Medical and dental bioceramic compositions for temporary use

Abstract

The present invention relates to a bioceramic composition for temporary intracanal medication, which promotes the constant, controlled and balanced release of metal ions, hydroxyl (OH ‑ ) and metal-salicylate complexes, capable of providing bioactive, antimicrobial and anti-inflammatory properties. The present invention also provides methods for preventing or controlling endodontic infections and promoting tissue regeneration and repair by using the bioceramic composition.

Description

Technical Field

[0001] This invention relates to adhesives for use in medical and dental applications, and more particularly to stable bioceramic compositions that can promote bioactivity for temporary intracanal drug therapy. Background Technology

[0002] Tooth decay is a process caused by bacteria that destroys tooth tissue and can lead to the loss of tooth components if left untreated. Once established, its evolution can be divided into three stages. In the first stage, decay only affects the enamel; in the second stage, it deepens and invades the dentin; in the third stage, it reaches the root canal, causing pulp infection. Toothache begins in the second stage, and primarily in the third, mainly due to the inflammatory process caused by bacterial invasion.

[0003] The goal is to repair the periroot structures and restore normal dental and oral health functions. The need to prevent or control root canal infections forms the solid foundation of modern endodontics. Endodontic treatment has three main infection control phases: chemical-mechanical preparation, intracanal drug therapy, and filling of the root canal system.

[0004] While a significant reduction in bacterial cells within the root canal can be achieved through the use of instruments and the chemomechanical effects of irrigation, bacteria may remain viable in areas that are difficult to access. Although minute anatomical irregularities can be incorporated into the preparation, areas such as crypts, isthmuses, lateral and apical branches, and dentinal tubules may harbor bacteria, jeopardizing treatment outcomes if not removed. These areas are typically unaffected by instruments and auxiliary chemicals used for irrigation and will not have sufficient time for intracanal action to penetrate deeply and avoid infection.

[0005] In this sense, endodontic treatment with antibacterial activity is more likely to reach areas unaffected by instruments used in the root canal, especially when it remains within the root canal for an extended period. Therefore, by exercising its antibacterial properties, endodontic treatment can definitively promote a maximum reduction in the pulp microbiota. By enhancing this reduction, the use of endodontic dressings is directly associated with better restoration of the periroot tissues.

[0006] calcium hydroxide

[0007] In dentistry, calcium hydroxide-based products have been used for endodontic treatment because they fulfill some of the properties expected of this type of treatment, such as promoting healing and controlling the microbial flora of the canal. Its main characteristic is, in particular, its ability to increase the alkalinity of the canal, due to the mechanism by which calcium hydroxide dissociates into calcium and hydroxyl ions. These ions have the ability to penetrate dentinal tubules, thereby preventing the growth of new microorganisms, controlling and inhibiting potential infections, and thus conferring antimicrobial function upon calcium hydroxide.

[0008] The problem with using calcium hydroxide-based endodontic treatments is that the high ion release rate over a short period can cause damage to surrounding tissues. Therefore, prolonged use of these calcium hydroxide-based products can impair the fracture resistance of dentin structures. Another drawback of these products is their high solubility, which allows for micropermeability and, in some cases, reabsorption by vital tissues (periapical region).

[0009] Another problem is that upon contact with the pulp, calcium hydroxide paste induces the formation of a layer of necrotic tissue, which develops into a calcified layer, and can dissolve and stimulate the release of bioactive dentin molecules, further stimulating calcified tissue formation [Yang SF, Rivera EM, Baumgardner KR, Walton RE, Stanford C. Anaerobic tissue-dissolving abilities of calcium hydroxide and sodium hypochlorite. J. Endod. 1995; 21:613-6]. Coagulative necrosis and the formation of a mineralized barrier signify the loss of vital tissue. To some extent, this fact can reduce the potential for pulp response in subsequent pathological conditions. As a drawback, it is relevant to emphasize the possibility of inducing ectopic calcification or forming irregular or incomplete mineralized barriers. In addition, calcium hydroxide is not considered a material that can promote biological activity, and its ability to completely eliminate bacteria in the root canal is questioned [Sathorn C., Parashos P. and Messer H. (2007), Antibacterial efficacy of calcium hydroxide intracanal dressing: a systematic review and meta-analysis. International Endodontic Journal, 40: 2-10).

