EA046983B1 - SILICIC ACID FOR USE IN TREATMENT OF PERIODONTITIS - Google Patents

Description

Field of technology to which the invention relates

The invention relates to a compound and pharmaceutical composition for use in the prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis.

Information about the prior art

Periodontitis and peri-implantitis are dental diseases. Periodontal destruction in periodontitis is caused by the host's response to pathogenic bacteria that are allowed to accumulate on the teeth, initially causing inflammation of the gums and ultimately leading to the destruction of the periodontal ligament and supporting bone. The latter can lead to loosening and potential loss of teeth. With peri-implantitis, the hard tissue around a dental implant degenerates, leading to bone loss and potential implant loss. Both diseases are initiated by periodontal pathogens and have similar clinical manifestations, including significant probing depth and bleeding. Even the microbiology cultured from both is similar. The diseases differ histologically and pathologically. What is most important for clinicians is that diseases do not respond equally to treatment. There is currently no suitable non-invasive treatment for any of these diseases. For better understanding, we will now discuss these two diseases in more detail.

Periodontitis

Periodontitis is an infectious disease that often results in painless destruction of the tissue supporting the teeth, the periodontium. In fact, a normal periodontium provides the necessary support to maintain healthy teeth. It consists of four main components: gingiva, 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 is the progressive loss of alveolar bone around the teeth and, if left untreated, can lead to loosening and subsequent tooth loss. In addition, periodontitis increases the risk of various systemic diseases, including atherosclerosis, coronary heart disease, stroke, and low birth weight infants. This periodontal destruction is caused directly and/or indirectly by a mixture of microorganisms (called plaque) in the periodontal pocket, which is the habitat between the roots of the teeth and the gums). The direct pathway involves the action of enzymes of pathogenic species. The indirect pathway involves the host's inflammatory response to bacterial antigens.

There are seven main categories of periodontal disease, of which 2-6 are called destructive periodontal diseases because the damage is essentially irreversible. The seven categories are: 1. gingivitis; 2. chronic periodontitis; 3. aggressive periodontitis; 4. periodontitis as a manifestation of a systemic disease; 5. necrotizing ulcerative gingivitis/periodontitis; 6. periodontal abscesses; 7. combined periodontal-endodontic lesions. If up to 30% of areas in the mouth are affected, the manifestation is classified as localized; for more than 30% the term generalized is used.

The severity of the disease depends on the amount of periodontal fibers and collagen ligaments lost, resulting in clinical attachment loss and pocketing. According to the American Academy of Periodontology, severity is categorized as mild, moderate, and severe, with mild meaning 1 to 2 mm of attachment loss; moderate means 3-4 mm attachment loss, severe means >5 mm (0.20 inch) attachment loss.

The development of periodontitis begins with inflammation caused by plaque. As plaque, or biofilm, accumulates on the teeth near and under the gums, there is a shift in the composition of the biofilm from essentially streptococcal plaque to actinomycete-dominated plaque. Motile bacteria are also more common. In this case, inflammation occurs in the gums. This initially takes the form of gingivitis, which is inflammation limited to the soft tissue above the bone level. Gum inflammation can remain at the level of gingivitis for a long period and will not develop into periodontitis unless local conditions or a general predisposition of the host are present. In this case, the immune system's response to plaque accumulation shifts from a predominantly neutrophil-mediated response to a lymphocyte- and plasma cell-mediated response. Clinically, the gums are swollen, red and prone to bleeding. This changes the environment, which changes the composition of the biofilm itself. This creates a predominantly gram-negative environment with the appearance of periodontal pathogens. These include A. actinomycetemcomitans, red complex bacteria (P. gingivalis, T. forsythia, T denticola) and, to a lesser extent, orange complex bacteria (F. nucleatum, P. micros, P. intermedia, P. nigrecens, E. nodatum and S. constellates). The strongest bacterial association with chronic periodontitis is P. gingivalis.

Numerous virulence factors have been identified for this pathogen. This allows P. gingivalis to escape defense mechanisms and maintain inflammation within the periodontium. Long-term periodontal inflammation leads to apical displacement of the gum attachment to the tooth, with deepening of the pockets and loss of bone mass around the teeth. Untreated periodontitis progresses over time

- 1 046983 erodes unevenly, but leads to loss of function, tissue destruction and tooth loss.

Primary treatment for periodontitis is aimed at removing bacterial plaque and hard tartar (tartar) that has formed. Good hygiene instructions, such as frequent brushing and flossing, help prevent plaque buildup, but hardened plaque must be removed by a professional dentist, i.e., scaling means scraping away the tartar above and below the gum line, and to align on the surface of the tooth roots, special instruments are used to remove hard deposits of tartar and bacteria from the surface of the roots under local anesthesia. Despite these treatments, patients may be left with residual deep pockets. There are currently no non-invasive treatments available to treat the connective tissue loss that causes residual deep pockets. To reduce pocket depth, only invasive gum surgery is used, often in combination with bone or tissue grafts, or special materials to replace or stimulate new growth of bone or gum tissue.

