Coating composition for treating or preventing peri-implantitis and method for preparing same

Abstract

The present invention relates to a method for preparing a coating composition comprising an anti-infective agent for the controlled release of the anti-infective agent, and to a coating composition or coated substrate obtained by said method. Such coating compositions are particularly useful in the dental field for the treatment or prevention of inflammatory processes such as mucositis or peri-implantitis, preferably peri-implantitis.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing a coating composition comprising an anti-infective agent for the controlled release of the anti-infective agent, and to a coating composition or coated substrate obtained by said method. Such coating compositions are particularly useful in the dental field for the treatment or prevention of inflammatory processes such as mucositis or peri-implantitis. [Background technology]

[0002] The use of titanium-based dental implants inserted into the oral cavity is a common treatment in modern dentistry. These implants generally have an 89% success rate, restoring the functionality and esthetics of replaced teeth. However, several complications can arise from the insertion of dental implants into patients. Among these complications, infection in the peri-implant area is common due to the accumulation of microbial plaque around the implant. Such infections can result from cross-contamination during the surgical insertion of the implant into the oral cavity or poor tissue healing. Such infections can also occur late after surgery as a result of bacterial plaque accumulation on the implant surface. Infections are caused by bacterial colonization around the implant, particularly at the bone-implant interface. Such complications often require implant removal. Peri-implantitis is defined as a destructive process around an implant during the osseointegration process, resulting in loss of bone support and incomplete or even complete implant integration in the bone. Therefore, a complication of peri-implantitis is implant loss. This condition is of concern in the field, as it occurs in 20% of implant recipients between one and five years after surgery.

[0003] Peri-implantitis typically develops as a result of bacterial colonization, followed by the formation of a biofilm by bacterial attachment to the implant surface or to existing bacteria. It has been observed in the art that various types of bacteria can be found on the implant surface one hour after the surgical procedure, and that it takes only two weeks for a bacterial biofilm to form. Consequently, prompt intervention is necessary to prevent the spread of infection and eradicate the biofilm that has formed. Several bacteria have been identified as being involved in the development of peri-implantitis. These bacteria include, for example, Bacteroides ( Bacteroides ), Campylobacter ( Campylobacter ), Eubacterium ( Eubacterium ), Fusobacterium ( Fusobacterium ), Treponema ( Treponema ) species, Aggregatibacter actinomycetemcomitans ( Aggregatibacter actinomycetemcomitans ), Prevotella ( Prevotella ), Intermedia ( intermediate ), Porphyromonas gingivalis ( Porphyromonas gingivalis ), Treponema denticola ( Treponema denticola ), Tannerella forsythia ( Tannerella forsythi ), and especially Staphylococcus aureus ( Staphylococcus aureus As a result, the search for surfaces capable of preventing bacterial adhesion, bacterial biofilm formation, and bacterial colonization around implants has become a goal of intense research.

[0004] Mucositis is an inflammatory process that occurs in patients with oral implants, where the tissues surrounding the implant become inflamed as a result of bacterial plaque accumulation. Mucositis usually precedes peri-implantitis. In this regard, European Patent EP1799186B1 discloses an orally administrable pharmaceutical composition comprising octenidine for the treatment or prevention of inflammatory diseases of the buccal and pharyngeal cavity.

[0005] Several antibacterial agents are known in the art for the prevention or treatment of peri-implantitis. These include salts, ions, or nanoparticles of metals such as silver, gold, copper, and zinc. Antibiotic compounds have also been widely used as antibacterial agents. However, bacterial strains tend to develop resistance when exposed to antibiotics, making preventative or therapeutic strategies ineffective. The most commonly used antibiotics include gentamicin, cephalothinin, amoxicillin, metronidazole, tobramycin, and vancomycin. These antibiotics are typically incorporated into biocompatible inorganic matrices, such as calcium phosphate or hydroxyapatite, or into polymer coatings or sol-gel matrices. In this regard, Radin and Ducheyne, Biomaterials 28 (2007) 1721-1729, disclose a sol-gel matrix prepared from tetraethyl orthosilicate (TEOS) and incorporating vancomycin. The disclosed multilayer matrix, in particular, allows for controlled release of the antibacterial agent and is resorbable. Furthermore, a correlation has been suggested between the rate of degradation of the sol-gel matrix and the rate of release of the antibiotic compound.

[0006] Other antibacterial agents known in the art include, inter alia, cationic compounds such as quaternary ammonium compounds, antibacterial peptides, and natural molecules such as chitosan. However, quaternary ammonium compounds lack selectivity against bacteria and may exhibit undesirable cytotoxic effects. Salts of chlorhexidine and octenidine are also known cationic compounds useful as antibacterial agents. Octenidine salts, especially its dihydrochloride, are active against a wide range of bacteria and are stable under a wide range of conditions. Advantageously, octenidine reacts with polysaccharides found on the walls of microorganisms to inhibit cellular function, thereby preventing the growth of bacterial plaque. Octenidine also exhibits low cytotoxicity.

[0007] Coatings that release antibacterial agents and are suitable for use in the treatment or prevention of peri-implantitis are known in the art. In this regard, I. Garcia-Arnaez, B. Palla, J. Suay, F. Romero-Gavilan, L. Garcia-Fernandez, M. Fernandez, I. Goni, and M. Gurruchaga (European Polymer Journal, Volume 113, 2019, pp. 289-296) disclose an organic-inorganic hybrid coating based on a sol-gel material with demonstrated osteogenic potential, incorporating either octenidine dihydrochloride or chlorhexidine diacetate as an antibacterial agent. The disclosed system is suitable for preventing biofilm formation and bacterial adhesion on implant surfaces. The matrix is ​​prepared by a sol-gel method using a mixture of tetraethyl orthosilicate (TEOS) and methyltrimethoxysilane (MTMOS) in a 3:7 molar ratio as the silicon-based agent. The resulting sol-gel matrix is ​​then doped with 0-2% by weight of an antibacterial agent, either chlorhexidine diacetate or octenidine dihydrochloride. According to this document, the release rate of the active ingredient is proportional to the decomposition rate of the sol-gel matrix material. The presence of TEOS in the sol-gel material also promotes the hydrophilicity of the material, thereby accelerating its hydrolysis.

[0008] International Patent Application WO2017 / 197510 A1 discloses a biocompatible composite material for the controlled release of octenidine. The biocompatible matrix comprises a mesoporous silicon oxide matrix that can be prepared as a coating. The active ingredient, i.e., octenidine, is released primarily by diffusion through the pores of the mesoporous material, so the silicon oxide material of the matrix is ​​substantially free from decomposition or hydrolysis. Tetraethyl orthosilicate is disclosed as the main raw material for the silicon oxide mesoporous matrix. Furthermore, octenidine is used in a loading of 30% to 40% by weight as an amphiphilic compound for the formation of micellar assemblies.

[0009] Spanish Patent Application ES201031831 discloses a method for preparing sol-gel coatings, specifically using mixtures of tetraethyl orthosilicate (TEOS) and methyltrimethoxysilane (MTMOS) as precursors in molar ratios of 4:1, 2:1, and 4:3. The document does not mention the use of such sol-gel matrices for the release of antibacterial agents such as octenidine. The document also discloses that curing of the sol material to form a gel can be carried out under harsh or mild conditions. Curing under mild conditions tends to promote rapid degradation of the material, as the cured material exhibits a low degree of cross-linking.

[0010] From what has been disclosed in the art, it follows that there remains a need to provide improved coatings suitable for the treatment or prevention of inflammatory processes such as mucositis or peri-implantitis, in particular coatings that are suitable (i) to form a physical barrier between the implant surface and a physiological medium suitable for encapsulating bacteria, preventing bacterial adhesion to the implant surface during soft tissue regeneration, (ii) to release anti-infective agents in a controlled manner, (iii) to harden in a minimal amount of time at physiological conditions, (ivi) for use in vivo, and (v) to degrade at physiological conditions and / or to prevent the formation of a fibrous capsule between the implant and the surrounding tissue. Summary of the Invention

[0011] After extensive research, the present inventors have discovered a novel tetraethyl orthosilicate having the formula Si(OR), such as tetraethyl orthosilicate (TEOS). 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C1-C4) alkyl chain) and compounds of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8)(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), in a molar ratio of 80:20 to 50:50, have been found to have beneficial properties for use in the prevention or treatment of inflammatory processes such as mucositis or peri-implantitis.

[0012] The first beneficial property is that the cations of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 In contrast to what is found with prior art octenidine compositions based on compounds of the same class (e.g., MTMOS), the coating composition can harden within about 10 minutes under conditions present in a patient's mouth, i.e., a temperature of about 37°C and humidity of about 100%. Advantageously, this coating composition can be applied directly during or after surgery, with minimal discomfort to the patient, within a timeframe commonly accepted for this type of surgery, and does not require external heating or activation to induce hardening.

[0013] A second advantage of the coating composition is that, when used to coat an implant or prosthesis, it advantageously allows the formation of a solid film on the implant surface, which acts as a physical barrier between bacteria from the physiological medium and the implant surface. The film is also suitable for embedding bacteria attached to the substrate surface, which is believed to result in the removal of bacterial populations attached to the substrate surface. In some embodiments, the physical barrier is strong enough to allow the regeneration of soft tissues around the implant, thereby effectively preventing the occurrence of infection-related inflammatory reactions around the implant. Surprisingly, this is true even when the antibacterial agent is omitted from the coating composition of the present invention.

[0014] A third advantage of the coating composition of the present invention is that it advantageously allows for the sustained release of a large amount of octenidine for one month after application of the coating. The release behavior of the coating composition of the present invention is particularly ideal for peri-implantitis, since the sustained release of octenidine can prevent early and long-term infection, thus providing a longer period of implant integration protected from infection. This is because the above-mentioned state of the art uses 2% octenidine and a relatively low amount of a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 This is unexpected because substantially all of the octenidine released within one month after application of the coating is released within a period of about seven days, which is lower than the amount of octenidine contained in the coating at the time of application. The prior art further teaches that increasing the amount of TEOS in the silicon-based sol-gel precursor results in faster degradation of the gel matrix, and matrix degradation is directly related to the release of octenidine. In other words, a person skilled in the art would have expected that the octenidine in the coating composition according to the present invention would be released in a more rapid manner compared to the prior art coating composition with low TEOS, and therefore would not have considered such a high-TEOS coating composition to be suitable for the treatment of peri-implantitis, where late-onset infection is a concern.

[0015] The coating compositions of the present invention are also advantageously biocompatible and exhibit excellent bactericidal properties. In particular, unlike coatings disclosed in the art, the coating compositions of the present invention advantageously and surprisingly do not result in the formation of a fibrous capsule between the implant and the tissue surrounding the implant, thus promoting efficient implant integration into bone. Furthermore, the method for preparing the coating composition is advantageously short (less than 30 minutes) and can therefore be carried out within a dental practice during a patient visit without causing any particular discomfort to the practitioner or patient. Additionally, because no special equipment is required to carry out the method, practitioners do not need additional equipment to prepare the coating compositions of the present invention.

[0016] Thus, in a first aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, wherein the mixture further comprises octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon-based sol-gel precursor; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature about the temperature of the mouth; The present invention relates to a method for preparing a coating composition comprising:

[0017] A second aspect of the present invention relates to a composition obtainable by the method defined in the first aspect of the present invention.

