Coating composition for treating or preventing periimplantitis and preparation method thereof

Abstract

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

[0002] In modern dentistry, the use of titanium-based dental implants for oral placement is common practice. These implants typically have an 89% success rate in restoring the function and aesthetics of the replaced tooth. However, several complications can occur with dental implant placement. Among these complications, the accumulation of microbial plaque around the implant often leads to infection of the peri-implant area. This infection can result from cross-contamination during the oral surgery to insert the implant or from inadequate tissue healing. These infections can also develop delayed after surgery due to the accumulation of bacterial plaque on the implant surface. Infections are caused by bacterial colonization around the implant, particularly at the bone-implant interface. These complications often require implant removal. Peri-implantitis is defined as a destructive process around the implant during osseointegration, which can lead to loss of bone support and incomplete or absent integration of the implant into the bone. Consequently, a complication of peri-implantitis is implant failure. This condition has attracted significant attention, as it is observed in 20% of patients undergoing implants within 1-5 years after surgery.

[0003] Peri-implantitis is typically caused by bacterial colonization, which then attaches to the implant surface and to already attached bacteria to form a biofilm. It has been observed in the art that different types of bacteria can be found on the implant surface within one hour of surgery, and that bacterial biofilms can form in just two weeks. Therefore, rapid intervention is needed to prevent the spread of infection and eradicate the formed biofilm. Several bacteria have been identified as playing a role in the development of peri-implantitis. These bacteria include, for example, Bacteroides, Campylobacter, Eubacterium, Fusobacterium, Treponema species, Actinobacillus actinomycetemcomitans, Prevotella, Intermedius, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and particularly Staphylococcus aureus. Therefore, finding surfaces that can prevent bacterial adhesion, bacterial biofilm formation, and bacterial colonization in the peri-implant area is the subject of intensive research.

[0004] Mucositis is an inflammatory process that occurs in patients with oral implants, in which the tissue surrounding the implant becomes inflamed due to the accumulation of bacterial plaque. Mucositis often precedes peri-implantitis. In this regard, European Patent EP1799186B1 discloses an oral pharmaceutical composition comprising octenidine for the treatment or prevention of inflammatory diseases of the buccal and pharyngeal cavity.

[0005] Several antimicrobial agents are known in the art for preventing or treating peri-implantitis. These include salts, ions, or nanoparticles of metals such as silver, gold, copper, and zinc. Antibiotic compounds are also widely used as antimicrobial agents. However, when exposed to antibiotics, bacterial strains tend to develop some resistance to the antibiotics, resulting in ineffective prevention or treatment strategies. The most commonly used antibiotics include gentamicin, cefalotinin, 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 disclosed a sol-gel matrix prepared from tetraethyl orthosilicate (TEOS) and incorporating vancomycin in Biomaterials 28 (2007) 1721–1729. The disclosed multilayer matrix particularly allows for the controlled release of the antimicrobial agent and is absorbable. Furthermore, there is a correlation between the degradation rate of the sol-gel matrix and the release rate of the antibiotic compound.

[0006] Other antimicrobial agents known in the art include cationic compounds such as quaternary ammonium compounds, antimicrobial peptides and natural molecules such as chitosan. However, quaternary ammonium compounds may lack selectivity for bacteria and may produce undesirable cytotoxic effects. Salts of chlorhexidine and octenidine are also known cationic compounds that can be used as antimicrobial agents. Octenidine salts, particularly its dihydrochloride, are active against a variety of bacteria and are stable under a variety of conditions. Octenidine reacts advantageously with polysaccharides on the walls of microorganisms and inhibits cell function, thereby preventing the growth of bacterial plaques. Octenidine also exhibits low cytotoxicity.

[0007] Coatings for releasing antimicrobial agents and suitable for treating or preventing peri-implantitis are known in the art. In this regard, I. García-Arnáez, B. Palla, J. Suay, F. Romero Gavilán, L. García Fernández, M. Fernández, I. GoñI and M. Gurruchaga disclosed in European Polymer Journal, Vol. 113, 2019, pp. 289-296, a hybrid organic-inorganic coating based on a sol-gel material having proven osteogenic ability and incorporating octenidine dihydrochloride or chlorhexidine diacetate as an antimicrobial agent. The disclosed system is suitable for preventing the formation of biofilms 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) as a silicon-based reagent in a molar ratio of 3:7. The resulting sol-gel matrix is loaded with an antimicrobial agent, which is either chlorhexidine diacetate or octenidine dihydrochloride, at a weight ratio of 0-2%. According to the document, the release rate of the active ingredient is proportional to the degradation rate of the sol-gel matrix material. Furthermore, the presence of TEOS in the sol-gel material is disclosed to enhance the hydrophilicity of the material, thereby promoting its hydrolytic degradation.

[0008] International patent application WO 2017 / 197510 A1 discloses a biocompatible composite material for controlled release of octenidine. The biocompatible matrix comprises a mesoporous silica matrix that can be prepared as a coating. The active ingredient, octenidine, is released primarily by diffusion through the pores of the mesoporous material, rendering the matrix silica material substantially unaffected by degradation or hydrolysis. Tetraethyl orthosilicate is disclosed as the primary source of the silica mesoporous matrix. In addition, octenidine is used as an amphiphilic compound to form micellar assemblies, with a loading of between 30% and 40% by weight.

[0009] Spanish patent application ES201031831 discloses a method for preparing a sol-gel coating using, for example, a mixture 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 using this sol-gel matrix to release antimicrobial agents such as octenidine. The document also discloses that curing of the sol material to form a gel can be performed under both harsh and non-harsh conditions. Curing under non-harsh conditions tends to promote rapid degradation of the material due to the low degree of crosslinking in the cured material.

[0010] From what is known in the art, it can be inferred that there is still a need to provide improved coatings suitable for the treatment or prevention of inflammatory processes such as mucositis or peri-implantitis, in particular coatings suitable for the following purposes: (i) forming a physical barrier between the implant surface and the physiological medium, suitable for embedding bacteria and preventing bacteria from adhering to the surface of the implant during soft tissue regeneration; (ii) releasing anti-infective agents in a controlled manner; (iii) curing under physiological conditions in the shortest possible time; (iv) being usable in an organism; and (v) degrading under physiological conditions and / or preventing the formation of a fibrous capsule between the implant and the surrounding tissue. Summary of the Invention

[0011] After exhaustive research, the inventors have discovered a coating composition comprising 1 wt% to 7.5 wt% of octenidine dihydrochloride embedded in a sol-gel material prepared from a mixture of silicon-based sol-gel precursors comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4) alkyl chain, such as tetraethyl orthosilicate (TEOS), and the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each is independently a (C1-C4)alkyl chain, such as methyltrimethoxysilane (MTMOS), in a molar ratio of 80:20 to 50:50, and the coating composition has beneficial properties for preventing or treating inflammatory processes (such as mucositis or peri-implantitis).

[0012] The first beneficial property is that the coating composition can be cured under the conditions existing in the patient's mouth, namely a temperature of about 37° C. and a humidity of about 100% for about 10 minutes, which is consistent with the curing time of the coating composition of the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 This is in contrast to prior art octenidine compositions in which a ) compound (e.g., MTMOS) is the primary component. Advantageously, the coating composition can be applied directly during or after surgery, with minimal patient discomfort within the generally accepted timeframe for such surgery, and does not require external heating or activation to trigger curing.

[0013] When used to coat an implant or prosthesis, a second benefit of the coating composition is that it advantageously allows the formation of a solid film on the implant surface that acts as a physical barrier between bacteria from the physiological medium and the implant surface. It is believed that the film is also suitable for embedding bacteria that adhere to the substrate surface, thereby eliminating the bacterial colonies that adhere to the substrate surface. In some embodiments, the physical barrier is strong enough to allow the soft tissue around the implant to regenerate, thereby effectively preventing the development of inflammatory reactions associated with peri-implant infection. Surprisingly, this is also the case when the coating composition of the present invention does not contain an antimicrobial agent.

[0014] A third benefit of the coating composition of the present invention is that it advantageously allows for the release of a substantial amount of octenidine in a sustained manner for up to one month after application of the coating. The release behavior of the coating composition of the present invention is particularly desirable in the context of peri-implantitis, as it can prevent both initial and long-term infection by sustained release of octenidine, thereby providing a longer window of infection protection for implant integration. This is surprising, as the prior art disclosed herein includes 2% octenidine and a relatively low amount of a compound of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) (e.g., TEOS), wherein substantially all of the octenidine released within one month after application of the coating is released within about 7 days and is less than the amount of octenidine included in the coating at the time of application. The prior art further teaches that an increase in the amount of TEOS in the silica-based sol-gel precursor results in faster degradation of the gel matrix, and that the degradation of the matrix is directly correlated to the release of octenidine. In other words, one of ordinary skill in the art would expect that the octenidine in the coating composition according to the present invention would be released in an even faster manner compared to the prior art coating composition with low TEOS, and therefore would not consider such a high TEOS coating composition suitable for treating peri-implantitis, where delayed infection is a concern.

[0015] The coating composition of the present invention also has favorable biocompatibility and exhibits excellent bactericidal properties. In particular, unlike coatings disclosed in the art, the coating composition of the present invention advantageously and surprisingly does not lead to the formation of a fibrous capsule between the implant and the tissue surrounding the implant, thereby promoting effective integration of the implant in the bone. In addition, the preparation process of the coating composition is advantageously short (less than 30 minutes), so that it can be performed during a dentist's consultation without particular discomfort to the practitioner and the patient, and can also be performed during a patient's visit. In addition, no specific equipment is required to carry out the method, so that the practitioner does not need additional equipment to prepare the coating composition of the present invention.

[0016] Therefore, in a first aspect, the present invention relates to a method for preparing a coating composition comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a silica-based sol-gel precursor having a formula of Si(R 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each of which is independently a (C1-C4)alkyl chain, preferably tetraethoxysilane, and the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each of which is independently a (C1-C4) alkyl chain, preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, the mixture further comprising octenidine in an amount of 1 to 7.5 grams per 100 grams of the silica-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 the material at a temperature of about oral temperature.

