Medical and Dental Bioceramic Composition for Temporary Use

Abstract

The present invention is related to a bioceramic composition for temporary intracanal medication ready for use which promotes the constant, controlled and balanced release of metal ions, hydroxyl (OH.sup.−) and metal-salicylate complexes, being able of providing bioactive, antimicrobial and anti-inflammatory properties. The present invention further provides methods for preventing or controlling endodontic infection and for promoting tissue regeneration and repair by using said bioceramic composition.

Claims

1. A bioceramic composition for temporary intracanal medication characterized in that it is ready for use and it comprises at least one complexing resin derived from salicylic acid ester and a metal ions source, in which said composition promotes the formation of cationic complexes with controlled release of metal ions upon being in contact with a physiological solution, thus providing a bioactive effect and antimicrobial and anti-inflammatory properties.

2. The bioceramic composition, according to claim 1, characterized in that the ratio of complexing resin to metal ions source is of less than 1:3.

3. The bioceramic composition, according to claim 1, characterized in that it also comprises a liquid carrier.

4. The bioceramic composition, according to claim 1, characterized in that it also comprises a radiopacifying agent.

5. The bioceramic composition, according to claim 1, characterized in that it comprises at least: ii) 1 to 10% by weight of a complexing resin; ii) 10 to 60% by weight of a liquid carrier; iii) 20 to 60% by weight of a radiopacifying agent; and iv) 3 to 30% by weight of a metal ions source.

6. The bioceramic composition, according to claim 1, characterized in that the salicylic acid ester derivatives are selected from the following group: methyl salicylate, ethyl salicylate, n-butyl salicylate, isobutyl salicylate, propyl salicylate, hexyl salicylate, benzyl salicylate and diester or a combination thereof.

7. The bioceramic composition, according to claim 5, characterized in that the salicylic acid ester derivatives are selected from the following group: methyl salicylate, ethyl salicylate, n-butyl salicylate, isobutyl salicylate, propyl salicylate, hexyl salicylate, benzyl salicylate and diester or a combination thereof.

8. The bioceramic composition, according to claim 3, characterized in that the liquid carrier is selected from ethylene glycol; propylene glycol; polyethylene glycol; polypropylene glycol; glycerin; diethylene glycol dimethyl ether; diethylene glycol monoethyl ether; butylene glycol or a combination thereof.

9. The bioceramic composition, according to claim 5, characterized in that the liquid carrier is selected from ethylene glycol; propylene glycol; polyethylene glycol; polypropylene glycol; glycerin; diethylene glycol dimethyl ether; diethylene glycol monoethyl ether; butylene glycol or a combination thereof.

10. The bioceramic composition, according to claim 4, characterized in that the radiopacifier agent is selected from the following group: barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, titanium oxide and calcium tungstate or a combination thereof.

11. The bioceramic composition, according to claim 5, characterized in that the radiopacifier agent is selected from the following group: barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, titanium oxide and calcium tungstate or a combination thereof.

12. The bioceramic composition, according to claim 1, characterized in that the metal ions source comprises at least one silicate containing metal ions selected from Ca, Mg, Sr, Zn, Zr or a combination thereof.

13. The bioceramic composition, according to claim 5, characterized in that the metal ions source comprises at least one silicate containing metal ions selected from Ca, Mg, Sr, Zn, Zr or a combination thereof.

14. The bioceramic composition, according to claim 1, characterized in that the metal ions source is selected from the group consisting of Alite (3CaO.SiO.sub.2), Belite (2CaO.SiO.sub.2), Strontium-akermanite (Sr.sub.2MgSi.sub.2O.sub.7), Akermanite (Ca.sub.2MgSi.sub.2O.sub.7), Baghdadite (Ca.sub.3ZrSi.sub.2O.sub.9), Hardistonite (Ca.sub.2ZnSi.sub.2O.sub.7) or a combination thereof.

