Silicic acid for treating periodontitis

Abstract

Oral administration of a bioavailable silicic acid, such as choline-stabilized silicic acid, daily for at least 3 months results in the prevention, inhibition, and / or treatment of periodontitis and peri-implantitis. This treatment is particularly suitable in combination with appropriate dental cleaning and oral disinfection by means of one or more antibacterial and / or antimicrobial agents, carried out at least once and appropriately regularly, such as once a year, twice a year, four times a year, or even once every two months or once a month. The treatment can be further enhanced by co-administering vitamins, trace elements, and by administering probiotics. Such other agents can be administered separately, but are preferably incorporated into a preparation of bioavailable silicic acid.

Description

Technical Field

[0001] The present invention relates to compounds and pharmaceutical compositions for preventing, inhibiting and / or treating periodontitis and / or peri-implantitis. Background Art

[0002] Periodontitis and peri-implantitis are dental diseases. In periodontitis, the periodontal destruction is triggered by the host's reaction to pathogenic bacteria that can accumulate on teeth, initially causing gingival inflammation and ultimately leading to the destruction of the periodontal ligament and supporting bone. The latter can result in tooth loosening and potential tooth loss. In peri-implantitis, the hard tissues around dental implants degenerate, leading to bone defects and potential implant loss. Both diseases are caused by periodontal pathogens and have similar clinical manifestations, including deep probing depths and bleeding. Even the microorganisms cultured from both are similar. Histologically and pathologically, the diseases are different. Most importantly for clinicians, the responses of these diseases to treatment are not similar. Currently, there is no suitable non-invasive treatment for any of these diseases. For better understanding, these two diseases will now be discussed in more detail.

[0003] Periodontitis

[0004] Periodontitis is an infectious disease that typically causes painless destruction of the tooth-supporting tissues, namely the periodontal ligament. In fact, the normal periodontal ligament provides the necessary support for maintaining the function of the teeth. It consists of four main components: the gingiva, the periodontal ligament, cementum, and alveolar bone. In all four of these components, collagen fibers play an important structural role as they determine the biomechanical properties of the tissue. Periodontitis involves a gradual loss of the alveolar bone around the teeth and, if left untreated, can lead to tooth loosening and subsequent tooth loss. Periodontitis also increases the risk of various systemic diseases, including atherosclerosis, coronary heart disease, stroke, and low birth weight in infants. This destruction of the periodontal ligament is caused directly and / or indirectly by a microbial mixture (called dental plaque) in the periodontal pocket, which is a breeding ground between the tooth root and the gingiva. The direct way involves the action of enzymes from pathogenic species. The indirect way involves the host inflammatory response to bacterial antigens.

[0005] Periodontal diseases are divided into 7 main categories, 2 to 6 of which are called destructive periodontal diseases because this damage is essentially irreversible. These seven categories are: 1. Gingivitis; 2. Chronic periodontitis; 3. Aggressive periodontitis; 4. Periodontitis associated with systemic diseases; 5. Necrotizing ulcerative gingivitis / periodontitis; 6. Periodontal abscess; 7. Periodontic-endodontic lesions. If up to 30% of the sites in the oral cavity are affected, the manifestation is classified as "local"; if more than 30%, the term "extensive" is used.

[0006] The "severity" of the disease is related to the amount of periodontal collagen ligament fibers that have been lost, resulting in the presence of "clinical attachment loss" and "periodontal pockets". According to the American Academy of Periodontology, severity is subdivided into mild, moderate, and severe, where mild means 1 - 2 mm of attachment loss, moderate means 3 - 4 mm of attachment loss, and severe means ≥5 mm (0.20 inches) of attachment loss.

[0007] The development of periodontitis begins with inflammation triggered by dental plaque. When dental plaque or biofilm accumulates on teeth near and below the gum line, the composition of the biofilm changes from being predominantly streptococcal to plaque dominated by Actinomyces. Motile bacteria also become more common. When this occurs, the gums become inflamed. Initially, this occurs in the form of gingivitis, which means the inflammation is confined to soft tissues above the bone level. The inflammation in the gums can remain at the gingivitis level for a long time and not progress to periodontitis unless there are local conditions or widespread host susceptibility. In this case, the immune system's response to dental plaque accumulation changes from a response mainly mediated by neutrophils to a response mediated by lymphocytes and plasma cells. Clinically, the gums appear swollen, red, and have a tendency to bleed. This changes the environment, leading to a change in the composition of the biofilm itself. When this occurs, a gram - negative - dominated environment is established, and periodontal pathogens emerge. These include Aggregatibacter actinomycetemcomitans, the red complex bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola), and to a lesser extent, the orange complex bacteria (Fusobacterium nucleatum, Peptostreptococcus micros, Prevotella intermedia, Prevotella nigrescens, Eubacterium nodatum, and Streptococcus constellatus). The strongest bacterial association with chronic periodontitis is with Porphyromonas gingivalis. A variety of virulence factors of this pathogen have been identified. This allows Porphyromonas gingivalis to evade defense mechanisms and perpetuate the inflammation within the periodontal membrane. Prolonged inflammation of the periodontal membrane leads to a sharp transition from the attached gingiva to the attached tooth, along with deepening of the periodontal pocket and bone defects around the tooth. Untreated periodontitis progresses unevenly over time but results in loss of function, tissue destruction, and tooth loss.

