Oral care compositions for treating dental health conditions

Abstract

The present invention relates to polymeric membranes and compositions for oral care and various methods of use thereof. In particular, the present invention relates to a composition comprising phosphoprotein and its use in the treatment and prevention of gingival bleeding and in the treatment and prevention of periodontal disease. Preferred compositions comprise osteopontin and derivatives thereof.

Description

Technical Field

[0001] This invention relates to compositions for oral care and various methods of using them. More specifically, this invention relates to compositions comprising phosphoproteins and their use in the treatment and prevention of periodontal diseases, particularly gingivitis and periodontitis. Background Technology

[0002] The following discussion is provided to help readers understand this disclosure, and the following discussion does not constitute any admission of the content or relevance of the prior art.

[0003] Periodontal disease is one of the most prevalent diseases worldwide, with an estimated 20-50 percent of the global population experiencing some form of periodontal disease [1]. This not only leads to serious dental health challenges, but there is also substantial evidence that periodontal disease increases the risk of systemic inflammatory conditions such as cardiovascular disease and diabetes.

[0004] Periodontal disease is a general description of the inflammatory response of the gingiva and surrounding connective tissue to plaque buildup on the teeth at the gingival margin. The inflammatory response can be divided into two main categories: gingivitis and periodontitis.

[0005] Gingivitis is very common and is associated with the accumulation of supragingival plaque along the gingival margin of the teeth. Clinically, gingivitis presents as bleeding gum tissue without signs of bone loss or periodontal pocket formation. At this stage, gingivitis is a reversible inflammatory phase of periodontitis and can be relieved with good oral hygiene and removal of bacterial biofilm. However, if left untreated, the condition can progress to periodontitis, characterized by permanent periodontal tissue loss.

[0006] Periodontitis occurs when an inflammatory response in the tissue leads to collagen loss, damage to the periodontal ligaments attached to the bone, alveolar bone loss, and the development of periodontal pockets. Periodontal pockets provide a breeding ground for pathogenic bacteria. Untreated periodontitis eventually leads to tooth loss.

[0007] The initial colonizing bacteria on teeth are species of the genus *Streptococci*, which proliferate and are subsequently colonized by other bacteria present in saliva, such as various species of the genera *Actinomyces* and *Veillonella*. The greatest plaque growth occurs at the gingival margin, where plaque accumulation can usually be seen after several days.

[0008] Dysbiosis of the subgingival microbiota adversely affects the host immune system, generating and maintaining unresolved inflammation in the gingiva and periodontal tissues. Recruitment of immune cells and the production of several inflammatory mediators lead to tissue damage and tooth loss. This persistent inflammation prevents immune destruction and tissue regeneration, which not only results in localized chronic inflammation in the oral cavity but also increases the risk of systemic diseases such as cardiovascular disease, diabetes, Alzheimer's disease, and cancer [1, 2].

[0009] Periodontal disease is no longer considered a simple bacterial infection. Instead, it is a complex disease of a multifactorial nature, involving complex interactions between the subgingival microbiota, host immunity and inflammatory response, and environmental alteration factors. Therefore, periodontal health cannot be considered solely from the perspective of plaque / bacterial levels and control, but must include a holistic consideration and assessment of all factors that contribute to the development of the disease [3].

[0010] Current treatments for periodontal disease involve minimizing biofilm buildup on the tooth surface, which is currently achieved through mechanical cleaning and antimicrobial agents. Antimicrobial agents attempt to kill pathogenic bacteria in the tooth biofilm, but they also affect symbiotic microbes in the soft tissues that contribute to microbial homeostasis. Indiscriminately killing these symbiotic bacteria can lead to an imbalance in the oral microbiota and increase the risk of developing systemic inflammatory diseases. Furthermore, patients with chronic periodontitis must adhere to a strict dental maintenance plan and visit their dental health provider regularly to help maintain periodontal stability and minimize further attachment loss.

[0011] In approximately 20-30% of all cases of chronic periodontitis, there is no good response to routine periodontal treatment. Many factors can contribute to this response, such as inadequate removal of bacterial deposits, poor plaque control, smoking, and systemic conditions, such as diabetes, which can impair the immune response. These factors are not always easily identified and may not be modifiable or properly controlled.

[0012] It should be understood that host determinants in clinical periodontology may include, but are not limited to, the following factors:

[0013] Local risk factors (susceptibility factors)

[0014] Dental plaque-biofilm retention factors:

[0015] Dental Anatomy

[0016] • Tooth restoration margins, etc.

[0017] Dry mouth

[0018] Poor saliva flow and quality

[0019] Mouth breathing

[0020] Systemic risk factors (modifying factors)

[0021] Smoking

[0022] • Metabolic factors (e.g., hyperglycemia)

[0023] Nutritional factors (e.g., vitamin C)

[0024] Pharmaceutical preparations

[0025] • Increased sex steroids (puberty, pregnancy)

[0026] Hematological conditions

[0027] With a better understanding of the pathogenesis of periodontal disease (including the importance of host immune response and oral microbiota), the main goal of periodontal therapy in recent years has shifted to restoring the homeostasis of the oral microbiota and its harmonious balance with the host periodontal tissues.

[0028] Recently, bovine milk osteopontin (OPN) has been proposed as a therapeutic agent to prevent the formation of dental biofilms, which can lead to the development of caries lesions [4]. Administration of OPN isolated from bovine milk has also been shown to inhibit bacterial adhesion, which delays the formation of biofilms on teeth and may reduce the incidence of dental caries or periodontal disease. In most studies, bacterial adhesion was tested during static incubation with saliva-free inoculated media, and therefore under conditions that do not accurately simulate the oral cavity, where bacterial adhesion occurs under a constant flow of saliva.

[0029] In one study, Kristensen et al. aimed to investigate the effects of OPN and major milk proteins on bacterial adhesion in a shear-controlled microfluidic device[5] that provided a salivary flow rate representative of the oral cavity[6]. Kristensen’s study investigated the ability of OPN to prevent the adhesion of three types of tooth biofilm-forming bacteria to a salivary coating surface under shear-controlled flow conditions compared to other milk proteins. OPN effectively reduced the adhesion of the following primary colonies: Actinomyces naeslundii, Lactobacillus paracasei subsp. paracasei, and Streptococcus mitis. However, crude skim milk protein appeared to be consistent with the effect of OPN[4]. The fact that inhibition was achieved through different milk proteins suggests a non-specific mode of action rather than targeted binding to specific bacterial adhesins.

[0030] This work demonstrates that different lactal proteins can reduce bacterial adhesion to salivary coating surfaces and delay the formation of dental biofilms and the onset of biofilm-related diseases without any observable harmful side effects on the symbiotic oral microbiota. However, conflicting evidence in WO2013 / 144247 suggests that OPN alone has no effect on biofilm growth in a caries biofilm flow cell model.

[0031] WO2013 / 144247 proposes the use of OPN nanoparticle aggregates in the treatment of diseases associated with biofilms. However, there is no evidence that such aggregates can be used to treat established periodontal disease or any condition with an established complex biofilm.

[0032] The work of Kristensen et al. and other studies have not resolved the impact of OPN on established periodontal diseases characterized by a diverse bacterial spectrum and known to be quite difficult to treat due to complex interactions with the immune system. Therefore, alternative compositions and approaches for treating periodontal disease remain necessary in the gingivitis stage and later, more severe stages of periodontitis. Finally, there remains a particular need for patients with chronic disease who do not respond to conventional therapies. Summary of the Invention

[0033] In a first aspect of the invention, a composition comprising a phosphopeptide is provided for the prevention or treatment of gingival bleeding in a subject with such need. Suitably, in some embodiments, the gingival bleeding is associated with or caused by gingivitis and / or periodontitis.

[0034] In a second aspect, a composition comprising a phosphopeptide is provided for the prevention or treatment of periodontal disease in a subject with this need. Suitably, in some embodiments, periodontal disease is gingivitis and / or periodontitis.

[0035] In a third aspect of the invention, a composition comprising a phosphopeptide is provided for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with such need.

[0036] In a fourth aspect, a method is provided for treating or preventing gingival bleeding in a subject with this need, said method comprising administering to the subject a therapeutically effective amount of a composition comprising a phosphatidylcholine. Suitably, in some embodiments, the gingival bleeding is associated with gingivitis and / or periodontitis.

[0037] In a fifth aspect, a method is provided for treating or preventing periodontal disease in a subject with this need, said method comprising administering to the subject a therapeutically effective amount of a composition comprising a phosphatidylcholine. Suitably, in some embodiments, periodontal disease is gingivitis and / or periodontitis.

[0038] In a sixth aspect, a method is provided for treating or preventing peri-implant mucositis and / or peri-implantitis in a subject with such need, said method comprising administering to the subject a therapeutically effective amount of a composition comprising a phosphopeptide.

[0039] In another aspect of the invention, a polymeric material comprising a composition comprising a phosphopeptide is provided.

[0040] In one aspect of the invention, a polymeric material comprising phosphopeptides is provided for the prevention or treatment of gingival bleeding in a subject.

[0041] On the other hand, a polymeric material containing phosphopeptides is provided for the prevention or treatment of periodontal disease in subjects who require it.

[0042] On the other hand, a polymeric material comprising phosphopeptides is provided for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in subjects with such need.

[0043] In another aspect of the invention, a polymeric material comprising phosphopeptides is provided for remineralization or prevention of demineralization of oral surfaces.

[0044] On the other hand, a polymeric material containing phosphopeptides is provided for the prevention or treatment of tooth sensitivity in subjects who require it.

[0045] On the other hand, a polymeric material containing phosphopeptides is provided for the prevention or treatment of white spot lesions in subjects who require such treatment.

[0046] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided. In some embodiments, the composition further comprises a fluoride source, optionally comprising monofluorophosphate.

[0047] In another aspect of the invention, an oral gel is provided comprising amorphous calcium phosphate stabilized by a calcium phosphate stabilizer, and optionally comprising monofluorophosphate.

[0048] Further features and implementation schemes of the foregoing aspects are defined in the heading sections listed below. Any feature in any section may be combined with any aspect or implementation scheme in any feasible combination.

[0049] Bleeding gums

[0050] Bleeding gums are a major symptom of gum diseases (including but not limited to gingivitis and periodontitis), and often serve as an early warning sign of infection. Bleeding can also occur in established periodontal pockets in patients with periodontitis. Furthermore, bleeding gums can also occur in wearers of orthodontic appliances, which may be caused by plaque buildup, irritation, or worsening of inflamed and / or diseased gums due to the wearing of orthodontic appliances.

[0051] Suitably, some aspects of the present invention relate to the use of compositions comprising phosphopeptides and methods for preventing or treating gingival bleeding in subjects with such need. Suitably, in some embodiments, the gingival bleeding is related to or caused by the use of orthodontic appliances. In another embodiment, the gingival bleeding is related to or caused by periodontal disease. Those skilled in the art will understand that a subject may suffer from gingival bleeding related to or caused by periodontal disease, and may also suffer from gingival bleeding related to or caused by the use of orthodontic appliances. Suitably, in some embodiments, a composition for preventing or treating gingival bleeding that is related to or caused by the use of orthodontic appliances, and / or related to or caused by periodontal disease is provided.

[0052] It should be understood that the term "related to" as used in this article means that bleeding gums may be a result of, related to, or a symptom of gingival diseases such as gingivitis and / or periodontitis, or may be a result of oral trauma or friction caused by the use of orthodontic appliances. "Caused by" means that bleeding gums is a direct result of gingival diseases such as gingivitis or periodontitis.

[0053] In embodiments relating gingival bleeding to the use of orthodontic appliances, the appliances may include, but are not limited to, fixed bracket braces, fixed orthodontic retainers, and removable appliances (such as dentures), including plastic aligner trays and removable braces. Suitably, in some embodiments, the orthodontic appliance is an orthodontic aligner or a fixed orthodontic bracket. Not wishing to be bound by theory, users of fixed and removable orthodontic appliances and dental prostheses may accumulate plaque more easily than non-users, which may increase the risk of gingival bleeding.

[0054] Periodontal disease

[0055] Some aspects of this invention relate to the use of compositions comprising phosphopeptides and methods for preventing or treating periodontal disease in a subject. As used herein, the term periodontal disease may include gingivitis and / or periodontitis, including any stage, grade, or severity of said disease. If gingivitis is not resolved, it may develop into periodontitis.

[0056] In some embodiments of any aspect described herein, periodontal disease is gingivitis and / or periodontitis. In some embodiments, periodontal disease is acute gingival disease. Those skilled in the art will understand that in some embodiments, gingivitis and / or periodontitis may be a cause of gingival bleeding.

[0057] Gingivitis

[0058] Gingivitis is a reversible plaque-induced inflammation of the gums. It is identified by redness, swelling, and bleeding when brushing or probing. Gingivitis is common, affecting at least 55% of the adult population with bleeding gums. Persistent gingivitis can lead to periodontitis and irreversible alveolar bone loss. While gingivitis is generally considered reversible, removing plaque alone may not be sufficient to resolve the inflammation and bleeding gums.

[0059] Gingivitis can be characterized as localized or widespread gingivitis. The British Society of Periodontology (BSP) clinically defines localized gingivitis as bleeding on probing (BOP) in 10-30% of the teeth. Widespread gingivitis is clinically defined as bleeding on probing in >30% of the teeth. Suitably, in some embodiments, the compositions used in this invention are used for the prevention or treatment of localized gingivitis. Suitably, in some embodiments of the method of this invention, the periodontal disease is localized gingivitis. In alternative embodiments, the compositions used in this invention are used for the prevention or treatment of widespread gingivitis. Suitably, in some embodiments of the method of this invention, the periodontal disease is widespread gingivitis. Those skilled in the art will understand that multiple indices can be used to measure localized or widespread gingivitis.

[0060] Suitably, in some embodiments, localized gingivitis may be characterized by at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% bleeding on probing (BOP). In some embodiments, extensive gingivitis may be characterized by at least 31%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% BOP. In some embodiments, gingivitis includes bleeding of gingival tissue but without signs of bone loss or periodontal pockets.

[0061] Appropriately, in some embodiments, gingivitis may be acute gingivitis. In some embodiments, gingivitis is acute neuroulcerative gingivitis.

[0062] Chronic periodontitis

[0063] Gingivitis does not always progress beyond the gingival margin. However, nearly half of the adult population is susceptible to an irreversible destructive process called chronic periodontitis, and approximately 10–15% of the adult population will experience severe periodontitis. Gingivitis can turn into periodontitis as it destroys the connective epithelium, leading to bone destruction and the formation of periodontal pockets, which are difficult to access with interdental cleaning aids[7].

[0064] To date, the classification of periodontal disease has allowed for clinical diagnosis of disease progression. Regardless of treatment, the staging and grading status of periodontitis does not improve because the interproximal / alveolar bone lost due to the disease does not regenerate. However, the compositions described herein may alter the state of active inflammation and prevent further disease progression. Depending on the depth of probing and the degree of bleeding on probing, a patient's current condition can vary between unstable, remission, and stable.

[0065] The British Periodontal Society (BPS) 2017 Periodontal Disease Classification[7] aims to enable diagnosis in clinical practice by assessing patient history, examining and screening for periodontal disease, including basic periodontal examination (BPE) and assessing history of periodontitis (interdental gingival recession).

[0066] Periodontal disease can be classified and diagnosed by the presence of gingivitis, periodontal pockets, and interdental bone loss.

[0067] Classification

[0068] Gingivitis—a reversible condition without signs of gum recession between teeth:

[0069] • Clinically healthy gingiva with bleeding on probing in less than 10% of cases

[0070] • Localized gingivitis presents with bleeding on probing in 10-30% of cases.

[0071] Extensive gingivitis with bleeding on probing in >30% of cases

[0072] Periodontitis is a site-specific disease, classified and diagnosed by signs of periodontal pockets larger than 4 mm and interdental alveolar bone loss caused by periodontitis.

[0073] BPS Periodontitis Classification

[0074] Periodontitis molar-incisor pattern

[0075] • Localized periodontitis, with interdental bone loss affecting less than 30% of teeth.

[0076] Extensive periodontitis, with interdental bone loss affecting >30% of teeth.

[0077] Radiographic assessment clinically documented the current periodontal disease status (BSP 2017) stage and grade. Individual risk factors, including genetic predisposition or altered factors such as smoking and diabetes, were also recorded during the periodontal assessment.

[0078] Installments

[0079] The staging records the degree of adjacent bone loss at the worst-affected site. The worst-affected site refers to the area most severely affected by the disease. The degree of bone loss can be categorized as initial, moderate, severe, or very severe.

[0080] Periodontitis can be characterized as stage I, stage II, stage III or stage IV. According to the British Periodontal Society (BPS) 2017 classification[7], the stages of periodontitis are clinically defined as follows:

[0081] Stage I: Initial Periodontitis

[0082] Stage II: Intermediate Periodontitis

[0083] Stage III: Severe periodontitis that may lead to further tooth loss.

[0084] Stage IV: Severe periodontitis that may lead to tooth loss.

[0085] Suitably, in some embodiments of any aspect described herein, prevention or treatment of periodontal disease is prevention of progression of periodontal disease stages. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression of periodontal disease stages. Suitably, in some embodiments, the compositions described herein are used to prevent progression of periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression of periodontitis. In some embodiments, compositions as described herein are provided for prevention of progression of periodontal disease stages. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression of periodontal disease stages. Suitably, in some embodiments, compositions are provided for prevention or treatment of stage I, II, III, or IV periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention or treatment of stage I, II, III, or IV periodontitis.

[0086] Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to stage I-II periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to stage I-III periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to stage I-IV periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to stage II-III periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to stage II-IV periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to stage III-IV periodontitis.

[0087] Suitably, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to stage I or II periodontitis. Suitably, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to stage I or III periodontitis. Suitably, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to stage I or IV periodontitis. Suitably, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to stage II or III periodontitis. Suitably, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to stage II or IV periodontitis. Suitably, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to stage III or IV periodontitis.

[0088] Classification

[0089] The grading recorded the percentage of bone loss at the worst site of proximal bone loss due to periodontitis (divided by the patient's age).

[0090] Periodontitis can be further classified into stages A, B, and C as follows:

[0091] Grade A: Slow progress

[0092] Tier B: Moderate progress rate

[0093] Tier C: Rapid progress

[0094] Appropriately, based on the patient's age and the extent of tissue damage, disease progression can be categorized as slow, moderate, or rapid.

[0095] Suitably, in some embodiments, prevention or treatment of periodontal disease is the prevention of progression of periodontal disease grades. Suitably, in some embodiments, prevention or treatment of periodontal disease is the prevention of progression of periodontitis grades. Suitably, in some embodiments, compositions for the prevention or treatment of grade A, B, and C periodontitis are provided. Suitably, in some embodiments, prevention or treatment of periodontal disease is the prevention or treatment of grade A, B, or C periodontitis. Suitably, in some embodiments, prevention or treatment of periodontal disease is the prevention or treatment of grade A, B, or C periodontitis.

[0096] Suitablely, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to grade A to B periodontitis. Suitablely, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to grade A to C periodontitis. Suitablely, in some embodiments, prevention or treatment of periodontal disease is prevention of progression to grade B to C periodontitis.

[0097] Suitablely, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to grade A to B periodontitis. Suitablely, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to grade A to C periodontitis. Suitablely, in some embodiments, the prevention or treatment of periodontal disease is the prevention of progression to grade B to C periodontitis.

[0098] Those skilled in the art will understand that in some embodiments, it may be necessary to prevent the progression of gingivitis to periodontitis. Suitably, in some embodiments provided herein, the compositions of the present invention are used to prevent the progression of gingivitis to periodontitis in a subject suffering from periodontal disease. Suitably, in some embodiments provided herein, prevention or treatment of periodontal disease is prevention of the progression of gingivitis to periodontitis. Suitably, in some embodiments provided herein, prevention or treatment of periodontal disease is prevention of the progression of gingivitis to periodontitis. Suitably, in some embodiments, prevention of progression or prevention of progression may refer to prevention of gingivitis or prevention of gingivitis, or improvement of gingivitis to healthy gingiva.

[0099] Periodontitis is a chronic, irreversible condition. Therefore, it is desirable to treat established periodontitis or truly stabilize it to prevent progression or recurrence. Stable periodontitis may mean that the condition is maintained or improved. According to the BPS classification system, maintenance of periodontitis may mean prevention of progression to the next stage of the disease. Suitablely, in some implementations, periodontitis may be maintained at stage I, II, or III. Suitablely, in some implementations, periodontitis may be maintained at stage A or B. Suitablely, in some implementations, improvement may mean disease stabilization or remission.

[0100] Technicians will understand that other clinical measurements can be used to measure disease progression and / or regression. It should be understood that any appropriate clinical measurement can be used to measure the treatment and / or prevention of the condition. For example, periodontal health can be defined as the absence of clinically detectable inflammation (<10%), gingivitis can be defined as non-regressing inflammation, and periodontitis can be defined as inflammation and chronic inflammation that has not resolved.

[0101] In some embodiments of the invention, treatment or prevention of periodontal disease means treating or preventing established periodontal disease. Suitably, in some embodiments, established periodontal disease is established gingivitis or periodontitis. In some embodiments, established gingivitis is localized or extensive gingivitis. In some embodiments, established periodontitis is any of molar-incisor type periodontitis, localized or extensive periodontitis, and stage I, II, III, or IV periodontitis. Suitably, in some embodiments, established periodontal disease is any stage of gingivitis or periodontitis and any grade of periodontitis as described above.

[0102] In one embodiment, periodontitis is chronic periodontitis. Those skilled in the art will understand that chronic periodontitis includes, but is not limited to, periodontitis that does not respond to conventional therapies or treatments. Subjects suffering from chronic periodontitis may be referred to as non-responders. In some embodiments, non-responders include patients or subjects with a need for treatment who have a non-responding site. Suitably, in some embodiments of the invention, compositions are provided for treating periodontitis in subjects with this need, wherein the subject is a non-responder. Suitably, in some embodiments, a non-responder may respond to conventional therapies after treatment with a composition comprising a phosphopeptide.

[0103] Appropriately, in some implementations, the response to therapy or improvement in periodontal disease can be indicated by a reduction in gingival bleeding or active bleeding from periodontal pockets during probing, which indicates that the disease process has stabilized or is in remission.

[0104] Suitablely, in some embodiments, stable disease is characterized by a BOP of less than 10%, less than 5%, less than 2%, or less than 1%. In one embodiment, stable disease is characterized by a BOP of less than 10%.

[0105] Suitably, in some embodiments, stable disease is characterized by a periodontal pocket depth (PPD) of less than 5 mm, less than 4 mm, less than 3 mm, less than 2 mm, or less than 1 mm. In one embodiment, stable disease is characterized by a PPD of 4 mm or less. In another embodiment, stable disease is characterized by a PPD of less than 4 mm.

[0106] Those skilled in the art will understand that disease stability can be measured by BOP, PPD, or a combination of BOP and PPD. In one embodiment, stable disease is characterized by a BOP of less than 10% and a PPD of 4 mm or less, with no bleeding at sites where the PPD is greater than 4 mm. In one embodiment, unstable disease is characterized by a BOP of greater than 10% and a PPD of 4 mm or greater. In another embodiment, unstable disease is characterized by a PPD of 5 mm or greater.

[0107] In some embodiments, stable periodontitis may be characterized by a BOP of 10%, a PPD of less than 4 mm, and no BOP at the 4 mm site. In some embodiments, unstable periodontitis may be characterized by a PPD greater than 5 mm or a PPD less than 4 mm and a BOP at the 4 mm site. In some embodiments, remission of periodontitis may be characterized by a BOP greater than 10%, a PPD less than 4 mm, and no BOP at the 4 mm site.

[0108] In some implementations, stability is characterized by minimized inflammation and optimal treatment response. Suitablely, in some implementations, stability is characterized by minimized inflammation, optimal treatment response and control of modifiable risk factors. It should be understood that remission / control may be a more realistic and achievable treatment goal for patients for whom it is impossible to fully control modifiable and precipitating factors [3].

[0109] Suitablely, in some embodiments, the mitigation is characterized by a BOP of 10% or less and a PPD of 4 mm or less. In one embodiment, the mitigation is characterized by the absence of BOP at the 4 mm PPD site.

[0110] Peri-implant disease

[0111] Peri-implant diseases include two common complications following dental implant placement: peri-implant mucositis and peri-implantitis. Oral biofilm is a major cause of both disease processes.

[0112] Peri-implantitis can be compared to gingivitis. It involves inflammation of the tissue compartment surrounding the implant. Peri-implantitis is similar to periodontitis because it is characterized by loss of implant-supporting bone and can progress more rapidly. Therefore, detection, maintenance, and treatment are very important.

