Dental paste

Abstract

A dental paste or gel is provided comprising a composition having: at least 2 to 4 % w / w agar; at least 62 to 95 % w / w glycerol; and at least 0.03 to 3 % w / w epithelial-adhering protein complex. The e

Description

Background Delivering a bioactive component intended to maintain and / or improve health in a human or an animal, such as a companion animal, presents varying challenges to formulators, particularly depending on the target site and type of agent for delivery. Many bioactive agents are susceptible to degradation and exposure to oxygen, heat, light and / or moisture may practically negate the health benefit of the bioactive. The formulation used to deliver the bioactive component may comprise a solid dose form, such as a capsule or tablet because inherent protection of the active is required. Unfortunately, traditional encapsulation or other processing methods that provide a physical barrier to help reach / access the target site successfully are not always useful. For example, in the mouth, which defines the oral cavity of mammals, humans or animals such as pets, comprising the oral mucosa (gums, lips, cheeks, palate and floor of the mouth), the tongue and the teeth. Where the target site is in a structure in the mouth, the formulation is required to remain proximal and remain local for a minimum period such that the bioactive component is delivered at the required efficacy. However, many oral health products formulated for use in the mouth, such as oral washes, lozenges and pastes, suffer the problem of unreliable and / or inconsistent delivery and a sufficient amount of the bioactive (on the mucosal membrane or tongue, for example) is never achieved which to yield a measurable effect. This is especially true when the challenge concerns administering an oral health product to a dependent e.g. a child, elderly person or an animal, such as a pet. Further, due to risk of involuntary ingestion of the active, undesirable effects associated with that specific challenge remain difficult to overcome; these include reliably controlling efficacy and toxicity and preventing the associated side effects, such as gastro-sensitivity and sickness, which may result. In particular, common diseases within the oral cavity often occur due to a change in the balance of the natural flora in the biofilm (plaque) covering the teeth and gums. The bacteria contained within the plaque is usually benign because the predominant components of the biofilm are typically commensal bacteria, such Lactobacillus. However, if pathogenic bacteria, such as E. coli and S. aureus become the dominating bacteria, oral health can decline. As a result, tooth decay and / or gum disease may start to occur in the mouth of the mammal, especially if teeth e.g. of pet animals, are not regularly cleaned to remove buildup of plaque. Colonization of the pathogenic species is known to weaken and then dissolve dental enamel leading to caries, or lesions in the teeth and calcified deposits begin to form providing localized focus for the colony to continue to thrive on the teeth, thereby aggravating the problem. These processes contribute to the frequently recorded symptoms of poor oral health: such as malodor of breath, inflammation and bleeding of the gingival tissue and gum. To prevent oral disease and / or maintain oral health, oral care products including those used in veterinary field, often include a bactericidal agent to reduce the pathogen levels. However, since these agents are usually non-selective, they act to destroy all the natural biofilm including the commensal species. This typically does not provide a useful remedy in mammals and especially pet animals, since a requirement to re-balance the flora is necessary to restore and / or maintain longterm oral health EP3424516 suggests a composition comprising binder lactic acid bacterium microorganism that is sensorically neutral and reduces Streptococci colonies. The composition may be added to pet food and does not suffer the taste / smell that the authors suggest typically prevent such compliance by a companion animal with use of effective bactericides. However, such a solution aims to reduce only streptococci rather than effectively restoring the natural balance of the entire mucosal flora. The solution described is formulated and administered as part of a feed that must be masticated for application. The invention herein comes about from a desire to overcome the challenges noted above, in particular, to provide a dental composition, which effectively restores and / or maintains oral health in mammals and particularly in companion animals. SUMMARY of INVENTION The invention disclosed herein concerns a dental paste or gel comprising a composition having at least 2 to 4 % w / w agar; 62 to 95 % w / w glycerol; and 0.03 to 3 % w / w of an epithelial-adhering protein complex. The epithelial-adhering protein complex may comprise one or more: 1) microbiome regulating proteins or a "protein fraction" and 2) a modified whey protein isolate (WPI) from milk. The microbiome regulating protein (s) may be selected from lactoperoxidase, lactoferrin, lysomal alpha-mannosidase, immunoglobulin G, angiogenin, ribonuclease 4 or quiescin sulfhydryl oxidase and / or combinations thereof. The modified WPI is formed from soluble native protein, protein aggregates and protein fibrils produced from whey protein isolates (WPIs). The dental paste or gel may be applied effectively by brushing or coating structures