A novel cleaning and / or debridement composition

Abstract

The present invention relates to a new multifunctional debridement and / or antifouling composition comprising sodium fluoride (NaF), poloxamer, and a phosphate citrate buffer, wherein the composition is in liquid form at room temperature, such as at a temperature of at the most 20°C and has a pH of approximately pH 5.5. The composition disclosed herein is antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory and is particularly useful in cleaning and / or debriding a biological surface and or a biomaterial surface in situ, such as for use in cleaning and / or debriding implants, dental prosthetics and / or teeth. It can be used for removal of calculus, prophylactic use and / or as a cosmetic composition.

Description

[0001] A NOVEL CLEANING AND / OR DEBRIDEMENT COMPOSITION

[0002] TECHNICAL FIELD

[0003] The present invention relates to a new multifunctional debridement and / or antifouling composition comprising sodium fluoride (NaF), poloxamer, and a phosphate citrate buffer comprising citric acid (C6H8O7) and disodium hydrogen phosphate (Na2HPO4), wherein the composition is in liquid form at room temperature, such as at a temperature of at the most 20°C and has a pH of between pH 5.2 - 6.2, such as approximately pH 5.5, and wherein said poloxamer in the composition displays micelle-forming capacity. The composition disclosed herein is antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory and is particularly useful in cleaning and / or debriding a biological surface and or a biomaterial surface in situ, such as for use in cleaning and / or debriding implants, dental prosthetics and / or teeth. It can be used for removal of calculus, prophylactic use and / or as a cosmetic composition.

[0004] The present invention further relates to the use of a composition according to the present invention for cleaning and / or debriding a biological surface and / or a biomaterial surface, such as, in particular, an implant, dental prosthetics and / or teeth in situ and / or a surface in the oral cavity. The composition according to the present invention can be used together with an implant cleaning and / or debridement tool, e.g. a brush, burr or a curette.

[0005] In one embodiment, the composition according to the present invention is provided in a kit, wherein the composition is provided in one vial and / or syringe ready for application.

[0006] BACKGROUND

[0007] Biological surface and / or biomaterial surfaces in situ are prone to fouling, i.e. the build-up of biofilms and necrotic tissue, as they are in constant contact with and frequently colonized by a plethora of microorganisms. They therefore require periodical cleaning and debridement with compositions that are antibacterial, bacteriostatic and / or antiinflammatory without causing harm to the surrounding biological tissue in the patient and without causing microbial resistance.

[0008] Biofilms

[0009] Biofilms are structured communities of microorganisms that can be firmly attached to a surface and enmeshed in a self-produced three-dimensional (3D) extracellular matrix. Biofilms can form on, or in, living or non-living surfaces and can exist in natural and industrial settings. Biofilms can be formed on the surface or within implanted medical tubing and medical devices, as well as on the surface and within the human body, e.g. on mucosal surfaces, or on surfaces of other bodily orifices, or in open wounds, which can lead to infections in patients. The inflammatory responses to this, in turn, lead to the build-up of necrotic tissue, which subsequently cause follow-up inflammatory responses of the body. In particular, biofilms can develop within the oral cavity and often result in oral diseases such as dental caries or periodontitis, gingivitis or peri-implantitis. The extracellular matrices of such biofilms contain polymeric substances, such as exopolysaccharides (EPS). The matrix produced by microorganisms can provide an essential scaffold for biofilm assembly. Additionally, it can promote microbial adhesion and cohesion while hindering diffusion, thereby making biofilms extremely difficult to treat or remove from surfaces.

[0010] The extracellular matrix contributes to the difficulty in the elimination of microbial biofilms within the oral cavity and human body, as well as on biomaterials, e.g., implants and medical devices, by antibodies, antibiotics and immune cells, which are largely unable to penetrate the dense extracellular matrix to kill the embedded microorganisms.

[0011] Biofilms on biological surfaces as well as on implants can be removed by chemical and / or mechanical cleaning and / or debridement.

[0012] Debridement

[0013] Debridement is the medical removal of a patient's dead, damaged and / or infected tissue to improve the healing potential of the remaining healthy tissue. Debridement removal may be surgical, mechanical, chemical, autolytic (self-digestion), and by maggot therapy, wherein certain species of live maggots selectively eat only necrotic tissue.

[0014] Still, the mechanical cleaning and / or debridement of a surface, is not enough as it is not able to provide any secondary chemical and / or biological cleaning / decontamination effect, thus e.g. leaving the surface open for immediate repopulation of microbes, or even leaving traces of the prior microbial populations, e.g. on the inaccessible areas of rough surfaces.

[0015] Thus, there are several antimicrobial and / or anti-inflammatory agents used in anti-fouling treatments today.

[0016] Poloxamers

[0017] Pluronics® or poloxamers are tri-block copolymers of poly(ethylene oxide) polypropylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO). This group of synthetic polymers is thermo- reversible in aqueous solutions. The sol-gel transition is governed by the composition, molecular weight, and concentration of each constituent block polymer. The hydrophilic ethylene oxide and the hydrophobic propylene oxide give poloxamers an amphiphilic structure - meaning they have a polar, water-soluble group attached to a nonpolar waterinsoluble hydrocarbon chain. Amphiphilic block copolymer molecules self-assemble into micelles (a packed chain of molecules) in aqueous solution. Micelle formation is temperature dependent and affects the degradation properties of the biomaterial: below a certain characteristic temperature known as the critical micelle temperature, both the ethylene and propylene oxide blocks are hydrated and the PPO block becomes soluble.

[0018] Poloxamers can be found either as liquids, pastes or solids. Due to their amphiphilic characteristics (presence of hydrophobic and hydrophilic components), poloxamers possess surfactant properties which allow them to interact with hydrophobic surfaces and biological membranes. Being amphiphilic also results in the ability of the individual block copolymers, known as unimers, to combine and form micelles in aqueous solutions. When the concentration of the block copolymers is below that of the critical micelle concentration (CMC), the unimers remain as molecular solutions in water. However, as the block copolymer concentration is increased above the CMC, the unimers will self-assemble and form micelles, which can take on spherical, rod-shaped or lamellar geometries. Their shapes depend on the length and concentration of the block copolymers (i.e. EO and PO), and the temperature. Micelles usually have a hydrophobic core, in this case the PO chains, and a hydrophilic shell, the EO chains.

[0019] Pluronic'8' F-127

[0020] Pluronic® F-127, also known as Poloxamer 407, is often used in tissue engineering because of the commercial availability of a consistent product that will undergo a sol-gel transition near physiological temperature and pH. A disadvantage of Pluronic F-127 is its fast degradation rate in vivo. To overcome this problem, Pluronic F-127 is frequently crosslinked with another a-hydroxy or amino acid in order to alter the chemical structure of its depsipeptide unit. Poloxamers form thermo-sensitive hydrogels, which are typically stabilized by addition of high-molecular-weight acids, such as hyaluronic acid.

[0021] Studies have documented the positive effects of poloxamer formulations in reducing inflammation, protect tissues against damage and hinder microbial adhesion.

[0022] Furthermore, it is EMA and FDA approved, completely biocompatible and safe to use clinically with no known harmful effects in human cells.

[0023] Still, it is hard to apply as a cleaning and debridement agent because it will automatically form a stable gel at over 18°C, or even between temperatures of 12-20°C (see Figure 1) dependent of its concentration, which makes it unsuitable to use in small passages and / or for use on rough surfaces and does not lend it to application with a syringe.

[0024] The current inventors have prior demonstrated a novel formula of a poloxamer-based hydrogel with strong, non-ionic detergent properties with improved sol-gel dynamics for solubilization and entrapment of debris and microbes for effectively cleaning and / or debriding a biological surface and / or a biomaterial surface in situ. It is easy rinsed off with water, and it completely decomposes to water, oxygen and carbon oxide.

[0025] The poloxamer hydrogel is based on a combination of hydrogen peroxide (H2O2) and poloxamer in such a concentration that the composition is in a liquid form in RT, i.e. at a temperature of no more than 30°C, but due to elevation of temperature to body temperature, converts into a gel-state at the application site in situ.

[0026] It has in praxis been found to effectively clean and / or debride a biological surface and / or a biomaterial surface in the oral cavity, but to suffer from an all too rapid degradation of the poloxamers in the composition, once mixed with H2O2. Thus, the H2O2 component of the composition is typically provided in the form of a concentrate in a separate vial for mixing with the poloxamer-based hydrogel immediately before use and is preferably applied with a mixing connector. Although the antimicrobial and / or anti-inflammatory effect of that composition is sufficient, the practitioner perceives the need for a two-vial storage solution and the need to apply the composition immediately as cumbersome.

[0027] Consequently, there is still a need for an improved means for cleaning and / or debriding fouled biological surface and / or a biomaterial surface in situ, or a means for preventing fouling of said biological surface and / or a biomaterial surface in situ by cleaning and / or sterilizing said surfaces e.g., in the oral cavity. The present invention for the first time presents such a means for effectively cleaning and / or debriding even difficult to access areas and / or rough hard surfaces such as in the oral cavity with a composition that is premixed and delivered in a single-vial solution. SUMMARY

[0028] The current invention relates to a composition in the form of a hydrogel comprising: a. sodium fluoride (NaF) at a final concentration of between 0.1 -0.4% w / v, b. poloxamer at a final concentration of between 15-40% w / v, c. citric acid (C6H8O7) at a final concentration of between 0.5-1 .5% w / v, and d. disodium hydrogen phosphate (Na2HPC>4) at a final concentration of of between 1 .5-2.0% w / v, wherein the final pH is adjusted to approximately pH 5.5, such as between pH 5.2 - 6.2, and wherein the composition is liquid at below RT, i.e. , at the most 20°C, and wherein said poloxamer in the composition displays micelle-forming capacity.

[0029] In one embodiment, the composition according to the current invention has a final concentration of poloxamer, such as, but not limited to Pluronics®, Pluronic acid, Pluronic F-127 and / or Poloxamer 407 of 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30% w / v.

[0030] In one embodiment, the composition according to the current invention has a final concentration of sodium fluoride (NaF) of 0.1 , 0.15, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.35, or 0.4% w / v.

[0031] The composition comprises a phosphate citrate buffer comprising citric acid (C6H8O7) and disodium hydrogen phosphate (Na2HPC>4) at a pH of 5.5, wherein the pH is adjusted using citric acid.

