RU2848189C1 - Anti-inflammatory and senolytic product for dental care with whitening properties - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to oral care products that are suitable for both dental care and the prevention or treatment of periodontal diseases, and their use. A dental care product and a pharmaceutical composition for teeth whitening and treatment of periodontal disease or peri-implantitis are proposed, each containing 0.4-40 wt% of calcium phosphate particles with a size of 0.01-50 μm; 0.001-5 wt% of a self-assembling peptide consisting of the sequence SEQ ID NO: 1 (QQRFEWEFEQQ); 1-5 wt% of Rhododendron ferrugineum leaf extract; 1-5 wt% of Leontopodium nivale leaf and flower extract; 1-5 wt% of Eleutherococcus senticosus root extract; wherein all plant extracts contained therein are alcohol-free glycerol extracts containing water, and wherein the product does not contain ethanol. Also proposed are: a method for treating gingivitis in a subject, comprising applying an effective amount of the above product to the subject's gums; a method for whitening teeth, comprising applying an effective amount of the above product to the subject's teeth once, twice or three times a day for 1, 2, 3, 4, 5, 6, 7 or more days.

EFFECT: combination of components in the above-mentioned product and composition ensures their effectiveness both for dental care, including teeth whitening, and for the treatment, prevention or reduction of the incidence of gingivitis, periodontitis and peri-implantitis.

9 cl, 1 tbl, 3 ex

Description

The present invention relates to the field of dental care, and in particular to a toothpaste, dental gel, mouthwash, mouth spray or foam for dental care. The present invention provides, in particular, an anti-inflammatory and senolytic dental care product with whitening properties. The dental care product comprises calcium phosphate particles of a certain size, a self-assembling peptide P11-4 or oligopeptide 104 with the sequence SEQ ID NO: 1, an extract of a plant of the genus Rhododendron, preferably alpine rose or Alpenrose, such as an extract of the plant Rhododendron ferrugineum or Rhododendron hirsutum, and an extract of a plant of the genus Leontopodium, such as an extract of the plant Leontopodium nivale, also called edelweiss. The dental care product may further comprise an extract of a plant of the genus Eleutherococcus, such as an extract of the plant Eleutherococcus senticosus, also known as Siberian ginseng or Acanthopanax senticosus. In addition to the proven teeth whitening properties of this product, it may also serve as a medicinal product or pharmaceutical composition, as it also exhibits senolytic and anti-inflammatory effects. Thus, the invention provides a method for teeth whitening, as well as a method for treating periodontal disease and/or eliminating or reducing the number of senescent cells in a subject's gums. This can rejuvenate the subject's gums, stabilize potential tooth loosening, and improve well-being.

Periodontal disease, also known as gum disease, is a group of inflammatory conditions affecting the periodontium, the tissues that surround and support the teeth. In the early stages of periodontal disease, called gingivitis, the gums become swollen, red, and may bleed. In a more severe form, called periodontitis, the gums may recede from the teeth, bone loss may occur, and teeth may become loose or fall out. Bad breath may also occur.

Periodontal disease is caused by microorganisms that attach to and grow on the tooth surface, as well as an overly aggressive immune response to these microorganisms. When the gingival fibers are destroyed, the gum tissue separates from the tooth, leading to a deepening of the sulcus called a periodontal pocket. Subgingival microorganisms, those located apical to the gum line, colonize the periodontal pockets and cause further inflammation in the gum tissue and progressive bone loss. If left undisturbed, the microbial plaque calcifies, forming hard deposits on the teeth, commonly known as tartar. The destruction of tissues, such as the periodontal ligament, and the resorption of alveolar bone can ultimately lead to tooth mobility and subsequent tooth loss.

Periodontal disease, also known as periodontitis, has very few symptoms in its early stages, and in many people, the disease has progressed significantly before seeking treatment. Periodontitis is diagnosed by examining the soft gum tissue around the teeth with a probe (i.e., clinical examination) and by evaluating the patient's X-rays (i.e., radiographic examination) to determine the extent of bone loss around the teeth.

Treatment includes good oral hygiene and regular professional teeth cleaning. Recommended oral hygiene includes daily brushing and flossing. In some cases, antibiotics or dental surgery may be recommended. An estimated 538 million people worldwide suffered from periodontitis in 2015. In the United States, nearly half of people over 30 have some degree of periodontitis, and approximately 70% of people over 65 have the disease. Factors that increase the risk of the disease include smoking, diabetes, HIV/AIDS, family history, and certain medications (https://en.wikipedia.org/wiki/Periodontal_disease).

Several years ago, Dr. Charles Cobb analyzed insurance claims for all dental services. Approximately 50% of adults aged 30 to 70 have some degree of periodontitis; however, his assessment revealed that periodontal therapy of all types accounted for only 5% to 6% of the total number of services covered by benefit codes submitted by insurance companies. At the same time, insurance claims for various cosmetic services, such as teeth whitening, have increased significantly (Nagelberg, RH, 2014. https://www.dentaleconomics.com/practice/article/16390423/tooth-whitening).

Both external and internal factors contribute to tooth discoloration. For example, coffee, tea, wine, carrots, oranges, and tobacco can stain the enamel surface. Certain antibiotics, excessive fluoride absorption, and hereditary diseases can cause internal discoloration. Tooth discoloration can be a significant aesthetic concern for dental patients. For example, in the UK, approximately 20% of people are dissatisfied with the color of their teeth. In the US, 34% of people consider themselves dissatisfied with the color of their teeth.

Surface stains can often be removed through thorough dental cleaning by the patient or a dental professional. Polishing with an abrasive material, such as pastes containing calcium phosphate, chalk, pumice, or silica particles, is sometimes used for this purpose. If the patient desires more significant tooth discoloration than natural tooth whitening, chemical bleaching is the classic option. Various bleaching methods are available, all based on the use of an oxidizing agent such as hydrogen peroxide. Bleaching can be performed by a dental professional in a dental clinic or by the patient at home. Prescription medications for overnight bleaching or whitening toothpastes can be used.

However, in recent years, there has been increased awareness of the adverse effects associated with bleaching, such as demineralization, erosion, and tooth sensitivity caused by peroxides (see e.g. Dahl et al., 2003), and for commonly available cosmetic products, peroxide concentrations above 0.1% have even been banned in the European Union since 2012. The use of hydroxyapatite nanocrystals has been proposed for the remineralization of tooth surfaces damaged, for example, by bleaching (Mohd et al., 2007, Jiang et al., 2008, Lim et al., 2009, Roveri et al., 2009). Crystalline hydroxyapatite particles, which closely mimic natural tooth material, can be deposited on tooth enamel. In addition to filling scratches or decayed portions of the tooth and preventing or treating caries, precipitated hydroxyapatite can counteract increased tooth sensitivity caused by exposure of dentinal tubules during gingival recession (WO 2007/137606 A1).

Amorphous calcium phosphate stabilized by phosphoproteins such as casein phosphopeptide (CPP-ACP) has been used in dental care products for the prevention and treatment of dental caries (see US 20050037948 A1, US 20080075675 A1, US 20100297203 A1).