in the oral mucosa directly. The novel form of the dental paste ensures the complex is maintained at the application location i.e. in close proximity to the relevant structure, such as the gum and teeth. The composition is not washed away or swallowed immediately and the remains stable upon delivery; when the active component is exposed to the target site, the selective antibacterial property is effective in-situ. Notably, bioactive components such as regulating proteins are routinely unstable and may lose their active capability prematurely, as compared to the lifetime of the paste product. The dental paste or gel reduces and / or prevents the absorption of oxygen, moisture and / or light thereby protecting the regulating protein, such that its potency is unaffected during storage or delivery. The formulation acts as a temporary barrier and protects the protein complex and inherently its microbiome supporting selective anti-bacterial property. The dental paste or gel specifically stablises the complex for longer, to ensure that the bioactive remains potent and effective when delivered upon site-specific structures within the oral mucosa. The gel or paste formulated according to the invention is nonetheless able to maintain the selective anti-bacterial activity and delivers the protein complex locally within the oral mucosa for an effective period to enable a tangible effect from that activity, in particular concerning the restoration and maintenance of oral health in a mammal, or animal such as a dog. Moreover, the dental paste or gel produced has a soft, malleable and moist structure that can be applied easily to the teeth and gums of companion animals, such as cats and / or dogs, for example with a brush, or instant fluid gel coating applied in or to the surface of a toy. Advantageously, as compared to traditional delivery vehicles such as tablets or capsules, the formulation is also highly palatable. The invention extends to a chew or animal toy with a coating of the dental paste or strip of gel of the invention. In embodiments, the agar component is 2 to 3% w / w and in the preferred embodiments, approximately 2.6% w / w. In embodiments, the glycerol component is 80 to 95% w / w. In embodiments, the composition comprises at least 0.03% w / w epithelial-adhering protein complex, optionally this component is present in the range of at least 0.1 to 3%, 0.5 to 3%, 1 to 3%, 2 to 3% or 2.5 to 3% w / w. The composition of the invention may comprise up to 32% w / w of other / further excipients designed to improve the texture of the composition including thickening, or stabilising agents, such as chitosan or rice flour. In embodiments, other gums and excipients may be utilised to improve the consistency of the composition, including but not limited to arable gum, xanthan gum, alginates, chitin, aloe extract, guar gum, hydroxypropyl cellulose, sodium casein, corn starch, carboxymethylcellulose, gelatin, agar, dextrin, methylcellulose, polyvinyl alcohol, microfiber cellulose, microcrystalline cellulose, seaweed cellulose, sodium polyacrylate, sodium polyphosphate, carrageenan or yeast cell wall. The invention extends to a dental paste or gel according to any previous claim, for use as a medicament, optionally a veterinary medicament. In embodiments, the paste or gel is for use in the treatment or prevention of oral disease, specifically canine oral disease mediated by an excess of pathogenic bacteria. The oral disease may be selected from but not limited to any of tooth decay, gum inflammation and / or calculus. The paste or gel composition may also be for use in veterinary treatment to restore animal oral health, particularly canine or feline oral health. The dental paste is useful to combat stubborn, adverse oral health conditions, such as a bacterial infection in an animal, particularly where disease may be due to an increase in pathogenic bacteria. As described previously, an increase in the pathogenic bacteria typically causes bad breath, plaque and gum disease in animals. In embodiments, the pathogenic bacteria may be psychrobacter. The adverse health of the animal, cat or dog may be due to a reduction in commensal bacteria, thereby creating an imbalance in the microbiota in the oral mucosa or specifically within the plaque. Such an imbalance may result in one or more conditions selected from bad breath (halitosis), plaque and / or gum disease and so use of the paste can help restore that balance especially in dogs. However, it is plausible it would be relevant to other animals particularly, such as cats, which regularly suffer periodontal disease and tooth loss, because of that decay. The paste if partially swallowed would nonetheless be gentle on the digestive system and thus may be employed for frequent use and / or part of a long-term viable oral solution to maintain oral health of the animal over a reasonable period of months or years. In embodiments, when the dental paste is used for the prevention, treatment and / or improvement of oral health and more specifically, dental health, a suitable dosage regimen can be followed. To reduce the pathogenic numbers and improve oral health significantly such a composition may be most effective when the final product is used repeatedly on a daily basis. When applied as a single daily dose, product delivers a minimum of a 15 to 50mg dose of the epithelial-adhering protein complex. In some embodiments, particularly where lower volumes of paste product are required to deliver the effective