Teughels et al., J. of Clinical Periodontology, 40 (2013), 1025-1035, disclose the administration of a composition of certain beneficial bacteria to improve the bacterial flora in the oral cavity of patients with chronic periodontitis. The beneficial bacteria strain is Lactobacillus reuteri. According to the authors, the clinical results showed a clinically significant benefit to the patient, as the outcome measures risk of disease progression and need for additional surgery were significantly improved when L. reuteri lozenges were used as an adjunct to scaling and root planing ( SRP) and oral hygiene instructions. The authors also note that although pathogens in the bacterial flora may initially be significantly reduced by SRP, periodontal pathogens quickly recolonize treated niches in the oral cavity.

Peri-implantitis

For many years, dental implants have served as a good replacement when one or more teeth are missing. Despite the high clinical success rate in terms of implant survival rates, problems associated with inflammation around already osseointegrated implants are frequently reported. When this inflammatory process is limited to the soft tissue around the implant, it is referred to as peri-implant mucositis. On the other hand, peri-implantitis involves degeneration of the hard tissue surrounding the implant with bone loss and pocket formation. This is not observed when the implant is installed, but is discovered only after several years. Five to ten years after implant placement, every fifth patient suffers from peri-implantitis.

Peri-implantitis is not only a common but also a serious complication. Implants are expensive, but can last the patient a lifetime. Unfortunately, peri-implantitis can lead to the destruction and premature loss of implants and the prostheses they support.

Treatment of peri-implantitis can be approached similarly to periodontitis, as both diseases share many common features. Both diseases can be initiated by periodontal pathogens, and both have similar clinical manifestations, including significant probing depth and bleeding. Even the microbiology cultured from both is similar. But histologically and pathologically the diseases differ. The microbiology of peri-implantitis is more diverse compared to the microbiology of periodontitis. Histologically, peri-implantitis is much more infiltrative near the alveolar ridge and often lacks the protective layer of tissue over the bone that we typically see with periodontitis. But most importantly for clinicians, diseases do not respond equally to treatment.

Peri-implantitis lesions respond poorly to improved oral hygiene and professional cleanings, as with periodontitis. This is not to downplay the importance of oral hygiene and professional care in preventing peri-implantitis. But after the development of peri-implantitis, conservative therapy is ineffective. Non-surgical treatment of peri-implantitis using laser or air abrasive systems has shown poor results. Studies evaluating chemotherapeutic agents and mechanical debridement have shown minimal resolution. A recent study that attempted the use of photodynamic therapy to treat peri-implant lesions was also unsuccessful. Thus, nonsurgical treatments have failed to predictably relieve peri-implantitis.

Thus, there is a need for improved non-invasive, non-surgical therapy since professional cleaning (oral disinfection) and the use of certain probiotic bacteria have not proven effective in treating i.e. They eliminate the cause of the infection, at least partially, but regeneration of the gums and alveolar bone is not achieved with these treatments. Additionally, the authors note that the results are only valid for specific bacteria. It is clear that colonization of such bacteria may be highly dependent on both human diet and oral development.

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Brief description of the invention

It is therefore an object of the present invention to provide improved, non-invasive, non-surgical prevention, inhibition and/or treatment of periodontitis and peri-implantitis that is not dependent on the colonization of specific bacteria.

Another object is to provide a compound and pharmaceutical composition for use in the prevention, inhibition and/or treatment of periodontitis and peri-implantitis.

According to a first aspect, the invention provides a bioavailable silicon compound for oral use in the prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis.

According to a second aspect, the invention provides an oral pharmaceutical composition containing a bioavailable silicon compound for use in the prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis.

In accordance with a third aspect, the invention provides a method for treating periodontitis and/or peri-implantitis, comprising orally administering a bioavailable silicon compound.

The bioavailable silicon compound has, in particular, the formula Y _x Si(OH) _4-x where Y is an optionally substituted (C.'|-C.' ₄ )alkyl. (C2-C5)alkenyl, (C-SDalkoxy, amino and x is 0-2, and/or oligomers thereof. More preferably x=0.

Surprisingly, it has been found that oral administration of a bioavailable silicon compound can reduce the clinical symptoms of periodontitis and peri-implantitis.

Specifically, pocket probing depth (PPD) and bleeding on probing (BOP) were improved in periodontitis and bone regrowth was observed in peri-implantitis with oral administration of a silica compound in tablet, granule, capsule or liquid form. Administration of a bioavailable silicon compound has proven effective in inhibiting and treating ongoing as well as chronic periodontitis. Administration of a bioavailable silicon compound has also proven effective in the treatment of peri-implantitis. Although pocket probing depth was not measured in the experiments to avoid risking implant loss, marked improvements in bone regrowth were observed, confirmed by x-rays.

