Materials and methods for manufacturing amorphous tricalcium phosphate and metal oxide alloys of amorphous tricalcium phosphate and methods of using the same

Abstract

Alloys of tricalcium phosphate and metal oxide such as TiO2 and SiO2 (ACP) are disclosed as well as method for making these alloys. Method for making these alloys include the steps of milling amorphous tricalcium phosphate and at least one metal oxide together in, for example, a ball mill operated under ambient conditions. Various aspects also relate to treating disease or damage to tissues such as enamel, dentine or bone by contacting tissue with these alloys. As well as formulations for oral care such as tooth pastes, mouth washes, tooth whiteners, and like that comprise ACP. Still another aspect is amorphous tricalcium phosphates that have antimicrobial activity. Various aspects disclosure methods for manufacturing these materials and for using them in various formulations and preparations such as dentifrices, mouth washes and rinses, teeth whiteners, gels, drenches, ointments, slaves, pastes, soaks, sprays, glues, cements, foodstuffs, and the like. Still another aspect is directed towards suing these compositions as parts of, or coatings for, devices such as needles, catheters, packagings, fillings, screws, pins, splints, implants, bandages, packings and the like.

Description

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Table 1, changes in VHN values measured after exposing samples of a bovine enamel to a dentifrice solution that includes substantially water.

FIG. 2. Table 2, changes in VHN values measured after exposing samples of bovine enamel to a dentifrice solution that includes CaCl₂ and K₂H₂PO₄.

FIG. 3. Table 3, changes in VHN values measured after exposing samples of a bovine enamel to a dentifrice solution that includes ACP100(No TiO₂).

FIG. 4. Table 4, changes in VHN values measured after exposing samples of a bovine enamel to a dentifrice solution that includes ACP95(5.0 wt. % TiO₂).

FIG. 5. Table 5, changes in VHN values measured after exposing samples of a bovine enamel to a dentifrice solution that includes ACP90(10 wt. % TiO₂).

FIG. 6. Table 6, changes in VHN values measured after exposing samples of bovine enamel to a dentifrice solution that includes ACP85(15 wt. % TiO₂).

FIG. 7. Table 6, compilation of mean changes in VHN reported in tables 1-6 (FIGS. 1-6)

FIG. 8. Graph of change in VHN values from Tables 1-6 in FIGS. 1-6, each group represents a different set of conditions to which enameled surfaces were exposed before measuring the change in their surface hardness.

FIG. 9. Table 7, summary of data collected from studying the effect of various calcium-phosphate treatments on surfaces undergoing remin/demin cycling.

FIG. 10. Table 8, summary of data collected from studying the effect of various calcium-phosphate treatment groups on surfaces undergoing remin/demin cycling; these data were compiled in the presence of artificial saliva.

FIG. 11. Table 9, summary of data collected from studying the effect of various calcium-phosphate treatment groups on surfaces undergoing remin/demin cycling; these data were compiled using pooled human saliva.

FIG. 12. Mean values of microhardness (VHN) enhancement measured for enamel surfaces treated with compositions comprising alloys of amorphous tricalcium phosphate and TiO₂. Although not shown, error bars similar to those expressed in the corresponding tables could be plotted for each data point in the graph.

FIG. 13. Table 10, a summary of data collected from studying the effect of various calcium-phosphate treatment groups on surfaces undergoing remin/demin cycling; these data include data collected using chewing gum formations that either include sugar or do not include sugar.

FIG. 14. Table 11, summary of data illustrating that alloys of amorphous tricalcium has antimicrobial properties.

FIG. 15. Plot of the level of water soluble calcium in 50 mg sample of ACP; ACP was prepared by milling for 1, 3 or 7 days before the level of soluble calcium was measured.

FIG. 16. Plot of the amount of water soluble calcium in 10 mg of various preparations of ACPS, ACPS comprising the following levels of SiO₂ were analyzed, 0.0, 5.0, 10.0, 25.0, 50, 75, and 90 wt. %, respectively. The line is a ternary (3^rd order polynomial) fit of the data, it indicates 3 distinct regions.