[0018] The compositions of the second aspect of the invention are particularly useful in the prevention or treatment of inflammatory processes such as mucositis or peri-implantitis, preferably peri-implantitis.

[0019] Thus, a third aspect of the invention relates to a composition according to the second aspect of the invention for use in medicine.

[0020] A fourth aspect of the invention relates to a composition according to the second aspect of the invention for use in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis.

[0021] As mentioned above, the composition of the second aspect of the invention can be prepared in two steps. A kit for preparing the product of the second aspect of the invention is also part of the invention, said kit comprising, in a first alternative, reagents for the preparation of the pre-cured material, and, in a second alternative, the pre-cured material. Thus, a fifth aspect of the invention is a kit of parts for producing a substrate coated with an anti-infective coating composition, comprising: in a first component the mixture provided in step (i) of the method defined in the first aspect of the present invention, in a second component, the aqueous acidic solution used in step (ii) of the method defined in the first aspect of the present invention, in an optional third component, means for mixing the contents of the first and second components, and optionally means for heating the resulting mixture; and an optional fourth member, a substrate for receiving an optionally heated mixture of the contents of said first member and second member, and optionally means for transferring said optionally heated mixture to said substrate; or in a first component, a sol material obtained by a method comprising steps (i) and (ii) as defined in the first aspect of the present invention, and a second member, a substrate for receiving said sol material, and optionally means for transferring said sol material to said substrate; The present invention relates to a kit of parts comprising:

[0022] A sixth aspect of the present invention relates to a mixture provided in step (i) of the method defined in the first aspect of the present invention.A seventh aspect of the present invention relates to a composition for use in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, said composition comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature about the temperature of the mouth; The method is obtained by a method comprising the steps of: [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 shows the hydrolysis rate of materials M1 to M5 of Example 1 as a measure of weight loss (expressed as a percentage) in function of time (expressed in days). [Figure 2] FIG. 2 shows the release profiles of octenidine (expressed as the ratio of the cumulative amount of octenidine released at a given time to the amount of octenidine present in the coating composition) as a function of time (expressed in days) for Samples M2 to M5 prepared in Example 1. [Figure 3] Figure 3 shows the cell viability of human fibroblasts (FBH, expressed as a percentage) in contact with samples M1 to M5 prepared in Example 1 and measured according to the MTT cell viability assay as a function of time ((a): 1 day, (b): 2 days, (c): 7 days). ANOVA test, *p<0.05 vs. control Ti discs (uncoated discs). [Figure 4] Figure 4 shows the cell viability of human osteoblasts (MG-63, expressed as a percentage) in contact with samples M1 to M5 prepared in Example 1 and measured according to the MTT cell viability assay as a function of time ((a): 1 day, (b): 2 days, (c): 7 days). ANOVA test, *p<0.05 vs. control Ti discs (uncoated discs). [Figure 5] FIG. 5 shows the cell proliferation of human fibroblasts (FBH, expressed as fluorescence intensity) in contact with samples M1 to M5 prepared in Example 1 and measured according to the Alamar Blue cell proliferation assay as a function of time ((a): 1 day, (b): 2 days, (c): 7 days). [Figure 6] FIG. 6 shows the cell proliferation of human osteoblasts (MG-63, expressed as fluorescence intensity) in contact with samples M1 to M5 prepared in Example 1 and measured according to the Alamar Blue cell proliferation assay as a function of time ((a): 1 day, (b): 2 days, (c): 7 days). [Figure 7]FIG. 7 shows the relative cell viability, expressed as a percentage, of cultures of Staphylococcus aureus CECT 86 that were brought into contact with titanium discs coated with materials M1 to M5 according to the procedure of Example 1 to measure the bactericidal effect. [Figure 8] FIG. 8 shows the release profiles of octenidine (expressed as the ratio of the cumulative amount of octenidine released at a given time to the amount of octenidine present in the coating composition) as a function of time (expressed in days) for Comparative Samples C1-C4 and Sample M3 prepared in Example 1. [Figure 9] Figure 9 shows the bone marrow response to implantation of (left) control titanium implants and (right) M3-coated titanium implants over a period of 1, 2, or 4 weeks, assessed semiquantitatively in terms of (1) aplasia, (2) structural loss, (3) aspect of the bone marrow area not in contact with the implant, and (4) fat percentage. [Figure 10] Figure 10 shows the response of the peri-implant fibrous capsule after implantation of (left) control titanium implants and (right) M3-coated titanium implants over a period of 1, 2, or 4 weeks, assessed semiquantitatively at the following locations: (1) bone marrow, (2) between the implant and cortical bone, (3) between the implant and cancellous bone, and (4) the degree of densification. [Figure 11] FIG. 11 shows photographs of metal substrates coated with materials M1, M2 or M5 of Example 1 (left column) and after carrying out the ISO 2409 adhesion test (cross-cut assay, right column). [Figure 12] FIG. 12 is a photograph of a steel substrate coated with materials C1, C2, or M6 from Example 1 after treatment at a temperature of 37° C. and 100% humidity for 10 minutes, and then wiping the top side of the metal coupon with tissue paper. [Figure 13]Figure 13 shows histological images of the cortical and cancellous bone regions in contact with coated titanium implants: (top left) implant coated with material M6, 2 weeks after implantation; (top right) implant coated with material M6, 8 weeks after implantation in cancellous bone; (bottom left) implant coated with a sol-gel material made from a mixture of 90% MTMOS and 10% TEOS (mol) after implantation in cancellous bone; (bottom right) implant coated with a sol-gel material made from a mixture of 90% MTMOS and 10% TEOS (mol) after implantation near the marrow cavity, 8 weeks after implantation. [Figure 14] Figure 14 is a photomicrograph of the mucosal area around the implant showing the areas of interest in a clinical study performed in beagle dogs: E: epithelium, TCI1: connective tissue infiltrating the connective papilla, TCI2: connective tissue infiltrating areas distant from the epithelium. [Figure 15] FIG. 15 shows photomicrographs of peri-implant mucosal samples taken at TO in clinical trials performed in beagle dogs. [Figure 16] FIG. 16 shows photomicrographs of peri-implant mucosal samples taken at T3 in a clinical trial conducted in beagle dogs. [Figure 17] FIG. 17 shows photomicrographs of peri-implant mucosal samples taken at T6 in a clinical trial conducted in beagle dogs. [Figure 18] FIG. 18 shows photomicrographs of peri-implant mucosal samples taken at T7 in a clinical trial conducted in beagle dogs. [Figure 19] FIG. 19 shows photomicrographs of peri-implant mucosal samples taken at T10 in a clinical trial (treated and control groups) conducted in beagle dogs. [Figure 20] FIG. 20 shows photomicrographs of peri-implant mucosal samples processed to detect substance P in immunohistochemical assays performed on samples from control (top) and treated (bottom) dogs. [Figure 21]FIG. 21 shows photomicrographs of stained bone samples obtained from histological examination of bones from beagle dogs receiving implants treated with compound M3 (top) and beagle dogs receiving untreated implants (bottom). [Figure 22] FIG. 22 shows photographs of Streptococcus Gordonii bacterial growth on the surface of grade IV titanium discs a) uncoated, b) coated with mixture M1 from Example 1, c) coated with mixture M3 from Example 1, and d) coated with octenidine solution after 1 day of incubation at 37° C. DETAILED DESCRIPTION OF THE INVENTION

[0024] All terms used herein in this application are to be understood in their ordinary meaning as known in the art unless otherwise specified. Other, more specific definitions for certain terms used in this application are set forth below and are intended to be applied uniformly throughout the specification and claims, unless another explicitly stated definition provides a broader definition.

[0025] For purposes of this invention, a given range includes both the lower and upper limits of the range. A given range or value, such as temperature, time, molar ratio, volume ratio, etc., should be considered approximate when defined by the term "about" (i.e., with a margin of variation of 5% around the stated point).

[0026] In the context of this invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon chain, straight or branched, having the number of carbon atoms as defined in the claims and the specification. Non-limiting examples of alkyl include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, neopentyl, and hexyl.

[0027] In the context of the present invention, the term "octenidine" refers to both octenidine and one of its known salts, such as the dihydrochloride salt of octenidine. Octenidine has the formula [ka] In the case of the dihydrochloride salt of octenidine, both imine groups are protonated. In a preferred embodiment, the octenidine is the dihydrochloride salt of octenidine.

[0028] In the context of the present invention, the term "silicon-based sol-gel precursor" refers to organosilicon compounds known in the art and suitable for forming sol-gel materials of the polysiloxane type. In certain embodiments of the present invention, the term "silicon-based sol-gel precursor" refers to a compound of the formula Si((O) n R a )(OR b )(OR c )(OR d ) wherein n is 0 or 1 and R a , R b , R c and R d are each independently, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl and (C6-C 20 ) aryl, wherein the alkyl and alkenyl chains are optionally substituted with one or more groups selected from halogen amino and groups suitable for crosslinking, such as glycidyl, (meth)acrylate, or thiol groups. Known examples of silicon-based sol-gel precursors include tetramethoxysilane, tetraethoxysilane (TEOS), methyltrimethoxysilane (MTMOS), vinyltrimethoxysilane, vinyltriethoxysilane, phenyltriethoxysilane, 3-aminopropyltriethoxysilane, (3-glycidyloxy)propyltrimethoxysilane (GPTMS), and 3-(trimethoxysilyl)propyl methacrylate. TEOS, MTMOS, and GMTPS are particularly useful. [ka]

[0029] In the context of the present invention, the term "effective amount," when used in the context of forming a sol material, refers to both the condensation of the silicon-based sol-gel precursor and the acid that induces the formation of the sol material. In certain embodiments, such an effective amount is given when the acidic aqueous solution has a pH of 1 to 2.

[0030] In the context of the present invention, the term "prophylaxis or treatment," as used herein, includes any type of therapy aimed at terminating, preventing, ameliorating, and / or reducing susceptibility to a clinical condition described herein, e.g., a bacterial infection. Thus, "prophylaxis or treatment," "preventing or treating," and the like, as used herein, refer to obtaining a desired pharmacological and / or physiological effect and include any treatment of a pathological condition or disorder in a mammal, including a human. The effect may be prophylactic, in that the disorder or its symptoms are completely or partially prevented, and / or may be therapeutic, in that the disorder and / or adverse effects resulting from the disorder are partially or completely cured. That is, "prevention or treatment" includes (1) preventing the occurrence or recurrence of a disorder in a subject, (2) inhibiting the disorder, such as by preventing its onset, (3) halting or terminating the disorder or at least its associated symptoms so that the host is no longer afflicted with the disorder or its symptoms, e.g., causing regression of the disorder or its associated symptoms by restoring or repairing lost, deficient, or defective function or stimulating an inefficient process, or (4) alleviating, alleviating, or ameliorating the disorder or its associated symptoms, where amelioration is used broadly to refer to at least a lessening in magnitude of a parameter. Those in need of treatment include those already with the condition or disorder as well as those prone to having the condition or disorder, or those in whom the condition or disorder is to be prevented.

[0031] In the context of the present invention, the term "sol material" refers to a colloidal solution or suspension of polysiloxane. In contrast, a "gel material" refers to an integrated network comprising reticulated or crosslinked polysiloxane and / or discrete particles of polysiloxane. Typically, during the sol-gel process, a silicon-based sol-gel precursor is converted into a sol material, which serves as the precursor to the gel material.