daily dose e.g. in a single small ball of paste (suitable for brushing or direct application) on the teeth, the epithelial-adhering protein complex is provided at the higher range e.g. 1.5 to 3% w / w. In other embodiments where larger volumes of gel product are necessary e.g. to cover a much larger surface area for coating a toy, a lower % composition may achieve the required daily dose for effect, for example, this may be as low as 0.03%. Depending on the final formulation and product form, the paste or gel required to provide an effective amount of the active component, for a given single application, may weigh around 1g to 50g and have a relevant % of EAPC, in accordance with the scope of the invention. Preferably, the product is applied daily for at least 5 of 7 consecutive days per week, and more preferably for at least 4 weeks. A reduced frequency of the same dose but every other day may be utilised to maintain health in a suitably re-balanced microbiome of the oral mucosa. However, regular administration will more effectively prevent re-occurrence of pathogen build-up and therefore maintain a suitably rebalanced oral mucosa. In embodiments, the invention therefore further relates to a method of improving or maintaining oral health comprising administering to a human or animal in need thereof the dental gel or paste composition as described above. In embodiments, the invention further comprises a method of prevention or treatment of oral disease comprising administering to a mammal and / or animal in need thereof in the composition as described herein. The invention further extends to a method for making a dental paste or gel, comprising the steps of at least: heating glycerol 62 to 95% w / w, optionally at around 95°C; adding and dissolving 2 to 4 % w / w agar in to the glycerol; optionally adding one or more excipients 0 to 32% w / w to the glycerol and agar combination and cooling, optionally to 40°C or below; adding and dissolving 0.03 to 3 % w / w epithelial-adhering protein complex; and cooling, optionally to approximately 18°C or below, to form the dental paste or gel. The dental paste resulting is formulated to deliver and maintain a local and tangible effect from the activity of the protein complex. In particular, its form enables the restoration and maintenance of oral and dental health when applied in the oral mucosa of a mammal, whether human or animal. The texture of the paste or gel produced is also more acceptable to allow for easier oral administration in certain mammal groups, such as infants, the elderly and companion animals, such as dogs. Once received into the mouth the recipient is more likely to accept the composition for example on a brush or other surface applicator, rather than automatically reject a hard or unpleasant tasting capsule or tablet. Preferably, the dental paste or gel composition may further comprise one or more excipient to maintain and improve palatability. BRIEF DESCRIPTION Further aspects of the invention will become apparent from the following description, given by way of example and with reference to the accompanying drawings in which: Figure 1 is a graph showing the nil effect of the complex used in the paste of the invention on the growth of the commensal bacteria L. acidophilus; Figure 2 is a graph showing the bactericidal effect of the complex used in the paste to the pathogenic bacteria E. coli; Figure 3 is a graph showing that the complex used in the paste adheres well to epithelial surfaces and retains its bactericidal activity towards the pathogenic bacteria S. aureus; and Figure 4 is a graphical representation of data demonstrating that the activity of a key microbiome regulating protein lactoperoxidase, is sufficiently retained in the dental paste of the invention following manufacture (in accordance with the disclosure herein and storage thereafter). DETAILED DESCRIPTION For the purposes of this specification, the term 'about' or 'approximately' and grammatical variations thereof mean a quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 0.1% to a reference quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length. The term 'substantially' or grammatical variations thereof refer to at least about 50%, for example 75%, 85%, 95% or 98%. The term 'comprise' and grammatical variations thereof shall have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. The applicant's work comes from additional investigation and improvement of their recently developed formulations for use in oral care, specifically as it relates to the restoration, improvement and maintenance of oral health in companion animals, especially canines. Milk protein fractions The enzyme lactoperoxidase is a protein that has been implicated in the microbiome regulating proteins isolated from bovine milk (NZ547859). This publication describes a combination of protein fractions from bovine dairy milk can be effective at preventing the growth of pathogenic bacteria such as E. coli and S. aureus while not effecting the growth of commensal bacteria from, for example, the Lactobacillus family. Formulations are disclosed in the art based on milk bioactive proteins that is extracted from milk. The components are produced naturally by the cow as an immune defense response against infection and inflammation. Such anti-inflammatory, antioxidant and antimicrobial action supports 'good' bacteria flora and kills 'bad' bacteria and has been shown to be safe in some clinical applications. However, their practical use in