NL8701141A - STABILIZED AMINEFLUORIDE DENTAL CREAM. - Google Patents

Description

-% E-VO 9148

Stabilized amine fluoride dental cream.

The invention relates to a stabilized dental cream containing amino fluoride. In particular, the invention relates to an amine fluoride containing dental cream which is stabilized against phase separation by the presence of low molecular weight polyethylene glycol.

Amine fluoride compounds have been proposed and used in dental creams and other types of oral preparations, such as mouthwash liquids, because of their effect in promoting oral hygiene. For example, they have the ability to increase tooth enamel's resistance to acids, improving the ability of teeth to resist cavity formation.

They can also reduce the formation of gingivitis and plaque in the oral cavity.

British Pat. Nos. 865,272 and 1,021,058 of 15 Gaba A.G. oral preparations are described, including toothpastes and dental creams containing amino fluoride compounds. In particular, specific examples of aminofluoric dental cream preparations are given in British Pat. No. 1,021,058, which uses insoluble sodium metaphosphate as a polishing agent, sorbitol is present as a wetting agent and also a gelling agent, including methyl cellulose. The patent also discusses glycerol (i.e., glycerin) as an alternative wetting agent.

Yankell's U.S. Pat. No. 3,914,406 also discloses amine fluoride oral preparations including toothpastes, and an example is given using insoluble sodium metaphosphate polishing agent, sorbitol wetting agent and hydroxyethyl cellulose gelling agent. The patent describes as a wetting agent "sorbitol, glycerine, polyhydric alcohols of a similar nature or mixtures thereof".

In the specific examples, however, the only mixtures (sorbitol solutions and glycerine) are used in mouthwash liquids, while the toothpastes contain either sorbitol solution or propylene glycol.

It has been observed that dental creams, as generally characteristic of the prior art, are subject to phase separation 870 1 1 4 i -2- • iv when the polishing agent has a significant content of insoluble alkali metal metaphosphate, the wetting agent is sorbitol or glycerine and gelling agent is non-polar cellulose type material. Use of alternative polyhydric alcohol of a similar nature as the sole or major wetting agent, for example in amounts of about 15% or more has not been found to be satisfactory. For example, when an aminofluoride dental cream containing 20% polyethylene glycol with an average molecular weight of about 600 is used, an undesirable flavor note occurs.

An advantage of the present invention is that separation in amine fluoride dental cream from a liquid phase and the solid or gelled portion of the dental cream is reduced or overcome. Further advantages of the invention will become apparent from consideration of the following discussion.

In accordance with certain aspects of the invention, the invention relates to a dental cream comprising a material that provides the dental cream with about 0.01-1 wt% soluble fluoride, with at least about 70 wt% of this material is an amine fluoride, provides about 25-80% of an aqueous liquid phase, which comprises a wetting agent in an amount of at least about 20% by weight of said dental cream, which wetting agent is selected from the group consisting of sorbitol, glycerine and mixture thereof, providing a solid phase comprising about 0.2-5 wt% of a nonionic cellulose-type gelling agent 25 and providing about 20-75 wt% of a polishing material containing insoluble alkali metal metaphosphate as at least the major component of said polishing material, wherein the dental cream is stabilized against phase separation by incorporation in said aqueous wetting phase of polyethylene glycol having an average molecular weight of about 200-1000, wherein the wetting agent-polyetylene glycol weight ratio is about 10: 1 to about 1: 2, the amount of polyethylene glycol being at least about 2% by weight.

The term amine fluoride used herein includes amine hydrofluorides and quaternary ammonium fluorides. These are used in quantities 8 7 0 i λ i a v 1 i ^ | / 4 -3- which provide about 0.01-1% by weight of soluble fluoride to the dental cream, preferably 0.05-1.15%.