[0032] In the context of the present invention, the term "oral temperature" refers to the average temperature of the oral cavity of the human body, ie a temperature between 30°C and 40°C, preferably a temperature of about 37°C.

[0033] As mentioned above, the first aspect of the present invention is (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C1-C4) alkyl chain) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain) in a molar ratio of 80:20 to 50:50, wherein said mixture further comprises octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon based sol-gel precursor; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating said material to a temperature of about mouth temperature. The present invention relates to a method for preparing a coating composition comprising:

[0034] In certain embodiments of the first aspect of the present invention, the silicon-based sol-gel precursor comprises a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) is tetraethyl orthosilicate (TEOS). The terms "tetraethyl orthosilicate," "tetraethoxysilane," and "TEOS" are all used interchangeably herein to refer to the same compound of formula Si(OEt)4.

[0035] In certain embodiments of the first aspect of the present invention, the silicon-based sol-gel precursor comprises a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is methyltrimethoxysilane (MTMOS). The terms "methyltrimethoxysilane" and "MTMOS" are all used interchangeably herein to refer to the same compound of formula MeSi(OMe)3.

[0036] In certain embodiments of the first aspect of the present invention, the silicon-based sol-gel precursor comprises a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 The molar ratio of the compounds is 70:30 to 50:50. Preferably, the molar ratio is 65:35 to 55:45. More preferably, the molar ratio is 60:40.

[0037] In certain embodiments of the first aspect of the present invention, the silicon-based sol-gel precursor of the mixture in step (i) comprises tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 65:35 to 55:45. Preferably, the silicon-based sol-gel precursor of the mixture in step (i) comprises tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40.

[0038] In certain embodiments, the silicon-based sol-gel precursor of the mixture of step (i) is of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) in an amount of at least 50% by weight, preferably at least 80% by weight, more preferably at least 95% by weight, and even more preferably at least 99% by weight, based on the total weight of the silicon-based sol-gel precursor.

[0039] In certain embodiments, the silicon-based sol-gel precursor of the mixture of step (i) comprises tetraethoxysilane and methyltrimethoxysilane in an amount of at least 50 wt %, preferably at least 80 wt %, more preferably at least 95 wt %, and even more preferably at least 99 wt %, based on the total weight of the silicon-based sol-gel precursor.

[0040] In certain embodiments, the silicon-based sol-gel precursor of the mixture of step (i) is of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ), preferably consisting of tetraethoxysilane and methyltrimethoxysilane. The molar ratio of tetraethoxysilane to methyltrimethoxysilane may be any of those described above.

[0041] In one embodiment, in any embodiment described herein, the silicon-based sol-gel precursor of the mixture in step (i) does not include glycidoxypropyltrimethoxysilane.

[0042] In a more particular embodiment of the first aspect of the present invention, the silicon-based sol-gel precursor consists of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2.

[0043] In certain embodiments of the first aspect of the present invention, the mixture of step (i) consists essentially of a silicon-based sol-gel precursor as defined above in any particular or preferred embodiment and octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon-based sol-gel precursor.

[0044] In the context of the present invention, the term "consisting essentially of" means that certain further components may be present in the mixture of step (i), i.e. components that do not substantially affect the essential properties of the mixture, in particular its ability to form a polysiloxane-type sol-gel material with preservative activity.

[0045] As defined in the first aspect of the present invention, the mixture of step (i) comprises octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon-based sol-gel precursor. Preferably, the mixture of step (i) comprises octenidine in an amount of 1 to 6 grams per 100 grams of silicon-based sol-gel precursor; more preferably, 1.5 to 5 grams; even more preferably, 2 to 4 grams. Even more preferably, the mixture of step (i) comprises octenidine in an amount of 2 to 3.5 grams per 100 grams of silicon-based sol-gel precursor; more particularly, 2 to 3 grams; and even more particularly, about 2 grams.

[0046] In certain embodiments of the first aspect of the present invention, the mixture of step (i) comprises octenidine in an amount of 1, 2, 5 or 7.5 grams per 100 grams of silicon based sol-gel precursor.

[0047] In another particular embodiment of the first aspect of the present invention, the mixture of step (i) comprises octenidine in an amount of 2 grams per 100 grams of silicon based sol-gel precursor.

[0048] In a preferred embodiment, the mixture of step (i) comprises a molar ratio of 65:35 to 55:45 of compounds of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ), preferably a mixture of tetraethoxysilane and methyltrimethoxysilane, and octenidine in an amount of 2 to 4 grams per 100 grams of silicon-based sol-gel precursor.

[0049] In a very particular preferred embodiment, the mixture of step (i) comprises a silicon-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40, and octenidine in an amount of 2 grams per 100 grams of silicon-based sol-gel precursor.

[0050] In a preferred embodiment of the first aspect of the present invention, the mixture of step (i) further comprises a solvent. Suitable solvents are those known in the art for forming polysiloxanes by sol-gel processes. Typically, suitable solvents are polar protic organic solvents such as alcohols. Such alcohols include, inter alia, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol. A preferred solvent is isopropanol.

[0051] When the mixture of step (i) comprises a solvent, the solvent is preferably present in an amount such that the ratio of the volume of the solvent to the volume of the silicon-based sol-gel precursor is 1:2 to 2:1. More preferably, the solvent is present in an amount such that the ratio of the volume of the solvent to the volume of the silicon-based sol-gel precursor is about 1:1.

[0052] Thus, in a more preferred embodiment of the first aspect of the present invention, the mixture of step (i) comprises a silicon based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2, and octenidine in an amount of 1, 2, 5 or 7.5 grams per 100 grams of silicon based sol-gel precursor, and further comprises isopropanol, preferably in an amount such that the ratio between the volume of solvent and the volume of silicon based sol-gel precursor is about 1:1.

[0053] The method of the first aspect of the present invention involves the formation of a crosslinked polysiloxane network in which octenidine is embedded. The second step of the method of the first aspect of the present invention involves the formation of said network under acidic aqueous conditions. The use of such conditions allows the polycondensation of silicon-based sol-gel precursors to be favored over their hydrolysis, thus favoring the formation of crosslinked polysiloxane compounds with linear moieties.

[0054] Thus, step (ii) of the first aspect of the present invention involves treating the mixture of step (i) with at least an effective amount of an aqueous acidic solution to form a sol material. The aqueous acidic solution may be any of hydrochloric acid, acetic acid, citric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid, and mixtures thereof. Preferably, step (ii) of the first aspect of the present invention involves treating the mixture of step (i) with at least an effective amount of an aqueous nitric acid solution.

[0055] The effective amount of the aqueous acid solution is preferably a sub-stoichiometric or stoichiometric amount of acid, which is useful for accelerating the hydrolysis of alkoxy groups contained in the silicon-based gel precursor.

[0056] In certain embodiments of the first aspect of the present invention, the acidic aqueous solution of step (ii) has a pH of 1 to 2. One skilled in the art would determine the amount of acidic solution to add to the mixture of step (i) based on the pH of the solution and the effective amount of acid to add to the mixture of step (i).

[0057] In another particular embodiment of the first aspect of the present invention, the acidic aqueous solution, preferably the nitric acid solution, of step (ii) has an acid concentration of 0.01 N to 0.5 N; preferably 0.01 N to 0.1 N. More preferably, it is a nitric acid solution with a concentration of 0.1 N.

[0058] In other particular embodiments of the first aspect of the present invention, step (ii) is carried out at a temperature of 25° C. to 100° C. Preferably, step (ii) is carried out at a temperature of 50° C. to 100° C., more preferably at a temperature of about 70° C. Step (ii) is carried out at a temperature of 70° C., which advantageously allows for the formation of the sol material in a short time, i.e., about 30 minutes. This advantageously allows for the coating composition to be prepared during a patient's visit for surgery or medical examination.

[0059] In a more specific embodiment of the first aspect of the present invention, the mixture of step (i) comprises a silicon-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2, and octenidine in an amount of 1, 2, 5, or 7.5 grams per 100 grams of silicon-based sol-gel precursor, and step (ii) comprises treating the mixture of step (i) with a nitric acid solution having a concentration of 0.01N to 0.5N at a temperature of 50°C to 100°C; preferably, the nitric acid solution has a concentration of 0.01N to 0.1N, and step (ii) is performed at 70°C. In said embodiment, it is further preferred that step (ii) is performed for about 30 minutes.

[0060] The combination of steps (i) and (ii) produces a sol material that, after hardening, forms a physical barrier between the implant surface and a physiological medium suitable for embedding bacteria, preventing bacterial adhesion to the implant surface during soft tissue regeneration. Furthermore, the sol material can continuously release octenidine over an extended period of time. Therefore, this composition is useful as an anti-infective coating for implants, such as dental or bone implants. Therefore, it is further contemplated that the method of the first aspect of the present invention comprises partially or completely coating a substrate for implantation or an implanted substrate with the sol material. In certain embodiments, the substrate is a substrate for implantation. In another specific embodiment, the substrate is an implanted substrate. In another specific embodiment, the substrate is a material for use as a dental closure cap. Materials suitable for use as a dental closure cap are well known in the art and will become apparent to those skilled in the art upon practicing the present invention. Materials suitable for use as a dental closure cap include, for example, collagen, titanium, stainless steel, polyethylene, polypropylene, medical-grade silicone, polyglycolic acid, polylactic acid, polydioxanone, and caprolactone. These materials, especially collagen, can be used to form sponges, membranes, plugs, and matrices useful in dentistry. In the coating process, the transfer of the sol product to a substrate can be performed after step (ii) in a first specific option. Since the product of step (ii) is a sol material, it has sufficient viscosity to allow coating of the substrate. Before transferring to the substrate, the sol material prepared in step (ii) can be further aged, preferably under ambient conditions of temperature and humidity, which can increase the viscosity of the sol material and allow for more precise application of the coating composition to the surface of the substrate or implant. While specific additives for improving the adhesion of the coating composition to the substrate are not required to perform the transfer, they may be added to the sol material to improve its adhesion to the substrate surface. However, it is preferable not to use such additives.

[0061] If step (iii) is carried out, the transfer of the sol product to the substrate can, in a second particular alternative, be carried out after step (iii).

[0062] In a preferred embodiment, the substrate comprises a metal or polymer surface, preferably comprising a metal selected from magnesium and magnesium alloys, titanium and titanium alloys, or a polymer such as PEEK. Preferably, the metal is of surgical grade. More preferably, the metal is titanium or an alloy thereof.

[0063] In a more specific embodiment, the substrate is a material for use as a dental closure cap. Materials suitable for use as a dental closure cap are well known in the art and will become apparent to those skilled in the art through the practice of the present invention. Materials suitable for use as a dental closure cap include, for example, collagen, titanium, stainless steel, polyethylene, polypropylene, medical-grade silicone, polyglycolic acid, polylactic acid, polydioxanone, and caprolactone. These materials, particularly collagen, can be used to form sponges, membranes, plugs, and matrices useful in dentistry.

[0064] The step of transferring the sol product of step (ii) or the gel product of step (iii) to a substrate is in one embodiment a non-therapeutic and / or non-surgical step in the sense that it is not performed on the human or animal body.

[0065] Alternatively, the step of transferring said product of step (ii) or step (iii) to a substrate is carried out to achieve a coating of an implant present in the oral cavity of a human or animal, in which case the present invention relates to said product for medical use as described herein below.