Calcium phosphate such as hydroxyapatite in particulate form has also been found to have whitening properties, whether used for tooth bleaching or polishing (Niwa et al., 2001, Dabanoglu et al., 2009). Dabanoglu et al. reported on the whitening properties of various materials, such as nano-hydroxyapatite or nano-tricalcium phosphate, or a soluble polymer film (made of methacrylic acid-ethyl acrylate copolymers) containing nano-hydroxyapatite. The authors achieved a color change, measured spectrometrically as ΔE (on the L*a*b scale), for all tested materials. This measurement can be performed according to ISO 28399. After three applications, the effect increased to a ΔE of approximately 3, and it decreased for some materials after subjecting the treated teeth to shear forces. It has been noted that the average casual observer can visually detect the difference between two colors that are 3-4 ΔE apart (on the L*a*b scale). A trained eye can distinguish two colors that are 2-3 ΔE apart. Thus, although noticeable changes have been achieved, there is still room for improvement in the whitening effect.

Publications WO 2013/068020, JPH 115722, JP 2008/081424, JP 2007/0176862, JP 2001/131041 and CN 101385856 disclose a dental care product containing hydroxyapatite in combination with various agents such as lactoferrin, hydrolyzed silk or lysozyme.

Raoufi et al., 2010, compared over-the-counter calcium peroxide and hydroxyapatite toothpastes (designed to whiten or brighten teeth, respectively) with a fluoride toothpaste (placebo), and found no objective whitening effect for any of the toothpastes tested in a 12-week clinical trial.

Publication WO 2015/044268 A1 proposes a much more effective dentifrice capable of whitening teeth, comprising 0.4-60% by weight of mineral particles such as hydroxyapatite, wherein the particles have a size of 10 nm to 50 μm, and 0.001-5% by weight, preferably 0.02-2% by weight, 0.04-1% by weight, 0.05-0.5% by weight, 0.05-0.2% by weight of an organic compound capable of forming a hydrogel, preferably a self-assembling peptide such as P 11-4, which is also called oligopeptide 104 (SEQ ID NO: 1). This publication indicates that by mixing mineral particles with a suitable organic matrix, such as a suitable protein matrix, the previously described whitening effect of hydroxyapatite particles on teeth can be significantly enhanced in a dentifrice according to the disclosed invention. Protein alone also does not provide comparable effects, and the combination works synergistically. Specifically, the disclosed invention relates to a dentifrice capable of providing a difference in tooth whiteness, measured on the CIELAB scale (i.e., the L*a*b* scale), of greater than 5 ΔE after three applications of the product, and preferably of greater than 5 ΔE after one application of the product.

A self-assembling peptide has been shown to be effective in the treatment of gingivitis, periodontitis, and peri-implantitis (WO 2018/033570 A1). However, the described treatment requires cleaning and/or debridement of at least one tooth affected by the disease and administration of the composition into the adjacent pocket caused by gum and/or bone recession caused by the oral disease.

In light of the above, the present inventors addressed the problem of creating a dental care material suitable for both teeth whitening and the treatment, prevention, or reduction of gingivitis, periodontitis, and peri-implantitis. This problem is solved within the scope of the present invention, in particular by the inventions defined in the claims.

The present invention relates to a dental care product comprising:

a) 0.4-40 wt.% calcium phosphate particles with a size of 0.01-50 μm,

b) 0.001-5 wt.% of a self-assembling peptide consisting of the sequence SEQ ID NO: 1,

c) 0.1-5 wt.% of the extract of the plant of the genus Rhododendron , and

d) 0.1-5 wt.% of the extract of the plant of the genus Leontopodium .

As noted above, teeth whitening products containing calcium phosphate and self-assembling peptides are already known in the art, for example from publication WO 2015/044268 A1, the contents of which are incorporated herein by reference in their entirety. The compositions and features thereof described in WO 2015/044268 A1 can be used in the context of the present invention in combination with the extracts described therein.

Self-assembling peptides are capable of forming a protein matrix or hydrogel through self-assembly. The protein matrix is preferably present in the dental care product in the form of a hydrogel, meaning that the proteins (e.g., self-assembling peptides) are not present as monomers.

The present inventors have demonstrated that a matrix of said self-assembling peptide and calcium phosphate particles can be formed on the tooth surface, which exhibits an enhanced whitening effect compared to a layer of mineral particles deposited on the tooth surface using known methods (see, for example, Dabanoglu et al., 2009). It is believed that structures incorporating mineral particles according to the present invention are preformed in a dental care product and are stable under oral conditions. They are also at least partially resistant to brushing with an ultrasonic toothbrush.

Self-assembling peptides are described, for example, in WO 2004/007532 A1, the contents of which are incorporated herein by reference in their entirety. WO 2004/007532 A1 describes peptides that are capable of forming three-dimensional scaffolds, thereby facilitating de novo nucleation of calcium phosphate. These artificial peptides assemble in one dimension, forming beta-sheets and higher-order assemblies, such as ribbon-like assemblies. Self-assembling proteins can form three-dimensional supramolecular structures that have affinity for calcium phosphate.

Several other self-assembling peptides (SAPs) that can be used in the present invention are described in the prior art. For example, WO 2010/041636 A1 describes a bioadsorbable peptide tissue closure agent comprising an artificial peptide having 8-200 amino acid residues with alternating linked hydrophilic amino acids and hydrophobic amino acids, which self-assembles into a beta structure at physiological pH. Self-assembling peptides with alternating hydrophobic and hydrophilic residues or regions that interact with the extracellular matrix are also described in WO 2008/113030 A2. WO 2010/103887 A1 describes self-assembling peptides that contain basic, hydrophobic, and acidic amino acids in a specific primary sequence, and peptide gels thereof that have high strength. Other self-assembling peptides are described in WO 2010/019651 A1.

Another application, published as WO 2007/000979 A1, describes self-assembling peptides with polar and non-polar amino acids. These peptides are capable of forming a beta-sheet structure, in which the non-polar amino acid residues are located on one side of the assembled structure. Amphiphilic self-assembling peptides for use as stable macroscopic membranes for various biomaterial applications, such as delayed-diffusion drug delivery, are described in US Patent No. 6,548,630.

EP 2327428 A2 describes a pharmaceutical composition comprising self-assembling peptide nanofibers that are complementary to each other and at least one cell for repairing damaged tissue, such as tissue after a myocardial infarction.

In the context of the present invention, the self-assembling peptides described in WO 2004/007532 A1 are particularly advantageous, in particular the self-assembling peptide designated as oligopeptide 104 (SEQ ID NO: 1, QQRFEWEFEQQ.)

Self-assembling peptides can be modified peptides containing an Ac-N-terminus and/or an NH2 _- C-terminus, or unmodified peptides. Preferably, they have an Ac-N-terminus and/or an NH2- _C -terminus.

Preferably, the concentration of the self-assembling peptide is 0.001-0.5 wt.%, and optionally 0.01-0.05 wt.%.

