Solid Phosphonate Salts as an Add-On In Endodontics

Abstract

A phosphonate salt for use in a dental treatment, in particular in a root canal treatment, for the manufacture of a pharmaceutical preparation, in particular as decalcifying agent and a pharmaceutical preparation for use in the dental treatment comprising a phosphonate salt and/or a phosphonate salt and a hydroxide compound in solid form are provided. A method of producing a pharmaceutical preparation and a kit of parts (1, 1) for manufacturing a pharmaceutical preparation for use in the dental treatment are provided.

Claims

1. A phosphonate salt for use in a dental treatment, in particular in a root canal treatment, for the manufacture of a pharmaceutical preparation, in particular as decalcifying agent.

2. The phosphonate salt for use in a dental treatment according to claim 1, wherein the phosphonate salt is a salt of (1-hydroxyethane)-1,1-di-phosphonic acid, the phosphonate salt preferably being tetrasodium (1-hydroxyethane)-1,1-di-phosphonate.

3. The phosphonate salt for use in a dental treatment according to claim 1, wherein the pharmaceutical preparation further comprises one or more of: an aqueous solution, and an alkaline agent, the alkaline agent preferably being an oxidant.

4. The phosphonate salt for use in a dental treatment according to claim 1, wherein the phosphonate salt is provided in a dose, in particular as a tablet or a capsule or in a water-soluble polymer foil, preferably in a water-soluble polymer foil comprising polyvinyl alcohol.

5. The phosphonate salt for use in a dental treatment according to claim 3, wherein the alkaline agent is sodium hypochlorite.

6. The phosphonate salt for use in a dental treatment according to claim 5, wherein sodium hypochlorite is provided as an aqueous, oxidizing solution comprising between 0.1 to 10 weight percentage, preferably between 0.5 to 7 weight percentage, particularly preferably between 1 to 5 weight percentage of sodium hypochlorite with reference to the total weight of the oxidizing solution.

7. The phosphonate salt for use in a dental treatment according to claim 3, wherein the pharmaceutical preparation comprises between 2 to 40 weight percentage, preferably between 5 to 20 weight percentage, particularly preferably between 8 to 10 weight percentage of tetrasodium (1-hydroxyethane)-1,1-di-phosphonate with reference to the total weight of the pharmaceutical preparation.

8. The phosphonate salt for use in a dental treatment according to claim 3, wherein the phosphonate salt and the alkaline agent are provided in a dose, in particular as a tablet or a capsule or in a water-soluble polymer foil, preferably in a water-soluble polymer foil comprising polyvinyl alcohol.

9. The phosphonate salt for use in a dental treatment according to claim 8, wherein the alkaline agent is a hydroxide compound in solid form, in particular an alkaline earth metal hydroxide compound in solid form, preferably solid calcium hydroxide.

10. The phosphonate salt for use in a dental treatment according to claim 9, wherein the pharmaceutical preparation comprises between 5 to 30 weight percentage, preferably about 10 weight percentage, of tetrasodium (1-hydroxyethane)-1,1-di-phosphonate with reference to the total weight of tetrasodium (1-hydroxyethane)-1,1-di-phosphonate and solid calcium hydroxide.

11. The phosphonate salt for use in a dental treatment according to claim 8, wherein the aqueous solution is sterile water or an aqueous sodium chloride solution, preferably an aqueous sodium chloride solution comprising between 0.5 to 1.5 weight percentage of sodium chloride, particularly preferably about 0.9 weight percentage of sodium chloride with reference to the total volume of the aqueous sodium chloride solution.

12. A pharmaceutical preparation for use in a dental treatment, in particular in a root canal treatment, comprising one of: a phosphonate salt, the phosphonate salt preferably being a salt of (1-hydroxyethane)-1,1-di-phosphonic acid, in particular tetrasodium (1-hydroxyethane)-1,1-di-phosphonate; and a phosphonate salt and a hydroxide compound in solid form, the phosphonate salt preferably being a salt of (1-hydroxyethane)-1,1-di-phosphonic acid, in particular tetrasodium (1-hydroxyethane)-1,1-di-phosphonate, and/or the hydroxide compound preferably being an alkaline earth metal hydroxide compound, in particular solid calcium hydroxide.

13. The pharmaceutical preparation according to claim 12, wherein tetrasodium (1-hydroxyethane)-1,1-di-phosphonate and/or tetrasodium (1-hydroxyethane)-1,1-di-phosphonate and solid calcium hydroxide are provided in a dose, in particular as a tablet or a capsule or in a water-soluble polymer foil, preferably in a water-soluble polymer foil comprising polyvinyl alcohol.