FIG. 17. Plot of the level of water soluble calcium in ACP metal oxide alloys measured for two sample sizes 10 and 50 mg. The following materials: were made during 1 day of milling, ACPS (10 wt. % SiO₂) or amorphous tricalcium phosphate alloyed with 10 wt. % TiO₂. These data indicate that both materials have about the same amount of water soluble calcium.

FIG. 18. Plot of the level of water soluble calcium in amorphous tricalcium phosphate alloyed with one of the following levels of TiO₂, 0, 5 or 10 wt. %. Values were measured for both 10 and 50 mg of sample.

FIG. 19. IR absorbance spectra of alloys that include amorphous tricalcium phosphate and the following levels of SiO₂: 0, 5, 90, 75, 50, 75, 90 wt. %, the remainder of these samples was TCP, as a control one sample comprised of 100 wt. % SiO₂ was also run. The asterisks indicate characteristics peaks associated with CaO moieties.

FIG. 20. Schematic diagram showing proposed structure of an amorphous P₂O₅ network.

FIG. 21. Table summarizing the principal covalent and ionic P-O vibrational bands obtained by deconvolution of the spectra reported in FIG. 19 between 700 and 1300 cm⁻¹.

FIG. 22. A graphical comparison of the deconvoluted peak centers for P-O vibrations listed in the table presented in FIG. 21 based on some of the spectra presented in FIG. 19.

FIG. 23. Schematic diagram showing proposed mechanisms of P₂O₅ network modification.

FIG. 24. The mass in mg of water soluble calcium measured for the following materials: amorphous tricalcium phosphate alloyed with various levels of SiO₂, the level of SiO₂ in the materials measured is as follows: 0, 5, 10, 25, 50, 75, or 90 wt. %, the remainder of each material is made up of TCP. Soluble calcium was measured for samples of 10, and 50 mg of material, the lines are isotherms.

FIG. 25. A plot of bioavailable fluoride measured after contacting a fluoride solution for 15 days at 22° C., plotted as a function of wt. % (0.0, 0.05, 0.1, 0.2) of the material in 25 ml of NaF_(aq). Data were collected for the following materials: CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂; 10% TCP, 90% SiO₂. The fits are fluoride stability isotherms, no surfactants were added in this example.

FIG. 26. A plot of bioavailable fluoride measured after contacting a fluoride solution for 15 days at 22° C. in the absence of surfactants, plotted as a function of wt. % (0.0, 0.05, 0.1, 0.2 respectively) of the material in 25 ml of NaF_(aq). Data were collected for the following materials: CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂: 10% TCP, 90% SiO₂. The plots are fluoride stability isotherms.

FIG. 27. A plot of bioavailable fluoride measured after contacting a fluoride solution for 7 days at 22° C. in the presence of 1.0 wt. % 600 Da PEG, plotted as a function of wt. % (0.0, 0.05, 0.1, 0.2 respectively) of the material in 25 ml of NaF_(aq). Data were collected for the following materials: CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂; 10% TCP, 90% SiO₂. The plots are fluoride stability isotherms.

FIG. 28. A plot of bioavailable fluoride measured after contacting a fluoride solution for 7 days at 22° C. in the presence of 0.5 wt. % SLS, plotted as a function of wt. % (0.0, 0.05, 0.1, 0.2 respectively) of the material in 25 ml of NaF_(aq). Data were collected for the following materials: CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂; 10% TCP, 90% SiO₂. The plots are fluoride stability isotherms.

FIG. 29. A plot of bioavailable fluoride measured after contacting a fluoride solution for 7 days at 22° C. in the presence of 0.5 wt. % CPC, plotted as a function of wt. % (0.0, 0.05, 0.1, 0.2 respectively) of the material in 25 ml of NaF_(aq). Data were collected for the following materials: CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂; 10% TCP, 90% SiO₂. The plots are fluoride stability isotherms.

FIG. 30. Photograph depicting the color change associated with CPC and test formulations in 25 ml NaF(aq) with 0.5 wt. % CPC at 7 days, 22° C. The labels represent the following formulations: A, CPC+NaF_(aq) control; B, CPC+12.5 mg CaCl₂+NaF_(aq); C, CPC+12.5 mg 100% TCP+NaF_(aq); D, CPC+12.5 mg 90% TCP, 10% SiO2+NaF_(aq); E, CPC+12.5 mg 50% TCP, 50% SiO₂+NaF(aq).