[0032] In one embodiment, the composition according to the current invention has a final concentration of (C6H8O7) citric acid of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1 .2, 1 .3, 1 .4, 1 .51 .6, 1.7, 1.8, 1.815, 1.9, or 2.0% w / v. The citric acid can be in anhydrous, monohydrate or dihydrate form.

[0033] In one embodiment, the citric acid (C6H8O7) is citric acid monohydrate, and the final concentration of the citric acid (C6H8O7) monohydrate is 1.051 % w / v.

[0034] In one embodiment, the citric acid (C6H8O7) is anhydrous citric acid, and the final concentration of the anhydrous citric acid (C6H8O7) is 0.96% w / v. In one embodiment, the composition according to the current invention has a final concentration of Na2HPO4of 0.8, 0.9, 0.9605, 1 .0, 1 .1 , 1.2, 1.3, 1.4, 1.5, 1 .6, 1 .7, 1 .8, 1.815, 1.9, 2.0, 2.1 , 2.0% w / v.

[0035] In a currently preferred embodiment, the composition according to the current invention is a hydrogel comprising or consisting of: a) Sodium Fluoride: 0.2%, b) Poloxamer 407: 20%, c) Citric acid monohydrate: 1.051%, d) Disodium hydrogen phosphate anhydrous: 1.815%, and e) Water for injection: 76.934%.

[0036] The composition according to the current invention is for use in cleaning and / or debriding a biological surface and / or a biomaterial surface in situ, such as, but not limited to, for use in cleaning an implant, dental prosthetics and / or a tooth. Typically, the composition is antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory.

[0037] In aspects, the composition can further comprise sodium benzoate at a final concentration of between 1-2.5% w / v, such as of approximately 1.7% w / v, as a preservative. It can further comprise a bioactive substance, a flavouring substance and / or microparticles having a mean particle diameter (D50) of 20-200 pm, wherein said microparticles are organic or inorganic. Preferably, said microparticles are biodegradable and / or bioresorbable.

[0038] In one aspect, the current invention provides a kit comprising a composition according to the invention wherein the components a. - d. are provided in one vial and / or syringe, further comprising e. a syringe and an applicator tip, and / or a vial, and f. an instruction leaflet and optionally g. a non-surgical debridement tool and / or device, and optionally again h. a further vial and / or syringe comprising a sealing composition, such as, but not limited to hyaluronic acid.

[0039] In one embodiment, the applicator tip has a single or double side-vent.

[0040] In one embodiment, the applicator has a blunt 30° bent tip. Aspects of the current invention relate to a composition and / or a kit as disclosed herein for use in removal of biofouling, biofilm and / or necrotic tissue from a biological surface and / or a biomaterial surface in situ, such as, but not limited to, for use in the assisting of the treatment and / or prevention of periimplantitis, gingivitis, mucositis, peri-implant mucositis, periodontitis, and / or chronic and / or infected dermal ulcers.

[0041] DEFINITIONS and ABREVIATIONS

[0042] The term "microparticle” is herein meant to describe a particle having a mean particle diameter (D50) between about 1 and 1000 pm. Typically, in the present invention, a microparticle is used that has a mean particle diameter (D50) between 20-200 pm.

[0043] The present invention provides the means to clean and / or debride a medical and / or dental implant. In the present context, the term “implant” typically means a medical and / or dental implant.

[0044] In the present context, the term “dental implant” includes within its scope any device intended to be implanted into the oral cavity of a vertebrate animal, in particular a mammal such as a human, for example in tooth restoration procedures. Dental implants are herein selected from the group consisting of implants, bars, bridges, abutments, crowns, caps, and prosthetic parts in the oral cavity. Dental implants may also be denoted as dental prosthetic devices. Generally, a dental implant is composed of one or several implant parts. For instance, a dental implant usually comprises a dental fixture coupled to secondary implant parts, such as an abutment and / or a dental restoration such as a crown, bridge or denture. However, any device, such as a dental fixture, intended for implantation may alone be referred to as an implant even if other parts are to be connected thereto.

[0045] In the present context, the term “orthopaedic implant” includes within its scope any device intended to be implanted into the body of a vertebrate animal, in particular a mammal such as a human, for preservation and restoration of the function of the musculoskeletal system, particularly joints and bones, including the alleviation of pain in these structures. Non-limiting examples of orthopaedic implants are hip-joint prostheses, knee prostheses, elbow prostheses, finger prostheses, cochlear prostheses, and fixation screws. In the present context, the term “vascular stent” refers to a tubular implant arranged for insertion into blood vessels of a vertebrate animal, in particular a mammal such as a human, in order to prevent or counteract a localized flow constriction, i.e. in order to counteract significant decreases in blood vessel diameter.

[0046] Hard tissues are, for example, bone, cementum, dentin, enamel, teeth, roots, cartilage and ligaments. Soft tissues are for example tissues that connect, support, or surround other structures and organs of the body, not being hard tissue such as bone. Soft tissue includes tendons, ligaments, fascia, skin, fibrous tissues, fat, and synovial membranes, muscles, nerves and blood vessels.

[0047] The term “debridement” in the present context means cleaning of a tissue surface, such as a surgically exposed hard and / or soft tissue surface, in order to remove, for example, biofilm, concrements, microbes, unwanted tissue, cells and cell residues, scar tissue, and / or necrotic tissue. Debridement may, for example, be performed in order to control and / or treat local infections, inflammations, foreign body reactions, pathological conditions, and / or regenerative processes (e.g. periodontitis, periimplantitis).

[0048] As used herein, a "biofilm" includes an extracellular matrix and one or more microorganisms such as, but not limited to, bacteria, fungi, algae and protozoa, which is attached to a surface. For example, but not by way of limitation, such surfaces can include tooth, mucosal, apatitic, bone and abiotic (e.g., implant, dentures, pipes, etc.) surfaces.

[0049] In dentistry, calculus or tartar is a form of hardened dental plaque. It is caused by precipitation of minerals from saliva and gingival crevicular fluid (GCF) in plaque on the teeth. This process of precipitation kills the bacterial cells within dental plaque, but the rough and hardened surface that is formed provides an ideal surface for further plaque formation. This leads to calculus buildup, which compromises the health of the gingiva (gums). Calculus can form both along the gumline, where it is referred to as supragingival ('above the gum'), and within the narrow sulcus that exists between the teeth and the gingiva, where it is referred to as subgingival ('below the gum'). Supragingival calculus consists primarily of calcium phosphate crystals. Sub-gingival calculus is composed almost entirely of two components: fossilized anaerobic bacteria whose biological composition has been replaced by calcium phosphate salts, and calcium phosphate salts that have joined the fossilized bacteria in calculus formations.

[0050] Calculus formation is associated with a number of clinical manifestations, including bad breath, receding gums and chronically inflamed gingiva. Brushing and flossing can remove plaque from which calculus forms; however, once formed, calculus is too hard (firmly attached) to be removed with a toothbrush. Calculus buildup can be removed with ultrasonic tools or dental hand instruments (such as a periodontal scaler).

[0051] In the present context, the term” peroxide” is used interchangeably with hydrogen peroxide (H2O2).

[0052] A microorganism, or microbe, is a microscopic organism, which may exist in its singlecelled form or in a colony of cells. Microorganisms include all unicellular organisms and so are extremely diverse. All the Archaea and Bacteria are microorganisms (Prokaryotes). Some protists are related to animals and some to green plants. Many of the multicellular organisms are microscopic, namely micro-animals, some fungi and some algae.

[0053] An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals are used against fungi. They can also be classified according to their function. Agents that kill microbes are microbicidal, while those that merely inhibit their growth are called biostatic both are included in the term” antimicrobial”. The use of antimicrobial medicines to treat infection is known as antimicrobial chemotherapy, while the use of antimicrobial medicines to prevent infection is known as antimicrobial prophylaxis.

[0054] The composition is described to be antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory. The wording bacteriostatic, is herein used to describe that it restricts the growth of microbes. The composition can at the same time acts to promote pro-resolution. In the current context this means that the composition is designed to stimulate the natural resolution phase of inflammation. In one embodiment, it has the ability to actively resolve inflammation rather than just suppressing it. A virus is a small infectious agent that replicates only inside the living cells of an organism. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea.

[0055] Antiviral drugs are a class of medication used specifically for treating viral infections rather than bacterial ones. Most antivirals are used for specific viral infections, while a broadspectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead, they inhibit their development.

[0056] Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural antivirals are produced by some plants such as eucalyptus and Australian tea trees.

[0057] As used in the present context, the term “antimicrobial”, means that the composition is effective against microbes and virus. In its broadest meaning, the composition of the present invention is antimicrobial, i.e. it is antibacterial, antiviral, a bactericide, a bacteriostatic and / or a viricide. It can also promote pro-resolution.

[0058] As used in the present context, the term room temperature (RT) given in Celsius and is meant to denote a temperature of approximately 20°C.

[0059] As used herein, the term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement method.

[0060] DETAILED DESCRIPTION

[0061] The presently described composition is a long sought for means for effectively cleaning and / or debriding a biological surface and / or a biomaterial surface in situ, e.g., but not limited to, a surface in the oral cavity for rapid and effectively assisting in the treatment without damaging the to be cleaned surface structure, and essentially without leaving contaminating material residues, at the same time displaying an antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory effect.

[0062] The presently described composition is a water soluble and easy to rinse off, tissuefriendly non-ionic surfactant. It comprises a non-toxic formulation of well-studied active ingredients in clinical use which is particularly suitable for injectable, oral and cutaneous applications. The herein for the first time described composition is proven to be non-sensitizing and non-irritating in clinical tests. The composition of the invention is compatible with other therapeutic agents against biofouling and inflammation. The herein for the first time disclosed composition is primarily intended for non-surgical use.

[0063] The composition described herein is liquid at room temperature, which facilitates troublefree mixing and application. At temperatures of no more than 20°C, such as at RT, it displays an easy flowing liquid consistence with surfactant effect that that allows the compositions to reach difficult places when applied into narrow defects. When applied, the patient’s natural body temperature initiates micelles to link and to quickly form a stable gel at body temperature, allowing prolonged and intimate contact with implant surfaces and tissue at the application site.

[0064] The composition currently described is slightly acidic, and thus antimicrobial and / or at least bacteriostatic. The lower pH, in turn, lowers the gelling temperature of the poloxamer-based hydrogel slightly. In addition, the effect of the citric buffer in combination with the NaF ions in the composition protects the enamel of the teeth that are to be cleaned and / or debrided from the more aggressive stronger acids in the composition. In essence, the composition, once applied, dissolves e.g., calcium carbonate from the surface, thus removing calculus, importantly though, due to the citric buffer induced low pH in combination with the NaF ions released, it can discriminate between hydroxyapatite and calcium carbonate (calculus).