[0066] In a more particular embodiment, the method of the first aspect of the invention further comprises step (iii) of curing the sol material of step (ii) by heating it at a temperature of about oral cavity temperature. The inventors have found that the sol material formed in step (ii) can form a gel in a minimum time of about 10 minutes when heated at 37°C. This is advantageous as it minimizes discomfort to the patient. Step (iii) of the first aspect of the invention can also be advantageously carried out in the presence of moisture, which advantageously allows step (iii) to be carried out under oral conditions.

[0067] A further aspect of the present invention is (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The product obtained according to said method also forms part of the present invention.

[0068] The process may further comprise the step of adding to the product of step (ii) or (iii) a solution comprising an antibacterial agent such as octenidine. The products obtained according to the process also form part of the present invention.

[0069] A further aspect of the present invention is (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, wherein said mixture further comprises an effective amount of an antimicrobial agent; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The product obtained according to said method also forms part of the present invention.

[0070] Suitable antimicrobial agents are known in the art and will become apparent to those skilled in the art upon learning the present invention, and include, among others, octenidine, chlorhexidine, triclosan, hydrogen peroxide, and quaternary ammonium compounds such as cationic surfactants, benzalkonium salts, cetylpyridinium salts, cetrimide, and domiphen salts.

[0071] As defined above, a second aspect of the present invention relates to a composition obtainable by the method defined in the first aspect of the present invention.

[0072] Thus, a second aspect of the present invention relates to a composition obtainable by a method as defined in any of the particular and preferred embodiments of the first aspect of the present invention as defined above.

[0073] Thus, in a first alternative, the second aspect of the invention may relate to a sol material, in particular when step (iii) of certain and preferred embodiments of the method of the first aspect of the invention as defined above is not carried out.

[0074] Thus, the first option of the second aspect of the present invention is, in a preferred embodiment, (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 providing a silicon-based sol-gel precursor comprising at least 80% by weight of a mixture of compounds of the formula (I), preferably a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 65:35 to 55:45, and octenidine in an amount of 2 to 4 grams per 100 grams of silicon-based sol-gel precursor; and (ii) treating the mixture of step (i) with an acid solution having a concentration of 0.01N to 0.1N at a temperature of 50°C to 100°C; The present invention relates to a sol material obtainable by a method comprising the steps of:

[0075] The first option of the second aspect of the invention is, in a preferred more specific embodiment, (i) providing a mixture comprising a silicon-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a 3:2 molar ratio, and further comprising octenidine in an amount of 1, 2, 5, or 7.5 grams per 100 grams of silicon-based sol-gel precursor; (ii) treating the mixture of step (i) with a nitric acid solution having a concentration of 0.01N to 0.1N at a temperature of 70°C; The present invention relates to a sol material obtainable by a method comprising the steps of:

[0076] Thus, in a second alternative, the second aspect of the invention may relate to a gel material, in particular when step (iii) of certain and preferred embodiments of the method of the first aspect of the invention as defined above is carried out.

[0077] Thus, the second option of the second aspect of the present invention, in particular in a preferred embodiment, (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 providing a silicon-based sol-gel precursor comprising at least 80% by weight of a mixture of compounds of the formula (I), preferably a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 65:35 to 55:45, and octenidine in an amount of 2 to 4 grams per 100 grams of silicon-based sol-gel precursor; (ii) treating the mixture of step (i) with a solution of an acid having a concentration of 0.01N to 0.1N at a temperature of 50°C to 100°C; and (iii) A step of curing the sol material obtained in step (ii) by heating at a temperature of 30°C to 40°C. The present invention relates to a gel material obtainable by a method comprising the steps of:

[0078] Thus, the second option of the second aspect of the present invention, in particular, in a preferred embodiment, (i) providing a mixture comprising a silicon-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2, and further comprising octenidine in an amount of 1, 2, 5, or 7.5 grams per 100 grams of silicon-based sol-gel precursor; (ii) treating the mixture of step (i) with a nitric acid solution having a concentration of 0.01N to 0.1N at a temperature of 70°C; and (iii) curing the sol material of step (ii) by heating at a temperature of about 37°C The present invention relates to a sol material obtainable by a method comprising the steps of:

[0079] In a third alternative, if the method of the first aspect of the invention comprises the transfer of a sol or gel material to a substrate, such as a dental, bone implant or closure cap material, the product of the second aspect of the invention relates to a substrate, such as a dental, bone implant or closure cap material, coated with a sol or gel as defined in the first and second alternatives of the second aspect of the invention as detailed above.

[0080] In certain embodiments, the substrate is suitable for receiving an anti-infective coating.

[0081] As mentioned above, the substrate preferably comprises a surface comprising a metal such as magnesium and magnesium alloys, titanium or titanium alloys, or a polymer such as PEEK, the metal preferably being of surgical grade. More preferably, the metal is titanium or an alloy thereof.

[0082] In a more specific embodiment, the substrate is a material for use as a dental closure cap. Materials suitable for use as a dental closure cap are well known in the art and will become apparent to those skilled in the art through the practice of the present invention. Materials suitable for use as a dental closure cap include, for example, collagen, titanium, stainless steel, polyethylene, polypropylene, medical-grade silicone, polyglycolic acid, polylactic acid, polydioxanone, and caprolactone. These materials, particularly collagen, can be used to form sponges, membranes, plugs, and matrices useful in dentistry.

[0083] A particular embodiment of the third option of the second aspect of the present invention therefore relates to a dental or bone implant cap comprising a surface comprising titanium, said surface being coated with a sol or gel as defined in the first and second options of the second aspect of the present invention as detailed above.

[0084] Another particular embodiment of the third option of the second aspect of the invention relates to a closure cap comprising a surface of a material suitable for a closure cap as defined above, said surface being coated with a sol or gel as defined in the first and second options of the second aspect of the invention as detailed above.

[0085] As defined above, a third aspect of the present invention relates to a product as defined in the second aspect of the invention for use in medicine.

[0086] Particular embodiments of the third aspect of the invention relate to products as defined in any of the particular or preferred embodiments of the first option (sol), the second option (gel) and the third option (substrate to be coated) of the second aspect of the invention for use in medicine.

[0087] As shown by the examples below, products of the second aspect of the invention are particularly useful in the prevention or treatment of inflammatory processes such as mucositis or peri-implantitis, preferably peri-implantitis.

[0088] A fourth aspect of the invention relates to a product as defined in the second aspect of the invention for use in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis. Particular embodiments of the fourth aspect of the invention relate to a product as defined in any of the particular or preferred embodiments of the first option (sol), the second option (gel) and the third option (substrate to be coated) of the second aspect of the invention for use in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis.

[0089] In a preferred embodiment of the present invention, the inflammatory process susceptible to treatment or prevention by the composition of the present invention is caused by one or more bacteria. Preferably, said one or more bacteria are from the genus Staphylococcus ( Staphylococcus Genus ) ; in particular, Staphylococcus aureus ( Staphylococcus aureus ) or Streptococcus spp. ( Streptococcus Genus ) one of the Streptococcus gordonii ( Streptococcus Gordonii ) or Bacteroides ( Bacteroides ), Campylobacter ( Campylobacter ), Eubacterium ( Eubacterium ), Fusobacterium ( Fusobacterium ), Treponema species ( Treponema species ), Actinobacillus actinomycetemcomitans ( Aggregatibacter actinomycetemcomitans ), Prevotella ( Prevotella ), Intermedia ( intermediate ), Porphyromonas gingivalis ( Porphyromonas gingivalis ), Treponema denticola ( Treponema denticola ), and Tannerella forsythia ( Tannerella forsythia In a more particular embodiment, said one or more bacteria is Staphylococcus aureus. In another more particular embodiment, said one or more bacteria is Streptococcus gordonii.

[0090] In a further embodiment, the invention relates to the use of a composition according to the second or sixth aspect of the invention as defined in any of the embodiments provided herein in the manufacture of a coating or coated substrate for the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis.

[0091] In a further embodiment, the present invention relates to a method for the treatment or prevention of an inflammatory process such as meningitis or peri-implantitis, preferably peri-implantitis, which method comprises the step of coating an implant or a prosthesis or a closure cap material with a therapeutically or prophylactically effective amount of a composition according to the second aspect of the invention as defined in any of the embodiments provided herein.

[0092] Kits for preparing the products of the second aspect of the invention are also part of the invention and constitute a fifth aspect of the invention.

[0093] Thus, a fifth aspect of the present invention provides a kit of parts for making a substrate coated with an anti-infective coating, comprising: in a first component the mixture provided in step (i) of the method defined in the first aspect of the present invention, in a second component, the aqueous acidic solution used in step (ii) of the method defined in the first aspect of the present invention, in an optional third component, means for mixing the contents of the first and second components, and optionally means for heating the resulting mixture; and an optional fourth member, a substrate for receiving an optionally heated mixture of the contents of said first member and second member, and optionally means for transferring said optionally heated mixture to said substrate; or - on a first component, a sol material obtained by a method comprising steps (i) and (ii) as defined in the first aspect of the present invention, and a second member, a substrate for receiving said sol material, and optionally means for transferring said sol material to said substrate; In certain embodiments, the first component of the first option of the kit of the fifth aspect of the invention relates to a mixture provided in step (i) of the method defined in any of the certain and preferred embodiments of the first aspect of the invention.

[0094] Thus, in a more particular embodiment, the first component of the first alternative of the kit of the fifth aspect of the present invention relates to a mixture comprising a silicon based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40, and further comprising octenidine in an amount of 1, 2, 5 or 7.5 grams per 100 grams of silicon based sol-gel precursor, said mixture preferably further comprising a solvent as defined above in relation to the first aspect of the present invention, said solvent preferably being isopropanol.

[0095] In certain embodiments, the second component of the first option of the kit of the fifth aspect of the invention relates to the acidic aqueous solution as defined in step (ii) of the method as defined in any of the certain and preferred embodiments of the first aspect of the invention.

[0096] Thus, in a more particular embodiment, the second component of the first option of the kit of the fifth aspect of the present invention relates to an aqueous solution of nitric acid at a concentration of 0.01 N to 0.1 N. Preferably, it relates to an aqueous solution of nitric acid at a concentration of 0.1 N.

[0097] In certain embodiments, the optional third component of the first option of the kit of the fifth aspect of the present invention relates to a means known in the art suitable for mixing the contents of two separate components comprising the composition to be mixed. The third component may further comprise a heating means suitable for heating the resulting mixture at a temperature of 50°C to 100°C. As will be apparent to those skilled in the art, the same heating means may also be used to harden the sol material to form a gel. As defined above, the hardening may preferably be carried out after transferring the sol material to the surface of a substrate such as a dental or bone implant or a closure cap material.

[0098] In certain embodiments, the optional fourth component of the first option of the kit of the fifth aspect of the invention relates to a substrate as defined in any of the particular and preferred embodiments of the first aspect of the invention.