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

[0018] The composition of the second aspect of the invention is particularly useful for preventing or treating inflammatory processes such as mucositis or peri-implantitis, preferably peri-implantitis.

[0019] A third aspect of the present invention therefore relates to a composition according to the second aspect of the invention for use in medicine.

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

[0021] As described 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 present invention, the kit comprising reagents for preparing a precured material in the first alternative and a precured material in the second alternative. Thus, a fifth aspect of the invention relates to a kit of parts for preparing a substrate coated with an anti-infective coating composition, comprising: - the mixture provided in step (i) of the method defined in the first aspect of the invention in a first component, - the acidic aqueous solution used in step (ii) of the process defined in the first aspect of the invention in a second component, - means for mixing the contents of the first and second parts in an optional third part, and optionally, means for heating the resulting mixture, and - a substrate in an optional fourth part for receiving the optionally heated mixture of the contents of the first and second parts, and optionally, means for transferring the optionally heated mixture to the substrate; Or, alternatively, - a sol material in the first component, which is obtainable by the method defined in the first aspect of the present invention comprising steps (i) and (ii), and - a substrate in a second component for receiving said sol material and, optionally, means for transferring said sol material to said substrate.

[0022] A sixth aspect of the present invention relates to the mixture provided in step (i) of the method as defined in the first aspect of the present invention. A seventh aspect of the present invention relates to a composition for use in preventing or treating an inflammatory process (such as mucositis or peri-implantitis, preferably peri-implantitis), wherein the composition is obtainable by a method comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(R 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each of which is independently a (C1-C4)alkyl chain, preferably tetraethoxysilane, and the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R7 and R 8 Each of the alkyl groups is 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 the material at a temperature of about oral temperature. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The hydrolytic degradation rates of materials M1-M5 from Example 1 are shown, measured as weight loss (expressed as a percentage) over time (expressed in days).

[0024] Figure 2 The octenidine release profiles (expressed as the ratio of the cumulative amount of octenidine released at a certain time point to the amount of octenidine present in the coating composition) of samples M2-M5 prepared in Example 1 are shown as a function of time (expressed in days).

[0025] Figure 3 Shown are changes in cell viability (FBH, expressed as a percentage) of human fibroblasts in contact with samples M1-M5 prepared in Example 1 over time ((a): 1 day; (b): 2 days; (c): 7 days)), as measured by MTT cell viability assay, ANOVA test, *p<0.05 relative to control Ti disks (uncoated disks).

[0026] Figure 4 Shown are changes in cell viability (MG-63, expressed as a percentage) of human osteoblasts in contact with samples M1-M5 prepared in Example 1 over time ((a): 1 day; (b): 2 days; (c): 7 days), as measured by MTT cell viability assay, ANOVA test, *p<0.05 relative to control Ti discs (uncoated discs).

[0027] Figure 5 Shown are changes in cell proliferation (FBH, expressed as fluorescence intensity) of human fibroblasts in contact with samples M1-M5 prepared in Example 1 over time ((a): 1 day; (b): 2 days; (c): 7 days)), as measured according to the ALAMAR BLUE cell proliferation assay.

[0028] Figure 6Shown are changes in cell proliferation (MG-63, expressed as fluorescence intensity) of human osteoblasts in contact with samples M1-M5 prepared in Example 1 over time ((a): 1 day; (b): 2 days; (c): 7 days)), as measured by the ALAMAR BLUE cell proliferation assay.

[0029] Figure 7 Shown are the relative values, expressed as a percentage, of cell viability of a culture of Staphylococcus aureus CECT 86 in contact with titanium disks coated with materials M1-M5, measuring the bactericidal effect according to the procedure of Example 1.

[0030] Figure 8 The octenidine release profiles (expressed as the ratio of the cumulative amount of octenidine released at a certain time point to the amount of octenidine present in the coating composition) of comparative samples C1-C4 and sample M3 prepared in Example 1 are shown as a function of time (expressed in days).

[0031] Figure 9 Semiqualitative assessment of the bone marrow transplant response to (left) control titanium implants and (right) M3-coated titanium implants over a period of 1, 2, or 4 weeks is presented, including (1) regenerative impairment, (2) architectural loss, (3) aspects of the bone marrow area not in contact with the implant, and (4) fat ratio.

[0032] Figure 10 Semiqualitative assessment of the peri-implant fibrous capsule response to implantation of (left) control titanium implants and (right) M3-coated titanium implants over a period of 1, 2, or 4 weeks at the following locations: (1) bone marrow, (2) between implant and cortex, (3) between implant and trabecular bone, and (4) degree of densification.

[0033] Figure 11 Photographs of metal substrates coated with the materials M1, M2 or M5 from Example 1 (left column) and after being subjected to the ISO 2409 adhesion test (cross-sectional analysis, right column) are shown.

[0034] Figure 12 Shown are photographs of steel substrates coated with materials C1, C2 or M6 of Example 1 after conditioning at 37°C, 100% humidity for 10 minutes and after wiping the top side of the metal piece with a paper towel.

[0035] Figure 13Histological images of areas of cortical bone and trabecular bone in contact with coated titanium implants are shown: (upper left) in contact with an implant coated with material M6 2 weeks after implantation; (upper right) in contact with an implant coated with material M6 8 weeks after implantation at the trabecular bone; (lower left) in contact with an implant coated with a sol-gel material made of a mixture of 90% MTMOS and 10% TEOS (mol) 8 weeks after implantation at the trabecular bone; (lower right) in contact with an implant coated with a sol-gel material made of a mixture of 90% MTMOS and 10% TEOS (mol) 8 weeks after implantation near the medullary cavity.

[0036] Figure 14 Microscopic photographs of the peri-implant mucosal area are shown, illustrating the target areas in the clinical study conducted in beagle dogs: E: epithelium; TCI1: infiltrating connective tissue in the connective tissue papilla; TCI2: infiltrating connective tissue in an area distal to the epithelium.

[0037] Figure 15 Shown are microscopic photographs of peri-implant mucosal samples collected at T0 in a clinical trial conducted on beagle dogs.

[0038] Figure 16 Shown are microscopic photographs of peri-implant mucosal samples collected at T3 during a clinical trial in beagle dogs.

[0039] Figure 17 Shown are microscopic photographs of peri-implant mucosal samples collected at T6 during a clinical trial in beagle dogs.

[0040] Figure 18 Shown are microscopic photographs of peri-implant mucosal samples collected at T7 during a clinical trial on beagle dogs.

[0041] Figure 19 Shown are microscopic photographs of peri-implant mucosal samples collected at T10 during a clinical trial conducted on beagle dogs (treated and control groups).

[0042] Figure 20 Microscopic photographs of peri-implant mucosal samples processed for the detection of substance P in immunohistochemical analysis of samples from dogs in the control (top) and treatment (bottom) groups are shown.

[0043] Figure 21 Microscopic pictures of stained bone samples obtained from histological experiments on bones of beagle dogs receiving implants treated with mixture M3 (top) and beagle dogs receiving untreated implants (bottom) are shown.

[0044] Figure 22Photographs showing the proliferation of Streptococcus gordonii on the surface of grade IV titanium disks coated with: a) nothing; b) mixture M1 of Example 1; c) mixture M3 of Example 1; d) octenidine solution after one day of incubation at 37°C. DETAILED DESCRIPTION

[0045] Unless otherwise specified, all terms used in this application should be understood to have the ordinary meaning known in the art. Other more specific definitions of certain terms in this application are described below and are intended to apply uniformly throughout the specification and claims, unless otherwise expressly provided.

[0046] For the purposes of the present invention, any range given includes the lower and upper endpoints of the range. When a given range or value (such as temperature, time, molar ratio, volume ratio, etc.) is defined by the term "about", it should be regarded as an approximation (i.e., there is a 5% variation around the indicated point).

[0047] In the context of the present invention, the term "alkyl" refers to a straight or branched aliphatic saturated hydrocarbon chain, the number of carbon atoms of which is as defined in the claims and the specification. Non-limiting examples of alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, and hexyl.

[0048] In the context of the present invention, the term "octenidine" refers to both octenidine and one of its known salts, such as octenidine dihydrochloride. Octenidine is a compound with the following chemical formula: Thereby the imine groups can be protonated. 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.

[0049] In the context of the present invention, the term "silicon-based sol-gel precursor" refers to an organosilicon compound known in the art and suitable for forming a polysiloxane type sol-gel material. In a specific embodiment of the present invention, the term "silicon-based sol-gel precursor" refers to an organosilicon 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 Each independently selected from (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 haloamino groups and groups suitable for crosslinking, such as glycidyl, (meth)acrylate or mercapto groups. Known examples of silicon-based sol-gel precursors include tetramethoxysilane, tetraethoxysilane (TEOS), methyltrimethoxysilane (MTMOS), vinyltrimethoxysilane, vinyltriethoxysilane, phenyltriethoxysilane, 3-aminopropyltriethoxysilane, (3-glycidoxy)propyltrimethoxysilane (GPTMS) and 3-(trimethoxysilyl)propyl methacrylate. Particularly useful are TEOS, MTMOS and GMTPS: In the context of the present invention, when used in the context of forming a sol material, the term "effective amount" refers to the amount of acid that induces condensation of the silica-based sol-gel precursor and formation of the sol material. In a specific embodiment, such an effective amount is given when the pH value of the acidic aqueous solution is between 1 and 2.

[0050] In the context of the present invention, the term "prevention or treatment" as used herein includes any type of treatment whose purpose is to terminate, prevent, ameliorate and / or reduce susceptibility to a clinical condition described herein (e.g., a bacterial infection). Thus, "prevention or treatment," "preventing or treating," and the like, as used herein, refers to obtaining a desired pharmacological and / or physiological effect and encompasses any treatment of a pathological condition or disease in a mammal (including a human). The effect may be prophylactic in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or an adverse effect attributable to the disease. That is, "prevention or treatment" includes (1) preventing the onset or recurrence of a disease in a subject, (2) inhibiting a disease, such as arresting its progression; (3) stopping or terminating a disease or at least symptoms associated therewith so that the host no longer suffers from the disease or its symptoms, such as causing regression of the disease or its symptoms, such as by restoring or repairing a lost, missing or defective function, or stimulating an inefficient process; or (4) alleviating, alleviating or ameliorating a disease or symptoms associated therewith, wherein improvement is broadly defined to include at least a reduction in the magnitude of a parameter. Those in need of treatment include those already with the condition or disease as well as those prone to having the condition or disease or those in which the condition or disease is to be prevented.