[0113] New or improved treatments are needed for gingivitis, periodontitis, peri-implantitis, and peri-implantitis. Furthermore, improved or new therapies are required to maintain or restore health.

[0114] Suitably, in another aspect of the invention, a composition comprising phosphopeptides is provided for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with such need.

[0115] Leukoplakia of the mucosa

[0116] Leukoplakia causes thick, white patches to form on the gums. These patches can also form on the inside of the cheeks and the floor of the mouth. Sometimes they even form on the tongue. These patches cannot be scraped off.

[0117] Leukoplakia of the mucous membranes is associated with persistent irritation from tobacco—whether it's smoking, dipping, or chewing tobacco—and long-term alcohol consumption is another possible cause. Most leukoplakia plaques are not cancerous. However, some plaques show early signs of cancer. Oral cancer can occur near areas of leukoplakia. A mixture of white and red areas, also known as speckled leukoplakia, may be a sign of cancer. One type of leukoplakia in the mouth is called hairy leukoplakia, which primarily affects people whose immune systems are weakened by disease, particularly HIV / AIDS. Leukoplakia is usually simply documented and observed by dental professionals—treatment methods include incision or laser treatment.

[0118] Suitablely, in another aspect of the invention, a composition comprising phosphopeptides is provided for the prevention or treatment of leukoplakia of the mucous membranes in a subject with such need.

[0119] Therapies and related methods

[0120] On the other hand, a method is provided for treating or preventing gingival bleeding in a subject who requires such treatment, wherein the method comprises administering to the subject a therapeutically effective amount of a composition comprising phosphopeptides as described herein.

[0121] On the other hand, a method is provided for treating or preventing periodontal disease in a subject with this need, said method comprising administering to the subject a therapeutically effective amount of a composition comprising a phosphopeptide as described herein. Suitably, in some embodiments, periodontal disease is gingivitis and / or periodontitis.

[0122] In another aspect, a method is provided for treating or preventing peri-implant mucositis and / or peri-implantitis in a subject with such need, wherein the method comprises administering to the subject a therapeutically effective amount of a composition comprising a phosphopeptide.

[0123] As used herein, "therapeuticly effective amount" can refer to any amount of the composition that results in the prevention, delay, or improvement of symptoms associated with the condition described herein. In some embodiments of the methods described herein, the method includes applying a therapeutically effective amount of the composition to an oral surface. Suitably, in some embodiments, the composition is applied directly to the tooth surface of a subject in need. Suitably, in some embodiments, the composition is applied directly to the gingiva of a subject in need. In alternative embodiments, the composition is applied to the oral cavity of a subject in need. In some embodiments, the composition is applied to a periodontal pocket. Suitably, in some embodiments, the composition is applied to a periodontal pocket by rinsing. In some embodiments, the composition is applied to a periodontal pocket using a biodegradable delivery system. Suitably, in some embodiments, the composition is applied to a periodontal pocket before, during, or after periodontal therapy.

[0124] In some embodiments of the methods or uses described herein, the composition may be applied in combination with other oral care products or compositions. As used herein, "combination" may refer to the application of the composition of the present invention as an adjunct to other oral care products or compositions, or it may refer to the application of a composition suitable for the present invention as an adjunct to other oral care products or compositions. Suitably, the methods or uses described herein may be performed as an adjunct to routine oral care procedures. Suitably, in some embodiments, the composition may be applied as part of or as an adjunct to dental medical procedures. These procedures may include, but are not limited to, mechanical cleaning of teeth and gums, periodontal therapy, orthodontic procedures (such as orthodontic treatment using braces), and dental (oral) surgeries (such as periodontal pocket reduction surgery, soft tissue grafts, and bone grafts).

[0125] In some embodiments of the methods or uses described herein, the composition is applied by means of a polymeric material containing the composition, such as a polymer strip. Suitable materials are described in detail below. Suitably, in some embodiments, the composition is applied to the oral cavity by means of an application of a polymeric material containing the composition. In some embodiments, the composition is applied directly to the periodontal pocket by means of an application of a polymeric material containing the composition. Application to the periodontal pocket is preferred when the subject has periodontitis or implant mucositis.

[0126] In some embodiments of the methods or uses described herein, the composition is applied using a biodegradable delivery system. Such suitable systems are described in detail below. In certain situations, it may be desirable to use a biodegradable delivery system to apply the composition to periodontal pockets.

[0127] In some embodiments, it may be desirable to apply the composition directly to the periodontal pocket using a syringe or dental instruments. In such embodiments, the composition may be a gel or serum formulation.

[0128] Composition

[0129] The compositions used in this invention are suitably oral care compositions and can be used in any of the aspects described herein.

[0130] Suitably, the compositions used in this invention may be fluids or solids. Suitably, the compositions used in this invention may be fluids selected from liquids or colloids. Suitably, the compositions may be oral sprays, mouthwashes, toothpaste, creams, gels, serums, chewing gum, powders or granules, wafer tabs, polymer oral films, tablets, capsules, foodstuffs, etc.

[0131] Suitably, the composition is an aqueous composition, and suitably, an aqueous fluid. Therefore, suitably, the composition may contain an aqueous medium. Suitably, the composition may contain about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, or about 90 wt% water. Suitably, the composition may contain about 20 wt% to about 75 wt% water.

[0132] Suitably, in one embodiment, the composition may be a liquid. Suitably, it is an aqueous liquid. Suitably, in such an embodiment, the composition contains at least 30% by weight, suitably at least 40% by weight, suitably at least 50% by weight of water. Suitably, in such an embodiment, the composition may be a mouthwash or oral spray.

[0133] Suitably, in an alternative embodiment, the composition may be a colloid. Suitably, the colloidal composition may include, for example, a gel, tablet, or paste. Suitably, in such an embodiment, the composition contains less than 25% by weight of water. Suitably, in such an embodiment, the composition may be toothpaste.

[0134] Suitably, in an alternative embodiment, the composition may be a gel. Suitably, in such an embodiment, the composition contains less than 50% by weight of water. Suitably, in such an embodiment, the composition may be a tooth gel.

[0135] Suitably, in some embodiments, unless otherwise stated, the composition may contain phosphates, fluorides, and / or calcium, or sources thereof. Suitable sources of these components are described elsewhere herein. Suitably, in some embodiments, the composition does not contain phosphates, fluorides, and / or calcium, or sources thereof.

[0136] Suitably, the composition may further comprise other components, which are preferably liquid or soluble. Suitably, the other components may be selected from one or more of the following: alcohols, humectants, surfactants, preservatives, flavoring agents, sweeteners, coloring agents, cariogenic agents, buffers, acids, bases, whitening agents, thickeners, and anti-tartar agents.

[0137] The amounts of the various components used in the compositions of this invention can, of course, be determined by those skilled in the art. Suitably, the total amount of the various components constituting the composition is 100% w / w of the composition.

[0138] Suitably, the composition may contain a pH buffer (or buffer solution). Various pH buffers are well known to those skilled in the art. Exemplary buffers include, but are not limited to, phosphate buffer, Tris (tris(hydroxymethyl)aminomethane) buffer, and sodium bicarbonate. In one embodiment, the buffer is sodium bicarbonate. It should be understood that when the composition does not contain phosphate or a phosphate source, an alternative buffer such as phosphate buffer will be used. Suitably, in some embodiments, the composition described herein does not contain phosphate buffer.

[0139] Suitably, the pH buffer maintains the composition at a pH above 7, suitably in the pH range of 7 to 9, suitably in the pH range of 7.1 to 8.5, and suitably in the pH range of 7.2 to 8. Suitably, the pH is maintained at room temperature for at least 6 weeks, 3 months, 6 months, and suitably for at least 1 year of storage. Suitable buffers for achieving this purpose are obvious to those skilled in the art, and their suitability for the purpose can be readily determined experimentally. In some embodiments, the composition is pH stable for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the composition is stable for at least 10 months.

[0140] Suitably, the initial pH of the composition can be adjusted as needed by adding hydrogen ions (acid) or hydroxide ions (base). Generally, any physiologically compatible or acceptable acid or base can be used, such as hydrochloric acid (HCl) and sodium hydroxide (NaOH). Suitably, once the desired pH is reached, the buffer acts to maintain the pH.

[0141] Suitably, the composition may or may not contain one or more alcohols. Exemplary alcohols include, but are not limited to, ethanol or isopropanol. Suitably, the compositions used in this invention may contain sweetener alcohols, as described below; however, other additional alcohols are suitably absent. Therefore, in one embodiment, the compositions used in this invention are free of ethanol or isopropanol.

[0142] Suitably, when an additional alcohol is present, the weight ratio of water to alcohol is in the range of about 1:1 to about 20:1. Suitably, in this type of formulation, the total amount of the water-alcohol mixture is typically in the range of about 70% by weight to about 99.9% by weight of the formulation. Suitably, the concentration of the additional alcohol can be between 1% and 99%.

[0143] Suitably, the composition may contain one or more sweeteners. Suitably, the sweetener may also be an alcohol. Alternatively, the sweetener may be a natural or synthetic sugar, such as saccharin. Suitably, the composition may contain both saccharin and an alcohol sweetener. Exemplary alcohol sweeteners include, but are not limited to, xylitol or mannitol. In one embodiment, suitably, when the composition is a liquid such as a mouthwash or oral spray, the sweetener is xylitol. In one embodiment, suitably, when the composition is a colloid such as toothpaste, the sweetener is mannitol.

[0144] Suitably, the composition may contain a whitening agent. Suitably, the whitening agent may be chemical or abrasive. Exemplary chemical whitening agents include, but are not limited to, sodium bicarbonate or hydrogen peroxide. Exemplary abrasive whitening agents include, but are not limited to, microparticles such as silica or charcoal. In one embodiment, suitably, when the composition is a colloid such as toothpaste, the whitening agent is Zeofree 113 microparticles.

[0145] Suitably, the composition may contain a thickener. Examples of thickeners include, but are not limited to, silica or xanthan gum. In one embodiment, suitably, when the composition is a gel such as toothpaste, the thickener comprises Zeofree 153 microparticles and xanthan gum.

[0146] Suitably, the composition may contain flavoring agents. Suitably, the flavoring agents contain a variety of different chemical substances, which may be natural or synthetic, such as sugars, oils, esters, etc. In one embodiment, the flavoring agent may contain a mixture of saccharin, cocamidopropyl betaine, and flavoring oil. Exemplary flavoring agents may contain the following ingredients (values ​​provided in the amount in the final composition):

[0147] - Sodium methylparaben; suitably, in an amount of about 0.02% w / w;

[0148] -Phenoxyethanol; suitably, in an amount of about 0.2% w / w;

[0149] - Saccharin; suitably, in an amount of about 0.08% w / w;

[0150] - Cocamidopropyl betaine; suitably, in an amount of about 0.6% w / w;

[0151] - Water; suitably, in an amount of about 6.3% w / w, preferably, wherein the water is deionized; and

[0152] - Seasoning oil; suitable, in an amount of about 0.5% w / w.

[0153] Suitably, the flavoring oil may contain natural or synthetic flavorings. Suitably, the flavoring oil may contain herbs or plant extracts. Suitably, the flavoring oil may contain peppermint flavoring.

[0154] Suitably, the composition may contain a preservative. Examples of preservatives include sodium methylparaben and phenoxyethanol. Suitably, the preservative may contain sodium methylparaben, suitably in an amount of about 0.02% w / w, and phenoxyethanol, suitably in an amount of about 0.2% w / w.

[0155] Suitably, the composition may comprise any of the following components: water, buffer, calcium ion source, phosphate ion source, phosphopeptide, fluoride ion source, flavoring agent, preservative, sweetener, acid, whitening agent and / or thickener.

[0156] Suitably, in some embodiments, the composition comprises at least the following components: water, a buffer, and a phosphopeptide. Suitably, in some embodiments, the composition comprises at least the following components: water, a buffer, a fluoride ion source, and a phosphopeptide. Suitably, in some embodiments, the composition comprises at least the following components: water, a buffer, a calcium ion source, and a phosphopeptide. Suitably, in some embodiments, the composition comprises at least the following components: water, a buffer, a phosphate ion source, and a phosphopeptide.

[0157] Suitably, in some embodiments, the composition comprises at least the following components: water, a buffer, a calcium ion source, and a phosphopeptide. In one embodiment, the composition comprises the following components: water, a buffer, a calcium ion source, a phosphopeptide, a fluoride ion source, a flavoring agent and preservative, a sweetener, and an acid. In another embodiment, the composition comprises the following components: water, a buffer, a calcium ion source, a phosphopeptide, a fluoride ion source, a flavoring agent and preservative, a sweetener, an acid, a whitening agent, and a thickener.

[0158] In some embodiments of the invention, the components of the composition may be provided individually or in any combination:

[0159] -Water – about 20% by weight to about 99% by weight; suitably, about 23% by weight to about 66% by weight;

[0160] - Buffer – about 1% to about 20% by weight; suitably, about 1% to about 15% by weight;

[0161] -Optionally, the calcium ion source (e.g., a soluble calcium salt or other options discussed herein) – from about 0.1% to about 15% by weight; suitably, from about 0.1% to about 5% by weight.

[0162] - Optionally, the phosphate ion source (e.g., soluble phosphate or other options discussed herein) – about 0.2 wt% to about 32 wt%, about 0.2 wt% to about 15 wt%; suitably, about 0.5% to about 5% w / v, suitably, about 0.7 wt% to about 2 wt%, for example, 0.8 wt% to 1.2 wt%;

[0163] -Phosphopeptide – about 0.5% to about 15% w / v; suitably, about 1% to about 10% by weight, suitably, about 1.5% to about 5% by weight, for example, 2% to 4% by weight; and

[0164] -Optionally, a fluoride ion source (e.g., a soluble fluoride salt, such as the monofluorophosphate discussed herein) – about 0.01% to about 3%; suitably, about 0.05% by weight to about 1.5% by weight.

[0165] In some embodiments, the composition may further comprise any of the following components, alone or in any combination:

[0166] - Flavorings, preservatives and / or other ingredients – from about 0% by weight to about 70% by weight; suitably, from about 0% by weight to about 20% by weight; suitably, from about 0% by weight to about 10% by weight;

[0167] - Sweeteners (e.g., sweetener alcohols such as mannitol or xylitol) – about 0.1% to about 20% (w / w); suitably, about 0.1% to about 10% (w / w).

[0168] - Acids (e.g., HCl) – approximately 5-40% (w / w); suitably, approximately 10-35% (w / w);

[0169] - Brightening agents (e.g., rubbing silica) – approximately 1-20% (w / w); suitably, approximately 5-10% (w / w); and

[0170] - Thickeners (such as xanthan gum and / or silica) – about 0.1-20% (w / w), suitably about 0.5-15% (w / w).

[0171] As described above, in one embodiment, the composition is an oral spray or mouthwash. Exemplary mouthwash and spray formulations are as follows.

[0172] Suitablely, mouthwashes and oral sprays according to the present invention may include the following exemplary components by weight:

[0173] - Water (appropriately, from about 45% to about 95%)

[0174] - Ethanol (suitably, from about 0% to about 25%).

[0175] - Wetting agent (suitably, from about 0% to about 50%).

[0176] - Surfactant (suitably, from about 0.01% to about 7%)

[0177] - Flavoring agent (suitably, from about 0.04% to about 2%)

[0178] - Sweeteners (suitably, from about 0.1% to about 8%)

[0179] - Coloring agent (suitably, from about 0% to about 0.5%)

[0180] - Xylitol (suitably, from about 0% to about 8%)

[0181] - Anti-caries agents, including but not limited to stabilized calcium phosphate and calcium fluoride (suitably, about 0.001% to 10%), and optionally...

[0182] - Anti-stone agent (suitably, from about 0% to about 13%).

[0183] An exemplary composition of the present invention comprises:

[0184] - Phosphatidylcholine; suitably, in an amount of about 3% w / w, wherein the phosphatidylcholine is OPN-10;

[0185] - Buffer; suitably, in an amount of about 15% w / w, suitably, as a 1M solution, suitably, wherein the buffer is sodium bicarbonate;

[0186] - Water; suitably, in an amount of about 54% to 66% w / w, wherein the water is deionized water;

[0187] - Calcium source; suitably, in an amount of about 3% w / w, suitably, 2.9% w / w, suitably, wherein the calcium source is a calcium chloride solution, suitably, wherein the calcium chloride solution is about 1M;

[0188] -Optionally, a fluoride source, suitably, in an amount of about 0.4% to 0.5% w / w, suitably, 0.4% w / w, suitably, wherein the fluoride source is monofluorophosphate;

[0189] - Sweetener; suitably, in an amount of about 5% w / w, wherein the sweetener is xylitol;

[0190] -Optionally, acid; suitably, in an amount of about 11% w / w, suitably, wherein the acid is hydrochloric acid, suitably, wherein the hydrochloric acid is about 1M; and

[0191] - Flavoring agents and preservatives; suitably, in an amount of about 8% w / w, suitably, 7.7% w / w, suitably, wherein the flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine and flavoring oil.

[0192] Suitably, this exemplary composition is a liquid. Suitably, this exemplary composition is a mouthwash or oral spray. Suitably, this exemplary composition may be referred to as "MOL". The MOL composition is described in detail in Example 2 below.

[0193] Another exemplary composition of the present invention comprises:

[0194] - Phosphatidylcholine; suitably, in an amount of about 3% w / w, wherein the phosphatidylcholine is OPN-10;

[0195] - Buffer; suitably, in an amount of about 15% w / w, suitably, as a 1M solution, suitably, wherein the buffer is sodium bicarbonate;

[0196] - Water; suitably, in an amount of about 30% w / w, wherein the water is deionized;

[0197] - Calcium source; suitably, in an amount of about 3% w / w, suitably, 2.9% w / w, suitably, wherein the calcium source is a calcium chloride solution, suitably, wherein the calcium chloride solution is about 1M;

[0198] - A phosphate source; suitably, wherein the phosphate source is a solution of trisodium phosphate in an amount of about 16% w / w and a solution of disodium hydrogen phosphate in an amount of about 16% w / w, suitably, wherein the trisodium phosphate solution is about 0.1 M and the disodium hydrogen phosphate solution is about 0.1 M;

[0199] -Optionally, a fluoride source, suitably, in an amount of about 0.4% to 0.5% w / w, suitably, 0.4% w / w, suitably, wherein the fluoride source is monofluorophosphate;

[0200] - Sweetener; suitably, in an amount of about 5% w / w, wherein the sweetener is xylitol; and

[0201] - Flavoring agents and preservatives; suitably, in an amount of about 8% w / w, suitably, 7.7% w / w, suitably, wherein the flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine and flavoring oil.

[0202] Suitably, this exemplary composition is a liquid. Suitably, this exemplary composition is a mouthwash or oral spray. Suitably, this exemplary composition may be referred to as "MOK". The MOK composition is described in detail in Example 1 below.

[0203] In some embodiments, the composition does not contain a fluoride source. Suitably, in some embodiments, the composition does not contain monofluorophosphate.

[0204] In some embodiments, the composition does not contain an acid. Suitably, in some embodiments, the composition does not contain hydrochloric acid.

[0205] Suitably, water is added to bring the final composition to 100% w / w. Suitably, water is further added in place of any other components. In one embodiment, the amount of water is 55% w / w. In one embodiment, the amount of water is 55.4% w / w, and suitably, in such an embodiment, the composition does not contain a fluoride source. In one embodiment, the amount of water is 66.4% w / w, and suitably, in such an embodiment, the composition does not contain a fluoride source or acid.

[0206] Suitablely, the MOL or MOK composition can be used in any aspect of the invention, for example, for the prevention or treatment of gingival bleeding or periodontal disease in a subject with this need. In another embodiment, the MOL or MOK composition can be used for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with this need.

[0207] Another exemplary composition of the present invention comprises:

[0208] - Phosphatidylcholine; suitably, in an amount of about 3% w / w; suitably, wherein the phosphatidylcholine is OPN-10;

[0209] - Buffer; suitably, in an amount of about 2% w / w, wherein the buffer is sodium bicarbonate;

[0210] - Brightening agent; suitably, in an amount of about 6% w / w, suitably, wherein the brightening agent comprises rubbing silica, such as Zeofree 113; water; suitably, in an amount of about 23 to 25% w / w, suitably, wherein the water is deionized water;

[0211] - Acid; suitably, in an amount of about 34% w / w, suitably, wherein the acid is hydrochloric acid, suitably, wherein the hydrochloric acid is about 1M;

[0212] - Calcium source; suitably, in an amount of about 0.5% w / w, wherein the calcium source is calcium chloride;

[0213] -Optionally, a fluoride source, suitably, in an amount of about 1% w / w, suitably, 1.1% w / w, suitably, wherein the fluoride source is monofluorophosphate;

[0214] - Sweetener; suitably, in an amount of about 9% w / w, wherein suitably, the sweetener is mannitol;

[0215] - Thickener; suitably, in an amount of about 13% w / w, suitably, 12.8% w / w, wherein suitably, the thickener comprises thickening silica and xanthan gum, such as Zeofree 153 and xanthan gum; and

[0216] - Flavoring agents and preservatives; suitably, in an amount of about 8% w / w, suitably, 7.7% w / w, suitably, wherein the flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine and flavoring oil.

[0217] Suitably, this exemplary composition is a colloid. Suitably, this exemplary composition is toothpaste. Suitably, this exemplary composition may be referred to as "MON". The MON composition is described in detail in Example 3 below.

[0218] In some embodiments, the exemplary composition described above does not contain a fluoride source. Suitably, it does not contain monofluorophosphate.

[0219] Suitably, water is added to bring the final composition to 100% w / w. Suitably, water is further added in place of any other components. In one embodiment, the amount of water is 23.9% w / w. In another embodiment, the amount of water is 25% w / w, and suitably, in such an embodiment, the composition does not contain a fluoride source.

[0220] Suitablely, the MON composition can be used in any aspect of the invention for the prevention or treatment of gingival bleeding or periodontal disease in a subject with this need. In another embodiment, the MON composition can be used for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with this need.

[0221] Another exemplary composition of the present invention comprises:

[0222] - Phosphatidylcholine; suitably, in an amount of about 3% w / w; suitably, wherein the phosphatidylcholine is OPN-10;

[0223] - Buffer; suitably, in an amount of about 15% w / w, wherein the buffer is sodium bicarbonate;

[0224] - Water; suitably, in an amount of about 47 to 49% w / w, suitably, 48.7%, suitably, wherein the water is deionized water;

[0225] - Acid; suitably, in an amount of about 15-16% w / w, suitably, 15.7%, suitably, wherein the acid is hydrochloric acid, suitably, wherein the hydrochloric acid is about 1M;

[0226] - Calcium source; suitably, in an amount of about 2-3% w / w, suitably, 2.87%, suitably, wherein the calcium source is calcium chloride;

[0227] - Sweetener; suitably, in an amount of about 5% w / w, wherein the sweetener is xylitol;

[0228] - Thickener; suitably, in an amount of about 1% w / w, wherein suitably, the thickener comprises xanthan gum,

[0229] -Optionally, a fluoride source, suitably, in an amount of about 1% w / w, suitably, 0.76% w / w, suitably, wherein the fluoride source is monofluorophosphate; and

[0230] - Flavoring agents and preservatives; suitably, in an amount of about 8% w / w, suitably, 7.7% w / w, suitably, wherein the flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine, deionized water and flavoring oil.

[0231] Suitably, this exemplary composition is a gel. Suitably, this exemplary composition is a gel formulated for use on teeth, such as a dental gel. Suitably, this exemplary composition may be referred to herein as "MOG". The MOG composition is described in detail in Example 4 below.

[0232] In some embodiments, the exemplary compositions described above do not contain a fluoride source. Suitably, in some embodiments, the compositions do not contain monofluorophosphate.

[0233] In some embodiments, the exemplary compositions described above do not contain a phosphate source. Suitably, in some embodiments, the exemplary compositions do not contain a phosphate buffer or a phosphate ion source.

[0234] In some embodiments, the exemplary compositions described above do not contain a calcium source. Suitably, in some embodiments, the exemplary compositions do not contain a calcium ion source.

[0235] In some embodiments, the exemplary compositions described above comprise at least 100 parts per million (ppm), at least 200 ppm, at least 300 ppm, at least 400 ppm, at least 500 ppm, at least 600 ppm, at least 700 ppm, at least 800 ppm, at least 900 ppm, at least 1000 ppm, at least 1100 ppm, at least 1200 ppm, at least 1300 ppm, at least 1400 ppm, and at least 1500 ppm of fluoride. In one embodiment, the composition comprises 1000 ppm of fluoride. In another embodiment, the composition comprises 500 ppm of fluoride.

[0236] Suitably, water is added to bring the final composition to 100% w / w. Suitably, water is further added in place of any other components. In one embodiment, the amount of water is 47.96% w / w. In another embodiment, the amount of water is 48.72% w / w. Suitably, in such embodiments, the composition does not contain a fluoride source.