15. The bioceramic composition, according to claim 5, characterized in that the metal ions source is selected from the group consisting of Alite (3CaO.SiO.sub.2), Belite (2CaO.SiO.sub.2), Strontium-akermanite (Sr.sub.2MgSi.sub.2O.sub.7), Akermanite (Ca.sub.2MgSi.sub.2O.sub.7), Baghdadite (Ca.sub.3ZrSi.sub.2O.sub.9), Hardistonite (Ca.sub.2ZnSi.sub.2O.sub.7) or a combination thereof.

16. The bioceramic composition, according to claim 14, characterized in that the complexing resin is a salicylic acid ester derivative, wherein said salicylic acid ester is methyl salicylate or diester.

17. A method for preventing or controlling endodontic infection characterized in that it comprises applying the bioceramic composition as defined in claim 1 in the root canal of a subject in need thereof.

18. A method for promoting tissue regeneration and repair characterized in that it comprises applying the bioceramic composition as defined in claim 1 in the root canal of a subject in need thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0039] FIG. 1 shows the results of the pH assay carried out for the bioceramic compositions of the present invention.

[0040] FIG. 2 illustrates the evaluation of sections stained with hematoxylin and eosin (HE) for each group for counting the number of inflammatory cells.

[0041] FIG. 3 shows the results for counting the number of inflammatory cells in the groups for the different days analyzed.

[0042] FIG. 4 illustrates the evaluation of the groups after induction of immunohistochemical reactions for detection of interleukin-6 (IL-6) and interleukin-10 (IL-10).

[0043] FIG. 5 shows the results for counting the number of interleukin-6 (IL-6) in the groups for the different days analyzed.

[0044] FIG. 6 shows the results for counting the number of interleukin-10 (IL-10) in the groups for the different days analyzed.

[0045] FIG. 7 illustrates the evaluation of the groups for the presence of collagens.

[0046] FIG. 8 shows the results of the presence of collagen in the groups for the different days analyzed.

[0047] FIG. 9 illustrates the results of the von Kossa method carried out for detecting calcium and phosphate deposits.

DETAILED DESCRIPTION OF THE INVENTION

[0048] Although the present invention can be presented in different embodiments, the present specification along with the drawings, indicate a preferential embodiment, emphasizing that it should be considered an example of the core of the invention and not a limitation.

[0049] The present invention is related to a bioceramic composition for temporary intracanal medication comprising at least one cation complexing resin derived from salicylic acid ester and a source of metal ions. The composition of the present invention has bioactive, anti-inflammatory and antimicrobial properties and is indicated for temporary intracanal medications for dental treatment.

[0050] In an preferred embodiment, the bioceramic composition for temporary intracanal medication of the present invention is composed by a paste ready for use comprising, essentially, one source of metal ions and at least one salicylic acid ester derivative.

[0051] The source of metal ions present in the bioceramic composition for intracanal medication of the present invention, when in contact with body fluid, release metal ions (M.sup.+=Ca.sup.+2, Mg.sup.+2, Sr.sup.+2, Zn.sup.+2, Zr.sup.+4) and hydroxyl ions (OH.sup.−) through the break of Si—O-M bonds. The reaction is shown below:

Si—O—M.sup.++H.sup.++OH—.fwdarw.Si—OH+M.sup.+.sub.(aq)+OH.sup.−.sub.(aq)

[0052] Further, the hydroxyl ions (OH.sup.−) remove the hydrogen from the salicylic acid ester group structure (R-C7H4O2-OH) resulting in a molecule of water and one salicylate ion (R—C.sub.7H.sub.4O.sub.2—O).sup.−. Next, a complexing reaction between the salicylate ion and the metal ion (M.sup.+x) with the formation of one metal salicylate complex is carried out, as described in the equation below:

2(R—C.sub.7H.sub.4O.sub.2—OH)+2OH.sup.−.fwdarw.(R—C.sub.7H.sub.4O.sub.2—O).sup.−+H.sub.2O

(R—C.sub.7H.sub.4O.sub.2—O).sup.−+M.sup.+x.fwdarw.(R—C.sub.7xH.sub.4xO.sub.2x—O-M)

[0053] In which, R is a group selected from methyl, ethyl, n-butyl, isobutyl, propyl, hexyl, benzyl and diester; and X represents the valence of the metal ion.

