AU695356B2 - Carbonated solutions for treating, mineralizing and fluoridating calcified tissues and methods for their use - Google Patents

Description

WO 96/25914 PCTIUS95/02364 -1- CARBONATED SOLUTIONS FOR TREATING, MINERALIZING AND FLUORIDATING CALCIFIED TISSJES AND METHODS FOR THEIR USE This invention was made in the course of research, supported partially by the Government under grant DE 08916, awarded by the National Institute of Dental Research. The Government may have certain rights in the invention.

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to certain carbonated calcium phosphate solutions that are unique in their applications as remineralizers of caries lesions, cavities and root erosions of the tooth, as mouth rinses and saliva substitutes. These solutions when further containing a fluoride compound can also be used for topical fluoridation of the teeth. When used for either fluoridation or mineralization these solutions prevent further tooth decay and actually restore the lesions caused by dental caries.

2. Description of the Prior Art Dental lesions, cavities, exposed roots and dentin sensitivity all develop due to the loss of minerals from the dental tissue. In recent years, a large amount of research has been done in the field of mineralization and fluoridation to prevent and counteract such mineral loss. Tooth minerals are generally impure forms of hydroxyapatite, Ca 5 (P0 4 )OH. Therefore, the objectives of the research has been to deposit fluoride and apatite on and into the tooth, thus preventing further tooth decay, restoring the tooth and/or obturating the dentinal tubules.

U.S. Patent No. 5,037,639 discloses the use of a carbonated solution for mineraliFzng and fluoridating calcified tissues. A continuation-in-part application (Serial No. 07/936,068) filed August 26, 1992 further discloses the use of a carbonated calcium phosphate solution under pressurized carbonated solutions for mineralizing and fluoridating calcified tissues. The carbonated solution under pressurized carbon dioxide atmosphere offers a novel and useful method and composition to mineralize and fluoridate the tooth at the sites needed by controlling the pH and stability of the calcium phosphate fluoride solutions. However, the prior carbonated solutions needed to be maintained in a pressurized carbon dioxide -I -L P A WO 96/25914 PCT/US95/02364 -2atmosphere prior to application to sustain its beneficial effects. The present invention encompasses simple methods to prepare carbonated remineralizing solutions without the need to use a pressurized aerosol.

1

P'

WO 96/25914 PCT/US95/02364 3 SUMMARY OF THE INVENTION The potential for application of dental remineralization is vast. Dentists fill millions of cavities each year. If these cavities where remineralized rather than filled the general dental health of the public would be increased substantially, since remineralization results in a whole tooth. The present invention seeks to provide remineralization compositions and methods that can practically be applied under a dentist's care and virtually replace the need for filling of the teeth.

This invention involves methods and compositions for preparation of unstable carbonated calcium phosphate solutions, which are supersaturated with respect to calcium phosphate solids and carbon dioxide. The invention takes advantage of the fact that at alkaline pH aqueous solutions are capable of maintaining a greater amount of phosphate ions and crarbonate ions in solution under atmospheric conditions. These alkaline solutions can then be mixed with acidic calcium solutions to create carbonated solutions useful for treating dental tissue.

When used to treat dental tissue the carbonated solutions of the present invention will deposit calcium phosphate compounds with or without fluoride on and in the tooth when applied for the prevention and/or repair of tooth weaknesses such as dental caries, exposed root, or dentin sensitivity. The deposition of the calcium phosphate compounds is controlled by the pH of the carbonated solutions.

The pH of the solutions increases as carbon dioxide escapes and this facilitates the precipitation of the calcium phosphates over a range of time as needed.

In addition, it has been discovered that high pH and relatively high pH carbonated solutions are useful as mouth rinses for preventing cavities. Such mouth rinses create a basic oral environment, thus removing acid from the teeth and preventing the resulting cavities, The advantages of the use of the calcium phosphate solution of the present invention as compared to the solutions and slurries of the prior art are many. Most importantly, the use of the compounds and methods of the invention allows for rapid formation of apatite upon dental tissues. Therefore, remineralization of the teeth can be achieved more quickly. In addition, the present invention provides for remineralization and fluoridation simultaneously when the carbonated solutions contain a fluorine compounds.

Another significant advantage is that the present invention will not damage the teeth due to a large change iii pH during the remineralization process.

WO 96/25914 PCT/US95/02364 -4- Yet another advantage of the present invention is the provision of a composition for remineralization of teeth which can be easily formulated and easily applied to the teeth.

Still another advantage of the present invention is the easy formulation of remineralizing carbonated solutions from solid powders.