The self-assembling peptide is capable of binding calcium phosphate particles and adhering to the tooth surface. Thus, the matrix contains calcium phosphate particle binding sites, which enable it to bind particles to the tooth surface. For example, charged amino acid residues, such as Glu, on the surface of self-assembling peptides bind to hydroxyapatite particles and to the tooth surface, which is also primarily composed of hydroxyapatite. Without intending to be bound by theory, it is believed that both reactions increase the stability of the formed complex, resulting in a more lasting whitening effect. The ability to three-dimensionally self-assemble, as demonstrated by self-assembling peptides, is important for binding. Generally, highly charged surfaces will promote calcium phosphate particle adhesion. Protein matrices are most effective when their surface contains glutamate residues, which can bind to calcium phosphate or other mineral particles, as is the case for the peptide with the sequence SEQ ID NO: 1.

The dental care product may further comprise a fluorophore. A preferred fluorophore is Trp. This fluorophore is an amino acid residue of the self-assembling peptide matrix and is preferably Trp, Tyr, and/or Phe. The self-assembling peptide with the sequence SEQ ID NO: 1 contains such fluorophores.

Optionally, the dentifrice product contains an additional fluorophore that is not an amino acid residue of the self-assembling peptide and, in one embodiment, is not covalently linked to the self-assembling peptide. In another embodiment, a covalent bond between the fluorophore and the self-assembling peptide is contemplated. For example, the fluorophore may be a phthalocyanine derivative, such as copper phthalocyanine (covarin blue). Incorporation of such a fluorophore into the matrix-mineral particle combination described above unexpectedly results in a more lasting and more intense whitening effect compared to incorporating such fluorophores into conventional toothpaste. However, the addition of an additional fluorophore to the dentifrice product of the invention is not required to achieve the whitening effect, since the self-assembling peptide contains a fluorescent amino acid residue, as described above.

The calcium phosphate particle used here includes calcium phosphate. In the context of the present invention, the calcium phosphate may be monocalcium phosphate monohydrate (MCPM) Ca(H ₂ PO4) ₂ *H ₂ O, anhydrous monocalcium phosphate (MCPA) Ca(H ₂ PO4) ₂ , dicalcium phosphate dihydrate (DCPD, brushite), CaHPO ₄ *2H ₂ O, anhydrous dicalcium phosphate (DCPA, monetite, CaHPO ₄ ), octacalcium phosphate (OCP) Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) ₄ *5H ₂ O, α-tricalcium phosphate (α-TCP) α-Ca ₃ (PO ₄ ) _2, β-tricalcium phosphate (β-TCP) β-Ca ₃ (PO ₄ ) _2, amorphous calcium phosphate (ACP) Ca _x (PO ₄ ) _y *nH ₂ O, calcium-deficient hydroxyapatite (CDHA) Ca _10-x (HPO ₄ ) _x (PO ₄ ) _6-x (OH) _2-x (0 < x < 1), hydroxyapatite (HA) Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ or tetracalcium phosphate (TTCP) Ca ₄ (PO ₄ ) ₂ O), or a mixture of different calcium phosphates. In a preferred embodiment of the invention, this may also be a particle containing calcium phosphate, such as a hydroxyapatite shell and a calcium carbonate core (e.g., Omyadent® 100, available from Omya, Oftringen, Switzerland).

In one embodiment of the invention, the particles have a degree of crystallinity of 40% or more, such as 40-60%, 60% or more, 80% or more, or 90% or more, or are crystalline. A higher degree of crystallinity is expected to result in a longer-lasting tooth whitening effect. In the context of the present invention, the calcium phosphate is preferably hydroxyapatite. The hydroxyapatite may be a substituted hydroxyapatite, such as zinc carbonate hydroxyapatite and zinc carbonate hydroxyapatite, or pure calcium phosphate, preferably in crystalline form. In the context of the present invention, reference to calcium phosphate or hydroxyapatite also includes reference to derivatized calcium phosphates or hydroxyapatites of this type, unless otherwise specified. Naturally, the calcium phosphate or hydroxyapatite particles may also consist solely of CaPO ₄ (and, of course, the crystal water required for the corresponding crystalline form).

Hydroxyapatite particles can be prepared according to the methods described, for example, in Roveri, Battistelli et al., 2009, in EP 1762215 A1, US 20050037948 A1, US 20080075675 A1, US 20100247589 A1, US 20100297203 A1, WO 2007/137606 A1 and WO 2013/068020 A1. Preferably, hydroxyapatite can be prepared according to the method described in WO 2007/137606 A1, or it can be obtained commercially from Budenheim (Budenheim, Germany).

Calcium phosphate particle size is preferably measured by granulometry, for example, using a light scattering particle size distribution analyzer (such as the LA-950, Horiba, Kyoto, Japan). The crystal shape is preferably acicular, but rod-shaped or needle-shaped crystals can also be present.

The particle size is 10 nm to 50 μm, preferably 0.1 μm to 25 μm. In one embodiment of the invention, the particle size is 10-1200 nm. The preferred size is 200-600 nm. In the context of the invention, this means that at least 30% of the particles, at least 50% of the particles, or at least 80% of the particles, preferably at least 90% of the particles, for example at least 95% or 100% of the particles have the appropriate size.

In one embodiment of the invention, 30-100% or 50-90% of the particles are 200-600 nm in size. This size was chosen for the experiments because it corresponds to the wavelength of ultraviolet light or visible light, which plays a key role in keeping teeth looking white. In the context of the present invention, the reference “approximately” means +/- 10%, preferably +/- 5%.

In one embodiment of the invention, the particles are presented as a mixture of particles of different sizes, which can provide an even more intense whitening effect. In particular, for example, 30-70% of the particles can have a size of 200-400 nm, 30-70% of the particles can have a size of 400-600 nm, and, optionally, 30-70% of the particles can have a size of 10-200 nm. Alternatively, for example, 30-70% of the particles can have a size of about 10-15 μm, about 30-70% of the particles can have a size of about 4-10 μm, and, optionally, about 10-40% of the particles can have a size of 0.1-4 μm (all % refer to wt %).

In a preferred embodiment of the invention, the particles are hydroxyapatite particles having a size of 1-25 μm, such as 4-20 μm.

In contrast to the teeth whitening products described in the prior art, the dental care product according to the invention additionally contains at least two or at least three extracts of certain plants.

In particular, the dental care product of the invention comprises an extract of a plant of the genus Rhododendron, preferably of the subgenus Rhododendron L., according to the classification of Chamberlain 1996. This subgenus is characterized by small leaves or scales, i.e., scales on the underside of the leaves. Plants of the genus Pognathum from the Himalayas and adjacent mountains and plants of the subgenus Rhododendron L. from the temperate to subarctic region of the Northern Hemisphere, and in particular plants from the Alps, are commonly used. An extract of the plant Rhododendron ferrugineum or Rhododendron hirsutum is preferably used. Extracts of the plant Rhododendron ferrugineum were used in the experiments underlying the present invention, but it is expected that extracts from closely related plant species, especially from other alpine roses, can also be used.