[0237] Suitably, the MOG composition can be used in any aspect of the invention for the prevention or treatment of gingival bleeding or periodontal disease in a subject with this need. In another embodiment, the MOG composition can be used for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with this need.

[0238] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided. In some embodiments, the composition further comprises a fluoride or a fluoride source, optionally comprising monofluorophosphate. In another aspect of the invention, a gel composition comprising a phosphopeptide is provided. In some embodiments, the gel composition further comprises a fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the gel composition further comprises calcium or a calcium source. In one embodiment, the gel composition comprises a phosphopeptide, calcium or a calcium source, and a fluoride or a fluoride source. This gel composition may be an oral gel composition.

[0239] In some embodiments, the gel composition does not contain phosphate or a phosphate source. In some embodiments, the gel composition does not contain calcium or a calcium source. In some embodiments, the gel composition does not contain fluoride or a fluoride source.

[0240] In another aspect of the invention, an oral gel is provided comprising amorphous calcium phosphate stabilized by a calcium phosphate stabilizer, and optionally comprising monofluorophosphate.

[0241] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided for treating or preventing gingival bleeding in a subject with this need. In some embodiments, the gel composition further comprises a fluoride source, optionally comprising monofluorophosphate.

[0242] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided for treating or preventing periodontal disease in a subject with this need. In some embodiments, the gel composition further comprises a fluoride source, optionally comprising monofluorophosphate. In some embodiments, periodontal disease is gingivitis or periodontitis.

[0243] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided for the treatment or prevention of peri-implantitis and / or peri-implantitis in subjects with such need. In some embodiments, the gel composition further comprises a fluoride source, optionally comprising monofluorophosphate.

[0244] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided for treating or preventing tooth sensitivity, preferably dentin hypersensitivity, in a subject with this need. In some embodiments, the gel composition further comprises a fluoride source, optionally comprising monofluorophosphate.

[0245] In another aspect of the invention, a gel composition comprising stable amorphous calcium phosphate is provided for treating or preventing leukoplakia in a subject with this need. In some embodiments, the gel composition further comprises a fluoride source, optionally comprising monofluorophosphate.

[0246] Suitably, in some embodiments, the calcium phosphate stabilizer is osteopontin or a phosphopeptide derived therefrom. Suitably, in some embodiments, the calcium phosphate stabilizer is casein or a phosphopeptide derived therefrom.

[0247] In another aspect of the invention, a gel composition comprising a phosphopeptide is provided for treating or preventing gingival bleeding in a subject with this need. In some embodiments, the gel composition further comprises fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the gel composition further comprises calcium or a calcium source. In some embodiments, the gel composition further comprises fluoride or a fluoride source and calcium or a calcium source. In some embodiments, the gel composition is a MOG.

[0248] In another aspect of the invention, a gel composition comprising a phosphopeptide is provided for treating or preventing periodontal disease in a subject with this need. In some embodiments, the gel composition further comprises fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the gel composition further comprises calcium or a calcium source. In some embodiments, the gel composition further comprises fluoride or a fluoride source and calcium or a calcium source. In some embodiments, the periodontal disease is gingivitis or periodontitis.

[0249] In another aspect of the invention, a gel composition comprising a phosphopeptide is provided for treating or preventing peri-implant mucositis and / or peri-implantitis in a subject with this need. In some embodiments, the gel composition further comprises a fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the gel composition further comprises calcium or a calcium source. In some embodiments, the gel composition further comprises a fluoride or a fluoride source and calcium or a calcium source.

[0250] In another aspect of the invention, a gel composition comprising a phosphopeptide is provided for treating or preventing tooth sensitivity, preferably dentin hypersensitivity, in a subject with this need. In some embodiments, the gel composition further comprises fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the gel composition further comprises calcium or a calcium source. In some embodiments, the gel composition further comprises fluoride or a fluoride source and calcium or a calcium source.

[0251] In another aspect of the invention, a composition comprising a phosphopeptide is provided for treating or preventing leukoplakia in a subject with this need. In some embodiments, the composition further comprises fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the composition further comprises calcium or a calcium source. In some embodiments, the composition further comprises fluoride or a fluoride source and calcium or a calcium source. Suitably, in some embodiments, the composition is a gel composition. Suitably, in some embodiments, the gel composition is MOG. Alternatively, or otherwise, the composition comprises any of the compositions described herein. Suitably, in some embodiments, the composition is a MOL composition. Suitably, in some embodiments, the composition is a MOK composition. Suitably, in some embodiments, the composition is a MOK composition. Suitably, in some embodiments, the composition is a MON composition.

[0252] In another aspect of the invention, a gel composition comprising phosphopeptides is provided for remineralization or prevention of demineralization of oral surfaces. In some embodiments, the gel composition further comprises fluoride or a fluoride source, optionally comprising monofluorophosphate. In some embodiments, the gel composition further comprises calcium or a calcium source. In some embodiments, the gel composition further comprises fluoride or a fluoride source and calcium or a calcium source. Suitably, in some embodiments, the gel composition is a MOG.

[0253] The gel composition described herein can also be used in any method according to the aspects described herein.

[0254] Phosphatopeptides:

[0255] The term "phosphopeptide" is used herein to describe phosphorylated polypeptides in a general sense. Unless the context otherwise requires, the term phosphopeptide is used interchangeably with phosphoprotein. A range of phosphopeptides that can be used in this invention are well known in the art, and several phosphopeptides are described in detail below.

[0256] Phosphatides capable of interacting with and stabilizing calcium phosphate complexes are of particular interest, although it should be noted that in this invention, phosphatides do not need to play such a role, for example, when no additional phosphate or additional phosphate source is available.

[0257] Specifically, osteopontin or its derived phosphopeptides, and casein or its derived phosphopeptides, may be mentioned. These two phosphoproteins and their phosphopeptides have been extensively discussed in the literature regarding the formation of stable calcium phosphate complexes. However, other phosphopeptides that can form stable calcium phosphate complexes include phosphoprotein yolk (Swiss-Prot accession number P67869), fetoglobulin A (FETUA) (Swiss-Prot accession number P02765), and proline-rich basic phosphoprotein 4 (PRB4) (Swiss-Prot accession number PI). 0163), matrix Gla protein (MGP) (Swiss-Prot accession number P08493), secreted phosphoprotein 24 (SPP-24) (Swiss-Prot accession number Q13103), riboflavin-binding protein (Swiss-Prot accession number P02752), integrin-binding salivary phosphoprotein II (IBSP-II) (Swiss-Prot accession number P21815), extracellular matrix bone phosphoglycoprotein (MEPE) (Swiss-Prot accession number Q9NQ76), dentin matrix acidic phosphoprotein 1 (OMP1) (Swiss-Prot accession number Q13316), human β-casein, bovine β-casein, and isotypes or derived phosphopeptides. Furthermore, a wide range of synthetic phosphopeptides may be available for use in this invention.

[0258] Although OPN has been illustrated in the Examples section below, those skilled in the art will recognize that other phosphopeptides commonly used in oral health care may have similar effects in treating gingival bleeding. Suitable phosphopeptides may include casein phosphopeptides.

[0259] Therefore, suitable phosphopeptides can come from any source and take many forms. For example, suitable phosphopeptides include full-length phosphoproteins, or smaller phosphopeptides derived from them, which can be naturally occurring or formed or isolated by trypsinizing or chemically (e.g., alkaline hydrolysis) digestion of such phosphoproteins, or obtained through chemical or recombinant synthesis. Phosphopeptides can be osteopontin or casein, or can be derived from osteopontin, casein, or other phosphate-rich amino acid proteins, such as phosphatidylcholine (Swiss-Prot accession number P67869), fetoglobulin A (FETUA) (Swiss-Prot accession number P02765), and proline-rich basic phosphatidylcholine 4 (PRB4) (Swiss-Prot accession number PI). 0163), matrix Gla protein (MGP) (Swiss-Prot accession number P08493), secreted phosphoprotein 24 (SPP-24) (Swiss-Prot accession number Q13103), riboflavin-binding protein (Swiss-Prot accession number P02752), integrin-binding salivary phosphoprotein II (IBSP-II) (Swiss-Prot accession number P21815), extracellular matrix bone phosphoglycoprotein (MEPE) (Swiss-Prot accession number Q9NQ76), dentin matrix acidic phosphoprotein 1 (OMP1) (Swiss-Prot accession number Q13316), human β-casein, bovine β-casein and its isotypes or derived phosphopeptides.

[0260] In one embodiment, phosphopeptides obtained by enzymatic digestion of osteopontin or casein (e.g., trypsin digestion) are used in this invention.

[0261] Osteopontoxin (OPN) is a protein that can be obtained from milk. For example, bovine OPN can be isolated from acidic whey, such as at pH 4.5, by anion exchange chromatography, as described in patent applications WO01 / 497741, WO02 / 28413, WO2012 / 117119, or WO2012 / 117120. OPN purity up to 90-95% can be obtained. The present invention can use naturally occurring fragments or peptides derived from OPN through proteolysis of milk, or gene splicing variants, phosphorylated variants, or glycosylated variants obtainable from methods such as those described in WO01 / 49741 and WO2013 / 144247. OPN can be derived from the milk of any dairy animal, such as cows, humans, camels, goats, sheep, dromedary camels, and llamas. Due to availability and characterization in the literature, OPN derived from bovine milk is generally preferred. OPN exists in bovine milk in the form of full-length bovine OPN (e.g., positions 17-278 of Swiss-Prot accession number P31096, or a peptide with at least 95% sequence identity to positions 17-278 of Swiss-Prot accession number P31096) and long N-terminal fragments of full-length bovine OPN (e.g., positions 17-163 of Swiss-Prot accession number P31096, or a peptide with at least 95% sequence identity to positions 17-163 of Swiss-Prot accession number P31096), see, for example, Bissonnette et al., Journal of Dairy Science Vol. 95 No. 2, 2012. Full-length OPN is an acidic, highly phosphorylated, sialic acid-rich calcium-binding protein. Each mole of full-length osteopontin binds 28 moles of phosphate and approximately 50 moles of calcium.

[0262] In some embodiments of the invention, the OPN or a phosphopeptide derived therefrom may be substantially pure full-length bovine OPN, may be a long N-terminal fragment of substantially pure full-length bovine OPN, and may be a mixture comprising full-length bovine OPN and a long N-terminal fragment of full-length bovine OPN. Such a mixture may, for example, contain 5-40% (w / w) of full-length bovine OPN relative to the total amount of OPN and 60-95% (w / w) of the long N-terminal fragment of full-length bovine OPN relative to the total amount of OPN.

[0263] In one embodiment, the composition used in this invention comprises an OPN-derived phosphopeptide (e.g., by OPN cleavage, such as by trypsinization of OPN or chemical digestion, such as alkaline hydrolysis). In one embodiment, the composition used in this invention comprises an OPN-derived phosphopeptide commercially available as Lacprodan® OPN-10. OPN-10 is commercially available from Arla Foods Ingredients (Arla Foods Ingredients Group P / S, Sønderhøj 10-12, 8260Viby J, Denmark) and contains graded osteopontin from bovine milk.

[0264] In some embodiments, the phosphopeptides used in this invention are modified. Suitably, the modification may include post-translational modification or synthetic modification. Suitably, in some embodiments, the phosphopeptide is phosphorylated. In some embodiments, the phosphopeptide is glycosylated. In some embodiments, the phosphopeptide is both phosphorylated and glycosylated.

[0265] In some embodiments, the compositions used in this invention comprise phosphorylated OPN or phosphopeptides derived therefrom. In some embodiments, the compositions used in this invention comprise phosphorylated casein or phosphopeptides derived therefrom.

[0266] Examination of the primary structure of OPN revealed 28 potential phosphorylation sites in bovine osteopontin [8]. Suitably, in some embodiments of the invention, the composition comprises an OPN, or a phosphopeptide derived therefrom, having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, or 28 phosphorylated phosphorylation sites. Suitably, in some embodiments, the phosphorylation sites are serine residues and / or threonine residues. Suitably, in some embodiments, phosphoserine is located in the Ser / Thr-X-Glu / Ser(P) / Asp motif and / or the Ser-XX-Glu / Ser(P) motif. Suitably, in some embodiments, phosphothreonine is located in the Ser / Thr-X-Glu / Ser(P) / Asp motif and / or the Ser-XX-Glu / Ser(P) motif.

[0267] In some embodiments, the compositions used in this invention comprise a highly phosphorylated form of OPN, or a phosphopeptide derived therefrom. Suitably, in some embodiments, the highly phosphorylated form of OPN or the phosphopeptide derived therefrom comprises phosphorylation of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of available phosphorylation sites. Suitably, in some embodiments, the highly phosphorylated form of OPN or the phosphopeptide derived therefrom comprises phosphorylation of at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, or 28 available phosphorylation sites. In one embodiment, the composition comprises OPN or a phosphopeptide derived therefrom, wherein at least 95% of the available phosphorylation sites are phosphorylated. In another embodiment, the composition comprises OPN or a phosphopeptide derived therefrom, wherein 100% of the available phosphorylation sites are phosphorylated.

[0268] In some embodiments, phosphorylation sites may be clustered together. Suitably, a group may contain at least 2, 3, 4, 5, or 6 phosphorylation sites. Suitably, in some embodiments, each group is spanned by an unphosphorylated region. The unphosphorylated region may contain at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, or 50 amino acids. In a preferred embodiment, the phosphorylation sites are clustered in groups of 3 phosphorylation sites. Suitablely, in even more preferred embodiments, the phosphorylation sites are clustered in groups of three phosphorylation sites, with the groups separated by non-phosphorylated regions of 11-32 amino acids.

[0269] In some embodiments, the compositions used in this invention comprise glycosylated OPN or phosphopeptides derived therefrom. In some embodiments, the compositions used in this invention comprise glycosylated casein or phosphopeptides derived therefrom.

[0270] Suitably, in some embodiments, glycosylation is O-linked glycosylation. In some embodiments, glycosylation is N-linked glycosylation. Suitably, in some embodiments, the glycosylated phosphopeptide may have both O-linked and N-linked glycosylation modifications simultaneously. In some embodiments, when the phosphopeptide is an OPN or a phosphopeptide derived therefrom, the O-linked glycosylation site is located in a threonine- and proline-rich region of the protein; for example, O-linked glycosylation sites may be found at Thr115, Thr124, and Thr129. In some embodiments, N-linked glycosylation sites may be present at Asn63, Asn85, and Asn193.

[0271] In some embodiments, the compositions used in this invention comprise phosphorylated and glycosylated OPN or phosphopeptides derived therefrom. In some embodiments, the compositions used in this invention comprise phosphorylated and glycosylated casein or phosphopeptides derived therefrom. Those skilled in the art will understand that the phosphopeptides may comprise any combination of the protein modifications described herein.

[0272] It is not desirable to be bound by theory, but rather to consider that phosphorylation and / or glycosylation can alter the function of phosphopeptides such as OPN and / or casein or phosphopeptides derived therefrom, and confer specific biological activities. Suitably, in one embodiment of the invention, the composition does not contain recombinant OPN. Suitably, in one embodiment of the invention, the composition does not contain recombinant casein. It should be understood that recombinant OPN and recombinant casein do not contain protein modifications such as phosphorylation and glycosylation.

[0273] As mentioned above, in some cases, the phosphopeptides used in this invention may require chemical synthesis. Suitably, in some embodiments, the phosphopeptides described herein are naturally occurring, chemically synthesized, or a combination of both.

[0274] In some embodiments, the compositions used herein comprise at least 1 mg / ml, at least 2 mg / ml, at least 5 mg / ml, at least 10 mg / ml, at least 15 mg / ml, at least 20 mg / ml, at least 25 mg / ml, at least 30 mg / ml, at least 35 mg / ml, at least 40 mg / ml, at least 45 mg / ml, or at least 50 mg / ml of OPN or phosphopeptides derived therefrom. Suitably, in some embodiments, the compositions described herein comprise at least 20 mg / ml of OPN. In preferred embodiments, the compositions used herein comprise at least 30 mg / ml of OPN or phosphopeptides derived therefrom. In some embodiments, the compositions used herein comprise at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5%, or at least 10% of OPN or phosphopeptides derived therefrom. In preferred embodiments, the compositions used herein comprise at least 3% of OPN or phosphopeptides derived therefrom.

[0275] Casein and casein-derived phosphopeptides are discussed in detail in WO98 / 40406 and WO2006 / 135982, and suitably, these phosphopeptides can also be used in this invention.

[0276] As described in WO2006 / 135982, CPP can form colloidal complexes with amorphous calcium phosphate, in which the core particles aggregate to form large (e.g., 100 nm) colloidal particles suspended in water. This general method for stabilizing calcium phosphate is believed to also apply to other phosphoproteins. Not wanting to be bound by theory, phosphopeptides appear to bind to amorphous calcium phosphate (ACP) clusters, producing metastable solutions in which ACPs grow to a size that initiates nucleation and prevents precipitation.

[0277] Suitablely, phosphopeptides containing the motif Ser(P)-Ser(P)-Ser(P)-Glu-Glu can be used in this invention, the motif being present in casein phosphopeptides. However, phosphopeptides containing other sequence motifs rich in phosphate amino acids can also be used in this invention.

[0278] Suitablely, as described in WO98 / 40406 and WO2006 / 135982, it includes the sequence α. s1 (59-79), β(1-25), α s2 (46-70) and α s1 Casein-derived phosphopeptides of (1-21) can be used in this invention. Additional flanking sequences may be present around these core sequences, in which case they may be wild-type sequences or optionally modified by deletion, addition, or conservative substitution of one or more residues.

[0279] In some embodiments, the compositions used herein comprise at least 1 mg / ml, at least 2 mg / ml, at least 5 mg / ml, at least 10 mg / ml, at least 15 mg / ml, at least 20 mg / ml, at least 25 mg / ml, at least 30 mg / ml, at least 35 mg / ml, at least 40 mg / ml, at least 45 mg / ml, or at least 50 mg / ml of CPP or phosphopeptides derived therefrom. Suitably, in some embodiments, the compositions described herein comprise at least 20 mg / ml of CPP or phosphopeptides derived therefrom. In a preferred embodiment, the compositions used herein comprise 30 mg / ml of CPP or phosphopeptides derived therefrom. In some embodiments, the compositions used herein comprise at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5%, or at least 10% of OPN. In a preferred embodiment, the compositions used herein comprise 3% OPN or phosphopeptides derived therefrom.

[0280] Therefore, in embodiments of the present invention, the phosphopeptide comprises osteopontin or a phosphopeptide derived therefrom, or casein or a phosphopeptide derived therefrom. In some embodiments, the calcium phosphate stabilizer comprises an osteopontin-derived phosphopeptide or a casein-derived phosphopeptide. In some embodiments, the composition used in the present invention does not contain casein or a phosphopeptide derived therefrom. In some embodiments, the calcium phosphate stabilizer does not contain a casein-derived phosphopeptide.

[0281] Alternatively or additionally, the phosphopeptide comprises one or more phosphoproteins selected from the group consisting of: phosphoprotein yolk (Swiss-Prot accession number P67869), fetoglobulin A (FETUA) (Swiss-Prot accession number P02765), and proline-rich basic phosphoprotein 4 (PRB4) (Swiss-Prot accession number PI). 0163), matrix Gla protein (MGP) (Swiss-Prot accession number P08493), secreted phosphoprotein 24 (SPP-24) (Swiss-Prot accession number Q13103), riboflavin-binding protein (Swiss-Prot accession number P02752), integrin-binding salivary phosphoprotein II (IBSP-II) (Swiss-Prot accession number P21815), extracellular matrix bone phosphoglycoprotein (MEPE) (Swiss-Prot accession number Q9NQ76), dentin matrix acidic phosphoprotein 1 (OMP1) (Swiss-Prot accession number Q13316), human β-casein, bovine β-casein and its isotypes or derived phosphopeptides.

[0282] The term "phosphopeptide derived therefrom" will be understood to refer to any phosphopeptide obtained by enzymatic digestion, chemical digestion, or any other suitable digestion method known in the art for digesting phosphoproteins used in this invention. Suitably, in some embodiments, the phosphopeptide derived therefrom comprises a complete complement of a phosphopeptide derived from enzymatic digestion, chemical digestion, or any other protein digestion method. Suitably, in some embodiments, the phosphopeptide derived from OPN comprises a complete complement of a phosphopeptide derived from enzymatic digestion (e.g., trypsin digestion), chemical digestion, or any other digestion method known in the art. Suitably, in some embodiments, the phosphopeptide derived from OPN comprises a complete complement of a phosphopeptide derived from OPN digestion. Suitably, in another embodiment, the phosphopeptide derived from OPN comprises a subset of phosphopeptides derived from OPN digestion. Suitably, in another embodiment, the phosphopeptide derived from OPN comprises an N-terminal fragment of a phosphopeptide derived from OPN digestion. Suitably, in another embodiment, the phosphopeptide derived from OPN comprises a C-terminal fragment of a phosphopeptide derived from OPN digestion. Suitablely, in some embodiments, OPN is digested by enzymatic digestion, preferably trypsin digestion. In another embodiment, OPN is digested by chemical digestion.

[0283] Suitably, in some embodiments, the casein-derived phosphopeptides comprise complete complements of phosphopeptides derived from enzymatic digestion (e.g., trypsin digestion), chemical digestion, or any other digestion method known in the art. Suitably, in some embodiments, the casein-derived phosphopeptides comprise complete complements of phosphopeptides derived from casein digestion. Suitably, in another embodiment, the casein-derived phosphopeptides comprise a subset of phosphopeptides derived from casein digestion. Suitably, in another embodiment, the casein-derived phosphopeptides comprise the N-terminal fragment of phosphopeptides derived from casein digestion. Suitably, in another embodiment, the casein-derived phosphopeptides comprise the C-terminal fragment of phosphopeptides derived from casein digestion. Suitably, in some embodiments, casein is digested by enzymatic digestion, preferably trypsin digestion. In another embodiment, casein is digested by chemical digestion.

[0284] To avoid confusion, it should be noted that in embodiments of the invention, the composition may comprise a mixture of different phosphopeptides. For example, the composition may comprise a mixture of different phosphopeptides derived from a single phosphoprotein (e.g., casein or OPN). Alternatively, the calcium phosphate stabilizer may comprise a mixture of different phosphoproteins (e.g., a mixture of casein and OPN, or other different phosphoproteins) and / or phosphopeptides derived from a mixture of more than one different phosphoprotein (e.g., a mixture of phosphopeptides derived from casein and OPN). In many cases, the composition will comprise a heterogeneous mixture of phosphopeptides obtained by cleavage of naturally occurring proteins such as OPN or casein.

[0285] Stable calcium phosphate complex:

[0286] A "stable calcium phosphate complex" is a complex comprising calcium, phosphate, and a calcium phosphate stabilizer (usually a phosphopeptide). Stable calcium phosphate complexes are typically soluble or at least metastable in the liquid medium containing them, i.e., in a liquid composition. Calcium phosphate stabilizers (such as phosphopeptides) can bind to calcium phosphate complexes, preventing them from precipitating. In particular, amorphous calcium phosphate complexes can be stabilized to maintain a soluble (or metastable) form and are capable of releasing calcium and phosphate.

[0287] Not wanting to be bound by theory, when a suitable liquid composition containing phosphopeptides and a calcium ion source is applied to the oral cavity, a small amount of phosphopeptide-stabilized calcium phosphate complex can be formed. The stable calcium phosphate complex can be formed when exogenous calcium ions interact with phosphate ions present in oral saliva.

[0288] Nevertheless, it is noteworthy how compositions of some aspects of the present invention, which do not contain additional phosphate or additional phosphate sources, can reduce gingival bleeding in patients, particularly those with periodontal disease. Suitably, in some embodiments of the invention, the compositions do not contain stable calcium phosphate complexes.

[0289] A "calcium phosphate stabilizer" is a reagent capable of binding and stabilizing calcium phosphate in a stable calcium phosphate complex. Suitablely, calcium phosphate can be stabilized as amorphous calcium phosphate. As mentioned above, suitable calcium phosphate stabilizers include phosphopeptides. Suitable phosphopeptides are defined herein.

[0290] Suitably, compositions of certain aspects of the present invention do not contain stable calcium phosphate complexes. Suitably, compositions of certain aspects of the present invention do not contain amorphous calcium phosphate. Suitably, in aspects or embodiments where the composition does not contain additional phosphate or additional phosphate sources, the composition suitably does not contain calcium phosphate complexes, such as amorphous calcium phosphate.