Oral administration of a silica compound has been found to be successful in reducing pocket probing depth and probing bleeding in patients with periodontitis who have deep pockets greater than 4 mm in depth on one or more teeth, even in cases of residual deep pockets. Residual pockets refer to pockets that remain even after scaling and planing of tooth roots. In the case of a residual deep pocket, over time there is a significant risk that the tooth or implant may become completely detached and lost. It is considered surprising that the introduction of a silicon compound is effective in such advanced conditions of periodontitis and peri-implantitis, since modern medical practitioners (for example, dentists) consider such advanced conditions to be largely incurable.

Given the surprising results obtained in particularly advanced stages of the disease, oral administration of a bioavailable silicon compound is also beneficial for patients who are at risk of developing periodontitis and/or peri-implantitis, and/or for patients in whom these diseases are at an early stage. In particular, when oral administration of a bioavailable silicon compound is administered to any patient receiving an implant for a treatment period of, for example, at least 6 months or preferably at least 12 months, it is believed that the overall risk of developing peri-implantitis will be reduced. The administration of a bioavailable silicon compound in the form of silicic acid with the stabilizer choline is considered even more beneficial, since choline is believed to be beneficial for collagen, which is necessary for the implant to be well encapsulated by tissue.

In one preferred embodiment, the silicon compound is used to treat patients with severe generalized periodontitis with at least 5 mm of attachment loss prior to initial non-surgical periodontal therapy, and even more preferably with at least 6 mm of attachment loss. The term generalized periodontitis is used for a situation where most teeth are affected, for example at least 8 teeth, especially at least 10 teeth, or even at least 14 teeth affected when there are 14 teeth. If the number of teeth is less than 14, 8-14 teeth should be affected. The treatment is especially beneficial for patients who have at least 3 natural teeth in each quadrant. The use of a bioavailable silicon compound herein is preferably combined with the topical use of an antiseptic. In addition, especially with regard to such generalized periodontitis, topical application of at least one of the antibiotics and the probiotic strain is considered beneficial.

Oral administration of a bioavailable silicon compound is also particularly beneficial for patients with aggressive periodontitis. The term aggressive periodontitis refers to the appearance of periodontitis in people who generally appear healthy and do not have high levels of plaque. It tends to run in families and has a high rate of disease progression.

- 3 046983 vaniya. Aggressive periodontitis occurs in localized and generalized forms. Aggressive periodontitis can be caused by the presence of bacteria. Thus, treatment preferably involves oral administration of a bioavailable silicon compound in combination with the administration of antibiotics.

In an alternative embodiment, the silicon compound is used to treat patients with peri-implantitis. For the treatment of peri-implantitis, administration for at least one year is highly preferred to achieve a good result and taking into account bone regrowth and individual differences. This dosing regimen is based on experimental results. In nonsmoking patients with peri-implantitis who had more than 3 mm of bone loss measured on intraoral radiographs at the affected site, one year of daily oral administration of a silica compound was found to halt progressive bone loss and even improve bone levels at the affected implant site. In addition, gingival color indicated improved vascularization and improved periodontal health without inflammation.

In yet another embodiment, the silicon compound is used in treatment following surgery. Surgery, in particular an incision into the tissue surrounding the tooth or implant, is necessary to subsequently clean the tooth or implant in question, for example with an antiseptic. This surgical step is especially necessary in the case of deep pockets that otherwise cannot be properly cleaned. The silicon compound is believed to help stimulate and renew bone growth, as well as tissue healing. In this application, it is believed that oral administration of a silicon compound along with a choline stabilizer is very beneficial since choline is believed to have a positive effect on tissue healing.

In yet another 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 microelements. Relevant vitamins and minerals for periodontitis and peri-implantitis include vitamin C, zinc, copper and selenium. Additional vitamins and minerals include vitamin D, vitamin K, boron, calcium and magnesium. It is believed that the administration of one or more of these additional vitamins and/or microelements is especially relevant for peri-implantitis.

The silicon compound is prescribed for oral use. In particular, oral administration is intended for absorption through the gastrointestinal tract. This absorption is also known as enteral administration. The result is systemic administration of the silicon compound rather than local topical administration.

The silicon compound is preferably administered in an oral dosage form and at a dose in the range of 1-50 mg Si per day, preferably 3-20 mg Si per day, for example 5-15 mg Si per day, such as 10 mg Si per day. When used for prophylactic treatment, the dose will be correspondingly lower than for treatment. Accordingly, the dose for prophylactic treatment is about 30-60% of the dose administered for treatment. For example, 3-6 mg Si per day is considered effective for prevention, while 6-15 mg Si per day is preferred for treatment. In particular, in the case of treatment, it is considered preferable to administer the silicon compound twice a day. It is surprising that such a small daily dose is sufficient to affect tissue in the oral cavity. The dosage is especially small when considering oral administration. In fact, when a silicon compound is absorbed by the human body from the gastrointestinal tract and becomes available to it.