Rhododendron ferrugineum (sometimes called alpine rose, alpenrose, snow rose, or rusty-leaved alpine rose) is an evergreen shrub that grows in acidic soils just above the tree line in the Alps, Pyrenees, Jura, and northern Apennines. Rhododendron ferrugineum is the type species of the genus Rhododendron. This plant can grow up to 1 m tall and produces clusters of pinkish-red, bell-shaped flowers throughout the summer. The undersides of the leaves are covered with rusty-brown spots. This distinguishes Rhododendron ferrugineum from Rhododendron hirsutum, which lacks this brown coloration but has pubescent leaf margins and grows on limestone. Where two plant species grow together (usually in soils with an intermediate pH), the hybrid Rhododendron × intermedium may occur; as its name suggests, it is intermediate in form between the two parent plant species, and this hybrid can also be used in the context of the present invention. The Alpine rose is one of the most typical and characteristic alpine plants, such as those of the Swiss Alps. This plant grows at high altitudes and is characterized by a very effective defense strategy against dehydration and attack by radicals and pathogens.

The extract may be an extract of the plant's leaves and/or flowers, but not necessarily of both the plant's leaves and flowers. For example, the leaves and/or flowers can be harvested without harming the plant, as they will regenerate the following year. Preferably, the extract should be a leaf extract.

The extract has been shown to have beneficial properties, in particular, it is capable of:

inhibit UVA-induced photoaging (protein carbonylation);

exhibit a senolytic effect, i.e. destroy senescent cells without negatively affecting healthy cells; this rejuvenates the entire tissue, since senescent cells contribute to inflammation and aging;

significantly reduce redness and increase elasticity.

The extract also has a powerful antimicrobial effect, for example against bacteria that cause periodontal disease.

This applies to an alcohol extract, such as an ethanol extract, a methanol extract, an oil extract, such as an extract obtained using sunflower oil, a propylene glycol extract, a PEG extract, a hexane extract, a _CO2 extract, or a glycerol extract, or a dry extract. In the context of the dental care product according to the invention, it may be desirable to obtain a product that does not contain ethanol, methanol, hexane, PEG, or propylene glycol. Thus, a glycerol extract or a dry extract, in particular a glycerol extract, can be successfully used. The glycerol extract may additionally contain water. Extracts from the Rhododendron ferrugineum plant are commercially available, for example, from Mibelle Biochemistry, Mibelle AG (Buchs, Aargau, Switzerland).

The dental care product may contain, for example, 0.1-5% by weight, such as 0.5-3% by weight of the said extract. It has been found that its use at a concentration of 1-2% by weight is preferable. The extract may be, for example, a leaf extract extracted at a ratio of medicinal substance to extracting agent, such as glycerin, of from 1:10 to 1:100, and preferably equal to approximately 1:50.

The inventors have discovered that the dental care product of the invention, containing a plant extract of the genus Rhododendron, is particularly beneficial when combined with a plant extract of the genus Leontopodium. Likely due to its high antioxidant content, said extract possesses anti-inflammatory properties and provides beneficial synergism with the plant extract of the genus Rhododendron in treating a subject's gums, as described in more detail below, for example in the treatment of gingivitis, periodontitis, and peri-implantitis, as well as in gum rejuvenation.

Thus, the dental care product additionally contains 0.1-5 wt.% of the extract of the plant of the genusLeontopodium.A dental care product may, for example, contain 0.5-3% by weight of the said extract. It has been established that its use at a concentration of 1-2% by weight is preferable.

Said plant of the genus Leontododium may be a plant of the species Leontopodium nivale, Leontopodium albogriseum, Leontopodium andersonii, Leontopodium antennarioides, Leontopodium artemisiifolium, Leontopodium aurantiacum, Leontopodium beerianum, Leontopodium blagoveshczenskyi, Leontopodium brachyactis, Leontopodium calocephalum, Leontopodium campestre, Leontopodium chuii, Leontopodium conglobatum, Leontopodium coreanum, Leontopodium dedekensii, Leontopodium delavayanum, Leontopodium discolor, Leontopodium fangingense, Leontopodium fauriei, Leontopodium forrestianum, Leontopodium franchetii, Leontopodium giraldii, Leontopodium gracile, Leontopodium haastioides, Leontopodium haplophylloides, Leontopodium hayachinense, Leontopodium himalayanum, Leontopodium jacotianum, Leontopodium japonicum, Leontopodium kamtschaticum, Leontopodium kurilense, Leontopodium leiolepis, Leontopodium leontopodinum, Leontopodium longifolium, Leontopodium melanolepis, Leontopodium meredithae, Leontopodium micranthum, Leontopodium microphyllum, Leontopodium monocephalum, Leontopodium mucoides, Leontopodium nanum, Leontopodium niveum, Leontopodium ochroleucum, Leontopodium omeiense, Leontopodium palibinianum, Leontopodium pusillum, Leontopodium roseum, Leontopodium rosmarinoides, Leontopodium shinanense, Leontopodium sinense, Leontopodium smithianum, Leontopodium souliei, Leontopodium stellatum, Leontopodium stoechas, Leontopodium stoloniferum, Leontopodium stracheyi, Leontopodium subulatum, Leontopodium villosulum, Leontopodium villosum, Leontopodium wilsonii . Preferably, the plant should be an alpine Leontopodium, such as Leontopodium nivale, also known as edelweiss.

The extract may be an extract of the leaves and/or flowers of the plant, preferably the leaves and flowers of the plant. The extract may, for example, be an extract of the leaves and flowers, extracted at a ratio of the medicinal substance to the extracting agent, such as glycerin, of from 1:10 to 1:100, and preferably approximately 1:50. This extract has antioxidant and anti-inflammatory properties. It also improves adsorption and eliminates free radicals, which helps combat gum aging. Its high tannin content also has a protective effect. Tannins also improve elasticity and promote gum regeneration. Flavoinoids protect the vascular network. Phenylpropanoids have an astringent effect. The extract stimulates blood circulation, improves cellular activity, and thus, particularly in combination with the active substances from the Rhododendron extract, stimulates tissue regeneration.

This refers to alcohol such as ethanol extract, methanol extract, oil extract such as extract obtained using sunflower oil, extract, propylene glycol extract, PEG extract, hexane extract, CO₂-extract, glycerin extract, or dry extract. In the context of the dental care product of the invention, it may be desirable to obtain a product that does not contain ethanol, methanol, hexane, PEG, or propylene glycol. Thus, a glycerin extract or dry extract, in particular a glycerin extract, can be successfully used. The glycerin extract may additionally contain water. Extract of the flowers/leaves of the plantLeontopodium Alpinumcommercially available, for example, from Lipoid Kosmetik AG (Steinhausen, Switzerland).

The dental care product of the invention may optionally further comprise e) an extract of a plant of the genus Eleutherococcus, optionally Eleutherococcus senticosus. Eleutherococcus senticosus is a species of small woody shrub of the family Araliaceae, native to Northeast Asia. It is colloquially known as Siberian ginseng, devil's bush, eleutherococcus, qiwujia, devil's bush, shigoka, touch-me-not, wild pepper, or kang-jang . Another synonym for this plant is Acanthopanax senticosus. E. senticosus has a history of use in folk medicine and traditional Chinese medicine. Typically, extracts of the root of E. senticosus are sold as a dietary supplement or cosmetic, usually under the name "Siberian ginseng."