mammals or pet animals was not enabled for dental or oral application at that time. This is because, such proteins do not alone enable their useful properties to be delivered and formulations encompassing these agents were not found to be effective. Until the author's own research and development of these components there was no means by which microbiome regulating activity of such proteins and / or fractions thereof (or very similar types of functioning agent) could exploited for effect in the oral mucosa successfully. Nonetheless, the present applicant determined a method to successfully complex the microbiome regulating proteins that both stablises the proteins and introduces a new physical function to enable the complexed proteins to adhere to an epithelial surface, upon topical application. Such an invention would enable a product to retain excellent protein functionality (selective bactericidal quality) but additionally have properties required to overcome unmet challenge (for example, local adherence, as would be relevant in the oral mucosa). This successful outcome of such a protein biocomplex is due in part to the important chemical and physical conditions under which the two components are reacted together in the applicant's process to form the complex, diligently researched and controlled, to optimise the functional activity of both components. This protein biocomplex or "epithelial adhering protein complex" is one of the essential components of the present dental paste or gel of the invention disclosed herein. However, at the time of making the present invention disclosure, the protein complex component remains undisclosed publically. A complete description of that component and how it is obtained is therefore provided herein, as was provided for in the applicant's recent patent application directed to the same, as well explaining for the first time how is used in the manufacture of the novel dental paste of the invention. Epithelial-adhering protein complex "EAPC" There is disclosed herein the applicant's protein complex comprising microbiome regulating proteins complexed with a modified whey protein isolate (WPI) from milk, wherein the complexed microbiome functional proteins configured for topical application and, on application, to adhere to epithelial surfaces. The microbiome regulating proteins are selectively toxic to pathogenic bacteria, but which minimise any reduction in commensal bacteria population. The regulating protein in the complex may comprise at least one or more of lactoperoxidase, lactoferrin, lysomal alpha-mannosidase, immunoglobulin G, angiogenin, ribonuclease 4, quiescin sulfhydryl oxidase, and combinations thereof. Microbiome regulating protein For brevity of description, the word 'protein' or grammatical variations thereof as used herein is intended to encompass one protein, multiple proteins, a protein fraction, or protein fractions and reference to a singular protein should not be seen as limiting. The microbiome regulating protein may be a blend of protein fractions from milk that are selectively toxic to pathogenic bacteria, but which minimise any reduction in commensal bacteria population. The microbiome regulating protein may comprise lactoperoxidase, lactoferrin, lysomal alpha-mannosidase, immunoglobulin G, angiogenin, ribonuclease 4, quiescin sulfhydryl oxidase, and combinations thereof. The protein may comprise all of the above listed proteins. The microbiome regulating protein selected for the above method may initially be in dried powder form. Modified WPI The term 'modified whey protein isolate' or grammatical variations thereof as used herein refers to soluble native protein, protein aggregates and protein fibrils produced from whey protein isolates (WPIs). The modified WPI selected for the above method may initially be in the form of an aqueous gel. The modified WPI selected may be derived from bovine species milk but may also be sourced from modified WPI obtained from other animals such as goats and sheep. The gel has the ability to bind active ingredients together, release the agents in a controlled manner and has shear thinning rheology (thixotropic) giving it good stability and positive skin feel. It has a semi-solid material composed of soluble native protein, protein aggregates and protein fibrils produced from whey protein isolates (WPIs) to form a modified WPI. The modified WPI gels of use typically have a viscosity from 0.25 to 4.5 Poise. EAPC Method of manufacture The method of producing the epithelial adhering protein complex includes selecting a microbiome regulating protein in a powder form; selecting a modified whey protein isolate (WPI) from milk in a gel form; solubilising the microbiome regulating protein in an aqueous salt solution, the aqueous salt solution having an ionic strength of 25-200mM NaCI; blending together the solubilised microbiome regulating protein and modified WPI; adjusting the pH to 2.0-6.0; optionally adjusting the temperature to 18-37°C; holding the blend at a pH of 2.0-6.0 and a temperature of 18-37°C for at least 30 minutes. The following flow chart explains the process for producing the EAPC: Dissolve microbiome regulating proteins in 50mM NaCI solution. 