And still a further advantage of the present invention is the provision of a composition which can be easily prepared and easily taken as an artificial saliva for individuals suffering from hyposalivation.

Thus, the present invention provides compositions and methods for remineralization of caries lesions that are practical for the use in a clinic environment. The invention also provides compositions and methods for the rapid Sfluoridation of teeth by the use of fluoride containing carbonated calcium |i phosphate solutions.

Further objects of the inventions will become apparent with the following description of the preferred embodiments and claims.

i i

I

ah- I Pe 3-l WO 96/25914 PCTUS95/02364 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The prese:,t invention provides the compositions and methods that can remineralize and/or fluoridate the tooth and, in the case of exposed root and dentin sensitivity, obstruct the dentinal tubules. The solution can be used as mouth rinse.

When properly formulated, this carbonated calcium phosphate solution can be used as an artificial saliva to serve as a replacement modality for individuals exhibiting hyposalivation. The solutions may further contain other beneficial ions such as fluorides, hydrogen peroxide and strontium.

The inventor has found that under atmospheric conditions, in an aqueous solution the maximum concentration of carbonate ions in equilibrium with the carbon dioxide in the air increases dramatically with the increase in the pH of the solution. The data is shown in the Table 1 below.

TABLE 1 CONCENTRATION OF TOTAL CARBONATE IN THE 30 mM POTASSIUM DIHYDROGEN PHOSPHATE SOLUTION UNDER 0.00033 ATM

CO

2 PRESSURE. THE pH WAS ADJUSTED BY ADDITION OF KOH.

TOTAL KOH CARBONATE ADDED pH (mM) (mM) 4.59 0.0116 0 6.62 0.0373 7.19 0.109 8.25 1.18 9.09 9.09 9.32 16.9 9.45 24.3 9.53 31.3 9.64 44.7 9.74 63.9 120 9.81 82.4 150 9.84 94.5 170 9.89 112 200 This property makes it possible to prepare stable alkaline carbonated solutions that contain a large quantity of carbonate ions. Therefore, by increasing the pH, a solution containing a high concentration of carbonate can be maintained without the need for maintaining the solution under a pressurized carbon dioxide atmosphere to keep the carbon dioxide from escaping the solution.

IB i 1- ~L r~l~PsBsl~ WO 96/25914 PCT/US95/02364 -6- These stable alkaline carbonated solutions are useful unto themselves as mouth rinses. The solutions act as buffers to create an oral environment with a basic pH. This basic environment will remove acid from the dental surface and thereby prevent the formation of cavities.

In a particularly preferred embodiment, the alkaline carbonated solutions of the present invention contain phosphate. Such solutions are stable with respect to both carbonate and phosphate. These alkaline carbonated phosphate solutions can be mixed with stable aqueous solutions containing high concentration of calcium ions at acidic pH. The resulting mixed solutions are supersaturated with respect to calcium phosphate and carbon dioxide. These mixed calcium phosphate solutions thus contain, high calcium and phosphate concentrations at lower pH (preferably to Because of the supersaturated nature of the mixed solutions, calcium phosphate compounds will precipitate out of the mixed solution as the pH of the solution increases due to the release of carbon dioxide to the air. Therefore, when the mixed solution is put in the mouth, carbon dioxide will be released and calcium phosphate will precipitate on and in the teeth. The calcium phosphate then reacts with the dental tissue and forms apatite.

The p1i of the alkaline carbonated solutions is preferably between 8 and 12 and more preferably between 9 and 10. The desired pH and concentrations of the mixed carbonated calcium phosphate solution will determine what the acid concentration of the acidic calcium soiutio should be; the acid concentration is such as to make the pH of the mixed carbonated calcium phosphate solutions in the preferred range of 5 to The mixed solutions with the same compositions and properties as the above solutions can also be obtained by mixing a stable alkaline carbonated solution that contains a large quantity of carbonate under atmospheric conditions with a stable acidic calcium phosphate solution. In this system, the phosphate originates from the acidic solution, rather than the alkaline solution. The phosphate ions may also originate from both solutions, both the alkaline carbonated solution and the acidic calcium solution may include phosphate ions.

A The mixed solution can also be obtained from the dissolution of solids in ;water. Stable solid powders containing all the ingredients in the mixed solutions can be created. These powders contain a mixture of calcium salts, phosphate salts, solid acid (such as acetic acid and/or citric acid) and carbonate salts with or without fluoride. When water is added to these powders, the solids will dissolve rapidly and c- u -H 4 1 I- WO 96125914 PCT/US95102364 -7the same carbonated calcium phosphate solutions as the mixed solutions can be obtained. These solutions can similarly be applied to dental surfaces for the prevention and repair of caries lesions, cavities, exposed roots and dentin sensitivity.