More preferably, the silicon compound is administered daily for a period of at least three months in the case of periodontitis. Improvements were noticed after just three months. However, daily administration for a period of at least six months is considered useful in the case of periodontitis to maintain and enhance the results achieved, also taking into account the individual characteristics of the human body.

Preferred patient populations are adult female and male patients. The first specific group of patients are those with increased bone turnover, which is known to be a risk marker for osteoporosis. Another specific group of patients are pregnant women. These groups of patients are more susceptible to periodontitis, which is not necessarily due to decreased hygiene, but to a lower silicon content in the body and/or a higher need for it. Another specific group of patients are smokers and/or patients with diabetes, who may have reduced gingival vascularity.

The term bioavailable silicon compound in the context of the invention refers to any silicon compound such that silicon (preferably in the form of silicic acid) is absorbed through the gastrointestinal tract into the bloodstream. The introduction of silicon into the body is difficult because absorption usually occurs in the form of monosilicic acid, and this monomeric (and dimeric, trimeric) silicic acid has an inherent tendency to polymerize, with the result that silicon is no longer soluble in water and cannot be absorbed through the gastrointestinal tract. tract. The silicon compound in the oral composition need not be monomeric, but is at least in such a form that it can produce silicic acid

- 4 046983 into monomeric and/or oligomeric form in the gastrointestinal tract. Preferably, for this application, the bioavailable silicon compound is stabilized with a stabilizing agent.

The preferred silicon compound for use in this treatment method is silicic acid. It is a form of silicon that is directly or indirectly bioavailable in terms of having the ability to be absorbed from the gastrointestinal tract into the blood. The bioavailable form of silicic acid is, in particular, its monomer, orthosilicic acid. However, it is possible that dimers, trimers and higher oligomers may also be absorbed. In addition, such higher oligomers can condense into lower oligomers (dimers, trimers, etc.) and monomers under conditions existing in the stomach (low pH). The final polymer that can be formed from silicic acid is silicon dioxide (SiO2). However, silica is no longer bioavailable.

Another preferred group of silicon compounds are alkyl- and hydroxyl-substituted silanols, such as monomethyltrisilanol. Like orthosilicic acid, these compounds can polymerize through intermolecular reactions between silanol (Si-OH) groups.

It is known that a stabilizer is added to prevent polymerization of the silicon compound. The stabilizer is believed to act as a complexing agent for silicon compounds, in particular silicic acid. Typical stabilizers include amino acids, salicylic acid, sorbitolic acid, ascorbic acid, lactic acid, caproic acid, peptides, carnitine, a phenolic or polyphenolic compound such as vanillin (4-hydroxy-3methoxybenzaldehyde), betaine and choline. Amino acids may be present in the form of protein hydrolysates, for example of animal or plant origin. Such proteins are preferably completely hydrolyzed to amino acids, although partial hydrolysis to compounds commonly referred to as polypeptides and peptides is possible. The stabilizer used preferably contains at least one of amino groups, including (charged) quaternary ammonium groups, taking into account that there may be a polar attraction between the positive charge of the ammonium group and the dipolar oxygen atoms of the silicon compound, and more preferably silicic acid, which, on the contrary, are negative . In addition, ammonium groups may be well attracted over short distances to the substantially tetrahedrally arranged silanol groups of silicic acid.

In a preferred embodiment of the invention, the silicon compound is stabilized or combined with choline or a choline derivative. Choline is a precursor to phospholipids, which are important components of cell membranes, and is also involved in cell signaling (eg, the neurotransmitter acetylcholine), lipid metabolism, protection against homocysteine-mediated breakdown of collagen fibers in bone and other connective tissues, and suppression of inflammation and oxidative stress. Choline is believed to contribute to positive treatment outcomes for patients suffering from periodontitis and/or peri-implantitis.

The choline compound can be administered separately from the silicon compound or integrated into the same composition as the silicon compound stabilizer.

Preferably, the choline is integrated into the same composition. The choline compound may be selected from the group consisting of choline, acetylcholine, betaine, glycerophosphorylcholine, sphingomyelin, phosphatidylcholine, lecithin and salts thereof. The preferred form is the use of choline and/or its salt. Various choline salts are known, including choline chloride, choline bitartate, choline hydroxide, choline dihydrogen citrate, choline 2-4-dichlorophenoxyacetate (2,4-D choline salt), choline acetate, choline carbonate, choline citrate, choline tartate, choline lactate, Choline Dibutyl Phosphate; Choline O,O'-diethyldithiophosphate, choline dihydrogen phosphate; Choline phosphate. Other choline salts are not excluded if they meet the requirements for pharmaceutically acceptable ingredients. Most preferably, choline or a salt thereof is used as a stabilizing agent for the silicon compound. This does not exclude the additional use of other stabilizing agents for silicon compounds.