[0291] Suitably, these compositions may comprise a negligible amount of a stable calcium phosphate complex. A negligible amount means that the compositions comprise less than 1% w / w of the stable calcium phosphate complex, suitably less than 0.9% w / w, suitably less than 0.8% w / w, suitably less than 0.7% w / w, suitably less than 0.6% w / w, suitably less than 0.5% w / w, suitably less than 0.4% w / w, suitably less than 0.3% w / w, suitably less than 0.2% w / w, and suitably less than 0.1% w / w. In one embodiment, the composition, which does not contain additional phosphate or an additional phosphate source, comprises less than 0.1% w / w of the stable calcium phosphate complex.

[0292] The use of OPN in forming calcium phosphate nanoparticle aggregates is extensively discussed, for example, in WO2013 / 144247, where its use in reducing biofilm growth is discussed. Suitably, in some embodiments of the invention, the phosphopeptide-containing compositions used in any aspect thereof do not include the OPN and calcium or strontium nanoparticle aggregates described in WO2013 / 144247. Suitably, in some embodiments of the invention, the phosphopeptide-containing compositions used in any aspect thereof do not include the OPN and calcium phosphate nanoparticle aggregates described in WO2013 / 144247. Suitably, in some embodiments of the invention, OPN aggregates are present, the aggregates having a hydrodynamic radius of up to 0.2 micrometers, more preferably the aggregates having a hydrodynamic radius of up to 0.1 micrometers [9]. Those skilled in the art will understand that the particle size of the aggregates can be determined by techniques known in the art. The particle size of the calcium phosphate nanoparticles of the present invention has a radius of gyration in the range of 19.5-25 nm, determined by elastic light scattering and small-angle neutron scattering [9]. This metric differs from the hydrodynamic radius, which represents the radius of a particle, just as it would be a solid sphere. However, both metrics yield results of the same order of magnitude, and therefore, in some embodiments of the invention where OPN aggregates exist, the aggregates are considered to be smaller than 100 nm (0.1 micrometers).

[0293] Calcium and calcium sources:

[0294] The compositions used in this invention may contain calcium or a calcium source.

[0295] In any embodiment of the aspects described herein, the composition may comprise calcium or a calcium source. Suitably, in some embodiments, the calcium is supersaturated calcium.

[0296] Suitably, compositions for the prevention or treatment of gingival bleeding may contain calcium or a calcium source. Suitably, compositions for the prevention or treatment of periodontal disease may contain calcium or a calcium source. Suitably, compositions for the prevention or treatment of gingivitis and / or periodontitis may contain calcium or a calcium source. Suitably, compositions for the prevention or treatment of peri-implant mucositis and / or peri-implantitis may contain calcium or a calcium source. However, in some embodiments, the composition according to any aspect does not contain calcium or a calcium source.

[0297] The calcium source used in this document refers to any suitable calcium ion source. The calcium ion source should be able to dissolve in a liquid medium to release calcium ions. Suitably, the calcium ion source may be a soluble calcium salt.

[0298] Suitably, the calcium or calcium source has a solubility of 1 g or more per 100 ml of liquid medium, 2 g or more per 100 ml of liquid medium, 3 g or more per 100 ml of liquid medium, 4 g or more per 100 ml of liquid medium, 5 g or more per 100 ml of liquid medium, 10 g or more per 100 ml of liquid medium, 20 g or more per 100 ml of liquid medium, 30 g or more per 100 ml of liquid medium, 40 g or more per 100 ml of liquid medium, or 50 g or more per 100 ml of liquid medium. The calcium ion source can be provided in solid form or dissolved in a suitable liquid medium.

[0299] A particularly suitable source of calcium ions is calcium chloride, but those skilled in the art can choose from many other suitable sources of calcium ions.

[0300] In one embodiment, the calcium source is calcium chloride. Suitably, the calcium chloride solution has a concentration of about 1 M.

[0301] When the solubility of a composition is discussed herein, it refers to its solubility in the relevant liquid medium used in the method at 25°C (or standard conditions). Typically, this medium is aqueous, and in some cases, water. It should be understood that the solubility of a given composition will vary depending on the relevant medium used, for example, according to its polarity, but this is perfectly appropriate in the context, as compositions such as calcium salts or phosphates are preferably soluble in the relevant medium used. However, given that the medium in the compositions used in this invention is typically aqueous, it may be more convenient and simpler to define solubility using solubility in water. Therefore, the solubility of the calcium ion source is suitably 5 g or more per 100 ml of water, 10 g or more per 100 ml of water, or 50 g or more per 100 ml of water.

[0302] Phosphate and phosphate sources:

[0303] In some embodiments, the compositions used in this invention may contain phosphates or phosphate sources. In some embodiments, the compositions used in this invention do not contain additional phosphates or additional phosphate sources. Suitably, in some embodiments, the compositions used in this invention may be substantially phosphate-free.

[0304] "Additional" phosphate or phosphate source means that the composition contains no phosphate or phosphate source other than the phosphopeptide and optional monofluorophosphate of the composition. Those skilled in the art will understand that the hydrolysis of monofluorophosphate in the oral cavity provides less than 2.1 g / L (<0.03 mol / < 30 mM) of free phosphate ions. Compositions containing monofluorophosphate can be considered substantially phosphate-free.

[0305] Therefore, suitably, in one embodiment, the composition does not contain phosphate or phosphate source other than phosphorylated OPN and / or monofluorophosphate.

[0306] Therefore, in one embodiment, the composition used in this invention comprises a phosphopeptide and optionally a monofluorophosphate, and does not contain any additional phosphate or additional phosphate source. Typical additional phosphate sources may comprise phosphate buffers, which suitably are not present in the composition.

[0307] In some embodiments, the compositions used in this invention do not contain additional phosphate ions or additional phosphate ion sources. In some embodiments, the compositions used in this invention do not contain additional free phosphate ions. In some embodiments, the compositions used in this invention do not contain any exogenous free phosphate ions. In some embodiments, the compositions used in this invention do not contain additional free phosphate ions. In some embodiments, the compositions used in this invention do not contain exogenous free phosphate ions.

[0308] "Exogenous" means a phosphate that is not derived from or contained in a compound that is part of the composition used in this invention. Suitably, it means a phosphate that is not derived from or contained in a phosphopeptide or optionally a monofluorophosphate of the composition used in this invention.

[0309] Suitably, the compositions used in this invention can be considered substantially phosphate-free. Suitably, these compositions may contain trace amounts of phosphate due to the presence of other components in the compositions, but suitably, they do not contain any significant amounts of phosphate or phosphate sources. Particularly suitably, the compositions do not contain phosphate buffers.

[0310] Therefore, suitably, the composition contains a small amount of phosphate. Suitably, negligible amounts of phosphate, for example, are less than 15% w / w, less than 14% w / w, less than 13% w / w, less than 12% w / w, less than 11% w / w, less than 10% w / w, less than 9% w / w, less than 8% w / w, less than 7% w / w, less than 6% w / w, less than 5% w / w, less than 4% w / w, less than 3% w / w, and less than 2% w / w. In one embodiment, the composition, which does not contain phosphate or a phosphate source, contains less than 7% w / w of phosphate. Suitably, as described above, negligible amounts of phosphate may be derived from components of the composition, such as monofluorophosphate and phosphopeptides, such as phosphorylated OPN.

[0311] Suitably, the composition, without additional phosphate or additional phosphate source, contains less than 100 mM, less than 90 mM, less than 80 mM, less than 70 mM, less than 60 mM, less than 55 mM, less than 50 mM, less than 45 mM, less than 40 mM, less than 35 mM, less than 30 mM, less than 25 mM, less than 20 mM, less than 15 mM of phosphate, less than 10 mM of phosphate, and less than 5 mM of phosphate. Suitably, the composition, without additional phosphate or additional phosphate source, contains less than 49 mM of phosphate. Suitably, the composition, without additional phosphate or additional phosphate source, contains less than 23 mM of phosphate.

[0312] Suitably, the concentration of phosphate in the composition is determined by a Smillie calculation based on the degree of phosphorylation of any compound in the composition. According to a preferred embodiment of the invention, an exemplary calculation of the phosphate concentration in a composition comprising a phosphopeptide and a monofluorophosphate is as follows:

[0313]

[0314] In one embodiment, the composition, which does not contain additional phosphate or an additional phosphate source, contains less than 48.5 mM of phosphate. Suitably, in such an embodiment, the composition still contains phosphopeptides and monofluorophosphate. Suitably, the composition contains about 3% w / w phosphorylated OPN.

[0315] In one embodiment, the composition, which does not contain additional phosphate or an additional phosphate source, contains less than 22.5 mM of phosphate. Suitably, in such an embodiment, the composition still contains phosphopeptides but not monofluorophosphate. Suitably, the composition contains about 3% w / w phosphorylated OPN.

[0316] Suitably, the composition in any embodiment of the method or use described herein may optionally contain additional phosphate or an additional phosphate source. Therefore, suitably, in any aspect described herein, the composition may contain phosphate or a phosphate source. However, in some embodiments, such a composition may not contain additional phosphate or an additional phosphate source.

[0317] As used herein, “phosphate” and “phosphate source” refer to any suitable phosphate ion source. If present in the composition, the phosphate ion source should be soluble in a liquid medium to release phosphate ions. Suitably, the phosphate ion source may be a soluble phosphate. Suitably, the phosphate ion source has a solubility of 5 g or more per 100 ml of liquid medium, 10 g or more per 100 ml of liquid medium, or 50 g or more per 100 ml of liquid medium. The phosphate ion source may be provided in solid form or dissolved in a suitable liquid.

[0318] A particularly suitable phosphate ion source is sodium phosphate (e.g., disodium hydrogen phosphate and / or trisodium phosphate), but those skilled in the art can choose from many other suitable phosphate ion sources.

[0319] As described above, given that the medium in the compositions used in this invention is typically aqueous, it may be more convenient and simpler to define solubility by its solubility in water. Therefore, the solubility of the phosphate ion source is suitably 5 g or more per 100 ml of water, 10 g or more per 100 ml of water, or 50 g or more per 100 ml of water.

[0320] Fluorides and fluoride sources:

[0321] The compositions used in this invention may contain fluorides or fluoride sources.

[0322] Suitably, compositions for the prevention or treatment of gingival bleeding may contain fluoride. Suitably, compositions for the prevention or treatment of periodontal disease may contain fluoride. Suitably, compositions for the prevention or treatment of gingivitis and / or periodontitis may contain fluoride. Suitably, compositions for the prevention or treatment of peri-implant mucositis and / or peri-implantitis may contain fluoride. However, in some embodiments, the compositions do not contain fluoride or a fluoride source.

[0323] The fluoride and fluoride source used herein refer to any suitable fluoride ion source. The fluoride ion source should be soluble in a liquid medium to release fluoride ions. Suitably, the fluoride ion source can be a soluble fluoride salt. Suitably, the fluoride ion source has a solubility of 5 g or more per 100 ml of liquid medium, 10 g or more per 100 ml of liquid medium, or 50 g or more per 100 ml of liquid medium. The fluoride ion source can be provided in solid form or dissolved in a suitable liquid.

[0324] Suitable fluoride ion sources include sodium fluoride, tin fluoride, calcium fluoride, and monofluorophosphate, but those skilled in the art can choose from many other suitable fluoride ion sources.

[0325] In one embodiment, the fluoride source is monofluorophosphate.

[0326] As described above, given that the medium in the compositions used in this invention is typically aqueous, it may be more convenient and simpler to define solubility by its solubility in water. Therefore, the solubility of the fluoride ion source is suitably 5 g or more per 100 ml of water, 10 g or more per 100 ml of water, or 50 g or more per 100 ml of water.

[0327] In some embodiments, the compositions used in this invention do not contain fluorides or fluoride sources. Suitably, such compositions can be considered substantially fluoride-free. Suitably, these compositions may contain trace amounts of fluoride due to the presence of other components in the composition, but suitably, these compositions do not contain any significant amount of fluoride or fluoride sources. Suitably, fluoride-free compositions are considered to have negligible amounts of fluoride, suitably less than 1% w / w of fluoride or fluoride source, suitably less than 0.9% w / w, suitably less than 0.8% w / w, suitably less than 0.7% w / w, suitably less than 0.6% w / w, suitably less than 0.5% w / w, suitably less than 0.4% w / w, suitably less than 0.3% w / w, suitably less than 0.2% w / w, suitably less than 0.1% w / w. In one embodiment, the composition that does not contain fluoride or fluoride sources contains less than 0.1% w / w of fluoride.

[0328] In some embodiments, the compositions used in this invention do not contain monofluorophosphate. Suitably, in some embodiments, the composition is a liquid. Suitably, the composition may be a “MOL” or “MOK” composition as described elsewhere herein. Suitably, in some embodiments, the composition is a colloid, paste, or gel. Suitably, the composition may be a “MON” composition as described elsewhere herein. Suitably, the composition may be a “MOG” composition as described elsewhere herein.

[0329] Oral cavity surface:

[0330] The compositions used in this invention can be applied to oral surfaces. Suitably, compositions for the prevention or treatment of gingival bleeding can be applied to oral surfaces. Suitably, compositions for the prevention or treatment of periodontal disease can be applied to oral surfaces. Suitably, compositions for the prevention or treatment of gingival bleeding may contain fluoride or may not contain fluoride. Suitably, compositions for the prevention or treatment of gingivitis and / or periodontitis may contain fluoride or may not contain fluoride. Suitably, compositions for the prevention or treatment of peri-implantitis and / or peri-implantitis may contain fluoride or may not contain fluoride. Suitably, compositions of any aspect of this invention may contain fluoride or may not contain fluoride.

[0331] Suitably, the oral cavity surface is a natural or synthetic surface. Suitably, the oral cavity surface can be a hard or soft surface. Suitably, the hard surface can be natural or synthetic. Suitably, the soft surface can be natural or synthetic.

[0332] Suitable hard surfaces include teeth, dentures, veneers, crowns, dental implants, orthodontic aligners, and orthodontic brackets, such as fixed orthodontic brackets. Suitably, in some embodiments, the hard surfaces are mineralized. Suitable hard-mineralized surfaces include enamel, dentin, or cementum. Suitably, the soft surfaces are not mineralized. Suitable soft surfaces include the gingiva, tongue, soft palate, hard palate, and floor of the mouth.

[0333] Suitable natural surfaces include teeth, gums, tongue, soft palate, hard palate, and floor of the mouth. Suitable synthetic surfaces include orthodontic appliances, or dental accessories and prostheses. Suitable synthetic surfaces can be formed of plastic or metal. Suitable dental accessories or orthodontic appliances can include dentures, veneers, crowns, bridges, dental implants, alignment devices, orthodontic brackets, etc.

[0334] Suitably, in aspects of the invention, the oral surface is a natural oral surface. In embodiments for preventing or treating gingival bleeding in a subject, suitably, the oral surface is the gingiva. In embodiments for preventing or treating gingival bleeding in a subject, suitably, the oral surface is the tongue. In embodiments for preventing or treating gingival bleeding in a subject, suitably, the oral surface is the teeth, particularly the tooth surface, and more particularly, the dentin of the teeth. In embodiments for preventing or treating periodontal disease in a subject, suitably, the oral surface is the gingiva. In embodiments for preventing or treating periodontal disease in a subject, suitably, the oral surface is the tongue. In embodiments for preventing or treating periodontal disease in a subject, suitably, the oral surface is the teeth, particularly the tooth surface, and more particularly, the dentin, enamel, and root surface of the teeth.

[0335] In embodiments for the prevention or treatment of gingivitis and / or periodontitis, the oral surface is the gingiva. In embodiments for the prevention or treatment of gingivitis and / or periodontitis in a subject, suitably, the oral surface is the tongue. In embodiments for the prevention or treatment of gingivitis and / or periodontitis, suitably, the oral surface is the teeth, particularly the tooth surfaces, and more particularly the dentin, enamel, and root surfaces of the teeth.

[0336] In embodiments for the prevention or treatment of peri-implant mucositis and / or peri-implantitis, the oral surface is the gingiva. In embodiments for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject, suitably, the oral surface is the tongue. In embodiments for the prevention or treatment of peri-implant mucositis and / or peri-implantitis, suitably, the oral surface is the surface of a dental implant, particularly the implant or implant mechanism. Suitably, in some embodiments, the oral surface is the tooth adjacent to the dental implant. Suitably, in some embodiments, the oral surface is the gingival tissue adjacent to or surrounding the dental implant.

[0337] In some embodiments, the composition is applied directly to the orthodontic appliance. Suitably, users of removable orthodontic appliances may apply the composition directly to the aligner, bracket, retainer, or mouthguard before placing the appliance back into their mouth. In some embodiments, the composition is applied to the interdental brush before use. In such embodiments, it should be understood that the composition will reach the interdental area when brushing. Suitably, in some embodiments, the composition may be applied by a dental professional to a fixed orthodontic appliance during implantation. Suitably, in one embodiment, the composition used herein is applied to an orthodontic appliance, aligner, mouthguard, and / or denture.

[0338] Suitably, the oral surface may be located inside the oral cavity. Suitably, it is inside the oral cavity of the subject. Suitably, the subject may be a human or an animal. Therefore, suitably, the use and method of the present invention can be performed on human or animal subjects. In one embodiment, the subject is a human. In one embodiment, the subject is a domestic animal, such as a cat, dog, or horse.

[0339] Suitably, the use and methods of the present invention include applying the compositions described herein to oral surfaces. Suitably, applying the compositions used in the present invention to oral surfaces may include applying the compositions to the oral cavity of a subject. Suitably, applying the compositions to the oral cavity of a subject brings the oral surfaces located within the subject's oral cavity into contact with the compositions. Suitable application steps are described below.

[0340] polymer materials

[0341] In one aspect of the invention, a polymeric material comprising a composition comprising a phosphopeptide is provided. Suitably, in some embodiments, the polymeric material comprises any of the compositions described herein for use in the invention.

[0342] Those skilled in the art will understand that the term "polymeric material" can include, but is not limited to, polymer sheets, polymer films, polymer gels, or any other polymeric material suitable for oral care or dentistry. While polymer sheets or films are most preferred in the embodiments described herein, it should be understood that polymeric materials can take any shape or form. It should also be understood that the term "polymeric sheet" as used herein can be used interchangeably with the term "polymer film." Suitably, in some embodiments, the polymeric material is a polymer sheet or film. In some embodiments, the polymeric material is a polymer gel. In some embodiments, the polymeric material can be applied directly to the oral cavity, or it can be applied to a dental device, such as a dental alignment device or protective denture, and then applied to the oral cavity.

[0343] The polymeric material of the present invention can be formulated into a combination containing surfactants. In some embodiments, the polymeric material comprises a MON composition. In another embodiment, the polymeric material comprises a MOL composition. In another embodiment, the polymeric material comprises a MOK composition. In another embodiment, the polymeric material comprises a MOG composition. In yet another embodiment, the polymeric material comprises a MON composition.

[0344] Suitably, in some embodiments, the composition comprises a fluoride or a fluoride source. Suitably, in some embodiments, the composition does not contain a fluoride or a fluoride source. In some embodiments, the composition comprises a phosphate or a phosphate source. In some embodiments, the composition does not contain a phosphate or a phosphate source. In some embodiments, the composition comprises calcium or a calcium source. In some embodiments, the composition does not contain calcium or a calcium source.

[0345] Suitably, in some embodiments, the polymeric material comprises a solid composition containing phosphopeptides. Suitably, in some embodiments, the polymeric material comprises a liquid composition containing phosphopeptides.

[0346] Those skilled in the art will understand that polymeric materials comprising the compositions described herein are suitable for any aspect or embodiment of the invention. Suitably, in some embodiments of various aspects of the invention, the compositions described herein can be applied to a patient's mouth via a polymeric material comprising any of the compositions described herein. In such embodiments, preferably, the polymeric material is soluble or at least substantially soluble. Substantially soluble means that when contacted with a solvent, preferably water (e.g., in saliva), the polymeric material will decompose to the extent that it releases the active ingredient. Suitable soluble and insoluble polymeric materials will be discussed in detail below.

[0347] In another aspect of the invention, a polymeric material comprising OPN or a phosphopeptide derived therefrom is provided. Suitably, in some embodiments, the polymeric material comprises OPN-10. Suitably, in some embodiments, the polymeric material comprises phosphorylated OPN or a phosphopeptide derived therefrom. In some embodiments, the polymeric material comprises glycosylated OPN or a phosphopeptide derived therefrom. Suitably, in some embodiments, the polymeric material comprises both phosphorylated and glycosylated OPN or a phosphopeptide derived therefrom.

[0348] In some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom, and calcium or a calcium ion source. Suitably, in some embodiments, the calcium source is any soluble calcium salt. Suitably, in some embodiments, the calcium source is calcium carbonate, calcium chloride, calcium citrate, or calcium lactate. Those skilled in the art will understand that any suitable calcium ion source can be used. Suitably, in some embodiments, the polymeric material comprises OPN in solid or liquid form. Suitably, in some embodiments, the polymeric material comprises calcium or a calcium ion source in solid or liquid form.

[0349] In one embodiment, the polymeric material comprises OPN in liquid form or a phosphopeptide derived therefrom, and calcium or a calcium ion source in liquid form.

[0350] In one embodiment, the polymeric material comprises OPN in solid form or a phosphopeptide derived therefrom, and calcium or a calcium ion source in solid form.

[0351] In some embodiments, the polymeric material comprises a stable calcium phosphate complex. Suitably, in some embodiments, the complex is stabilized by any of the phosphopeptides described herein. In some embodiments, the polymeric material comprises an OPN and a calcium complex. In another embodiment, the polymeric material comprises a casein and a calcium complex.

[0352] In some embodiments, the polymeric material comprises a complex of calcium and OPN or a phosphopeptide derived therefrom. Suitably, in some embodiments, the polymeric material comprises a phosphopeptide-stabilized amorphous calcium phosphate (ACP) complex. Suitably, in some embodiments, the polymeric material comprises an OPN-stabilized calcium phosphate complex. Suitably, in some embodiments, the polymeric material comprises an OPN-stabilized amorphous calcium phosphate complex. Suitably, in some embodiments, the polymeric material comprises a casein-stabilized calcium phosphate complex. Suitably, in some embodiments, the polymeric material comprises a casein-stabilized amorphous calcium phosphate complex. Those skilled in the art will understand that in some manufacturing methods, such as those suitable for manufacturing the polymeric films described herein, the manufacturing method includes dissolving the components in water prior to a film-forming step. The film-forming step causes partial dehydration of the product. Reaction conditions may result in the formation of a calcium-phosphopeptide complex in the liquid and in the final product film. Alternatively, the manufacturing method may include preparing a liquid composition comprising a stable calcium phosphate complex or a calcium-phosphopeptide complex according to the method described in Example 1 or 2 below or any of the methods of use described in WO / 2018 / 087532. Those skilled in the art will understand that liquid compositions containing stable calcium phosphate complexes or calcium phosphopeptide complexes can be freeze-dried after the liquid composition is prepared, and then the freeze-dried product is incorporated into a polymer. However, those skilled in the art will understand that in some cases, it is desirable for phosphopeptides (e.g., OPN or casein) and Ca... 2+ The polymeric material is not compounded on the polymeric material. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom and calcium or a calcium ion source, wherein the OPN or a phosphopeptide derived therefrom and calcium or a calcium ion source do not form a complex on the polymeric material. Suitably, in some embodiments, the polymeric membrane does not contain a phosphopeptide-stabilized amorphous calcium phosphate complex. Suitably, in some embodiments, the polymeric membrane does not contain an OPN-stabilized calcium phosphate complex. Suitably, in some embodiments, the polymeric membrane does not contain an OPN-stabilized amorphous calcium phosphate complex. Suitably, in some embodiments, the polymeric membrane does not contain a casein-stabilized amorphous calcium phosphate complex.

[0353] In another aspect of the invention, a polymeric material comprising casein or phosphopeptides derived therefrom is provided. Suitably, in some embodiments, the polymeric material comprises phosphorylated casein or phosphopeptides derived therefrom. In some embodiments, the polymeric material comprises glycosylated casein or phosphopeptides derived therefrom. Suitably, in some embodiments, the polymeric material comprises both phosphorylated and glycosylated casein or phosphopeptides derived therefrom.

[0354] In some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom, and calcium or a calcium ion source. Suitably, in some embodiments, the calcium source is any soluble calcium salt. In some embodiments, the calcium source is calcium carbonate, calcium chloride, calcium citrate, or calcium lactate. Those skilled in the art will understand that any suitable calcium ion source can be used. Suitably, in some embodiments, the polymeric material comprises casein in solid or liquid form. Suitably, in some embodiments, the polymer membrane comprises calcium or a calcium ion source in solid or liquid form.

[0355] In one embodiment, the polymeric material comprises casein in solid form or phosphopeptides derived therefrom, and solid calcium or a calcium ion source.

[0356] In one embodiment, the polymeric material comprises casein in liquid form or phosphopeptides derived therefrom, and calcium or a calcium ion source in liquid form.