[0099] In a specific embodiment, the optional fourth component of the first option of the kit of the fifth aspect of the present invention relates to a substrate comprising a surface, preferably a metal or polymer surface, such as magnesium and magnesium alloys, titanium or titanium alloys, preferably surgical-grade metals, or a polymer such as PEEK. In a more specific embodiment, the optional fourth component of the first option of the kit of the fifth aspect of the present invention relates to a dental or bone implant, preferably comprising a surface comprising titanium or its alloys. In an even more specific embodiment, the optional fourth component of the first option of the kit of the fifth aspect of the present invention relates to a dental closure cap. Materials suitable for use as closure caps in dentistry are well known in the art and will become apparent to those skilled in the art through the practice of the present invention. Materials suitable for use as closure caps in dentistry include, for example, collagen, titanium, stainless steel, polyethylene, polypropylene, medical-grade silicone, polyglycolic acid, polylactic acid, polydioxanone, and caprolactone. These materials, particularly collagen, can be used to form sponges, membranes, plugs, and matrices useful in dentistry.

[0100] In another particular embodiment, the first component of the second alternative of the kit of the fifth aspect of the invention relates to a sol material obtainable by a method comprising steps (i) and (ii) as defined in any of the particular and preferred embodiments of the first alternative of the second aspect of the invention, or as defined in any of the particular and preferred embodiments of the first alternative of the second aspect of the invention.

[0101] In a particular embodiment, the second member of the second option of the kit of the fifth aspect of the invention relates to a substrate comprising a surface comprising a metal such as magnesium and magnesium alloys, titanium or titanium alloys, or a polymer such as PEEK, said metal preferably being of surgical grade, more preferably titanium or an alloy thereof. In a more particular embodiment, said optional fourth member of the first option of the kit of the fifth aspect of the invention relates to a dental or bone implant preferably comprising a surface comprising titanium, preferably surgical grade titanium.

[0102] In an even more particular embodiment, the second component of the second option of the kit of the fifth aspect of the invention relates to a substrate comprising a surface of a material suitable for use as a closure cap in dentistry, such as collagen, titanium, stainless steel, polyethylene, polypropylene, medical grade silicone, polyglycolic acid, polylactic acid, polydioxanone, and caprolactone. These materials, particularly collagen, can be used to form sponges, membranes, plugs, and matrices useful in dentistry.

[0103] The essential components of the kit that allows for the preparation of a sol or gel material are the first and second items of the first option of the kit of the fifth aspect of the invention.

[0104] The essential components of the kit that allow for the production of a substrate coated with the anti-infective coating composition are the first, second and fourth elements of the first option or the first and second elements of the second option of the kit of the fifth aspect of the invention.

[0105] The mixture of precursor reagents used in step (i) of the method of the first aspect of the invention is also part of the invention. Thus, a sixth aspect of the invention relates to a mixture as provided in step (i) of the method defined in any of the particular and preferred embodiments of the first aspect of the invention defined above.

[0106] In certain embodiments of the sixth aspect of the present invention, the silicon-based sol-gel precursor comprises a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) is tetraethyl orthosilicate (TEOS).

[0107] In certain embodiments of the sixth aspect of the present invention, the silicon-based sol-gel precursor comprises a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is methyltrimethoxysilane (MTMOS).

[0108] In certain embodiments of the sixth aspect of the present invention, the silicon-based sol-gel precursor comprises a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 The molar ratio of the compounds is 70:30 to 50:50. Preferably, the molar ratio is 65:35 to 55:45. More preferably, the molar ratio is 60:40.

[0109] In certain embodiments of the sixth aspect of the present invention, the silicon-based sol-gel precursor of the composition of the sixth aspect of the present invention comprises tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 65:35 to 55:45. Preferably, the silicon-based sol-gel precursor of the composition of the sixth aspect of the present invention comprises tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40.

[0110] In certain embodiments, the silicon-based sol-gel precursor of the composition of the sixth aspect of the present invention has the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds of formula Si(R 5 )(OR6 )(OR 7 )(OR 8 ) in an amount of at least 50% by weight, preferably at least 80% by weight, more preferably at least 95% by weight, and even more preferably at least 99% by weight, based on the total weight of the silicon-based sol-gel precursor.

[0111] In certain embodiments of the sixth aspect of the present invention, the silicon based sol-gel precursor of the composition of the sixth aspect of the present invention comprises tetraethoxysilane and methyltrimethoxysilane in an amount of at least 50 wt. %, preferably at least 80 wt. %, more preferably at least 95 wt. %, and even more preferably at least 99 wt. %, based on the total weight of the silicon based sol-gel precursor.

[0112] In certain embodiments of the sixth aspect of the present invention, the silicon-based sol-gel precursor of the composition of the sixth aspect of the present invention is of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ), preferably consisting of tetraethoxysilane and methyltrimethoxysilane. The molar ratio of tetraethoxysilane to methyltrimethoxysilane may be any of those described above.

[0113] In certain embodiments of the sixth aspect of the present invention, the silicon-based sol-gel precursor of the composition of the sixth aspect of the present invention does not comprise glycidoxypropyltrimethoxysilane.

[0114] In a more particular embodiment of the sixth aspect of the present invention, the silicon-based sol-gel precursor consists of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2.

[0115] In particular embodiments of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention consists essentially of a silicon based sol-gel precursor as defined above in any of the particular or preferred embodiments and octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon based sol-gel precursor.

[0116] As defined in the sixth aspect of the present invention, the composition of the sixth aspect of the present invention comprises octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon based sol-gel precursor. Preferably, the composition of the sixth aspect of the present invention comprises 1 to 6 grams of octenidine per 100 grams of silicon based sol-gel precursor; more preferably, 1.5 to 5 grams; and even more preferably, 2 to 4 grams of octenidine.

[0117] In particular embodiments of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention comprises octenidine in an amount of 1, 2, 5 or 7.5 grams per 100 grams of silicon based sol-gel precursor.

[0118] In another particular embodiment of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention comprises octenidine in an amount of 2 grams per 100 grams of silicon based sol-gel precursor.

[0119] In a preferred embodiment of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention has the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )) and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ), preferably a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 65:35 to 55:45, at least 80% by weight, and octenidine in an amount of 2 to 4 grams per 100 grams of silicon-based sol-gel precursor.

[0120] In a preferred very specific embodiment, the composition of the sixth aspect of the present invention comprises a silicon-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40, and octenidine in an amount of 2 grams per 100 grams of silicon-based sol-gel precursor.

[0121] In a preferred embodiment of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention further comprises a solvent. Suitable solvents are those known in the art for forming polysiloxanes by sol-gel processes. Typically, suitable solvents are polar protic organic solvents such as alcohols. Such alcohols include, inter alia, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol. A preferred solvent is isopropanol.

[0122] When the composition of the sixth aspect of the present invention comprises a solvent, the solvent is preferably present in an amount such that the ratio of the volume of the solvent to the volume of the silicon-based sol-gel precursor is 1:2 to 2:1. More preferably, the solvent is present in an amount such that the ratio of the volume of the solvent to the volume of the silicon-based sol-gel precursor is about 1:1.

[0123] A seventh aspect of the present invention relates to a composition for use in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, said composition comprising: (iii) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (iv) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The products obtained according to said process also form part of the present invention.

[0124] In a preferred embodiment of the present invention, the inflammatory process susceptible to treatment or prevention with the compositions of the present invention is caused by one or more bacteria. Preferably, said one or more bacteria are one of the genus Staphylococcus, in particular Staphylococcus aureus, or one of the genus Streptococcus, in particular Streptococcus gordonii, or one of the genus Bacteroides, Campylobacter, Eubacterium, Fusobacterium, Treponema species, Actinobacillus actinomycetemcomitans, Prevotella, Intermedia ( intermediate ), Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. In more specific embodiments, the one or more bacteria is Staphylococcus aureus. In other more specific embodiments, the one or more bacteria is Streptococcus gordonii.

[0125] Thus, a seventh aspect of the invention also relates to the use of a composition in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, said composition comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The products obtained according to said process also form part of the present invention.

[0126] Thus, a seventh aspect of the invention also relates to the use of a composition for the preparation of a medicament for the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, said composition comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The products obtained according to said process also form part of the present invention.

[0127] Thus, a seventh aspect of the invention also relates to a method for the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The present invention also provides a method for treating a rheumatoid arthritis, comprising administering to a patient in need thereof an effective amount of a composition obtained by a method comprising the steps of: a.

[0128] In a preferred embodiment of the seventh aspect of the present invention, the composition does not contain an active pharmaceutical ingredient such as an antibacterial agent, particularly octenidine. In a preferred embodiment of the seventh aspect of the present invention, the composition does not contain any or all of bioactive particles, drugs, or peptides. In a preferred embodiment of the seventh aspect of the present invention, the composition does not contain any or all of the antibacterial agents: octenidine, bioactive particles, drugs, or peptides. In a specific embodiment of the seventh aspect of the present invention, the composition is obtained by the method as described above, comprising steps (i) to (iii).

[0129] In a further preferred embodiment of the seventh aspect of the present invention, the composition is as defined in any of the preferred embodiments of the first aspect of the present invention, wherein the silicon-based sol-gel precursors of the mixture of step (i) and their relative amounts are defined above.

[0130] In a further preferred embodiment of the seventh aspect of the present invention, the composition is such that the mixture of step (i) comprises a solvent as defined in any of the preferred embodiments of the first aspect of the present invention as defined above, preferably in an amount as defined in any of the preferred embodiments of the first aspect of the present invention as defined above.

[0131] In a further preferred embodiment of the seventh aspect of the invention, step (ii) is defined in any of the preferred embodiments of the first aspect of the invention defined above which defines step (ii).

[0132] In a further preferred embodiment of the seventh aspect of the invention, step (iii) is defined in any of the preferred embodiments of the first aspect of the invention defined above which defines step (iii).

[0133] In a further aspect, the present invention relates to a composition for use in the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, said composition comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, wherein said mixture further comprises an effective amount of an antimicrobial agent; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The product obtained according to said process also forms part of the present invention. The antimicrobial agent may be as described above.

[0134] Thus, in said further aspect, the present invention also provides a method for the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, comprising administering to a patient in need thereof an effective amount of: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5 , R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, wherein said mixture further comprises an effective amount of an antimicrobial agent; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The product obtained according to said method also forms part of the invention. The antibacterial agent may be as described above.

[0135] Thus, in said further aspect, the present invention also relates to the use of a composition for the preparation of a medicament for the prevention or treatment of an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, said composition comprising: (i) Formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 )(wherein, R 1 , R 2 , R 3 and R 4 are each independently a (C-C) alkyl chain), preferably tetraethoxysilane, and a compound of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 )(wherein, R 5, R 6 , R 7 and R 8 are each independently a (C1-C4) alkyl chain), preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, said mixture further comprising an effective amount of an antimicrobial agent; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature of about oral cavity temperature. The product obtained according to said process also forms part of the present invention. The antimicrobial agent may be as described above.

[0136] In a further preferred embodiment of said further aspect of the invention, the composition is as defined in any of the preferred embodiments of the first aspect of the invention, wherein the silicon-based sol-gel precursors of the mixture of step (i) and their relative amounts are defined above.

[0137] In a further preferred embodiment of said further aspect of the invention, the composition is such that the mixture of step (i) comprises a solvent as defined in any of the preferred embodiments of the first aspect of the invention defined above, preferably in an amount as defined in any of the preferred embodiments of the first aspect of the invention defined above.

[0138] In a further preferred embodiment of said further aspect of the invention, step (ii) is as defined in any of the preferred embodiments of the first aspect of the invention defined above which defines step (ii).

[0139] In a further preferred embodiment of said further aspect of the invention, step (iii) is as defined in any of the preferred embodiments of the first aspect of the invention defined above which defines step (iii).