In another embodiment, the preparation additionally contains a trace element. Examples include magnesium, zinc, calcium, copper, boron and selenium. These elements, and 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 may be included in a preparation containing silicic acid with a stabilizer such as choline. In yet another embodiment, the formulation further comprises a vitamin. Examples include vitamin D, vitamin K and vitamin C. These vitamins promote the formation of connective tissue by stimulating bone metabolism and/or collagen biosynthesis. Instead of being part of the same preparation, vitamins and/or microelements can be additionally administered separately from the preparation of silicon compounds. However, it is considered beneficial to include vitamins and/or micronutrients in the same preparation to ensure compliance with the treatment regimen. Since patients often recognize the need for vitamin C, it is most preferable to include vitamin D and vitamin K.

The drug may be a liquid formulation or a solid formulation. As a solid composition

- 5 046983 you can use encapsulated granules made by extrusion-spheronization. Alternatively, filled liquid capsules may be used with a capsule shell containing hydroxyalkylcellulose or hydroxyalkylalkylcellulose, preferably hydroxypropylmethylcellulose, as described in unpublished application EP 18164045, which is incorporated herein by reference. The capsule-in-capsule concept disclosed therein may be suitable for providing oral administration of a second drug or nutrient in addition to a bioavailable silicon compound in a single dosage form. In addition, the second drug or nutrient may be chemically incompatible with the bioavailable silicon compound.

In another embodiment, the treatment comprises orally administering a combination of a bioavailable silicon compound, preferably in the form of silicic acid, optionally with at least one compound selected from the group consisting of stabilizers, trace elements and anti-inflammatory agents. In both periodontitis and peri-implantitis, gum inflammation occurs, causing the gums to become red, swollen, and painful. Anti-inflammatory drugs will quickly reduce these symptoms, while the silicon compound will help regenerate the soft and hard periodontal structures.

In another embodiment, the treatment comprises orally administering a combination of a bioavailable silicon compound, preferably in the form of silicic acid, optionally with one or more of said stabilizers, trace elements and vitamins, as well as a probiotic strain and/or a prebiotic composition. The use of viable strains of probiotics is known to improve the balance of bacterial flora in the oral cavity, thereby reducing the accumulation of periopathogenic bacteria around teeth and implants, thereby preventing, at least in part, the cause of periodontitis and/or peri-implantitis. Prebiotics are non-digestible fibers that stimulate the growth of beneficial bacteria. It is also believed that the use of probiotic strains and/or prebiotics promotes a well-balanced, healthy bacterial flora in the gut, which may increase silicon absorption.

In another embodiment, the treatment comprises the oral administration of a bioavailable silicon compound, preferably in the form of silicic acid, optionally with one or more of these stabilizers, trace elements and vitamins, in combination with the topical application of antimicrobial agents, synthetic antiseptics and/or natural antiseptics. Topical application is, in particular, introduction into the oral cavity, for example, using a liquid preparation for washing or rinsing the mouth, or as an ingredient in a paste, microspheres, gel, chip, fiber or other means. The antimicrobial agent can alternatively or additionally be administered systemically. Antibiotics are preferably administered orally or topically into the pocket. The duration of antibiotic treatment is preferably from 3 to 10 days, for example daily, twice a day, three times a day or four times a day. Suitable antibiotics include penicillin, amoxicillin, augmentin, demeclocycline, doxycycline, minocycline, tetracycline, metronidazole or other nitroimidazoles, triamcinolone, clindamycin, azithromycin or other macrolides, moxifloxacin, ciprofloxacin or other quinolones, azithromycin or other lincomycin derivatives, any pharmaceutically acceptable salts and their combinations. This antibiotic is used, for example, at a concentration of up to 25 wt.%. In the most preferred application, the antimicrobial agent is applied subgingivally, for example in the form of a gel, or it is encapsulated in bioavailable microspheres that are suspended in a gel vehicle. It is also possible to combine, respectively, an oral bioavailable silicon compound, systemic antibiotics and a local antiseptic rinse.

Antiseptics are suitable for disinfecting the oral cavity and irrigating the affected area. A suitable antiseptic is chlorhexidine and/or any of its pharmaceutically acceptable salts, such as chlorhexidine digluconate. As an adjunct to scaling and root planing, chlorhexidine solution can be used to rinse the mouth, irrigate periodontal pockets, and clean implants, respectively, while chlorhexidine gel is used to clean teeth and/or implants and the tongue, respectively. Chlorhexidine solutions and gels are usually used at a concentration of 0.5-1.5%, preferably 1 wt.%, although lower concentrations, for example 0.1-0.5 wt.%, are not excluded. Alternative antiseptics include sodium hypochlorite, povidone-iodine, and hydrogen peroxide. Surgical intervention may be required to create access through a flap to facilitate the removal of subgingival bacterial and nonbacterial debris that adheres to the lower periodontal tissue and/or implants. Such surgery may be combined, in cases of significant bone loss, with topical application of a bioactive substance that promotes bone growth, such as deproteinized bone mineral, bone grafts or other bone substitutes with or without collagen membranes.