FIG. 31. A plot of bioavailable fluoride measured after contacting test materials with 25 ml slurry that included 12.5 g Aquafresh Extreme Clean™ for 289 days at 22° C. plotted as a function of wt. % ACPS added to the dentifrice slurry. Data were collected for the following test materials: 100 wt. % TCP 0 wt. % CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂; 10% TCP, 90% SiO₂.

FIG. 32 A plot of bioavailable fluoride measured after contacting test materials with 25 ml slurry that included 12.5 g Aquafresh Cavity Protection™ for 289 days at 22° C. plotted as a function of wt. % ACPS added to the dentifrice slurry. Data were collected for the following test materials: 100 wt. % TCP 0 wt. % SiO₂; CaCl₂, 100% TCP, 0% SiO₂; 95% TCP, 5% SiO₂; 90% TCP, 10% SiO₂; 85% TCP, 15% SiO₂, 75% TCP, 25% SiO₂; 50% TCP, 50% SiO₂; 25% TCP, 75% SiO₂; 10% TCP, 90% SiO₂.

FIG. 33. Histograms illustrating the amount of Enamel Fluoride Uptake (ppm) measured in the presence of the following test materials: water; NaF; ACP90+NaF; ACP90+PEG+NaF; ACP90+SLS+NaF; and ACP90+CPC+NaF.

FIG. 34. Histograms illustrating the amount of Enamel Fluoride Uptake (ppm) measured in the presence of the following test materials: water; NaF; ACP+CPC+NaF; ACP90+CPC+NaF; and ACP50+CPC+NaF.

FIG. 35. Histograms illustrating the amount of Enamel Fluoride Uptake (ppm) measured in the presence of the following test materials: water; NaF; ACP90+CPC+NaF; ACP50+CPC+NaF; ACP90+SLS+NaF; and ACP50+SLS+NaF.

FIG. 36. Histograms illustrating the change in enamel surface acid-etch depths measured in the presence of the following materials: water; NaF; ACP90+Naf; ACP90+PEG+NaF; ACP90+SLS+NaF; and ACP90+CPC+NaF. Larger negative values indicate better enamel resistance to acid attack.

FIG. 37. Histograms illustrating the change in enamel surface acid-etch depths measured in the presence of the following materials: water; NaF; ACP+CPC+Naf; ACP90+CPC+NaF; and ACP50+CPC+NaF. Larger negative values indicate better enamel resistance to acid attack.

FIG. 38. Histograms illustrating the change in enamel surface acid-etch depths measured in the presence of the following materials: water; NaF; ACP90+CPC+NaF; ACP50+CPC+NaF; ACP90+SLS+NaF; and ACP50+SLS+NaF.

FIG. 39. Histograms illustrating the change in Vickers microhardness resulting from a 6-day remin/demin pH cycling study carried out in vitro on bovine enamel. The results are presented as a function of test materials added to the cycling run. Test materials used in the example are as follows: water; 1100 ppm F; ACP100+1100 ppm F; ACP75+1100 ppm F; ACP50+1100 ppm F; ACP25+1100 ppm F; and ACP10+1100 ppm F.

FIG. 40. Histograms illustrating the change in Vickers microhardness resulting from a 6-day remin/demin pH cycling study carried out in vitro on bovine enamel. The results are presented as a function of test materials added to the cycling run. Test materials used in the example are as follows: water; 1100 ppm F; ACP90+1100 ppm F; and ACP50+1100 ppm F.

FIG. 41. A trace generated using a Nanopac 151 particle analyzer manufactured by Microtrac™. All samples were prepared and analyzed in conformity with the manufacturer's instructions. The material analyzed was un-milled tricalcium phosphate.

FIG. 42. A trace generated using a Nanopac 151 particle analyzer manufactured by Microtrac™. All samples were prepared and analyzed in conformity with the manufacturer's instructions. The material analyzed, amorphous tricalcium phosphate, was prepared by milling tricalcium phosphate for 24 hours at 350 rpm in the presence of about 5 ml of ethanol added to prevent caking, in a 150 ml stainless steel vessel which also included 20 stainless steel balls. Each ball had a diameter of 10 mm. The mill was operated at 350 rpm for 24 hours under ambient conditions.