[0140] Throughout the specification and claims, the word "comprises," and variations of that word, are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprises" encompasses the terms "consist of" and "consists essentially of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of the specification or may be learned by practice of the present invention. The following examples are offered by way of illustration and are not intended to limit the invention. [Example]

[0141] Example 1: Preparation and characterization of hybrid organic-inorganic materials as anti-infective coating compositions General Procedure for Preparation of Coating Compositions Methyltrimethoxysilane (MTMOS) and tetraethyl orthosilicate (TEOS) were mixed in various molar ratios shown in Table 1 and dissolved in 2-propanol at a 1:1 volume ratio. Octenidine was added to this solution at several different concentrations (1.0, 2.0, 5.0, and 7.5% by weight). A stoichiometric amount of aqueous nitric acid (0.1 N HNO3) was added dropwise to catalyze the sol-gel reaction. The solution was stirred at 70°C for 30 minutes to allow sol-gel polymerization via siloxane bonds. The resulting compound was then further cured at 37°C for 10 minutes.

[0142] Table 1 below summarizes the materials prepared.

[0143] [Table 1]

[0144] Those skilled in the art will appreciate that Samples C1-C4 contain molar ratios of TEOS:MTMOS outside the scope of the present invention, and therefore, these materials are provided as comparative examples.

[0145] Samples M1 to M5 were all characterized by FT-IR spectroscopy. All samples showed a vibrational mode of 1075 cm, which corresponds to the vibrational mode of polysiloxane compounds. -1 , 1105cm -1 and 760 cm -1 The gel material was successfully formed, showing an absorption peak at 1655 cm -1 and 2920 cm -1 The presence of these peaks indicates the presence of octenidine in the formed materials M2 to M5. The intensity of these peaks increases with the concentration of octenidine in the materials.

[0146] General procedure for coating surface preparation : A fixed volume of a mixture of methyltrimethoxysilane (MTMOS) and ethyltetraorthosilicate (TEOS) at various molar ratios, as shown in Table 1, was added to the same volume of an octenidine solution in 2-propanol. The amounts of octenidine were as shown in Table 1 (1.0, 2.0, 5.0, and 7.5 wt %, based on the weight of the siloxane precursor). A stoichiometric amount of aqueous nitric acid (0.1 N HNO3) was added dropwise to catalyze the sol-gel reaction. The solution was stirred at 70 °C for 30 min to allow hydrolysis and condensation of the precursor through siloxane bonds. The solution was transferred to an SAE-Ti disk by dip coating. The disk was immersed in the sol-gel solution at a speed of 60 cm / min, immersed for 1 min, and removed at a speed of 100 cm / min. Furthermore, the material was applied to a glass slide by casting to evaluate hydrolysis and antimicrobial release. The sample was then cured at 37 °C for 10 min.

[0147] As shown in Figure 11, which shows the results of cross-cut assays performed on metal surfaces coated with M1, M2, or M5, the coating compositions adhere well to the metal surfaces, as no material appears to peel off from the metal surface.

[0148] Compositions C1, C2, and M6 were coated onto square 316L steel coupons following a similar procedure. The coated coupons were placed in a 100% humidity, 37°C atmosphere for 10 minutes. After this, the top side of the coated surface of the coupons was wiped with tissue paper to qualitatively assess the degree of curing and adhesion of the material to the substrate surface. As shown in Figure 12, sample M6 is the only sample in which the coating cured and adhered to the surface, as no material appears to have been wiped off the metal surface.

[0149] General Procedure for Hydrolysis Testing To obtain samples for hydrolysis testing, the sol prepared according to the above procedure was coated onto microscope slides using the drop-casting method. The resulting coated slides were heated at 37 °C for 10 min to cure the coating. Prior to preparing the coated slides, the slides were ultrasonically cleaned (Sonoplus HD 3200) in a HNO3 (25%, w / w) solution for 15 min, and then washed three times with distilled water. Finally, the slides were dried in an oven at 100 °C and stored in a desiccator.

[0150] The polysiloxane network decomposes by hydrolysis in aqueous media as follows. SiO2(s)+2H2O→SiOH)4(aqueous solution) Hydrolysis was assessed gravimetrically by comparing the weight of the coating compositions before and after immersion for various periods of time in distilled water at 37° C. Approximately 25 mg samples of each coating composition were used.

[0151] The results of the assay are shown in Figure 1. These results show that the rate of hydrolysis of the material comprising octenidine is faster than the rate of decomposition of the material without octenidine (M1).

[0152] General procedure for determining the release rate of octenidine The amount of antimicrobial agent released during network degradation was assessed using UV-visible spectroscopy. 1 g of coated samples were immersed in 50 mL of distilled water and placed in an incubator at 37 °C for up to one month. 5 mL samples were removed at various time points to measure the biocide concentration. The absorbance of octenidine was measured at λ = 282 nm. A linear calibration curve for octenidine was obtained. Measurements were performed in triplicate.

[0153] Figure 2 shows the release rate of octenidine from materials M2 to M5, and Figure 8 shows the release rate of octenidine from comparative materials C1 to C4.

[0154] The results in Figure 2 show that materials M2 to M5 behave similarly in the release of octenidine. The release of octenidine is sustained for at least 14 days. This is advantageous because it allows: (i) Providing anti-infective agents during the first few days after surgery, if specifically needed to prevent or treat the development of infections ultimately caused by the surgical procedure; and (ii) Gradual release of anti-infective agents after several days to prevent or treat new infection outbreaks.

[0155] It can also be inferred from the data in Figure 2 that the higher the octenidine concentration in the gel material, the faster the amount of octenidine released.

[0156] Furthermore, when the material comprises at least 2% by weight of octenidine, the concentration of octenidine released into the medium is 2 mg / L or more after 2 hours under the conditions of this assay. Such a concentration is particularly advantageous because it is known in the art to exceed both the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) for Staphylococcus aureus and is therefore suitable for bacterial eradication.

[0157] Furthermore, the results in Figure 8 show that increasing the proportion of TEOS in the prior art sol-gel materials increases the hydrophilicity of the resulting materials, thereby promoting hydrolysis and increasing the immediate release of octenidine. For example, composition C2 (10% TEOS) shows that substantially all of the octenidine released on day 28 was released on day 14; composition C3 (20% TEOS) shows that substantially all of the octenidine released on day 28 was released on day 7; and composition C4 (30% TEOS) shows that substantially all of the octenidine released on day 28 was released on day 3.

[0158] However, composition M3 (60% TEOS) according to the present invention shows sustained release of octenidine up to day 14. This is completely unexpected in view of the results of comparative compositions C2 to C4 in Figure 8, where a shortening, rather than a prolongation, of the octenidine release period would be expected with further increases in the amount of TEOS. Thus, the composition according to the present invention is unexpectedly capable of releasing a large amount of octenidine without sacrificing release rate.

[0159] The sustained release of octenidine advantageously has a positive effect on the prevention or treatment of peri-implantitis by making it possible to provide an anti-infective agent for a longer period of time, allowing the antibacterial agent to be delivered for at least 14 days after surgery or application of the coating material to avoid the development of new infections and prevent recurrence of infection.

[0160] General procedure for cell viability assay Cell culture: Human fibroblasts (HFB) and human osteoblasts (MG-63) were used for in vitro material evaluation. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 1% penicillin / streptomycin and 10% FBS in a humidified (95%) CO2 incubator at 37°C. Coated Ti disks were sterilized by UV irradiation for 30 minutes before cell culture. An uncoated Ti sample served as a control.

[0161] Cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazole bromide (MTT) assay. Titanium disk samples coated with various compounds were immersed in 5 mL of culture medium and placed on a shaker at 37 °C. After various periods (2, 7, 14, and 21 days), the medium was removed and replaced with 5 mL of fresh medium. All extracts were obtained under sterile conditions and cryopreserved. Meanwhile, cells were cultured at 9 × 10 in complete medium in sterile 96-well cultures. 4 Cells were seeded at a density of 1000 cells / mL and cultured for 24 hours at 37°C in a humidified atmosphere containing 5% CO2. To examine the toxicity of the extracts, the medium was replaced with the corresponding extract, and the cultures were incubated for another 24 hours. Cell viability was analyzed after adding a solution of MTT (0.5 mg / mL) in PBS and incubating at 37°C for 3 hours. Excess medium and MTT were removed and washed with PBS. Dimethyl sulfoxide was added to solubilize formazan crystals formed within live cells. The mixture was stirred for 10 minutes, and the absorbance was measured at 570 nm using a Biotek Synergy HT detector. Cell viability was calculated as follows: Cell viability (%)=100×(ODS-ODB) / (ODC-ODB) where ODS, ODB and ODC are the optical densities of the formazan product of the sample (S), blank (B) (culture medium without cells) and control (C), respectively.

[0162] Figure 3 shows the cell viability (FBH, expressed as a percentage) of human fibroblasts measured according to the MTT cell viability assay after contact with samples M1 to M5 prepared in Example 1 as a function of time ((a): 1 day, (b): 2 days, (c): 7 days). The results in Figure 3 indicate that materials M1 to M5 are not cytotoxic, as cell viability remains above 70% even after 7 days.

[0163] Figure 4 shows the cell viability (MG-63, expressed as a percentage) of human osteoblasts contacted with samples M1 to M5 prepared in Example 1 and measured according to the MTT cell viability assay as a function of time ((a): 1 day, (b): 2 days, (c): 7 days).

[0164] General procedure for adhesion assay Titanium disks (with and without coating) were placed in a 24-well plate and incubated for 10 min. 5 FBH cells or MG-63 cells / mL were seeded onto the discs and incubated for 24 hours at 37°C and 5% CO2. To eliminate cells adhering to the wells, various discs were transferred to new 24-well plates. After various periods (1, 2, and 7 days), the medium was removed, and cell attachment and proliferation on the discs were quantified using the Alamar Blue assay. Cells were incubated with 10% Alamar Blue solution in fresh phenol red-free medium. After 3 hours, the solution was transferred to a 96-well plate and replaced with fresh medium. Fluorescence of the transferred medium was measured at 530 nm (excitation) and 600 nm (emission) using a UV Biotek Synergy HT detector. The mean baseline fluorescence of the control medium without cells (negative control) was subtracted to obtain the fluorescence of the samples. All experiments were repeated five times, and a one-way ANOVA test (compared to Ti) was performed to determine significant differences between results.

[0165] 5 and 6 show the cell proliferation as a function of time of human fibroblasts (FBH) and human osteoblasts (MG-63) in contact with samples M1 to M5, respectively.

[0166] General procedure for measuring bactericidal efficacy The antibacterial activity of the materials was measured using Staphylococcus aureus CECT 86 according to the method described in ISO Standard 22196:2011. The bacterial inoculum was obtained as follows: a preculture was grown overnight at 37°C to stationary phase in Luria broth (LB; 0.5% yeast extract, 1% tryptone, and 1% NaCl, all from Difco Laboratories, Detroit, MI, USA). A bacterial stock solution was prepared from the preculture, and an aliquot was taken with a sterile inoculating loop and diluted with PBS to an optical density at 550 nm of 0.1 (OD550 = 0.1) (A600 BOECO S-22 spectrophotometer). This value was calculated as 1.6 × 10 7Equivalent to bacterial concentration in CFU / mL (interpolate the A550 value in the standard curve of CFU versus optical density). The final test culture was 6 x 10 5 The concentration of CFU / mL was obtained by resuspending the stock solution in 1 / 500 LB.