It has been found that simultaneous disinfection of the oral cavity by, respectively, irrigating pockets, cleaning and disinfecting implants or teeth, and/or using topical and oral

- 6 046983 antimicrobial agents, and/or the use of subgingival biologically active substances together with oral administration of bioavailable silicic acid brings the best results.

Brief description of the figures

These and other aspects of the invention will be further explained with reference to examples and figures, where:

in fig. Figure 1 shows the change in BOR indicators in patients with periodontitis after 6 months of standard treatment in combination with oral administration of bioavailable silicic acid compared to standard treatment alone (control);

in fig. 2A and 2B show PPD scores (Figure 2A) and BOP scores (Figure 2B) in periodontitis patients (n = 10) with residual pockets (after standard treatment) before oral administration of bioavailable silicic acid (baseline) and after 3 and 6 months of introduction of bioavailable silicic acid; * p <0.05 compared to baseline;

in fig. 3A and 3B schematically illustrate the periodontitis scoring system for two separate patients. The situation is shown in the form of a dental chart both at baseline and after treatment for three and six months with oral administration of bioavailable silicic acid;

in fig. 4A and 4B show x-rays of an implant from a patient suffering from peri-implantitis before and after treatment for one year with oral bioavailable silicic acid;

in fig. 5A-5C show x-rays of the implant of a patient suffering from peri-implantitis with severe bone loss (A) and damaged gingiva, at baseline, after 6 months and after 12 months of treatment with oral bioavailable silicic acid;

in fig. 6 is a photograph of the oral cavity of a patient with an implant showing the condition after treatment with a compound of the present invention.

Examples

Example 1.

Clinical trials were conducted in a dental office on patients with periodontitis. Forty patients with periodontitis were randomly selected. All 40 patients underwent standard treatment to remove tartar and level the surface of the tooth roots. 40 patients were divided into two treatment groups of 20 patients each. Patients in the first treatment group were given a bioavailable solid form of silicon (bioavailable silicic acid) to be taken orally twice daily. A biological form of silicon was commercially available under the trade name BioSil® from Bio Minerals N.V., Destelbergen, Belgium. This formulation contains choline stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride. The composition further contains microcrystalline cellulose as a carrier. The solid encapsulated formulation is extruded and packaged in high-density polyethylene bottles, magnetically sealed to ensure consistent moisture levels. The remaining 20 patients represented the control group. Patients were instructed to take two capsules per day, each containing 5 mg Si, for six months. Treatment was assessed by measuring, respectively, pocket probing depth (PPD), percentage of teeth with PPD, and bleeding on probing (BOP) before treatment (t = 0) and after treatment (t = 6 months). Pocket depth probing was performed with a calibrated probe (periodontal probe, North Carolina, Hu-Friedy, Chicago, IL, USA).

Treatment results based on pocket probing depth (PPD) are summarized in Table. 1. These results demonstrate that the use of a silicon product as an adjunct to standard therapy resulted in greater improvement for deep pockets, i.e. pockets >4 mm, reaching statistical significance for pockets >5 mm (see Table 1: change in controls versus change in treatment group). After six months of oral silica treatment, the percentage of teeth with deep pockets decreased by 10% compared to controls (change in treatment group: - 70%, change in control group: - 60%). The improvement in BOP over six months of treatment was also greater when standard therapy was combined with bioavailable silicic acid administration, as shown in FIG. 1.

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Variable Time (months) Treatment group Control(n=20) Treatment with bioavailable silicic acid Average * Change* Average* Change* Total 0 4.47 ± 0.83 4.89 ± 1.04 Total 6 2.67 ± 0.34 -1.80 ±0.81 2.75 ± 0.37 -2.14 ±0.92 Shallow pockets (<4mm) 0 3.39 ±0.36 3.40 ± 0.26 Shallow pockets (<4mm) 6 2.39 ± 0.27 -1.00 ±0.47 2.46 ± 0.36 -0.94 ± 0.45 Deep pockets (4 < P < 0 5.00 ± 0.46 5.17 ±0.63 7 mm) Deep pockets (4 < P < 7 mm) 6 2.89 ± 0.43 -2.10 ±0.63 2.80 ±0.33 -2.38 ± 0.65 Deeper pockets (>5mm) 0 5.57 ±0.41 5.69 ±0.51 Deeper pockets (>5mm) 6 3.24 ± 0.63 -2.33 ± 0.70 2.93 ± 0.39 -2.76 ± 0.59** Very deep pockets (> 6 mm) 0 6.27 ±0.21 6.42 ± 0.26 Very deep pockets (>6mm) 6 3.34 ±0.69 -2.94 ± 0.67 3.26 ± 0.63 -3.16 ±0.59 Deepest pockets (>7mm) 0 7.17 ±0.24 7.14 ±0.19 Deepest pockets (>7mm) 6 4.01 ±0.26 -3.16 ±0.02 3.55 ±0.95 -3.59 ± 1.03

Pocket probing depth (PPD) in mm;

* including standard deviation, * * p <0.05 compared to control

Example 2.