[0065] The hydrogel is applied in a liquid state and gellifies at body temperature. This behaviour is facilitated purposefully by selecting the right balance between poloxamer concentration and citric acid concentration because the cleaning and debriding effect of the gel is most effective during the initial gelling process, but also throughout the entire process of sol-gel transition, i.e. , the forming of micelles. Particles and debris is / are during that window of time effectively encapsulated into the forming hydrogel.

[0066] The presently described composition can further be formulated to contain bio-resorbable microparticles to assist in the mechanical debridement of micro-rough implant surfaces, resulting in a clean surface with intact original structure. The gel-particle suspension can be used with debridement tools, such as brushes (e.g., TiBrush®), or other cleaning devices.

[0067] The presently described composition has been found to effectively clean and / or debride a biological surface and / or a biomaterial surface in the oral cavity, without suffering from an all too rapid degradation of the poloxamers in the composition, once mixed with the other components. Thus, the composition is typically provided in one vial and / or syringe, without the need to keep the components separate before application. The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory effect of the herein described composition is sufficient, and the practitioner perceives storage and application to be easy to handle in the clinical and / or praxis setting.

[0068] Consequently, the currently described composition is a substantially improved means for cleaning and / or debriding fouled biological surface and / or a biomaterial surface in situ, and / or a means for preventing fouling of said biological surface and / or a biomaterial surface in situ by cleaning and / or sterilizing said surfaces e.g., in the oral cavity. The present invention for the first time presents such a means for effectively cleaning and / or debriding even difficult to access areas and / or rough hard surfaces such as in the oral cavity with a composition that is pre-mixed and delivered in a single-vial and / or syringe solution.

[0069] The composition can effectively dissolve biofilm, debris and mineral deposit as well as dissolve extracellular organics at the application site.

[0070] The acidity of the citric acid (C6H8O7) in the phosphate citrate buffer at pH 5.5 helps the poloxamer micelles to dissolve mineral deposits as well as break down and remove extracellular organics and calcifications, such as calculus, from teeth and / or contaminated implants. The herein presented composition also removes carbon contamination from a titanium-containing implant surface and reactivates the titanium dioxide layer of the implant. This process re-establishes the original charge and hydrophilicity of the implant, restoring the optimal biological surface properties. This is a major factor for further survival, or even successful reintegration, of said treated implant.

[0071] The present composition is an advanced micelle forming gel formulation that works in synergy with a slightly acidic pH to break down and remove biofouling, eliminate microbes, keep tissue and implant moist and to reactivate the titanium implant surfaces

[0072] The hydrogel component of the composition and the acidity of the citric acid (C6H8O7) and the disodium hydrogen phosphate (Na2HPO4) buffer at pH 5.5 in combination with the NaF ions work in synergy to prevent foaming and to keep a slightly acidic pH at the surface for a prolonged biological and chemical effect. The use of the composition ensures a moist and acidic milieu during the procedure, without risk of the tissue and / or implant being damaged, while microbes are suspended and entrapped in the gel forming at the body temperature. Organic contaminants are in turn denatured thanks to the strong detergent character of the composition and dissolved and entrapped in the gel. Both gel consistence and acidic pH of the composition contribute to inflammation reduction and support tissue health. The gel formed at the body temperature helps maintain a prolonged local effect of the acidic milieu that in turn strengthens the cellular defence network. As a result, the forming hydrogel both removes contaminants and reactivates an implant surface.

[0073] The presently described composition is a novel formula of a biocompatible hydrogel with strong, non-ionic detergent properties with improved sol-gel dynamics for solubilization and entrapment of debris and microbes for effectively cleaning and / or debriding a biological surface and / or a biomaterial surface in situ. It is easily rinsed off with water and is fully biodegradable and / or decomposable.

[0074] The presently disclosed composition provides a novel and improved means for assisting in the treatment and elimination of biofilms; prevention of biofilm formation; biofilm extracellular matrix degradation; and inhibition of bacterial viability and growth within the biofilm. In particular, the presently disclosed subject matter provides a composition for the prevention and / or assisting in treatment of an oral disease (e.g., dental caries, periodontitis, gingivitis, mucositis and / or peri-implantitis).

[0075] The invention itself is based on a combination of sodium fluoride (NaF), citric acid (C6H8O7), disodium hydrogen phosphate (Na2HPC>4), and poloxamer in such a concentration that the composition is in a liquid form in RT, i.e. at a temperature of no more than 20°C, but due to elevation of temperature to body temperature, converts into a gel-state at the application site. The components of the composition can either be in the form of a concentrate in a separate vial for mixing immediately before use, in one embodiment applied with a mixing connector (typically of Luer-lock design), or preferably provided as dissolved directly into a hydrogel consisting of poloxamers, such as, but not limited to, pluronic acid, and water (or physiological saline) with a typical final concentration of a) sodium fluoride (NaF) at a final concentration of between 0.1 -0.4% w / v, b) poloxamer at a final concentration of between 15-40% w / v, c) citric acid (C6H8O7) at a final concentration of between 0.5-1 .5% w / v, d) disodium hydrogen phosphate (Na2HPC>4) at pH 5.5 at a final concentration of between 1 .5-2.0% w / v, wherein the final pH of the composition is adjusted to approximately pH 5.5, such as to between pH 5.2 - 6.2. The poloxamer component itself can be any of the Pluronic acids, e.g. the F-127 variety or the Poloxamer 407 wherein said poloxamer in the composition displays micelleforming capacity. Poloxamer / Pluronic acid works both as solubilizer and detergent in the composition disclosed herein, as well as a moisturizer and dynamic viscosity modifier. The hydrogel formulation forms a sticky gel when heated to body temperature by self-organizing micelles of poloxamer into a packed structure. Thus, the gel stays at the application site and exerts its activity where it is needed. The hydrogel forming process facilitates efficient solubilization and entrapment of particles, microbes and pollutants during the debridement procedure.

[0076] The present innovation is based on a synergetic effect between poloxamer and a slightly acidic milieu. Poloxamer has a reversed thermodynamic ability to form a “packed” micelle structure with several micelles combining to form a hydrogel. This ability increases with increasing temperature and is shifted toward the gel state at physiological conditions (such as at >20°C). This sol-gel transition forms a stable gel on e.g. living skin, mucosa, wounds for prolonged function as moisture and / or as wound dressing that can to some extent absorb organic contaminants.

[0077] However, when mixed with sodium fluoride (NaF) at a final concentration of between 0.1- 0.4% w / v, b) poloxamer at a final concentration of between 20-40% w / v, c) citric acid (C6H8O7) at a final concentration of between 0.5-1 .5% w / v, d) disodium hydrogen phosphate (Na2HPC>4) at a final concentration of Na2HPO4 between 1.5 -2.0% w / v, the present invention discloses that the sol-gel transition is slightly more dynamic and less stable, so that the transition between sol-state (single solubilized micelles) and gel-state (packed micelle structure) is in a dynamic equilibrium.

[0078] Combined with the effect of the slightly acidic pH on viral particles, microbes and necrotic tissue, the sol-gel transition of the hydrogel dissolves and entraps organic contamination that is then removed when the gel is washed off.

[0079] The addition of sodium fluoride (NaF), and the phosphate citrate buffer comprising citric acid (C6H8O7) and disodium hydrogen phosphate (Na2HPC>4) at pH 5.5, to the poloxamers slightly lowers the temperature at which the packed micelle structure forms. Le., that the poloxamer gel, containing low concentrations of sodium fluoride (NaF), citric acid (C6H8O7) and disodium hydrogen phosphate (Na2HPC>4), is liquid at room temperate, such as up to 20°C and thus can be applied through a syringe needle or from a dispenser bottle without clogging the nozzle.

[0080] The improved effect from the combination of a slightly acidic milieu and poloxamer / Pluronic acid on cleaning and / or debridement of surfaces was unforeseen and surprising. The induction of the gellification process of the poloxamer hydrogel in combination with sodium fluoride (NaF), citric acid (C6H8O7) and disodium hydrogen phosphate (Na2HPO4) in the phosphate citrate buffer, assists the bacteriostatic and / or antimicrobial effect. It enables the cleaning and / or debridement composition to be more efficient in cleaning surfaces.

[0081] Compositions

[0082] The present invention relates to a novel antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition for cleaning and / or debriding a biological surface and / or a biomaterial surface in situ, comprising: a. sodium fluoride (NaF) at a final concentration of between 0.1 -0.4% w / v, b. poloxamer at a final concentration of between 20-40% w / v, c. citric acid (C6H8O7) at a final concentration of between 0.5-1 .5% w / v, d. disodium hydrogen phosphate (Na2HPC>4) at a final concentration of between 1 .5 -2.0% w / v, wherein the final pH is adjusted to pH 5.5, such as between pH 5.2 - 6.2, and wherein the composition is liquid at below RT, i.e., at no more than approximately 20°C.

[0083] The presently disclosed composition is characterized in that it comprises components a) - d) in such a ratio that the composition is in a liquid state at room temperature (RT) i.e., at approximately 20°C, instead of in a gel-state, and so that the poloxamers retain their ability to form micelles. Typical ratios of concentrations between component a) and components b) - d) are approximately 10:1 , such as of between 10:1- 20:1 , such as no more than 20:1 (concentration of poloxamer: concentration of components b) - d)).

[0084] In aspects, the presently disclosed composition comprises a final concentration of the poloxamer between 10-40%, such as between 10-20%, 15-20%, 10-15%, 10-17.5%, 20- 22%, 20-25%, 17.5-22.5%, 20-22.5%, 17.5-20%, 22-25%, 21-23%, 22-24%, or 10-30% w / v , such as 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30% w / v, such as no more than 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30% w / v. In a presently preferred embodiment, the composition comprises a final concentration of the poloxamer of 20-25% w / v. In a presently preferred embodiment, the composition comprises a final concentration of the poloxamer of 20% w / v.

[0085] In a further preferred embodiment, the poloxamer comprised in the composition is Pluronic acid, poloxamer 407.

[0086] The composition disclosed herein in one aspect comprises sodium fluoride (NaF) of a final concentration of between 0.1-0.4% w / v, such as between 0.1-0.2% w / v, 0.1-0.3%, w / v0.2- 0.4% w / v, 0.3-0.4% w / v, or 0.2-0.3% w / v, such as no more than 0.1 % w / v, 0.2% w / v, 0.3% w / v, or 0.4% w / v. In one embodiment, the composition disclosed herein comprises a final concentration of sodium fluoride (NaF) of 0.2% w / v.