[0010] Bioactive properties

[0011] Bioceramics are a promising alternative to calcium hydroxide. Based on their surface chemical reactivity, bioceramics can be classified as bioinert, bioactive, or bioabsorbable materials [Heness G, Ben-Nissan B (2004). Innovative bioceramics. Materials Forum, 27, 104-14; Hench LL, Thompson I (2010) "Twenty-first century challenges for biomaterials." Journal of the Royal Society Interface, 7, S379-S391]. Bioactive materials are those capable of forming chemical bonds with living tissue. In the case of bone substitutes, the bioactivity of the material is often characterized by its ability to induce the formation of an apatite layer on its surface after immersion in a biofluid [Hench LL, Splinter RJ, Allen W, Greenlee T (2004) "Bonding mechanisms at the interface of ceramic prosthetic materials." Journal of Biomedical Materials Research, 5, 117-141].

[0012] After biomaterials were initially defined in the 1950s based primarily on the criteria of maximum biochemical and biological inertness in contact with bodily fluids (the first generation of implantable materials), bioactive glass, discovered by Larry L. Hench in 1969, was the first inorganic material to exhibit biological activity and served as a replacement for materials used in implants at the time.

[0013] One of the main characteristics of the bioactivity of this bioactive glass is based on the activity of Ca and Si ions present in its composition, which can induce the formation of a carbonized hydroxyapatite layer on its surface that is similar to the mineral phase of bone [Baino F, Hamzehlou S, Kargozaar S (2018) "Bioactive Glasses: Where Are We and Where Are We Going?" Journal of Functional Biomaterials 9, 25].

[0014] Second-generation bioactive glasses can promote positive responses in living systems by forming strong and stable tissue-implantation complexes with the tissues they are implanted with, thus expanding the concept of biocompatibility [Fiume E, Barberi J, Verné E, Baino F (2018) "Bioactive Glasses: From Parent 45S5 Composition to Scaffold-Assisted Tissue-Healing Therapies." Journal of Functional Biomaterials 9, 24].

[0015] In the 1980s, it was discovered that bioactive glass, when used in granular form, could promote regeneration and stimulate osteogenic and bone formation processes. Later, it was found that metal ions present in the composition and released upon dissolution of the bioactive glass were the cause of the stimulation of growth factors and cell differentiation factors [Hench LL and Jones JR (2015) "Bioactive Glasses: Frontiers and Challenges." Frontiers in Bioengineering and Biotechnology 3, 194]. One approach to the use of bioactive glass has been limited to "scaffold" forms, restricting its clinical application [Wu C and Chang J (2013) "A review of bioactive silicate ceramics." Biomedical Materials 8, 0320017].

[0016] In the late 1960s, interest emerged in using various ceramic materials as alternatives to bioactive glasses for biomedical applications, primarily due to their low solubility and improved mechanical strength. These materials were soon termed bioceramics [Dorozhkin SV (2010) "Calcium Orthophosphates as Bioceramics: State of the Art." Journal of Functional Biomaterials, 1, 22-107].

[0017] In recent years, novel dental compositions based on bioceramics have been proposed to replace calcium hydroxide and glass ionomer cements, primarily with the aim of improving bioactivity. These new bioceramics, in particular, are a class of calcium silicate-based cements, which exist as an alternative source of calcium themselves, and can be obtained in powder / liquid form or as a paste.

[0018] In the context of using bioactive materials in dentistry, Torabinejad proposed a Portland cement-based ceramic material for restoring tooth structures in U.S. Patent 5,415,547, issued May 16, 1995, which is capable of releasing ions believed to be MTA. Although calcium silicate, which is less soluble than calcium hydroxide, is used as the calcium ion source, the product has low physicochemical properties because it is essentially made into powder by adding a radiation-impermeable agent to the Portland cement.

