JPH0123404B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for stabilizing dicalcium phosphate dihydrate. Stabilized against spontaneous hydrolysis and/or degradation with small amounts of tetrasodium pyrophosphate, or trimagnesium orthophosphate, for example, as described in Moss et al., US Pat. No. 2,287,699. Dicalcium orthophosphate dihydrate ( _CaHPO4.2H2O ) has been used in dentifrices _for many years. In fact, dicalcium phosphate dihydrate is often stabilized against spontaneous hydrolysis and/or degradation when small amounts of both tetrasodium pyrophosphate and trimagnesium phosphate are used in dentifrices. Furthermore, as is well known to those skilled in the art,
Dentifrice formulations using dicalcium phosphate dihydrate often contain sodium or potassium monofluorophosphate as a source of fluoride ions to inhibit or retard caries formation. That is, sodium or potassium monofluorophosphates stabilized against spontaneous hydrolysis and/or degradation using tetrasodium pyrophosphate and/or trimagnesium phosphate, with or without a separate abrasive. The accompanying use of dicalcium phosphate dihydrate is well known to those skilled in the art. Although satisfactory results are obtained using the above-described dentifrice formulation, it has been found that soluble fluoride ions are lost from the dentifrice formulation over time. For example, up to 1% by weight of P ₂ O ₅ as pyrophosphate
Tetrasodium pyrophosphate equivalent to or about 2
wt % of dicalcium phosphate dihydrate stabilized with trimagnesium phosphate octahydrate and approx.
It has been found that dentifrice formulations containing sufficient sodium monofluorophosphate to provide 1000 ppm of soluble fluoride lose substantial amounts of soluble fluoride after long periods of storage. There is only a slight improvement in soluble fluoride stability when both trimagnesium phosphate and tetrasodium pyrophosphate are used together. Although we do not wish to be bound by any particular theory, it is believed that the loss of soluble fluoride in the formulation is related to the hydrolytic instability of dicalcium phosphate dihydrate. .
It is believed that fluoride ions catalyze the formation of calcium hydroxyapatite, which then reacts with soluble fluoride to form water-insoluble calcium fluoroapatite and/or calcium fluoride. It is therefore recognized that the improved fluoride stability of dicalcium phosphate dihydrate may improve stability against spontaneous hydrolysis and/or degradation. In any event, there is a need for a process for making dicalcium phosphate dihydrate that provides large amounts of soluble fluoride even after long-term storage. A method is now provided to meet this need. These and other requirements are as follows: (A) 0.1% to 5% by weight calculated as P ₂ O ₅ based on the weight of dicalcium phosphate dihydrate (DCPD);
% by weight of dicalcium phosphate dihydrate, (B) the dicalcium phosphate dihydrate containing from 0.1% by weight based on the weight of the dicalcium phosphate dihydrate;
5% by weight of trimagnesium phosphate is added, and (C) from 0.1% by weight based on the weight of the dicalcium phosphate dihydrate to the dicalcium phosphate dihydrate.
This is achieved by a process consisting of adding 3% by weight of a pharmaceutically acceptable condensed phosphate. As used herein, the term "DCPD" refers to dicalcium phosphate dihydrate. The term "pyrophosphate complex" refers to the chemical compound formed when a soluble pyrophosphate or a calcium-alkali metal salt of pyrophosphate is added to PCPD during the precipitation step to impart normal hydrolytic stability to DCPD. means substance. The term "hydrolytically stable" with respect to DCPD refers to DCPD that is stabilized against spontaneous hydrolysis and/or degradation. DCPD containing pyrophosphate complexes may be produced by a number of methods known to those skilled in the art. Generally, calcium carbonate, calcium oxide, calcium hydroxide and mixtures thereof (usually slaked lime,
A basic calcium-containing material, such as quicklime and a mixture known as hydrated lime), is added to a dilute aqueous solution of orthophosphoric acid to precipitate DCPD. Then, for example, US Pat. No. 2,287,699, US Pat. No. 3,012,852, US Pat.