[0008] It should be noted that there seems to be an error in the original text where the description of moderate severity is incorrect. It should be 3 - 4 mm of attachment loss as per the standard classification of periodontal disease severity. The translation has been made according to the corrected content for a more accurate reflection of the knowledge.The main treatment focus for periodontitis is the removal of plaque and the resulting calculus ("tartar"). Good hygiene instructions (such as regular brushing and flossing) help prevent plaque accumulation, but professional cleaning by a dentist is necessary to remove hardened plaque. "Scaling" refers to removing tartar from above and below the gum line, while "root planing" involves special tools to remove tenacious calculus and bacterial deposits on the root surface under local anesthesia. Despite these treatments, patients may still retain residual deep periodontal pockets. Currently, non-invasive treatments are not available for treating connective tissue loss, which leads to residual deep periodontal pockets. Only invasive gum surgery is used to reduce the depth of periodontal pockets, usually in combination with bone or tissue grafts or special materials to replace or stimulate new growth of bone or gum tissue.

[0009] Teughels et al., J. of Clinical Periodontology, 40(2013), 1025 - 1035 discloses compositions incorporating certain "beneficial" bacteria to improve the oral flora in patients with chronic periodontitis. The beneficial bacterial strain is Lactobacillus reuteri. According to the authors, when Lactobacillus reuteri lozenges are used as an adjunct to scaling and root planing (SPR) and oral hygiene instructions, the clinical results show clinically relevant benefits for the patients, as the efficacy indicators of "risk of disease progression" and "need for additional surgery" are significantly better. The authors further observed that although the number of pathogens in the flora can be greatly reduced initially by SRP, periodontal pathogens rapidly recolonize the treated niches in the oral cavity.

[0010] Peri-implantitis

[0011] For many years, dental implants have proven to be good substitutes when one or more teeth are missing. Despite the high clinical success rate in terms of implant survival, problems with peri-implant inflammation are frequently reported. When this inflammatory process is limited to the soft tissue around the implant, it can be referred to as peri-implant mucositis. On the other hand, peri-implantitis involves the degradation of the hard tissue around the implant, resulting in bone defects and periodontal pocket formation. This is not observed at the time of implant placement but can only be detected several years later. Five to ten years after implant placement, one in five patients has peri-implantitis.

[0012] Peri-implantitis is not only common but also a serious complication. Implants are expensive and are intended to last a patient's lifetime. Unfortunately, peri-implantitis can lead to the disintegration and premature loss of the implant and its supporting prosthesis.

[0013] Since both diseases share many common features, the treatment of peri-implantitis may be similar to that of periodontitis. Both diseases can be triggered by periodontal pathogens and have similar clinical manifestations, including deep probing depths and bleeding. Even the microorganisms cultured from both are similar. However, histologically and pathologically, the diseases are different. The microorganisms in peri-implantitis are more diverse than those in periodontitis. Histologically, peri-implantitis is much more infiltrative near the alveolar ridge and usually lacks the tissue protective layer on the bone as we commonly see in periodontitis. But most importantly for clinicians, the response of these diseases to treatment is not similar.

[0014] Similar to periodontitis, peri-implantitis lesions do not respond well to improved oral hygiene and professional cleaning. This is not to underestimate the importance of oral hygiene and professional maintenance in preventing peri-implantitis. However, once peri-implantitis develops, conservative therapies appear ineffective. Non-surgical treatment of peri-implantitis using lasers or air abrasion systems has shown poor results. Studies evaluating chemotherapy and mechanical debridement have shown minimal resolution. Recent attempts to use photodynamic therapy to treat peri-implantitis lesions have also been unsuccessful. In summary, non-surgical treatment has not been able to predictably halt peri-implantitis.

[0015] Therefore, improved non-invasive, non-surgical therapies are needed, as professional cleaning (oral disinfection) and the use of specific probiotics have not shown curative effects, that is, they at least partially eliminate the cause of the infection, but these treatments cannot achieve the regeneration of the gingiva and alveolar bone. In addition, the authors observed that the results were only effective against specific bacteria. Apparently, the colonization of such bacteria may depend to a large extent on an individual's diet and oral development. Summary of the Invention

[0016] Accordingly, an object of the present invention is to provide improved, non-invasive, non-surgical methods for preventing, inhibiting, and / or treating periodontitis and peri-implantitis that do not rely on the successful colonization of certain bacteria.

[0017] Another object is to provide compounds and pharmaceutical compositions for preventing, inhibiting, and / or treating periodontitis and peri-implantitis.

[0018] According to a first aspect, the present invention provides a bioavailable silicon compound for oral use, the silicon compound being used for preventing, inhibiting, and / or treating periodontitis and / or peri-implantitis.

[0019] According to a second aspect, the present invention provides a pharmaceutical composition for oral administration, the pharmaceutical composition comprising a bioavailable silicon compound for preventing, inhibiting, and / or treating periodontitis and / or peri-implantitis.

[0020] According to a third aspect, the present invention provides a method for treating periodontitis and / or peri-implantitis, the method comprising orally administering a bioavailable silicon compound.

[0021] The bioavailable silicon compound particularly has the formula Y x Si(OH) 4-x and / or its oligomers, where Y is optionally a substituted (C1-C4) alkyl group, (C2-C5) alkenyl group, (C1-C4) alkoxy group, amino group, and x is from 0 to 2. More preferably, x = 0.

[0022] Surprisingly and unexpectedly, it has been found that orally administering a bioavailable silicon compound can alleviate the clinical symptoms of periodontitis and peri-implantitis.