In the context of the present invention, the extract may be an extract of the roots, berries, and/or leaves of the plant, and, optionally, the whole plant. Preferably, the extract is an extract of the roots.

It has been shown that the predominantly biologically active substances in the root and extract, which can be used in the claimed product, are polyphenolic compounds. These components impart beneficial properties to Eleutherococcus, including anti-inflammatory, anti-irritant, and anti-stress effects. During the screening of herbal remedies, they were selected based on their anti-inflammatory activity in blood samples, and Eleutherococcus senticosus root extract was found to be one of the nine most active anti-inflammatory extracts. Thus, such extracts can be successfully used in the context of the present invention, and they additionally contribute to the anti-inflammatory and rejuvenating effects. The extract also improves wound healing.

Since active anti-inflammatory agents can be found in an alcoholic extract, such as an ethanol extract, a methanol extract, an oil extract, such as an extract obtained using sunflower oil, a propylene glycol extract, a PEG extract, a hexane extract, a _CO2 extract, or a glycerol extract, or in a dry extract, the results of the anti-inflammatory study can be considered valid for all of these extracts. In the context of the dental care product according to the invention, it may be desirable to obtain a product that does not contain ethanol, methanol, hexane, PEG, or propylene glycol. Thus, a glycerol extract or a dry extract, in particular a glycerol extract, can be successfully used. Extracts are commercially available, for example, as Herbasol® Pro extracts from Lipoid Kosmetik AG (Steinhausen, Switzerland). In the context of the dental care product according to the invention, it may be desirable to produce a product that does not contain ethanol or propylene glycol. For example, glycerin extract may be advantageously used. The glycerin extract may additionally contain water.

The dental care product of the invention may contain, for example, 0.1-5% by weight of said Eleutherococcus plant extract, for example, 0.5-2% by weight of said extract. Typically, the product contains 1-2% by weight of the extract, if present in the product. The extract may be, for example, an extract from roots extracted at a ratio of medicinal substance to extracting substance, for example glycerin, of from 1:10 to 1:100, and preferably equal to approximately 1:50.

The dental care product according to the invention, comprising the herb extract c) and, optionally, d) and/or e), may optionally contain additional herbal extracts, for example from peppermint, chamomile and/or Chinese herbs, such as, for example, Centella Asiatica, Magnolia officinalis, Panax ginseng or Bletilla Striata .

The dental care product is preferably ethanol-free. Thus, in a preferred embodiment of the invention, all plant extracts are alcohol-free extracts, such as glycerin, oil extracts, or dry extracts. Such glycerin extracts may also contain other ingredients or solvents, preferably water, and are ethanol-free. The dental care product according to the invention may be halal and/or vegetarian.

The form of the dental care product is selected from a group including toothpaste, tooth gel, dental mousse, mouthwash, mouth spray, and dental care foam.

The toothpaste may be a regular toothpaste used with a regular toothbrush, but it may also be a toothpaste for an ultrasonic toothbrush. In one embodiment of the invention, the dentifrice product is not a liquid, but a paste or gel, most preferably a toothpaste or tooth gel, which contains 0.5-40% by weight of the said calcium phosphate particles and 0.002-1% by weight, preferably 0.05-0.5% by weight, of the said self-assembling peptide. The gel is a non-flowing colloidal network or polymer network distributed throughout the volume of liquid in the gel. In the case of a hydrogel, the liquid is water. Unlike a liquid, a gel has a finite, usually low yield point. The toothpaste may contain fluoride in the form of sodium fluoride or sodium monofluorophosphate with a fluoride content of up to 1500 parts per million.

The dental care product may additionally contain one or more typical ingredients characteristic of the corresponding dental care product. Such typical ingredients may include:

- abrasives such as carbonates, phosphates, silicates, acrylates, aluminum oxide;

- suspending agents such as glycerin, polyethylene glycols (PEG), sorbitol, xylitol;

- binders such as cellulose and its derivatives, carrageenan, paraffin, xylose;

- detergents such as hydrogenated castor oil, sodium lauryl sulfate, cocamidopropyl betaine;

- flavoring such as caramel, vanillin, menthol, synthetic flavoring;

- preservative such as sodium benzoate, potassium sorbate, propylene glycol, parabens;

- dyes such as soluble red, acid blue 3;

- active agents such as fluorides, preferably in the form of tertiary amines such as amine fluoride, or organic fluoride such as sodium monofluorophosphate, potassium nitrate and/or oxalate, potassium nitrate.

Dental foam is an oral care product that can be sprayed directly into the mouth. The foam is then rinsed and spat out. This allows you to brush your teeth virtually anywhere, without a toothbrush. Dental foams can be used as a supplement to your daily oral care routine, such as after each meal or drink, when using a toothbrush is difficult or inconvenient. Foams can also be used while traveling or throughout the day. They are also suitable for those wearing braces or other orthodontic appliances. Dental foam may contain, for example, water, sodium citrate, zinc lactate, xylitol, hydrolyzed hydrogenated starch, D-panthenol USP, stevia extract, glycerin, Alpin Rose Active, Siberian Ginseng Pro, sodium lauroyl sarcosinate, 1N. sodium hydroxide solution, oligopeptide-104, citric acid, L-menthol, propylene glycol, peppermint oil ( Mentha arvensis ), glycolipids, sodium benzoate, potassium sorbate, Omyadent 100-OG.

Due to the presence of a herbal extract or herbal extracts in the dental care product of the invention, the dental care product exhibits a senolytic effect when applied to a subject's gums. Furthermore, the dental care product exhibits an anti-inflammatory effect when applied to a subject's gums.

Thus, the invention also provides a pharmaceutical composition containing the dental care product according to the invention. Alternatively, the composition may be classified as a cosmetic or medicinal product, depending on national legislation.

In a particular embodiment, the present invention relates to a method for treating gingivitis, periodontitis, or peri-implantitis in a subject, comprising applying an effective amount of a dentifrice of the invention to the subject's gums. Periodontal disease and its early stage, gingivitis, are inflammatory conditions affecting the periodontium, i.e., the tissues surrounding and supporting the teeth. Similarly, peri-implantitis is an inflammatory condition of the tissues surrounding a dental implant. The inventors have unexpectedly discovered that these conditions can be successfully treated with the dentifrices of the invention. They can be applied to the gums of a subject suffering from said disease. Alternatively, they can prevent the disease in a subject who has not yet been affected. The present invention also relates to a method for eliminating or reducing the number of senescent cells in the gums of a subject, comprising applying an effective amount of a dentifrice of the invention to the subject's gums. Furthermore, the invention also relates to a method for stabilizing at least one loose tooth, comprising applying an effective amount of the dental care product of the invention to the gums of a subject. The dental care product of the invention can also be used to improve wound healing, particularly gingival wounds.