Hydrolytic stability of DCPD by pyrophosphate complexes is obtained by adding calcium/sodium pyrophosphate or soluble pyrophosphate to DCPD as disclosed in each of the patents. In preferred embodiments, the DCPD is about 5.5 to about 6.5
In an aqueous mixture containing DCPD with a pH of
It is prepared by adding 0.3% by weight, expressed as P ₂ O ₅ , of a tetraalkali metal pyrophosphate and then adding sufficient lime to the DCPD slurry to give a pH of about 6.5 to about 8.0. Soluble pyrophosphates useful for making pyrophosphate complexes are well known to those skilled in the art. For forming the pyrophosphate complex, tetraalkali metal pyrophosphate salts such as tetrasodium pyrophosphate and tetrapotassium pyrophosphate are preferred, with tetrasodium pyrophosphate being particularly preferred. The amount of soluble pyrophosphate to be added to DCPD to obtain partial hydrolytic stability is between 0.1 and 5% by weight calculated as P ₂ O ₅ based on the weight of DCPD.
Based on the weight of DCPD, approximately as pyrophosphate
Preferably, the soluble pyrophosphate is added in an amount corresponding to an addition of 0.5 to about _2.5 % by weight _P2O5 . Based on yet another criterion, soluble pyrophosphate is added _in an amount to yield a DCPD containing 0.2-2.5% by weight of pyrophosphate, calculated as _P2O5 , which is a representative stabilized Represents DCPD. After the DCPD containing the pyrophosphate complex is recovered from the slurry and then dried, trimagnesium phosphate is added by methods known in the art, such as by blending powdered trimagnesium phosphate with the DCPD. The amount of trimagnesium phosphate that can be used in the compositions of the invention can vary within a wide range. The beneficial effects of trimagnesium phosphate are generally not observed at concentrations below about 0.1% by weight, based on the weight of DCPD, and no additional stability is observed at concentrations above about 5% by weight, based on the weight of DCPD. do not have. Preferably, from about 0.5% to about 3% by weight is added based on the weight of the DCPD. Furthermore, the trimagnesium phosphate used in the process of the invention is generally added as an octahydrate. However, other hydrates of magnesium phosphate may be equivalent as the exact form of magnesium phosphate that is effective after it is incorporated into a DCPD-based toothpaste is not known.
Therefore, trimagnesium phosphate anhydride or 8
Even trimagnesium phosphate or dimagnesium phosphate hydrate containing ~22 molecules of water of hydration are considered equivalent for the present invention; however, using trimagnesium phosphate with 8 molecules of water of hydration is more preferable. Also according to the method of the present invention, from about 0.1% to about 3% by weight, based on the weight of DCPD, of at least one pharmaceutically acceptable condensed phosphate is added. The pharmaceutically acceptable condensed phosphate can be added to the DCPD by methods known to those skilled in the art, such as by blending the powdered condensed phosphate with the DCPD. In the method of the invention, the pharmaceutically acceptable condensed phosphate and trimagnesium phosphate can be added to the DCPD containing the pyrophosphate complex at any stage before the DCPD is incorporated into the toothpaste formulation. . The order of addition is not believed to be critical, but it is preferred to add the trimagnesium phosphate to the DCPD before adding the pharmaceutically acceptable condensed phosphate. A large number of pharmaceutically acceptable condensed phosphates known to those skilled in the art can be used in the method of the present invention. Generally, sodium, ammonium and potassium salts, alone or mixed together or with, for example, calcium salts, are pharmaceutically acceptable. Therefore, examples of suitable condensed phosphates include, for example, tetrasodium pyrophosphate,
Pyrophosphates such as tetrapotassium pyrophosphate, disodium dihydrogen pyrophosphate (commonly referred to as acidic sodium pyrophosphate) (anhydrous or octahydrate), trisodium or tripotassium pyrophosphate, e.g. Sodium, pentapotassium tripolyphosphate and hydrogen-containing sodium or potassium tripolyphosphate (Na ₄ HP ₃ O ₁₀ ,