[0023] More particularly, when orally administering the silicon compound in the form of tablets, granules, capsules or liquids, an improvement in the probing pocket depth (PPD) and bleeding on probing (BOP) has been observed in periodontitis, and bone regrowth has been observed in peri-implantitis. It has been demonstrated that administering a bioavailable silicon compound is effective in inhibiting and treating ongoing periodontitis as well as chronic periodontitis. Administering a bioavailable silicon compound has been further demonstrated to be effective in the treatment of peri-implantitis. Although the probing pocket depth was not measured in the experiment for fear of risking implant defect, a significant improvement in bone regrowth has been observed and recorded by radiographs.

[0024] It has been found that orally administering a silicon compound is successful in reducing the probing pocket depth reduction and bleeding on probing in periodontitis patients with deep periodontal pockets having a depth greater than 4 mm on one or more teeth, even in the case of residual deep periodontal pockets. A residual periodontal pocket refers to a periodontal pocket that still exists even after scaling and root planing. In the case of residual deep periodontal pockets, there is a significant risk that the teeth or implants may become completely exfoliated and lost over time. Surprisingly, administering a silicon compound is effective in such advanced states of periodontitis and peri-implantitis, which current practitioners (such as dentists) consider quite difficult to cure.

[0025] Given the surprising results obtained especially in advanced stages of the disease, orally administered bioavailable silicon compounds are also beneficial for patients at risk of developing periodontitis and / or peri-implantitis and / or for patients in the early stages of said diseases. In particular, when orally administered bioavailable silicon compounds are prescribed for any patient receiving implants during a treatment period of, for example, at least 6 months or preferably at least 12 months, it is considered that the overall risk of developing peri-implantitis will be reduced. The administration of bioavailable silicon compounds in the form of silicic acid in combination with a choline stabilizer is considered to be more advantageous since choline is considered beneficial for collagen, which is necessary in order for the implant to be well encapsulated by the tissue.

[0026] In a preferred embodiment, the silicon compound is used to treat patients suffering from severe generalized periodontitis who have an attachment loss of at least 5 mm, and even more preferably at least 6 mm, prior to initial non-surgical periodontal treatment. The term "generalized periodontitis" is used for a situation where, when there are 14 teeth present, most of the teeth are affected, for example at least 8 teeth, especially at least 10 teeth, or even at least 14 teeth. If the number of teeth is less than 14, then 8 to 14 teeth should be affected. The treatment is particularly useful for patients with at least 3 natural teeth in each quadrant. The use of bioavailable silicon compounds is preferably combined in the present case with the local application of an antibacterial agent. In addition, especially with regard to such generalized periodontitis, it is considered beneficial to locally apply at least one of an antibiotic and a probiotic strain.

[0027] For patients suffering from aggressive periodontitis, the oral administration of bioavailable silicon compounds is also particularly advantageous. The term "aggressive periodontitis" refers to the manifestation of periodontal disease in patients who in most cases appear healthy and do not have a high level of dental plaque. It tends to have a familial aggregation and the disease progresses rapidly. Aggressive periodontitis occurs in local and generalized forms. Aggressive periodontitis may be due to the presence of bacteria. Thus, the treatment preferably involves the combined oral administration of a bioavailable silicon compound and the administration of an antibiotic.

[0028] In an alternative embodiment, the silicon compound is used to treat patients with peri-implantitis. For the treatment of patients with peri-implantitis, in order to obtain good results and taking into account bone regeneration and individual differences, administration for at least one year is highly preferred. This dosing regimen is based on experimental results. For non-smoking patients with peri-implantitis with a bone defect measured by intraoral X-ray at the affected site of more than 3 mm, it was found that the daily oral administration of the silicon compound for one year stopped the progressing bone defect and even improved the bone level at the implant site. In addition, the color of the gingiva indicates an improvement in angiogenesis and an improvement in the periodontal health condition without inflammation.

[0029] In yet a further embodiment, the silicon compound is used in treatment after a surgical operation has been performed. More specifically, the surgical operation provides an incision in the tissue around a tooth or an implant, which is required for subsequent cleaning of each tooth or implant, for example, using an antibacterial agent. In the case of deep periodontal pockets, such a surgical step is particularly necessary, otherwise the periodontal pockets cannot be properly cleaned. The silicon compound is considered to contribute to bone stimulation and regeneration and to contribute to tissue healing. In the present application, oral administration of the silicon compound together with a choline stabilizer is considered to be very advantageous, since choline is considered to have a positive effect on tissue healing.

[0030] In yet a further embodiment, the silicon compound is used for the prevention of periodontitis and / or peri-implantitis. Particularly but not exclusively for prophylactic use, the administration of a bioavailable silicon compound is suitably combined with the administration of one or more vitamins and trace elements. The relevant vitamins and trace elements for periodontitis and peri-implantitis include vitamin C, zinc, copper, and selenium. Other vitamins and trace elements include vitamin D, vitamin K, boron, calcium, and magnesium. The administration of one or more of these additional vitamins and / or trace elements is considered to be particularly relevant for peri-implantitis.

[0031] The silicon compound is administered for oral use. More particularly, oral use is for absorption through the gastrointestinal tract. Such absorption is also referred to as enteral use. As a result, the silicon compound is systemically administered rather than topically, externally administered.

[0032] The silicon compound is preferably administered in an oral dosage form in a dose range of 1 mg to 50 mg Si per day, preferably 3 mg to 20 mg Si per day, such as 5 mg to 15 mg Si per day, such as 10 mg Si per day. When used for prophylactic treatment, the dose is suitably lower than the dose in curative treatment. Suitably, the dose for prophylactic treatment is about 30% to 60% of the dose in curative treatment. For example, 3 mg to 6 mg Si per day is considered effective for prevention, while 6 mg to 15 mg Si per day is preferably used for treatment. Particularly in the case of curative treatment, it is considered preferable to administer the silicon compound twice a day. Surprisingly, it has been demonstrated that such a small daily dose is sufficient to have an impact on the tissues in the oral cavity. The dose is particularly small when considering oral administration. In fact, when the silicon compound is absorbed by the human body from the gastrointestinal tract, the silicon compound becomes available to the body.