[0087] The composition comprises a phosphate citrate buffer comprising citric acid (C6H8O7) and disodium hydrogen phosphate (Na2HPC>4) at a pH of 5.5.

[0088] In one embodiment, the composition according to the current invention has a final concentration of (C6H8O7) citric acid of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1 .3, 1 .4, or 1 .5 % w / v. The citric acid can be in anhydrous, monohydrate or dihydrate form.

[0089] The composition disclosed herein in one aspect comprises citric acid (C6H8O7) at a final concentration of between 0.5-1 .5% w / v, such as of between 0.75-1 % w / v, 0.8-1 % w / v, 0.9-1 % w / v, 1-1 .25% w / v, 1-1 .3% w / v, 1-1 .4% w / v, 1-1 .5% w / v, or between 0.8-1 .35% w / v, such as no more than 0.8% w / v, 0.9% w / v, 1 .051 % w / v, 1 .05% w / v, 1.1 % w / v, 1 .3% w / v or 1 .5% w / v.

[0090] In one embodiment, the composition disclosed herein comprises a final concentration of anhydrous (C6H8O7) citric acid of 0.9605% w / v.

[0091] In one embodiment, the composition disclosed herein comprises a final concentration of (C6H8O7) citric acid in monohydrate form of 1 .051 % w / v.

[0092] The composition disclosed herein in one aspect comprises a final concentration of Na2HPC>4 between 1 .5 -2.0% w / v, such as between 1 .5-1 .7% w / v, 1 .5-1 .6% w / v, 1 .5-1 .8% w / v, 1 .5-1 .9% w / v, 1 .6-1 .7% w / v, 1 .6-1 .8% w / v, 1 .6-1 .9% w / v, 1 .6-2.0% w / v, 1 .7-1 .8% w / v, 1 .7-1 .9% w / v, 1 .7-2.0% w / v, 1 .8-1 .9% w / v, 1 .8-2.0% w / v, or 1 .9-2.0% w / v, such as no more than 1 .5% w / v, 1 .6% w / v, 1 .7% w / v, 1 .8% w / v, 1 .9% w / v or 2.0% w / v.

[0093] In one embodiment, the composition disclosed herein comprises disodium hydrogen phosphate Na2HPC>4 at a final concentration of 1 .815% w / v.

[0094] In a presently preferred embodiment, the composition comprises a final concentration of poloxamer of 20% w / v, a final concentration of citric acid (C6H8O7) of 0.9605% w / v, a final concentration of sodium fluoride (NaF) of 0.2% w / v and a final concentration of disodium hydrogen phosphate Na2HPC>40f 1 .815% w / v. An antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention can further comprise water and / or physiological saline.

[0095] The composition of the current invention is designed so as to serve the purpose of cleaning and / or debriding a biological surface and / or a biomaterial surface in situ, which mouthwashes are not suited for, although their chemical compositions may appear partly overlapping with the one disclosed here. The micelle-forming capacity of the poloxamer component allows for encapsulation of the contaminants, by which measure they become physically separated and ultimately washed away. Hence, thorough homogenization of the micelle-forming poloxamer molecules with the solvent is not desired and should be avoided.

[0096] The sustained acidic environment and the presence of NaF contribute to the proresolution effect of the composition of the current invention.

[0097] The components of the antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory composition according to the present invention is preferably in one solution. Alternatively, the components can be kept separate from each other until they are combined and applied to a biological surface and / or a biomaterial surface in situ.

[0098] In a preferred embodiment, the components a)-d) are provided in one vial and / or syringe and are administered as one composition to a surface in the oral cavity.

[0099] The syringe can have a blunt 30° bent tip. In aspects, the syringe has an applicator tip with a single vent, such as a single side-vent. In a currently preferred embodiment, said applicator tip has a double side-vent.

[0100] Emulsifier(s) and / or viscosity modifier(s)

[0101] In one embodiment, the antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory composition according to the present invention further comprises one or more emulsifier(s) and / or viscosity modifier(s). Said emulsifier and / or viscosity modifier may be selected from the group consisting of glycerine, glycols, polyethylene glycols (PEG), polyoxyethylene polyoxypropylene block copolymer (pluronic polyols), polyglycol alginate (PGA), CMC (carboxyl methyl cellulose), glycerol, Aloe Vera gel, alginate, hyaluronic acid (HA) and citosan.

[0102] The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention may also comprise one or more detergent(s) selected from the group consisting of SDS (sodium dodecyl sulphate), sodium stannate, sodium pyrophosphate, oxine and SLS (sodium lauryl sulphate). The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the invention may further comprise one or more flavouring oil(s), such as, but not limited to oils of spearmint, peppermint, Wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon and methyl salicylate and menthol.

[0103] The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the invention may further comprise one or more weak acidic buffers.

[0104] Microparticles

[0105] A composition according to the present invention can further comprise microparticles having a mean particle diameter (D50) of 20-200 pm. Said microparticles are typically in a concentration between about 0.5-1000 g / L, such as between about 0.5-300 g / L.

[0106] A composition according to the present invention can comprise microparticles which are releasing one or more of ions selected from the group consisting of Ca2+1F’, Sr2and Mg2+.

[0107] In one aspect, a composition according to the present invention comprises microparticles consisting of calcium salt compound powder which is selected from the group consisting of calcium sulphate, calcium carbonate, calcium aluminate, calcium lactate, calcium nitrate, calcium citrate, calcium acetate, calcium stearate, calcium fumarate, calcium malate, calcium chloride, calcium bromide, calcium fluoride, calcium iodide, calcium saccharate, calcium oxalate, calcium gluconate, calcium propionate, calcium caseinate, calcium glycerophosphate, and combinations thereof.

[0108] In another aspect, a composition according to the present invention comprises microparticles consisting of calcium oxide compound powder which is selected from the group consisting of calcium oxide, calcium peroxide, calcium hydroxide, and combinations thereof.

[0109] In another aspect, a composition according to the present invention comprises microparticles providing a calcium ion source which are selected from the group consisting of calcium chloride, calcium sulphate, calcium aluminosilicate, calcium carbonate, calcium chloride, calcium ascorbate, and calcium oxide, and wherein the phosphate ion source is sodium phosphate, diphosphate.

[0110] In yet another aspect, a composition according to the present invention comprises microparticles consisting of a calcium phosphate compound powder which is selected from the group consisting of octacalcium phosphate, heptacalcium phosphate, pentacalcium phosphate, tetracalcium phosphate, tricalcium phosphate, dicalcium phosphate, monocalcium phosphate, calcium pyrophosphate, calcium metaphosphate, calcium phosphinate, amorphous calcium phosphate, calcium hydroxide phosphate and combinations thereof.

[0111] In yet another aspect, a composition according to the present invention comprises additional microparticles consisting of a compound selected from the group consisting of silica, silicate glasses, quartz, zinc oxide, barium sulphate, barium silicate, strontium silicate, barium borosilicate, strontium borosilicate, borosilicate, lithium silicate, amorphous silica, bismuth compounds, ammoniated or deammoniated calcium phosphate, alumina, zirconia, tin oxide, titania, apatites, silica glass fillers, calcium silicate based fillers, hydroxyapatites, barium sulphate, bismuth subcarbonate, Iron, Silicon magnesium, zinc, Silver, Manganese, Palladium, Radium or mixtures thereof.

[0112] In yet another aspect, a composition according to the present invention comprises microparticles being polymer particles, mineral particles, metal particles, barium boroaluminosilicate glass, fluoroaluminosilicate glass, silica, silicate glass, quartz, barium silicate glass, strontium silicate glass, bariumboro silicate glass, borosilicate glass, barium aluminofluorosilicate glass, lithium silicate, amorphous silica, barium magnesium aluminosilicate glass, barium aluminosilicate glass, strontium aluminum-borosilicate glass; strontium aluminofluorosilicate glass, amorphous silica, zirconium silicate glass, or mixtures thereof.

[0113] In another aspect, a composition according to the present invention can further include a fluoride ion source, wherein the fluoride ion source can be selected from the group consisting of Na2SiFe, CaF2, SrF2, NaF, NaPOsF, NaKFePOs, K2SiFe, Fe, NaP, NaSbFe, KSbFe, FeKP and mixtures thereof.

[0114] When the composition according to the present invention is intended for use in cleaning and / or debriding dental implants with a metal surface, the microparticles are preferably biocompatible and solid (hard) and may also be biodegradable.

[0115] The solid microparticles may be selected from the group of material consisting of TiC>2, zirconium oxide, diamond dust (carbons), polymers, polylactic acid (beans), mineral, ceramic, dialuminium trioxide, calcium carbonate, calcium phosphate, apatite crystals, bone ceramic particles (hydroxyapatite / calcium phosphate), titanium, zirconium, aluminium oxide, carborundum, pumice, and silica.

[0116] The choice of material for the solid microparticles is preferably made depending on which material, e.g. a metal implant or a hard tissue surface, is to be cleaned / debrided by the composition of the invention, in order to match the roughness of the material to allow for efficient cleaning / debriding of the material while still not damaging it. One advantage with the selection of the above specified size of the microparticles is that surface treatment of dental implants typically results in a diameter size of indents formed which is between 80-180 pm. Therefore, the presence of the solid microparticles in the composition of the invention makes the composition particularly suitable for the in situ cleaning and / or debridement of implants in the oral cavity, as the microparticles are of a size that allows their entry into the indents to clean these, while still being large enough to not cause inflammatory reactions and / or to be encapsulated by the body in fibrous capsules.

[0117] Said microparticles can be organic or inorganic.

[0118] Organic microparticles comprised in a composition according to the present invention can be selected from the nonlimiting group consisting of crystals of amino acids, biopolymers, chitosan, alginates, poloxamer, collagen, hyaluronic acid, PEG, and organic acids (including insoluble salts thereof such as but not limited to tartar).

[0119] Inorganic microparticles comprised in a composition according to the present invention can be selected from metallic compounds, e.g. selected from the group consisting of iron, titanium, silicon magnesium, zinc, zirconium, silver, manganese, palladium, radium, calcium and barium.

[0120] In one aspect, said microparticles comprised in a composition according to the present invention are biodegradable, such as selected from the group consisting of bare zinc, iron, silicon, magnesium, manganese, silver and palladium.

[0121] An antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention which comprises microparticles is typically formulated as a suspension of solid particles in a liquid.