Clinical trials were conducted in a dental office on patients with periodontitis with residual pockets. We randomly selected 10 patients with periodontitis who had received standard treatment (scaling and root planing) but who remained with deep pockets despite standard treatment.

After standard treatment, all 10 patients were orally administered a bioavailable solid form of the silicon compound commercially available under the trade name BioSil® from Bio Minerals N.V., Destelbergen, Belgium. This formulation contains choline stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride. The composition further contains microcrystalline cellulose as a carrier. The solid encapsulated formulation is extruded and packaged in high-density polyethylene bottles, magnetically sealed to ensure consistent moisture levels. Treatment was assessed by measuring pocket probing depth (PPD) and bleeding on probing (BOP), respectively, before treatment (t = 0) and after treatment (t = 6 months). Pocket depth probing was performed using a calibrated probe (periodontal probe, Hu-Friedy, Chicago, IL, USA).

The results are presented in Fig. 2a and 2b. With oral ch-OSA alone, both PPD and BOP scores decreased after only 3 months. Additional improvement was noted for VOR after 6 months of treatment. PPD scores were statistically significantly lower after 3 and 6 months of oral ch-OSA compared to baseline.

Example 3.

Two separate patients with chronic periodontitis were administered bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), the silicic acid being stabilized by choline chloride. The first patient was a non-smoking patient aged 56 years. The second patient was a non-smoking patient aged 36 years. The results are shown in Fig. 3A and 3B, where the color indicates the depth of the pocket. The actual depth is also indicated for each tooth. Data was obtained by measuring the pocket depth around each tooth in the mouth 6 times. In both cases, periodontitis decreased significantly. Before treatment, patients had very deep pockets. After treatment, the depth decreased to small (less than 3 mm).

Example 4.

A 66-year-old nonsmoker with peri-implantitis had severe bone loss at two implant sites (as shown in Figure 4A). The patient took 5 drops of liquid BioSil® 2 times a day for a year. This formulation contains choline stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride. Compound

- 8 046983 additionally contains glycerin as a diluent. After one year, the bone level at the implantation site increased significantly (see Fig. 4B).

A second patient with peri-implantitis, aged 73 years, a non-smoker, with severe bone loss at the implant sites and damaged gingiva (Fig. 5a), took 5 drops of liquid BioSil® twice a day for one year. After one year, the bone level also increased significantly at the implantation site (Fig. 5b, after 6 months; Fig. 5c, after 12 months). In fig. Figure 6 shows that the gum has returned to its normal appearance with good color, indicating an improvement in vascularization within 1 year of treatment.

The following examples of therapy can be used to complement good oral hygiene, scaling, and root planing.

Example 5. Combined treatment for the prevention of periodontitis.

Daily oral administration of 5 mg of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride, for example, in capsule form;

daily intake of a tablet containing 200 mg vitamin C, 150 mcg selenium, 10 mg zinc, 1 mg copper.

Example 6. Combination therapy for the prevention of peri-implantitis.

Daily oral administration of 5 mg of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride, for example, in capsule form;

daily intake of 1000 mg calcium, 6 mcg vitamin D, 50 mcg vitamin K, preferably in two formulations such as tablets;

daily intake of 200 mg vitamin C, 100 mcg selenium, 10 mg zinc, 1 mg copper, 0.5 mg boron, 200 mg magnesium, for example, in the form of a single formulation such as a tablet.

Example 6. Combination for use in the treatment of periodontitis.

Oral administration for 6 months of 10 mg of a bioavailable silicon compound per day, wherein the bioavailable silicon compound is in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride; 10 mg of bioavailable silicon is preferably administered in two dosage units, each containing 5 mg of bioavailable silicon, for example, in the form of a tablet;

rinsing the mouth with a 1% chlorhexidine solution 2 times a day for 4 weeks.

In this case, it is preferable that the administration of bioavailable silicic acid and mouth rinse be started simultaneously.

Example 7. Combination for use in the treatment of periodontitis.

Initial one-step disinfection of the entire oral cavity by rinsing for 2 minutes with a 0.12% chlorhexidine solution.

Oral administration for 6 months of 10 mg of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), the silicic acid being stabilized by choline chloride, preferably in the form of two dosage units, each containing 5 mg of bioavailable silicic acid.

Take two probiotic chewable tablets, each containing 2 viable strains of Lactobacillus reuteri (1x ¹⁰⁸ CFU), such as DSM17938 and ATCC PTA5289, daily for 6 months.