The final mixed carbonated solutions of the present invention may further include other beneficial components including: complex fluorides, such as monofluorophosphate, fluorosilicates and fluorostannates; antiseptic agents, such as chlorhexidine; and further mineralizing materials, such as strontium. When used as artificial saliva, the final mixed carbonated solution of the present invention may further contain mucins, carboxymethylcellulose (CMC), and a sweetner, such as sorbitol or xylitol. The final mixed solution may also include hydrogen peroxide as an antiseptic agent. However, hydrogen peroxide is particularly preferred when the final mixed carbonated solution is created by dissolving powder in water. While hydrogen peroxide can be included in the alkaline carbonated solution and acidic solution mixture, under some conditions, it may render those solutions unstable.

The following examples serve to illustrate the composition and method of invention, but are in no way limiting thereto.

EXAMPLE 1 A first carbonated solution contains 50.6 mM of KCO 3 7.4 mM of KH 2

PO

4 and 12.6 mM of H 3

PO

4 with pH of 9.69 and a second solution contains 33 mM of Ca(NO 3 2 and 50.6 mM of acetic acid with pH of 2.5. Both solutions are stable under atmospheric pressure. When the two solutions are mixed, the mixed solution has the pH of 6.4 and is supersaturated with respect to calcium phosphate and carbon dioxide under atmospheric pressure. As the carbon dioxide evaporates the pH of the solution increases and calcium phosphate precipitates out of solution.

EXAMPLE 2 The procedure of EXAMPLE 1 is repeated, except that phosphate compounds are added to the acidic calcium solution, instead of the alkaline solution. A first solution contains 50.6 mM K 2

CO

3 with a pH of 11.24, and a second stable calcium 1 phosphate solution contains 7.4 mM KH 2 PO4, 12.6 mM H 3

PO

4 33 mM Ca(N0 3 2 and 50.6 mM acetic acid with a pH of 2.29. Both solutions are stable under atmospheric pressure. When the two solutions are mixed, the mixed solution has the pH of 6.4 Sand is supersaturated with respect to calcium phosphate and carbon dioxide under atmospheric pressure. As the carbon dioxide evaporates, the pH of the solution increases and calcium phosphate precipitates out of the solution.

NIL, 9r B I ~L~ WO 96/25914 PCT/US95/02364 r -8- I! EXAMPLE 3 A solid powder containing 54 mg calcium nitrate, 38 mg tripotassium phosphate, 3.5 mg potassium monohydrogen phosphate, 30.4 mg acetic acid and 50.7 Smg potassium bicarbonate is created. 20 mL of water is added to the solid powder, the powders dissolve quickly and creates a solution having the same properties as the mixed solution in EXAMPLE 1, i.e. the solution has the pH of 6.4 and is supersaturated with respect to calcium phosphate and carbon dioxide under atmospheric pressure. As the carbon dioxide evaporates the pH of solution increases and calcium phosphate precipitates. Therefore, this solution can be applied directly to the tooth as a mineralizing solution.

EXAMPLE 4 A carbonated solution is prepared according to the procedure of EXAMPLE 1. The mixed solution is promptly applied directly to the dental tissue. Carbon dioxide escapes from the solution and calcium phosphate precipitates out of solution and is deposited on and into the dental tissue.

EXAMPLE S A carbonated solution is prepared according to the procedure of EXAMPLE 3. The solution is then promptly applied directly to the dental tissue, Carbon dioxide escapes from solution and calcium phosphate precipitates out of solution and is deposited on and into the dental tissue, EXAMPLE 6 A carbonated solution is prepared according to the procedure of EXAMPLE 1, except that the acidic calcium solution also includes 1 mM fluorosilicate ions.

EXAMPLE 7 A carbonated solution it prepared according to the procedure of EXAMPLE j1 1, except that the acidic calcium solution also includes 1 mM fluorostannate ions.

EXAMPLE 8 A carbonated solution is prepared according to the procedure of EXAMPLE 1, except that the carbonated phosphate solution also contains 5 mM fluoride ions.

WO 96/25914 PCT/US95/02364 -9- EXAMPLE 9 A carbonated solution is prepared according to the procedure of EXAMPLE 1, except that the acidic calcium solution also contains 33 mM strontium ions.

EXAMPLE A carbonated solution is prepared according to the procedure of EXAMPLE 3, except that the solid mixture also includes 2.5 mM fluorine compound.

EXAMPLE 11 A carbonated solution is prepared according to the procedure of EXAMPLE 3, except that the solid mixture also includes 0.33 mM strontium compound.

