, perillartine, D-tryptophan, dihydrochalcones and the like, preferably saccharin.

In the practice of the invention, the toothpastes are regularly used in the oral cavity, in particular dental enamel, preferably from about 1 to 3 times a day for times of preferably at least about 10 seconds and most preferably at least about 60 seconds in the usual amount required when brushing the teeth.

The invention is further elucidated by means of the examples below. The amounts stated therein are by weight unless stated otherwise.

In the following example, the stability of the KPDP can be evaluated by watching the active oxygen (A.O.) levels according to the method below; KPDP readily hydrolyses in an acidic medium as follows: P2 ° 8 ~ 4 + 2H2 ° -> *> 4'S ° 2

An excess of iron (II) ammonium sulfate is added to reduce the peroxide: 2Fe (NH4) 2 (SO4) 2 + H202 + H2S04 - * Fe2 (SO4 + 2 (NH4> 2S04 + 2H20)

The excess iron (II) ion is back-titrated with cerium sulfate: 2Fe (NH4) 2 (S04) 2 + 2Ce (S04) 2 - * Ce2 (S04) 3 + Pe2 (S04) 3 + 2 (NH4) 2SC > 4 35 The AO is found by difference.

8301052 -10- TABLE &

Example (wt%)

I II III

Water, distilled 19.69 17.0 18.0 5 Laponite XLG 2.4 2.4 2.5 PEG 600 8.7 8.0 7.0

Pluronic F108 4.3 4.0 4.5 -1 sodium benzoate 0.54 0.5 0.54 '10 sodium saccharin 0.22 0.2 0.22 -ί * flavoring 0.55 0.5 0.55 -; - j water, distilled 7.6 7.0 7.6 KPDP 3.0 3.0 3.0 -1 hydrated alumina 53.0 50.0 53.0 - | 15 Active oxygen

Theoretically 0.126 0.126 0.126 start at RT 0.123 0.130 0.122 aged 7 weeks at 100 ° F 0.123 0.131 0.130 i i.

8301052 -11-

TABLE B

Example (wt%)

IV V

Laponite XLG 2.0 5 Laponite XLS 5.8

Natrosol 250 MR * 0.5 KPDP 3.0 3.0 sodium benzoate 0.5 sodium saccharin 0.2 0.2 10 PEG 600 10.0 15.0 hydrated alumina 49.0 37.0 SLS 1.5 1, 5 flavoring 0.5 0.5 water 32.8 37.0 15 (pH) (10.0) (9.6)

Active oxygen

Start at RT 0.124 0.127 aged 3 weeks at 120 ° F 0.130 0.127 aged 6 weeks at 120 ° F 0.120 0.112 aged 9 weeks at 120 ° F 0.116 0.119 * Hydroxyethyl 1 -cellulose i!

_I

8301052 -12-

TABLE C

Example (wt%) VI VII

Syloid 244 7.15 7.3 5 Zeo49 (Huber silica) 19.36 19.8 PEG 600 50.6 51.7 KPDP 3.0 3.4 Sodium saccharin 0.2 0.22 Sodium benzoate 0.5 0. 56 10 TiO2 0.55 0.56 water 17.14 14.8 SLS 1.0 1.66 - * flavoring 0.5 -1 (pH adjusted with 50% NaOH) (9.7) (9.2) 15 Active oxygen

Start at RT 0.125 0.148 aged 3 weeks at 120 ° F 0.118 0.126 aged 6 weeks at 12 ° F 0.110 0.128 aged 9 weeks at 120 ° F 0.108 0.132 t / 8301052 w «

-13-TABLE D

Example (wt%) VIII IX hydroxy_ hydroxyethyl cellulose 1.0 1.0 1.0 5 PEG 600 20.0 20.0 20.0 sodium benzoate 0.5 0.5 0.5 sodium saccharin 0.2 0 .2 0.2 hydrated alumina 47.0 47.0 48.0 KPDP 3.0 3.0 3.0 10 H2 O 26.05 26.05 25.6 flavoring 0.75 0.75. 0.5 SLS * 1.5 1.5 --- non-ionic surfactant ** '15 (pH) (10) (10)

Active oxygen

Start at RT 0.136 0.131 0.130 aged 6 weeks at 120 ° F 0.134 0.133 aged 9 weeks at 120 ° F 0.130 20 * Sodium lauryl sulfate ** polyoxyethylated (20 E.O.) sorbitan monoisostearate

The formulations of the examples described above exhibit good to excellent active oxygen stability upon storage. In contrast, the sole dentifrice composition disclosed in U.S. Patent 4,041,149, namely in Example I, and which contains incompatible components (glycerol, precipitated calcium carbonate and dicalcium phosphate dihydrate) exhibits unacceptable active oxygen stability. Some of the above examples show the order of addition of underlined individual or pooled components.