[0051] 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 of discrete particles comprising polysiloxane and / or a reticulated or cross-linked polysiloxane. Typically, during the sol-gel process, a silica-based sol-gel precursor is converted into a sol material, which in turn serves as a precursor to the gel material.

[0052] In the context of the present invention, the term "oral temperature" refers to the average temperature of the human oral cavity, ie a temperature between 30°C and 40°C, preferably a temperature of about 37°C.

[0053] As mentioned above, the first aspect of the present invention relates to a method for preparing a coating composition, comprising the following steps: (i) providing a mixture comprising a compound of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 1 、R 2 、R 3 and R 4 Each independently represents a (C1-C4) alkyl chain, R 5 、R 6 、R 7 and R 8 each independently being a (C1-C4)alkyl chain, the mixture further comprising octenidine in an amount of 1 to 7.5 grams per 100 grams of the silica-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 the material at a temperature of about oral temperature.

[0054] In a specific embodiment of the first aspect of the present invention, the silicon-based sol-gel precursor includes a compound of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) is tetraethyl orthosilicate (TEOS). The terms "tetraethyl orthosilicate," "tetraethoxysilane," and "TEOS" herein all refer to the same compound of formula Si(OEt) 4 and are used interchangeably.

[0055] In a specific embodiment of the first aspect of the present invention, the silicon-based sol-gel precursor includes a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8) is methyltrimethoxysilane (MTMOS). The terms "methyltrimethoxysilane" and "MTMOS" herein both refer to the same compound of formula MeSi(OMe)3 and are used interchangeably.

[0056] In a specific embodiment of the first aspect of the present invention, the silicon-based sol-gel precursor includes a compound of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and the compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is 70:30 to 50:50, preferably 65:35 to 55:45, and more preferably 60:40.

[0057] In a specific embodiment of the first aspect of the present invention, the silica-based sol-gel precursor of the mixture of step (i) comprises tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 65:35 to 55:45. Preferably, the silica-based sol-gel precursor of the mixture of step (i) comprises tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40.

[0058] In a specific embodiment, the silica-based sol-gel precursor of the mixture of step (i) comprises the following amounts of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ): at least 50 wt %, preferably at least 80 wt %, more preferably at least 95 wt %, even more preferably at least 99 wt %, relative to the total weight of the silica-based sol-gel precursor.

[0059] In a specific embodiment, the silica-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 %, even more preferably at least 99 wt %, relative to the total weight of the silica-based sol-gel precursor.

[0060] In a specific embodiment, the silica-based sol-gel precursor of the mixture of step (i) is composed of the formula Si(OR 1 )(OR 2 )(OR 3)(OR 4 ) and compounds of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is composed of a compound, preferably tetraethoxysilane and methyltrimethoxysilane. The molar ratio of tetraethoxysilane to methyltrimethoxysilane can be any of the above.

[0061] In an embodiment, in any of the embodiments described herein, the silica-based sol-gel precursor of the mixture of step (i) does not include glycidoxypropyltrimethoxysilane.

[0062] In a more specific embodiment of the first aspect of the present invention, the silica-based sol-gel precursor consists of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2.

[0063] In a specific embodiment of the first aspect of the present invention, the mixture of step (i) consists essentially of the silica-based sol-gel precursor defined in any of the specific or preferred embodiments above and octenidine, and the amount of octenidine is 1 to 7.5 grams per 100 grams of silica-based sol-gel precursor.

[0064] In the context of the present invention, the term "essentially consisting of..." means that certain other components may be present in the mixture of step (i), i.e., those components that do not substantially affect the basic properties of the mixture, in particular its ability to form a polysiloxane-based sol-gel material with antimicrobial activity.

[0065] 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 the silica-based sol-gel precursor. Preferably, the mixture of step (i) comprises octenidine in an amount of 1 to 6 grams per 100 grams of the silica-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 the silica-based sol-gel precursor; more particularly, 2 to 3 grams; even more particularly, about 2 grams.

[0066] In a particular embodiment 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 the silica-based sol-gel precursor.

[0067] In another embodiment of the first aspect of the present invention, the mixture of step (i) comprises 2 grams of octenidine per 100 grams of silica-based sol-gel precursor.

[0068] In a preferred embodiment, the mixture of step (i) comprises a silica-based sol-gel precursor comprising at least 80% by weight of a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds 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, and octenidine in an amount of 2 to 4 grams per 100 grams of silica-based sol-gel precursor.

[0069] In a preferred very specific embodiment, the mixture of step (i) comprises a silica-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 g per 100 g of silica-based sol-gel precursor.

[0070] In a preferred embodiment of the first aspect of the present invention, the mixture of step (i) further comprises a solvent. Suitable solvents are solvents known in the art for forming polysiloxanes by sol-gel methods. Typically, suitable solvents are polar protic organic solvents, such as alcohols. Such alcohols include methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol and the tert-butyl alcohol etc. Preferred solvent is isopropyl alcohol.

[0071] When the mixture of step (i) includes a solvent, the amount of the solvent is preferably such that the ratio of the volume of the solvent to the volume of the silica-based sol-gel precursor is from 1:2 to 2:1. More preferably, the amount of the solvent is such that the ratio of the volume of the solvent to the volume of the silica-based sol-gel precursor is about 1:1.

[0072] Therefore, in a more preferred embodiment of the first aspect of the present invention, the mixture of step (i) comprises a silica-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 silica-based sol-gel precursor, and further comprises isopropanol, wherein the amount of isopropanol is preferably such that the ratio of the volume of the solvent to the volume of the silica-based sol-gel precursor is approximately 1:1.

[0073] The method of the first aspect of the present invention involves the formation of a cross-linked polysiloxane network, into which octenidine is embedded. The second step of the method of the first aspect of the present invention involves forming the network under acidic aqueous conditions. The use of such conditions favors polycondensation of the silica-based sol-gel precursor over hydrolysis, thereby favoring the formation of a cross-linked polysiloxane compound having a linear cross-section.

[0074] Therefore, 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 acidic aqueous solution to form a sol material. The acidic aqueous solution may be an acidic solution of any one 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.

[0075] The effective amount of the acidic aqueous solution is preferably a substoichiometric or stoichiometric amount of acid. The acid can be used to accelerate the hydrolysis of the alkoxy groups included in the silicon-based gel precursor.

[0076] In a specific embodiment of the first aspect of the present invention, the pH value of the acidic aqueous solution of step (ii) is between 1 and 2. A person skilled in the art will design the volume of the acidic solution to be added to the mixture based on the pH value of the solution and the effective amount of acid to be added to the mixture of step (i).

[0077] In other specific embodiments of the first aspect of the present invention, the acidic aqueous solution of step (ii), preferably a nitric acid solution, has an acid concentration of 0.01N to 0.5N, preferably 0.01N to 0.1N, and more preferably a nitric acid solution with a concentration of 0.1N.

[0078] In other specific embodiments of the first aspect of the present invention, step (ii) is performed at a temperature of 25°C to 100°C. Preferably, step (ii) is performed at a temperature between 50°C and 100°C, more preferably at about 70°C. When step (ii) is performed at a temperature of 70°C, it advantageously allows the sol material to be formed in a short time (i.e., about 30 minutes). This advantageously allows the coating composition to be prepared during surgery or during a patient visit.

[0079] In a more specific embodiment of the first aspect of the present invention, the mixture of step (i) comprises a silica-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2, and 1, 2, 5, or 7.5 grams of octenidine per 100 grams of the silica-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 concentration of the nitric acid solution is 0.01N to 0.1N, and step (ii) is performed at 70° C. In this embodiment, it is further preferred that step (ii) is performed for a period of about 30 minutes.

[0080] The combination of steps (i) and (ii) allows the preparation of such a sol material that, after solidification, can form a physical barrier between the implant surface and the physiological medium, suitable for embedding bacteria and preventing bacteria from adhering to the surface of the implant during soft tissue regeneration. In addition, the sol material can release octenidine in a sustained manner over a long period of time. Therefore, this composition is particularly useful as an anti-infective coating for implants (such as dental or bone implants). Therefore, it is further considered that the method of the first aspect of the present invention includes partially or completely coating a substrate for implantation or an implanted substrate, such as a dental or bone implant, with a sol material. In a specific embodiment, 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 used as a dental closure cap. Materials suitable for use as dental closure caps are well known in the art and will become apparent to those of ordinary skill in the art after practicing the present invention. Materials suitable for use as dental closure caps include, for example, collagen, titanium, stainless steel, polyethylene, polypropylene, medical grade silicone, polyglycolic acid, polylactic acid, polydioxanone and caprolactone. In the coating step, the colloidal sol product can be carried out in the first specific alternative after step (ii) to the transfer of substrate. Because the product of step (ii) is a colloidal sol material, it has enough viscosity to coat the substrate. Before transferring to substrate, the colloidal sol material prepared in the step (ii) can further age, preferably under the environmental conditions of temperature and humidity, which allows to increase the viscosity of the colloidal sol material, and allows coating composition to be more accurately applied to the surface of substrate or implant. It is not necessary to carry out the transfer with the specific additive for improving coating composition and substrate adhesion, although they can be added in the colloidal sol material to improve the adhesion of the colloidal sol material and substrate surface. However, it is preferred not to use this additive.

[0081] When step (iii) is carried out, the transfer of the sol product to the substrate can, in a second specific alternative, be carried out after step (iii).

[0082] In a preferred embodiment, the substrate comprises a surface, preferably a metal or polymer surface, 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 quality. More preferably, the metal is titanium or an alloy thereof.

[0083] In a further specific embodiment, the substrate is a material used as a dental closure. Materials suitable for use as dental closures 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 dental closures 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.

[0084] In an embodiment, the step of transferring the sol product of step (ii) or the gel product of step (iii) to a substrate is a non-therapeutic and / or non-surgical step in that it is not performed on a human or animal.