[0019] Although considered to be materials with some biological activity and whose degradation products do not cause inflammatory responses, calcium silicate-based adhesives have many drawbacks regarding their physical and biological properties, including: low mechanical resistance, making them unsuitable for load-support applications; and low chemical instability (high degradation rate), resulting in highly alkaline conditions in the surrounding environment, which is detrimental to cellular activity and limits their long-term biological use.

[0020] Studies have shown a link between ion release rate and the bioactivity of materials. Although calcium-rich compositions may appear to provide Ca... 2+ The faster release of ions and the ease with which an apatite hydroxide layer forms on its surface are more attractive, but calcium does not appear to be an essential element for bioactive ceramics.

[0021] In U.S. Patent 8,475,811, issued July 2, 2013, Yang describes a formulation of a calcium silicate-based hydraulic cementitious agent for use in dentistry and orthodontic surgery, which is a single, injectable paste. The focus of this invention is to obtain a premixed paste containing calcium silicate and a liquid carrier, which has the ability to cure upon contact with moisture in physiological media. In the formulation developed by Yang, a curing mechanism occurs through contact with moisture in physiological media, causing the tricalcium silicate (Ca3SiO5) and dicalcium silicate (Ca2SiO4) phases to hydrate and form two new phases—a calcium hydroxide (Ca(OH)2) phase and a hydrated gel silicate phase called CSH (3CaO.2SiO2.3H2O). This CSH phase becomes entangled with the calcium hydroxide (Ca(OH)2) plates due to media saturation, reducing particle flowability and promoting material curing (hardening). However, the ready-to-use cement developed by Yang is not used as a temporary intracanal treatment because it hardens after hydration in the physiological environment, making it unsuitable as a temporary material.

[0022] Intracanal drug therapy

[0023] Conventional endodontic treatment has specific limitations and is sometimes restricted to irrigation fluids. For example, sodium hypochlorite and calcium hydroxide do not have the ability to eliminate all bacteria in the root canal system. Sodium hypochlorite and calcium hydroxide require direct contact to be effective, which is difficult to achieve. Direct contact cannot be achieved when calcification, which is a natural barrier, is present. Furthermore, as described in U.S. Patent 10,226,403B2, issued March 12, 2019, when chlorhexidine is mixed with sodium hypochlorite during instrumentation, a difficult-to-remove and staining orange-brown precipitate is formed.

[0024] Therefore, it is important to understand that the different methods of antibacterial irrigation in the root canal are themselves part of a collective effort to control infection in the pulp. Success cannot be guaranteed by relying solely on these methods if the quality of other parts of the treatment is compromised.

[0025] Therefore, intracanal medications are defined as biocompatible drugs temporarily placed in the root canal to inhibit bacterial invasion of the crown. To achieve this goal, ideal intracanal medications must be effective antimicrobial agents with long-term effects. Other desirable characteristics include, but are not limited to, non-irritation of periroot tissues so as not to hinder their repair, and activity in the presence of blood, serum, and tissue protein derivatives.

[0026] Although one of the main goals of endovascular drug therapy is to inhibit microbial growth over a period of time, currently available calcium hydroxide-based compositions do not significantly stimulate tissue regeneration and repair during treatment.

[0027] U.S. Patent 4,240,832A, issued on December 23, 1980, discloses a composition based on calcium hydroxide, a salicylate condensate, and pull capping aldehydes.

[0028] U.S. Patent Application 2013 / 0023601A1, published on January 24, 2013, discloses a cementation composition based on calcium silicate and salicylate, which has indications for intermediate restoration and root canal filling dental procedures.

[0029] The two documents differ from this invention in that the compositions are presented as a two-paste system and have the characteristic of hardening at the application site upon application. Therefore, apart from the need for a homogenization step between the two different pastes (which could cause problems involving the material application process), both compositions have the characteristic of hardening during use, which prevents them from being used as temporary endodontic treatments.