Normally these compounds are characterized by the formula 1 of the formula sheet, wherein R represents alkyl, alkenyl, alkylol, alkoxyalkyl, aryl, aryloxyalkyl, aralkyl, cycloalkyl, cycloalkenyl or a heterocyclic group or may be an additional quaternary ammonium which may be the nitrogen atom bonded via a bridging group or a group of the formula -Rj-C0.Y, wherein Y represents OH, alkoxy, cycloalkoxy, aralkoxy or the group -NR2R2, wherein alkylene or arylene-alkylene and each of R2 ® Κβ is hydrogen or an alkyl , alkenyl, alkylol, aryl, aralkyl, cycloalkyl or heterocyclic group, or R2 and R1 together with the nitrogen atom form a heterocyclic core, each of the three free valencies is saturated with alkyl, alkenyl, alkylol, alkoxyalkyl, aryl * aryloxyalkyl, aralkyl, cycloalkyl, or a heterocyclic group or at least two of the previous valencies? d are by a group which, together with the nitrogen atom, forms a saturated or unsaturated, substituted or unsubstituted heterocyclic core.

The following compounds are specific examples of amine fluorides used in the present invention.

The invention is not intended to be limited to these compounds.

Octyl trimethyl ammonium fluoride, dodecyl ethyl dimethyl ammonium fluoride, tetraethylammonium fluoride, dilauryl dimethyl ammonium fluoride, A 8,9 octadecenyl benzyl dimethyl ammonium fluoride, furfuryl lauryl dimethyl ammonium fluoride, dimethyl ammonium fluoride ammonium fluoride, N, N-tetra-methyl-N, N-dilauryl-ethylene-diammonium difluoride, N-cetyl-pyridinium fluoride, N, N-dilauryl-morpholinium fluoride, N-myristyl-N-ethyl-morpholinium fluoride, 30 N (octylamyl-carbohydrate) ) -N-benzyl-dimethyl-ammonium fluoride, N-2 ethoxy-ethyl) -N-dodecyl-dimethyl-ammonium fluoride, N- (4P-hydroxy-dodecyl) -trimethyl-ammonium fluoride, N- (2-carbomethoxy-e thy1) -N-benzyl-dimethyl-ammonium fluoride, N- (2-carbocyclohexoxyethyl) -N-myristyl-dimethyl-35 ammonium fluoride, N- (2-carbobenzyloxyd: hi) -ii-dodecyl-dimethyl- ammonium- 870 1 14 1 -4- S, fluoride, N- (2- (N \ N ^ -dimethylamino-carbonyl) -ethyl) -N-dodecyl-dimethyl-ammonium fluoride, and N-carboxymethyl-N-eicosyl- dimethyl ammonium fluoride.

The amine fluorides of the present invention are soluble in water and most of them are also soluble in methanol and ethanol. They are usually hygroscopic crystalline solids or syrups. The quaternary ammonium fluorides having long chain substituents dissolve in water to form foaming solutions.

Further amine fluoride compounds that may be used and indeed preferred in the present invention are amine hydrofluoride of the formula RXHF, wherein R represents alkyl or alkenyl groups having about 10 to about 24 carbon atoms, preferably 14-21 carbon atoms; X represents the group or group of formula 2, wherein y is an integer of 1-3 and R 1, R 1, and R 1 is hydrogen; lower alkyl, lower alkenyl or lower alkanol with up to 5 carbon atoms-

Examples of compositions of the invention are those comprising the 20's which include the hydrofluoride salts of decylamine, dodecylamine, dodecenylamine, tetradecylamine, tetradecenylamine, pentadecylamine, hexadecylamine, hexadecenylamine, octadecylamine, ticosylamine, eicosylamine, eicosylamine, eicosylamine -N- (hydroxyethyl) alkylamine wherein the alkylamine is a mixture of 25 alkylamine groups having from about 12 to about 18 carbon atoms.

Compositions of the invention with beneficial properties are those containing 9-octadecenylamine hydrofluoride, hexadecylamine hydrofluoride, N- (bis- (hydroxyethyl) aminopropyl) -N- (hydroxyethyl) octadecylamine dihydrofluoride, or N, N, N-tris- (2 -hydroxyethyl 1) -30 N-octadecyl-1,3-diamino-propane dihydrofluoride.

Furthermore, a mixture of N- (bis- (hydroxyethyl) -aminopropyl) -N- (hydroxyethyl) octadecylamine dihydrofluoride and hexadecylamine hydrofluoride is also desired.

According to preferred aspects of the invention, the topical material providing soluble fluoride is the amine fluoride.