[0033] More preferably, in the case of periodontitis, the silicon compound is administered daily for at least three months. Improvement was seen after three months. However, in the case of periodontitis, in order to maintain and enhance the results obtained and taking into account the individual differences of the human body, it is considered beneficial to administer daily for at least six months.

[0034] Preferred patient groups are adult female and male patients. A first specific patient group consists of patients with increased bone turnover, which is considered a marker for being at risk of osteoporosis. Another specific patient group is pregnant women. These patient groups are more prone to periodontitis, not necessarily due to poorer hygiene, but due to a reduced silicon content in the body and / or a higher demand for silicon. Another specific patient group is smokers and / or diabetic patients in whom the blood vessels of the gums may be reduced.

[0035] In the context of the present invention, the term "bioavailable silicon compound" refers to any silicon compound that enables silicon (preferably in the form of silicic acid) to be absorbed into the blood circulation through the gastrointestinal tract. Administering silicon to the body is troublesome because absorption generally occurs as monomeric silicic acid, and this monomeric silicic acid (as well as dimeric and trimeric silicic acids) has an inherent tendency to polymerize, which results in silica that is no longer water-soluble and cannot be absorbed through the gastrointestinal tract. The silicon compound in the composition for oral administration does not need to be monomeric, but at least in such a form that silicic acid can be in monomeric and / or oligomeric form in the gastrointestinal tract. Preferably, for this use, the bioavailable silicon compound is stabilized with a stabilizer.

[0036] A preferred silicon compound for this treatment is silicic acid. This is a form of silicon that is directly or indirectly bioavailable in the sense of having the ability to be absorbed from the gastrointestinal tract into the blood. The bioavailable form of silicic acid is more particularly its monomer, orthosilicic acid. However, it is not excluded that dimers, trimers, and higher oligomers can also be absorbed. In addition, under the conditions (low pH) present in the stomach, such higher oligomers can condense into lower oligomers (dimers, trimers, etc.) and monomers. The final polymer that can be formed from silicic acid is silica (SiO2). However, silica is no longer bioavailable.

[0037] Another group of preferred silicon compounds are alkyl- and hydroxy-substituted silanols, such as monomethyltrisilanol. Similar to orthosilicic acid, these compounds can polymerize through intermolecular reactions between the silanol (Si-OH) groups.

[0038] To prevent the polymerization of silicon compounds, it is known to add stabilizers. The stabilizers are considered to act as complexing agents for silicon compounds, especially silicic acid. Typical stabilizers include amino acids, salicylic acid, sorbitol acid, ascorbic acid, lactic acid, caproic acid, peptides, carnitine, phenols or polyphenol compounds (such as vanillin (4-hydroxy-3-methoxybenzaldehyde)), betaine, and choline. Amino acids can be present in the form of protein hydrolysates, for example, in the form of protein hydrolysates of animal or plant origin. Such proteins are preferably completely hydrolyzed into amino acids, although partial hydrolysis into substances widely known as polypeptides and peptides is not excluded. Considering the possible polar attraction between the positive charge of the ammonium group and the dipole oxygen atom of the silicon compound (more preferably the more negatively charged silicic acid), the applied stabilizer preferably contains at least one amino group (including the (charged) quaternary ammonium group). Moreover, the ammonium group can be well matched at a short distance from the silanol groups of the substantially tetrahedral arrangement of silicic acid.

[0039] In a preferred embodiment of the present invention, the silicon compound is stabilized or combined with choline or a choline derivative. Choline is a precursor of phospholipids, which are essential components of cell membranes, and is also involved in cell signaling (such as the neurotransmitter acetylcholine), lipid metabolism, preventing the breakdown of collagen fibers in bone and other connective tissues mediated by homocysteine, and inhibiting inflammation and oxidative stress. It is believed that choline contributes to positive outcomes in treating patients with periodontitis and / or peri-implantitis.

[0040] The choline compound can be administered separately from the silicon compound or integrated as a stabilizer of the silicon compound in the same composition. Preferably, choline is integrated in the same composition. The choline compound can be selected from the group consisting of choline, acetylcholine, betaine, glycerophosphocholine, sphingomyelin, phosphatidylcholine, lecithin, and their salts. The preferred form is to use choline and / or its salts. There are various known choline salts, among which choline chloride, choline bitartrate, choline hydroxide, choline dihydrogen citrate, choline 2,4-dichlorophenoxyacetate (2,4D choline salt), choline acetate, choline carbonate, choline citrate, choline tartrate, choline lactate, dibutyl phosphate choline; choline O,O'-diethyldithiophosphate, choline dihydrogen phosphate; choline phosphate. Other choline salts are not excluded as long as they meet the requirements of pharmaceutically acceptable ingredients. Most preferably, choline or its salt is used as a stabilizer for the silicon compound. The use of other stabilizers for the silicon compound is not excluded.

[0041] In another embodiment, the formulation further comprises trace elements. Examples of trace elements include magnesium, zinc, calcium, copper, boron, and selenium. These elements, especially magnesium and / or calcium, have a beneficial effect on bone formation and are considered very useful in the prevention and / or treatment of peri-implantitis. They can be incorporated into the formulation containing silicic acid together with a stabilizer (such as choline). In a further embodiment, the formulation further comprises vitamins. Examples of vitamins are vitamin D, vitamin K, and vitamin C. These vitamins promote connective tissue formation by stimulating bone metabolism and / or the biosynthesis of collagen. The vitamins and / or trace elements can be administered further separately from the formulation of the silicon compound, rather than as part of the same formulation. However, for compliance, it is advantageous to include the vitamins and / or trace elements in the same formulation. Since patients are often aware of the need to consume vitamin C, it is most preferred to include vitamin D and vitamin K.