Mention may be made of the pharmaceutically acceptable salts of polyphosphates such as K ₃ H ₂ P ₃ O ₁₀ ), superphosphates, and metaphosphates such as sodium metaphosphate and potassium metaphosphate. Pentanasodium tripolyphosphate is preferred. In addition to the above-mentioned condensed phosphates, amorphous condensed phosphates, such as sodium phosphate glasses ranging in composition from pure P ₂ O ₅ to a Na ₂ O/P ₂ O ₅ molar ratio of 1.7, may be used in the method of the invention. can do. Glasses with a molar ratio of 1.0 are called hexametaphosphates (sometimes called ``Graham's salts'') and other glasses with a constant degree of polymerization by approximate analysis are called polyphosphates. It's here. Although pharmaceutically acceptable salts of compounds with only one phosphorus atom, such as orthophosphates, do not impart as much stability to DCPD as condensed phosphates, they can be prepared in the process of the present invention. Its presence in DCPD is not harmful. Indeed, to obtain maximum fluoride stability, it is desirable to add such compounds along with condensed phosphates. The amount of pharmaceutically acceptable condensed phosphate can vary within a wide range. Approximately 0.1% based on the weight of DCPD
Although beneficial effects are observed at moderately low concentrations, it is preferred to use higher concentrations, such as about 0.3% by weight or higher. No beneficial effect is observed using more than about 3% by weight, based on the weight of DCPD, and the presence of higher concentrations of condensed phosphate impairs soluble fluoride stability to some extent. As will be apparent to those skilled in the art from this disclosure, the exact concentration of pharmaceutically acceptable condensed phosphate depends on a number of factors, such as the amount of trimagnesium phosphate and the amount of pyrophosphate complex, the quality of the DCPD. , depending on the particular condensed phosphate used, etc. however,
Preferably, from about 0.3% to about 2% by weight is added based on the weight of the DCPD. The mechanism by which pyrophosphate complexes and trimagnesium phosphate and condensed phosphates confer superior soluble fluoride stability to DCPD is not understood. It was initially thought that the excellent results were achieved by the action of condensed phosphates, since they are strong calcium sequestrants. However, the hydrolytic stability of DCPD obtained when a DCPD composition containing a pyrophosphate complex and a trimagnesium complex is mixed with trisodium nitrilotriacetate or tetrasodium ethylenediaminetetraacetate is similar to that obtained by the method of the present invention. It wasn't that good. DCPD produced by the method of the invention can be used in toothpaste formulations with alkali metal monofluorophosphates, such as sodium monofluorophosphate, potassium monofluorophosphate, and the like.
More preferred is sodium monofluorophosphate for use with DCPD. DCPD produced by the method of the present invention can be combined with other dental abrasives as will be apparent to those skilled in the art. Examples of such dental abrasives include, but are not limited to, insoluble metaphosphates, silica gel, alumina, and silica. Although satisfactory results have been obtained using the DCPD produced by the method of the present invention, for example, anhydrous dicalcium orthophosphate can be used to clean teeth that are very heavily covered with discolored substances, food particles, tartar, etc. Thus, it may be desirable to add additional dental abrasives such as precipitated anhydrous dicalcium orthophosphate. The preparation of such DCPDs containing small amounts of additional abrasives is known to those skilled in the art, as described, for example, in US Pat. No. 3,334,979. In preparing the final dentifrice composition containing the DCPD produced by the method of the present invention, virtually all of the adjuvants conventionally used in toothpaste and/or tooth powder formulations can be used. Toothpastes, for example, generally contain a source of fluoride ions (e.g. sodium monofluorophosphate), sweeteners (e.g. saccharin), humectants (e.g. sorbitol or glycerin), binders (e.g. hydroxyethylcellulose, carboxymethylcellulose, etc.), emulsifiers (e.g. lauryl sulfate) sodium, sucrose monolaurate, or tridecyl alcohol reacted with about 3 to about 10 moles of ethylene oxide per mole of alcohol) and flavoring agents. In toothpastes, the amount of DCPD used can generally vary from about 20 to about 60% by weight of the agent, with about 30 to about 45% being preferred. As previously mentioned, the DCPD made by the method of the present invention need not be the only abrasive in the dentifrice, but it is generally preferred that it constitute at least about half of the total abrasive in the dentifrice. EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited thereto. In the examples, all percentages are by weight unless otherwise specified. Examples Phosphoric acid and lime in aqueous media
A DCPD-containing aqueous slurry is prepared by reaction with The resulting slurry contains approximately 30% DCPD and the PH of the slurry is 5.8. PH using lime slurry (13.5% CaO)
2780 g of this DCPD aqueous slurry adjusted to 6.5 is charged to a 3.785 (1 gallon) reactor equipped with an agitator. To this slurry was added 188 g of a 9% aqueous tetrasodium pyrophosphate (TSPP) solution (DCPD present).