Application to the subject's gums can occur during normal use of a dental care product, such as brushing with toothpaste, dental gel, or dental mousse according to the invention, or rinsing with mouthwash or dental foam. Typically, the dental care product according to the invention is applied to both the gums and teeth of the subject.

Thus, the present invention also relates to a method of whitening teeth, comprising applying an effective amount of the dentifrice of the invention to a tooth of a subject, typically to the teeth of the subject.

The present invention also relates to the cosmetic use of the dentifrice of the invention for teeth whitening. The present invention also relates to a method for whitening teeth for cosmetic reasons, comprising applying the dentifrice of the invention to the teeth. In the context of the invention, unless expressly stated or clearly evident from the context, the use of a feature or attribute in the singular may also mean "one or more." For example, the use of the term "teeth" includes the possibility of designating both a single tooth and more than one tooth, in particular all the teeth of a single person. The dentifrice of the invention may also be used to whiten crowns, implants, dental filling materials, and other oral appliances.

In the method of the invention, the composition is preferably applied once, twice, or three times a day for 1, 2, 3, 4, 5, 6, 7, or more days, and in one embodiment, daily. It can also be applied less frequently, for example, once a week or once a month. The frequency of application depends largely on the whitening effect desired by the user, as well as the degree of mechanical abrasion to which the teeth are subjected. This includes lifelong use, preferably beginning with the eruption of permanent teeth, in particular after a change in tooth color has been noticed. Application means that the gum or tooth, or preferably all teeth, of the subject are in contact with the dental care product in the manner in which the corresponding type of product is typically used. For example, toothpaste is typically used to brush teeth for 1-5 minutes, in particular approximately 2-3 minutes.

Since the dental care product according to the invention does not cause the unwanted side effects typical of whitening products containing peroxides, it can be used daily in all dental care routines without harming teeth or gums. Furthermore, the product can be used to prevent tooth demineralization. In particular, the dental care product or toothpaste according to the invention can be used every time you brush your teeth.

Alternatively, the product according to the invention can be used in addition to or alternately with another dental care product, such as an alternative fluoride-containing toothpaste. For example, the alternative fluoride-containing toothpaste can be used in the morning, while the toothpaste according to the invention can be used in the evening after the last meal of the day. The dental care product can also be used after regular dental care, such as in the evening after brushing.

Advantageously, applying an effective amount of the dentifrice product according to the invention to a subject's gums and teeth simultaneously produces a teeth-whitening effect by eliminating or reducing the number of senescent cells in the subject's gums and preventing dental caries. Thus, the dentifrice product according to the invention can be used to treat any or all of these conditions.

Thus, unlike most current teeth whitening methods, the method of the invention does not irritate the subject's gums, but instead helps address issues such as inflammation and aging of the gums, which are often exacerbated by therapeutic teeth whitening. Thus, in one embodiment, the dentifrice of the invention is used by a subject who has previously used bleaching agents, such as hydrogen peroxide, for teeth whitening, and said treatment has caused at least one side effect, such as demineralization, erosion, and increased tooth sensitivity. In this context, the dentifrice of the invention results in additional tooth whitening, while also helping to treat side effects, treat periodontal disease, rejuvenate gums, and/or restore the subject's well-being.

The following examples are intended to illustrate, but not limit, the invention. The contents of all literature sources and references cited in this application are incorporated herein in their entirety.

Examples

Example 1

Materials and methods

Suspensions of oligopeptide 104 (5 mg/ml) with or without hydroxyapatite particles (average size d50 ≤ 300 nm (Horiba); crystallinity 40-60%, 25 wt %) were obtained.

The suspensions were applied directly to the tooth enamel surface, and the residue was rinsed off (10 seconds). The sample was stored in distilled water for 24 hours at 37°C. The procedure was repeated three times.

Tooth color was measured using a dental spectrophotometer (VITA Easyshade). Lighting conditions during measurement were standardized using a black box as a background for the teeth. The tip was applied perpendicular to the tooth surface, and the average L*a*b values from three replicates were used to evaluate the color. Tooth color was measured at baseline (t1 = no treatment), 24 hours after the first application (t1), 24 hours after the second application (t3), and 24 hours after the third application (t4).

The mean changes in L*a*b values between different measurements in each group were expressed as ΔE (according to ISO 28399).

Results

The results are presented in Table 1 below:

Table 1 Control (HA only) Test (HA +
oligopeptide 104) ΔE (t2-t1) - 1st application 2.3 4.6 ΔE (t3-t2) - 2nd application 1.1 1.9 ΔE (t4-t3) - 3rd application 1.5 0.6

The experiment showed the unexpected result that the combination of the protein matrix of the invention with HA significantly increases the whitening effect observed when applying HA alone.

It should be noted that the results are presented as ΔE values for different time points, as indicated in the first column of the table. Consequently, ΔE values indicate additional increases between applications. To calculate the overall effect of all applications, the ΔE values must be summed. Calculations show that the overall ΔE value for the control (HA only) is 4.9, and the overall ΔE value for the combination (HA + Oligopeptide 104) is 7.5. Therefore, each application resulted in an improvement compared to the control.

However, the improvement is limited by the peculiar saturation of the tooth surface with light-scattering particles. While the HA+oligopeptide 104 combination attaches a near-optimal amount of HA particles to the tooth in a single application, the control group (HA only) requires more than one application to attach as many HA particles as possible to the tooth surface. This explains why the ΔE value for the HA+oligopeptide group is higher after the first application, and the increase (not the overall ΔE value) for the control (HA only) is higher after the third application. Thus, the HA-only group may have continued to benefit from additional applications, while the HA+oligopeptide group was already close to the optimum after a single application. Thus, subsequent applications also showed some improvement, albeit not as strong as in the HA+oligopeptide group in the first application.

This shows that although HA itself has a whitening effect, the effect of the combination was unexpectedly significantly greater.

The average degree of teeth whitening according to the invention is comparable to modern methods of teeth whitening, leading, for example, to the following ΔE values:

- ΔE up to 4 for home whitening,

- ΔE is approximately 2.4-5.7 after 7 days, or 2.9-5.5 after 14 days for whitening strips,

- and ΔE up to 12 in the case of mechanical bleaching (used only in medical institutions) (Gerlach et al., 2002; Demarco et al., 2009; Delfino et al., 2009).

However, the dental care product and method according to the invention have significant advantages over chemical bleaching with respect to undesirable effects such as dental erosion, increased tooth sensitivity, etc.

To confirm that the combination of self-assembling peptides and calcium phosphate particles had a synergistic effect, the above experiment was repeated using the self-assembling peptide alone (without excipients). Oligopeptide 104 was used at a concentration of 7.5 mg/ml, i.e., its concentration was higher than that of the peptide used in the invention. The ΔE value was determined 24 hours after application, with three measurements per tooth and 10 teeth examined. The ΔE value was 0.62. Accordingly, the self-assembling peptide used alone did not exert a noticeable whitening effect. Using HA alone, a ΔE value of 2.3 was obtained after 24 hours, and for the combination of the self-assembling peptide and HA, as proposed in the present invention, the ΔE value was 4.6, which should be considered a synergistic effect.