[0054] Depending on the X valence, the metal-salicylate complex forms different structures, and may have one to four salicylate groups attached to the metal.

[0055] Depending on the group R, the metal-Salicylate complex undergoes different rates of dissociation, supplying metal ions to the medium in a modulated manner, following the equation below:

(R—C.sub.14H.sub.8O.sub.4—O-M.sub.1).fwdarw.(R—C.sub.7H.sub.4O.sub.2—O).sup.−+M.sub.1.sup.+x

[0056] This process occurs continuously as the source of metal ions undergoes hydration by the physiological environment.

[0057] Therefore, the dissociation of the metal salicylate complex is carried out for a long period of time giving the bioceramic composition potential application as an intracanal medication, since it provides for a sufficient exposure time allowing the development of bioactivity.

[0058] In order to maintain this modulating effect of the proposed bioceramic composition, it is necessary that the ratio of complexation resin/metal ions source is lower than 1:3. The correct proportion of metal ions and complexing resin in the same composition allows the formation of metal-salicylate complexes without the phenomenon of setting/hardening of the composition, which therefore allows easy removal of the composition after it has been maintained in the root canal during the treatment.

[0059] Furthermore, the metal-salicylate complex formed shows anti-inflammatory properties due to its activity in free radicals. Free radicals are highly reactive species generated in living organisms for the protecting purpose. However, in some circumstances, they are responsible for the tissue damage or aggravation thereof. Metal-salicylate complex has direct activity on free radicals and non-radicular reactive species, which contributes to its activity against inflammation. The metal complexation of different salicylates has been a strategy used for improving pharmacological activity of different molecules and for reducing their side effects.

[0060] After the total formation of the metal-salicylate complex, the consumption of ions M.sub.1.sup.+x and OH.sup.− ceases. The increase in the concentration of hydroxyl ions (OH.sup.−) in physiological medium promotes the increasing of the pH of the solution to values greater than 10, turning the medium alkaline and unsuitable for microorganisms growth, thus, giving antimicrobial properties to the bioceramic composition for intracanal medication.

[0061] In addition, the steady concentration of multiple metal ions in the media, enables enzymatic changes which influence and stimulate tissue formation, promoting repair and regeneration of the affected area and, then, giving bioactive properties to the bioceramic composition for intracanal medication.

[0062] In a preferred embodiment of the present invention, the bioceramic compositions for temporary intracanal medication will be made available in the form of a single paste, ready for use, also comprising an inert liquid carrier. Suitable and non-limiting examples of inert liquid carrier are materials derived from the glycol group, for example, ethylene glycol; propylene glycol; polyethylene glycol; polypropylene glycol; glycerin; diethylene glycol dimethyl ether; diethylene glycol monoethyl ether; butylene glycol, or the combination thereof.

[0063] The metal ions source used in the materials of the present invention are able to release metal ions from Ca, Mg, Sr, Zn, Zr or a combination of them. Suitable but not limiting examples, are selected from the group of metal silicates and aluminates, preferably from the group of metal silicates.

[0064] In preferred embodiments, metallic silicates are selected from Alite (3CaO.SiO.sub.2), Belite (2CaO.SiO.sub.2), Strontium-akermanite (Sr.sub.2MgSi.sub.2O.sub.7), Akermanite (Ca.sub.2MgSi.sub.2O.sub.7), Baghdadite (Ca.sub.3ZrSi.sub.2O.sub.9), Hardistonite (Ca.sub.2ZnSi.sub.2O.sub.7) or combinations thereof.

[0065] Suitable complexing resin belongs to the group of compositions of salicylic acid ester derivative. Nonlimiting examples are selected from the group consisting of methyl salicylate, ethyl salicylate, n-butyl salicylate, isobutyl salicylate, propyl salicylate, hexyl salicylate, benzyl salicylate and diester or combinations thereof.