[0042] The formulation can be a liquid preparation or a solid preparation. As a solid preparation, coated pellets prepared by the extrusion-spheronization method can be used. Alternatively, liquid-filled capsules with a capsule shell containing hydroxyalkylcellulose or hydroxyalkylalkylcellulose (preferably hydroxypropylmethylcellulose) can be used, as described in the unpublished application EP18164045 in the name of the applicant (which document is incorporated herein by reference). The capsule-in-capsule concept disclosed therein may be suitable for achieving oral administration of a second drug or nutrient in addition to the bioavailable silicon compound in a single dosage form. Furthermore, the second drug or nutrient can be chemically incompatible with the bioavailable silicon compound.

[0043] In another embodiment, the treatment involves oral administration of a bioavailable silicon compound (preferably silicic acid) optionally in combination with at least one from the group consisting of a stabilizer, trace elements, and an anti-inflammatory agent. In both periodontitis and peri-implantitis, gingival inflammation occurs, leading to redness, swelling, and softening of the gums. The anti-inflammatory agent will rapidly improve these symptoms, while the silicon compound will help regenerate the soft and hard periodontal ligament structures.

[0044] In another embodiment, the treatment involves oral administration of a bioavailable silicon compound (preferably silicic acid) optionally in combination with one or more of said stabilizers, trace elements and vitamins, and a probiotic strain and / or prebiotic composition. The use of viable probiotic strains is known to improve the balanced oral microbiota, which reduces the accumulation of periodontal pathogenic bacteria around teeth and implants, thereby at least partially preventing the causes underlying periodontitis and / or peri-implantitis. Prebiotics are indigestible fibers that stimulate the growth of beneficial bacteria. It is also believed that the use of probiotic strains and / or prebiotics contributes to a healthy balanced microbiota in the intestine, which can increase the absorption of silicon.

[0045] In another embodiment, the treatment involves oral administration of a bioavailable silicon compound (preferably silicic acid) optionally in combination with one or more of said stabilizers, trace elements and vitamins, and topical use in combination with an antimicrobial agent, a synthetic antibacterial agent and / or a natural antibacterial agent. Topical use is particularly for administration in the oral cavity, for example by a liquid formulation for washing or rinsing the oral cavity, or as a paste, microspheres, gel, tablet, fiber or other ingredient for administration in the oral cavity. Alternatively or additionally, the antimicrobial agent can be administered systemically. Antibiotics are preferably administered orally or topically within the periodontal pocket. The duration of treatment with antibiotics is further preferably 3 to 10 days, for example administered once a day, twice a day, three times a day or four times a day. Suitable antibiotic agents include penicillin, amoxicillin, augmentin, demeclocycline, doxycycline, minocycline, tetracycline, metronidazole or other nitroimidazoles, triamcinolone, clindamycine, azithromycin or other macrolides, moxifloxacin, ciprofloxacin or other quinolones, azithromycin or other lincomycin derivatives, any pharmaceutically acceptable salts thereof and combinations thereof. The antibiotic agent is administered, for example, at a concentration of up to 25 wt%. In the most preferred administration, the antimicrobial agent is administered subgingivally, for example in the form of a gel, or encapsulated in bioavailable microspheres suspended in a gel carrier. A combination of oral administration of a bioavailable silicon compound, systemic antibiotics and topical antimicrobial rinses is also possible.

[0046] The antimicrobial agent is suitable for oral disinfection and irrigation of the affected area. Suitable antimicrobial agents are chlorhexidine and / or any pharmaceutically acceptable salts thereof, such as chlorhexidine digluconate. As an adjunct to scaling and root planing, chlorhexidine solution can be used for gargling, irrigating the periodontal pocket, and cleaning implants respectively, while chlorhexidine gel is used for brushing the teeth and / or implants and the tongue respectively. Chlorhexidine solution and gel are usually administered at a concentration of 0.5% to 1.5%, preferably 1 wt%, although lower concentrations, such as 0.1 wt% to 0.5 wt%, are not excluded. Alternative antimicrobial agents include sodium hypochlorite, povidone iodine, and hydrogen peroxide. Surgical intervention may be required to create an access flap to facilitate the removal of subgingival bacteria and non-bacterial residues adhering to the periodontal membrane and / or the lower part of the implant. In the case of advanced bone defects, such surgical intervention can be combined with the local application of bioactive substances that promote bone growth, such as deproteinized bone mineral, bone grafts, or other bone substitutes with or without a collagen membrane.

[0047] It has been found that optimal results are obtained by simultaneously performing oral sterilization and oral administration of bioavailable silicic acid by irrigating the periodontal pocket, cleaning and disinfecting the implant or teeth and / or using local and oral antimicrobials and / or using subgingival bioactive substances. Description of the Drawings

[0048] With reference to the exemplary embodiments and the drawings, these and other aspects of the invention will be further elucidated, wherein

[0049] Figure 1 shows the change in the BOP score of periodontitis patients after 6 months of standard treatment combined with oral administration of bioavailable silicic acid compared to standard treatment alone (control).