[0030] Patent application EP 2 736 519 A1, published January 31, 2013, discloses an alkaline composition with antimicrobial activity comprising calcium hydroxide and a triol compound. U.S. patent application 2014 / 0234442A1, published August 21, 2014, discloses a composition for filling dental root canals comprising linezolid antibiotic, calcium hydroxide, and other pharmaceutically acceptable excipients.

[0031] Patent application WO 2011 / 102724 A2, published on August 25, 2011, discloses a composition for antimicrobial treatment of root canals, which is achieved by combining calcium hydroxide with potassium iodide and chlorhexidine to promote antimicrobial activity.

[0032] These documents differ from the present invention because the compositions they disclose are based on the use of calcium hydroxide as a source to impart antimicrobial properties. Furthermore, the compositions proposed in these documents do not possess any regenerative biological activity properties when applied.

[0033] Therefore, the endovascular drug therapy to be developed needs to possess broad antimicrobial, anti-inflammatory, and physicochemical properties, be easy to manipulate, and be readily removed after use. Furthermore, it needs to exhibit bioactivity through the controlled and stable release of metal ions, providing a better biological response. To achieve this, the electron distribution of the chemical elements used needs to allow the formation of metal ions arranged in a specific crystal pattern, thereby stimulating the desired biological response.

[0034] Therefore, the technical problem solved by the present invention relates to providing a biomaterial that, in addition to having antimicrobial and anti-inflammatory properties, is easily manipulated and can provide bioactive metal ions without solidification, thereby allowing it to be used as a temporary intracanal drug therapy. Summary of the Invention

[0035] In view of the foregoing, there is a lack in the art of endodontic therapy that exhibits suitable bioactive and physicochemical properties for use as a temporary material. To meet these requirements, the present invention uses a controlled source of metal ions in a constant and balanced manner, which allows for the induction of cell differentiation and, in this way, enhances the repair and regeneration capacity of the tissue-bone and dentin-pulp complex.

[0036] Therefore, the object of the present invention is to provide a temporary intracanal drug therapy exhibiting antimicrobial and anti-inflammatory properties, which promotes the absorption of metal ions (M1) upon contact with the physiological environment. x+ ), hydroxyl (OH) - The constant, controlled, and balanced release of ) and metal salicylate cation complexes provides bioactive effects and has antimicrobial and anti-inflammatory properties.

[0037] This invention provides a bioceramic composition for temporary intracanal medications, comprising at least one complexing resin and a source of metal ions. Upon contact with a salt solution, the composition forms a cationic complex with controlled release of metal ions, thus endowing the composition with bioactivity, antimicrobial, and anti-inflammatory properties.

[0038] The present invention also provides a method for preventing or controlling pulp infection and promoting tissue regeneration and repair by applying the bioceramic composition of the present invention to the root canals of a subject in need. Attached Figure Description

[0039] Figure 1 The results of pH analysis of the bioceramic composition of the present invention are shown.

[0040] Figure 2 The evaluation of sections from each group stained with hematoxylin and eosin (HE) to count the number of inflammatory cells is shown.

[0041] Figure 3 The results show the number of inflammatory cells counted in each group on different analysis days.

[0042] Figure 4 The evaluation of each group is shown after inducing immunohistochemical reactions to detect interleukin-6 (IL-6) and interleukin-10 (IL-10).

[0043] Figure 5 The results show the counts of interleukin-6 (IL-6) in each group on different analysis days.

[0044] Figure 6 The results show the counts of interleukin-10 (IL-10) in each group on different analysis days.

[0045] Figure 7 The assessment of the presence of collagen in each group is shown.

[0046] Figure 8 The results show the presence of collagen in each group on different analysis days.

[0047] Figure 9 The results of the von Kossa method, used to detect calcium and phosphate deposition, are shown.