8301052 «4B- -14-

Example XI

wt%

Natrosol -250 MR 1.0 PEG 600 20.0 5 hydrated alumina 52.0 SLS 1.5 sodium benzoate 0.5 sodium saccharin 0.2 KPDP * 3.0 10 deionized water 25.8 (pH at 10.2)

The above chemically, physically and cosmetically stable compositions of the invention and a comparative composition in which the KPDP was omitted were evaluated for effectiveness in reducing gingivitis and plaque in a scientifically conducted 12-week trial on a group of 10 beagle dogs (5 males and 5 females). The results (average of 10 dogs) were as follows;

Control Example XI

20 Gingiva Index

Start 0.85 0.88

End 0.79 0.47

Paste unit index 1.22 0.96

These results confirmed that the addition of the KPDP to the comparative preparation significantly reduced both the gingival index and the slice index. In contrast, in a concurrent run using a non-aqueous formulation containing propylene glycol wetting agent, hydroxypropyl cellulose thickener and Dical polishing agent, the tack index was increased and in a similar run using an aqueous neutral. mixture containing PEG 600 wetting agent, hydroxyethyl cellulose thickener and IMP abrasive increased both the gingival and adhesive index.

i 8301052 -15- \

It has been shown that compositions of the invention containing polyethylene glycol (PEG) humectant are very stable against loss of available oxygen. The criticality of combinations of required components in such compositions and the reciprocity of stabilization therein is established, for example, by the fact that PEG affects and drastically reduces the efficiency of KPDP as a source of available oxygen in the absence of other defined components. For example, aqueous KPDP solutions buffered at pH 7 are stable at 120 ° F for 9 weeks, but the addition of 10 varying amounts (3%, 15%, 40%) of PEG to 3% KPDP solutions (performed in triplicate) yield when aged for 9 weeks at 100eF and 120 ° F the following mean results: _% available oxygen

1 week 3 weeks 6 weeks 9 weeks 6 weeks 9 weeks 15 Start 120 ° F 120 ° F 120 ° F 120 ° F 100 ° F 100 ° F

3% PEG 0.126 0.107 0.050 0.041 0 0.086 0.061 15% PEG - 0.115 0.113 0.066 0.053 0.023 0.088 0.066 40% PEG. 0.120 0.116 0.091 0.084 0.029 0.091 0.072 average loss 20 6.7 42.4 50.4 85.2 26.5 44.9 y f 8301052 _______; _; _ y

Claims (10)

A toothpaste mixture comprising: I an oral carrier, II as essentially the only oral chemically active agents, A. 0 to about 2 wt% of a fluorine-providing anti-caries compound and B. about 1 to about 7 wt. % of a peroxydiphosphate salt ,. III about 10 to about 75 wt% of at least one polishing material selected from the group consisting of 10 silica and hydrated alumina, IV about 0.5 to about 10 wt% of at least one thickener selected from the group consisting of colloidal silica synthetic hectorite, poly (methyl vinyl ether / maleic anhydride), carboxy vinyl polymer, carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose and hydroxyethyl cellulose, and V about 5 to about 75 weight percent polyethylene glycol as a wetting agent. Mixture according to claim 1, characterized in that the polishing material contains hydrated alumina. Mixture according to claim 2, characterized in that the thickener contains synthetic hectorite. 4. Mixture according to claim 2, characterized in that the thickener contains hydroxyethyl cellulose, Mixture according to claim 1, characterized in that the polishing agent contains silica. Mixture according to claims 1 to 5, characterized in that said peroxy diphosphate salt is tetrapotassium peroxide diphosphate. Mixture according to claim 6, characterized in that it has a pH from 7.8 to about 10.5. A method comprising applying in the oral cavity a mixture as defined according to claims 1-5. 9. Method comprising placing in the oral cavity a mixture as defined in claim 6. 8301052 r_ _ ___ ^ 2> r -17- A method comprising introducing into the oral cavity a mixture as defined in claim 7. 8301052