FIG. 43. A trace generated using a Nanopac 151 particle analyzer manufactured by Microtrac™. All samples were prepared and analyzed in conformity with the manufacturer's instructions. The material analyzed was an alloy of amorphous tricalcium phosphate and TiO₂. The alloys were prepared by milling a total of about 20 g of a mixture of 95 wt. % tricalcium phosphate and about 5 wt. % TiO2. The material, along with about 5 ml of ethanol, was added to a 150 ml stainless steel vessel along with 20 stainless steel balls, each ball having a diameter of 10 mm. The vessel was sealed and the contents were milled for 24 hours at 350 rpm under ambient conditions.

FIG. 44. Is a trace generated using a Nanopac 151 particle analyzer manufactured by Microtrac™. All samples were prepared and analyzed in conformity with the manufacturer's instructions. The material analyzed here was an alloy comprising 90 wt. % amorphous tricalcium phosphate and 10 wt. % titanium oxide. The material was prepared by using a ball mill. Briefly, a 150 ml stainless steel vessel was loaded with 20 balls each having a diameter of about 10 ml, about 20 grams of total material (90 wt. % tricalcium phosphate and 10 wt. % TiO₂). The vessel was closed, placed in the mill and the mill was operated for 24 hours at 350 rpm under ambient conditions.

Claims

1. An alloy, comprising; amorphous tricalcium phosphate; andat least one metal oxide.

2. The alloys according to claim 1, wherein the alloy has an average particle size in the range of about 5.0 microns to about 0.01 microns.

3. The alloys according to claim 1, wherein said alloy has an average particle size in the range of about 1.2 microns to about 0.07 microns.

4. The alloy according to claim 1, wherein said metal oxide is selected from the group consisting of: TiO2 and SiO2.

5. The alloy according to claim 1, wherein the amount of the amorphous tricalcium phosphate in the alloy is the range of about 99.5 to about 1.0 wt. % of the alloy and the amount of the metal oxide in the composition is in the range of about 0.5 to about 99.0% wt. % of the alloy.

6. The alloy according to claim 1, wherein the amount of the amorphous tricalcium phosphate in the alloy is the range of about 99.5 to about 85 wt. % of the alloy and the amount of the metal oxide in the composition is in the range of about 0.5 to about 15% wt. % of the alloy.

7. A method of forming an alloy, comprising the steps of: providing a portion of amorphous tricalcium phosphate;supplying a portion of at least one metal oxide; andpulverizing said portion of amorphous tricalcium phosphate and said portion of at least one metal oxide together to form an alloy.

8. The method according to claim 7, wherein the alloys has an average particle size in the range of about 5.0 microns to about 0.01 microns.

9. The method according to claim 7, wherein said alloy has an average particle size in the range of about 1.2 microns to about 0.07 microns.

10. The method according to claim 7, wherein said pulverizing step is carried out in a ball mill, wherein said ball mill is operated at between about 250 to about 600 rpms, for between about 5 hours to about 5 days.

11. A formulation for treating tissue, comprising: at least one alloy, wherein said alloy includes amorphous tricalcium phosphate and at least one metal oxide.

12. The formulation according to claim 11, wherein the alloys has an average particle size in the range of about 5.0 microns to about 0.1 microns.

13. The formulation according to claim 11, wherein said alloy has an average particle size in the range of about 1.2 microns to about 0.1 microns.

14. The formulation according to claim 11, wherein the at least one metal oxide is selected from the group consisting of: TiO2 and SiO2.

15. The formulation according to claim 11, wherein the amount of the amorphous tricalcium phosphate the alloy is between about 99.5 to about 1.0 wt. % of the alloy and the amount of the metal oxide in the alloy is between about 0.5 to about 99.0% wt. % of the alloy.

16. The formulation according to claim 11, wherein the amount of the amorphous tricalcium phosphate in the alloy is the range of about 99.5 to about 85 wt.

17. The formulation according to claim 11, further including at least one of the following additives selected from the group consisting of: fluoride, surfactants, antimicrobials, flavoring agents, detergents, coloring agents, buffering agents, thickening agents, cooling agents, glues, cements, and polishes.