14. A method of producing a pharmaceutical preparation for use in a dental treatment, in particular in a root canal treatment, comprising the steps of adding a phosphonate salt, preferably a salt of (1-hydroxyethane)-1,1-di-phosphonic acid, particularly preferably tetrasodium (1-hydroxyethane)-1,1-di-phosphonate, and preferably an alkaline agent such as sodium hypochlorite or a hydroxide compound in solid form, to an aqueous solution, the hydroxide compound preferably being an alkaline earth metal hydroxide compound such as solid calcium hydroxide.

15. A kit of parts for manufacturing a pharmaceutical preparation for use in a dental treatment, in particular in a root canal treatment, comprising one of: a first kit including: in a separate compartment, a phosphonate salt, preferably a salt of (1-hydroxyethane)-1,1-di-phosphonic acid, particularly preferably tetrasodium (1-hydroxyethane)-1,1-di-phosphonate; and instructions for the manufacture of the pharmaceutical preparation comprising the step of adding the phosphonate salt to an alkaline solution comprising an oxidizing agent, preferably to a sodium hypochlorite solution; and a second kit including: in a separate compartment, a phosphonate salt, preferably a salt of (1-hydroxyethane)-1,1-di-phosphonic acid, particularly preferably tetrasodium (1-hydroxyethane)-1,1-di-phosphonate, and a hydroxide compound in solid form, preferably an alkaline earth metal hydroxide compound, particularly preferably solid calcium hydroxide; and instructions for the manufacture of the pharmaceutical preparation comprising the step of adding the phosphonate salt and the hydroxide compound in solid form to an aqueous solution.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,

[0055] FIG. 1 shows the decomposition of a sodium hypochlorite solution comprising 5 weight percentage of sodium hypochlorite stabilized with a 0.5 molar sodium hydroxide solution stored for one year and for two years at two different temperature settings, i.e. at a room temperature of 23 C. and at 5 C.;

[0056] FIG. 2 shows the relative amount of chlorine from mixtures of a chelator and a sodium hypochlorite solution comprising 1 weight percentage of sodium hypochlorite compared to a pure NaOCl control solution during one hour. Four different mixtures, namely Na.sub.4EDTA mixed with NaOCl and Na.sub.4HEDP mixed with NaOCl at two different concentrations each, and a sodium hypochlorite solution are compared;

[0057] FIG. 3 shows the relative amount of chlorine from mixtures of a chelator and a sodium hypochlorite solution comprising 5 weight percentage of sodium hypochlorite compared to a pure NaOCl control solution during one hour. Four different mixtures, namely Na.sub.4EDTA mixed with NaOCl and Na.sub.4HEDP mixed with NaOCl at two different concentrations each, and a sodium hypochlorite solution are compared;

[0058] FIG. 4 shows the evolution of the pH-value of a solution of calcium hydroxide and Na.sub.4HEDP in distilled water and the pH-value of a solution of calcium hydroxide in distilled water during 10 minutes;

[0059] FIG. 5 shows a kit of parts according to a first embodiment;

[0060] FIG. 6 shows a first illustration of the manufacture of a pharmaceutical preparation;

[0061] FIG. 7 shows a kit of parts according to a second embodiment;

[0062] FIG. 8 shows a second illustration of the manufacture of a pharmaceutical preparation.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0063] As already mentioned above, sodium hypochlorite solutions are inherently non-stable. Their stability is generally dependent on the concentration, the temperature, the pH-value and the exposure to light of the sodium hypochlorite solution as well as to the concentration of impurities which catalyze the decomposition in the sodium hypochlorite solution. It has been found that a decomposition of sodium hypochlorite proceeds quicker as the concentration of the hypochlorite solution increases. Furthermore, it has been shown that the decomposition increases over time and that the decomposition is greater at higher temperatures.

[0064] As an illustration of the decomposition behavior of a sodium hypochlorite solution, FIG. 1 depicts the decomposition of a sodium hypochlorite solution comprising 5 weight percentage of sodium hypochlorite stabilized with a 0.5 molar sodium hydroxide solution stored for one year and for two years at room temperature of 23 C. and at 5 C. It follows from FIG. 1 that the sodium hypochlorite solution stored at room temperature decomposes to about 35 percentage and to about 50 percentage of available chlorine after one year of storage and two years of storage, respectively. However, the sodium hypochlorite solution stored at 5 C. decomposed to a much less degree, namely to about 5 percentage and to about 10 percentage of available chlorine after one year of storage and two years of storage, respectively. Hence, it is readily apparent from FIG. 1 that the stability of a sodium hypochlorite solution over time is greatly enhanced if it is stored at low temperatures. Besides, a sodium hypochlorite solution can generally be stabilized if a lye such as a sodium hydroxide (NaOH) solution is added.