8 7 0 1 14 1 -5-

Also included is the possibility that up to 30% by weight of the material providing soluble fluoride is an additional non-toxic water-soluble fluoride providing compound or mixture thereof.

Such additional compounds (including mixtures 5 thereof) include inorganic salts supplying fluoride, such as suitable alkali metal, alkaline earth metal, and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, a copper fluoride, such as copper (I) fluoride, zinc fluoride, a tin fluoride, such as tin (II) fluoride or tin (II) chlorofluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorosirconate, sodium monofluorophosphate, aluminum mono and difluorophosphate, and calcium fluorophosphate. When present, alkali metal salts such as sodium fluoride and sodium monofluorophosphate are preferred.

In dental cream compositions, such amounts of the liquids and solids are used that a creamy mass of desired consistency is formed which can be extruded from an extensible tube (for example, painted aluminum, waxed lead or laminated plastic) or 20 a mechanically driven or differential pressure delivery device. The liquid phase comprises about 25-80% by weight of the dental cream and comprises water together with at least one compound from the group of sorbitol and glycerine as a wetting agent, the amount of sorbitol and / or glycerin being at least about 20% by weight of the dental cream is preferably about 20-40%. Sorbitol is the preferred humectant and is normally used as a 70% aqueous solution. Water is present, normally in an amount of at least about 5% by weight, preferably about 15-40%.

The gelling agent for use in the dental cream compositions of the invention is a nonionic cellulose type gelling agent such as methyl cellulose, hydroxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, hydroxypropyl cellulose and the like. Hydroxyethyl cellulose is preferred. The gelling agent is present in an amount of about 0.2-5% by weight of the dental cream, preferably about 0.8-2.0%.

870 1 14 1 -6-

Qualities of hydroxyethyl cellulose that can be used include the following qualities: supplier HEC quality viscosity (CPS)

Hercules Natrosol 250M and MR 4500 - 6500 5 "Natrosol 250 HR * 1500 - 2500 and 250 H *" Natrosol 250 HHR * 3400 - 5000

and 250 HH

B.P. Chemicals Cellobond 5000 A 4200 - 5600 10 "Cellobond 7000 A 6000 - 7000

Hoechst Tylose H 4000 P ** 3000 - 5000 "Tylose H 10000 P ** 7000 - 12000 Λ o 1% solution (Brookfield; 25 C) **

Hoeppler Viscometer (2%; 20 ° C)

Natrosol 250 M is preferred. The polishing material used in the dental cream compositions is present in amounts of about 20-75% by weight, preferably about 35-65%. Most preferably, it consists wholly or almost entirely of insoluble alkali metal metaphosphate. It is within the scope of the present invention that insoluble alkali metal metaphosphate is present as the main polishing agent (at least 50.0%) mixed with a minor amount of a secondary polishing agent, such as calcined alumina, dL calcium phosphate (anhydrous or dihydrate) , calcium pyrophosphate, tricalcium phosphate, calcium carbonate, trimagnesium phosphate trihydrate and magnesium carbonate. When secondary polishing agent is present, it is preferred in an amount up to about one third of the amount of insoluble alkali metal metaphosphate, the weight ratio of insoluble alkali metal metaphosphate to secondary polishing agent being about 3: 1 to about 99: 1, preferably about 8: 1 to about 12: 1.

8701141 -7- \

Insoluble sodium metaphosphate is the preferred salt of the water-insoluble alkali metal polymetaphosphates. For example, it is known as Maddrell or Kurrol salt. Water-soluble polymetaphosphates such as di-, tri-, tetra-, or hexa-metaphosphates are not contemplated in the invention. However, the latter compounds may be present as impurities in the water-insoluble polymetaphosphates usable in the present invention. to be. For example, the commercially available water-insoluble sodium polymeta phosphates may contain up to 4% of a water-soluble metaphosphate.