[0085] Optionally, a step of transferring said product of step (ii) or step (iii) onto a substrate is performed in order to achieve a coating of an implant present in the human or animal oral cavity. In this case, the invention relates to said product for use in medicine as described below.

[0086] In a further specific embodiment, the method of the first aspect of the present invention further comprises a step (iii) of solidifying the material by heating the sol material of step (ii) at a temperature of about oral temperature. The inventors have found that when heated at 37°C, the sol material formed in step (ii) can form a gel in a short time of about 10 minutes. This is advantageous because it minimizes the patient's discomfort. Step (iii) of the first aspect of the present invention can also be advantageously carried out in the presence of moisture. This advantageously allows step (iii) to be carried out under oral conditions.

[0087] A further aspect of the present invention relates to a method for preparing a coating composition comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising 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 a (C1-C4)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 R8 Each independently is 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 the material at a temperature of about oral temperature. Products obtainable according to the method also form part of the present invention.

[0088] The method may further comprise the step of adding a solution comprising an antimicrobial agent (such as octenidine) to the product of step (ii) or (iii). The product obtained according to the method also forms part of the present invention.

[0089] A further aspect of the present invention relates to a method for preparing a coating composition comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising 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 a (C1-C4)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 Each independently is a (C1-C4) alkyl chain, preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, the mixture further comprising an effective amount of an antibacterial 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 the material at a temperature of about oral temperature. Products obtainable according to the method also form part of the present invention.

[0090] Suitable antimicrobial agents are known in the art and will become apparent to those skilled in the art after practicing the present invention. These include octenidine, chlorhexidine, triclosan, hydrogen peroxide, and quaternary ammonium compounds, such as cationic surfactants, benzalkonium salts, cetylpyridinium chloride salts, cetrimide bromide, and domiphen salts, among others.

[0091] As stated above, the second aspect of the present invention relates to a composition obtainable by the method defined in the first aspect of the present invention.

[0092] Therefore, the second aspect of the present invention relates to a composition obtainable by the method defined in any of the specific and preferred embodiments of the first aspect of the present invention above.

[0093] In a first alternative, the second aspect of the invention may therefore relate to a sol material. This is particularly the case when step (iii) of the specific and preferred embodiment of the method of the first aspect of the invention described above is not performed.

[0094] Therefore, the first alternative of the second aspect of the present invention relates in a preferred embodiment to a sol material, which can be obtained by a method comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor and octenidine, wherein the silica-based sol-gel precursor comprises at least 80% by weight of a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds 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, and an amount of octenidine of 2 to 4 grams per 100 grams of silica-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.

[0095] The first alternative of the second aspect of the present invention relates in a preferred more specific embodiment to a sol material which can be obtained by a method comprising the following steps: (i) providing a mixture comprising a silica-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 the silica-based sol-gel precursor, and (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.

[0096] In a second alternative, the second aspect of the invention may therefore relate to a gel material. This is particularly the case when performing step (iii) of the specific and preferred embodiment of the method of the first aspect of the invention described above.

[0097] Therefore, the second alternative of the second aspect of the present invention in a preferred embodiment particularly relates to a gel material which can be obtained by a method comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor comprising at least 80 wt. % of a silica-based sol-gel precursor of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds 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, and 2 to 4 grams of octenidine per 100 grams of silica-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, and (iii) solidifying the sol material obtained in step (ii) by heating the material at a temperature of 30°C to 40°C.

[0098] Therefore, the second alternative of the second aspect of the present invention in a preferred embodiment particularly relates to a sol material, which can be obtained by a method comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2, and further comprising 1, 2, 5 or 7.5 grams of octenidine per 100 grams of the silica-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 the material at a temperature of about 37°C.

[0099] In a third alternative, when the method of the first aspect of the invention comprises transferring the sol or gel material onto a substrate (such as a dental, bone implant or material for a closure cap), 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 the sol or gel defined in the first and second alternatives of the second aspect of the invention as detailed above.

[0100] In specific embodiments, the substrate is adapted to receive an anti-infective coating.

[0101] 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 quality. More preferably, the metal is titanium or an alloy thereof.

[0102] In a further specific embodiment, the substrate is a material used as a dental closure. Materials suitable for use as dental closures 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 dental closures 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.

[0103] Therefore, a particular embodiment of the third alternative of the second aspect of the invention relates to a dental bone implant cap comprising a surface comprising titanium, said surface being coated with a sol or gel as defined in the first and second alternatives of the third aspect of the invention as described in detail above.

[0104] Another specific embodiment of the third alternative of the second aspect of the invention relates to a closure cap comprising a surface of a material suitable for a closure cap as described above, said surface being coated with a sol or gel as defined in the first and second alternatives of the second aspect of the invention as detailed above.

[0105] As mentioned above, the third aspect of the present invention relates to a product according to the second aspect of the present invention for use in medicine.

[0106] Specific embodiments of the third aspect of the invention relate to the product defined in any specific or preferred embodiment of the first (sol), second (gel) and third (coated substrate) alternatives of the second aspect of the invention, for use in medicine.

[0107] As shown in the examples below, the products of the second aspect of the invention are particularly useful for preventing or treating inflammatory processes such as mucositis or peri-implantitis, preferably peri-implantitis.

[0108] A fourth aspect of the present invention relates to a product as defined in the second aspect of the present invention for use in preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis. Specific embodiments of the fourth aspect of the present invention relate to a product as defined in any specific or preferred embodiment of the first (sol), second (gel) and third (coated substrate) optional embodiments of the second aspect of the present invention for use in preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis.

[0109] In a preferred embodiment of the invention, the inflammatory process susceptible to treatment or prevention of the composition of the invention is an inflammatory process caused by one or more bacteria. Preferably, the one or more bacteria are a species of Staphylococcus, in particular Staphylococcus aureus, or a species of Streptococcus, in particular Streptococcus gordonii, or are selected from the group consisting of: Bacteroides, Campylobacter, Eubacterium, Fusobacterium, Treponema species, Actinobacillus actinomycetemcomitans, Prevotella, Intermedius, Porphyromonas gingivalis, Treponema denticola, and Forsythia. In a more specific embodiment, the one or more bacteria are Staphylococcus aureus. In other more specific embodiments, the one or more bacteria are Streptococcus gordonii.

[0110] In a further embodiment, the present invention relates to the use of a composition according to the second or sixth aspect of the invention as defined in any embodiment provided herein for the preparation of a coating or a coating substrate for preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis.

[0111] In a further embodiment, the present invention relates to a method for treating or preventing an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis, comprising the step of coating an implant or prosthesis or a material for a closure cap 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.

[0112] A kit for preparing the product of the second aspect of the invention also forms part of the present invention and constitutes a fifth aspect of the invention.

[0113] Thus, a fifth aspect of the present invention relates to a kit of parts for preparing a substrate coated with an anti-infective coating, comprising: - the mixture provided in step (i) of the method defined in the first aspect of the invention in a first component, - the acidic aqueous solution used in step (ii) of the method defined in the first aspect of the invention in a second component, - means for mixing the contents of the first and second parts in an optional third part, and optionally, means for heating the resulting mixture, and - a substrate in an optional fourth part for receiving the optionally heated mixture of the contents of the first and second parts, and optionally, means for transferring the optionally heated mixture to the substrate; Or, alternatively, - a sol material in the first component obtainable by a process comprising steps (i) and (ii) as defined in the first aspect of the invention, and - a substrate for receiving the sol material in the second component, and optionally, means for transferring the sol material to the substrate. In a specific embodiment, the first component of the first alternative of the kit of the fifth aspect of the invention relates to the mixture provided in step (i) of the method defined in any specific and preferred embodiment of the first aspect of the invention.

[0114] Thus, in a more specific embodiment, the first component of the first alternative of the kit of the fifth aspect of the invention relates to a mixture comprising a silica-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 silica-based sol-gel precursor. The mixture further preferably comprises a solvent as defined above for the first aspect of the invention, preferably isopropanol.

[0115] In a specific embodiment, the second component of the first alternative of the kit of parts of the fifth aspect of the invention relates to an acidic aqueous solution as defined in step (ii) of the method as defined in any specific and preferred embodiment of the first aspect of the invention.

[0116] Therefore, in a more specific embodiment, the second component of the first alternative of the kit of the fifth aspect of the invention relates to an aqueous solution of nitric acid with a concentration of 0.01 N to 0.1 N. Preferably, it relates to an aqueous solution of nitric acid with a concentration of 0.1 N.

[0117] In a specific embodiment, the optional third component of the first alternative of the kit of the fifth aspect of the present invention is a device known in the art suitable for mixing the contents of two separate components comprising the composition to be mixed. The third component may further include a heating device 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 device can be used to solidify the sol material to form a gel. As described above, the solidification can preferably be performed after the sol material has been transferred to the surface of a substrate, such as a dental or bone implant or a material for a closure cap.

[0118] In a particular embodiment, the optional fourth component of the first alternative 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.

[0119] In a specific embodiment, the optional fourth component of the first alternative of the kit of the fifth aspect of the present invention relates to a substrate comprising a surface, preferably a metal or polymer surface, including a metal (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 alternative 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 a further more specific embodiment, the optional fourth component of the first alternative of the kit of the fifth aspect of the present invention relates to a dental closure. Materials suitable for dental closures are known in the art and will become apparent to those skilled in the art after practicing the present invention. Materials suitable for dental closures 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.

[0120] In another specific embodiment, the first component of the second optional scheme of the kit of the fifth aspect of the present invention relates to a sol material, which can be obtained by a method consisting of steps (i) and (ii) defined in any specific and preferred embodiment of the first aspect of the present invention or defined in the first optional scheme of any specific and preferred embodiment of the second aspect of the present invention.

[0121] In a specific embodiment, the second component of the second alternative of the kit of the fifth aspect of the invention relates to a substrate comprising a surface, 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 quality, and more preferably being titanium or an alloy thereof. In a more specific embodiment, the optional fourth component of the first alternative of the kit of the fifth aspect of the invention relates to a dental or bone implant, preferably comprising a surface, the surface comprising titanium, preferably being of surgical grade quality.