EXAMPLE 12 A stable alkaline carbonated solution is created, containing 30 mM K 2

CO

3 and 50 mM K 2

HPO

4 at a pH of 10.6. This alkaline carbonated solution is used as a mouth rinse and removes acidic residue from the teeth thereby preventing cavities which might have resulted from the acidic residue.

The preferred embodiment of the present invention is now fully described.

The above description, however, is only illustrative of the invention and is not intended to limit the invention in spirit or scope. Only the following claims and their equivalents limit the scope of the invention.

b -l i -r Ip~L~ll

Claims (31)

1. A method of preparing an aqueous carbonated calcium phosphate solution supersaturated with respect to calcium phosphates and carbon dioxide under atmospheric conditions for use in treatment of dental tissue, comprising, mixing a stable alkaline solution containing carbonate with a stable acidic solution containing calcium ions and either or both solutions further contain phosphate ions.

2. The method of Claim 1 wherein either or both solutions further contain fluoride ions.

3. The method of Claim 2 wherein the fluoride is monofluorophosphate.

4. The method of Claim 1 wherein the stable acidic solution further contains the complex fluoride ions.

The method of Claim 4 wherein the complex fluoride is fluorosilicate.

6. The method of Claim 4 wherein the complex fluoride is fluorostannate.

7. The method of Claim 1 wherein the acidic solution further contains strontium ions.

8. The method of Claim 1 wherein either or both solutions further contain chlorhexidine compounds.

9. A method of preparing an aqueous carbonated calcium phosphate solution capable of remineralization of the teeth comprising adding water to solid containing calcium salt, phosphate salt and carbonate salt. peroxide.

The method of Claim 9 wherein the water further contains hydrogen WO 96/25914 PCT/US95/02364

11. The method of Claim 9 wherein the water further contains chlorhexidine compound.

12. A method of Claim 9 wherein the solid further contains fluorine compound.

13. A method of Claim 9 wherein the solid further contains strontium compound.

14. A method of treating dental tissue comprising; mixing a stable nonpressurized alkaline carbonated solution containing carbonate with a stable nonpressurized acidic solution containing calcium ions where either or both said solutions contain phosphate ions, to create a mixed solution supersaturated with calcium phosphate and carbon dioxide; and promptly applying the mixed solution to the dental tissue Swhereby the carbon dioxide escapes and calcium phosphate is deposited on and in I the dental tissue.

15. The method of Claim 14 wherein either or both alkaline solutions further contain fluoride ions.

16. The method of Claim 14 wherein the stable acidic solution further i contains complex fluoride ions.

17. The method of Claim 16 wherein the complex fluoride is fluosilicate.

18. The method of Claim 16 wheren the complex fluoride is I fluorostannate.

19. The method of Claim 14 wherein the stable acidic solution further contains strontium ions. The method of Claim 14 wherein either or both solutions further contain chiorhexidine compounds.

II. i -I WO 96125914 PCT/US95/02364 -12-

21. The method of Claim 14 wherein the pH of the stable alkaline solution is at least about 8.

22. A method of treating dental tissue comprising: adding water to a solid mixture containing calcium salt, phosphate salt and carbonate salt to create an unstable carbonated solution supersaturated with respect to calcium phosphate and carbon dioxide; and promptly applying the solution to the dental tissue whereby the carbon dioxide escapes and calcium phosphate is deposited on and in the dental tissue. 10

23. A method of Claim 22 wherein the water further contains hydrogen peroxide.

24. A method of Claim 22 wherein the water further contains chlorhexidine compounds.

A method of Claim 22 wherein the solid further contains fluorine compound.

26. A method of Claim 22 wherein the solid further contains strontium compound.

27. A method of treating dental tissue comprising contacting the dental tissue with a nonpressurized alkaline carbonated mouth rinse whereby the alkaline carbonated mouth rinse interacts with the dental tissue to remove acidic materials,