18. A method of treating tissue, comprising the steps of: providing a formulation that includes at least one alloy, said alloy including amorphous tricalcium phosphate and at least one metal oxide; andcontacting said preparation with at least one surface of a tissue.

19. The method according to claim 18, wherein the alloy has an average particle size in the range of about 5.0 microns to about 0.01 microns.

20. The method according to claim 18, wherein the alloy has an average particle size in the range of about 1.2 microns to about 0.07 microns.

21. The method according to claim 18, wherein the at least one metal oxide is selected from the group consisting of: SiO2 and TiO2.

22. The method according to claim 18, wherein the tissue is selected from the group consisting of: bone, enamel and dentin.

23. The method according to claim 18, wherein said formulation further includes at one of the compounds selected from the group consisting of: a form of bioavailable fluoride, surfactants, flavoring agents, coloring agents, thickening agents, antimicrobial agents, buffering agents, and gums.

24. A foodstuff, comprising: an alloy, wherein said alloy includes amorphous tricalcium phosphate and at least one metal oxide.

25. The method according to claim 24, wherein the alloys has an average particle size in the range of about 5.0 microns to about 0.01 microns.

26. The method according to claim 24, wherein said alloy has an average particle size in the range of about 1.2 microns to about 0.07 microns.

27. The foodstuff according to claim 24, wherein said metal oxide is selected from the group consisting of: SiO2 and TiO2.

28. The foodstuff according to claim 24, wherein the amount of said amorphous tricalcium phosphate in the alloy is between about 99.5 to about 1.0 wt. % of the alloy and the amount of the metal oxide in the alloy is between about 0.5 to about 99.0 wt. % of the alloy.

29. The foodstuff according to claim 24, further including at least one compound selected from the group consisting of: a form of fluoride, a gum, a flavoring agent, a coloring agent, a cooling agent, a surfactant, a buffer, an antimicrobial agent, and a stabilizer.

30. An antimicrobial compound comprising: amorphous tricalcium phosphate, wherein said amorphous tricalcium phosphate has an average particle size less than about 1.5 microns or less.

31. The method of manufacturing an antimicrobial composition, comprising the steps of: providing at least one form of tricalcium phosphate;pulverizing said at least one form of tricalcium phosphate until it is amorphous and has a particle size on the order the particle size of amorphous tricalcium phosphate manufactured by pulverizing about tricalcium phosphate in a PM 100 planetary ball mill, the mill having a stainless steel vessel with a volume of about 150 ml, said vessel including 25 stainless steel balls, wherein each of the balls has a diameter of about 10 mm, and about 2 ml of ethanol, said ball mill is operated at about 450 rpms for about 5 days.

32. The composition according to claim 31, wherein said tricalcium phosphate is formed by: combining about equal amounts of calcium carbonate (CaCO3) and calcium phosphate dehydrate (CaHPO4)2.2H2O); andheating said mixture to about 1050 degrees centigrade for about 24 hours.

33. A method of controlling microbes, comprising the steps of: providing amorphous tricalcium phosphate; andcontacting said powder with at least one surface.

34. The method according to claim 22, wherein said amorphous tricalcium phosphate has a particle size on the order of the particle size of amorphous tricalcium phosphate manufactured by pulverizing tricalcium phosphate in a PM 100 planetary ball mill, the mill having a stainless steel vessel with a volume of about 150 ml, said vessel including 25 stainless steel balls, wherein each of the balls has a diameter of about 10 mm, and about 2 ml of ethanol, and said mill is operated at about 450 rpms for about 5 days.

35. The method according to claim 33, wherein said amorphous tricalcium phosphate is contacted with a device selected from the group consisting of: bandages, screws, fillings, straps, packings, nails, splints, implants, catheters, prosthetic devices, stent needles, lances, surgical tools, meshes, sutures, and endoscopes.

36. The method according to claim 33, wherein said amorphous tricalcium phosphate added to at least one of the following formulations: a dentifrice, a mouth wash, a mouth rinse, a mouth spray, a tooth whitener, a periodontal packing, a surgical packing, a foodstuff, a glue, a cement, a filling material, and a disinfectant.