[0122] In a further more specific embodiment, the second component of the second alternative of the kit of the fifth aspect of the invention is directed to a substrate comprising a surface of a material suitable for use as a dental closure, 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.

[0123] The basic components of the kit allowing for the preparation of sol or gel materials are the first and second components of the first alternative of the kit of the fifth aspect of the invention.

[0124] The basic components of the kit allowing for the preparation of substrates coated with the anti-infective coating composition are the first, second and fourth components of the first alternative or the first and second components of the second alternative of the kit of the fifth aspect of the invention.

[0125] The mixture of precursor reagents used in step (i) of the method of the first aspect of the present invention is also part of the present invention. Therefore, the sixth aspect of the present invention relates to the mixture provided in step (i) of the method as defined in any specific and preferred embodiment of the first aspect of the present invention above.

[0126] In a specific embodiment of the sixth aspect of the present invention, the silicon-based sol-gel precursor includes a compound of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) is tetraethyl orthosilicate (TEOS).

[0127] In a specific embodiment of the sixth aspect of the present invention, the silicon-based sol-gel precursor includes a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is methyltrimethoxysilane (MTMOS).

[0128] In a specific embodiment of the sixth aspect of the present invention, the silicon-based sol-gel precursor includes a compound of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and the compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is in a molar ratio of 70:30 to 50:50, preferably 65:35 to 55:45, and even more preferably 60:40.

[0129] In a specific embodiment of the sixth aspect of the present invention, the silica-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 silica-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.

[0130] In a specific embodiment, the silica-based sol-gel precursor of the composition of the sixth aspect of the present invention comprises a silica-based sol-gel precursor of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) in an amount of at least 50 wt %, preferably at least 80 wt %, more preferably at least 95 wt %, even more preferably at least 99 wt %, relative to the total weight of the silica-based sol-gel precursor.

[0131] In a specific embodiment 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 includes tetraethoxysilane and methyltrimethoxysilane, and the content thereof is at least 50 weight %, preferably at least 80 weight %, more preferably at least 95 weight %, and even more preferably at least 99 weight % relative to the total weight of the silicon-based sol-gel precursor.

[0132] In a specific embodiment 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 composed of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) is composed of a compound, preferably tetraethoxysilane and methyltrimethoxysilane. The molar ratio of tetraethoxysilane to methyltrimethoxysilane can be any of the above.

[0133] In a specific embodiment of the sixth aspect of the present invention, the silica-based sol-gel precursor of the composition of the sixth aspect of the present invention does not include glycidoxypropyltrimethoxysilane.

[0134] In a more specific embodiment of the sixth aspect of the present invention, the silica-based sol-gel precursor consists of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 3:2.

[0135] In a specific embodiment of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention is essentially composed of the silica-based sol-gel precursor as defined above in any specific or preferred embodiment and octenidine, and the amount of octenidine is 1 to 7.5 grams per 100 grams of silica-based sol-gel precursor.

[0136] 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 the silica-based sol-gel precursor. Preferably, the composition of the sixth aspect of the present invention comprises octenidine in an amount of 1 to 6 grams per 100 grams of the silica-based sol-gel precursor; more preferably, 1.5 to 5 grams; even more preferably, 2 to 4 grams.

[0137] In a 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 1, 2, 5 or 7.5 grams per 100 grams of the silica-based sol-gel precursor.

[0138] In another 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 the silica-based sol-gel precursor.

[0139] In a preferred embodiment of the sixth aspect of the present invention, the composition of the sixth aspect of the present invention comprises a silica-based sol-gel precursor comprising at least 80 wt % of a silica-based sol-gel precursor having a molar ratio of 65:35 to 55:45 of formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and compounds of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ), preferably a mixture of tetraethoxysilane and methyltrimethoxysilane, and 2 to 4 grams of octenidine per 100 grams of silica-based sol-gel precursor.

[0140] In a preferred very specific embodiment, the composition of the sixth aspect of the invention comprises a silica-based sol-gel precursor consisting of a mixture of tetraethoxysilane and methyltrimethoxysilane in a molar ratio of 60:40, and 2 grams of octenidine per 100 grams of silica-based sol-gel precursor.

[0141] 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 solvents known in the art for forming polysiloxanes by sol-gel methods. Typically, suitable solvents are polar protic organic solvents, such as alcohols. Such alcohols include methanol, ethanol, propanol, isopropanol, butanol, and tert-butyl alcohol. A preferred solvent is isopropanol.

[0142] When the composition of the sixth aspect of the invention includes a solvent, the amount of the solvent is preferably such that the ratio of the volume of the solvent to the volume of the silica-based sol-gel precursor is from 1:2 to 2:1. More preferably, the amount of the solvent is such that the ratio of the volume of the solvent to the volume of the silica-based sol-gel precursor is about 1:1.

[0143] A seventh aspect of the present invention relates to a composition for preventing or treating an inflammatory process (such as mucositis or peri-implantitis, preferably peri-implantitis), wherein the composition is obtainable by a method comprising the following steps: (iii) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and the formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each independently is a (C1-C4) alkane 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 the material at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention.

[0144] In a preferred embodiment of the present invention, the inflammatory process susceptible to treatment or prevention of the composition of the present invention is an inflammatory process caused by one or more bacteria. Preferably, the one or more bacteria are a species of Staphylococcus, in particular Staphylococcus aureus, or a species belonging to the genus Streptococcus, in particular Streptococcus gnaeus, or are selected from the group consisting of Bacteroides, Campylobacter, Eubacterium, Fusobacterium, Treponema species, Actinobacillus actinomycetemcomitans, Prevotella, Intermedium, Porphyromonas gingivalis, Treponema denticola and Forsythia. In a more specific embodiment, the one or more bacteria are Staphylococcus aureus. In other more specific embodiments, the one or more bacteria are Streptococcus gnaeus.

[0145] Therefore, a seventh aspect of the present invention also relates to the use of a composition for preventing or treating an inflammatory process (such as mucositis or peri-implantitis, preferably peri-implantitis), wherein the composition is obtainable by a method comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and a 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each independently is a (C1-C4) alkyl chain, preferably methyltrimethoxysilane; the molar ratio is 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 the material at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention.

[0146] Therefore, a seventh aspect of the present invention also relates to the use of a composition for the preparation of a medicament for preventing or treating an inflammatory process (such as mucositis or peri-implantitis, preferably peri-implantitis), wherein the composition can be obtained by a method comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and a 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each independently is a (C1-C4) alkane 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 the material at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention.

[0147] Therefore, a seventh aspect of the present invention also relates to a method for preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis, comprising administering to a patient in need thereof an effective amount of a composition obtainable by a method comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and a 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8Each independently is a (C1-C4) alkane 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 the material at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention.

[0148] In a preferred embodiment of the seventh aspect of the invention, the composition does not include an active pharmaceutical ingredient, such as an antimicrobial agent, in particular octenidine. In a preferred embodiment of the seventh aspect of the invention, the composition does not include biologically active particles, drugs or peptides and / or does not include peptides. In a preferred embodiment of the seventh aspect of the invention, the composition does not include an antimicrobial agent, such as octenidine, biologically active particles, drugs or peptides and / or does not include peptides. In a specific embodiment of the seventh aspect of the invention, the composition can be obtained by the above-mentioned method consisting of steps (i) to (iii).

[0149] In a further preferred embodiment of the seventh aspect of the present invention, the composition is a composition wherein the silica-based sol-gel precursors of the mixture of step (i) and their relative amounts are as defined above in any preferred embodiment of the first aspect of the present invention.

[0150] In a further preferred embodiment of the seventh aspect of the present invention, the composition is a composition wherein the mixture of step (i) comprises a solvent as defined in any preferred embodiment of the first aspect of the present invention described above. Preferably, the amount of the solvent is as defined in any preferred embodiment of the first aspect of the present invention described above.

[0151] In a further preferred embodiment of the seventh aspect of the present invention, step (ii) is as defined in any preferred embodiment of the first aspect of the present invention defined above with respect to step (ii).

[0152] In a further preferred embodiment of the seventh aspect of the present invention, step (iii) is as defined in any preferred embodiment of the first aspect of the present invention defined above with respect to step (iii).

[0153] In a further aspect, the present invention relates to a composition for preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis, wherein the composition is obtainable by a method comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and a 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each independently is a (C1-C4) alkyl chain, preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, and the mixture further comprises an effective amount of an antibacterial 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 it at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention. The antibacterial agent may be as described above.

[0154] In said further aspect, the present invention therefore also relates to a method for preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis; comprising administering to a patient in need thereof an effective amount of a composition obtainable by a process comprising: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and a 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each independently is a (C1-C4) alkyl chain, preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, and the mixture further comprises an effective amount of an antibacterial 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 it at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention. The antibacterial agent may be as described above.

[0155] In said further aspect, the present invention therefore also relates to the use of a composition for the preparation of a medicament for preventing or treating an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, wherein said composition is obtainable by a process comprising the following steps: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a compound of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) wherein R 1 、R 2 、R 3 and R 4 Each independently is a (C1-C4)alkyl chain, preferably tetraethoxysilane, and a 5 )(OR 6 )(OR 7 )(OR 8 ) wherein R 5 、R 6 、R 7 and R 8 Each independently is a (C1-C4) alkyl chain, preferably methyltrimethoxysilane, in a molar ratio of 80:20 to 50:50, and the mixture further comprises an effective amount of an antibacterial 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 it at a temperature of about oral temperature. The product obtained according to the method also forms part of the present invention. The antibacterial agent may be as described above.

[0156] In a further preferred embodiment of said further aspect of the invention, the composition is one wherein the silica-based sol-gel precursors of the mixture of step (i) and their relative amounts are as defined above in any preferred embodiment of the first aspect of the invention.

[0157] In a further preferred embodiment of said further aspect of the invention, the composition is a composition wherein the mixture of step (i) comprises a solvent as defined in any preferred embodiment of the first aspect of the invention described above. Preferably, the amount of the solvent is as defined in any preferred embodiment of the first aspect of the invention described above.

[0158] In a further preferred embodiment of said further aspect of the invention, step (ii) is as defined in any preferred embodiment of the first aspect of the invention defined above as regards step (ii).