2% TSPP) is added and the mixture is stirred for 45 minutes at about 29°C. The pH was then adjusted to about 7.7 with an aqueous lime slurry solution (13.5% CaO) and the solid DCPD product was separated from the slurry.
Dry and mill. Separate a small portion of the sample and correspond to the pyrophosphate complexes present
The amount of P <sub>2</sub> O <sub>5</sub> is determined substantially according to the well-known ion exchange method for the analysis of sodium triphosphate [entitled ``Standard Method for the Analysis of Sodium Triphosphate by a Simplified Ion Exchange Method''. ASTM D
-2671-70 (reauthorized in 1975)]. The pyrophosphate complex content is measured to be approximately 0.5% by weight based on DCPD. After drying and milling each portion of the DCPD containing the pyrophosphate complex, it is blended with powdered trimagnesium phosphate and/or powdered condensed phosphate and similar to that disclosed in U.S. Pat. No. 3,308,029. toothpaste formulations (which are representative of those commercially available, except for fragrance). It contains approximately 1000 ppm of added fluoride. This formulation is as follows. Parts by Weight Glycerin 21.8 DCPD 49.6 Sodium Lauryl Sulfate 1.5 Saccharin 0.2 Water 25.2 Sodium Monofluorophosphate 0.8 Carboxymethyl Cellulose 0.9 100.0 Transfer each sample of the paste to a plastic bottle. The plastic bottles are then capped and placed in a 50°C oven for 6 weeks as an accelerated aging test simulating 2 years of storage at ambient temperature. After 6 hours of storage, the bottles are removed from the oven and the soluble fluoride concentration of the formulation is measured potentiometrically. The storage results after 6 weeks are shown in Table 1.

[Table] Glassy sodium polyphosphate 1〓
Um ^b

[Table] Example Repeat the operation of Example. The soluble fluoride content of the added toothpaste is approximately 1000 ppm. The results are shown in Table 2.

[Table] Rium

[Table]
*Comparative Example A sample of DCPD from the example is blended with 2% trimagnesium phosphate, 1% pentanosodium tripolyphosphate and 0.05% monosodium phosphate. DCPD was used in an example toothpaste containing about 1000 ppm soluble fluoride and at 50°C.
When stored for a week, approximately 610 ppm of soluble fluoride remains after testing. Although the invention has been described in detail with respect to particular embodiments, this is for illustrative purposes only and is not intended to be limiting. Other aspects of the invention and methods of operation will be apparent to those skilled in the art from this disclosure. Therefore, such obvious aspects are included in the present invention without departing from the gist of the present invention.

Claims (1)

[Claims] 1 (A) 0.1% to 5% by weight calculated as P ₂ O ₅ based on the weight of dicalcium phosphate dihydrate
(B) the dicalcium phosphate dihydrate contains from 0.1% by weight based on the weight of the dicalcium phosphate dihydrate;
5% by weight of trimagnesium phosphate is added, and (C) from 0.1% by weight based on the weight of the dicalcium phosphate dihydrate to the dicalcium phosphate dihydrate.
A method for stabilizing dicalcium phosphate dihydrate, comprising adding 3% by weight of a pharmaceutically acceptable condensed phosphate. 2. The method according to claim 1, wherein the pyrophosphate complex is present in an amount of 0.5% to _2.5 % by weight calculated as _P2O5 . 3. The method of claim 2, wherein 0.5% to 2.5% by weight of trimagnesium phosphate is added to the dicalcium phosphate dihydrate, based on the weight of the dicalcium phosphate dihydrate. 4. Adding to dicalcium phosphate dihydrate 0.3% to 2% by weight, based on the weight of dicalcium phosphate dihydrate, of at least one pharmaceutically acceptable condensed phosphate salt. The method described in Section 3. 5 Pharmaceutically acceptable condensed phosphates include pentanasodium tripolyphosphate, sodium trimetaphosphate,
5. The method of claim 4, wherein the method is selected from the group consisting of disodium dihydrogen metaphosphate, tetrasodium pyrophosphate, and mixtures thereof.