[0048] Figure 10 The results show the survival curves of Enterococcus faecalis (E. faecalis) relative to the bioceramic composition (TP3), calcium hydroxide paste (CHP), and standard chlorhexidine (CLX). Detailed Implementation

[0049] While the invention may be presented in various embodiments, this specification, together with the accompanying drawings, indicates preferred embodiments and emphasizes that they should be considered as examples of the core of the invention rather than limitations.

[0050] This invention relates to bioceramic compositions for temporary endodontic treatment, comprising at least one cationic complexing resin derived from salicylates and a source of metal ions. The compositions of this invention possess bioactive, anti-inflammatory, and antimicrobial properties and are suitable for temporary endodontic treatment in dental procedures.

[0051] In a preferred embodiment, the bioceramic composition of the present invention for temporary endodontic treatment consists of a paste, which may or may not be a backup, generally comprising a metal ion source and at least one salicylate derivative.

[0052] The metal ions present in the bioceramic composition for intracanal drug therapy of the present invention are released by the breaking of Si-OM bonds upon contact with body fluids. + =Ca 2+ Mg 2+ Sr 2+ Zn 2+ Zr 4+ ) and hydroxyl ions (OH) - The reaction is shown below:

[0053] Si-OM + +H + +OH-→Si-OH+M + (aq) +OH - (aq)

[0054] In addition, hydroxyl ions (OH-) - Hydrogen is removed from the salicylate group structure (R-C7H4O2-OH) to produce a water molecule and a salicylate ion (R-C7H4O2-O). - Next, the reaction of salicylate ions with metal ions (M) will be carried out. x+ The complexation reaction between the two forms a metal salicylate complex, as shown in the following formula:

[0055] 2(R-C7H4O2-OH)+2OH - →(R-C7H4O2-O) - +H2O

[0056] (R-C7H4O2-O) - +M x+ →(RC 7x H 4x O 2x-OM)

[0057] Wherein, 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.

[0058] Depending on the valence of X, metal-salicylic acid ester complexes form different structures and can have one to four salicylic acid ester groups attached to the metal.

[0059] Depending on the group R, metal-salicylic acid ester complexes undergo different dissociation rates, thereby supplying metal ions to the medium in a regulated manner, following the formula:

[0060] (RC 14 H8O4-O-M1)→(R-C7H4O2-O) - +M1 x+

[0061] This process continues as the metal ions are hydrated by the physiological environment.

[0062] Therefore, the prolonged dissociation of metal salicylate complexes gives bioceramic compositions a potential application as endodontic therapy because they provide sufficient exposure time to allow for the development of biological activity.

[0063] To maintain this modulating effect of the proposed bioceramic composition, a complexing resin / metal ion source ratio of less than 1:3 is necessary. The correct ratio of metal ions and complexing resin in the same composition allows for the formation of metal-salicylic acid ester complexes without composition curing / hardening, thus allowing for easy removal of the composition after it has been maintained in the root canal during treatment.

[0064] Furthermore, the resulting metal-salicylic acid ester complexes exhibit anti-inflammatory properties due to their activity against free radicals. Free radicals are highly reactive substances generated in living organisms for protective purposes. However, in some cases, they are the cause of tissue damage or its deterioration. Metal-salicylic acid ester complexes have direct activity against free radicals and non-radical reactive substances, which contributes to their anti-inflammatory activity. Metal complexation of different salicylates has been a strategy used to improve the pharmacological activity of different molecules and reduce their side effects.

[0065] After the metal-salicylic acid ester complex is fully formed, ion M1 x+ and OH - The consumption ceases. Hydroxyl ions (OH-) in physiological media... - The increased concentration of ) causes the pH of the solution to rise to a value greater than 10, making the medium alkaline and unsuitable for microbial growth, thus endowing the bioceramic composition used for endovascular drug therapy with antimicrobial properties.

[0066] In addition, the stable concentration of various metal ions in the medium enables enzymatic changes that influence and stimulate tissue formation, promote the repair and regeneration of the affected area, and subsequently endow the bioceramic composition used for intracanal drug therapy with bioactive properties.