[0050] Figure 2A and Figure 2B shows the PPD score ( Figure 2A ) and BOP score ( Figure 2B ) of periodontitis patients (n = 10) with residual periodontal pockets (following standard treatment) before oral administration of bioavailable silicic acid (baseline) and 3 and 6 months after administration of bioavailable silicic acid; * p < 0.05 relative to baseline.

[0051] Figure 3A and 3B schematically shows the stages of periodontitis in two individual patients. The situation is shown in the form of a map of dents at baseline and 3 and 6 months after treatment with oral administration of bioavailable silicic acid.

[0052] Figure 4A and 4BX-ray photographs of implants in female patients with peri-implantitis before and after one year of oral administration of bioavailable silicic acid.

[0053] Figure 5A-5C X-ray photographs of implants in female patients with peri-implantitis with severe bone defect (A) and damaged gingiva (as baseline) after 6 months and 12 months of treatment with orally administered bioavailable silicic acid.

[0054] Figure 6 Oral photographs of patients with implants, showing the state after treatment with the compounds of the present invention. Examples

[0055] Example 1

[0056] In dental practice, a clinical test was conducted on patients with periodontitis. 40 patients with periodontitis were randomly selected. All 40 patients were given the standard treatment of scaling and root planing. The 40 patients were divided into two treatment groups, with 20 patients in each group. The patients in the first treatment group were given a solid form of bioavailable silicon (bioavailable silicic acid) for oral administration twice a day. The bioform of silicon can be obtained commercially from Bio Minerals N.V., Sterbeekhoven, Belgium, under the trade name The preparation contains choline-stabilized orthosilicic acid wherein silicic acid is stabilized with choline chloride. The preparation also contains microcrystalline cellulose as a carrier. The solid encapsulated preparation was prepared by extrusion and packaged in magnetically inductively sealed high-density polyethylene bottles to ensure a constant humidity level. The remaining 20 patients were the control group. The patients were instructed to take 2 capsules per day for six months, each capsule containing 5 mg Si. The treatment was evaluated by measuring the probing pocket depth (PPD), the percentage of teeth with PPD, and bleeding on probing (BOP) before the start of treatment (t = 0) and after treatment (t = 6 months). Periodontal pocket depth probing was performed using a calibrated probe (North Carolina periodontal probe, Hu-Friedy, Chicago, IL, USA).

[0057] Table 1 summarizes the treatment results for the probing pocket depth (PPD). These results show that the use of the silicon product as an adjunct to the standard therapy led to a better improvement in deep periodontal pockets (i.e., periodontal pockets > 4 mm), and for periodontal pockets > 5 mm, a statistically significant improvement was achieved (see Table 1: control change vs. treatment change). After six months of oral silicon treatment, the percentage of teeth with deep periodontal pockets was also reduced by 10% compared to the control group (change in the treatment group: -70%, change in the control group: -60%). When the standard therapy was combined with the administration of bioavailable silicic acid, a greater improvement in BOP was also observed after six months of treatment, as Figure 1as shown

[0058]

[0059] Probing pocket depth (PPD) (mm); including standard deviation, **p < 0.05 relative to control.

[0060] Example 2

[0061] Clinical testing was carried out on periodontitis patients with residual periodontal pockets in dental practice. 10 periodontitis patients were randomly selected. These periodontitis patients had received standard treatment (scaling and root planing), but still had deep periodontal pockets despite the standard treatment.

[0062] After standard treatment, all 10 patients were orally administered a bioavailable form of silicon in solid form. The bioavailable form of silicon is commercially available from Bio Minerals N.V., Sterrebeek, Belgium, under the trade name The preparation contains choline-stabilized orthosilicic acid wherein silicic acid is stabilized with choline chloride. The preparation also contains microcrystalline cellulose as a carrier. The solid encapsulated preparation is prepared by extrusion and packaged in a magnetically inductive sealed high-density polyethylene bottle to ensure a constant humidity level. The treatment was evaluated by measuring the probing pocket depth (PPD) and bleeding on probing (BOP) before the start of treatment (t = 0) and after treatment (t = 6 months) respectively. The periodontal pocket depth was probed with a calibrated probe (North Carolina periodontal probe, Hu-Friedy, Chicago, IL, USA).

[0063] The results are shown in Figure 2A and Figure 2B For the results of only oral ch-OSA supplement, both PPD and BOP decreased after 3 months. After 6 months of treatment, other benefits were visible for BOP. After 3 months and 6 months of oral ch-OSA supplement, PPD was significantly lower than the baseline statistically.

[0064] Example 3

[0065] Two individual patients with chronic periodontitis were administered choline-stabilized orthosilicic acid in the form of a bioavailable silicic acid, wherein silicic acid is stabilized with choline chloride. The first patient was a 56-year-old non-smoking male patient. The second patient was a 36-year-old non-smoking female patient. The results are shown in Figure 3A and Figure 3BAs shown, where the color provides an indication of the periodontal pocket depth. The actual depth is also indicated for each tooth. The data was obtained by measuring the periodontal pocket depth around each tooth in the oral cavity 6 times. In two cases, periodontitis was significantly reduced. Before treatment, the patients had very deep periodontal pockets. After treatment, this was reduced to a low depth (less than 3 mm).

[0066] Example 4

[0067] A 66-year-old non-smoking female patient with peri-implantitis had severe bone defects at two implant sites (as Figure 4A shown). For one year, the patient received 5 drops of the liquid twice daily. The preparation contained choline-stabilized orthosilicic acid wherein silicic acid was stabilized with choline chloride. The preparation also contained glycerol as a diluent. After one year, the bone level at the implant sites increased significantly (see Figure 4B ).