[0122] Mesh-forming and / or scaffolding component

[0123] A composition according to the present invention can further comprise at least one meshforming and / or scaffolding component. Typically, the at least one mesh-forming and / or scaffolding component is selected from the group consisting of silk fibres, carbon fibres, silicates, borosilicates, collagens, and spider web silk, which improves physical strength and / or chemical longevity of the composition after application.

[0124] Bioactive substance

[0125] Alternatively, or in addition, a composition according to the present invention can comprise a bioactive substance, typically selected from the group consisting of EMD, peptides, drugs, bioactive ions, small molecules, radioactive molecules, antimicrobial molecules and radioopaque molecules.

[0126] Debridement components and antimicrobial substances

[0127] What is more, a composition according to the present invention can also comprise a further antimicrobial substance and / or debridement component.

[0128] In the present context, a further antimicrobial substance comprised in the composition according to the present invention can be selected from the non-exclusive list consisting of amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole and trimethoprim.

[0129] In one aspect, a further antimicrobial substance comprised in the composition according to the present invention is tetracycline, doxycycline, macrolides, penicillins (stabilized), chlorhexidine, chloramines and mixtures thereof.

[0130] In one aspect, a composition according to the present invention comprises a further antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory substance.

[0131] Shelf-life of at least 1 year in room temperature (RT)

[0132] A composition according to the present invention in one aspect has a shelf-life of at least 1 year in RT.

[0133] A kit

[0134] The present invention also relates to a kit comprising a composition according to the present invention, comprising preferably one container and / or syringe comprising said composition comprising at least components a)-d), if the kit comprises a syringe, it also comprises, an applicator tip and an instruction leaflet and optionally a sealing composition and / or a debridement toll, such as but not limited to a brush. Said kit can alternatively provide the components a)-d) in a two-chamber syringe, in which case the kit further can also comprise an instruction leaflet, an applicator tip and optionally a sealing composition and / or a debridement toll, such as but not limited to a brush a brush.

[0135] An antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention can be mixed before application and eventual storage or stored separately and mixed directly or shortly before and / or at the time of application. The invention, therefore, in another aspect is directed to a kit comprising a first container comprising the composition, and optionally at least one more container comprising a component e), f), g) etc.) which can e.g., comprise microparticles and / or a mesh-forming substance and / or a bioactive substance and / or a debridement component and / or a further antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory substance.

[0136] Optionally such a kit may also comprise instructions for the preparation of the composition of the invention. The kit may also comprise one or more device(s) for the application of the composition to a subject. Such a device may e.g. be a syringe or an implant cleaning and / or debridement tool for cleaning and / or debriding an implant, such as in the oral cavity. In a presently preferred embodiment, said syringe has an applicator tip, wherein the applicator tip has a single or double side vent.

[0137] Preferably, the implant cleaning and / or debridement tool comprises an elongated base member formed of at least two wires being twisted with each other, and a plurality of bristles fixed between said twisted wires and extending away from said twisted wires, whereby said bristles are positioned in a cleaning section at a first end of said base member; and that said bristles consist of titanium and / or a titanium alloy. A kit of the invention may also comprise the composition of the invention preferably in one container and an implant cleaning and / or debridement tool for cleaning and / or debriding an implant in the oral cavity.

[0138] One example of such an implant cleaning / debridement tool for cleaning a dental implant and / or debriding a hard tissue surface is disclosed in US 6,345,406, another example is given in WO 2009 / 083281.

[0139] The implant cleaning / debridement tool disclosed in WO 2009 / 083281 has bristles with diameters of 0.2 mm. In one aspect of the invention, a composition of the invention is particularly suitable to be used with this tool comprising solid microparticles in the composition of a size that will allow for an efficient cleaning of an implant and / or hard surface in the oral cavity. For this aspect, the microparticles optimally have a size about 150 pm, such as between 100 and 150 pm, because the body tends to integrate particles in fibrous capsules when the particles are between 10-100 pm.

[0140] The present invention in one aspect thus relates to a kit comprising a composition according to the current invention, comprising a. one container comprising said composition, b. a syringe and a vial, c. a connector device, d. an applicator tip, and e. an instruction leaflet.

[0141] In another aspect, the present invention relates to a kit further comprising f. a mixing device and g. a debridement tool.

[0142] The present invention in one aspect relates to a kit comprising a composition according to the current invention, comprising a. one syringe comprising said composition, b. a connector device, c. an applicator tip, and d. an instruction leaflet.

[0143] In another aspect, the present invention relates to a kit further comprising e. a mixing device and f. a debridement tool.

[0144] In an alternative aspect, a kit comprising a composition according to the present invention typically provides the two components a. and b.-d. in a two-chamber syringe, further comprising an instruction leaflet, a mixing device, an applicator tip and optionally a debridement tool.

[0145] In one aspect of the present invention, the kit further comprises a bone graft material, such as any commercially available bone graft material (titanium dioxide scaffold, BioOss®, Emdogain®, bioceramic, SmartBone® etc.).

[0146] In one aspect of the present invention, the kit further comprises a sealing composition, such as, but not limited to hyaluronic acid (HY).

[0147] Sterilized Compositions

[0148] In general, surgical instruments and medications that enter an already aseptic part of the body (such as the bloodstream or penetrating the skin) must be sterile. Thus, in aspects, a composition of the current invention, suitable and / or intended for medical and / or dental use is a sterile composition.

[0149] Validated processes that are used to render a product free from viable microorganisms, or at least to inactivate viable microorganisms to a level previously specified as being appropriate for a defined purpose are termed sterilization.

[0150] The term sterilization thus in the current context refers to any process that removes, kills, or deactivates forms of life (particularly microorganisms such as fungi, bacteria, spores, and unicellular eukaryotic organisms) and other biological agents (such as prions or viruses) present in a composition as described herein. Sterilization can be achieved through various means, including heat, chemicals, irradiation, high pressure, and / or filtration. Sterilization is distinct from disinfection, sanitization, and pasteurization, in that those methods reduce rather than eliminate all forms of life and biological agents present. A sterilized composition as described herein can also be referred to as being sterile or aseptic.

[0151] Steam sterilized

[0152] Steam sterilization, also known as moist heat sterilization, uses heated saturated steam under pressure to inactivate or kill microorganisms via denaturation of macromolecules, primarily proteins. This method is a faster process than dry heat sterilization. Steam sterilization is performed using an autoclave, sometimes called a converter or steam sterilizer. As can be seen in the experimental section, a composition according to the current invention can easily be sterilized at 121 °C for 20 minutes in an autoclave without changed gelling behaviour. The gelation test in the experimental section shows that the composition kept the same gelling behaviour after sterilization.

[0153] Thus, the current invention in one aspect also relates to a composition as disclosed herein, which has been sterilized, such as, but not limited to, by autoclaving.

[0154] In one aspect, the current invention in consequence relates to a method for preparing a sterilized composition according to the current invention, wherein the composition is steam sterilized, such as, but not limited to, by autoclaving, such as at 121 °C for 20 minutes in an autoclave.

[0155] Use

[0156] The presently disclosed composition is intended for use in cleaning and / or debriding a biological surface and / or a biomaterial surface in situ, such as, but not limited to, for removal of calculus, both supragingival calculus and / or sub-gingival calculus.

[0157] The presently disclosed composition is especially useful for application in peri-implant defects, but the composition may be tailored to fit with various clinical procedures.

[0158] E.g. a composition for use in treating and / or preventing periimplantitis will typically comprise a higher content of active oxygen and micro-mechanical debridement particles

[0159] A typical composition for treating and / or preventing peri-implant mucositis will comprise increased active oxygen and increased sol-gel activity. A typical composition for peri-implant maintenance, peri-implant prophylaxis and postoperative follow-up comprises high active oxygen concentration.

[0160] However, the presently disclosed composition can also be used for other oral procedures, such as during surgical debridement of periodontal defects, for preparation before regenerative procedures, in periodontal maintenance treatment, in periodontitis prophylaxis (dental hygienist), as well as in endodontics, both endodontally and in apical surgery.

[0161] What is more, the presently disclosed composition can further be used for cleaning and / or debriding outside the oral cavity, such as, but not limited to in orthopaedic revision surgery, debridement of transdermal devices, in dermal wound care for cleaning of acute wounds and / or in debridement of chronic ulcers and burn.

[0162] An antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention can typically be employed for use in assisting in the treatment and / or prevention of periimplantitis, gingivitis and / or mucositis, peri-implant mucositis and / or periodontitis.

[0163] Periimplantitis is a typical complication related to oro-dental rehabilitation through the use of implants, i.e. a peri-implant disease, which is well known to the person skilled in the art as an inflammatory reaction in which there is a loss of the bony support of the implant accompanied by inflammation. The aetiology of the disease is conditioned by the status of the tissue surrounding the implant, implant design, degree of roughness, the poor alignment of implant components, external morphology and excessive mechanical load.

[0164] The presently described antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory composition for the first time offers the means for an effective and rapid cleaning of an implant and / or for debriding a hard surface in the oral cavity essentially without damaging of the anatomical structure or of the implant and / or hard surface itself, and essentially without leaving contaminating material residues on the treated surface.

[0165] The invention therefore in one aspect is directed to the antimicrobial, bacteriostatic, proresolution and / or anti-inflammatory composition as defined herein and / or the kit for preparing the composition of the invention as defined herein, for use as a medicament.

[0166] Thus, the present invention relates to the use of an antimicrobial, bacteriostatic, proresolution and / or anti-inflammatory composition according to the present invention for cleaning and / or debriding an implant in the oral cavity, such as an implant in situ, a hard surface in the oral cavity, such as an outer surface of a hard tissue in the oral cavity, a surgically exposed hard surface in the oral cavity, a wound in the oral cavity, such as a wound resulting from periimplantitis or a surgical wound, a periodontal defect and / or periodontal wound, and / or an oral hard tissue defect.

[0167] The invention also relates to the use of the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition as defined herein and / or the kit for preparing the composition of the invention as defined herein, for the preparation of a medicament and / or a pharmaceutical and / or cosmetic composition, for cleaning and / or debriding an implant in the oral cavity, such as an implant in situ, a hard surface in the oral cavity, such as an outer surface of a hard tissue in the oral cavity, a surgically exposed hard surface in the oral cavity, a wound in the oral cavity, such as a wound resulting from periimplantitis or a surgical wound, a periodontal defect and / or periodontal wound, and / or an oral hard tissue defect.