[0067] In a preferred embodiment of the invention, the bioceramic composition for temporary intracanal drug therapy can be obtained in the form of a single paste, the composition also comprising an inert liquid carrier. Suitable and non-limiting examples of inert liquid carriers are substances derived from glycol groups, such as ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glycerin, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, butanediol, or combinations thereof.

[0068] The metal ion source in the materials used in this invention is capable of releasing metal ions from Ca, Mg, Sr, Zn, Zr, or combinations thereof. Suitable, but non-limiting examples are selected from the group consisting of metal silicates and metal aluminates, preferably the group consisting of metal silicates.

[0069] In a preferred embodiment, the metal silicate is selected from tricalcium silicate (3CaO.SiO2), dicalcium silicate (2CaO.SiO2), strontium magnesium feldspar (Sr2MgSi2O7), magnesium feldspar (Ca2MgSi2O7), zirconium silicate (Ca3ZrSi2O9), zinc feldspar (Ca2ZnSi2O7), or combinations thereof.

[0070] Suitable complexing resins belong to the group consisting of compositions of salicylate derivatives. Non-limiting 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 salicylate, or combinations thereof.

[0071] In a preferred embodiment, the salicylate is methyl salicylate or salicylate diester.

[0072] An important feature of compositions used for temporary endodontic treatment is radiopermeability, i.e., the ability of the composition to block X-rays used in radiological examinations. To impart this property to the compositions of the present invention, several radiopermeable agents can be used, particularly, but not limited to, barium, bismuth, rare earth derivatives, strontium, zirconium, silicon, aluminum, titanium, and tungsten.

[0073] Suitable radiation-impermeable agents are barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, titanium oxide, and calcium tungstate, or combinations thereof.

[0074] In a preferred embodiment, the bioceramic composition of the present invention comprises at least:

[0075] i) 1 to 10% by weight of a complex resin derived from salicylate;

[0076] ii) 10 to 60% by weight of liquid carrier;

[0077] iii) 20 to 60% by weight of a radiation-impermeable agent; and

[0078] iv) 3 to 30% by weight of metal ion sources.

[0079] In the most preferred embodiment, the bioceramic composition of the present invention comprises at least:

[0080] i) 5 to 7% by weight of a complex resin derived from salicylate;

[0081] ii) 42 to 44% by weight of liquid carrier;

[0082] iii) 25 to 27% by weight of a radiation-impermeable agent; and

[0083] iv) 20 to 22% by weight of metal ion source.

[0084] In another embodiment, the present invention provides a method for preventing or controlling pulp infection by applying the bioceramic composition of the present invention into the root canal of a subject in need.

[0085] In another embodiment, the present invention provides a method for promoting tissue regeneration and repair by applying the bioceramic composition of the present invention into the root canals of a subject in need.

[0086] In another embodiment, the present invention provides the use of the bioceramic composition of the present invention in the preparation of a product for the prevention or control of pulp infection in subjects in need.

[0087] In another embodiment, the present invention provides the use of the bioceramic composition of the present invention in the preparation of a product for promoting tissue regeneration and repair in subjects in need.

[0088] To better understand the present invention and clearly demonstrate the resulting technological advancements, the results of various experiments conducted with respect to non-limiting embodiments of the invention are now presented.

[0089] Example:

[0090] The bioceramic composition for temporary endodontic treatment of the present invention (Table 1) was prepared by mixing the liquid carrier component and complexing resin with a mechanical stirrer and then adding the following solid components: metal silicate (metal ion source) and radiation impermeable agent, wherein the speed was less than 500 rpm for about 45 minutes until completely homogenized.

[0091] Table 1: Examples of Bioceramic Compositions

[0092]

[0093] The compositions prepared in the examples were subjected to pH, ion release, anti-inflammatory, bioactivity and antimicrobial analysis.