Example 2

Evaluation of the antimicrobial activity and cytotoxic effect of leaf extracts of plants of the genus Rhododendron in relation to epithelial cells of the epidermis and intestine (Rezk A, et al., 2005. BMC Complement Altern Med. 2015; 15:364).

Rhododendron ferrugineum extracts have been shown to have high antimicrobial activity and are non-toxic to IEC6 cells.

For this purpose, the described experiment was repeated with oral mucosal cells and Rhododendron ferrugineum extract (e.g. from Mibelle Biochemistry, Mibelle AG (Buchs, Aargau, Switzerland) at concentrations of 1, 2 and 3% (w/w). Antimicrobial activity was tested against bacteria associated with periodontal disease, i.e., predominantly Gram-negative anaerobic bacteria such as A. actinomycetemcomitans, P. gingivalis, P. intermedia, B. forsythus, C. rectus, E. nodatum, P. micros, S. intermedius and Treponema sp .

Example 3:

To study the effect of plant extracts, a scratch test or wound healing assay was used to determine the positive effect of the extract on wound healing.

A wound healing assay is a laboratory method used to study cell migration and cell-cell interactions. It is also called a scratch test because it is performed by creating a scratch on a cell monolayer and capturing images at regular intervals using time-lapse microscopy.

Specifically, this two-dimensional approach for assessing cell migration is used to semiquantitatively measure cell migration on a flat cell layer. This scratch can be generated by various means, such as mechanical, thermal, or chemical damage. The purpose of this scratch is to create a cell-free area to induce cells to migrate and close the gap. The scratch test is only ideal for cell types that migrate as collective epithelial sheets and is useless for non-adherent cells. (https://en.wikipedia.org/wiki/Wound_healing_assay). The scratch test can be performed, for example, as described in the publication by Rodriguez LG, et al. (2005. Methods in Molecular Biology. 294: 23-9).

In a scratch test using oral mucosal epithelial cells, Rhododendron ferrugineum extract (e.g. from Mibelle Biochemistry, Mibelle AG (Buchs, Aargau, Switzerland)), Leontopodium Alpinum flower/leaf extract (e.g. from Lipoid Kosmetik AG (Steinhausen, Switzerland)) and Siberian ginseng extract (e.g. from Lipoid Kosmetik AG (Steinhausen, Switzerland)) were tested individually and in combination (at a concentration of 2% (w/w) each).

Variants of the invention

The present invention provides for the following embodiments:

1. A dental care product containing:

a) 0.4-40 wt.% calcium phosphate particles with a size of 0.01-50 μm,

b) 0.001-5 wt.% of a self-assembling peptide consisting of the sequence SEQ ID NO: 1,

c) 0.01-5 wt.% of the extract of the plant of the genus Rhododendron, and

d) 0.01-5 wt.% of Leontopodium plant extract.

2. The dental care product according to embodiment 1, wherein the concentration of the self-assembling peptide is 0.001-0.5 wt.%, optionally 0.01-0.05 wt.%.

3. A dental care product according to any one of embodiments 1 or 2, wherein said plant of the genus Rhododendron is Rhododendron ferrugineum.

4. A dental care product according to any one of embodiments 1 or 2, wherein said plant of the genus Rhododendron is Rhododendron hirsutum.

5. A dental care product according to any of embodiments 1-4, wherein the dental care product comprises 1-2 wt.% of an extract of said plant of the genus Rhododendron.

6. A dental care product according to any one of embodiments 1-5, wherein said plant of the genus Leontododium is Leontopodium nivale, Leontopodium albogriseum, Leontopodium andersonii, Leontopodium antennarioides, Leontopodium artemisiifolium, Leontopodium aurantiacum, Leontopodium beerianum, Leontopodium blagoveshczenskyi, Leontopodium brachyactis, Leontopodium calocephalum, Leontopodium campestre, Leontopodium chuii, Leontopodium conglobatum, Leontopodium coreanum, Leontopodium dedekensii, Leontopodium delavayanum, Leontopodium discolor, Leontopodium fangingense, Leontopodium fauriei, Leontopodium forrestianum, Leontopodium franchetii, Leontopodium giraldii, Leontopodium gracile, Leontopodium haastioides, Leontopodium haplophylloides, Leontopodium hayachinense, Leontopodium himalayanum, Leontopodium jacotianum, Leontopodium japonicum, Leontopodium kamtschaticum, Leontopodium kurilense, Leontopodium leiolepis, Leontopodium leontopodinum, Leontopodium longifolium, Leontopodium melanolepis, Leontopodium meredithae, Leontopodium micranthum, Leontopodium microphyllum, Leontopodium monocephalum, Leontopodium mucoides, Leontopodium nanum, Leontopodium niveum, Leontopodium ochroleucum, Leontopodium omeiense, Leontopodium palibinianum, Leontopodium pusillum, Leontopodium roseum, Leontopodium rosmarinoides, Leontopodium shinanense, Leontopodium sinense, Leontopodium smithianum, Leontopodium souliei, Leontopodium stellatum, Leontopodium stoechas, Leontopodium stoloniferum, Leontopodium stracheyi, Leontopodium subulatum, Leontopodium villosulum, Leontopodium villosum, Leontopodium wilsonii .

7. A dental care product according to any one of embodiments 5 or 6, wherein said plant of the genus Leontododium is Leontopodium nivale.

8. A dental care product according to any one of embodiments 1-7, further comprising e) an extract of a plant of the genus Eleutherococcus, optionally Eleutherococcus senticosus.

9. A dental care product according to any one of embodiments 1-8, wherein said extract c) is a glycerol extract.

10. A dental care product according to any one of embodiments 1-9, comprising extract d), wherein said extract d) is a glycerol extract.

11. A dental care product according to any one of embodiments 1-10, comprising extract e), wherein said extract e) is a glycerol extract.

12. A dental care product according to any one of embodiments 1-8, wherein said extract c) is an alcohol extract, such as an ethanol extract.

13. A dental care product according to any one of embodiments 1-8 and 12, comprising extract d), wherein said extract d) is an alcohol extract, such as an ethanol extract.

14. A dental care product according to any of embodiments 1-8 and 12-13, comprising extract e), wherein said extract e) is an alcohol extract, such as an ethanol extract.

15. A dental care product according to any one of embodiments 1-14, wherein said extract c) is an extract of leaves and/or flowers of a plant, optionally leaves and flowers of a plant.

16. A dental care product according to embodiment 15, wherein said extract c) is an extract of plant leaves.

17. A dental care product according to any of embodiments 15-16, wherein said extract c) is an extract of plant flowers.

18. A dental care product according to any one of embodiments 1-17, comprising 0.5-3 wt. % of said extract c), optionally 1-2 wt. %

19. A dental care product according to any one of embodiments 1-18, comprising extract d), wherein said extract d) is an extract of leaves and/or flowers of a plant, optionally leaves and flowers of a plant.