Low molecular weight polyethylene glycol having an average molecular weight of about 200-1000, preferably about 400-1000, readily disperse in the liquid vehicle and can effectively prevent dental cream phase separation or syneresis. In order to achieve easy dispersion, polyethylene glycol grades normally solid at room temperature are heated to liquefy them. Low molecular weight polyethylene glycol is used in an amount such that the weight ratio of wetting agent (glycerine and / or sorbitol) to polyethylene glycol 20 is about 10: 1 to about 1: 2, preferably about 2: 1 to about 1: 1. The polyethylene glycol is present in an amount of at least about 2% by weight, normally about 2-10%, and preferably about 4-10%. Organic surfactants can be used in the dental cream of the present invention to achieve enhanced prophylactic action, promote thorough and complete dispersion of the compositions of the invention throughout the oral cavity, and make the dental creams more cosmetically acceptable to make. The organic surfactant is normally non-ionic, ampholytic or cationic in nature, and preferably a detergent material is used as surfactant which imparts detergent properties to the composition.

Suitable surfactants include nonionics such as condensates or sorbitan monostearate with about 20 moles of ethylene oxide, condensates of ethylene oxide with propylene glycol ("Pluronic" materials), and amphoteric agents, such as long chain (alkyl) amino-8701141 i -8-alkylene alkylated amine derivatives, which are available under the trademark "Miranol", such as · Miranol C ^ M. Cationic surfactant germicides and antibacterial compounds such as diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, 5-benzyldimethylstearylammonium chloride, benzyldimethylstearyl ammonium chloride, tertiary-18-ammonium chloride, tert-18 ammonium chloride, tert-18 ammonium chloride ) and two (poly) oxyethylene groups bound to the nitrogen (normally with a total of about 2-50 ethanoxy groups per molecule) and salts thereof with acids, as well as compounds of the structure of formula 3 of the formula sheet, wherein R is a fatty alkyl group with about 12-18 carbon atoms, and x, y and z total equal to 3 or higher, as well as salts thereof with inorganic or organic acids can also be used. It is preferred that about 0.05-5 wt% surfactant active material is used.

Any suitable flavoring or sweetening agent can be used in formulating a taste for the composition of the present invention. Examples of suitable flavoring ingredients include the aromatizing oils, for example, oils of deer mint, peppermint, wintergreen, sassafras, cloves, sali, eucalyptus, marjoram, cinnamon, lime and orange, as well as methyl salicylate.

Suitable sweeteners include sucrose, lactose, maltose, xylitol, sodium 6-methyl-3,4-dihydro-1,2,3-oxathiazine-4-one, sodium cyclamate, perillartine, sodium saccharin, and saccharic acid. Preferably, flavor and sweetener together may comprise about 0.01-5% or more of the compositions of the present invention.

Various other materials can be included in the dental cream. Examples thereof are coloring or whitening agents or dyes, preservatives, anti-corrosive agents, silicones, chlorophilic compounds, further ammonia type materials such as urea, diammonium phosphates and mixtures thereof and other ingredients. Whitening agents, such as titanium dioxide, normally in amounts of about 0.05-2%, may be beneficial for the appearance of the denal composition because some discoloration may occur with aging.

The adjuvants are included in the present compositions in amounts that do not materially adversely affect the desired properties and are selected and used in appropriate amounts depending on the type of composition involved.

Antibacterial agents can. and also used in the oral compositions of the present invention in an amount of about 0.01-5 wt%.

When an insoluble alkaline earth metal salt is present as a secondary polishing agent, various calcium and magnesium ion suppressants are typically used to adjust the physical properties of the compositions. Suitable agents are the water-soluble inorganic pyphosphetzoutai such as tetrasodium pyrophosphate or disodium diacid pyrophosphate, with the partially neutralized or acidic polyphosphate being preferred. Other suitable agents are the alkali metal, preferably sodium salts of citric acid.

In general, such compounds will make up a minor amount of the formulation. The exact amount will vary depending on the specific composition, such as the physical properties of the dental cream, but will usually be from about 0.1 to about 3% by weight.

The dental creams should preferably have a pH useful for use. A pH range of about 3.5-9 is particularly preferred. The reference to pH is intended to refer to the pH determination directly on the dental cream. If desired, citric acid materials can be added to adjust the pH or, preferably, about 4-8.

The following illustrative examples serve to further illustrate the nature of the present invention without limiting the invention thereby. All quantities are by weight unless otherwise indicated.