[0094] pH analysis

[0095] For pH analysis, a small amount of the composition was added to an Eppendorf flask, and this was repeated three times. Then, 1 mL of distilled deionized water was added. After centrifugation at 1400 RPM for 3 minutes, pH analysis was performed using 900 μL aliquots of the recovered supernatant. After each analysis, 900 μL of distilled deionized water was added to each sample at 24 h (1 day), 3, 5, 10, 20, and 30 days to allow for ion exchange.

[0096] Metal ion release analysis

[0097] For metal ion release analysis, a small amount of the composition was added to an Eppendorf flask, and this was repeated three times. Then, 1.5 mL of distilled deionized water was added. After centrifugation at 10,000 rpm for 3 minutes, 1000 μL aliquots of the recovered supernatant were used for metal ion release analysis. The 1000 μL aliquots were then transferred to a 5 mL beaker and diluted to 2 mL with distilled water. Analysis was performed using a pH meter and a properly calibrated calcium electrode. After each analysis, 1000 μL of distilled deionized water was added to each sample at 24 h (1 day), 3, 5, 10, 20, and 30 days to enable ion exchange.

[0098] Table 2 below shows the results obtained from pH analysis and metal ion release analysis. The results show that the composition exhibits a pH ≈ 10 sufficient for antimicrobial activity and releases metal ions consistently over the 30-day test period.

[0099] Table 2. Results of physicochemical analysis of bioceramic compositions

[0100]

[0101]

[0102] In addition, the results of pH analysis are in Figure 1 As shown in the image.

[0103] Anti-inflammatory and bioactive potential analysis

[0104] For anti-inflammatory and bioactivity potential analysis, polyethylene tubes were implanted into the dorsal subcutaneous tissue of 60 rats, divided into the following groups: bioceramic composition (TP3), calcium hydroxide paste (CHP), and control (empty CG tubes). At 7, 15, 30, and 60 days, the animals were anesthetized, and blood was collected by cardiac puncture to obtain analytical serum. Subsequently, the animals were euthanized, and the implants with adjacent tissue 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. Immunohistochemistry was induced to detect interleukin-6 (IL-6) and interleukin-10 (IL-10). Bioactivity potential was assessed by the von Korsa method and by analysis of unstained sections under a microscope with polarized light, both to detect calcium and calcite crystal deposition. Following the von Korsa reaction, some sections underwent immunohistochemistry to detect alkaline phosphatase, an enzyme produced by mineralized tissue cells.

[0105] Figure 2 , 3 Images 4, 5, and 6 show the results obtained from the anti-inflammatory potential assay. The results show the number density of inflammatory cells and cells immunostained against IL-6 and IL-10. Significant differences in the number of IL-6 and IL-10 cells were observed between TP3 and CHP at days 7, 15, 30, and 60. This was accompanied by a decrease in immunoreactivity to IL-6 and IL-10. Figure 5 and 6 The significant reduction in inflammatory processes indicates that the proposed composition TP3 has significant anti-inflammatory properties.

[0106] Figure 7 , 8 Figures 9 and 1 show the results obtained by measuring the bioactivity potential using the von Korsa method. It can be seen that for the TP3 composition, in... Figure 9 Calcium nodule formation was significantly increased in C and 9D, and in Figure 9 The significantly increased formation of phosphate nodules in G and 9H indicates that the composition of the present invention can enhance osteoblast mineralization capacity. The presence of the von Korsa positive structure and birefringent structure suggests that the TP3 composition possesses expressive biological activity potential.