[0065] In FIGS. 2 and 3, the oxidizing effect of the hypochlorite anion over time is illustrated for the admixture of Na.sub.4HEDP compared to the commonly used admixture of Na.sub.4EDTA into a sodium hypochlorite solution comprising 1 and 5 weight percentage of sodium hypochlorite, respectively.

[0066] Although the chlorine reduction of the total solution is presented in FIG. 1 and the available chlorine is presented in FIGS. 2 and 3, respectively, the tissue dissolving capability is depending on the available hypochlorite OCl.sup., which is directly related to chlorine. To measure the amount of hypochlorite, it has to be transferred by acidification to chlorine, which oxidizes potassium iodide to iodine. The latter is then titrated with a sodium thiosulfate solution.

[0067] In particular, FIG. 2 illustrates the amount of chlorine over time from mixtures of Na.sub.4HEDP as chelator and a sodium hypochlorite solution and of Na.sub.4EDTA as chelator and a sodium hypochlorite solution, respectively. In particular, the chlorine reduction from a 9 weight percentage and 18 weight percentage of Na.sub.4HEDP with reference to the total weight of the sodium hypochlorite solution as well as the chlorine reduction from a 3 weight percentage and 18 weight percentage of Na.sub.4EDTA with reference to the total weight of the sodium hypochlorite solution, respectively, was monitored over one hour, which is the normal duration of an endodontic treatment. The Na.sub.4HEDP and the Na.sub.4EDTA were each dissolved in a sodium hypochlorite solution comprising 1 weight percentage of sodium hypochlorite with reference to the total weight of the sodium hypochlorite solution.

[0068] The amount of chlorine over time was compared with a control solution of 1 weight percentage of pure sodium hypochlorite. In order to determine the amount of the available chlorine, aliquots of each solution (approximately 0.5 grams) were removed after 1 minute, 10 minutes, 20 minutes, 30 minutes and 60 minutes and assessed for their amount of available chlorine using a titration apparatus. Thereby, a 0.1 molar sodium thiosulfate solution was used as titrator. As is apparent from FIG. 2, the reduction of the chlorine from the decomposition of 9 weight percentage and 18 weight percentage of Na.sub.4HEDP mixed with a NaOCl solution comprising 1 weight percentage of NaOCl decays from almost 100 percentage to about 90 weight percentage and about 75 weight percentage, respectively. The chlorine reduction from the decomposition of a 3 weight percentage and 18 weight percentage of Na.sub.4EDTA mixed with a NaOCl solution comprising 1 weight percentage of NaOCl decays from about 95 weight percentage and 75 weight percentage, respectively, to below 25 weight percentage.

[0069] Hence, the admixture of Na.sub.4HEDP into the sodium hypochlorite solution maintained a high hypochlorite anion content, which is in clear contrast to low amount obtained from the commonly used admixture of Na.sub.4EDTA into the sodium hypochlorite solution. The latter caused a pronounced loss of available hypochlorite anions because EDTA strongly interacts with oxidizing agents such as NaOCl and thus renders the oxidizing agent ineffective. The immediate mixing procedure of Na.sub.4HEDP however does not cause any significant loss in available hypochlorite anions over the course of one hour and therefore enables the use of an effective oxidizing agent throughout the endodontic treatment.

[0070] In FIG. 3, the same measurements are performed using the same amounts of Na.sub.4HEDP and Na.sub.4EDTA as in FIG. 2, whereby these chelators are each admixed into a NaOCl solution comprising 5 weight percentage of NaOCl. As follows from FIG. 3, the reduction of the chlorine from the decomposition of Na.sub.4HEDP mixed with a NaOCl solution comprising 5 weight percentage of NaOCl is and remains much greater than the amount of the chlorine formed from the decomposition of Na.sub.4EDTA mixed with a NaOCl solution comprising 5 weight percentage of NaOCl. In fact, whereas the amount of the chlorine dropped by less than 25 percentage in the former case, a decrease to almost zero percentage occurred for the latter case over the course of one hour.

[0071] Besides, it has been shown that aqueous solutions of Na.sub.4HEDP are compatible with NaOCl irrigants and give the ability of a mild decalcification effect to these mixtures, which helps preventing the formation of a smear layer and debris accumulation during instrumentation.

[0072] As already mentioned, a disinfectant is placed in the root canal system so as to destroy remaining microorganisms and prevent reinfection. It is common to use calcium hydroxide (Ca(OH).sub.2) due to it its antibacterial effect, which exerts its antibacterial effect as long as a high pH value is maintained.