[0357] In some embodiments, the polymeric material comprises a complex of calcium and casein or a phosphopeptide derived therefrom. Suitably, in some embodiments, the polymeric material comprises a casein-stabilized calcium phosphate complex. Those skilled in the art will understand that in some manufacturing methods, such as those suitable for manufacturing the polymer films described herein, the manufacturing method includes dissolving the components in water prior to a film-forming step. The film-forming step causes partial dehydration of the product. Reaction conditions may result in the formation of a calcium-phosphopeptide complex in the liquid and in the final product film. Alternatively, the manufacturing method may include preparing a liquid composition comprising a stable calcium phosphate complex or a calcium phosphopeptide complex according to the method described in Example 1 or 2 below or any of the usage methods described in WO / 2018 / 087532. Those skilled in the art will understand that the liquid composition comprising a stable calcium phosphate complex or a calcium phosphopeptide complex can be freeze-dried after the preparation of the liquid composition, and then the freeze-dried product is incorporated into the polymer. However, those skilled in the art will understand that in some cases, it is desirable that the phosphopeptide (e.g., OPN or casein) and calcium phosphate complex are present in a mixture of calcium phosphate and casein. 2+The polymeric material is not compounded on the polymeric material. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and calcium or a calcium ion source, wherein the casein or a phosphopeptide derived therefrom and calcium or a calcium ion source do not form a complex on the polymeric membrane. Suitably, in some embodiments, the polymeric material does not contain a casein-stabilized calcium phosphate complex.

[0358] Without being bound by theory, it is believed that when the active ingredient is delivered to the oral cavity, for example when the polymer dissolves in the mouth, the addition of calcium and phosphopeptides (e.g., casein, OPN, or phosphopeptides derived therefrom) as discrete components to the polymer will result in the formation of stable calcium phosphopeptide complexes (e.g., stable amorphous calcium phosphopeptide complexes).

[0359] As described above, in some cases, it is desirable for the polymeric material to be soluble. Suitably, in some embodiments, the polymeric material is a soluble polymeric film. Alternatively, in some embodiments, the polymeric material is an insoluble polymeric film. In a preferred embodiment, the soluble polymeric material may have and / or contain no or substantially no insoluble components. Therefore, when used in the oral cavity for periods such as about 10 to 30 seconds, about 10 seconds to 1 minute, about 1 to 2 minutes, about 1 to 3 minutes, about 1 to 4 minutes, about 1 to 5 minutes, about 1 to 10 minutes, about 1 to 15 minutes, about 1 to 20 minutes, about 1 to 30 minutes, about 1 to 60 minutes, about 1 to 5 hours, about 1 to 10 hours, or about 1 to 22 hours, the soluble polymeric material may be intended to dissolve completely or substantially completely. Alternatively, the film may dissolve in about 10 to 60 minutes or about 30 minutes to 2 hours. Those skilled in the art will understand that the formulation of the soluble polymeric material can be modified to ensure that the dissolution time is suitable for the user's requirements. Appropriately, the ratio of polymer to plasticizer can be adjusted to change the dissolution time in the mouth.

[0360] The polymeric materials described herein may contain a range of other components, including any one or a combination of the following:

[0361] One or more active agents (e.g., OPN and calcium or any combination described herein).

[0362] One or more polymers,

[0363] One or more plasticizers, and / or

[0364] One or more emulsifiers.

[0365] In some embodiments, the polymeric material comprises one or more surfactants. The surfactants may include any composition described herein, including but not limited to MOK, MOL, MON, or MOG compositions. Suitably, in some embodiments, the one or more surfactants are OPN or phosphopeptides derived therefrom, or casein or phosphopeptides derived therefrom. Suitably, in some embodiments, the one or more surfactants are OPN or phosphopeptides derived therefrom, along with calcium or a calcium source. Suitably, in some embodiments, the one or more surfactants are casein or phosphopeptides derived therefrom, along with calcium or a calcium source.

[0366] The one or more surfactants may be present in the polymeric material in the following amounts: about 0.1% to about 70% w / w; about 0.1% to about 60% w / w; about 0.1% to about 50% w / w; about 0.1% to about 40% w / w; about 0.1% to about 30% w / w; about 0.1% to about 20% w / w; about 0.1% to about 15% w / w; about 0.1% to about 10% w / w; about 0.1% to about 5% w / w. In some embodiments, the one or more surfactants may be present in the following amounts: about 0.1% to about 5% w / w; about 0.5% to about 5% w / w; about 1% to about 5% w / w; about 2% to about 5% w / w; about 3% to about 5% w / w; about 4% to about 5% w / w.

[0367] In a preferred embodiment, one or more active agents are present in a total amount of 3% w / w.

[0368] In a preferred embodiment, one or more active agents are present in a total amount of 22% w / w.

[0369] In another preferred embodiment, the one or more active agents are present in a total amount of 12-20% w / w.

[0370] In some embodiments, the maximum amount of the active agent is 50-70% w / w of the total amount.

[0371] Suitably, in some embodiments, the active agent comprises OPN or a phosphopeptide derived therefrom. Suitably, in some embodiments, the OPN or phosphopeptide derived therefrom is present in the polymeric material in a total amount of 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt% or more. Suitably, in some embodiments, the OPN or phosphopeptide derived therefrom is present in the polymeric material in a total amount of 0.876 wt% - 21.91% of the polymeric material. In a preferred embodiment, the OPN or phosphopeptide derived therefrom is present in the polymeric material in a total amount of 22 wt% of the polymeric material.

[0372] Suitably, in some embodiments, the active agent comprises casein or a phosphopeptide derived therefrom. Suitably, in some embodiments, the casein or phosphopeptide derived therefrom is present in the polymeric material in a total amount of 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt% or more of the polymeric material. Suitably, in some embodiments, the casein or phosphopeptide derived therefrom is present in the polymeric material in a total amount of 0.876 wt% to 21.91% of the polymeric material. In a preferred embodiment, the casein or phosphopeptide derived therefrom is present in the polymeric material in a total amount of 22% of the polymeric material by weight.

[0373] Suitably, in some embodiments, the activator comprises calcium or a calcium source. Suitably, in some embodiments, the calcium source is any suitable calcium salt. Suitably, in some embodiments, the calcium source is calcium chloride dihydrate. Suitably, in some embodiments, the calcium is supersaturated calcium. Suitably, in some embodiments, the calcium source is present in the polymeric material in a total amount of 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt% or more. Suitably, in some embodiments, the calcium source is present in the polymeric material in a total amount of 0.123-3.08 wt%. In a preferred embodiment, the calcium source is present in the polymeric material in a total amount of 3% by weight of the polymeric material.

[0374] In some embodiments, the polymeric material comprises at least 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of OPN or a phosphopeptide derived therefrom per 20 mg of active agent. Suitably, in one embodiment, the polymeric material comprises 17 mg of OPN or a phosphopeptide derived therefrom per 20 mg of active agent. In another embodiment, the polymeric material comprises 17.5 mg of OPN or a phosphopeptide derived therefrom per 20 mg of active agent.

[0375] In some embodiments, the polymeric material comprises at least 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of casein or a phosphopeptide derived therefrom per 20 mg of active agent. Suitably, in one embodiment, the polymeric material comprises 17 mg of casein or a phosphopeptide derived therefrom per 20 mg of active agent. In another embodiment, the polymeric material comprises 17.5 mg of casein or a phosphopeptide derived therefrom per 20 mg of active agent.

[0376] In some embodiments, the polymeric material comprises at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, at least 1.1 mg, at least 1.2 mg, at least 1.3 mg, at least 1.4 mg, at least 1.5 mg, at least 1.6 mg, at least 1.7 mg, at least 1.8 mg, at least 1.9 mg, at least 2 mg, at least 2 mg, at least 2.1 mg, at least 2.2 mg, at least 2.3 mg, at least 2.4 mg, at least 2.5 mg, at least 2.6 mg, at least 2.7 mg, at least 2.8 mg, at least 2.9 mg, at least 3 mg, at least 4 mg, or at least 5 mg of calcium source per 20 mg of activator. Suitably, in one embodiment, the polymeric material comprises 2 mg of calcium source per 20 mg of activator. In another embodiment, the polymeric material comprises 2.5 mg of calcium source per 20 mg of activator.

[0377] In one embodiment, the polymeric material comprises OPN or a phosphopeptide derived therefrom and a calcium source. In some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom and a calcium source in a ratio of 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In one embodiment, the polymeric material comprises OPN or a phosphopeptide derived therefrom and a calcium source in a ratio of 7:1. In another embodiment, the polymeric material comprises OPN or a phosphopeptide derived therefrom and a calcium source in a ratio of 7:1.4.

[0378] In one embodiment, the polymeric material comprises casein or a phosphopeptide derived therefrom and a calcium source. In some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and a calcium source in a ratio of 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In a preferred embodiment, the polymeric material comprises casein or a phosphopeptide derived therefrom and a calcium source in a ratio of 7:1. In another embodiment, the polymeric material comprises casein or a phosphopeptide derived therefrom and a calcium source in a ratio of 7:1.4.

[0379] In some embodiments, the polymeric material comprises 19-22% OPN or a phosphopeptide derived therefrom and 1-4% a calcium source, preferably calcium chloride. In some embodiments, the polymeric material further comprises a fluoride or a fluoride source, preferably sodium monofluorophosphate. Suitably, in some embodiments, the polymeric material further comprises 0.1-5% fluoride.

[0380] In some embodiments, the polymeric material comprises 0.5-5% OPN or a phosphopeptide derived therefrom, 0.1-0.5% of a calcium source, preferably calcium chloride, and optionally, 0.1-0.5% of a fluoride source, preferably sodium monofluorophosphate.

[0381] In one embodiment, the polymeric material comprises 22% OPN or a phosphopeptide derived therefrom, 3% calcium source, preferably calcium chloride, and optionally, 0.4% fluoride source, preferably sodium monofluorophosphate.

[0382] In one embodiment, the polymeric material comprises 21.92% OPN or a phosphopeptide derived therefrom and 3.08% a calcium source, preferably calcium chloride.

[0383] In one embodiment, the polymeric material comprises 21.92% OPN or a phosphopeptide derived therefrom, 3.08% a calcium source, preferably calcium chloride, and 0.4% a fluoride source, preferably monofluorophosphate.

[0384] In one embodiment, the polymeric material comprises 3% OPN or a phosphopeptide derived therefrom and 0.4% calcium source, preferably calcium chloride.

[0385] In one embodiment, the polymeric material comprises 3% OPN or a phosphopeptide derived therefrom, 0.4% a calcium source, preferably calcium chloride, and 0.4% a fluoride source, preferably monofluorophosphate.

[0386] In one embodiment, the polymeric material comprises 9% OPN or a phosphopeptide derived therefrom and 1.27% calcium source, preferably calcium chloride.

[0387] In one embodiment, the polymeric material comprises 9% OPN or a phosphopeptide derived therefrom, 1.27% a calcium source, preferably calcium chloride, and 0.4% a fluoride source, preferably monofluorophosphate.

[0388] In another embodiment, the polymeric material comprises 0.88% OPN or a phosphopeptide derived therefrom and 0.12% calcium source, preferably calcium chloride.

[0389] In another embodiment, the polymeric material comprises 0.88% OPN or a phosphopeptide derived therefrom, 0.12% of a calcium source, preferably calcium chloride, and 0.4% of a fluoride source, preferably monofluorophosphate.

[0390] In one embodiment, the polymeric material comprises a standard formulation as described in Table 9.

[0391] In one embodiment, the polymeric material comprises the 3X Boost formulation as described in Table 9.

[0392] In some embodiments, the polymeric material comprises 19-22% casein or a phosphopeptide derived therefrom and 1-4% a calcium source, preferably calcium chloride. In some embodiments, the polymeric material further comprises a fluoride or a fluoride source, preferably sodium monofluorophosphate. Suitably, in some embodiments, the polymeric material further comprises 0.1-5% fluoride.

[0393] In some embodiments, the polymeric material comprises 0.5-5% casein or a phosphopeptide derived therefrom and 0.1-0.5% of a calcium source, preferably calcium chloride. In some embodiments, the polymeric material further comprises a fluoride or a fluoride source, preferably sodium monofluorophosphate. Suitably, in some embodiments, the polymeric material further comprises 0.1-5% fluoride.

[0394] In one embodiment, the polymeric material comprises 21.92% casein or phosphopeptides derived therefrom and 3.08% a calcium source, preferably calcium chloride. In another embodiment, the polymeric material comprises 21.92% casein or phosphopeptides derived therefrom, 3.08% a calcium source, preferably calcium chloride, and 0.4% a fluoride source, preferably monofluorophosphate.

[0395] In a preferred embodiment, the polymeric material comprises 22% casein or phosphopeptides derived therefrom and 3% a calcium source, preferably calcium chloride. In another preferred embodiment, the polymeric material comprises 22% casein or phosphopeptides derived therefrom, 3% a calcium source, preferably calcium chloride, and 0.4% a fluoride source, preferably monofluorophosphate.

[0396] In one embodiment, the polymeric material comprises 3% casein or a phosphopeptide derived therefrom and 0.4% of a calcium source, preferably calcium chloride. In another embodiment, the polymeric material comprises 3% casein or a phosphopeptide derived therefrom, 0.4% of a calcium source, preferably calcium chloride, and 0.4% of a fluoride source, preferably monofluorophosphate.

[0397] In one embodiment, the polymeric material comprises 9% casein or a phosphopeptide derived therefrom and 1.27% calcium source, preferably calcium chloride. In another embodiment, the polymeric material comprises 9% casein or a phosphopeptide derived therefrom, 1.27% calcium source, preferably calcium chloride, and 0.4% fluoride source, preferably monofluorophosphate.

[0398] In another embodiment, the polymeric material comprises 0.88% casein or a phosphopeptide derived therefrom and 0.12% of a calcium source, preferably calcium chloride. In another embodiment, the polymeric material comprises 0.88% casein or a phosphopeptide derived therefrom, 0.12% of a calcium source, preferably calcium chloride, and 0.4% of a fluoride source, preferably monofluorophosphate.

[0399] Suitably, in some embodiments, the polymeric material comprises a combination of phosphopeptides. Suitably, in one embodiment, the polymeric material comprises both casein and OPN.

[0400] In some embodiments, the polymeric material comprises one or more polymers. In some embodiments, the polymeric material comprises one or more water-soluble polymers. In such embodiments, it should be understood that the polymeric material is a soluble polymeric material, such as a soluble polymer film. Suitably, in some embodiments, the polymeric material comprises a hydrophilic polymer. The hydrophilic polymer may include, but is not limited to, polyvinyl acetate, pullulan, or polyvinylpyrrolidone. Suitably, in some embodiments, the polymeric material comprises a polysaccharide polymer. Suitably, in one embodiment, the polysaccharide polymer is pullulan. In an alternative embodiment, the polymeric material comprises polyvinylpyrrolidone. In another embodiment, the polymeric material comprises polyvinyl acetate.

[0401] The one or more polymers may contain the following total amounts of polymeric material: about 40% by weight to about 95% by weight; about 50% by weight to about 95% by weight; about 60% by weight to about 95% by weight; about 50% by weight to about 80% by weight; about 50% by weight to about 70% by weight.

[0402] Preferably, the one or more polymers may be present in a total amount of about 50% to about 90% by weight of the polymeric material. More preferably, the one or more polymers may be present in a total amount of about 60% to about 85% by weight of the polymeric material. Even more preferably, the one or more polymers may be present in a total amount of about 65% to about 80% by weight.

[0403] The polymeric material may contain one or more plasticizers. In some embodiments, the one or more plasticizers may be selected from the group consisting of: polyols, such as glycerol, polyalkylene glycols, polyalkylene glycol monomethyl ethers, monosaccharides, oligosaccharides, sorbitol, and anhydrosorbitol, wherein the alkylene group is independently selected from Ci-alkylene groups, preferably methylene, ethylene, or propylene. Preferred polyalkylene glycols are one or both of polyethylene glycol and polypropylene glycol. Preferred polyalkylene glycol monomethyl ethers are polyethylene glycol monomethyl ethers. In a preferred embodiment, the plasticizer is glycerol.

[0404] The one or more plasticizers may be present in the polymeric material in a total amount of about 0.1% to about 15% by weight. Preferably, the plasticizers may be present in a total amount of about 1% to about 12% by weight. More preferably, the one or more plasticizers may be present in the polymeric material in a total amount of about 3% to about 10% by weight. The ratio of polymer to plasticizer can be varied to change the time required for the polymeric material to dissolve in the oral cavity.

[0405] The polymeric material comprises one or more emulsifiers. In one embodiment, the one or more emulsifiers may be selected from ionic emulsifiers and nonionic emulsifiers. In another embodiment, the one or more emulsifiers may be selected from the group consisting of fatty acid derivatives, lecithin, and polysorbate.

[0406] Preferably, the emulsifier, such as a nonionic emulsifier, may be selected from the group consisting of saturated fatty acid derivatives, lecithin, or polysorbate esters. The fatty acids may be saturated or unsaturated. More preferably, the nonionic emulsifier comprises one or both of at least one unsaturated fatty acid (such as oleic acid and / or linoleic acid) and optionally at least one saturated fatty acid (such as palmitic acid and / or stearic acid) or a polysorbate ester.

[0407] More preferably, the emulsifier, such as a nonionic emulsifier, is selected from the group consisting of saturated or unsaturated fatty acids and polysorbate esters. More preferably, the emulsifier, such as a nonionic emulsifier, comprises (i) one or two of at least one unsaturated fatty acid (such as oleic acid and / or linoleic acid) and optionally at least one saturated fatty acid (such as palmitic acid and / or stearic acid) and (ii) a polysorbate ester. The polysorbate ester is a polyethoxylated ester of sorbitol, dehydrated sorbitol, and isosorbide. Preferred saturated fatty acid derivatives include sucrose esters of saturated fatty acids; mono-, di-, or triglycerides of saturated fatty acids; or dehydrated sorbitol esters of saturated fatty acids.

[0408] The one or more emulsifiers may be present in the polymeric material in a total amount of about 0.1% to 10% by weight. Preferably, the one or more emulsifiers are present in a total amount of about 1% to 5% by weight, more preferably about 2% to 4% by weight.

[0409] In one embodiment, the polymeric material may further contain water. The water may be present in the polymeric material in an amount less than or equal to about 15% by weight, particularly from about 0.1% by weight to 15% by weight. Typically, the polymeric material may further contain about 3% by weight to 12% by weight, preferably about 5% by weight to 10% by weight, of water.

[0410] In one embodiment, the polymeric material may further comprise one or more optional components selected from the group consisting of colorants, gelling agents, flavoring agents, sweeteners, acidifiers, antioxidants, solubilizers, and chelating agents.

[0411] Suitablely, the gelling agent may be an aqueous colloidal adhesive.

[0412] Other components of the polymeric material, such as some types of water-soluble film-forming polymers like polyvinylpyrrolidone and certain polysaccharides like hydroxypropyl cellulose, may exhibit gelation. For the purposes of this disclosure, when a gelling agent is present as an optional additional component of the polymeric material, it is considered separate from and independent of any other component that may exhibit gelling behavior.

[0413] The flavoring agent may be selected from the group consisting of menthol, peppermint and alkyl alkyl esters, wherein the alkyl group may be straight-chain or branched and may contain 1 to 8 carbon atoms, and the alkyl group may contain 1 to 5 carbon atoms.

[0414] The sweetener may be selected from one or more of the group consisting of aspartame, acesulfame K, sucralose, cyclamate, erythritol, mannitol, sorbitol, stevia, and xylitol.

[0415] The acidifying agent can be any suitable inorganic acid. Suitably, the acidifying agent can be any one of phosphoric acid, sulfuric acid, hydrochloric acid, or nitric acid. In one embodiment, the acidifying agent is phosphoric acid. In one embodiment, the acidifying agent is sulfuric acid. In one embodiment, the acidifying agent is hydrochloric acid. In another embodiment, the acidifying agent is nitric acid.

[0416] The acidifying agent can be any suitable organic acid. Suitably, the acidifying agent can be any one of malic acid, lactic acid, acetic acid, or citric acid. In one embodiment, the acidifying agent is malic acid. In one embodiment, the acidifying agent is lactic acid. In one embodiment, the acidifying agent is acetic acid. In another embodiment, the acidifying agent is citric acid.

[0417] The antioxidant may be one or more selected from the group consisting of tocopherol (vitamin E), tert-butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene, and ethylenediaminetetraacetic acid or their salts.

[0418] Suitably, in some embodiments, the polymeric material comprises pullulan, polyvinylpyrrolidone or polyvinyl acetate, glycerol, polysorbate 80, calcium or a calcium ion source, and a phosphopeptide. Suitably, the phosphopeptide is OPN or a phosphopeptide derived therefrom, or casein or a phosphopeptide derived therefrom. In some embodiments, the polymeric material comprises pullulan, polyvinylpyrrolidone or polyvinyl acetate, glycerol, polysorbate 80, and any compositions described herein for use in the invention.

[0419] In one embodiment, the polymeric material comprises pullulan, glycerol, polysorbate 80, calcium or a calcium ion source, and OPN or a phosphopeptide derived therefrom. Suitably, in such an embodiment, the polymeric material is a soluble polymer film.

[0420] In one embodiment, the polymeric material comprises pullulan, glycerol, polysorbate 80, calcium or a calcium ion source, and casein or a phosphopeptide derived therefrom. Suitably, in such an embodiment, the polymeric material is a soluble polymer film.

[0421] In another embodiment, the polymeric material comprises polyvinylpyrrolidone, glycerol, polysorbate 80, calcium or a calcium ion source, and OPN or a phosphopeptide derived therefrom. Suitably, in such an embodiment, the polymeric material is a soluble polymer film.

[0422] In another embodiment, the polymeric material comprises polyvinylpyrrolidone, glycerol, polysorbate 80, calcium or a calcium ion source, and casein or a phosphopeptide derived therefrom. Suitably, in such an embodiment, the polymeric material is a soluble polymer film.

[0423] In another embodiment, the polymeric material comprises polyvinyl acetate, glycerol, polysorbate 80, calcium or a calcium ion source, and OPN or a phosphopeptide derived therefrom. Suitably, in such an embodiment, the polymeric material is a soluble polymer film.

[0424] In another embodiment, the polymeric material comprises polyvinyl acetate, glycerol, polysorbate 80, calcium or a calcium ion source, and casein or a phosphopeptide derived therefrom. Suitably, in such an embodiment, the polymeric material is a soluble polymer film.

[0425] In one embodiment, the polymeric material comprises pullulan, glycerol, polysorbate 80, and a composition comprising phosphopeptides. In another embodiment, the polymeric material comprises polyvinylpyrrolidone, glycerol, polysorbate 80, and a composition comprising phosphopeptides. In yet another embodiment, the polymeric material comprises polyvinyl acetate, glycerol, polysorbate 80, and a composition comprising phosphopeptides.

[0426] In some cases, it may be desirable to use an insoluble material comprising calcium or a calcium source and phosphopeptides as described herein (e.g., phosphopeptides such as OPN, casein, or phosphopeptides derived therefrom). In some embodiments, it may also be desirable to use an insoluble membrane comprising any composition containing phosphopeptides as described herein and suitable for use in this invention. Insoluble membranes are known in the art. Such insoluble membranes may include those containing water, glycerol, hydrogen peroxide, carbomer, polyvinylpyrrolidone (PVP), PEG (wetting agent), acrylate copolymers, sodium hydroxide, sodium saccharin, and polypropylene.

[0427] In some embodiments, the polymeric material is a dental polymer membrane. The thickness range of the film or membrane of the present invention can be: about 50 μm to about 500 μm, about 50 μm to about 250 μm, about 50 μm to about 100 μm, or about 100 μm to about 200 μm.

[0428] In some cases, it may be desirable to provide a thicker film. Suitably, in some embodiments, the thickness range of the film or membrane of the present invention can be:

[0429] Approximately 10 to 1,000 µm.

[0430] In one embodiment, the polymeric material comprises 65% w / w PVP, 3% w / w plasticizer, 2% w / w emulsifier, 5% w / w water, 3.08% w / w calcium chloride, and 21.92% w / w osteopontin or phosphopeptides derived therefrom.

[0431] In one embodiment, the polymeric material comprises 65% w / w PVP, 3% w / w plasticizer, 2% w / w emulsifier, 5% w / w water, 3.08% w / w calcium chloride, and 21.92% w / w casein or phosphopeptides derived therefrom.

[0432] In one embodiment, the polymeric material comprises 80% w / w PVP, 10% w / w plasticizer, 4% w / w emulsifier, 5% w / w water, 0.12% w / w calcium chloride, and 0.88% w / w osteopontin or phosphopeptides derived therefrom.