[0107] Antimicrobial analysis

[0108] For antimicrobial analysis, 150 mg of each of the bioceramic composition (TP3), calcium hydroxide paste (CHP), and standard chlorhexidine (CLX) were prepared in a Falcon tube, and 5 mL of ultrapure water was added and the mixture was vortexed for 1 min. Then, 2.8 mL of each mixture was taken and added to a 3 × 10⁻⁶ mol / L Enterococcus faecalis suspension (TP3, CHP, CLX ... 7Mix 100 μL aliquots of the sample (CFU / mL) with dilute chlorhexidine solution. Use sterile 0.85% saline solution (equivalent to MacFarland 1 scale (3 × 10⁻⁶)). 8 CFU / mL) was used to prepare a suspension of Enterococcus faecalis and the concentration was measured on a MacFarland densitometer (DEN-1). The suspension was vortexed for 1 minute. 100 μL aliquots were taken from the sample at 1, 3, 6, 15, and 24 hours. These samples were first transferred to a second tube containing a neutralizing agent and subjected to 10... -1 Up to 10 -5 Decimal serial dilutions were performed. For TP3 and CHP solutions, the neutralizing agent used was 0.5% (w / v) citric acid, and for chlorhexidine, it was a 0.3% (w / v) soy lecithin and polysorbate solution. 100 μL aliquots of each dilution were inoculated three times onto the surface of trypsin-soy agar (TSa) plates and incubated at 37°C for 24 to 48 hours. CFU / g (colony forming units / gram) counts were performed using a colony counter, and all CFU values ​​were converted to logarithmic values. 10 10 .

[0109] Figure 10 The results show the survival curves of Enterococcus faecalis relative to the bioceramic composition (TP3), calcium hydroxide paste (CHP), and standard chlorhexidine (CLX). It can be seen that the bioceramic composition (TP3) exhibits higher antimicrobial activity against Enterococcus faecalis compared to calcium hydroxide paste (CHP) and standard chlorhexidine (CLX).

[0110] Although only some embodiments of the invention have been shown, it will be understood that those skilled in the art may make omissions, substitutions and changes without departing from the spirit and scope of the invention.

[0111] Furthermore, it is explicitly stated that the content of documents mentioned in this specification is incorporated herein by reference.

Claims

1. A bioceramic composition for temporary intracanal drug therapy, characterized in that... It includes: a) 1 to 10% by weight of a complex resin derived from salicylate; b) 10 to 60% by weight of liquid carrier; c) 20 to 60% by weight of a radiation-impermeable agent; and d) 3 to 30% by weight of metal ion source. The metal ions are selected from tricalcium silicate (3CaO.SiO2), dicalcium silicate (2CaO.SiO2), strontium magnesium feldspar (Sr2MgSi2O7), magnesium feldspar (Ca2MgSi2O7), zirconium silicate (Ca3ZrSi2O9), and zinc feldspar (Ca2ZnSi2O7), or combinations thereof; and The composition is in the form of a single paste composition that, upon contact with a physiological solution, promotes the formation of a cationic complex between the resin and the metal ions and the controlled release of the metal ions.

2. The bioceramic composition according to claim 1, characterized in that... It includes at least: i) 5 to 7% by weight of a complex resin derived from salicylate; ii) 42 to 44% by weight of liquid carrier; iii) 25 to 27% by weight of a radiation-impermeable agent; and iv) 20 to 22% by weight of metal ion source.

3. The bioceramic composition according to claim 1, characterized in that... The complexing resin is derived from methyl salicylate, ethyl salicylate, n-butyl salicylate, isobutyl salicylate, propyl salicylate, hexyl salicylate, benzyl salicylate, and diester salicylate, or combinations thereof.

4. The bioceramic composition according to claim 1, 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, butanediol, or combinations thereof.

5. The bioceramic composition according to claim 1, characterized in that... The radiation-impermeable agent is selected from the group consisting of barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, titanium oxide, and calcium tungstate, or combinations thereof.

6. The bioceramic composition according to claim 1, characterized in that... The complexed resin is derived from salicylate, wherein the salicylate is methyl salicylate or salicylate diester.

7. Use of the bioceramic composition as defined in any one of claims 1 to 6 in the preparation of a medicament for the prevention or control of pulp infection in the root canal of a subject in need of such treatment.

8. Use of the bioceramic composition as defined in any one of claims 1 to 6 in the preparation of a medicament for promoting tissue regeneration and repair in the root canals of a subject in need of such a medicament.

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