[0167] Titanium discs (φ = 16 mm) coated with M1–M5 were inoculated with 100 μL of the test inoculum and incubated for 24 h at 37°C in a humidified atmosphere. Samples were washed several times with 900 mL of PBS, and this suspension was used for final CFU determination using the standard agar diffusion method. Reported results are relative to the control value (uncoated titanium disc). Tests were performed in triplicate.

[0168] The results are relative cell viability (RCV): RCV (%) = N / N control × 100 where N is the square root of 1 cm 2 The CFU count of the sample.

[0169] All data are expressed as mean ± standard deviation. Statistical analysis was performed using one-way ANOVA. * p<0.05 and ** A value of p<0.001 indicated a significant difference.

[0170] Figure 7 shows the results of the tests carried out: when the material comprises at least 1% by weight of octenidine, a clear bactericidal effect is observed.

[0171] Elution of the protein layer and proteomic analysis Protein layers on different sol-gel formulations were examined after 3 hours of incubation in a humidified atmosphere (37°C, 5% CO2) with 1 mL of human serum collected from male AB plasma (Sigma-Aldrich). Serum was removed, and unadsorbed proteins were removed by five successive washes with ddH2O and 100 mM NaCl, 50 mM Tris-HCl, pH 7.0. Adsorbed proteins were eluted by washing the surface with 0.5 M triethylammonium bicarbonate buffer (TEAB) supplemented with 4% sodium dodecyl sulfate (SDS) and 100 mM dithiothreitol (DTT). Experiments were performed four times for each material, and each replicate represented a pool of four differently treated samples.

[0172] Eluted proteins were characterized using electrospray tandem mass spectrometry using a nanoACQUITY UPLC (Waters, Milford, MA, USA) coupled to an Orbitrap XL (Thermo Electron, Bremen, Germany). The protocol described in Romero-Gavilan et al. Biofouling 2017, vol. 33(8), pp. 676-689, incorporated herein by reference, was followed. Each condition was analyzed in quadruplicate. Proteomic results were examined using PEAKS (Bioinformatics Solutions Inc., Waterloo, Canada). Statistical analysis was performed using Student's t-test using PEAKS. Differences in protein adsorption were considered statistically significant if p ≤ 0.05 and the ratio in either direction was greater than 1.5.

[0173] Table 2 shows a comparative proteome analysis between proteins adsorbed to sol-gel composition M3 with 2% octenidine and control M1 (0% octenidine).

[0174] [Table 2]

[0175] The results in Table 2 show that the compositions according to the invention are biocompatible and suitable for in vivo applications, since there was no statistically relevant variation in the p-values ​​obtained for samples M3 and M1. In fact, variations between 0% and 2% are considered to be statistically irrelevant.

[0176] Clinical Trials and Results New Zealand White Rabbit ( Oryctolagus cuniculus A comparative study was conducted between uncoated and M3-coated titanium implants by inserting the implants into the tibia of a male (14 years old). The implants used in this study were obtained from GMI Dental Implantology and are suitable for titanium dental implants with an internal connection, measuring 3.75 mm in diameter and 8 mm in length. The coated implants were prepared by immersion coating the implants in the sol prepared above in a white chamber and curing according to the procedure described above. The prepared implants were packaged and sterilized by UV light irradiation prior to clinical testing.

[0177] The implants were surgically inserted as follows: female rabbits were weighed and administered a corresponding dose of a mixture of ketamine and xylazine as preanesthetic, followed by torbugesic and prophylactic antibiotic treatment. Propofol was administered as a sedative and administered continuously throughout the surgery. The tibial bone was drilled using a progressive milling technique with drills of increasing diameter until the diameter of the implant was reached. Control and test implants were inserted into the right and left legs of the animals, respectively. The animals were sacrificed 4 weeks after surgery.

[0178] After sacrificing the animals, the tibiae were cut using an osteotomy saw and immersed in 40% ethanol at 4°C for fixation and preservation. The samples were dehydrated under vacuum through increasing ethanol solutions until absolute ethanol was reached. Once dehydrated, the ethanol in the tissue was replaced with xylene. The samples were then inserted into a polymethyl methacrylate matrix to preserve the mineral phase and allow visualization of the cementation line using stains. Insertion into the matrix consisted of immersing the samples in solutions containing increasing concentrations of methyl methacrylate (monomer, Sigma-Aldrich), dibutyl phthalate (plasticizer, Sigma-Aldrich), and benzoyl peroxide as an initiator. Finally, the samples were placed in a glass flask, and the monomer was added. The mixture was polymerized by heating at 40°C. The resulting samples were then sectioned (EXAKT) and treated with stain (Gomori trichrome). Staining allowed differentiation of developing bone and osteoid (red) from more mature bone tissue (blue). Fibrous tissue and cytoplasm are also stained red and can be identified by their morphology.

[0179] The response to the presence of a foreign body, such as an implant, has been assessed by subjective and semiquantitative assessment of the inflammatory response associated with the presence of the implant. This response is a preparatory reaction of the organism when confronted with a foreign body, with the goal of isolating and, if possible, rejecting the foreign body. The organism's response to the presence of a foreign body is a non-allergic inflammatory reaction in which histiocytes and giant cells intervene to sequester the foreign body, followed by phagocytes.

[0180] The bone response to implants is a natural response that occurs to achieve damage repair, and prolonged prognosis can induce a secondary fibrotic reaction. Fibrotic reactions are determined by assessing 12 factors on a scale of 0 to 3, depending on whether they are undetectable or mild, moderate, or severe. A semiquantitative assessment system based on ISO 10993-6 (2009) was used to assess parameters in five categories. 1. Bone marrow status (defined as the degree of trauma to the bone); aplasia (1), structural loss (2), appearance of bone marrow areas not in contact with the implant (3), and fat percentage (4). 2. Necrosis, defined as the level of trauma to the cortical (5) and cancellous (6) bone caused by the impact of the implant. 3. The presence of giant foreign body-reacting cells (7) attached to the different surfaces (titanium in the case of the control and coating in the case of the sol-gel material). 4. The presence of fibrosis / fibrous capsule in the bone marrow (8), between the cortical bone and the implant (9), between the cancellous bone and the implant (10), and the degree of densification (11). 5. Neovascularization (12). Based on the scores obtained, the implants were determined to be non-irritating (0-6), mildly irritating (6-18), moderately irritating (18-30), or severely irritating (30-36).

[0181] Biocompatibility evaluation results The biocompatibility of a material can be defined as its biological acceptability by the body. This biological acceptability can be examined at several levels, one of which is the interaction between the material and the surrounding tissue. For this reason, during the development of biomaterials, it is essential to study the effects of the material on the surrounding tissues after its in vivo implantation. In this regard, as shown in Figures 9 and 10, it was confirmed that the newly developed coating composition did not induce any adverse reactions in the tissues.

[0182] Fibrous capsule formation As shown in Figure 13, coating implants with a coating according to the present invention made from silicon-based precursors with a high content of tetra(alkoxy)silane compounds can prevent the formation of a fibrous capsule. In particular, when a coating with a low content of tetra(alkoxy)silane (e.g., 10% TEOS) is used on the implant, the formation of a fibrous capsule is observed (Figure 13). *Such coatings are surprisingly not observed when the implants are coated with the material according to the invention.

[0183] Clinical trials in beagle dogs Research into the pathogenesis and treatment of peri-implantitis has been carried out in experimental studies performed in animal models in which peri-implantitis was developed in the hard and soft tissues supporting the implant, achieved by placing ligatures in the peri-implant sulcus and subsequently abandoning hygienic plaque control.

[0184] Clinical trial test procedure: Eight adult female beagle dogs underwent the following steps: (1) Extraction of mandibular premolars; (2) insertion of an internally connected implant with a sandblasted and etched surface frontier (GMI, Barcelona, ​​Spain) in place of the mandibular premolar – 3 months after step 1 (T0 sample corresponds to the mucosal sample taken immediately before implant insertion); (3) Onset of peri-implantitis due to implant ligation and abandonment of hygienic plaque control - 3 months after step 2; (T3 sample corresponds to the mucosal sample taken immediately before implant ligation); (4) release of ligation—3 months after step 3 (T6 sample corresponds to the mucosal sample taken immediately after cessation of ligation); (5) Examination of peri-implant tissues and randomization assay of implants treated with composition M3 or placebo - 1 month after step 4 (T7 sample corresponds to the mucosal sample taken immediately before said treatment); (6) Examination of peri-implant tissue and implant - 3 months after step 5; (T10 sample corresponds to the mucosal sample taken 3 months after the procedure in step (5)); (7) Sacrifice of animals for isolation of bone samples - 3 months after step 6.

[0185] Histological study of peri-implant mucosa Samples from dogs at time points T0, T3, T6, T7, and T10 were embedded in paraffin, and 4-μm-thick sections were stained with hematoxylin and eosin according to standard microscopic procedures. As shown in Figure 14, various regions of the peri-implant mucosa proved to be of particular interest for histological study: the epithelium (E), the infiltrated connective tissue of the connective papilla (TCI1), and the infiltrated connective tissue in areas distal to the epithelium (TCI2). Inflammatory infiltrates in these regions, associated with the presence of plasma cells, lymphocytes, neutrophils, and macrophages, were qualitatively assessed according to the following scale: 0—no infiltration, 1—almost no infiltration, 2—moderate infiltration, and 3—extensive infiltration.

[0186] FIG. 15 shows a photomicrograph of the mucosa at TO.

[0187] FIG. 16 shows a photomicrograph of the mucosa at T3.

[0188] FIG. 17 shows a photomicrograph of the mucosa at T6.

[0189] FIG. 18 shows a photomicrograph of the mucosa at T7.

[0190] FIG. 19 shows a photomicrograph of the mucosa at T10.

[0191] Table 3 below summarizes, for each test dog, the scores resulting from samples taken in different areas of the mucosa (TCI1 and TCI2) and at different time points in the assay.

[0192] [Table 3]

[0193] The results in Table 3 show that the inflammatory process, especially in the area close to the epithelium, is reversible when the implants are treated with mixture M3.

[0194] Immunohistochemical studies were also performed on the above samples to detect the presence of biomarkers related to the inflammatory response (substance P and NKx1 receptor). To do so, the samples were removed from paraffin, hydrated, and then heated in citrate buffer at pH 6. Endogenous peroxidase was then inhibited, and the samples were treated with normal donkey serum. Subsequently, the samples were incubated overnight with a rat monoclonal antibody against substance P (bio-Rad, rat monoclonal, clone NC1 / 34, dilution 1:50 vol / vol) and an anti-neurokinin-1 receptor (bioss rabbit polyclonal antibody, dilution 1:50 vol / vol). The LSAB system (vectastain, Vector) and diaminobenzidine (Sigma-Aldrich) were used as coloring agents.

[0195] The NKx1 receptor was visible and identified in all samples, but the extent and intensity of staining increased with increasing inflammatory response and was weaker in pre-implantation samples. NKx1 is expressed on epithelial and endothelial cells, neural pathways, leukocytes, macrophages, and plasma cells.

[0196] The amount of substance P increases with a chronic inflammatory response. As shown in Figure 20, a relationship between substance P and the inflammatory response is observed, with substance P expression being restored upon treatment of dogs with compound M3.