[0066] In a preferred embodiment, the salicylic acid ester is methyl salicylate or diester.

[0067] An feature of the composition important for its use as a temporary intracanal medication is radiopacity, that is, the ability of the composition to block the X-rays used in a radiological examination. To impart this property to the composition of the present invention, several radiopacifying agents can be used, for example, but not limited to, barium, bismuth, rare earth derivatives, strontium, zirconium, silicon, aluminum, titanium, tungsten, among other radiopacifying agents.

[0068] Suitable radiopacifying agents are barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, titanium oxide and calcium tungstate, or a combination thereof.

[0069] In a preferred embodiment, the bioceramic composition of the present invention comprises at least:

[0070] i) 1 to 10% by weight of a complexing resin;

[0071] ii) 10 to 60% by weight of a liquid carrier;

[0072] iii) 20 to 60% by weight of a radiopacifying agent; and

[0073] iv) 3 to 30% by weight of a metal ion source.

[0074] In another embodiment, the present invention provides a method for preventing or controlling endodontic infection by applying the bioceramic composition of the present invention in the root canal of a subject in need thereof.

[0075] In a further embodiment, the present invention provides a method for promoting tissue regeneration and repair by applying the bioceramic composition of the present invention in the root canal of a subject in need thereof.

[0076] To allow a better understanding of the present invention and to clearly demonstrate the obtained technical advances, the results of different tests carried out with respect to a non-limiting example of the invention are now presented.

Example

[0077] The bioceramic composition for temporary intracanal medication of the present invention (Table 1) are prepared by mixing the liquid carrier component and the complexing resin with a mechanical stirrer, and then adding the solid components: the metal silicate (metal ion source) and the radiopacifying agent with speed of less than 500 rpm, for approximately 45 minutes, until complete homogenization.

TABLE-US-00001 TABLE 1 Examples of the Bioceramic Compositions. Metal ion Radiopacifier Liquid Complexing Sample source agent carrier resin TP1 Akermanite Calcium Polyethylene Methyl (Ca.sub.2MgSi.sub.2O.sub.7) tungstate glycol salicylate 20% 30% 45% 5% TP2 Baghdadite Zirconium Polyethylene Diester (Ca.sub.2ZrSi.sub.2O.sub.7) oxide glycol 5% 20% 30% 45% TP3 Alite Calcium Polyethylene Methyl (Ca.sub.3SiO.sub.5) tungstate glycol salicylate 20% 30% 45% 5% TP4 Belite Zirconium Polyethylene Diester (Ca.sub.2SiO.sub.4) oxide glycol 5% 20% 30% 45%

[0078] pH, ion release, anti-inflammatory and bioactivity assays were conducted with the compositions prepared in the Example.

[0079] pH Assay

[0080] For the pH assay a small amount of the compositions were added into Eppendorf flasks and carried out in triplicate. Then, 1 mL of distilled and deionized water was added. The pH assay was carried out with a 900 μL aliquot of the supernatant retrieved after centrifugation at 1,400 RPM for 3 minutes. After each assay, in 24 h (1 day), 3, 5, 10, 20 and 30 days, 900 μL of distilled and deionized water was added into each sample to enable the ion exchange.

[0081] Metal Ion Release Assay

[0082] For the metal ion release assay, a small amount of the compositions were added into Eppendorf flasks and carried out in triplicate. Then, 1.5 mL of distilled and deionized water was added. The metal ion release assay was carried out with a 1,000 μL aliquot of the supernatant retrieved after centrifugation at 10,000 rpm for 3 minutes. The 1,000 μL aliquot was then transferred to a 5 mL beaker and diluted to 2 mL with distilled water. The assay was performed using the pH meter with a properly calibrated calcium electrode. After each assay, in 24h (1 day), 3, 5, 10, 20 and 30 days, 1,000 μL of distilled and deionized water was added into each sample to enable the ion exchange.

[0083] Table 2, below, shows the results obtained in the pH and metal ions release assays. The results show that the compositions presented pH≈10 that is sufficient for antimicrobial activity and constant release of metal ions during the tested period of 30 days.