[0068] A second 73-year-old non-smoking patient with peri-implantitis had severe bone defects and damaged gums at the implant sites ( Figure 5A ), and this patient received 5 drops of the liquid twice daily for one year. After one year, the bone level at the implant sites also increased significantly ( Figure 5B , at 6 months; Figure 5C , at 12 months). Figure 6 It was shown that the gums regained their normal appearance and had a good color, indicating improved angiogenesis during the one-year treatment.

[0069] The following treatment examples can be used as an adjunct to good oral hygiene, scaling, and root planing:

[0070] Example 5: Combined treatment for preventing periodontitis

[0071] - Administer 5 mg of choline-stabilized orthosilicic acid in the form of bioavailable silicic acid orally daily, wherein silicic acid is stabilized with choline chloride, for example, administered in the form of capsules.

[0072] - Administer a tablet containing 200 mg of vitamin C, 150 micrograms of selenium, 10 mg of zinc, and 1 mg of copper daily.

[0073] Example 6: Combined treatment for preventing peri-implantitis

[0074] - Administer 5 mg of choline-stabilized orthosilicic acid in the form of bioavailable silicic acid orally daily, wherein silicic acid is stabilized with choline chloride, for example, administered in the form of capsules.

[0075] - Administer 1000 mg of calcium, 6 micrograms of vitamin D, and 50 micrograms of vitamin K daily, preferably in two formulations (e.g., tablets).

[0076] - Administer 200 mg of vitamin C, 100 micrograms of selenium, 10 mg of zinc, 1 mg of copper, 0.5 mg of boron, and 200 mg of magnesium daily, e.g., in the form of a single formulation (e.g., tablet).

[0077] Example 6: Combination for treating periodontitis

[0078] - Administer 10 mg of a bioavailable silicon compound orally daily for 6 months, where the bioavailable silicon compound is choline-stabilized orthosilicic acid in the form, where silicic acid is stabilized with choline chloride; 10 mg of bioavailable silicon is preferably administered in two dosage units, each dosage unit containing 5 mg of bioavailable silicon (e.g., as a tablet);

[0079] - Rinse the oral cavity twice daily with a 1% chlorhexidine solution for 4 weeks.

[0080] Preferably, the administration of bioavailable silicic acid starts simultaneously with the oral rinsing.

[0081] Example 7: Combination for treating periodontitis

[0082] - Perform an initial full-mouth one-stage disinfection by rinsing with a 0.12% chlorhexidine solution for 2 minutes.

[0083] - Administer 10 mg of choline-stabilized orthosilicic acid orally for 6 months in the form of bioavailable silicic acid, where silicic acid is stabilized with choline chloride, suitably in the form of two dosage units, each dosage unit containing 5 mg of bioavailable silicic acid,

[0084] - Administer two probiotic lozenges daily for 6 months, each containing live strains of 2 Lactobacillus reuteri (1×10 8 CFU), e.g., DSM17938 and ATCC PTA5289.

[0085] Preferably, the administration of bioavailable silicic acid starts simultaneously with the administration of the probiotic lozenges. Alternatively, during a preparation period of, e.g., 3 to 14 days (e.g., 1 week), the administration of bioavailable silicic acid can be before the administration of the probiotic lozenges.

[0086] Example 8: Combination for treating aggressive periodontitis

[0087] - Administer 10 mg of choline-stabilized orthosilicic acid orally daily for 6 months A bioavailable form of silicic acid, wherein the silicic acid is stabilized with choline chloride;

[0088] - Oral administration of amoxicillin (250 mg three times a day) and metronidazole (250 mg three times a day) for 1 week, and

[0089] - Twice daily rinsing of the oral cavity with a 1% chlorhexidine solution for 4 weeks.

[0090] Example 9: Treatment of aggressive periodontitis

[0091] - Oral administration of 10 mg of choline-stabilized orthosilicic acid per day for 6 months A bioavailable form of silicic acid, wherein the silicic acid is stabilized with choline chloride, for example, administered in the form of 2 dosage units,

[0092] - Combined oral administration of amoxicillin (250 mg three times a day) and metronidazole (250 mg three times a day) for 1 week, and

[0093] - Subgingival placement of 2.5 mg of chlorhexidine gluconate in a hydrolyzed gelatin matrix chip (PerioChip). The chip degrades within 7 to 10 days.

[0094] Preferably, the administration of the bioavailable silicic acid and the administration of the antibiotic start simultaneously and are carried out simultaneously with the subgingival placement. However, alternative regimens are not excluded.

[0095] Example 10: Treatment of aggressive periodontitis

[0096] - Oral administration of 10 mg of choline-stabilized orthosilicic acid per day for 6 months A bioavailable form of silicic acid, wherein the silicic acid is stabilized with choline chloride, preferably administered in the form of 2 dosage units (e.g., tablets).

[0097] - Local application in the affected periodontal pocket of ethylene / vinyl acetate copolymer fibers containing tetracycline (12.7 mg per 9 inches) for 10 days.

[0098] - Twice daily rinsing of the oral cavity with a 1% chlorhexidine solution for 4 weeks.

[0099] Example 11: Combination for the treatment of peri-implantitis

[0100] - Oral administration of 10 mg of choline-stabilized orthosilicic acid per day for 12 months A bioavailable form of silicic acid, wherein the silicic acid is stabilized with choline chloride, preferably administered in the form of 2 dosage units (e.g., capsules).

[0101] - Administer 1000 mg of calcium, 6 micrograms of vitamin D, and 50 micrograms of vitamin K daily, preferably in the form of 2 dosage units (e.g., tablets).