[0159] In a further preferred embodiment of said further aspect of the invention, step (iii) is as defined in any preferred embodiment of the first aspect of the invention defined above as regards step (iii).

[0160] Throughout the specification and claims, the word "comprising" and its variations are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprising" encompasses "consisting of" and "consisting essentially of." Other objects, advantages, and features of the present invention will become apparent to those skilled in the art upon reading the specification or may be learned through practice of the invention. The following examples are provided for illustration only and are not intended to limit the present invention.

[0161] Example Example 1: Preparation and characterization of hybrid organic-inorganic materials as anti-infective coating compositions General procedure for coating composition preparation As shown in Table 1, methyltrimethoxysilane (MTMOS) and tetraethyl orthosilicate (TEOS) were mixed in different molar ratios and dissolved in 2-propanol at a volume ratio of 1:1. Octenidine was added to the solution at several different concentrations (1.0, 2.0, 5.0, and 7.5 wt%). 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 to proceed through siloxane bonding. The resulting compound was cured at 37°C for another 10 minutes.

[0162] Table 1 below summarizes the materials prepared: Table 1 It will be apparent to one skilled in the art that the TEOS:MTMOS molar ratios of samples C1-C4 are outside the scope of the present invention. Therefore, these materials are provided as comparative examples.

[0163] All samples M1-M5 were characterized by FT-IR spectroscopy. -1 、1105cm-1 and 760cm -1 There are absorption peaks at 1655cm, which correspond to the vibration mode of polysiloxane compounds, which can verify whether the gel material is successfully formed. -1 and 2920cm -1 The presence of a peak at explains the presence of octenidine in the formed materials M2 to M5. The intensity of the peak increases with the concentration of octenidine in the material.

[0164] General procedure for coating surface preparation : A certain volume of a mixture of methyltrimethoxysilane (MTMOS) and tetraethyl orthosilicate (TEOS) in different molar ratios as shown in Table 1 was added to a solution of the same volume of octenidine in 2-propanol. The amount of octenidine is shown in Table 1 (1.0, 2.0, 5.0 and 7.5 wt%, the weight % being based on the weight of the siloxane precursor). A stoichiometric amount of aqueous nitric acid solution (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 the precursor to hydrolyze and condense through the siloxane bonds. The solution was transferred to a SAE-Ti disk by dip coating. The disk was placed at 60 cm / min. -1 The sol-gel solution was immersed in the solution for 1 min and then heated at 100 cm min -1 The materials were also cast onto glass slides to evaluate hydrolytic degradation and antimicrobial release. The samples were then cured at 37°C for 10 minutes.

[0165] like Figure 11 As shown, the results of cross-section analysis performed on metal surfaces coated with M1, M2 or M5 are presented. The coating composition adhered well to the metal surface as no material appeared to be detached from the metal surface.

[0166] Following a similar procedure, compositions C1, C2, and M6 were coated on 316L square steel sheets. The coated sheets were placed in a 100% humidity environment at 37°C for 10 minutes. After this, the top side of the coated surface of the workpiece was wiped with a paper towel to qualitatively assess the degree of curing and adhesion of the material to the substrate surface. Figure 12 As shown, sample M6 was the only sample where the coating cured and adhered to the surface as no material appeared to have been rubbed off the metal surface.

[0167] General procedure for hydrolytic degradation tests To obtain samples for hydrolytic degradation studies, glass microscope slides were coated with the sol prepared according to the above procedure using the drop casting method. The coated slides were heated at 37°C for 10 minutes to cure the coating. Before preparing the coated slides, the wettability of the slides was improved by ultrasonic cleaning. The slides were ultrasonically treated (Sonoplus HD 3200) in a HNO3 (25%, w / w) solution for 15 minutes, and then the ultrasonicated slides were rinsed three times in distilled water. Finally, the slides were dried in an oven at 100°C and stored in a desiccator.

[0168] The polysiloxane network degrades in aqueous media by hydrolysis as follows: SiO2(s) + 2 H2O → Si(OH)4(aq) Hydrolytic degradation was assessed using gravimetric measurements by comparing the weight of the coating compositions before and after immersion for different periods of time in distilled water at 37° C. Approximately 25 mg samples of each coating composition were used.

[0169] Figure 1 The results of the assay are presented. The results show that the hydrolytic degradation rate of the material containing octenidine is faster than the degradation rate of the material without octenidine (M1).

[0170] General procedure for octenidine release rate measurements The amount of antimicrobial released during network degradation was assessed using UV-visible spectroscopy. A 1g sample of the coating was immersed in 50mL of distilled water and placed in an incubator at 37°C for up to 1 month. At several time points, 5mL samples were removed and the biocide concentration was determined. The absorbance of octenidine was measured at λ = 282nm. A linear calibration curve for octenidine was obtained. Measurements were performed in triplicate.

[0171] Figure 2 The release kinetics of octenidine from materials M2-M5 are shown. Figure 8 The release kinetics of octenidine for comparative materials C1-C4 are shown.

[0172] Figure 2 The results show that materials M2-M5 have similar performance in releasing octenidine. The release of octenidine lasts for at least 14 days. This is advantageous because it allows: (i) provide anti-infective medications during the first few days after surgery when specifically needed to prevent or treat the development of an infection that may ultimately result from the surgical procedure, and (ii) Gradual release of anti-infective agents over several days to prevent or treat the development of new infections.

[0173] from Figure 2It can also be inferred from the data that when the concentration of octenidine in the gel material increases, the amount of octenidine released will be faster.

[0174] Furthermore, when the material includes at least 2% octenidine by weight, the concentration of octenidine released into the medium after two hours under the assay conditions is greater than 2 mg / L. This is particularly advantageous because such concentrations are known in the art to be above the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for Staphylococcus aureus and are therefore suitable for eradicating the bacteria.

[0175] also, Figure 8 The results show that increasing the proportion of TEOS in the sol-gel material according to the prior art results in increasingly immediate release of octenidine, due to the resulting material's more hydrophilic nature, making it more susceptible to hydrolytic degradation. For example, composition C2 (10% TEOS) showed that almost all of the octenidine released at 28 days was released at day 14; composition C3 (20% TEOS) showed that almost all of the octenidine released at 28 days was released at day 7; and composition C4 (30% TEOS) showed that almost all of the octenidine released at day 28 was released at day 3.

[0176] However, composition M3 (60% TEOS) according to the present invention showed a sustained release of octenidine until day 14. Figure 8 Comparing the results of compositions C2 to C4 in Figure 3, this is completely unexpected, as further increasing the amount of TEOS would have been expected to shorten rather than extend the release period of octenidine. Thus, the compositions of the present invention are unexpectedly able to release large amounts of octenidine without sacrificing the release rate.

[0177] Sustained release of octenidine advantageously allows for provision of anti-infective agents over a longer period of time and has a positive effect on the prevention or treatment of peri-implantitis because it allows for delivery of the antimicrobial agent for at least 14 days after surgery or coating application to avoid the development of new infections and prevent recurrence of infections.

[0178] General procedure for cell viability assay Cell culture The material was evaluated in vitro using human fibroblasts (HFB) and human osteoblasts (MG-63). The cells were cultured at 37°C in a humidified (95%) CO2 incubator in Dulbecco's modified Eagle's medium (DMEM) supplemented with 1% penicillin / streptomycin and 10% FBS. Prior to cell culture, the coated Ti disks were sterilized by exposure to UV radiation for 30 minutes. Uncoated Ti samples served as controls.

[0179] Cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Titanium disc samples were coated with different compounds, and the Ti was immersed in 5 mL of culture medium and placed on a shaker at 37°C. The culture medium was removed after different time periods (2, 7, 14, and 21 days) and replaced with 5 mL of fresh culture medium. All extracts were obtained under sterile conditions and frozen. At the same time, cells were cultured at 9×10 4 Cells were plated at a density of 10 cells / mL in complete medium in a 96-well sterile culture and incubated for 24 hours at 37°C in a humidified atmosphere of 5% CO2. To test the toxicity of the extracts, the culture medium was replaced with the corresponding extract and incubated for another 24 hours. Cell viability was analyzed after adding MTT (0.5 mg / mL) solution in PBS and incubating at 37°C for 3 hours. Excess culture medium and MTT were removed and washed with PBS. Dimethyl sulfoxide was added to dissolve the formazan crystals formed in the living cells. The mixture was stirred for 10 minutes and the absorbance was measured at a wavelength of 570 nm using a Biotek Synergy HT detector. The percentage of cell viability was calculated as follows: Cell survival rate (%) = 100 × (ODS-ODB) / (ODC-ODB), where ODS, ODB and ODC are the optical densities of the formazan products of the sample (S), blank (B) (culture medium without cells) and control (C), respectively.

[0180] Figure 3 Shown are changes in cell viability (FBH, expressed as a percentage) of human fibroblasts in contact with samples M1-M5 prepared in Example 1 over time ((a): 1 day, (b): 2 days, (c): 7 days) and measured according to the MTT cell viability assay. Figure 3 The results showed that materials M1-M5 did not exhibit cytotoxicity, as the cell viability was above 70% even after 7 days.

[0181] Figure 4 The cell viability of human osteoblasts (MG-63, expressed as a percentage) in contact with samples M1-M5 prepared in Example 1 is shown over time ((a): 1 day, (b): 2 days, (c): 7 days)) and was measured according to the MTT cell viability assay.

[0182] General procedure for adhesion assay Titanium disks (with and without coating) were placed in a 24-well plate. 5FBH or MG-63 cells / mL are seeded on the dish and (at 37 ℃ and 5%CO 2 ) hatched 24h.Different dishes are transferred to new 24-well plates to exclude cells adhering to the holes.After different time periods (1, 2 and 7 days), culture medium is removed and cell adhesion and proliferation on the quantitative disc are measured using alamarBlue assay.Cells are incubated together with 10% alamarBlue solution in fresh culture medium without phenol red.After 3h, the solution is transferred to a 96-well plate and replaced with fresh culture medium.On a UV Biotek Synergy HT detector, the fluorescence of the culture medium after transfer is measured at 530nm (excitation) and 600nm (emission).The average baseline fluorescence of the control culture medium (negative control) without cells is subtracted to obtain sample fluorescence.All experiments were repeated five times, and one-way analysis of variance (relative to Ti) was performed to determine the significant differences between the results. Figure 5 and Figure 6 Shown are the changes in cell proliferation over time of human fibroblasts (FBH) and human osteoblasts (MG-63) in contact with samples M1-M5, respectively.