[0168] The invention is also directed to the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition as defined herein or the kit for preparing the composition of the invention as defined herein for use for cleaning and / or debriding an implant in the oral cavity, such as an implant in situ, a hard surface in the oral cavity, such as an outer surface of a hard tissue in the oral cavity, a surgically exposed hard surface in the oral cavity, a wound in the oral cavity, such as a wound resulting from periimplantitis or a surgical wound, a periodontal defect and / or periodontal wound, and / or an oral hard tissue defect.

[0169] Another presently preferred embodiment is directed to the use of an antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention together with an implant cleaning and / or debridement tool, for cleaning an implant and / or debriding a hard surface in the oral cavity. Said implant cleaning and / or debridement tool is e.g. characterized by comprising an elongated base member formed of at least two wires being twisted with each other, and a plurality of bristles fixed between said twisted wires and extending away from said twisted wires, whereby said bristles are positioned in a cleaning section at a first end of said base member; and that said bristles comprise or consist of titanium and / or a titanium alloy.

[0170] Many medical implants, such as e.g. dental implants, orthopaedic implants and vascular stents, are metallic, i.e. they are made of a metal material. The present invention consequently relates to the use of an antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, for cleaning and / or debriding an implant made of a metal material. Examples of metal materials commonly utilized for constructing metallic medical implants are steel, titanium, zirconium, tantalum, niobium, hafnium and alloys thereof. In particular, titanium and titanium alloys have proven to be suitable to utilize for constructing medical implants. On the other hand, both medical and dental implants can at least partially, as well as in full (full-ceramic implants) consist of porcelain and / or ceramic, such as of zirconium oxide and / or hydroxyapatite, or any other ceramic or porcelain material known to the person skilled in the art as being suitable for implants. Thus, the present invention equally relates to the use of an antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, for cleaning and / or debriding an implant made of, or comprising, porcelain and / or ceramic. Consequently, the present invention is also directed to the use of a composition of the invention for the preparation of a medicament and / or a pharmaceutical and / or cosmetic composition for the cleaning and / or debridement of an implant made of or comprising porcelain and / or ceramic. Also, the invention is directed to a composition of the invention alternatively for use for cleaning and / or debriding an implant made of or comprising porcelain and / or ceramic.

[0171] Dental implants are typically utilized in dental restoration procedures in patients having lost one or more of their teeth. A dental implant comprises a dental fixture, which is utilized as an artificial tooth root replacement. Thus, the dental fixture serves as a root for a new tooth. The dental fixture is typically a screw, i.e. it has the shape of a screw, and it is typically made of titanium, a titanium alloy, zirconium or a zirconium alloy. The screw is surgically implanted into the jawbone, where after the bone tissue grows around the screw and the screw is fixated in the bone with the bone in close contact with the implant surface. Once the implant screw is firmly anchored in the jawbone, it may be elongated by attachment of an abutment to the screw. The abutment may, just as the screw, be made of titanium, a titanium alloy, zirconium or a zirconium alloy. The shape and size of the utilized abutment are adjusted such that it precisely reaches up through the mucosa after attachment to the screw. A dental restoration such as a crown, bridge or denture may then be attached to the abutment. Alternatively, the implant screw has such a shape and size that it reaches up through the mucosa after implantation, whereby no abutment is needed, and a dental restoration such as a crown, bridge or denture may be attached directly to the screw.

[0172] The present invention consequently relates to the use of an antimicrobial and / or antiinflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, for cleaning and / or debriding any parts of a dental implant, selected from the group consisting of dental fixture such as a screw, abutment, and dental restoration such as a crown, bridge or denture. Consequently, the present invention is also directed to the use of a composition of the invention for the preparation of a medicament and / or pharmaceutical and / or cosmetic composition for cleaning and / or debriding any parts of a dental implant, selected from the group consisting of dental fixture such as a screw, abutment, and dental restoration such as a crown, bridge or denture. Also, the invention is directed to a composition of the invention for use for cleaning and / or debriding any parts of a dental implant, selected from the group consisting of dental fixture such as a screw, abutment, and dental restoration such as a crown, bridge or denture.

[0173] The present invention further relates to the use of an antimicrobial and / or antiinflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, for cleaning and / or debriding orthopaedic implants, such as orthopaedic implants which are utilized for the preservation and restoration of the function in the musculoskeletal system, particularly joints and bones, including alleviation of pain in these structures, and / or for cleaning and / or debriding vascular stents, i.e. tubular implants arranged for insertion into blood vessels in order to prevent or counteract a localized flow constriction. Consequently, the present invention is also directed to the use of a composition of the invention for the preparation of a medicament for cleaning and / or debriding orthopaedic implants, such as orthopaedic implants which are utilized for the preservation and restoration of the function in the musculoskeletal system, particularly joints and bones, including alleviation of pain in these structures, and / or for cleaning and / or debriding vascular stents. Also, the invention is directed to a composition of the invention for use for cleaning and / or debriding orthopaedic implants, such as orthopaedic implants which are utilized for the preservation and restoration of the function in the musculoskeletal system, particularly joints and bones, including alleviation of pain in these structures, and / or for cleaning and / or debriding vascular stents.

[0174] The surface of medical implants such as e.g. dental implants, orthopaedic implants and vascular stents, or the vicinity thereof, has sometimes to be cleaned after placing. This is particularly important when an infection or contamination occurs, causing a progressive degenerative process in the bone adjacent to the implant known as periimplantitis. In these cases, the surface of the ailing implant has to be cleaned from microbes and contaminants to stop the progression of the disease and ensure re-integration of the implant. Failure to clean the implant surface will eventually lead to loss of bone and implant and make further alternative treatments difficult and sometimes even impossible. Furthermore, the surface of vascular stents may have to be cleaned during implantation in order to remove coagulum, and the interior of vascular stents, i.e. the cavity within vascular stents, may have to be cleaned in an endoscopic procedure during a later treatment due to restenosis, i.e. blocking of the blood vessel.

[0175] The present invention therefore relates to the use of an antimicrobial and / or antiinflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, for cleaning and / or debriding an implant or the vicinity thereof after placing. Consequently, the present invention is also directed to the use of a composition of the invention for the preparation of a medicament for cleaning and / or debriding an implant or the vicinity thereof after placing. Also, the invention is directed to a composition of the invention for use for cleaning and / or debriding an implant or the vicinity thereof after placing.

[0176] In addition, for different reasons, it may be advantageous or necessary to debride surgically exposed hard tissue surfaces. For example, debriding of surgically exposed hard tissue surfaces may be advantageous or necessary to perform before regenerative treatment, i.e. in order to prepare the hard tissue surfaces for regenerative treatment. Examples of conditions, which may be associated with a treatment in which debridement of a surgically exposed hard tissue surface is advantageous or necessary to perform in order to prepare the surface for regenerative treatment, are: periimplantitis, periodontitis lesions, marginal periodontitis, apical periodontitis, furcation defects, apical granulomas and cysts, bone cysts, bone tumours, bone granulomas, bone cancers, (infected) extraction sockets, alveolitis sicca ("dry socket"), cleaning of apicectomy defects, localized osteomyelitis, trauma induced defects, resection or revision of implants, resection or revision of fractures, and removal of temporary bone implants (such as orthopaedic bone plates, retainers and screws). Furthermore, debridement of articular surfaces in joints affected by arthritis and debridement of such surfaces before regenerative treatment for cartilage and ligaments is instituted may also be advantageous or necessary to perform.

[0177] The present invention thus relates to the use of an antimicrobial, bacteriostatic, proresolution and / or anti-inflammatory according to the present invention, alternatively together with an implant cleaning and / or debridement tool, for cleaning and / or debriding surgically exposed hard tissue surfaces before regenerative treatment. Consequently, the present invention is also directed to the use of a composition of the invention for the preparation of a medicament and / or a pharmaceutical and / or cosmetic composition for cleaning and / or debriding surgically exposed hard tissue surfaces before regenerative treatment. Also, the invention is directed to a composition of the invention for use for cleaning and / or debriding surgically exposed hard tissue surfaces before regenerative treatment.

[0178] The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, may be utilized during surgery for cleaning of the surface of a metallic medical implant after infection and / or bone resorption. For example, it may be utilized for cleaning the surface of a metallic dental implant and / or a metallic orthopaedic implant. Thus, it may be utilized for removing e.g. bacterial biofilm, debris, calculus or fibrous tissue from the surface of a dental implant, such as a titanium screw. Alternatively, it may be utilized together with a further cleaning agent (i.e. an antibacterial, bacteriostatic or pro-resolution agent) in order to remove the bacterial biofilm from the vicinity of the dental fixture during implantation. It may also be utilized for cleaning the surface of, or the vicinity of, an abutment. Consequently, the present invention is also directed to the use of a composition of the invention for the preparation of a medicament for cleaning, e.g. removing bacterial biofilm, debris, calculus or fibrous tissue from the surface of a metallic dental implant, such as a titanium screw or an abutment, or a metallic orthopaedic implant. Also, the invention is directed to a composition of the invention for use for cleaning, e.g. removing bacterial biofilm, debris, calculus or fibrous tissue the surface of a metallic dental implant, such as a titanium screw or an abutment, or a metallic orthopaedic implant.

[0179] In addition, the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, may be utilized for removing cement remnants, bacterial biofilm, debris, calculus or fibrous tissue from the surface of an orthopaedic implant or for removing plaque from the surface of a vascular stent. Alternatively, it may be utilized for cleaning the interior of a vascular stent, i.e. the cavity within a vascular stent, in an endoscopic procedure during a later treatment due to restenosis, i.e. blocking of the blood vessel.

[0180] A procedure involving the use of the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, may, for example, involve the steps of: surgically exposing a hard tissue surface to be treated; removal of inflamed soft tissue; debriding the surface by means of applying the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool; applying (regenerative) treatment as needed; replacing soft tissue; suturing for good primary closure and wound stability; and allowing the wound to heal.

[0181] In particular, the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, is an efficient tool for debridement of surgically exposed tooth root surfaces, furcation defects and bony defects before regenerative treatment (i.e. by means of, for example Straumann® Emdogain®, bone graft materials, autologous bone, membranes, etc.), the antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, is especially effective for removing granulation tissue, and for removing concrements of calcified biofilms (plaques) and subgingival calcus / calculus. The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, it is advantageous to utilize for cleaning and / or debriding both “hard” metallic medical and / or dental implants having relatively hard surfaces, such as e.g. medical implants of steel, and “soft” metallic medical implants having delicate surfaces, such as e.g. medical and / or dental implants of titanium, a titanium alloy, zirconium or a zirconium alloy.