20. The dental care product according to embodiment 19, wherein said extract d) is an extract of plant leaves.

21. A dental care product according to any of embodiments 19-20, wherein said extract d) is an extract of plant flowers.

22. A dental care product according to any of embodiments 1-21, comprising 0.5-3 wt.% of said extract d), optionally 1-2 wt.%.

23. A dental care product according to any one of embodiments 1-22, comprising extract e), wherein said extract e) is an extract of the roots, berries and/or leaves of a plant, not necessarily the whole plant.

24. A dental care product according to embodiment 23, wherein said extract is an extract of plant roots.

25. A dental care product according to any of embodiments 23-24, containing 0.5-3 wt.% of said extract e), optionally 1-2 wt.%

26. A dental care product according to any one of embodiments 1-25, wherein the self-assembling peptide is in an assembled form.

27. A dental care product according to any one of embodiments 1-26, wherein said calcium phosphate particles comprise hydroxyapatite and, optionally, consist of the same.

28. A dental care product according to any one of embodiments 1-27, wherein 30-70% of said calcium phosphate particles have a size of 200-600 nm.

29. A dental care product according to any one of embodiments 1-28, wherein the dental care product is selected from the group consisting of a toothpaste, a dental gel, a mouthwash, a mouth spray, and a dental care foam.

30. A dental care product according to any one of embodiments 1-29, wherein the dental care product is a toothpaste.

31. A dental care product according to any one of embodiments 1-29, wherein the dental care product is a mouthwash.

32. The dental care product according to any one of embodiments 1-29, wherein the dental care product is a mouth spray.

33. A dental care product according to any one of embodiments 1-29, wherein the dental care product is a dental care foam.

34. A dental care product according to any one of embodiments 1-33, comprising 0.5-40 wt.% of said calcium phosphate particles and 0.001-1 wt.%, optionally 0.05 wt.%, of said self-assembling peptide, and wherein the dental care product is a toothpaste.

35. The dental care product of any one of embodiments 1-34, wherein the dental care product has a senolytic effect when applied to the gums of a subject.

36. The dental care product according to any one of embodiments 1-35, wherein the dental care product has an anti-inflammatory effect when applied to the gums of a subject.

37. A pharmaceutical composition comprising a dental care product according to any one of embodiments 1-36.

38. A method for treating periodontal disease or peri-implantitis in a subject, comprising applying an effective amount of a dental care product according to any one of embodiments 1-37 to the gums of the subject.

39. The method according to embodiment 38, wherein the periodontal disease is gingivitis.

40. The method according to embodiment 38, wherein the periodontal disease is periodontitis.

41. The method according to embodiment 38, wherein the method is a method for treating peri-implantitis.

42. A method for eliminating or reducing the number of senescent cells in the gums of a subject, comprising applying an effective amount of a dental care product according to any one of embodiments 1-37 to the gums of the subject.

43. A method for stabilizing at least one loose tooth, comprising applying an effective amount of a dental care product according to any one of embodiments 1-37 to the gums of a subject.

44. A method for whitening teeth, comprising applying an effective amount of a dental care product according to any one of embodiments 1-37 to the teeth of a subject, wherein the composition is optionally applied once, twice or three times a day for 1, 2, 3, 4, 5, 6, 7 or more days, such as daily.

45. The method according to embodiment 44, wherein the method is a cosmetic method.

46. The method according to any one of embodiments 38-45, which is a method for whitening teeth, eliminating or reducing the number of senescent cells in the gums of a subject and treating periodontal disease, comprising applying an effective amount of a dental care product according to any one of embodiments 1-37 to the gums and teeth of the subject.

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Demarco et al., 2009. Braz Oral Res. 23 Suppl 1:64-70.

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EP 1762215 A1, EP 2327428 A2

US 20050037948 A1, US 20080075675 A1, US 2008199431 A1, US 20100247589 A1, US 20100297203 A1, US 2010/0247457 A1

US 6548630

WO 2004/007532 A1, WO 2006/073889 A2, WO 2007/000979 A1, WO 2006/047315 A2, WO 2007/137606 A1, WO 2008/113030 A2, WO 2009/026729 A1, WO 2010/041636 A1, WO 2010/103887 A1, WO 2013/068020 A1, WO2010/019651 A1, WO 2015/044268 A1, WO 2018/033570 A1

JP 2008/081424, JPH 115722

JPH 115722, JP 2008/081424, JP 2007/0176862, JP 2001/131041, CN 101385856

--->

SEQUENCE LIST

<110> Credentis AG

<120>Anti-inflammatory and senolytic dental care product with whitening properties

<130> 12749 P 6575 US

<160> 1

<170> BiSSAP 1.3.6

<210> 1

<211> 11

<212> Peptide

<213> Artificial sequence

<220>

<223> P11-4/oligopeptide 104

<400> 1

Gln Gln Arg Phe Glu Trp Glu Phe Glu Gln Gln

1 5 10

<---

Claims (21)

1. A dental care product containing a) 0.4-40 wt.% calcium phosphate particles with a size of 0.01-50 μm, b) 0.001-5 wt.% of a self-assembling peptide consisting of the sequence SEQ ID NO: 1. c) 1-5 wt.% of Rhododendron ferrugineum leaf extract, and d) 1-5 wt.% of the extract of leaves and flowers of Leontopodium nivale, e) 1-5 wt.% of Eleutherococcus senticosus root extract, where all plant extracts contained are non-alcoholic glycerol extracts containing water, and where the product does not contain ethanol. 2. The dental care product of claim 1, wherein the self-assembling peptide is in assembled form. 3. The dental care product of claim 1, wherein said calcium phosphate particles comprise hydroxyapatite. 4. The dental care product according to claim 1, wherein 30-70% of said calcium phosphate particles have a size of 200-600 nm. 5. The dental care product of claim 1, wherein the dental care product is selected from the group consisting of toothpaste, dental gel, mouthwash, mouth spray, and dental care foam. 6. The dental care product according to claim 1, comprising 0.5-40 wt.% of said calcium phosphate particles and 0.02-1 wt.%, preferably 0.05 wt.%, of said self-assembling peptide, wherein the dental care product is a toothpaste. 7. A pharmaceutical composition for whitening teeth and treating periodontitis or peri-implantitis in a subject, comprising a) 0.4-40 wt.% calcium phosphate particles with a size of 0.01-50 μm, b) 0.001-5 wt.% of a self-assembling peptide consisting of the sequence SEQ ID NO: 1. c) 1-5 wt.% of Rhododendron ferrugineum leaf extract, and d) 1-5 wt.% of the extract of leaves and flowers of Leontopodium nivale , e) 1-5 wt.% of Eleutherococcus senticosus root extract, where all plant extracts contained are non-alcoholic glycerol extracts containing water, and where the product does not contain ethanol. 8. A method of treating gingivitis in a subject, comprising applying an effective amount of the dental care product of claim 1 to the gums of the subject. 9. A method for whitening teeth comprising applying an effective amount of the dental care product of claim 1 to the teeth of a subject, wherein the composition is applied one, two or three times a day for 1, 2, 3, 4, 5, 6, 7 or more days.