[0433] In one embodiment, the polymeric material comprises 80% w / w PVP, 10% w / w plasticizer, 4% w / w emulsifier, 5% w / w water, 0.12% w / w calcium chloride, and 0.88% w / w casein or phosphopeptides derived therefrom.

[0434] In some embodiments, the polymeric material is dental floss. Dental floss is typically made of waxed polytetrafluoroethylene, but can also be made of any suitable material known in the art. In some embodiments, the polymeric material is dental floss comprising any composition as described herein.

[0435] In one embodiment, the polymeric material is dental floss containing 22% OPN or phosphopeptides derived therefrom and 3% calcium source, preferably calcium chloride. In one embodiment, the dental floss contains 3% OPN or phosphopeptides derived therefrom and 0.4% calcium source, preferably calcium chloride. In one embodiment, the dental floss contains 9% OPN or phosphopeptides derived therefrom and 1.27% calcium source, preferably calcium chloride. In one embodiment, the dental floss contains 21.92% casein or phosphopeptides derived therefrom and 3.08% calcium source, preferably calcium chloride. In one embodiment, the dental floss contains 22% casein or phosphopeptides derived therefrom and 3% calcium source, preferably calcium chloride. In one embodiment, the dental floss contains 3% casein or phosphopeptides derived therefrom and 0.4% calcium source, preferably calcium chloride. In one embodiment, the dental floss contains 9% casein or phosphopeptides derived therefrom and 1.27% calcium source, preferably calcium chloride. Suitablely, in some embodiments, the dental floss may further contain fluoride or a fluoride source, such as monofluorophosphate.

[0436] It should be understood that polymeric materials comprising the compositions used in this invention, or polymeric materials comprising OPN or phosphopeptides derived therefrom, OPN or phosphopeptides derived therefrom, and calcium or a calcium ion source, casein or phosphopeptides derived therefrom, or casein or phosphopeptides derived therefrom, and calcium or a calcium ion source, are suitable for any aspect or embodiment described herein.

[0437] Suitablely, in one aspect, a polymeric material comprising phosphopeptides is provided for the prevention or treatment of gingival bleeding in a subject.

[0438] Suitablely, on the other hand, a polymeric material comprising phosphopeptides is provided for the prevention or treatment of periodontal disease in subjects who require it.

[0439] Suitablely, in another aspect, a polymeric material comprising phosphopeptides is provided for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in subjects with such need.

[0440] Suitably, in another aspect, a polymeric material comprising a phosphopeptide is provided for the prevention or treatment of tooth sensitivity in a subject with this need. Suitably, in some embodiments, the tooth sensitivity is dentin hypersensitivity. Suitably, in some embodiments, the phosphopeptide is OPN or a phosphopeptide derived therefrom. Suitably, in some embodiments, the phosphopeptide is casein or a phosphopeptide derived therefrom. Suitably, in some embodiments, the polymeric material further comprises calcium or a calcium source. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom and calcium or a calcium source. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and calcium or a calcium source. Suitably, in some embodiments, the polymeric material comprises any of the compositions described herein. Suitably, in some embodiments, the polymeric material comprises a MOL composition. Suitably, in some embodiments, the polymeric material comprises a MON composition. Suitably, in some embodiments, the polymeric material comprises a MOK composition; suitably, in some embodiments, the polymeric material comprises a MOG composition.

[0441] Suitably, in another aspect, a polymeric material comprising a phosphopeptide is provided for the prevention or treatment of leukoplakia in a subject with this need. Suitably, in some embodiments, the phosphopeptide is OPN or a phosphopeptide derived therefrom. Suitably, in some embodiments, the phosphopeptide is casein or a phosphopeptide derived therefrom. Suitably, in some embodiments, the polymeric material further comprises calcium or a calcium source. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom and calcium or a calcium source. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and calcium or a calcium source. Suitably, in some embodiments, the polymeric material comprises any of the compositions described herein. Suitably, in some embodiments, the polymeric material comprises a MOL composition. Suitably, in some embodiments, the polymeric material comprises a MOK composition. Suitably, in some embodiments, the polymeric material comprises a MON composition; suitably, in some embodiments, the polymeric material comprises a MOG composition.

[0442] Those skilled in the art will understand that "carious white spots" are white, opaque deposits seen on teeth after the subsurface enamel has been demineralized, but the demineralized inner enamel remains beneath the remineralized outer enamel. This may be an early sign of tooth decay due to poor oral hygiene and the accumulation of plaque, bacteria, and acid on the teeth.

[0443] On the other hand, polymeric materials comprising OPN or phosphopeptides derived therefrom are provided for the prevention or treatment of gingival bleeding in a subject. Suitably, in some embodiments, the polymeric material comprises OPN or phosphopeptides derived therefrom, and calcium or a calcium source, for the prevention or treatment of gingival bleeding in a subject.

[0444] On the other hand, a polymeric material comprising OPN or a phosphopeptide derived therefrom is provided for the prevention or treatment of periodontal disease in a subject with this need. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom, and calcium or a calcium source, for the prevention or treatment of periodontal disease in a subject with this need.

[0445] On the other hand, a polymeric material comprising OPN or a phosphopeptide derived therefrom is provided for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with this need. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom, as well as calcium or a calcium source, for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject.

[0446] On the other hand, polymeric materials comprising casein or phosphopeptides derived therefrom are provided for the prevention or treatment of gingival bleeding in a subject. Suitably, in some embodiments, the polymeric material comprises casein or phosphopeptides derived therefrom, and calcium or a calcium source, for the prevention or treatment of gingival bleeding in a subject.

[0447] On the other hand, a polymeric material comprising casein or a phosphopeptide derived therefrom is provided for the prevention or treatment of periodontal disease in a subject with this need. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and calcium or a calcium source for the prevention or treatment of periodontal disease in a subject with this need.

[0448] On the other hand, a polymeric material comprising casein or a phosphopeptide derived therefrom is provided for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject with this need. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom, and calcium or a calcium source, for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in a subject.

[0449] As described above, the polymeric materials described herein can also be used in any method according to any aspect or embodiment described herein.

[0450] WO2022013552 describes compositions comprising the phosphopeptides described herein for remineralization and prevention of demineralization of oral surfaces. Suitably, in another aspect of the invention, a polymeric material is provided comprising a composition comprising the phosphopeptides described herein for remineralization or prevention of demineralization of oral surfaces. In another aspect of the invention, a polymeric material comprising phosphopeptides is provided for remineralization or prevention of demineralization of oral surfaces. In another aspect of the invention, a polymeric material comprising phosphopeptides and calcium or a calcium source is provided for remineralization or prevention of demineralization of oral surfaces. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom for remineralization or prevention of demineralization of oral surfaces. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom and calcium or a calcium source for remineralization or prevention of demineralization of oral surfaces. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom, and calcium or a calcium source, for remineralization or prevention of demineralization of the oral surface. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom, and calcium or a calcium source, for remineralization or prevention of demineralization of the oral surface. Suitably, in some embodiments, the oral surface is enamel erosion damage. Suitably, in some embodiments, the oral surface is enamel caries damage.

[0451] WO2023285797 describes compositions comprising the phosphopeptides described herein for the prevention or treatment of tooth sensitivity. Suitably, in another aspect of the invention, a polymeric material comprising a composition comprising the phosphopeptides described herein for the prevention or treatment of tooth sensitivity is provided. Suitably, in some embodiments, the polymeric material comprises the phosphopeptides and calcium or a calcium source for the prevention or treatment of tooth sensitivity. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom for the prevention or treatment of tooth sensitivity. Suitably, in some embodiments, the polymeric material comprises OPN or a phosphopeptide derived therefrom and calcium or a calcium source for the prevention or treatment of tooth sensitivity. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and calcium or a calcium source for the prevention or treatment of tooth sensitivity. Suitably, in some embodiments, the polymeric material comprises casein or a phosphopeptide derived therefrom and calcium or a calcium source for the prevention or treatment of tooth sensitivity.

[0452] application

[0453] In any aspect of the invention described herein, suitably, the composition is applied to the oral cavity of a subject in need. In any aspect of the invention described herein, suitably, the polymeric material is applied to the oral cavity of a subject in need. Alternatively, or otherwise, the composition or polymeric material may be applied to devices such as dental implants, alignment devices, retainers, oral trays, and / or protective dentures. Suitably, after the composition or polymeric material is applied to the device, the device is placed in the subject's mouth. Those skilled in the art will understand that the following embodiments describing the application of the composition can also be applied to the application of the polymeric material described herein.

[0454] In some embodiments, the composition is administered to a subject for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, or at least 15 days. Suitably, in some embodiments, the composition is administered continuously for several days. Alternatively, in some embodiments, the composition is administered discontinuously for several days. In some aspects, the composition is administered to a subject at least once a day, at least twice a day, at least three times a day, at least four times a day, or at least five times a day. In some embodiments, the composition is administered orally to a subject at least once a day, at least twice a day, at least three times a day, at least four times a day, or at least five times a day. In some embodiments of the invention, the composition is administered once or twice daily for at least 5 days. In some embodiments of the invention, the composition is administered five times daily for at least 14 days.

[0455] Suitably, the composition can be applied to the oral cavity of a subject after eating or drinking. Suitably, in some embodiments, the composition can be applied to such a device before the orthotherm, retainer, oral tray, and / or protective denture are returned to the oral cavity after eating or drinking.

[0456] Suitablely, the composition can be applied during the day or at night. In some embodiments, the composition is applied before bedtime. Suitable specific application procedures are discussed in the relevant sections above.

[0457] In some embodiments, the composition is used as an adjunct to routine oral care procedures. In some embodiments, the composition is applied before or after brushing with toothpaste. Suitably, in some embodiments, the composition is used before or after interdental cleaning such as flossing. Suitably, in some embodiments, the composition is applied by a dental clinician / professional. Suitably, in some embodiments, the composition is applied directly to the demineralized tooth surface by a dental clinician / professional. Suitably, in some embodiments, the composition is applied to the subgingival region. Suitably, in some embodiments, the composition is applied to the periodontal pocket. Suitably, in some embodiments, the composition is applied to the periodontal pocket using a biodegradable delivery system. A biodegradable delivery system includes any biodegradable dental drug delivery system known in the art. Such a biodegradable delivery system may include any soluble material suitable for delivering an active agent to the oral cavity. Biodegradable delivery systems include, but are not limited to, biodegradable dental chips (e.g., gelatin-based chips), hydrogels, and polymer sheets, such as those of the present invention. In some embodiments, the biodegradable delivery system used in the present invention is a gelatin-based chip. In another embodiment, the biodegradable delivery system is a hydrogel. In another embodiment, the biodegradable delivery system is a polymer sheet, preferably the polymer sheet of the present invention. In some embodiments, the biodegradable delivery system comprises gelatin, glutaraldehyde, glycerol, and water in combination with any of the compositions described herein. Suitably, in some embodiments, the biodegradable delivery system comprises a composition containing phosphopeptides, optionally wherein the phosphopeptide is osteopontin or a phosphopeptide derived therefrom. In another embodiment, the biodegradable delivery system comprises a composition containing phosphopeptides, optionally wherein the phosphopeptide is casein or a phosphopeptide derived therefrom. Suitably, in some embodiments, the biodegradable delivery system may comprise a combination of any of the compositions described herein with gelatin. In one embodiment, a composition for use in the present invention is provided, comprising osteopontin or a phosphopeptide derived therefrom and gelatin, preferably the composition comprising OPN-10. Suitably, in some embodiments, the composition may further comprise a calcium source. In one embodiment, a composition for use in the present invention is provided, comprising casein or a phosphopeptide derived therefrom and gelatin. Suitablely, in some embodiments, the composition may further comprise a calcium source.

[0458] In some embodiments, the composition is applied before, during, or after a dental procedure. In such embodiments, the procedure may include mechanical cleaning, periodontal irrigation, plaque removal, orthodontic procedures, and / or dental surgery. Suitably, in some embodiments, dental surgery includes procedures used for the treatment of periodontal disease, such as periodontal pocket reduction surgery, soft tissue grafts and / or bone grafts, and dental implants. In some embodiments, the composition is applied before, during, or after root surface debridement.

[0459] In some embodiments, the compositions described herein can be applied directly to periodontal pockets. Suitably, in some embodiments, the composition is a gel composition. Suitably, in some embodiments, the composition is a serum composition. Suitably, in some embodiments, the composition is a colloidal composition. Suitably, in some embodiments, the composition is a liquid composition. In some embodiments, the polymeric material can be applied directly to periodontal pockets.

[0460] In some embodiments, the composition is applied by rinsing. Suitably, the composition is a liquid composition.

[0461] In some embodiments, the composition is applied to the periodontal pocket using a syringe. Suitably, in such embodiments, the composition is preferably a liquid or gel formulation.

[0462] In some embodiments, the composition is applied to periodontal pockets using dental instruments. Suitably, in such embodiments, the composition is preferably a colloid, liquid, or gel formulation.

[0463] Those skilled in the art will understand that additional delivery systems or application routes can be used to administer the compositions described herein for any aspect of the invention. Suitably, in some embodiments, it is desirable to apply the compositions to food. The term "food" should be understood to mean any material, substance, etc., that can be used as food or used in food. Non-limiting examples of food may be chewing gum (e.g., chewing gum, chewing tablets, or candy), mints and tablets, powders, etc. Suitably, in one embodiment, the compositions of the invention are provided in the form of chewable chewing gum or candy. Suitably, in a preferred embodiment, the chewable chewing gum or candy contains OPN or phosphopeptides derived therefrom and / or calcium or a calcium source. Suitably, in a preferred embodiment, the chewable chewing gum or candy contains casein or phosphopeptides derived therefrom and / or calcium or a calcium source.

[0464] Treatment subjects / patient groups

[0465] In some embodiments of various aspects of the present invention, the composition is administered to a subject or patient selected from one or more of the following groups:

[0466] - Patients with periodontal disease who do not respond or respond poorly to conventional treatment;

[0467] - Patients with gingivitis who do not respond or respond poorly to conventional treatment;

[0468] - Patients with gingivitis who do not respond or respond poorly to routine oral hygiene procedures (such as daily home care brushing and flossing);

[0469] - Patients with periodontitis who do not respond or respond poorly to conventional treatment;

[0470] - Patients with periodontitis who do not respond or respond poorly to routine oral hygiene procedures (such as daily home care brushing and flossing);

[0471] - Patients with established periodontal disease, gingivitis, periodontitis, peri-implantitis, or peri-implant mucositis;

[0472] - Patients with dry mouth who have an increased risk of periodontal disease;

[0473] - Patients who smoke or use e-cigarettes

[0474] -Patients with disabilities or limited mobility who find routine oral hygiene procedures difficult;

[0475] -Patients wearing partial dentures

[0476] - Orthodontic patients - Fixed or removable appliances, clear aligners, or retainers

[0477] - Diabetic patients with an increased risk of periodontal disease and whose condition is difficult to stabilize;

[0478] - Patients with root bifurcation damage;

[0479] - Patients with non-reactive sites (such as sites that are harder to reach when brushing or cleaning between teeth, or sites where bleeding cannot be controlled).

[0480] - Patients with compromised immune systems

[0481] - Patients with inflammatory diseases, such as metabolic and systemic diseases, including cardiovascular diseases, Alzheimer's disease, rheumatic conditions, respiratory conditions, including hospitalized patients with aspiration pneumonia and colorectal cancer.

[0482] Impaired patients may include, but are not limited to, patients whose immune systems are weakened due to specific health conditions or due to drugs or treatments that suppress the immune system. Suitablely, in some implementations, impaired patients may include patients receiving chemotherapy, patients receiving immunosuppressive drugs (such as corticosteroids, biologics, monoclonal antibody therapy, cell therapy (such as T-cell therapy), and kinase inhibitors), HIV patients, cancer patients, and patients with autoimmune conditions.

[0483] Surprisingly, the compositions described herein have been found to be effective in treating established periodontal disease that is difficult to cure with conventional treatments, including those involving the removal of biofilm and elimination of bacteria. Suitably, poor response to conventional treatment may include the inability to stabilize and / or improve the disease. The stabilization, progression, and improvement of the disease have been discussed above. In some embodiments, gingival bleeding is treated in patients with established or chronic periodontal disease, for example, to reduce or eliminate symptoms. In some embodiments, gingival bleeding is treated in patients with acute gingival disease, for example, to reduce or eliminate symptoms. Acute gingival disease includes, but is not limited to, patients with acute neuroulcerative gingivitis (ANUG). ANUG can occur in patients with poor immune responses caused by stress, smoking, and poor plaque control. Suitably, in some embodiments of any aspect, periodontal disease is acute gingival disease. In some embodiments of any aspect, periodontal disease is acute neuroulcerative gingivitis.

[0484] Established or chronic diseases can be those that have existed for 1 month, 2 months, 3 months, 6 months, 12 months, or 24 months or longer.

[0485] Package

[0486] In one aspect of the invention, packaging comprising a composition according to any aspect of the invention is provided.

[0487] Suitably, the packaging comprises the composition of the present invention. Suitably, the packaging is also operable to suitably deliver the composition of the present invention to the oral cavity surface. Suitably, the packaging may comprise a container to hold the composition. Suitably, the packaging may further comprise an applicator or actuator.

[0488] Suitably, the packaging may include an actuator. Suitably, upon actuation of the actuator, the composition is discharged from the packaging, suitably from the container of the packaging. Suitably, the actuator is operable when actuated to deliver a measured amount of the composition. Suitably, the measured amount is a suitable quantity of the composition to achieve the desired effect. Suitably, the measured amount is a quantity suitable for the subject's oral cavity, for example, between 0.1 ml and 5 ml.

[0489] Suitable actuators may include nozzles. Suitably, when the nozzle is actuated, droplets of the composition are expelled from the packaging.

[0490] Suitably, the packaging may further contain a propellant, which suitably aids in discharging the composition from the packaging. Suitably, in such an embodiment, the nozzle is an atomizing nozzle.

[0491] In one embodiment, the package includes a nozzle. Suitably, in such an embodiment, the package may be referred to as a "spray pack". Suitably, in such an embodiment, the composition is an oral spray.

[0492] In some embodiments, the packaging comprises an oral film containing the composition described herein. Suitably, in some embodiments, the oral film is a polymer oral film. In some embodiments, the oral film is impregnated with the composition described herein.

[0493] It should be understood that liquid formulations such as mouthwash can be packaged in commonly used, suitable packaging (such as bottles, typically plastic or glass). In contrast, colloidal compositions such as pastes or gels are typically in collapsible tubes.

[0494] Embodiments of the invention will now be described by way of non-limiting examples with reference to the accompanying drawings. Attached Figure Description

[0495] Figure 1 Summary of a 14-day consumer orthodontic aligner trial using Toothboost. Data represent the mean Likert scores for each dental health issue at baseline and 14 days after using the Toothboost MOL formulation.

[0496] Figure 2: Bleeding index chart. (A) Pre-trial bleeding index of patient 1 with stage 3 extensive periodontitis. (B) Post-trial index of patient 1 after 14 days of daily treatment with Toothboost MOL preparation. A dot represents a bleeding point.

[0497] Figure 3: Bleeding index chart. (A) Pre-trial bleeding index of patient 2 with stage 4 extensive periodontitis. (B) Post-trial bleeding index of patient 2 after 14 days of daily treatment with Toothboost MOL preparation. (C) Follow-up bleeding index of patient 2 14 days after discontinuation of Toothboost treatment. (D) Follow-up bleeding index of patient 2 3 months after treatment with Toothboost. A dot represents a bleeding point.

[0498] Figure 4: Bleeding scores after a 3-week trial using Toothboost oral spray (MOL formulation). (A) Bleeding indices before and after the trial for Patient 1 with stage 3 B stable periodontitis and Patient 2 with stage 2 / 3 A currently stable periodontitis; (B) Bleeding scores (%) of patients after a 3-week trial using Toothboost oral spray (N = 10).

[0499] Figure 5: Bleeding scores after a 3-week trial using Toothboost oral spray (MOL formulation) in dental implant patients. (A) Bleeding index before and after the trial in patients with stage 2 grade A upper left 1 and 4 currently stable implants; (B) Bleeding score (%) of patients after a 3-week trial using Toothboost oral spray (N = 10).

[0500] Figure 6 (A) Enamel hardness after treatment with polymer films containing 3% OPN and 0.43% calcium chloride (standard formulation), 3% OPN, 0.43% calcium chloride, and 0.38% sodium monofluorophosphate (standard formulation + F), 9% OPN and 1.27% calcium chloride (3X Toothboost formulation), 9% OPN, 1.27% calcium chloride, and 0.38% sodium monofluorophosphate (3X Toothboost formulation + F), or polymer films without surfactant (placebo). N = 10 samples per group. Detailed Implementation

[0501] Although the preparation and use of various embodiments of the present invention are discussed in detail below, it should be understood that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific environments. The specific embodiments discussed herein are merely illustrative of specific ways of preparing and using the present invention and do not limit the scope of the invention.

[0502] To facilitate understanding of this invention, several terms are defined below. The terms defined herein have meanings commonly understood by one of ordinary skill in the art related to this invention. Terms such as “an,” “a,” and “the” are not intended to refer to a single entity, but rather to encompass general categories that can be illustrated using specific examples. The terms herein are used to describe specific embodiments of the invention, but their use does not limit the invention unless set forth in the claims.

[0503] The term “about” as used in this article may refer to + / -20%, + / -15% or + / -10% of the recorded value, appropriately + / -10% of the recorded value.

[0504] As used herein, the terms “treatment” or “manipulation” can refer to the reduction, improvement, or elimination of one or more signs, symptoms, or effects of a disease or condition. As used herein, “treatment” includes any treatment of diseases in mammals, particularly humans, including: (a) preventing the occurrence or recurrence of disease in subjects who are susceptible to the disease or at risk of developing it but have not yet been diagnosed with the disease; (b) suppressing the disease, i.e., preventing its development; and (c) alleviating the disease, i.e. causing its remission.

[0505] As used herein, the term “prevention” or “avoidance” can mean stopping, suppressing, or reducing one or more signs, symptoms, or effects of a disease or condition. As used herein, “prevention” includes: (a) preventing a subject who is susceptible to or at risk of developing a disease but has not yet been diagnosed with a disease from developing the disease; and (b) suppressing the disease, i.e., preventing its development.

[0506] The term "remission" as used in this article can refer to the reduction or disappearance of one or more signs, symptoms, or effects of a disease or condition. Remission can be considered partial or complete. Complete remission, also known as total remission, refers to the complete disappearance of the signs and symptoms of the disease. Partial remission may include a reduction in the signs, symptoms, or effects of the disease or condition.

[0507] As used herein, the term “application” can refer to introducing or delivering the composition to a subject by any means to achieve its intended function.

[0508] As used herein, the term "subject" may be used interchangeably with "individual" or "patient," and unless otherwise stated, refers to any individual subject suffering from a disease or condition requiring prevention or treatment. For the purposes of this disclosure, the subject may be a mammal, preferably a human or livestock animal such as a dog, cat, or horse.

[0509] The term “Toothboost” is used in certain places in the embodiments herein to describe liquid compositions according to the invention, such as “MOK” prepared in Example 1 or “MOL” prepared in Example 2. “MOK” refers to a liquid formulation containing phosphate in the form of a phosphate buffer.

[0510] The term "Boostpaste" is used in certain places in the embodiments herein to describe the paste compositions according to the invention, such as "MON" prepared in Example 3.

[0511] The term “MOG” as used herein describes gel compositions, such as the gel composition prepared in Example 4.

[0512] The term "established periodontitis" can refer to any stage or grade of periodontitis described herein that is present in a subject prior to treatment with any of the compositions described herein. Those skilled in the art will understand that, in some embodiments, established periodontitis can be defined as manifested clinical attachment loss. In some embodiments, established periodontitis can be defined as the presence of periodontal pockets. Alternatively, in some embodiments, established periodontitis can be defined as clinical attachment loss of at least 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm in at least one or more teeth. In some embodiments, established periodontitis can be defined as the presence of the aforementioned clinical attachment loss and the presence of at least one or more periodontal pockets. Staging or grading of periodontitis will not improve post-clinical or therapeutic treatment, as this documents the interproximal bone loss to date. However, stabilization and / or remission can prevent further alveolar bone loss.

[0513] Gingivitis is characterized by swollen and red gums. Gingivitis can be defined as localized or widespread. The British Society of Periodontology (BSP) clinically defines localized gingivitis as bleeding on probing in >10%-30% of the gums. Widespread gingivitis is clinically defined as bleeding on probing in >30% of the gums.

[0514] The term "peri-implant mucositis" can refer to an inflammatory condition of the soft tissue surrounding an intraosseous implant in the absence of supporting bone loss or persistent marginal bone loss.

[0515] The term "peri-implantitis" refers to a more severe form of peri-implant disease characterized by inflammation, abscesses, and bone loss around an osseointegrated dental implant.