[0182] In addition, the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention does not leave contaminants, i.e. material residues, incompatible with reintegration of the implanted structure. Thus, the inflammation risk is minimal.

[0183] In particular, a relatively rapid debridement procedure of surfaces, which are otherwise hard to clean and / or hard to reach by hand instrumentation, may be performed by means of the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool. Rapid treatment ensures a better treatment outcome. As mentioned above, it is a well-known fact that the morbidity and frequency of adverse effects, such as e.g. post-surgery effects, are directly related to, and often proportional to, the time used for the debridement of surgically exposed hard tissue surfaces. Thus, rapid debridement treatment ensures a better total treatment outcome.

[0184] The use of the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, alternatively together with an implant cleaning and / or debridement tool, is especially favourable where the treatment plan for a defect includes placing of a titanium implant or any other device made of titanium, since only titanium and no other metallic ions or polymers that can provoke unwanted and / or adverse clinical and / or biological effects can contaminate the treated area, hampering the outcome of planned and / or future implant procedures.

[0185] Oral hygiene

[0186] In oral hygiene and dentistry, debridement refers to the removal of plaque and calculus that have accumulated on the teeth, which can be performed routinely by the technician, for medical, hygienic, as well as for purely cosmetic reasons. Thus, in one embodiment, the antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention, again alternatively together with an implant cleaning and / or debridement tool, is used for removal of plaque and calculus that have accumulated on the patient’s natural teeth, or tooth implants. The antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention comprises radicalized oxygens and is thus particularly suitable for use in the bleaching of natural and / or artificial teeth.

[0187] Microorganisms

[0188] An antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention is in general intended for use in debriding and / or cleaning a biological surface and / or a biomaterial surface in situ, e.g. for use in removal of biofouling, biofilm and / or necrotic tissue from such a biological surface and / or a biomaterial surface in situ.

[0189] Biofilms that can be prevented, eliminated and / or treated by the composition of the present disclosure include, but are not limited to, biofilms present within the oral cavity, e.g., on the surface of teeth, on the surface of mucosal / soft tissues such as gingivae / periodontium and inside a tooth canal (e.g. the endodontic canal).

[0190] In certain embodiments, biofilms that can be prevented, eliminated and / or treated by the composition of the present disclosure include biofilms on the urinary tract, lung, gastrointestinal tract, on and / or within chronic wounds, and present on the surface (e.g., implants) and within medical devices and medical lines, e.g., catheters, medical instruments and medical tubing.

[0191] The composition of the present disclosure can be used to reduce the growth and / or inhibit the viability of one or more microorganisms, e.g., bacteria in a biofilm. For example, and not by way of limitation, the bacteria can include Streptococcus mutans (S. mutans), Streptococcus sobrinussanguinis (sanguinis), Streptococcus gordonii, Streptococcus omlis, Streptococcus mitis, Actinomyces odontolyticus, Actinomyces viscosus, Aggregatibacter actinomycetemcomitans, Lactobacillus spp., Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, Treponema denticola, Fusobacterium nucleatum, Campylobacter rectus, Eikenella corrodens, Veillonella spp., Micromonas micros, Porphyromonas cangingivalis, Haemophilus actinomycetemcomitans Actinomyces spp., Bacillus spp., Mycobacterium spp., Fusobacterium spp., Streptococcus spp., Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Proteus mirabilis, Clebsiella pneumoniae, Acinetobacter spp., Enterococcus spp., Prevotella spp., Porphyromonas spp., Clostridium spp., Stenotrophomonas maltophilia, P. cangingivalis, Candida albicans, Escherichia coli and / or Pseudomonas aeruginosa. In certain embodiments, the bacteria are S. mutans, which is present within biofilms found in the oral cavity, e.g., on the surface of teeth.

[0192] The microorganisms most commonly associated with implant failure are spirochetes and mobile forms of Gram-negative anaerobes. Diagnosis can be based on changes of colour in the gum, bleeding and probing depth of peri-implant pockets, suppuration, x-ray and gradual loss of bone height around the tooth. The antibiotic therapy proven to be most efficacious in the antibiogram has so far been the association of amoxycillin and clavulanic acid. In addition to bacterial infections, microbial infections in the oral cavity can of course also include fungal and / or viral infections.

[0193] An antimicrobial, bacteriostatic, pro-resolution and / or anti-inflammatory composition according to the present invention is effective for killing bacteria, fungus and / or virus.

[0194] What is more, the composition described herein is antimicrobial and / or bacteriostatic, without causing microbial resistance, as well as anti-inflammatory and pro-resolution.

[0195] In consequence, the present invention relates to a method for treating and / or preventing periimplantitis, gingivitis and / or mucositis, peri-implant mucositis and / or periodontitis, comprising cleaning and / or debriding a biological surface and / or a biomaterial surface in situ by applying a composition according to the present invention to said fouled, filmed and / or necrotized surface.

[0196] EXAMPLES

[0197] The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. Considering the present invention and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter.

[0198] Example 1

[0199] Aim:

[0200] Prepare a formulation containing sodium fluoride, citric acid, and Pluronic® F-127 with a target pH range of pH 5.5-6.0.

[0201] Materials

[0202] • Milli-Q Water (pH 6.55)

[0203] • Sodium Fluoride (NaF) - BioReagent grade, > 99% purity (Sigma Aldrich)

[0204] • Citric Acid (C6H8O7) - ACS grade (VWR Chemicals)

[0205] • Pluronic® F-127 (PF-127) - MW = 12.6 kDa, BioReagent grade (Sigma Aldrich) Formulations

[0206] Table 1: Formulations

[0207] Methods

[0208] Add.

[0209] 1 . Add sodium fluoride and citric acid to 10 mL of Milli-Q water, then measure the pH.

[0210] 2. Add Pluronic® F-127, mixing manually to ensure thorough incorporation.

[0211] 3. Store the mixture at 4°C overnight to allow complete dissolution.

[0212] 4. Once dissolved, measure the pH of the hydrogel to check whether it meets the target range.

[0213] Table 2: pH readouts

[0214] Gelation

[0215] The hydrogels were kept in a fridge at 4°C. 1 ml of each formulation was introduced into a vial and gelation was verified visually upon vial inversion and defined as complete when the hydrogel stopped flowing. All the samples gelled within 2 minutes at room temperature.

[0216] Conclusions

[0217] No formulation matches the required pH range.

[0218] Actions

[0219] Repeat the experiment using a phosphate-citrate buffer.

[0220] Example 2

[0221] Materials

[0222] • Milli-Q Water (pH = 6.55) • Sodium Fluoride (NaF) - BioReagent grade, > 99% purity (Sigma Aldrich)

[0223] • Citric Acid (C6H8O7) - ACS grade (VWR Chemicals)

[0224] • Di-sodium hydrogen phosphate anhydrous (Na2HPO4) - GPR Rectapur®, >99% (VWR Chemicals)

[0225] • Pluronic® F-127 (PF-127) - MW = 12.6 kDa, BioReagent grade (Sigma Aldrich)

[0226] Formulations

[0227] Table 3: Formulations

[0228] Formulation A (Prophylaxis)

[0229] 1 . Prepare 100 mL of a phosphate-citrate buffer by dissolving 1 .815 g of Na2HPC>4 and 0.9605 g of C6H8O7in 100 mL of Milli-Q water mimicking the commercial GMP Phosphate-Citrate Buffer at pH 5.5 (Fisher Chemical™, Fisher Scientific).

[0230] Measure the pH.

[0231] 2. Add NaF to the buffer to a final cone, of 0.2% w / v. Measure the pH.

[0232] 3. Add Pluronic® F-127 to a final cone, of 30%w / v, mixing manually to ensure thorough incorporation.

[0233] 4. Store the mixture at 4°C overnight to allow for complete dissolution.

[0234] 5. Once dissolved, measure the pH of the hydrogel to confirm it meets the target range. Adjust the pH if necessary.

[0235] Table 4: pH readouts Gelation

[0236] The hydrogels were kept in a fridge at 4°C. 1 ml of each formulation was introduced into a vial and gelation was verified through vial inversion and defined as complete when the hydrogel stopped flowing.

[0237] Formulation A gelled within 2 minutes at room temperature.

[0238] Conclusions

[0239] Both formulations A meets the target pH specification.

[0240] Autoclaving

[0241] The hydrogels were sterilized at 121 °C for 20 minutes in a SX-700E Autoclave (Tomy, Japan). The gelation experiment (paragraph 4.5.) was repeated and kept the same gelling behaviour.

[0242] Table 5: Formulations

[0243] Conclusions

[0244] Formulations A met the target pH specification.

[0245] Experiment 3

[0246] Materials

[0247] • Milli-Q Water (pH = 6.55)

[0248] • Sodium Fluoride (NaF) - BioReagent grade, > 99% purity (Sigma Aldrich)

[0249] • Citric Acid (C6H8O7) - ACS grade (VWR Chemicals)

[0250] • Disodium hydrogen phosphate anhydrous (Na2HPO4) - GPR Rectapur®, >99% (VWR Chemicals)

[0251] • Pluronic® F-127 (PF-127) - MW = 12.6 kDa, BioReagent grade (Sigma Aldrich)

[0252] • Sodium Benzoate (C / HsNaO?) - ReagentPlus®, 99% (Sigma Aldrich)

[0253] Table 6: Method - Formulation A (Prophylaxis)

[0254] 1 . Prepare 100 mL of a phosphate-citrate buffer by dissolving 1 .815 g of Na2HPC>4 and 0.9605 g of C6H8O7in 100 mL of Milli-Q water mimicking the commercial GMP Phosphate-Citrate Buffer at pH 5.5 (Fisher Chemical™, Fisher Scientific).

[0255] Measure the pH.

[0256] 2. Add NaF to the buffer to the final cone, of 0.2% w / v. Measure the pH.

[0257] 3. Add Pluronic® F-127 to the final cone, of 25% w / v, mixing manually to ensure thorough incorporation.

[0258] 4. Store the mixture at 4°C overnight to allow for complete dissolution.

[0259] 5. Once dissolved, measure the pH of the hydrogel to confirm it meets the target range.

[0260] Table 7: pH readouts

[0261] Gelation

[0262] The hydrogels were kept at 4°C. 1 ml of each formulation was introduced into a vial and gelation was verified through vial inversion and defined as complete when the hydrogel stopped flowing.

[0263] Formulation A gelled within 2 minutes at room temperature.