[0183] General procedure for determining the effectiveness of fungicides The antimicrobial activity of the materials was determined using Staphylococcus aureus CECT 86, following the method described in ISO 22196:2011. The bacterial inoculum was obtained by growing a preculture in Luria Broth (LB; 0.5% yeast extract, 1% tryptone, and 1% NaCl, all provided by Difco Laboratories, Detroit, Michigan, USA) at 37°C overnight until stationary phase was reached. A bacterial stock solution was prepared from the preculture; a sample was taken with a sterile inoculating loop and diluted with PBS to obtain an optical density of 0.1 at 550 nm (OD550 = 0.1) (A600 BOECO S-22 spectrophotometer). This value corresponds to 1.6 × 10 7 The bacterial concentration in CFU / mL was calculated by interpolating the A550 value from the standard curve of CFU versus optical density. 5 The final test inoculum was obtained by inoculating titanium discs (ø = 16 mm) coated with M1-M5 with 100 μL of the test inoculum and incubating for 24 h at 37°C in a humidified atmosphere. The samples were washed several times with 900 mL of PBS; this suspension was used to determine the final CFU using a standard agar diffusion method. The results reported are relative to the control value (uncoated titanium disc). The experiment was performed in triplicate.

[0184] The results are expressed as relative cell viability (RCV): RCV(%)=N / N 对照 ×100 Where N is 1cm 2- The number of CFU on the sample.

[0185] All data are presented as mean ± SD. Statistical analysis was performed using one-way ANOVA. *P < 0.05 and **P < 0.001 indicate significant differences.

[0186] Figure 7 The results of the tests performed are shown: A clear bactericidal effect can be seen when the material comprises at least 1% by weight of octenidine.

[0187] Protein layer elution and proteomic analysis The protein layers on the different sol-gel formulations were examined after incubation for 3 hours with 1 mL of human serum from male AB plasma (Sigma-Aldrich) in a humidified atmosphere (37°C, 5% CO2). The serum was removed, and unadsorbed proteins were removed by five consecutive washes with ddH2O and one wash with 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), 4% sodium dodecyl sulfate (SDS), and 100 mM dithiothreitol (DTT). Four replicates were performed for each material, with each replicate pooling the results of four different treatments.

[0188] The eluted proteins were characterized using electrospray tandem mass spectrometry using a nanoACQUITY UPLC (Waters, Milford, MA, USA) coupled to an Orbitrap XL (ThermoElectron, Bremen, Germany). The protocol described by Romero Gavilán et al. in Biofouling 2017, Vol. 33 (8), pp. 676-689 was followed and incorporated herein by reference. Four replicates were analyzed for each condition. Proteomic results were examined using PEAKS (Bioinformation Solutions Inc., Waterloo, Canada). For statistical analysis, a Student's t-test was performed using PEKS, and differences in protein adsorption were considered statistically significant at p ≤ 0.05 and when the ratio was higher than 1.5 in either direction.

[0189] Table 2 shows the comparative proteomic analysis between proteins adsorbed on the sol-gel composition M3 with 2% octenidine relative to the control M1 (0% octenidine). The results of Table 2 show that the composition according to the invention is biocompatible and suitable for in vivo use, since there is no statistically relevant variation between the p-values obtained for samples M3 and M1. In fact, variations between 0% and 2% are considered to have no statistical relevance.

[0190] Clinical trials and results By introducing the implant into the tibia of New Zealand white rabbits (Oryctolagus cuniculus), a comparative study was conducted between uncoated titanium implants and titanium implants coated with material M3. The implants used in this study were purchased from GMI Dental Implantology and were suitable for internally connected titanium dental implants with a diameter of 3.75 mm and a length of 8 mm. The coated implants were prepared in an absolute clean room by dipping the implants in the sol prepared as described above and solidified according to the above procedure. Prior to the clinical study, the prepared implants were packaged and sterilized by UV irradiation.

[0191] The implants were surgically introduced as follows: female rabbits were weighed and administered a pre-anesthetic dose of a mixture of ketamine and xylazine, followed by a dose of butorphanol and prophylactic antibiotics. Propofol was administered as a sedative and was administered continuously during surgery. Using a progressive milling technique, the tibia was perforated with drill bits 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.

[0192] After sacrifice, the tibia was cut open with a saw for osteotomy and fixed and preserved by immersion in 40% ethanol at 4°C. The samples were dehydrated under vacuum using increasing ethanol solutions until anhydrous 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 enable visualization of the bond lines using stains (taints). Insertion into the matrix involved immersing the samples in a solution of methyl methacrylate (monomer, Sigma-Aldrich), dibutyl phthalate (plasticizer, Sigma-Ardrich), and increasing concentrations of benzoyl peroxide as an initiator. Finally, the samples were introduced into glass flasks, and once the monomers were added, the mixture was heated at 40°C to polymerize. The resulting samples were then cut (EXAKT®) and treated with a stain (Gomoritrichrome). The stained samples can distinguish growing bone and osteoid (red tints) from more mature bone tissue (blue tints). Fibrous tissue and cytoplasm also stain red and can be identified by their morphology.

[0193] The response to the presence of foreign objects, such as implants, was assessed by subjective and semiquantitative evaluation of the inflammatory response associated with the presence of implants. This response is a preparatory reaction of the organism to a foreign object, aimed at isolating it from the organism and, if possible, rejecting it. The organism's response to the presence of a foreign object is a non-allergic inflammatory reaction, whereby tissue cells and macrophages intervene to isolate the foreign object, followed by the involvement of phagocytes.

[0194] The bone's response to an implant is a natural reaction that occurs to repair damage, and its prolonged duration will trigger a fibrotic response. It is determined by evaluating 12 factors ranging from 0 to 3, depending on whether they are undetectable or their frequency is mild, moderate or severe. A semi-quantitative evaluation system based on ISO 10993-6 (2009) is used, and 5 categories of parameters are evaluated: 1. Bone marrow condition (defined as the degree of bone damage); hypoplasia (1), loss of architecture (2), presence in areas of the bone marrow not in contact with the implant (3), fat ratio (4); 2. Necrosis, defined as the degree of trauma to the cortical bone (5) and trabecular bone (6) caused by the implant effect; 3. The presence of large foreign body reaction pools (7) attached to different surfaces (titanium in the case of the control and coatings 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), and between the trabecular bone and the implant (10), and the degree of densification (11); 5. Neovascularization (12). Based on the obtained scores, the implants were determined to be non-irritating (0-6), mildly irritating (6-18), moderately irritating (18-30), and severely irritating (30-36).

[0195] Biocompatibility evaluation results The biocompatibility of a material can be defined as its biological acceptability to the body. This biocompatibility can be examined at several levels, one of which is the interaction between the material and the surrounding tissue. Therefore, during the development of biomaterials, it is crucial to study their effects on adjacent tissues after implantation in the body. To this end, Figure 9 and Figure 10 As shown, it has been confirmed that the developed new coating composition does not cause adverse reactions on tissues.

[0196] Fibrous capsule formation like Figure 13As shown, coating an implant with the coating of the present invention, which is made from a silicon-based precursor containing a high content of a tetra(alkoxy)silane compound, can prevent the formation of a fibrous capsule. Of particular note is that when a low content of tetra(alkoxy)silane (e.g., 10% TEOS) coating is used on an implant, a fibrous capsule is formed (in the presence of Figure 13 When the implant is coated with the material according to the invention, surprisingly no such capsules are observed.

[0197] Clinical trials in beagle dogs The pathogenesis and treatment of peri-implantitis are investigated in experimental studies in animal models in which the hard and soft tissues supporting the implants develop peri-implantitis. This is achieved by placing a ligature around the peri-implant groove and subsequently abandoning plaque control measures.

[0198] Experimental procedures of clinical trials: Eight adult female beagle dogs underwent the following procedures: (1) Mandibular premolar extraction; (2) 3 months after step 1, an internally connected implant Frontier® (GMI, Barcelona, Spain) with a sandblasted and etched surface was inserted in place of the mandibular premolar (T0 sample corresponds to the mucosal sample collected before implant insertion); (3) development of peri-implantitis 3 months after step 2 by ligating the implant and abandoning sanitary plaque control measures; (T3 samples correspond to mucosal samples collected before implant ligation); (4) ligature removed 3 months after step 3 - (T6 sample corresponds to the mucosal sample collected immediately after ligature removal); (5) One month after step 4, the tissue surrounding the implant was examined and the implant was randomly treated with composition M3 or placebo; (T7 sample corresponds to the mucosal sample collected before the treatment); (6) 3 months after step 5, examine the tissue surrounding the implant and the implant; (T10 sample corresponds to the mucosal sample collected 3 months after step (5) treatment) (7) Three months after step 6, the animals were sacrificed to isolate bone samples.

[0199] Histological study of the mucosa surrounding the implant Samples obtained from dogs at T0, T3, T6, T7, and T10 were enclosed in paraffin, and samples were cut at a thickness of 4 μm and stained with hematoxylin-eosin according to standard procedures for microscopic observation. Figure 14As shown, different areas of the mucosa surrounding the implant were found to be particularly attractive for histological study: the epithelium (E), the infiltrating connective tissue in the connective tissue papillae (TCI1), and the infiltrating connective tissue in areas distal to the epithelium (TCI2). The inflammatory infiltrate was associated with the presence of plasma cells, lymphocytes, neutrophils, and macrophages in these areas and was qualitatively scored according to the following scoring system: 0 - no infiltration, 1 - slight infiltration, 2 - moderate infiltration, 3 - heavy infiltration.

[0200] Figure 15 Microscopic photographs of mucosal samples at T0 are shown.

[0201] Figure 16 Microscopic photographs of mucosal samples at T3 are shown.

[0202] Figure 17 Microscopic photographs of mucosal samples at T6 are shown.

[0203] Figure 18 Microscopic photographs of mucosal samples at T7 are shown.