1 Warm the solution to 25°C Dissolve modified whey protein isolate in sodium phosphate buffer at pH 2 I Warm the solution to 25°C Gently combine the two solutions ensuring that the proteins are not denatured I Adjust the pH of the solution to pH 4.0 using HCI I Increase ionic strength of the solution to 75mM NaCI. I Hold for 60 mins at 25°C without stirring Freeze the product in trays in thin layers so that the product is no more than 1cm thick Product can be used in an undried format Load into freeze dryer and decrease air pressure in dryer to <0.1 Bar I Dry at <0.1 Bar pressure and at <37°C for 28hrs so that the finished product meets critical parameters including water activity <0.1. I Remove from trays, mill and pack I Check protein complex for selective bactericidal activity The resulting complexed protein EAPC may be a semi-solid aqueous gel with a viscosity of approximately 0.25 to 4.5 Poise. The viscosity of the modified whey protein isolate is important to facilitate the complexing, and the optimum temperature for the most suitable viscosity is in the range of 18-37°C. Ionic strength of the mixture is important for the correct interaction of the protein groups on both components and the optimum ionic environment is maintained by 25-200mM NaCI at pH 2.0-6.0. The ratio of microbiome regulating protein to modified WPI used in the method and / or present in the disclosed complexed protein may be : 1:1, or 1:2, or 1:3, or 1:4, or 1:5, or 1:6, or 1:7, or 1:8, or 1:9, or 1:10. In examples, the ratio may be from 1:1 to 1:10; i.e. 1 part microbiome regulating protein to 1-10 parts modified whey protein isolate. The ratio may be a 1:1 ratio. It may be necessary to have at least as much modified WPI to protein to ensure the necessary extent of complexing is reached. Lower ratios could be used but with waste or non-complexed protein resulting from the method due to insufficient modified WPI being present at lower ratios. Salt The salt solution may comprise a mix of water and a chemical salt. The chemical salt may be NaCI although other salts such as MgCI may also be used. Salt may be added to the extent needed to provide the indicated ionic strength. The ionic strength of the salt solution may be approximately 25, or 50, or 75, or 100, or 125, or 150, or 175, or 200mM NaCI. As noted above, the ionic strength may vary from 25-200mM NaCI. The ionic strength be approximately 75mM NaCI. This ionic strength is maintained in the complexed blend of protein and modified WPI during and after holding. This ionic strength range appears to be desirable for complexing or dissolution of the microbiome regulating protein into the modified WPI although, there may be some variation depending on the pH, temperature and holding time used. The salt solution is important to create the correct ionic nature of the solution and enable the powdered protein to dissolve and the protein to be correctly charged to create the complex. Blending Blending occurs gently so that no or minimal foaming of the mixture occurs during blending. Blending may be completed, for example, using a planetary mixer. Blending may continue during pH adjustment, temperature adjustment and / or holding. Gentle or slow blending of the protein may be important to minimise or avoid denaturing and loss of functionality. pH The pH of the blend prior to pH adjustment may be approximately 6.5 to 7.5 or, around neutral pH 7.0. This start point in pH may be dependent on the pH of the water used to form the aqueous salt solution. The pH of the blend after pH adjustment may be approximately 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0. In one embodiment as noted above, the pH may be from 2.0 to 6.0. In one embodiment, the pH may be approximately 4.0. This pH range and value appears to be an optimum for complexing or dissolution of the protein into the modified WPI although there may be some variation depending on the ionic strength, temperature and holding time used. The acid conditions post adjustment appear to maintain the appropriate charges on the protein to ensure bonding of the complex. The pH may be adjusted by use of an acid. The acid may be hydrochloric acid although other acids may also be used. In the inventor's experience, no buffers are required to maintain the reduced pH once adjusted. Temperature The temperature of the blend after any adjustment (if needed) may be approximately 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30, or 31, or 32, or 33, or 34, or 35, or 36, or 37°C. As noted above, the temperature, post any adjustment may be from 18-37°C. In one embodiment, the temperature post adjustment may be approximately 25°C. The temperature may be adjusted to maintain the modified WPI at a desired viscosity to enable optimum complexing. This desired viscosity may be in the range of approximately 0.25 to 4.5 Poise. The temperature range and values described appear to be an optimum for complexing or dissolution of the proteins into the modified WPI although there may be some variation depending on the ionic strength, pH and holding time used. The temperature may be adjusted from ambient conditions (or retained at ambient conditions if the ambient temperature is within the desired range). Temperature adjustment may be up or down depending on the difference between the desired temperature and the ambient temperature. Holding time The holding time may be at least 30 minutes. The holding time may be from 30 minutes to 24 hours. In one embodiment, the holding time may be approximately 60 minutes. In the inventor's experience, most of the complexing occurs within 30-60 minutes based on the chosen parameters. Extended durations could be used and, based on the inventor's experience; there is no harm or risk of loss of functionality in holding the mixture for longer