[0102] - Administer 200 mg of vitamin C, 100 micrograms of selenium, 10 mg of zinc, 1 mg of copper, 0.5 mg of boron, and 200 mg of magnesium daily, preferably in the form of tablets.

[0103] - Irrigate the periodontal pocket with a 1% chlorhexidine solution and clean the implant.

[0104] - Gargle the oral cavity with a 1% chlorhexidine solution twice daily for 4 weeks.

[0105] Example 12: Combination for treating peri-implantitis

[0106] - Administer orally 10 mg of choline-stabilized orthosilicic acid daily for 12 months in the form of bioavailable silicic acid, where silicic acid is stabilized with choline chloride, e.g., in the form of 2 dosage units (e.g., capsules).

[0107] - Perform surgical intervention to create an access flap, remove subgingival bacterial and non-bacterial residues, irrigate the periodontal pocket with a 1% chlorhexidine solution and clean the implant. Use deproteinized bone mineral on a collagen membrane.

[0108] - Gargle the oral cavity with a 1% chlorhexidine solution twice daily for 4 weeks.

[0109] - Administer 1000 mg of calcium, 6 micrograms of vitamin D, and 50 micrograms of vitamin K daily, e.g., in the form of 2 dosage units (e.g., tablets).

[0110] - Administer 200 mg of vitamin C, 100 micrograms of selenium, 10 mg of zinc, 1 mg of copper, 0.5 mg of boron, and 200 mg of magnesium daily, e.g., in the form of tablets.

[0111] In any of the above examples of combined oral administration of an antimicrobial agent and / or an antibiotic with a bioavailable silicon compound, it is preferred that the administration of the silicon compound starts simultaneously with the use of the antimicrobial agent and / or the antibiotic. However, alternatively, during a preparation period of, for example, 3 to 14 days (e.g., 1 week), the administration of the bioavailable silicic acid can be before the administration of the antimicrobial agent and / or the antibiotic.

[0112] In summary, these examples show that oral administration of a bioavailable silicon compound (such as silicic acid) daily for at least 3 months results in the inhibition of periodontitis and peri-implantitis, and is thus a therapeutically effective non-invasive, non-surgical treatment. In cases where plaque is subgingival and difficult to reach, which may require a surgically created access flap, this treatment is particularly suitable in combination with appropriate oral hygiene with one or more antibacterial and / or antimicrobial agents. The treatment can be further enhanced by co-administering vitamins (such as vitamin C, vitamin D, vitamin K) and / or trace elements (such as magnesium, calcium, selenium, boron, and copper), and by administering probiotics or using subgingival bioactive substances. The positive results in chronic periodontitis demonstrate the main benefit of the present invention. The positive results in peri-implantitis provide a non-invasive treatment for this disease. Given that the daily dose of bioavailable silicic acid can inhibit and even cure a disease already in an advanced state, both positive results are very surprising in themselves. The present invention further relates to a method for preventing, inhibiting, or treating periodontitis and / or peri-implantitis, which comprises orally administering a bioavailable silicic acid.

Claims

1. Use of a bioavailable silicon compound in the preparation of an oral medicament for preventing, inhibiting and / or treating periodontitis and / or peri-implantitis by systemic administration of the bioavailable silicon compound, wherein, The bioavailable silicon compound is silicic acid or monomethyltrisilanol stabilized by a choline compound.

2. The use according to claim 1, wherein The silicon compound is orthosilicic acid.

3. The use according to claim 1 or 2, wherein, The choline compound is selected from the group consisting of choline, choline hydroxide, acetylcholine, betaine, glycerophosphocholine, sphingomyelin, phosphatidylcholine, lecithin or a salt thereof.

4. The use according to claim 3, wherein, The salts of the choline compound are selected from the group consisting of: choline chloride, choline bitartrate, choline dihydrogen citrate, choline 2-4-dichlorophenoxyacetate, choline acetate, choline carbonate, choline citrate, choline tartrate, choline lactate, dibutyl phosphate choline; choline O,O'-diethyldithiophosphate, choline dihydrogen phosphate; choline phosphate.

5. Use according to claim 1 or 2, wherein, The silicon compound is administered in the form of capsules, tablets, liquids or granules.

6. The use according to claim 1 or 2, wherein The drug is formulated into a dosage form for absorption through the gastrointestinal tract.

7. Use according to claim 1 or 2 above, wherein, The silicon compound is used to reduce probing bleeding and / or periodontal pocket probing depth.

8. The use according to claim 7, wherein The compound is used to reduce the periodontal pocket probing depth in patients with a periodontal pocket probing depth value of at least 4 mm in one or more teeth.

9. Use of a pharmaceutical composition in the preparation of an oral drug for preventing, inhibiting and / or treating periodontitis and / or peri-implantitis by systemic administration of the pharmaceutical composition, the pharmaceutical composition comprising a bioavailable silicon compound and at least one pharmaceutically acceptable excipient, the bioavailable silicon compound being silicic acid or monomethyltrisilanol stabilized by a choline compound.

10. The use according to claim 9, wherein, The pharmaceutical composition further comprises trace elements and / or vitamins, the trace elements being selected from the group consisting of magnesium, zinc, calcium, copper, boron and selenium, and the vitamins being selected from the group consisting of vitamin C, vitamin D and vitamin K.

11. Use according to claim 9 or 10, the pharmaceutical combination comprising an antibacterial agent, an antimicrobial agent, a probiotic, a prebiotic and / or trace elements and / or vitamins, the trace elements being selected from the group consisting of magnesium, zinc, calcium, copper, boron and selenium, and / or the vitamins being selected from the group consisting of vitamin C, vitamin D and vitamin K.

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