[0197] Bone histology results The bone samples obtained in step (7) were placed in a 10% vol / vol formalin solution. The dog's jaw was placed intact in a vial labeled with a numerical code identifying the animal. Once the implants were separated into individual containers, the samples were first identified with the last four digits of the dog's code, an R or L for left or right side, and a number identifying the proximal to distal position. Samples were prepared according to the method described in Donath & Breuner, J. Oral Pathol. Med. 11, 318-326 (1982), the contents of which are incorporated herein by reference. Briefly, the samples were dehydrated in graded alcohols and immersed in a mixture of ethanol and methacrylate glycol (Technovit 7200 VLC, Heraus Kulzer, Wertheim, Germany). They were then immersed in pure resin (Technovit 7200) using a specific light source and polymerized by heating at 37°C for 24 hours to ensure complete polymerization.

[0198] Next, (i) radiographs of each sample were taken, and (ii) the center of each implant was sectioned by cutting with a hacksaw on a diamond band (Exakt Apparatebau, Norderstedt, Germany). The samples were then polished to a flat, defect-free surface. Next, the blocks were glued to final slides using Technovit 7210, and approximately 200-micron sections were prepared. These were then thinned by micropolishing (Exakt Apparatebau, Norderstedt, Germany) using 1200–4000 grit silicon carbide abrasive cloths (Struers, Copenhagen, Denmark). Once the sections were approximately 40 microns thick, they were all stained together using the Leby-Laczko method. This stain combines two blues (methylene blue and Azure II) with basic fuchsin (purple). This stain is commonly used for resin-embedded bone. Bone is stained pink, cartilage is stained purple, and collagen fibers are stained blue-purple. Slides were scanned using a digital camera (BX51, DP71, Olympus Corporation, Japan) connected to a motorized optical microscope and computer. Images were acquired at 40x magnification.

[0199] Analyses were performed by investigators blinded to the treatment groups used and were only revealed once the analyses were completed. Measurements were acquired using the Cell-sens 1.5 image analysis program (Olympus, Japan).

[0200] The results showed that in the control implants, bone resorption in the area adjacent to the implant at crown level was evident, usually accompanied by a large number of cells of the lymphocyte lineage, which indicates a chronic inflammatory process. This resulted in the formation of pockets around the implants. This phenomenon was observed to a lesser extent in the treated group. This fact was studied when measuring dishing.

[0201] The results in Figure 21 show that treatment with the coating allows for soft tissue regeneration with little or no inflammation-related pocket formation around the implant, thus demonstrating the benefit of the coating in preventing the occurrence of inflammatory processes such as peri-implantitis.

[0202] Mechanism of action The mechanism of action of the composition of Example 1 was further investigated in parallel assays by examining the growth of bacterial populations of Streptococcus gordonii on grade IV titanium plates that were uncoated or coated with a solution of M1 (no octenidine) or M3 (2% by weight octenidine), or an octenidine solution with an amount of octenidine equivalent to that of composition M3. The following experimental procedure was used.

[0203] All materials used were sterile or had been pre-sterilized in an autoclave. The assays were carried out in a level 2 biosafety cabinet. Three different grade IV-Ti discs were used to carry out the assays. This procedure was followed for each assay. First, a suspension of Streptococcus gordonii (CECT 804) of known concentration was prepared. For this purpose, a test tube containing 10 mL of ddH2O was prepared and the bacteria were added to the desired concentration (concentration = 1 × 10 6 These data were verified by direct measurement by spectrophotometry at 600 nm. 6 500 μL of bacterial suspension (CFU / mL) was added to the wells of a sterile 24-well plate. Grade IV Ti disks were then inoculated by immersing them in the bacterial suspension for 1 minute (one disk per well). After inoculation, the Grade IV Ti disks were immersed in 500 μL of Mixture M1, Mixture M3, or octenidine solution for 1 minute (one disk per well; a control without any mixture was also performed for control purposes). This procedure was repeated three times per disk. The coated Grade IV Ti disks were then allowed to harden in the sterile 24-well plate. Once the product Grade IV Ti disks had hardened, they were placed on sterile agar plates. This procedure was repeated on three different plates (one disk per well). Finally, the agar plates were incubated at 37°C for 24 hours to allow for proper bacterial growth, according to the Streptococcus gordonii culture protocol.

[0204] After this time, the bacterial population was counted. The inoculated Grade IV Ti discs were removed for bacterial counting. Three minidiscs of known diameter were then extracted from each plate (extracted from the same location as the inoculated discs) using a punch. Once the minidiscs were obtained, they were transferred to a falcon tube containing 1 mL of ddH2O and vortexed to suspend the bacteria attached to the agar. Once suspended in the falcon tube, the CFUs attached to the agar were obtained according to the following protocol: a) nine serial dilutions (1:10) were made from the resulting bacterial suspension for each replicate and condition; b) each of these dilutions (100 µL per agar plate) was added to a sterile agar plate; c) they were placed in an incubator at 37 °C for 24 hours; d) plates containing 30–300 colonies were subsequently counted for CFU.

[0205] The results in Figure 22 show that disks coated with M1 or M3 showed no growth in bacterial populations after 24 hours of incubation, whereas disks coated with octenidine solution showed a significant reduction in bacterial growth.

[0206] These samples were subjected to a bacterial count of the bacteria attached to the titanium surface, and the average results (three samples were measured for each disc) are shown in Table 9.

[0207] [Table 4]

[0208] This experiment demonstrates that M1 and M3 are suitable for preventing bacterial growth on the surface of substrates coated with M1 or M3. Surprisingly, coating an implant substrate with a composition lacking the antibacterial agent, such as Composition M1, prevents bacterial adhesion to the surface of the substrate. Octenidine alone cannot achieve this effect, as some bacterial growth is still observed. Therefore, without being bound by any theory, it is believed that the sol-gel precursor of the mixture, upon hardening, forms a physical barrier that seals the substrate site from potential bacterial intrusion. This film is also suitable for embedding bacteria attached to the substrate surface, thereby eliminating the bacterial population attached to the substrate surface. In some embodiments, the physical barrier is strong enough to allow soft tissue regeneration around the implant, thereby effectively preventing the development of an infection-related inflammatory response around the implant.

[0209] Furthermore, octenidine is believed to act as a supplementary antibacterial agent once released from the cured sol-gel material as a physical barrier between bacteria from the physiological medium and the implant surface.

Claims

1. (i) a compound of the formula Si(OR １ ) (OR ２ ) (OR ３ ) (OR ４ ) (wherein, R １ , R ２ , R ３ and R ４ are each independently (C １ -C ４ ) alkyl chain) and a compound of formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ ) (wherein, R ５ , R ６ , R ７ and R ８ are each independently (C １ -C ４ providing a mixture comprising a silicon-based sol-gel precursor comprising a compound of the formula Si(OR) １ ) (OR ２ ) (OR ３ ) (OR ４ ) compounds of the formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ ) is a molar ratio of the compounds of from 80:20 to 50:50, and said mixture further comprises octenidine in an amount of from 1 to 7.5 grams per 100 grams of silicon-based sol-gel precursor; (ii) treating the mixture provided in step (i) with an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature about that of the mouth. A method for preparing a composition comprising:

2. Formula Si(OR １ ) (OR ２ ) (OR ３ ) (OR ４ ) is tetraethyl orthosilicate, and has the formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ 2. The method of claim 1 wherein the compound of formula (I) is methyltrimethoxysilane.

3. Formula Si(OR １ ) (OR ２ ) (OR ３ ) (OR ４ ) and a compound of formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ 3. The method of claim 1, wherein the molar ratio of the compounds of formula (I) is about 60:

40.

4. The silicon-based sol-gel precursor of the mixture of step (i) is of the formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ ) and a compound of formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ 4. The method according to claim 1, wherein the silicon-based sol-gel precursor comprises a compound of the formula (I) and (II) in an amount of at least 80% by weight based on the total weight of the silicon-based sol-gel precursor.

5. The method of any one of claims 1 to 4, wherein the silicon-based sol-gel precursor of the mixture of step (i) does not comprise glycidoxypropyltrimethoxysilane.

6. 6. The method of any one of claims 1 to 5, wherein the mixture of step (i) comprises octenidine in an amount of 1 to 5 grams per 100 grams of silicon based sol-gel precursor; preferably, the mixture of step (i) comprises octenidine in an amount of 2 to 4 grams per 100 grams of silicon based sol-gel precursor.

7. 7. The method according to any one of claims 1 to 6, wherein the acidic aqueous solution in step (ii) is a nitric acid solution with a concentration of 0.01N to 0.5N; preferably 0.01N to 0.1N.

8. A process according to any one of claims 1 to 7, wherein step (ii) is carried out at a temperature of from 50°C to 100°C, preferably at about 70°C.

9. The method according to any one of claims 1 to 8, wherein step (iii) is carried out.

10. A composition obtainable by the method according to any one of claims 1 to 9.

11. 11. The composition of claim 10 for use in medicine.

12. 11. The composition according to claim 10 for use in the prevention or treatment of the inflammatory process of mucositis or peri-implantitis, preferably peri-implantitis.

13. 1. A kit of parts for making a substrate coated with an anti-infective coating composition, comprising: - in a first component, the mixture provided in step (i) of the method according to any one of claims 1 to 9, - on a second member, the aqueous acidic solution used in step (ii) of the method defined in the first aspect of the present invention; in an optional third component, means for mixing the contents of the first and second components, and optionally means for heating the resulting mixture; and in an optional fourth member, a substrate for receiving an optionally heated mixture of the contents of said first and second members, and optionally means for transferring said optionally heated mixture to said substrate; or - on a first component, a sol material obtained by the method comprising steps (i) and (ii) according to any one of claims 1 to 9, and a substrate for receiving said sol material in the second member, and optionally means for transferring said sol material to said substrate; A kit comprising:

14. Formula Si(OR １ ) (OR ２ ) (OR ３ ) (OR ４ ) (wherein, R １ , R ２ , R ３ and R ４ are each independently (C １ -C ４ ) alkyl chain) and a compound of formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ ) (wherein, R ５ , R ６ , R ７ and R ８ are each independently (C １ -C ４ and a compound of the formula Si(OR) １ ) (OR ２ ) (OR ３ ) (OR ４ ) compounds of the formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ ) is in a molar ratio of 80:20 to 50:50, and further comprising octenidine in an amount of 1 to 7.5 grams per 100 grams of silicon based sol-gel precursor.

15. 1. A composition for use in the prevention or treatment of the inflammatory process of mucositis or peri-implantitis, preferably peri-implantitis, comprising: (i) a compound of the formula Si(OR １ ) (OR ２ ) (OR ３ ) (OR ４ ) (wherein, R １ , R ２ , R ３ and R ４ are each independently (C １ -C ４ ) alkyl chain), preferably tetraethoxysilane, and a compound of formula Si(R ５ ) (OR ６ ) (OR ７ ) (OR ８ ) (wherein, R ５ , R ６ , R ７ and R ８ are each independently (C １ -C ４ ) a compound of formula (I) wherein the alkyl chain is alkyl, preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50; (ii) treating the mixture provided in step (i) with at least an effective amount of an acidic aqueous solution to form a sol material; (iii) optionally curing the sol material of step (ii) by heating at a temperature about that of the mouth. A composition obtained by a method comprising:

16. 16. A composition for use according to claim 15, which does not contain or does not contain any bioactive particles, drugs or peptides.

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