[0073] FIG. 4 depicts the evolution of the pH-value over time determined for the admixture of Na.sub.4HEDP and calcium hydroxide in solid form and only calcium hydroxide in solid form, respectively, into distilled water. The solutions are prepared by mixing 1 gram of calcium hydroxide in solid form and 0.1 gram of Na.sub.4HEDP in a glass vial. 10 milliliter of distilled water was added, and the pH measurement was started immediately and continued for 10 minutes. As a control, the pH value of 1 gram pure calcium hydroxide dissolved in 10 milliliter of distilled water was recorded, too. As directly follows from FIG. 4, when particulate, i.e. solid Na.sub.4HEDP is mixed with the calcium hydroxide powder in an aqueous environment, the resulting slurry has a higher pH value which increases faster at the beginning as compared to the pH value obtained for a calcium hydroxide solution. This indicates that the Na.sub.4HEDP binds the calcium Ca.sup.2+, thus liberating more hydroxyl ions. Consequently, the addition of Na.sub.4HEDP to calcium hydroxide can trigger an earlier onset of the desired disinfecting effect. In addition, the binding capacity of Na.sub.4HEDP to Ca.sup.2+ makes it easier to remove the calcium hydroxide slurry from the root canal system before the canal is filled with an alloplastic material.

[0074] FIGS. 5 and 7 show two embodiments of a kit of parts 1, 1 for manufacturing a pharmaceutical preparation for use in a root canal treatment. In particular, FIG. 5 shows a kit of part 1, which comprises a capsule 2 containing solid Na.sub.4HEDP in a first compartment 11 of the kit. Thereby, it is preferred to provide a container or the like containing a plurality of such capsules 2. In a second and third compartment 12, 13, the kit 1 comprises instructions 4 such as adding an aqueous, oxidizing solution to Na.sub.4HEDP for the manufacture of the pharmaceutical preparation and a measuring and mixing device 3 in the form of a mixing cup with a volume indication a, b for providing a specified amount of the aqueous, oxidizing solution. In the present example, the capsule contains about 1 gram of Na.sub.4HEDP and the instructions indicate to place either 10 milliliter or 20 milliliter of a sodium hypochlorite solution 5 comprising between 0.5 to 5 weight percentage of sodium hypochlorite with respect to the total mass of the sodium hypochlorite solution. As illustrated in FIG. 6, the capsule 2 containing the Na.sub.4HEDP can be opened or cracked at a predetermined breaking point in order to expose and release the Na.sub.4HEDP into the measuring cup. Once the Na.sub.4HEDP is dissolved in the sodium hypochlorite solution 5, the thus prepared pharmaceutical preparation is drawn up into a syringe 6 and can be discharged at a place of interest.

[0075] The kit of parts 1 shown in FIG. 7 comprises a capsule 2 containing solid Na.sub.4HEDP and solid calcium hydroxide in a first compartment 11 of the kit 1. Thereby, it is preferred to provide a container or the like containing a plurality of such capsules 2. In a second and third compartment 12, 13, the kit 1 comprises instructions 4 such as adding water or a saline solution to Na.sub.4HEDP and calcium hydroxide for the manufacture of the pharmaceutical preparation and a measuring and mixing device 3 in the form of a sealable microcentrifuge tube with a volume indication for providing a specified amount of water or of the saline solution. In the present example, the capsule contains about 1 gram of Na.sub.4HEDP and Ca(OH).sub.2 and the instructions indicate to place about 0.5-2 milliliter of a sodium chloride solution 5 comprising 0.9 percentage of sodium chloride with respect to the total volume of the sodium chloride solution or of sterile water into the microcentrifuge tube 3. As illustrated in FIG. 8, the capsule 2 containing the Na.sub.4HEDP and the calcium hydroxide can be opened in order to expose and release the Na.sub.4HEDP and the calcium hydroxide onto a glass plate 7. Once the Na.sub.4HEDP and the calcium hydroxide are placed on the glass plate 7, the measured amount of the sodium chloride solution or of the sterile water is admixed to the Na.sub.4HEDP and the calcium hydroxide. The thus prepared pharmaceutical preparation is of a slurry consistency and is placed on a point of interest by means of a Lentulo spiral 8.

[0076] It is to be noted that the kits of parts can comprise further compartments, for example a fourth compartment which comprises the glass plate or any further mixing or measuring devices or further components to be used in a root canal treatment. Instead of providing the instructions in a separate compartment in the kit, it is also possible to simply provide them within the kit or to imprint them onto the kit.

TABLE-US-00001 LIST OF REFERENCE SIGNS 1, 1 kit of parts 11, 11 first compartment 12, 12 second compartment 13, 13 third compartment 2, 2 capsule 3, 3 mixing and measuring device 4, 4 instructions 5, 5 solution 6 syringe 7 glass plate 8 Lentulo spiral