[0264] Autoclaving

[0265] The hydrogels were sterilized at 121 °C for 20 minutes in a SX-700E Autoclave (Tomy, Japan). The gelation experiment was repeated and kept the same gelling behaviour.

[0266] Table 8: Conclusions

[0267] Formulation A met the target pH specification.

[0268] Actions

[0269] • Prepare a formulation with a lower Poloxamer 407 concentration, i.e., 22.5% w / v, 20% w / v and 17.5% w / v.

[0270] • Define a flavouring agent (e.g., citrus taste).

[0271] Experiment 4

[0272] Materials

[0273] • Milli-Q Water (pH = 6.55)

[0274] • Sodium Fluoride (NaF) - BioReagent grade, > 99% purity (Sigma Aldrich)

[0275] • Citric Acid (C6H8O7) - ACS grade (VWR Chemicals)

[0276] • Di-sodium hydrogen phosphate anhydrous (Na2HPO4) - GPR Rectapur®, >99% (VWR Chemicals)

[0277] • Pluronic® F-127 (PF-127) - MW = 12.6 kDa, BioReagent grade (Sigma Aldrich)

[0278] Table 9:

[0279] Method - Formulations A, B, C (Prophylaxis)

[0280] 1 . Prepare 100 mL of a phosphate-citrate buffer by dissolving 1 .815 g of Na2HPC>4 and 0.9605 g of C6H8O7in 100 mL of Milli-Q water mimicking the commercial GMP Phosphate-Citrate Buffer at pH 5.5 (Fisher Chemical™, Fisher Scientific).

[0281] Measure the pH.

[0282] 2. Add NaF to the buffer to a final cone, of 0.2% w / v. Measure the pH. 3. Add Pluronic® F-127 to a final cone, as indicated in Table 9, mixing manually to ensure thorough incorporation.

[0283] 4. Store the mixture at 4°C overnight to allow complete dissolution.

[0284] 5. Once dissolved, measure the pH of the hydrogel to confirm it meets the target range.

[0285] Table 10: pH readouts

[0286] Gelation

[0287] The hydrogels were kept in a fridge at 4°C. 1 ml of each formulation was introduced into a vial and gelation was verified through vial inversion and defined as complete when the hydrogel stopped flowing.

[0288] Formulation A and B gelled within 2 minutes at room temperature, while C did not gel.

[0289] Autoclaving

[0290] The hydrogels were sterilized at 121 °C for 20 minutes in a SX-700E Autoclave (Tomy, Japan). The gelation experiment (paragraph 6.5.) was repeated and all the formulations kept the same gelling behaviour.

[0291] Table 11 :

[0292] Conclusions

[0293] Formulations A, B and C meet the target pH specification.

[0294] Actions

[0295] Formulation B is chosen for MucoPrep.

[0296] Formulation:

[0297] MucoPrep - 20%w / v Poloxamer 407 + 0.2% NaF in phosphate-citrate buffer Experiment 5

[0298] Detection of peroxide groups

[0299] The Pierce™ Quantitative Peroxide Assay Kit - Aqueous Compatible Formulation (Thermo Fisher Scientific, US) was used to examine and quantify the formation of peroxide groups resulting from possible degradation reactions during the sterilization processes. Hydrogen peroxide standard dilutions were prepared according to the manufacturer’s instructions. The absorbance was measured at 562 nm using a BioTek ELx800 Absorbance Microplate Reader (BioTek Instruments, Inc., Winooski, VT, US). A one-tailed homoscedastic t-test was performed on Microsoft® Excel® for Microsoft 365 MSO (Version 2411 Build 16.0.18227.20082) 64-bit to identify any statistically significant differences between the groups.

[0300] Table 12: Peroxide groups concentration, Mean ± SD, n=3;

[0301] * indicates a statistically significant difference (p < 0.05) compared to the non-sterile sample (t-test).

[0302] Experiment 6

[0303] Detection of carbonyl groups

[0304] A MAK486 Carbonyl Assay Kit (Merck Life Science AS, Norway) was used to examine and quantify the formation of carbonyl groups resulting from possible degradation reactions during the sterilization processes. Carbonyl standard dilutions were prepared according to the manufacturer’s instructions, while the hydrogel samples were diluted 1:20 with MilliQ water. The absorbance was measured at 405 nm using a BioTek ELx800 Absorbance Microplate Reader (BioTek Instruments, Inc., Winooski, VT, US). A one-tailed homoscedastic t-test was performed on Microsoft® Excel® for Microsoft 365 MSO (Version 2411 Build 16.0.18227.20082) 64-bit to identify any statistically significant differences between the groups.

[0305] Table 13: Carbonyl groups concentration, Mean ± SD, n=3;

[0306] * indicates a statistically significant difference (p < 0.05) compared to the non-sterile sample (t-test).

[0307] Experiment 7

[0308] Swelling test

[0309] In the swelling study, 0.5 ml of hydrogel was introduced into a vial, weighed, and placed in a TS8056 incubator (Termarks, Sweden) at 37°C for 15 min. Subsequently, 1 .5 ml of MilliQ water was added to the vial and kept at 37°C for 1 h, 3 h, and 6 h. After the specified incubation period, MilliQ water was removed from the vial, and weight changes were assessed to evaluate the swelling percentage. The study was conducted with three samples of each hydrogel. A one-tailed homoscedastic t-test was used to ascertain any statistically significant changes between the samples’ initial and final time points and to identify any statistically significant differences between the groups. The statistical analyses were performed on Microsoft® Excel® for Microsoft 365 MSO (Version 2411 Build 16.0.18227.20082) 64-bit.

[0310] Experiment 8

[0311] Rheology

[0312] The rheological properties of the hydrogels were investigated through amplitude sweeps (shear strain: 0.01 % - 100%; angular frequency: 10 rad / s) and frequency sweeps (shear strain: 0.05%; angular frequency: 0.1 rad / s - 100 rad / s) at a temperature of 37°C through a Peltier temperature controller (H-PTD 220). In addition, the temperature-dependent behaviour was investigated through temperature sweeps (angular frequency: 10 rad / s, shear strain: 0.05%) in the 10°C - 40°C temperature range. The analyses were conducted using an Anton Paar MCR 702e rheometer (Anton Paar, Austria) and a smooth 12 mm parallel plate (PP12) at a 1 mm gap.

Claims

CLAIMS1 . A composition in the form of a hydrogel comprising: a. sodium fluoride (NaF) at a final concentration of between 0.1 -0.4% w / v, b. poloxamer at a final concentration of between 15-40% w / v, c. citric acid (C6H8O7) at a final concentration of between 0.5-1.5% w / v, and d. disodium hydrogen phosphate (Na2HPC>4) at a final concentration of between 1 .5 -2.0% w / v, wherein the final pH is adjusted to between pH 5.2-6.2, wherein the composition is liquid at a temperature of at the most 20°C and wherein said poloxamer in the composition displays micelle-forming capacity.

2. The composition according to claim 1 , wherein the final concentration of the poloxamer is 20% w / v.

3. The composition according to claim 1 or 2, wherein the poloxamer is Pluronic acid (Poloxamer 407).

4. The composition according to any one of preceding claims, wherein the final concentration of the sodium fluoride (NaF) is 0.2% w / v.

5. The composition according to any one of preceding claims, wherein c. citric acid (C6H8O7) at a final concentration of between 0.5-1 .5% w / v, and d. disodium hydrogen phosphate (Na2HPO4) at a final concentration of between 1.5 -2.0% w / v, are formulated as a citrate phosphate buffer with a pH of 5.5 and wherein the pH of said buffer is adjusted with citric acid.

6. The composition according to any one of preceding claims, wherein the citric acid (C6H8O7) is citric acid monohydrate.

7. The composition according to claim 5, wherein the final concentration of the citric acid (C6H8O7) monohydrate is 1.051 % w / v.

8. The composition according to any one of preceding claims, wherein the final concentration of Na2HPC>4 is 1 .815% w / v.

9. The composition according to any one of preceding claims, wherein the final pH is adjusted to pH 5.5.

10. The composition according to any one of the preceding claims, further comprising water for injection of a final concentration of 76.934%w / v.

11. The composition according to any one of the preceding claims, comprising or consisting of: a) sodium fluoride (NaF) at a final concentration of 0.2%, b) poloxamer 407 at a final concentration of 20%, c) citric acid monohydrate (C6H8O7) at a final concentration of 1 .051 %,d) anhydrous disodium hydrogen phosphate (Na2HPC>4) at a final concentration of 1.815%, and e) water for injection at a final concentration of 76.934%, wherein the final pH is adjusted to pH 5.5, wherein the composition is liquid at below RT, and wherein said poloxamer in the composition displays micelleforming capacity.

12. The composition according to any one of preceding claims, wherein the composition is antimicrobial, bacteriostatic, pro-resolution and / or antiinflammatory.

13. The composition according to any one of preceding claims, wherein the composition further comprises sodium benzoate at a final concentration of between 1-2.5% w / v as a preservative, such as at a final concentration of approximately 1.7% w / v, a flavouring substance, a bioactive substance and / or microparticles having a mean particle diameter (D50) of 20-200 pm, wherein said microparticles are organic or inorganic, biodegradable and / or bioresorbable.

14. A composition according to any one of the preceding claims, which has been sterilized, such as by autoclaving.

15. The composition according to any one of preceding claims, wherein the composition is for use in cleaning and / or debriding a biological surface and or a biomaterial surface in situ, such as for use in cleaning and / or debriding an implant, a dental prosthetic and / or a tooth, such as for removing calculus from said surface.

16. A kit comprising a composition according to any one of the preceding claims, comprising a. a syringe and an applicator tip, and / or a vial, and b. an instruction leaflet, and optionally c. a non-surgical debridement tool and / or device.

17. A kit according to claim 16, wherein the applicator tip is blunt, or has a single or double side-vent.

18. A kit comprising a composition according to any one of claims 1-15, wherein the components a. - d. of claim 1 are provided in one vial.

19. A kit according to any one of claims 16 -18, further comprising a further vial and / or syringe comprising a sealing composition, such as hyaluronic acid.

20. A composition according to any one of claims 1-15, or as provided in a kit according to any one of claims 16-19, for use in assisting in the treatment and / or prevention of calculus, periimplantitis, gingivitis, mucositis, peri-implant mucositis, periodontitis, and / or chronic and / or infected dermal ulcers, wherein thecomposition is used to remove biofouling, biofilm and / or necrotic tissue from a biological surface and / or a biomaterial surface in situ.

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