8701141 ν ’* ^ -10-

EXAMPLE I

The following dental creams are prepared: parts

A B

Glycerin 23.0 13.0

Polyethylene glycol 600-10.0 5-hydroxyethyl cellulose (Natrosol 250M) 1.5 1.5

Sodium saccharin 0.4 0.4

Water (deionized) 27.1 27.1

Titanium dioxide 4.0 4.0

Amine fluoride * 33% 10 Insoluble sodium metaphosphate 42.0 42.0

Polyoxyethylene sorbitan ethylene oxide (20: 1)

Monostearate 0.5 0.5

Flavor 1.1 1.1 15 * The amine fluoride is Ν, Ν, Ν-tris (2-hydroxyethyl) -N-octadecyl-1,3-diaminopropane dihydrofluoride,

In preparing the aforementioned dental cream, polyethylene glycol 600 is dispersed with glycerine before adding hydroxyethyl cellulose to form a product of creamy consistency.

After aging for 12 weeks at 43 ° C, dental cream B remains virtually stable theologically, while significant syneresis of dental cream A is observed within 4 weeks.

EXAMPLE II

Dental creams C and D are prepared in accordance with dental creams A and B, respectively, provided that sorbitol (70%) replaces glycerine.

After aging for 12 weeks at 43 ° C, only very little phase separation is observed with dental cream D, while a significant syneresis of dental cream C is observed within 2 weeks.

8701141 ir τα -11-

VCOR FIGURE III

The amounts of glycerine and polyethylene glycol 600 in dental cream B are varied as follows:

Dental cream Glycerine Polyethylene glycol 600 - parts parts_ 5g 20.0 2.0 F 19.0 3.0 G 18.0 4.0 H 16.0 6.0 x 14.0 8.0 10 After aging for 3 weeks at 49 ° G, only a very small phase separation is observed with dental cream E, only a very slight phase separation with dental creams F and G after 9 weeks at 49 ° C, and virtually no phase separation is observed with dental creams H and I even after aging for 9 weeks with 49 ° C.

EXAMPLE IV

Average molecular weight polyethylene glycol as indicated below replaces polyethylene glycol 600 in dental cream B with amounts of glycerin and polyethylene glycol which were also varied in the manner indicated: Dental cream Glycerine Polyethylene glycol parts average molecular weight. parts j 18,000 400 4,000 K 16,000 400 6,000 25 L 18,000 1000 4,000 M 16,000 1000 6'000

After aging for 9 weeks at 49 ° C there was virtually no phase separation at the dental creams J and L, only very very little phase separation at the dental cream K and only a very light phase separation at the dental cream M. In the dental creams J and L, glycerine heated to 50 ° C before dispersing polyethylene glycol 10OC in it.

8 7 0 1 14 1 -12-

EXAMPLE V

The amounts of sorbitol (70%) and polyethylene glycol 600 in the dental cream D are varied as follows:

Dental cream Sorbitol (70%) Polyethylene glycol 600 5 _ parts_ _ parts_ N 18,000 4,000 0 17,000 5,000 P 16,000 6,000

After aging for 9 weeks at 49 ° C, there is virtually no phase separation at the dental creams N and P and only an indication of very little phase separation at the dental cream 0.

EXAMPLE VI

A dental cream that does not separate into phases upon aging is prepared by varying dental cream D such that the how-

The amount of insoluble sodium metaphosphate therein is lowered to 37.8 parts and incorporating 4.2 parts of calcined aluminum oxide. EXAMPLE VII

The following dental creams do not phase-separate with aging: 20 parts

A B

Glycerin 16,000 16,000 "Polyethylene Glycol 600 6,000 6,000

Hydroxyethyl cellulose 1,500 1,500 (Natrosol 250M) 25 Sodium saccharin 0.400 0.400

Water (deionized) 29,133 29,053

Titanium dioxide 0.500 0.500

Amine fluoride * (33%) 2,800 2,800

Sodium Monofluorophosphate - 0.114 30 Sodium Fluoride 0.067 0.033

Insoluble sodium metaphosphate 42,000 42,000

Polyoxyethylene sorbitan ethylene- 0.500 0.500 oxide (20: 1) monostearate

Flavor 1.1 1.1 35 * The amine fluoride is N, N, N-tris (2-hydroxyethyl) -N-octadecyl-1,3-diaminopropane dihydrofluorLè 87 0 1 14 1 -13-

In the above examples, the 4.0 parts of the 33% solution of the amine fluoride can be replaced by 4.344 parts of a 1: 4 mixture of N- (Bis- (hydroxyethyl) -aminopropyl) -N- (hydroxyethyl) octadecylamine dihydrofluoride and hexadecylamine hydro-5 fluoride with similar results.