In this case, it is preferable to start taking bioavailable silicic acid and taking probiotic chewable tablets at the same time. Alternatively, administration of bioavailable silicic acid may precede administration of the probiotic chewable tablets by a run-in period, eg 3 days to 14 days, eg 1 week.

Example 8. Combination for the treatment of aggressive periodontitis.

Oral administration for 6 months of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride;

oral amoxicillin (250 mg three times daily) with metronidazole (250 mg three times daily) for 1 week, and 1% chlorhexidine mouth rinse twice daily for 4 weeks.

Example 9. Treatment of aggressive periodontitis.

For 6 months, oral administration of 10 mg per day of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride, for example, in the form of 2 dosage units;

combined oral administration of amoxicillin (250 mg 3 times a day) with metronidazole (250 mg 3 times a day) for 1 week; and subgingival placement of a chip containing 2.5 mg chlorhexidine gluconate in a hydrolyzed gelatin matrix (PerioChip). The chip degrades within 7-10 days.

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Claims (2)

Here, it is preferable that the administration of bioavailable silicic acid and the administration of the antibiotic begin simultaneously and coincide with the subgingival placement. However, alternative protocols are not excluded. Example 10. Treatment of aggressive periodontitis. For 6 months, oral administration of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), with silicic acid stabilized by choline chloride; preferably in the form of two dosage units, such as tablets; topical application of ethylene/vinyl acetate copolymer fiber containing tetracycline (12.7 mg per 9 inches) to the affected periodontal pocket for 10 days; mouth rinse with 1% chlorhexidine solution 2 times a day for 4 weeks. Example 11. Combination in the treatment of peri-implantitis. For 12 months, oral administration of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride, preferably in the form of two dosage units, such as capsules; daily intake of 1000 mg calcium, 6 mcg vitamin D, 50 mcg vitamin K, preferably in two dosage units such as tablets; daily intake of 200 mg vitamin C, 100 mcg selenium, 10 mg zinc, 1 mg copper, 0.5 mg boron, 200 mg magnesium, preferably in tablet form; irrigation of periodontal pockets and cleaning of implants with a 1% chlorhexidine solution; mouth rinse with 1% chlorhexidine solution 2 times a day for 4 weeks. Example 12. Combination for the treatment of peri-implantitis. For 12 months, oral administration of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein the silicic acid is stabilized by choline chloride, for example, in the form of two dosage units such as capsules; surgical intervention to create an access flap, removal of subgingival bacterial and non-bacterial debris, irrigation of periodontal pockets and cleaning of implants with 1% chlorhexidine solution. Using deproteinized bone mineral on a collagen membrane; rinse your mouth with a 1% chlorhexidine solution 2 times a day for 4 weeks; taking 1000 mg calcium, 6 mcg vitamin D, 50 mcg vitamin K daily, for example in two dosage units such as tablets; daily intake of 200 mg vitamin C, 100 mcg selenium, 10 mg zinc, 1 mg copper, 0.5 mg boron, 200 mg magnesium, for example, in tablet form. In any of the above examples, where the use of an antiseptic and/or antibiotics is combined with the oral administration of a bioavailable silicon compound, it is preferable that the administration of the silicon compound begin simultaneously with the use of the antiseptic and/or antibiotics. However, alternatively, the administration of bioavailable silicic acid may precede the administration of the antiseptic and/or antibiotics by a preparatory period, for example, a period of from 3 days to 14 days, for example 1 week. Thus, these examples demonstrate that oral administration of a bioavailable silicon compound, such as silicic acid, for a period of at least 3 months daily, results in inhibition of periodontitis and peri-implantitis and is thus therapeutically effective, non-invasive, non-surgical way of treatment. This method of treatment is particularly suitable in combination with appropriate cleaning of the oral cavity with one or more antiseptic and/or antimicrobial agents; in case the plaque is subgingival and difficult to access, an access flap can be surgically created. Treatment can be further enhanced by the concomitant intake of vitamins such as vitamin C, vitamin D, vitamin K and/or microelements such as magnesium, calcium, selenium, boron and copper, as well as by taking a probiotic or applying subgingival bioactive substances. Positive results in chronic periodontitis indicate the main advantage of the present invention. Positive results in peri-implantitis provide non-invasive treatment for this disease. Both positive results are quite surprising in themselves, since a daily dose of bioavailable silicic acid can inhibit and even treat a disease that is already in an advanced state. The invention also relates to a method for preventing, inhibiting or treating periodontitis and/or peri-implantitis, comprising the oral administration of bioavailable silicic acid. CLAIM 1. The use of a bioavailable silicon compound, which is silicic acid or an oligomer thereof, with a choline compound, as a stabilizing agent, for oral administration by absorption through the gastrointestinal tract for the prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis. 2. Use according to claim 1, wherein the silicon compound is silicic acid, preferably