periods. This timing appears to be an optimum for complexing or dissolution of the protein into the modified WPI although there may be some variation depending on the ionic strength, temperature and pH used. Drying Optionally, drying may be completed in advance of subsequent formulation. In this embodiment, the dried complex may be a solid. Drying may be to a water activity of less than 0.6. In selected embodiments, the water activity may be as low as 0.2-0.3. Drying of the complex may be done under specific conditions of low temperature and low pressure over a time course that ensures the epithelial adhering nature and the selective bactericidal activity of the components of the complex are retained. Pressure during drying may be important in that, at low pressure the moisture boils off the gel at a lower temperature so that the drying can be undertaken at low temperatures. In addition, a very gradual lowering of pressure may be important so that the complexed protein solution in the dryer does not foam. Drying may be completed by freeze-drying or any other gentle drying process using a non-denaturing temperature / pressure e.g. less than 30°C, in a vacuum. The complexed protein remains functional when rehydrated post drying. Only through careful experimentation and balance of these parameters, were the useful effects obtained in the resulting protein complex. Indeed, the extent of adherence of protein on epithelial surfaces post complexing was more than double that of each component alone and in the inventors experience synergistic in nature or at least well beyond that anticipated suggesting a synergistic effect was possible but that could not have been previously expected or predicted. It was observed that the selective bactericidal activity of the protein described herein can be adversely effected if the temperature of any step of the process exceeds 37°C, and the pH drops below 2.0 or greater than 9.0. Adherence protein complex to epithelial surfaces To determine if the complex was adherent to epithelial layers a portion of pig's skin was soaked in a solution of 50mg / mL of the complex (containing 50mg / mL protein), washed twice in phosphate buffer at pH 7.4 and stained with Coomassie Blue, which stains for protein. This gave an intensely stained skin compared to pig's skin that had not been soaked in the complex (Figure 1). Treatment of pig skin with 50mg / mL modified whey protein isolate fraction (containing 50mg / mL protein) or the microbiome regulating proteins from bovine milk (containing 50mg / mL protein) alone, then washed, showed some binding of these components to the skin, but not as much as with 50mg / mL of the complex of both components. Portion of pigskin treated without or with the complex, and the components of the complex, washed twice and stained for protein attached to the epidermal layer of the pig's skin. Treatment Pig skin Pig skin soaked in 50mg / ml of microbiome regulating proteins from bovine milk for 60 secs, then washed. Pig skin soaked in 50mg / ml modified whey protein isolate for 60 secs then washed. Pig skin soaked in 50mg / ml of the complex for 60 secs then washed. Result [1¾ Relative increase in protein binding 1.0 1.13 1.63 2.35 The epithelial binding activity of the complex was much greater (more than double) than the modified whey protein isolate alone or the microbiome regulating proteins alone. The modified whey protein isolate has been specifically prepared to attach to epithelial surfaces. Thus, it would be expected that the amount of binding to the pig's skin of this component would be similar to the amount of binding of the complex. However, the complex binding was 44% greater than the modified whey protein isolate alone, suggesting a synergistic effect of the components, or that the process used to generate the complex was increasing the adhering ability of the protein complex. Retention of the enzyme bioactivity The enzyme lactoperoxidase is a protein that has been implicated in the microbiome regulating proteins isolated from bovine milk (NZ547859 and PCT / NZ2017 / 050043). Lactoperoxidase activity was measured by the addition of the complex, or the components of the complex separately, to a solution of hydrogen peroxide in 100 mM Phosphate buffer, pH 5.5, and monitoring the oxidation of 2,2-Azino-bis(3-Ethylbenzthiazoline-6-sulphonic acid) (ABTS) spectrophotometrically at 436nm. Lactoperoxidase activity of the combination of the microbiome regulating proteins from bovine milk was retained when the microbiome regulating proteins were complexed with the modified whey protein isolate. As would be expected, the modified whey protein isolate had no peroxidase activity. Lactoperoxidase activity of the complex compared to the components of the complex: Component Lactoperoxidase activity (Units) Modified whey protein isolate (50mg / ml) 0 Microbiome regulating proteins (including lactoperoxidase 16mg / ml) 205005 Complex of whey protein isolate and protein fractions from bovine milk (50mg / ml) 223339 Specific bactericidal activity Commensal bacteria Microbiome regulating proteins isolated from bovine milk have been shown to have no effect on the growth of commensal bacteria such as those from the Lactobacillus family PCT / NZ2017 / 050043. In order to determine the effect of the complex containing these microbiome regulating proteins on a commensal bacteria Lactobacillus acidophilus bacteria were cultured anaerobically and the complex was added to the cultures and numbers of bacteria