[0204] Figure 19 Microscopic photographs of mucosal samples at T10 are shown.

[0205] Table 3 below summarizes the scores for samples collected from different areas of the mucosa (TCI1 and TCI2) at different times of the assay for each dog tested: Table 3 *Mixture M3 treatment for dogs The results in Table 3 show that after treatment of the implants with mixture M3, the inflammatory process could be reversed, especially in the area close to the epithelium.

[0206] Immunohistochemistry was also performed on the samples to detect the presence of biomarkers associated with inflammatory responses, namely substance P and NKx1 receptor. To this end, the samples were removed from paraffin and hydrated, followed by heating at pH 6 (citrate buffer). Endogenous peroxidases were then inhibited and the samples were treated with normal donkey serum. The samples were then 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 / vo). An LSAB system (vectastain, Véctor) and diaminobenzidine (Sigma-Aldrich) were used as chromogenic agents.

[0207] The receptor NKx1 could be identified in all samples. It was recognized in all samples; however, the extent and intensity of staining were greater with increasing inflammation and weaker in pre-implantation samples. NKx1 is expressed in epithelial cells, endothelial cells, neural pathways, leukocytes, macrophages, and plasma cells.

[0208] The amount of substance P increases with chronic inflammatory response. Figure 20 As shown, a relationship between substance P and inflammatory response was observed, and substance P expression was restored after dogs were treated with mixture M3.

[0209] Bone histological results The bone samples obtained from step (7) were placed in a 10% vol / vol formalin solution. The canine mandibles were intact in vials with a numerical code that was used to identify the animal. Once the implants were separated in separate containers, the samples were first labeled with the last 4 digits of the canine code, R or L, depending on whether they were left or right and the numbers were labeled from mesial to distal. The samples were prepared according to the method described by 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 alcohol at increasing concentrations and infiltrated in a mixture of ethanol and methacrylic diol (Technovit 7200 VLC, Heraus Kulzer, Werheim, Germany). Subsequently, they were polymerized by immersion in pure resin (Technovit 7200) using a specific light source and heated at 37°C for 24 hours to ensure complete polymerization.

[0210] Each implant was then centrally sectioned by: (i) radiographing each sample; and (ii) sectioning with a diamond band saw (Exakt Apparatebau, Norderstedt, Germany). The sample was then polished to a flat, defect-free surface. The block was then bonded to a shaped glass slide using a Technovit 7210, and sections of approximately 200 microns were made and reduced by micropolishing (Exakt Apparatebau, Norderstedt, Germany) using 1200 to 4000 grit silicon carbide polishing cloths (Struers, Copenhagen, Denmark). When they reached approximately 40 microns in thickness, they were all stained together using the Levai–Laczkó method. This staining technique combines two blues (methyl blue and sky blue II) with basic fuchsin (violet). This staining is commonly used for bone embedded in resin. Bone stains pink, cartilage stains violet, and collagen fibers stain bluish-violet. Slides were scanned using a motorized optical microscope and a digital camera (BX51, DP71, Olympus Corporation, Japan) connected to a computer. The images were taken at a magnification of x40 (increase).

[0211] The analysis was performed by researchers who were blinded to the treatment groups used and were not disclosed to these groups until their analysis was complete. Measurements were obtained using the Cell-sens 1.5 image analysis program (Olympus Corporation, Japan).

[0212] The results demonstrated that control implants exhibited bone resorption in the coronal contact area with the implant, often accompanied by an increased number of lymphocytes, indicating a chronic inflammatory process. This resulted in the observation of a pocket around the implant. This phenomenon was also observed to a lesser extent in the treated group. This fact was investigated during the disc surgery measurements.

[0213] Figure 21 The results showed that treatment with the coating allowed regeneration of soft tissue with little or no inflammation-related pocket formation around the implants, demonstrating the coating's benefit in preventing the development of inflammatory processes such as peri-implantitis.

[0214] Mechanism of action The mechanism of action of the composition of Example 1 was further investigated by parallel experiments investigating the proliferation of Streptococcus gordonii on grade IV titanium plates that were uncoated, coated with M1 (no octenidine), M3 (2% octenidine by weight), or coated with an octenidine solution containing an equal amount of octenidine and composition M3. The following experimental procedure was used.

[0215] All materials used were sterile or had been previously autoclaved. The assays were performed in a Class 2 biosafety cabinet. Three different Class IV Ti dishes were used for the assays. The following procedure was followed for each assay: First, a suspension of Streptococcus gordonii (CECT 804) of known concentration was prepared. To do this, an experimental tube was prepared with 10 mL of ddH2O, to which the bacteria were added until the desired concentration (concentration = 1 x 10 6 CFU / mL). These data were verified by direct measurement at 600 nm by spectrophotometry. 500 μL of a bacterial suspension of known concentration (1 x 10 6 CFU / mL) was added to the wells of a sterile 24-well plate. Subsequently, the Grade IV Ti disc was immersed in the bacterial suspension for 1 minute (1 disc per well) to inoculate the disc. After inoculation, the Grade IV Ti disc was immersed in 500 μL of mixture M1, mixture M3 or octenidine solution for 1 minute (1 disc per well - for comparison, a control experiment with no mixture at all was also performed). This procedure was performed 3 times for each disc. Once coated, the Grade IV Ti disc was cured in a sterile 24-well plate. When the product Grade IV Ti disc was cured, the Grade IV Ti disc was placed on a sterile agar plate. This procedure was completed using 3 different plates (1 disc per well). Finally, the agar plate was incubated at 37°C for 24 hours according to the culture protocol for S. gattii to allow the bacteria to proliferate correctly.

[0216] After this period, the bacterial population is counted. For bacterial counts, the inoculated Ti-grade IV discs are removed. Afterwards, three mini discs of known diameter are extracted from each plate using a punch (at the same location where the inoculated disc was placed). Once the mini discs are obtained, they are placed in a falcon tube containing 1 mL of ddH2O and vortexed to suspend the bacteria attached to the agar. Once the suspension is inside the falcon, the CFUs adhering to the agar are obtained according to the following protocol: a) From the obtained bacterial suspension, nine serial dilutions (1:10) are made for each replicate and condition; b) Each dilution (100 μL per agar plate) is added to a sterile agar plate; c) After addition, it is placed in an incubator at 37°C for 24 h; d) After this, the CFU count is performed on those plates where 30–300 colonies can be counted.

[0217] Figure 22 The results showed that after 24 hours of incubation on discs coated with M1 or M3, the bacterial population did not proliferate at all, while a significant decrease in bacterial proliferation was observed on discs coated with octenidine solution.

[0218] The bacteria counts attached to the titanium surface were performed on these samples. The average results (three samples were measured for each disc) are shown in Table 9: Table 9 The experimental surfaces M1 and M3 are suitable for preventing the proliferation of bacterial populations on the surface of a substrate coated with M1 or M3. Surprisingly, coating an implant substrate with a composition that does not contain an antimicrobial agent (such as composition M1) can prevent bacteria from adhering to the surface of the substrate. This effect cannot be achieved using octenidine alone because some bacterial proliferation is still observed. Therefore, without being bound by any theory, it is believed that the sol-gel precursor of the mixture forms a physical barrier after curing, sealing the substrate site to prevent possible entry of bacteria. It is also believed that the film is also suitable for embedding bacteria adhered to the surface of the substrate, thereby eliminating bacterial populations adhered to the surface of the substrate. In some embodiments, the physical barrier is strong enough to allow regeneration of soft tissue around the implant, thereby effectively preventing the development of inflammatory reactions associated with peri-implant infection.

[0219] Furthermore, octenidine is thought to have an adjuvant effect and, once released from the cured sol-gel material, provide an antimicrobial effect, acting as a physical barrier between bacteria in the physiological medium and the implant surface.

Claims

1. A method for preparing a composition, comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising 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 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 Each independently is a (C1-C4) alkyl chain, formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) compounds: formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) in a molar ratio of 80:20 to 50:50, the mixture further comprising octenidine in an amount of 1 to 7.5 grams per 100 grams of the silica-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 the material at a temperature of about oral temperature.

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

3. The method according to any one of claims 1 to 2, wherein the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) and the compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) in a molar ratio of about 60:

40.

4. The method according to any one of claims 1 to 3, wherein the silica-based sol-gel precursor of the mixture of step (i) comprises at least 80% by weight of the silica-based sol-gel precursor relative to the total weight of the silica-based sol-gel precursor. 5 )(OR 6 )(OR 7 )(OR 8 ) and the compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) compounds.

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

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

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

8. The process according to any one of claims 1 to 7, wherein step (ii) is performed at a temperature between 50°C and 100°C, preferably about 70°C.

9. The process according to any one of claims 1 to 8, wherein step (iii) is performed.

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

11. The composition according to claim 10 for use in medicine.

12. The composition according to claim 10, for use in preventing or treating an inflammatory process, such as mucositis or peri-implantitis, preferably peri-implantitis.

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

14. A composition comprising a mixture comprising a silica-based sol-gel precursor comprising 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 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 Each independently is a (C1-C4) alkyl chain, formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ) compounds: formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ) in a molar ratio of 80:20 to 50:50, and the mixture further comprises octenidine in an amount of 1 to 7.5 grams per 100 grams of the silica-based sol-gel precursor.

15. A composition for use in preventing or treating an inflammatory process such as mucositis or peri-implantitis, preferably peri-implantitis, wherein the composition is obtainable by a method comprising the steps of: (i) providing a mixture comprising a silica-based sol-gel precursor comprising a silica-based sol-gel precursor having a molar ratio of 80:20 to 50:50 of the formula Si(OR 1 )(OR 2 )(OR 3 )(OR 4 ), preferably tetraethoxysilane and a compound of formula Si(R 5 )(OR 6 )(OR 7 )(OR 8 ), preferably methyltrimethoxysilane, wherein R 1 、R 2 、R 3 and R 4 Each independently represents a (C1-C4) alkyl chain, R 5 、R 6 、R 7 and R 8 are each independently a (C1-C4) alkane chain; (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 the material at a temperature of about oral temperature.

16. The composition for use according to claim 15, wherein the composition does not comprise biologically active particles, drugs or peptides / does not comprise peptides.

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