28. The method of Claim 27 wherein the alkaline carbonated mouth rinse further contains phosphate. t t

29. The method of Claim 27 wherein the alkaline mouth rinse further contains chlorhexidine.

30. The method of Claim 27 wherein the alkaline mouth rinse further contains fluoride, a c -B I~PPB I~ INTERNATIONAL SEARCH REPORT I Applo Int .onal Applicaton No PCT/US 95/02364 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 A61K7/16 According to Intemaronal Patent Clasafication (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC 6 A61K Documentation searched other than minimum documentation to the extent that such documents re included in the fields searched Electronic data base consulted during the intemational search (name of data base and, where pracucal, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No. E US,A,5 427 768 (TUNG MING S) 27 June 1995 1-30 see the whole document X US,A,5 037 639 (TUNG MING S) 6 August 1991 1-30 see column 3, line 53 column 4, line 57; claims; examples 3,6 X US,E,RE33161 BROWN) 6 February 1990 1-5,7-9, 12,13 see column 3, line 40 column 4, line 41 see column 8, line 11 line 18 see claims; examples X GB,A,1 090 340 (WARNER-LAMBERT 1-12 PHARMACEUTICAL COMPANY) 8 November 1967 see page 2, line 83 page 3, line 57 Further documents are listed in the continuation of box C. Patent family members are listed in annex. Special categones of cited documents: later document published after the international filing date A document defnng the general state of the art which s not or pnonty date and not n conflict with the application but cAouentidered ing to geerbe of cited to understand the pnrinciple or theory underlying the considered to be of particular relevant= inventon E'8 earlier document but published on or after the international X* document of particular relevance; the claimed inventi.:, filing date cannot be considered novel or cannot be considered to document which may throw doubts on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an nventive step when the document refernng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published pnor to the international filing date but in the art. later than the prnonty date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 12 October 1995 26.10.95 Name and mailing address of the ISA Authonzed officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rilswilk Tel. 3170) 340-2040, Tx.

31 651 cpo ni, C ns n S n, Fax (4 31.70) 340.3016 Cousins-Van Steen, G Forn PCTIISA/210 (second sheet) (July 1992) page 1 of 2 II Ii. II INTERNATIONAL SEARCH REPORT [nt anal Application No PCT/US 95/02364 C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant paasages ~Rlvn oclaim No. US,A,4 348 381 (GAFFAR ABDUL ET AL) 7 September 1982 see column 3, line 65 column 5, line 19; claims; examples US.,A,4 606 912 (RUDY MICHAEL A ET AL) 19 August 1986 GB,A,2 188 548 (BEECHAM GROUP PLC) 7 October 1987 1-30 Form PCT/ISA'210 (continuation ofrsecondl sheet) (July 1992) page 2 of 2 INTERNATIONAL SEARCH REPORT rnational appi:cation No. PCT/ US 95/ 02364 Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 1 for the following reasons: 1. Claims Nos.: 14-30 because they relate to subject matter not required to be searched by this Authority, namely: Remark: Although claims 14 to 30 are directed to a method of treatment of the human/animal body, the search has been carried out and based on the alleged effeets of the compound/composition. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such extent that no meaningful internatonal search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: i As all required .dditional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. L_ As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. A s only some of the required additional search fees were timely paid by the applicant, this internauonal search report covers only those claims for which fees were paid, specifically claims Nos.: 4. i No required additional search fees were timely paid by the applicant. Consequently, this internauonal search report is restricted to the invenuon first mentioned in the claims; it is covered by claims Nos.: Remark on Protest O The additional search fees were accompanied by the applicant's protesL SNo protest accompanied the payment of additional search fees. Form PCT;ISA,210 (continuation of first sheet (July 1992) I P. INTERNATIONAL SEARCH REPORT In-, onal Application No Informnaton on patent family mbesPCT/US 95/02364 Paetdocument Publicatio Patent family Publication ctdin search report Tdate r'ember(s) date US-A-5427768 27-06-95 NONE US-A-5037639 06-08-91 US-A- 5437857 01-08-95 US-A- 5268167 07-12-93 US-E-RE33161 06-02-90 US-A- 4518430 21-05-85 US-E- RE33221 22-05-90 US-A- 4612053 16-09-86 GB-A- 1090340 DE-A- 1492247 06-11-69 FR-A- 1434455 20-06-66 US-A-4348381 07-09-82 AT-B- 389443 11-12-89 AU-B- 553823 31-07-86 AU-B- 8065282 11-11-82 BE-A- 892359 06-09-82 GA-A- 1165953 24-04-84 CH-A- 652301 15-11-85 DE-A- 3206711 02-12-82 FR-A,B 2505180 12-11-82 GB-A,B 2097674 10-11-82 JP-C- 1579850 13-09-90 JP-B- 2002860 19-01-90 JP-A- 57185213 15-11-82 NL-A- 8200891 01-12-82 SE-B- 452401 30-11-87 SE-A- 8201086 07-11-82 US-A-4606912 19-08-86 US-A- 4610873 09-09-86 GB-A-2188548 07-10-87 AU-B- 596161 26-04-90 AU-B- 7102187 08-10-87 Form PCT/ISA1210 (patent family ane) (July 1992)