In the above examples, sodium cyclamate can be used in place of sodium saccharin.

It is clear that the above examples are merely illustrative of the invention and that various modifications can be made therein.

/ 8701141

Claims (14)

A dental cream comprising a material which provides about 0.01-1% by weight of soluble fluoride to said dental cream, at least about 70% by weight of this material being an amine fluoride, providing about 25-80% of an aqueous liquid phase containing wetting agent in an amount of at least about 20% by weight of said dental cream, which wetting agent is selected from the group consisting of sorbitol, glycerine and mixtures thereof, yielding a solid phase containing about 0.2-5% wt. % of a nonionic cellulose type gelling agent and providing about 20-75% by weight of a polishing material containing insoluble alkali metal metaphosphate as at least the major component of said polishing material, the dental cream being stabilized against phase separation by incorporation into said aqueous wetting agent phase of polyethylene glycol having an average molecular weight of about 200-1000, the weight ratio from the wetting agent to the polyethylene glycol is from about 10: 1 to about 1: 2, the amount of polyethylene glycol being at least about 2% by weight. The dental cream of claim 1, wherein the amine fluoride is present in an amount providing about 0.05-0.15 wt% soluble fluoride. The dental cream according to claim 2, wherein the amine fluoride is Ν, Ν, Ν-tris (2-hydroxyethyl) -N-octadecyl-1,3-diaminopropane dihydrofluoride. The dental cream of claim 1, wherein the nonionic cellulose-type gelling agent is present in an amount of about 0.8-2% by weight, The dental cream according to claim 4, wherein the nonionic cellulose type gelling agent is hydroxyethyl cellulose. The dental cream according to claim 1, wherein the polishing material 30 is present in an amount of about 20-75% by weight and the insoluble alkali metal metaphosphate is insoluble sodium metaphosphate. The dental cream of claim 6, wherein the polishing agent is present in an amount of about 35-65% by weight and the insoluble sodium metaphosphate is the only polishing material present. 8701141 - 15- Dental cream according to claim 1, wherein the polyethylene glycol is present in an amount of about 2-10% by weight. Dental cream according to claim 8, wherein the polyethylene glycol is present in an amount of about 4-10%. The dental cream of claim 9, wherein the polyethylene glycol has an average molecular weight of about 400-1000. The dental cream of claim 10, wherein the polyethylene glycol has an average molecular weight of about 600. Dental cream according to claim 1, wherein the amine fluoride 10 is the only fluoride-providing material present. The dental cream of claim 1, wherein up to about 30% of the fluoride-providing material is inorganic fluoride-providing salt. Dental cream according to claim 13, wherein the inorganic fluoride-providing salt is selected from the group consisting of sodium fluoride, sodium monofluorophosphate and mixtures thereof. 8701141 COMPLETED PATENT OFFICES Dutch patent application No. 87.01141 "& 4RAVENHA6E (hollano) beh. when writing dd. October 20, 1987 Ln / 657 -ié- Improvement (s) of erratum (a) in the description associated with patent application No. 87.01141 proposed by applicant (star) under date October 20, 1987 ceccsccoccececeaccccececcsce On page 10, line 6 the value "0.4" "in columns A and B changed to" 0.3 ". On page 10, line 30, "within 2 weeks" is changed to "within 12 weeks" kt 545 $ 7 0 1 k 1 2 - * - <c>> 2) - <^ 2 3 (CH2CH20) 2H (CH2CS20) xH Ri-CH2CH2CH2H ^ (CH2CH20) yH »§7 01 141 'Cs x · -,.>' Srr: -year: v