[0516] The term "pathogenic bacteria" as used in this article refers to any kind of bacteria that may cause or contribute to periodontal disease. Technicians will understand that pathogenic bacteria do not include symbiotic bacteria, i.e., those beneficial to a healthy oral microenvironment. The types of pathogenic bacteria may include, but are not limited to, *Porphyromonas gingivalis*, *Tannerella forsythia*, *Treponema denticola*, *Filifactoralocis*, *Porphyromonas*, Synergistetes, Peptostreptococcaceae, and *Actinomyces actinomycetemcomitans*.

[0517] The term "non-responder" as used herein can refer to any subject who does not respond to conventional therapies or treatments. Those skilled in the art will understand that a non-responder includes subjects who do not respond to conventional therapies or treatments or who partially respond to them. For example, in the context of this invention, a non-responder may include a subject with periodontal disease in which any of conventional therapies or treatments, such as mechanical plaque removal, deep cleaning of gingival tissue, or application of antimicrobial agents such as antibiotics and chlorhexidine solutions, fails to improve or treat the periodontal disease. Suitable examples of non-responders include, but are not limited to, subjects with compromised immunity, subjects with autoimmune conditions, subjects whose plaque cannot be controlled by routine oral hygiene procedures, subjects with multiple risk factors such as diabetes, subjects with non-responder sites, and subjects with root bifurcation damage.

[0518] The term "unresponsive site" can refer to a site of unresolved periodontal disease in the mouth, or a site that remains unstable during routine therapy or treatment. These sites may be more difficult to access when brushing or cleaning between teeth because routine therapy and treatment must be supported by daily oral hygiene procedures.

[0519] As used herein, the term "biofilm" refers to a microbial community in which cells adhere to each other on the oral cavity surface. These adherent cells are typically embedded in a self-produced matrix of extracellular polymeric substances. Those skilled in the art will understand that the term oral biofilm is used interchangeably with the term "dental plaque."

[0520] Example 1—A liquid composition comprising phosphoproteins, phosphates, and fluorides—“MOK”

[0521] The recipe for MOK is as follows:

[0522]

[0523] To prepare the flavoring system of intermediate A:

[0524] 1. Mix phenoxyethanol with the flavoring oil.

[0525] 2. Cocamidopropyl betaine is dispersed into the solution by mixing.

[0526] 3. Mix saccharin, methylparaben, and deionized water until the solution is clear.

[0527] 4. Quickly add this solution to the cocamidopropyl betaine suspension and stir. After about an hour, it will be a clear, straw-colored solution.

[0528] In order to prepare the finished product:

[0529] 1. Add 2 / 3 of the total volume of deionized water to 3.0% w / w OPN-10 and mix rapidly for two hours until the solution is clear.

[0530] 2. Add 1M calcium chloride at a rate of 0.3 ml / min while stirring rapidly.

[0531] 3. Add trisodium phosphate and disodium hydrogen phosphate to the OPN-10 solution at a rate of 0.4 g / min.

[0532] 4. Add the monofluorophosphate solution prepared by dissolving MFP to 1 / 3 of the total volume of deionized water. Add it back to the OPN solution at a rate of 0.2 ml / min. This will result in a very slightly turbid, pale yellow / white solution.

[0533] 5. Add sodium bicarbonate solution at a rate of 0.3 ml / min, and maintain the pH at 7.5 ± 0.3 with 1M HCl / 1M NaOH.

[0534] 6. Add intermediate A to the OPN solution at a rate of 0.2 ml / min while stirring rapidly. This will yield a clear solution.

[0535] 7. Add 5.0% w / w xylitol.

[0536] 8. Adjust the pH of the solution to 7.5.

[0537] 9. Add deionized water to bring the total to 100.0g.

[0538] After 10.24 hours, it is filtered through a 0.22µm sterile filter.

[0539] If a single transfer tube is used for reagents, it must be thoroughly cleaned before adding each reagent.

[0540] Example 2—A liquid composition containing phosphoproteins (phosphate-free)—“MOL”

[0541]

[0542]

[0543] Manufacturing of flavoring system intermediate A.

[0544] 1. Mix phenoxyethanol with the flavoring oil.

[0545] 2. When the solution is clear, disperse cocamidopropyl betaine into the solution and mix until completely dispersed.

[0546] 3. Mix saccharin and methylparaben into deionized water and mix until dissolved.

[0547] 4. Quickly add the saccharin mixture to the cocamidopropyl betaine suspension and stir. After about an hour, it will be a clear, straw-colored solution.

[0548] Manufacturing of the finished product (100g).

[0549] 1. Add 49g of deionized water and 3.0g of OPN to a beaker and stir for two hours.

[0550] 2. Add calcium solution.

[0551] 3. Mix MFP with 5 ml of deionized water, add it to the bicarbonate solution, add xylitol, and stir until dissolved.

[0552] 4. Add sodium bicarbonate.

[0553] 5. Add intermediate A.

[0554] 6. Add HCl solution.

[0555] 7. Check and adjust the pH after 24 hours.

[0556] 8. Filtered through a 0.2µm sterile filter.

[0557] Except for the absence of monofluorophosphate (MFP), phosphate-free and fluoride-free formulations of MOL can be prepared with the same components in the same manner as detailed above, as shown in the table above.

[0558] Example 3—Paste Composition Containing Phosphoproteins (Phosphate-Free) – “MON”

[0559]

[0560]

[0561] Manufacturing of flavoring system intermediate A.

[0562] 1. Mix phenoxyethanol with the flavoring oil.

[0563] 2. When the solution is clear, disperse cocamidopropyl betaine into the solution and mix until completely dispersed.

[0564] 3. Mix saccharin and methylparaben into deionized water and mix until dissolved.

[0565] 4. Quickly add the saccharin mixture to the cocamidopropyl betaine suspension and stir. After about an hour, it will be a clear, straw-colored solution.

[0566] Manufacturing of the finished product (100g).

[0567] 1. Add deionized water, 1M HCl and OPN, and stir for 30 min.

[0568] 2. Add sodium bicarbonate, calcium, Zeofree silica and triboelectric silica, MFP and mannitol.

[0569] 3. Mix with a high-shear mixer until fully dispersed.

[0570] 4. Add intermediate A.

[0571] 5. Mix in xanthan gum.

[0572] 6. Prepare a 25% suspension by taking 2g of the paste and check the pH. Adjust to 7.0 if necessary.

[0573] Except for the absence of monofluorophosphate (MFP), MON's phosphate-free and fluoride-free formulations can be prepared with the same components in the same manner as detailed above, as shown in the table above.

[0574] Example 4—A gel composition containing phosphoproteins (phosphate-free)—“MOG”

[0575]

[0576]

[0577] Manufacturing of flavoring system intermediate A.

[0578] 1. Mix phenoxyethanol with the flavoring oil;

[0579] 2. When the solution becomes clear, disperse cocamidopropyl betaine into the solution and mix until completely dispersed;

[0580] 3. Mix saccharin and methylparaben into deionized water until dissolved;

[0581] 4. Quickly add the saccharin mixture to the cocamidopropyl betaine suspension and stir. After about an hour, it will be a clear, straw-colored solution.

[0582] Manufacturing of the finished product (100g)

[0583] 1. Add deionized water to the OPN and stir;

[0584] 2. Add calcium solution;

[0585] 3. Add sodium bicarbonate;

[0586] 4. Add HCl solution;

[0587] 5. Mix in xylitol;

[0588] 6. Stir until fully dispersed;

[0589] 7. Adjust the pH to 7.2 ± 0.2;

[0590] 8. Add xanthan gum;

[0591] 9. Add intermediate A and mix thoroughly.

[0592]

[0593]

[0594] Manufacturing of flavoring system intermediate A

[0595] 1. Mix phenoxyethanol with the flavoring oil;

[0596] 2. When the solution becomes clear, disperse cocamidopropyl betaine into the solution and mix until completely dispersed;

[0597] 3. Mix saccharin and methylparaben into deionized water until dissolved;

[0598] 4. Quickly add the saccharin mixture to the cocamidopropyl betaine suspension and stir. After about an hour, it will be a clear, straw-colored solution.

[0599] Manufacturing of the finished product (100g)

[0600] 1. Add deionized water to the OPN and stir;

[0601] 2. Add calcium solution;

[0602] 3. Add sodium bicarbonate;

[0603] 4. Add HCl solution;

[0604] 5. Mix in xylitol;

[0605] 6. Mix in MFP;

[0606] 7. Stir;

[0607] 8. Adjust the pH to 7.2 ± 0.2;

[0608] 9. Add xanthan gum;

[0609] 10. Add intermediate A and mix thoroughly.

[0610] Example 5 – Consumer Trial – Orthodontic Aligner Consumer Survey

[0611] introduce

[0612] Online survey of adult orthodontic alignment device patients

[0613] Orthodontic aligners are a common choice for adult patients who seek treatment not only for cosmetic purposes but also to address more serious dental health issues, such as malocclusion, which can eventually lead to oral health complications if left untreated. During treatment periods that typically last 6-24 months, aligner users must wear their aligners for 22 hours a day. Therefore, the inventors conducted a confidential consumer survey to explore the challenges faced by consumers and patients wearing aligners. The consumer survey, which included 37 participants, highlighted several issues, including difficulty cleaning teeth and aligners after eating or drinking, halitosis, dry mouth, and increased sensitivity (Table 1).

[0614] Table 1: Self-reported dental health problems by patients undergoing orthodontic treatment

[0615]

[0616] Orthodontic appliances make effective brushing more difficult because they interfere with brushing and promote the accumulation of plaque (biofilm), leading to quantitative and qualitative changes in the oral microbiota. This increase in periodontal pathogens and cariogenic bacteria can cause side effects such as gingivitis, periodontitis, leukoplakia, tooth decay, and halitosis.

[0617] Based on the findings, a confidential consumer trial (Consumer Trial A) was designed to gain a deeper understanding of the use of the Toothboost composition described herein (i.e., the composition containing phosphopeptides) in consumers receiving orthodontic alignment treatment.

[0618] Orthodontic alignment device consumer Toothboost oral spray test A.

[0619] The Toothboost oral spray mentioned in this embodiment refers to the MOL composition that does not contain phosphates and fluorides, as described in Example 2 above.

[0620] method

[0621] Ten participants were selected to participate in the 14-day Toothboost trial. Patients were provided with the phosphate-free and fluoride-free liquid composition of Toothboost, the MOL formulation described in Example 2.

[0622] Before using Toothboost, participants were asked to complete a dental health questionnaire, identifying which of the following dental problems they were currently experiencing and recording the severity of the problems using a Likert scale from 1 to 7:

[0623] • Bad breath, morning / daytime / nighttime

[0624] Dry mouth

[0625] Bleeding gums

[0626] • Tooth sensitivity, especially when eating, drinking, or brushing.

[0627] A score of 1 indicates that the problem is considered not bad at all and will hardly affect the patient, while a score of 7 indicates that the problem is very bad and will continue to affect the patient.

[0628] Each participant was then given two 15ml bottles of Toothboost oral spray and instructed to use Toothboost daily for 14 days. Participants were told not to change their daily oral care routine or regular dental products. No instructions were given regarding the direct application of the spray before or after brushing. No instructions were given regarding the minimum or maximum recommended daily dosage. Participants were described to be a no-rinse spray to be used after consuming food and drinks and before replacing the alidade. Participants were instructed to use one or two sprays directly into the mouth, dispersing the spray around the teeth with their tongue, and then replacing the alidade. Participants were also advised that at the end of the 14-day trial, they could apply the product directly into the clear alidade in their mouth before replacing it.

[0629] During the trial, consumers were assigned tasks to perform.

[0630] The final task was a 1:1 interview, which included completing a dental health questionnaire to measure any changes in dental problems after the trial was completed.

[0631] result

[0632] Existing dental problems

[0633] Participants experienced a range of dental health problems of varying severity (Table 2); Figure 1 Of particular note, 6 out of 10 participants reported gingival bleeding as a pre-existing dental problem, and 2 of these 6 participants reported their gingival bleeding to be very severe (Licette score 7) (Table 2). Figure 1 ).

[0634] Table 2: Pre-existing dental problems experienced by participants prior to Toothboost oral spray consumer trial A

[0635] Likert scale categories: 0. I haven't encountered this problem; 1. It's not bad at all, I barely noticed it; 7. It's very bad, it's been affecting me.

[0636]

[0637] Due to administration error, participant 9's ratings were not recorded before the trial.

[0638] Dental problems after a 14-day Toothboost trial

[0639] Participants completed a dental health questionnaire to reassess their dental health issues after daily use of Toothboost spray (a MOL composition without fluoride and phosphate) (Table 3). Participants were also interviewed after the trial was completed.

[0640] Table 3: Dental problems experienced by participants after the Toothboost oral spray consumer trial

[0641] Likert scale categories: 0. I haven't encountered this problem; 1. It's not bad at all, I barely noticed it; 7. It's very bad, it's been affecting me.

[0642]

[0643] Feedback received from participants included unexpected findings related to pre-existing gingival bleeding in many participants. Further observations revealed continued improvement in dry mouth, allergies, and morning halitosis in all participants after the 14-day trial period.

[0644] Bleeding gums

[0645] Of the six participants who initially reported gum bleeding as a problem, four reported a reduction in gum bleeding during the trial. Figure 1 ).

[0646] Two participants (P1 and P2) who previously recorded gingival bleeding as a score of 7 ("very bad, it has been affecting me") showed a significant reduction in gingival bleeding when using Toothboost oral spray, to 2 / 7 and 0 / 7 respectively (Table 3). Figure 1 ).

[0647] Both P1 and P2 reported that their gum bleeding stopped within the 14-day trial period.

[0648] Participants 1 and 2 after Toothboost oral spray trial

[0649] Participant 1

[0650] Gender: Female

[0651] Age: 51

[0652] Participant 2

[0653] Gender: Female

[0654] Age: 30

[0655] In the consumer trial, participants 1 and 2 both reported a reduction in gingival bleeding. Figure 1 In a 14-day consumer trial, reports of reduced gum bleeding were surprising and unexpected. The informational leaflets provided to participants contained no references or instructions regarding gum health or gum bleeding, and the inventors did not prior to the trial state that using Toothboost spray could prevent or stop bleeding. After completing the 14-day trial, two participants with severe gum bleeding reported that their bleeding had stopped within a week of using the product.

[0656] Example 6 - A follow-up Toothboost oral spray test conducted to further explore the effect of Toothboost spray on gingival bleeding.

[0657] introduce

[0658] As mentioned earlier, bleeding gums are a symptom of periodontal disease, and both gingivitis and active periodontitis can cause bleeding. Therefore, to explore the finding that Toothboost significantly reduces bleeding gums, Participants 1 and 2, who reported extremely severe bleeding gums, were recruited for further research to further investigate this finding.

[0659] method

[0660] The trial consisted of two phases. Phase 1 required participants to confirm they had completed a sample of Toothboost spray before starting the trial and to abstain from daily use of Toothboost spray for 14 days. After this 14-day abstinence period, participants completed a dental health questionnaire. Phase 2 then proceeded, during which participants resumed daily spray use for another 14 days and completed a further dental health questionnaire.

[0661] Applying Toothboost spray does not require mechanical cleaning or plaque removal. No instructions are given to apply the spray directly after brushing. This is to ensure that Toothboost is applied not only to cleaned tooth surfaces but also to areas where bacteria have already adhered. Participants used the spray at different times of day and night as an adjunct to their daily oral care routine and dental product use.

[0662] Phase 1 of the experiment

[0663] Participants were asked to complete a dental health questionnaire in Consumer Trial A. Additionally, participants were asked to answer questions reflecting their frequency of discontinuing Toothboost from their daily routine over a 14-day period.

[0664] Phase 1 - Participant 1 Case Study Questions:

[0665] Q: Can you list any benefits you experienced or observed during the initial consumer trial?

[0666] A: It freshens breath, leaves the mouth feeling clean, reduces tooth sensitivity, and decreases gum bleeding.

[0667] Q: Could you please inform me whether any of the benefits you listed decreased or stopped within the two weeks you did not use Toothboost spray? Please provide details.

[0668] A: "My breath wasn't as fresh in the morning, and I started to experience more tooth sensitivity and bleeding gums, which decreased when I used a Toothboost sample."

[0669] Q: Could you please inform me whether any of the benefits you listed continued to occur within two weeks of not using Toothboost spray? Please elaborate.

[0670] A: "My tooth sensitivity and bleeding gums were not as severe as they were before I used Toothboost."

[0671] After receiving the responses, based on their answers, some follow-up questions were asked to Participant 1:

[0672] Q: A brief follow-up question about your bleeding gums: During the Mark I trial, was there a period when the bleeding gums completely stopped? Participants reported that the bleeding gums completely stopped about a week after using Toothboost.

[0673] Q: According to the questionnaire, you started experiencing bleeding gums again. Can you estimate when you noticed it? The participant reported that the bleeding gums recurred 5 days to 1 week after stopping Toothboost.

[0674] Phase 1 - Participant 2 Case Study Questions:

[0675] Q: After the initial 14-day trial period, did you maintain, reduce, or increase your daily use of Toothboost spray? If you reduced or increased your use, please explain why.

[0676] A: "I increased the frequency of spraying my alignment device when I discovered that I could spray it with a sprayer. This was a moment that suddenly occurred to me when I was using Toothboost."

[0677] Q: Can you list any benefits you experienced or observed during the consumer trial—before you finished your Toothboost spray bottle?

[0678] A: "The biggest benefit was that my gums stopped bleeding—which was completely unexpected. The second benefit was that my breath improved throughout the day. Wearing the alignment device all day isn't the most comfortable (or the most hygienic) thing, but in the end, the odor wasn't noticeable."

[0679] Q: Could you please inform me whether any of the benefits you listed decreased or stopped within the two weeks you did not use Toothboost spray? Please provide details.

[0680] A: "Sadly, my gums are bleeding again, not as much as before I used Toothboost, but it happened on 4 out of 14 nights I didn't use the spray."

[0681] Table 4: Dental Health Questionnaire - Phase 1: Participants stopped using Toothboost spray for 14 days; Phase 2: Participants resumed daily use of Toothboost spray for 14 days.

[0682] Likert scale categories: 0. I haven't encountered this problem; 1. It's not bad at all, I barely noticed it; 7. It's very bad, it's been affecting me.

[0683]

[0684] Both participants reported that their gum bleeding returned within two weeks after they stopped using Toothboost spray. However, both participants reported that their gum bleeding decreased or stopped after they resumed daily use of Toothboost spray for 14 days.

[0685] Although both patients who initially presented with severe gingival bleeding (Licott score 7; Table 2) reported recurrence of gingival bleeding after discontinuation of Toothboost, the recurrence was not as severe as previously reported (Table 4 and ). Figure 1 ).

[0686] Example 7 – Toothboost Oral Spray Treatment for Clinical Periodontal Disease Patients – Clinical Evaluation

[0687] introduce

[0688] Consumer trials conducted on orthodontic aligner patients yielded surprising and unexpected results, showing that compositions containing phosphopeptides can prevent and treat gingivitis characterized by bleeding gums.

[0689] Another Toothboost spray trial aimed to obtain clinical insights into the effects of using Toothboost oral spray for 14 days on patients with existing periodontal conditions.

[0690] A dental hygienist selected two patients exhibiting different stages of periodontitis to participate in the Toothboost oral spray trial.

[0691] method

[0692] Two patients were selected according to the British Periodontal Association's 2017 classification.

[0693] Patient 1 was classified as having a moderate rate of periodontal disease progression, while Patient 2 was classified as having a rapid rate of periodontal disease progression.

[0694] Patients 1 and 2 verbally agreed to participate in the trial and signed waiver documents before the trial began.

[0695] Clinical assessment

[0696] Patients 1 and 2 underwent clinical evaluation by dental hygienists who used the Practice Works Dental Software Periodontal Bleeding Index Chart to record their gingival health before the trial began and after the 14-day trial period. Both patients were instructed to continue their routine oral care routine and dental products, as Toothboost oral spray was used as an adjunct product.

[0697] Bleeding Index

[0698] Bleeding gums during probing around the teeth is associated with gingival sulcus inflammation. Easily ulcerated gingival sulcus epithelium, representing inflammation originating from plaque, is a major cause of bleeding during probing. The bleeding index is an indicator of gingival sulcus health. Excessive pressure on the probe can also trigger bleeding.

[0699] Dental health questionnaire

[0700] Both patients were asked to complete a dental health questionnaire before the Toothboost spray trial and after using Toothboost daily for 14 days.

[0701] result

[0702] Clinical assessment

[0703] Patient 1: Moderate rate of periodontal disease progression

[0704] Gender: Female

[0705] Age: 54

[0706] Regular attendance: Dental check-ups twice a year, dental hygienist check-ups four times a year.

[0707] Dental history: BSP periodontal assessment

[0708] Stage 3 extensive periodontitis

[0709] Grade B

[0710] Currently stable

[0711] • Moderate periodontal risk.

[0712] A bleeding index was performed before the test, identifying 16 bleeding points in the upper teeth and 8 bleeding points in the lower teeth, for a total of 24 bleeding points. Figure 2A ).

[0713] After 14 days of routine daily oral hygiene care, a post-trial bleeding index was performed, showing a reduction in the number of bleeding points on both upper and lower teeth to 2. Notably, after 14 days of treatment with Toothboost spray, the total number of bleeding points decreased from 24 to 4. Figure 2B These results indicate a clinical reduction in periodontal bleeding points in this patient with pre-existing stable periodontal disease. Therefore, Toothboost oral spray, as an adjunct to dental care procedures, is effective in preventing and treating periodontal disease.

[0714] Clinical assessment

[0715] Patient 2: Rapid progression of periodontal disease

[0716] Gender: Female

[0717] Age: 69

[0718] Regular attendance: 6 dental checkups per month, 3 dental hygienist checkups per month.

[0719] Dental history: BPS periodontal assessment

[0720] Stage 4 extensive periodontitis

[0721] ·Class C

[0722] • Currently unstable

[0723] High periodontal risk

[0724] A bleeding index was performed before the test, identifying 35 bleeding points in the upper teeth and 28 bleeding points in the lower teeth, for a total of 63 bleeding points. Figure 3A ).

[0725] After 14 days of routine daily oral hygiene care, a post-trial bleeding index was performed, showing a reduction in the number of bleeding points on the upper teeth to 22 and on the lower teeth to 21. After 14 days of treatment with Toothboost spray, the total number of bleeding points decreased from 63 to 43. Figure 3B These results indicate a clinical reduction in periodontal bleeding points in this patient with pre-existing unstable periodontitis.

[0726] Patient 2 had a scheduled oral hygiene appointment 14 days after completing a Toothboost spray sample. The dental hygienist recorded a periodontal bleeding index chart (...). Figure 3C ( ), to assess the gingival health of patients after discontinuing Toothboost use.

[0727] The third bleeding index test on patient 2 showed 19 bleeding points in the upper teeth and 20 bleeding points in the lower teeth, for a total of 39 bleeding points.

[0728] Another periodontal bleeding index chart records the occurrence of bleeding 14 days after not using Toothboost spray. Figure 3C (39 bleeding points). The results indicate that Toothboost spray has a preventative or therapeutic effect on periodontal disease and potentially a sustained or prolonged effect after a period of non-use, such as... Figure 3C As shown.

[0729] Patient 2 continued Toothboost treatment for 3 months and underwent another periodontal bleeding index test. Figure 3D As shown, 26 bleeding points were recorded after 3 months of using Toothboost (5 times daily, then reduced to 2 times daily). Patients reported a slight increase in bleeding after reducing to twice-daily application. These results further support the idea that using Toothboost spray can reduce gingival bleeding in patients with established periodontal disease.

[0730] Dental health questionnaire

[0731] Table 5: Dental health questionnaire survey of Patient 1 and Patient 2 before and 14 days after the Toothboost spray trial.

[0732] Likert scale categories: 0. I haven't encountered this problem; 1. It's not bad at all, I barely noticed it; 7. It's very bad, it's been affecting me.

[0733]

[0734] Clinical evaluations of patients with moderate and rapid periodontal disease progression (measured by the bleeding index) showed that daily application of the MOL preparation Toothboost resulted in a significant reduction in gingival bleeding. Patient 2 reported a significant reduction in gingival bleeding (Table 5).

[0735] Patient 1 was unaware of gingival bleeding, which is very common when the number of bleeding points is small. Although gingivitis was recorded in the bleeding index, the bleeding from these points was so minimal that the patient was unaware of the problem and recorded gingival bleeding as 1. “Not bad at all” on the Likert scale (Table 5) Despite the patient’s lack of awareness of gingival bleeding, clinical assessment using the bleeding index showed a reduction in bleeding points, even in patients with minimal gingival bleeding.