TABLE-US-00002 TABLE 2 Results of the physical-chemical assays of the bioceramic compositions. Ionic concentration (ppm) pH Days TP 1 TP 2 TP 3 TP 4 TP 1 TP 2 TP 3 TP 4 1 Ca (182) Ca (112) Ca (223) Ca (201) 10.9 10.5 11.9 11.6 Mg (64) Zr (32) Si (35) Si (43) Si (58) Si (45) 3 Ca (180) Ca (109) Ca (121) Ca (198) 10.5 9.9 11.6 11.2 Mg (61) Zr (36) Si (33) Si (42) Si (56) Si (44) 5 Ca (177) Ca (108) Ca (120) Ca (195) 10.5 9.8 11.5 11 Mg (60) Zr (30) Si (32) Si (40) Si (54) Si (42) 10 Ca (176) Ca (107) Ca (118) Ca (194) 10.6 9.9 11.4 11.2 Mg (59) Zr (28) Si (29) Si (39) Si (53) Si (39) 20 Ca (173) Ca (101) Ca (115) Ca (189) 10.2 9.6 11.2 10.9 Mg (42) Zr (27) Si (25) Si (35) Si (51) Si (32) 30 Ca (171) Ca (100) Ca (111) Ca (184) 10 9.4 11.2 10.6 Mg (57) Zr (27) Si (23) Si (29) Si (49) Si (31)

[0084] Furthermore, the results of the pH assay are illustrated in FIG. 1.

[0085] Anti-Inflammatory and Bioactive Potential Assay

[0086] For the anti-inflammatory and bioactive potential assay, polyethylene tubes were implanted in the dorsal subcutaneous tissue of 60 rats, divided in groups of: bioceramic composition (TP3), Ca hydroxide paste (CHP) and control (empty CG-tubes). After 7, 15, 30 and 60 days, the animals were anesthetized and blood was collected by cardiac puncture to obtain serum for analysis. Subsequently, the animals were sacrificed and the implants with the adjacent tissues were removed and fixed in formaldehyde. Longitudinal sections were stained with Hematoxylin and Eosin (HE) for morphological analysis, and to obtain the number of inflammatory cells. Immunohistochemical reactions were induced for detecting interleukin-6 (IL-6) and interleukin-10 (IL-10). The bioactive potential was evaluated by the von Kossa method and by the analysis of non-colored sections under the microscope with polarized light, which were carried out to detect calcium and calcite crystals deposits, respectively. Some sections, after the von Kossa reaction, were subjected to immunohistochemical reaction to detect alkaline phosphatase, an enzyme produced by mineralized tissues cells.

[0087] FIGS. 2, 3, 4, 5 and 6 show images of the results obtained for the measurement of the anti-inflammatory potential. The obtained results show numerical density of inflammatory cells and cells immunostained for IL-6 and IL-10. Significant differences in the number of IL-6 and IL-10 cells were seen between TP3 and CHP at 7, 15, 30 and 60 days. The significant decrease of the inflammatory process concomitant to the decrease of the immunoreactivity for IL-6 and IL-10 (FIGS. 5 and 6) indicates that proposed composition TP3 has significant anti-inflammatory features.

[0088] FIGS. 7, 8, and 9 show the results obtained for measuring the bioactive potential by the von Kossa method. It is possible to see a significant increase in the formation of calcium nodules in FIGS. 9C and 9D, as well as a significant increase in the formation of phosphate nodules in FIGS. 9G and 9H for TP3 composition, indicating that the composition of the present invention was able to increase osteoblasts mineralizing capacity. The presence of von Kossa positive structures and of birefringent structures suggests that the TP3 composition has expressive bioactive potential.

[0089] Although only some embodiments of the present invention have been shown, it will be understood that omissions, substitutions and changes may be made by a person of skill in the art without deviating from the spirit and scope of the invention.

[0090] Furthermore, it is expressly provided that the content of the documents mentioned in this specification is incorporated herein by reference.