after 24 hours were determined as the optical density at 650nm. The complex of the modified whey proteins and the microbiome regulating protein isolated from bovine milk had no effect on the growth of the commensal bacteria Lactobacillus, acidophilus (Figure 1) Pathogenic bacteria Microbiome regulating proteins isolated from bovine milk have been shown to be bactericidal to pathogenic bacteria such as E. coli PCT / NZ2017 / 050043. In order to determine the effect of the complex containing these protein on E. coli these bacteria were cultured and the complex was added to the cultures and numbers of bacteria after 24 hours were determined as the optical density at 650nm. The complex inhibited growth of the pathogenic bacteria E. coli to a similar extent as the microbiome regulating protein from bovine milk (Figure 2). Note that the square data points in Figure 2 correspond to results seen for addition of the microbiome regulating proteins from bovine milk and the circular data points correspond to results seen for addition of the complex of the microbiome regulating proteins with the modified whey protein isolate. Effect of the complex bound to skin on growth of pathogenic bacteria S. aureus is a pathogenic bacteria often associated with skin disease. The microbiome regulating proteins isolated from bovine milk has been shown to be bactericidal to S. aureus grown in culture PCT / NZ2017 / 050043. Samples of pig skin treated with the microbiome regulating proteins from bovine milk then washed showed a modest inhibition of S. aureus growth. However, samples of pig skin treated with the complex, then washed showed significantly greater inhibition of 5. aureus growth (Figure 3). This confirms the results seen in Table 1 confirming that the complex binds well to epithelial surfaces such as skin and also retains the bactericidal activity of the microbiome regulating proteins from cow's milk. Dental paste or gel method of manufacture The method for making a dental paste or gel according to embodiments of the invention, comprises the steps of at least: heating glycerol 62 to 95% w / w, optionally at around 95°C; blending 2 to 4 % w / w agar in to the glycerol; optionally adding one or more excipients 0 to 32% w / w to the glycerol and agar combination and cooling, optionally to 40°C or below; adding and dissolving 0.03 to 3 % w / w epithelial-adhering protein biocomplex; and cooling, optionally to approximately 18°C or below, to form the dental paste or gel. In examples, blending agar is performed in a step wise manner, preferably at approximately 90 -100°C. In examples, the cooling is undertaken in a step-wise manner from 40°C to 18°C. Table 1 below exemplifies embodiments of the composition of the dental paste of the invention including examples and the working ranges of the key components. Composition component Working range w / w % Example #1 w / w % Example #2 w / w % Example #3 w / w / % Example #4 w / w% Example #5 w / w% Agar 2 to 3 2.6 2.6 2.6 2 3 Glycerol 62 to 95 86.4 86.4 94.5 90.5 79 Thickening agent (Rice flour, chitosan etc) Oto 32 10.5 10 0 5 15 Epithelial-adhering protein complex (EAPC) 0.03 to 3 0.5 1 2 2.5 3 The applicant has generated a novel process and new dental gel or paste composition with the view that such a composition, when applied to the teeth of a companion animal, such as a canine, will for the first time enable selective bactericidal activity to be delivered specifically in and be retained at the oral mucosa sufficiently long enough to consistently deliver an effective amount of the EAPC. In doing so, oral health may be restored and the symptomatic signs of oral disease educed in canines and companion animals. However, to ensure such effect, it was crucial to determine that the relevant level of bioactivity is maintained in the product as claimed and produced by the process described herein. Activity maintenance in dental paste The paste / gel of the invention was tested using lactoperoxidase as an indicator of microbiome activity. As discussed previously, the enzyme lactoperoxidase is a protein implicated in the microbiome regulating proteins isolated from bovine milk. Lactoperoxidase activity was therefore measured by the addition of the dental paste as provided in Example 3 of the table above, to a solution of hydrogen peroxide in 100 mM Phosphate buffer, pH 5.5, and monitoring the oxidation of 2,2 -Azino-bis(3-Ethylbenzthiazoline-6-sulphonicacid) (ABTS) spectrophotometrically at 436nm. The level of lactoperoxidase activity was 56 U / g immediately after manufacture and 75 U / g 10 days after manufacture, as also shown in graphical form of Figure 4. 5 Lactoperoxidase activity of the combination of the microbiome regulating proteins formulated from the complex within the dental paste was retained and these levels are approximately what would be expected in the original complexed form indicating that formulating the complex further into the new dental paste, does not reduce the biological activity of the antibacterial component. While certain representative embodiments and details have been shown for purposes of illustrating 10 the invention, it will be apparent to those skilled in the art that various changes may be made without departing from the scope of the disclosure, which is further described in the following appended claims. The embodiments described above may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, 15 and any or all combinations of any two or more said parts, elements or features.