[0736] The MOL formulation Toothboost not only reduced the severity of gingival bleeding during use, but also showed that patient 2 experienced a continued reduction in gingival bleeding 14 days after discontinuing Toothboost spray.

[0737] Example 8: Three-week Toothboost oral spray trial 1. Patients with established periodontal disease

[0738] Introduction: To further evaluate the efficacy of compositions containing phosphopeptides in treating and preventing gingival bleeding in patients with different stages of periodontal disease, a three-week trial was conducted using Toothboost oral spray (MOL formulation).

[0739] method:

[0740] Initial selection criteria

[0741] • Patients can be of any age / gender

[0742] • Patients must be able to give consent and follow the instructions to use the product.

[0743] • This trial is not suitable for vegans or patients who are intolerant to cow's milk / dairy products because the formulation contains phosphopeptides—dairy proteins.

[0744] • The ingredients in the formulation are generally considered to be GRAS safe.

[0745] Clinical selection criteria

[0746] The patient should have at least 11 teeth.

[0747] The patient should have at least 10 bleeding points.

[0748] The patient should not be taking anticoagulants.

[0749] The patient should be a non-smoker.

[0750] Information of patients in Trial 1

[0751] Of the 10 patients, 4 had periodontal disease classified as:

[0752] Stage 4 - Very Severe

[0753] Tier C - Rapid Progression

[0754] Currently unstable

[0755] This is the severe, late stage of the disease; if the condition cannot be stabilized or alleviated, the patient is at risk of tooth loss. The stabilization or improvement of periodontal condition is recorded by bleeding on probing (BOP).

[0756] • Stable – No BOP in areas with a BOP < 10% + 4mm

[0757] • Relief – No bleeding at BOP < 10% + 4mm

[0758] This standard is based on the British Society of Periodontology (BSP) – Implementing the 2017 Classification of Periodontal Diseases to Reach a Diagnosis in Clinical Practice (10).

[0759] Before the start of the 3-week trial period, dental professionals recorded gingival bleeding scores as described in Example 7 above. Patients were then instructed to use Toothboost oral spray 3 times daily, spraying 1-2 sprays directly into the mouth and spreading it around the teeth with the tongue.

[0760] During the 3-week trial, all patients used Toothboost oral spray three times daily at different times to adapt to their own lifestyles and routines. Nine patients maintained their normal oral care and brushing routines at least twice daily. One patient (Patient 3) increased their daily brushing frequency from once daily to twice daily during the trial, as participation in the trial was a catalyst for improving their existing once-daily brushing habit. All patients continued to use their regular fluoride toothpaste and / or mouthwash products / brands. Two patients (Patients 9 and 10) used Corsodyl Toothpaste, a regular fluoride toothpaste product that also contained chlorhexidine.

[0761] At the end of the 3-week trial period, patients reported their own observations, and dental professionals recorded their gingival bleeding scores.

[0762] result:

[0763] Self-reported observations of using Toothboost oral spray three times a day for three weeks.

[0764] Halitosis: Improvement in halitosis was observed in 2 patients.

[0765] Dry mouth: Improvement of dry mouth symptoms was observed in 5 patients.

[0766] Gingival bleeding: Reduced bleeding was observed in 7 patients while brushing their teeth.

[0767] Tooth sensitivity: A reduction in tooth sensitivity was observed in 2 patients.

[0768] Clinical bleeding score

[0769] All patients participating in the 3-week trial experienced a significant reduction in gingival bleeding scores after treatment with Toothboost oral spray (see Figure 4b). A typical bleeding chart is shown in Figure 4a (Patient 1). This effect was achieved across all stages and grades of periodontitis (see Tables 6a-c).

[0770] Table 6a: Clinical status and bleeding scores of patients in the 3-week Toothboost trial 1.

[0771]

[0772] Table 6b: Bleeding Score Statistics - Experiment 1

[0773]

[0774] Table 6c: Bleeding Score Statistics - Experiment 1

[0775]

[0776] Clinical observations recorded by dentists in Experiment 1.

[0777] All patients gave very positive feedback while using the product, reporting that it was easy to use and had a pleasant taste and texture. Patients participating in the study reported reduced gum swelling and bleeding. Examination revealed a significant decrease in the number of bleeding sites. Overall, their gums were less swollen and inflamed, and even at the bleeding sites, the amount of blood was significantly reduced.

[0778] Overall, during the three-week trial period, the use of Toothboost oral spray significantly reduced bleeding on probing and the amount of inflammation.

[0779] in conclusion:

[0780] These results indicate a clinical reduction in periodontal bleeding points in patients with varying degrees of periodontal disease severity. Therefore, Toothboost oral spray, as an adjunct to dental care procedures, is effective in preventing and treating periodontal disease.

[0781] Example 9: Three-week Toothboost trial 2. Dental implant patients with established periodontal disease.

[0782] Introduction: To further evaluate the efficacy of phosphopeptide-containing compositions in treating and preventing gingival bleeding in dental implant patients (N=10), a three-week trial was conducted using Toothboost oral spray (MOL formulation).

[0783] method:

[0784] The initial selection and clinical criteria are the same as those described in Example 8, with the additional criterion being that the patient should have one or more dental implants.

[0785] Information from patients in trial 2

[0786] Of the 10 patients, 4 had periodontal disease classified as: early / intermediate stage 1.

[0787] Of the 10 patients, 6 had periodontal disease classified as stage 2, intermediate.

[0788] All 10 patients had periodontal disease classified as: Grade A, slow-progressing, currently stable.

[0789] Implant patients need to maintain good oral hygiene and stable periodontal condition before and after surgery.

[0790] This standard is based on the classification of periodontal disease based on clinical practice studies conducted by the British Society of Periodontology in 2017

[10] .

[0791] Before the start of the 3-week trial period, dental professionals recorded gingival bleeding scores as described in Example 7 above. Patients also reported current problems related to their dental condition or symptoms they experienced. Patients were then instructed to use Toothboost oral spray 3 times daily, spraying 1-2 sprays directly into the mouth and spreading it around the teeth with the tongue.

[0792] During the 3-week trial, all patients used Toothboost oral spray three times daily at different times to adapt to their own lifestyles and daily routines. All patients continued their normal oral care and brushing routine at least twice daily using their regular fluoride toothpaste and / or mouthwash products / brands.

[0793] At the end of the 3-week trial period, patients reported their own observations, and dental professionals recorded their gingival bleeding scores.

[0794] result:

[0795] Self-reported observations of using Toothboost oral spray three times a day for three weeks.

[0796] Halitosis: Improvement in halitosis was observed in 6 out of 8 patients.

[0797] Dry mouth: Improvement of dry mouth symptoms was observed in 1 / 8 of the patients.

[0798] Gingival bleeding: 8 out of 8 patients observed a decrease in bleeding while brushing their teeth.

[0799] Sensitivity: Reduced sensitivity was observed in 2 out of 8 patients.

[0800] Clinical bleeding score

[0801] Of the 10 dental implant patients who participated in the 3-week trial, 8 experienced a significant reduction in gingival bleeding scores after treatment with Toothboost oral spray (see Figure 5b and Table 7). Figure 5a shows representative bleeding charts before and after the trial (Patient 12).

[0802] Table 7: Clinical status and bleeding scores of dental implant patients in the 3-week Toothboost trial 2.

[0803]

[0804]

[0805] Table 8a: Bleeding score statistics - Dental implant patients trial 2

[0806]

[0807]

[0808] Clinical observations recorded by dentists in Experiment 2.

[0809] Results showed improved bleeding scores. Even with plaque present, interdental (ID) bleeding improved, with plaque clearly visible around the implants. Although implant patients typically have good oral hygiene and high motivation, peri-implant inflammation and bleeding were present but had resolved at the post-trial follow-up. Gingival reactivity to plaque appeared to be less pronounced than before.

[0810] The results of trials 1 and 2 showed that Toothboost significantly reduced bleeding in patients classified by BSP as early / mild / moderate and severe periodontitis.

[0811] Example 10: Remineralization of Erosive Damage in Human Tooth Enamel with Polymer Sheets Containing OPN and Calcium

[0812] introduce:

[0813] To evaluate polymer sheets as a suitable delivery carrier for phosphopeptide-containing compositions to the oral cavity, microindentation remineralization studies were conducted, in which human tooth enamel samples were first attacked with citric acid to create erosive damage. The remineralization potential of several different formulations delivered in polymer sheets was evaluated.

[0814] Materials and methods:

[0815] Material

[0816] Human tooth enamel was provided by SB Discovery, and enamel sections were prepared by Modus Laboratories.

[0817] Preparation of water-soluble polymer films containing the formulations shown in Table 7:

[0818] Table 9: Formulations incorporated into water-soluble polymer films

[0819]

[0820] FastAP thermosensitive alkaline phosphatase.

[0821] Microindenter: Buehler micromet 5104 UKAS calibration certified with Vickers diamonds #DIR1418.

[0822] Polishing machine: Buehler Automet / Ecomet 250.

[0823] pH meter: Hanna 213.

[0824] The deionized water comes from the laboratory's tap water RO supply.

[0825] The citric acid used in the initial formation of the damage was 1% citric acid monohydrate, with the pH adjusted to 3.75.

[0826] Table 10: Artificial Saliva

[0827]

[0828] Sample preparation

[0829] A 3mm square block of enamel was cut from a healthy, disease-free molar. The molar was then mounted in a 25mm diameter resin sheet, and the underside of the sheet was flattened with P60 sandpaper. The enamel surface was then ground with P800 paper to expose the enamel, followed by polishing with 1200 and 2500 grit paper, and finally polished with 1µm diamond to reveal a highly polished enamel surface. The sheet was then rinsed with deionized water, sonicated for 5 minutes, and stored in a humid environment at 5°C until needed.

[0830] Formation of citric acid erosive damage

[0831] An erosive lesion was created on the enamel plaque using a 1% w / w citric acid solution adjusted to pH 3.75. The enamel plaque was placed face up in a water bath. Excess citric acid was poured onto the surface and allowed to stand at room temperature for 20 minutes. After 20 minutes, the enamel plaque was rinsed thoroughly with deionized water and allowed to dry.

[0832] Microindentation method

[0833] The microhardness of tooth enamel was determined by indentation using a Vickers diamond tip hardness tester. Each hardness value was determined by averaging ten individual measurements taken from the center of multiple locations at multiple locations for each enamel sample, applied with a force of 1.98 N over a 20-second indentation time. At the beginning of each set of measurements, a calibration check was performed using a standard metal block to ensure that the reproducibility of the microhardness was within 3% of the test block's microhardness.

[0834] Processor

[0835] Fifty enamel samples were selected for the study, with N=10 samples used in each treatment group. Each hardness measurement was the mean of 10 individual indentation measurements. First, the samples were demineralized in citric acid by placing them enamel-side up in an excess of citric acid solution (1% w / w, pH 3.75) for 10 minutes at room temperature. Then, they were removed, rinsed, and air-dried before microindentation measurements. Based on the indentation measurements of enamel damage, the samples were graded and grouped into ten samples per treatment group, ensuring each group had a similar range of hardness values. They then underwent the following protocol:

[0836] 1. Place the enamel sheets in a dedicated water bath, along with one of each of the five formulations, and add an excess of artificial saliva. Incubate them at room temperature for 30 minutes.

[0837] 2. Then remove the enamel sheet from the artificial saliva and place it enamel-side up. Remove the polymer sheet of the test formulation from the pouch and cut it into approximately four squares. Then apply one square polymer sheet to each of the 10 lesions in the test group. Use the same procedure for all five formulations.

[0838] 3. Place the enamel samples back into their dedicated water bath and on a shaking plate inside the incubator. The shaking plate is set to a gentle shaking speed to simulate the turbulence that might be expected in the mouth. The samples are observed periodically to estimate the time required for the polymer sheet to dissolve. This is done without analytical procedures. After 30 minutes, no observable polymer residue remains on the enamel. The enamel sheets are then placed in artificial saliva at 37°C until the next day.

[0839] 4. Remove the enamel plaque from the water bath, rinse and dry. Then measure the microhardness of the damaged area by microindentation.

[0840] 5. Repeat steps 1 to 4 each day for five consecutive days.

[0841] result

[0842] Micro-indentation results

[0843] Table 11 and Figure 6 a and 6b show the Vickers hardness values.

[0844] Table 11. Changes in microhardness of enamel samples relative to damage microhardness.

[0845]

[0846] Statistical analysis of indentation results

[0847]

[0848]

[0849]

[0850] in conclusion

[0851] The changes in microhardness after five days follow this pattern:

[0852] 3X Boost + F = 3X Boost = Standard + F = Standard > Placebo Day 1.

[0853] 3X Boost + F = 3X Boost = Standard + F = Standard > Placebo Day 2.

[0854] 3X Boost + F = 3X Boost = Standard = Standard + F > Placebo Day 3.

[0855] 3X Boost + F = 3X Boost = Standard + F = Standard > Placebo Day 4.

[0856] 3X Boost + F = 3X Boost = Standard + F = Standard > Placebo Day 5.

[0857] Microhardness results and remineralization calculations provide evidence that the application of polymer films containing OPN and calcium induces rapid remineralization of citric acid erosion damage in human tooth enamel. Compared to polymer films alone (placebo), polymer films containing OPN and calcium, with or without fluoride, induced statistically significant enamel remineralization. Mineralization at 3X boost concentrations of OPN and calcium, with or without fluoride, showed a directional increase compared to standard formulations with or without fluoride. Figure 6 a). The fluoride-containing 3x boost formulation consistently produced the greatest remineralization over a five-day period.

[0858] References

[0859]

Claims

1. A composition comprising phosphopeptides for the prevention or treatment of periodontal disease in a subject with such need.

2. A composition comprising a phosphopeptide for the prevention or treatment of gingival bleeding in a subject with such need.

3. The composition of claim 2, wherein gingival bleeding is associated with the use of orthodontic appliances, fixed or removable prostheses and / or dental implants.

4. The composition of claim 3, wherein the orthodontic device comprises an orthodontic aligner or a fixed orthodontic bracket.

5. The composition of claim 2, wherein gingival bleeding is related to or caused by periodontal disease.

6. The composition according to any one of claims 1 or 5, wherein the periodontal disease is gingivitis or periodontitis.

7. The composition according to claim 6, wherein the gingivitis is characterized as localized gingivitis or extensive gingivitis.

8. The composition according to any one of claims 1, 5 or 6, wherein the periodontitis is stage I, II, III or IV periodontitis.

9. The composition according to any one of claims 1 or 5-8, wherein the composition is used for the treatment or prevention of established periodontal disease.

10. The composition according to any one of claims 1 or 5-9, wherein the composition is used to prevent the progression of gingivitis to periodontitis in a subject with periodontal disease.

11. A composition comprising a phosphopeptide for the prevention or treatment of peri-implantitis and / or peri-implantitis in a subject with such need.

12. A method for treating or preventing gingival bleeding in a subject who requires it, wherein the method comprises administering to the subject a therapeutically effective amount of a composition comprising a phosphopeptide.

13. A method for treating or preventing periodontal disease in a subject who requires it, wherein the method comprises administering to the subject a therapeutically effective amount of a composition comprising a phosphopeptide.

14. A method for treating or preventing peri-implant mucositis and / or peri-implantitis in a subject with such need, wherein the method comprises administering to the subject a therapeutically effective amount of a phosphopeptide-containing composition.

15. The composition according to any one of claims 1-11 or the method according to any one of claims 12-14, wherein the subject is a non-responder to conventional therapy.

16. The composition according to any one of claims 1-11 and 15 or the method according to any one of claims 12-15, wherein the composition does not contain additional phosphate or additional phosphate source.

17. The composition according to any one of claims 1-11 or 15 or the method according to any one of claims 12-15, wherein the composition does not contain phosphate buffer.

18. The composition according to any one of claims 1-11 and 15-17 or the method according to any one of claims 12-17, wherein the phosphopeptide comprises osteopontin or a phosphopeptide derived therefrom, and / or casein or a phosphopeptide derived therefrom, preferably wherein the phosphopeptide is OPN-10.

19. The composition according to any one of claims 1-11, 15-16 and 18 or the method according to any one of claims 12-16 and 18, wherein the composition comprises less than 50 mM of phosphate.

20. The composition according to any one of claims 1-11 and 15-19 or the method according to any one of claims 12-19, wherein the composition further comprises a fluoride or a fluoride source, preferably the fluoride source being a monofluorophosphate.

21. The composition according to any one of claims 1-11 and 15-19 or the method according to any one of claims 12-19, wherein the composition does not contain fluoride or a fluoride source.

22. The composition according to any one of claims 1-11 and 15-21 or the method according to any one of claims 12-21, wherein the composition further comprises calcium or a calcium source, preferably calcium chloride.

23. The composition according to any one of claims 1-11 and 15-21 or the method according to any one of claims 12-21, wherein the composition does not contain calcium or a calcium source.

24. The composition according to any one of claims 1-11 and 15-23 or the method according to any one of claims 12-23, wherein the composition comprises about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, or about 90% by weight of water.

25. The composition according to any one of claims 1-11 and 15-24 or the method according to any one of claims 12-24, wherein the composition is a liquid and wherein the composition contains at least 50% by weight water.

26. The composition according to any one of claims 1-11 and 15-24 or the method according to any one of claims 11-24, wherein the composition is a colloid and wherein the composition contains less than or equal to 25% by weight of water.

27. The composition according to any one of claims 1-11 and 15-26 or the method according to any one of claims 12-26, wherein the composition comprises one or more other components selected from the group consisting of alcohols, humectants, surfactants, preservatives, flavoring agents, sweeteners, coloring agents, cariogenic agents, buffers, acids, bases, whitening agents, thickeners, and anti-tartar agents.

28. The composition according to any one of claims 1-11 and 15-27 or the method according to any one of claims 12-27, wherein the composition comprises: About 0.5% by weight to about 15% by weight of phosphopeptides; suitably about 1% by weight to about 10% by weight, preferably about 1.5% by weight to about 5% by weight; Water of about 20% to about 99% by weight; preferably about 23% to about 66% by weight. About 1% to about 20% by weight of the buffer; preferably about 1% to about 15% by weight. From 0% by weight to about 70% by weight, preferably from about 0% by weight to about 20% by weight, flavoring agents, preservatives and / or other ingredients; preferably from about 0% by weight to about 10% by weight. From about 0.1% by weight to about 20% by weight of a sweetener; preferably from about 0.1% by weight to about 10% by weight. Optionally, a calcium ion source of about 0.1% to about 15% by weight; preferably about 0.1% to about 5% by weight. Optionally, a phosphate ion source of about 0.2 wt% to about 32 wt%, preferably about 0.2 wt% to about 15 wt%, preferably about 0.5% to about 5% w / v, and preferably about 0.7 wt% to about 2 wt%; Optionally, a fluoride source of about 0.01 wt% to about 3 wt%; preferably about 0.1 wt% to about 1.5 wt%, more preferably about 0.4 wt% to about 1.5 wt%; and Optionally, about 0.1% to about 20% by weight, suitably about 0.5% to about 15% by weight, of a thickener.

29. The composition according to any one of claims 1-11 and 15-26 or the method according to any one of claims 11-26, wherein the composition comprises the following components: Approximately 3% w / w of phosphopeptide, preferably said phosphopeptide is OPN-10; A buffer at approximately 15% w / w, preferably sodium bicarbonate; The amount of water is approximately 54 to 66% w / w, preferably said water is deionized water; A calcium source of approximately 3% w / w, preferably a calcium chloride solution; The flavoring agent and preservative are in an amount of about 8% w / w, preferably wherein the flavoring agent and preservative comprises a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine and flavoring oil; Optionally, a fluoride source of about 0.4% w / w, preferably said fluoride source is monofluorophosphate; A sweetener in an amount of about 5% w / w, preferably xylitol; and Optionally, an amount of acid of about 11% w / w, preferably said acid is hydrochloric acid.

30. The composition according to any one of claims 1-11 and 15-26 or the method according to any one of claims 12-26, wherein the composition comprises the following components: Approximately 3% w / w of phosphopeptide; preferably, said phosphopeptide is OPN-10; A buffer of approximately 2% w / w, preferably sodium bicarbonate; A whitening agent in an amount of about 6% w / w, preferably wherein the whitening agent comprises rubbish silica; The amount of water is approximately 23 to 25% w / w, preferably deionized water; An amount of acid of approximately 34% w / w, preferably hydrochloric acid; A calcium source of approximately 0.5% w / w, preferably said calcium source is calcium chloride; A sweetener in an amount of approximately 9% w / w, preferably mannitol; A thickener in an amount of approximately 13% w / w, preferably xanthan gum and silica; Approximately 8% w / w of flavoring agents and preservatives, preferably wherein said flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine, and flavoring oil; and Optionally, a fluoride source of about 1% w / w is used, preferably said fluoride source is monofluorophosphate.

31. The composition according to any one of claims 1-11 and 15-26 or the method according to any one of claims 12-26, wherein the composition comprises the following components: Approximately 3% w / w of phosphopeptide, preferably said phosphopeptide is OPN-10; A buffer at approximately 15% w / w, preferably sodium bicarbonate; Approximately 30% w / w of water, preferably deionized water; A calcium source of approximately 3% w / w, preferably a calcium chloride solution; The phosphate source, preferably, is a trisodium phosphate solution of about 16% w / w and a disodium hydrogen phosphate solution of about 16% w / w. A sweetener in an amount of about 5% w / w, preferably xylitol; Approximately 8% w / w of flavoring agents and preservatives, preferably wherein said flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine, and flavoring oil; and Optionally, the fluoride source, suitably, is in an amount of about 0.4% to 0.5% w / w, preferably said fluoride source is monofluorophosphate.

32. The composition according to any one of claims 1-11 and 15-26 or the method according to any one of claims 12-26, wherein the composition comprises the following components: Approximately 3% w / w of phosphopeptide; preferably, said phosphopeptide is OPN-10; A buffer at approximately 15% w / w, preferably sodium bicarbonate; The amount of water is approximately 47 to 50% w / w, preferably deionized water; An amount of acid of approximately 15.7% w / w, preferably hydrochloric acid; A calcium source of approximately 2% to 3% w / w, preferably said calcium source is calcium chloride; Xanthan gum at approximately 1% w / w Approximately 8% w / w of flavoring agents and preservatives, preferably wherein said flavoring agents and preservatives comprise a mixture of sodium methylparaben, phenoxyethanol, saccharin, cocamidopropyl betaine, and flavoring oil; and Optionally, a fluoride source of about 0.8% w / w, preferably said fluoride source is monofluorophosphate.

33. The composition according to any one of claims 1-11 and 15-32 or the method according to any one of claims 12-32, wherein the composition is administered to a subject at least once a day, preferably at least twice, at least three times, at least four times, or at least five times a day.

34. The composition according to any one of claims 1-11 and 15-33 or the method according to any one of claims 12-33, wherein the composition is used for administration to the oral cavity of a subject.

35. The composition according to any one of claims 1-11 and 15-34 or the method according to any one of claims 12-34, wherein the composition is applied to the oral cavity of the subject before sleep, after eating, and / or after drinking.

36. The composition according to any one of claims 1-11 and 15-35 or the method according to any one of claims 12-35, wherein the composition is applied by direct rinsing into the subgingival periodontal pocket.

37. The composition according to any one of claims 1-11 and 15-35 or the method according to any one of claims 12-35, wherein the composition is applied to orthodontic appliances, alignment devices, protective dentures and / or prostheses.

38. A polymeric material comprising a composition, wherein the composition comprises a phosphopeptide.

39. A polymeric material comprising phosphopeptides for the prevention or treatment of gingival bleeding in a subject with such need.

40. A polymeric material comprising phosphopeptides for the prevention or treatment of periodontal disease in a subject with such need.

41. A polymeric material comprising phosphopeptides for the prevention or treatment of peri-implant mucositis and / or peri-implantitis in subjects with such need.

42. A polymeric material comprising phosphopeptides for the prevention or treatment of tooth sensitivity in a subject with such need.

43. A polymeric material comprising phosphopeptides for the prevention or treatment of leukoplakia in a subject with such need.

44. The polymeric material according to claim 38 or the polymeric material used according to any one of claims 39-43, wherein the polymeric material comprises OPN or a phosphopeptide derived therefrom.

45. The polymeric material of claim 44, wherein the polymeric material further comprises calcium or a calcium source.

46. ​​The polymeric material according to claim 44 or 45, or the polymeric material used according to claim 44 or 45, wherein OPN is OPN-10.

47. The polymeric material according to any one of claims 38-45 or the polymeric material used according to any one of claims 39 to 45, wherein the polymeric material is a soluble polymer film.

48. An oral gel comprising amorphous calcium phosphate stabilized by a calcium phosphate stabilizer, and optionally comprising monofluorophosphate.

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