Claims

1. A dental paste or gel comprising a composition having:at least 2 to 4 % w / w agar;at least 62 to 95 % w / w glycerol; andat least 0.03 to 3% w / w epithelial-adhering protein complex.

2. The dental paste or gel wherein the epithelial-adhering protein complex comprises: microbiome regulating proteins or a "protein fraction" and a modified whey protein isolate (WPI) from milk.

3. The dental paste or gel of claim 2, wherein the microbiome regulating protein (s) is selected from lactoperoxidase, lactoferrin, lysomal alpha-mannosidase, immunoglobulin G, angiogenin, ribonuclease 4 or quiescin sulfhydryl oxidase and / or combinations thereof and or the modified WPI is formed from soluble native protein, protein aggregates and protein fibrils produced from whey protein isolates.

4. The dental paste or gel according to any preceding claim wherein the agar component of the composition is 2 to 3% w / w, preferably 2.6% w / w.

5. The dental paste or gel according to any preceding claim wherein the epithelial-adhering protein complex component of the composition is at least 0.5 and / or no more than 3%, 2.5%, 2 % or 1 % w / w.

6. The dental paste or gel of any preceding claim wherein the composition comprises at least 90-95% w / w glycerol, preferably 94.9% w / w / glycerol.

7. The dental paste or gel according to any preceding claim wherein the composition of the may comprise up to 32% w / w of one or more excipient selected from one or more of arable gum, xanthan gum, alginates, chitin, aloe extract, guar gum, hydroxypropyl cellulose, sodium casein, corn starch, carboxymethylcellulose, gelatin, agar, dextrin, methylcellulose, polyvinyl alcohol, microfiber cellulose, microcrystalline cellulose, seaweed cellulose, sodium polyacrylate, sodium polyphosphate, carrageenan or yeast cell wall.

8. The dental paste or gel according to any previous claim, for use as a medicament, optionally for use as a veterinary medicament.

9. The dental paste or gel according to Claim 8, wherein the use as a veterinary medicament comprises use of the dental paste or gel once a day.10 The dental paste or gel according to claim 8 or 9, for use in the treatment or prevention of oral disease in mammals and / or animals, preferably canines, mediated by an excess of pathogenic bacteria.

11. The dental paste or gel according to claim 10, wherein the oral disease includes one or more of the following conditions: tooth decay, gum inflammation, calculus, periodontal disease, halitosis.

12. The dental paste or gel according to any previous claim for use as a veterinary medicament, in the once-daily maintenance of canine or feline oral health.

13. A chew or animal toy at least partially coated with or comprising the dental paste or gel of any preceding claim.

14. A method of preventing or treating oral or dental disease and / or improving or maintaining oral health, comprising administering to a mammal or animal, preferably a canine, in need thereof the dental gel or paste composition according any of claims 1 to 7.

15. A method of making a dental paste or gel, comprising the steps of at least:heating glycerol 62 to 95% w / w, optionally at around 95°C;adding and dissolving 2 to 4 % w / w agar in to the glycerol;optionally adding one or more excipients 0 to 32% w / w to the glycerol and agar combination and cooling, optionally to 40°C or below;adding and dissolving 0.03 to 3 % w / w epithelial-adhering protein complex, optionally wherein the epithelial-adhering protein complex comprises: microbiome regulating proteins or a "protein fraction" and a modified whey protein isolate (WPI) from milk and optionally wherein the microbiome regulating protein (s) is selected from lactoperoxidase, lactoferrin, lysomal alpha-mannosidase, immunoglobulin G, angiogenin, ribonuclease 4 or quiescin sulfhydryl oxidase and / or combinations thereof and or the modified WPI is formed from soluble native protein, protein aggregates and protein fibrils produced from whey protein isolates; andcooling, optionally to approximately 18°C or below, to form the dental paste or gel.

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