Silicic Acids for Use in the Treatment of Periodontitis

Abstract

The oral administration of bioavailable silicic acid, such as choline-stabilized silicic acid during a period of at least 3 months daily leads to the prevention, inhibition and or treatment of periodontitis and peri-implantatis. The treatment is particularly suitable in combination with appropriate cleaning of the teeth and disinfecting the mouth, by one or more antiseptic and/or antimicrobial agent(s), as carried out at least once and suitably regularly, such as once per year, twice per year, four times per year or even every second month or every month. The treatment may be further enhanced by simultaneous administration of vitamins, trace elements, as well as by administration of a probioticum. Such additional agents may be applied separately, but are preferably incorporated in the formulation of bioavailable silicic acid.

Claims

1. A bioavailable silicon compound for oral use in prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis, wherein the bioavailable silicon compound is a silicon compound according to formula (I) or an oligomer thereof
Y.sub.xSi(OH).sub.4-x  (I) wherein: Y is optionally substituted (C.sub.1-C.sub.4)-alkyl, (C.sub.2-C.sub.5)-alkenyl, (C.sub.1-C.sub.4)-alkoxy, amino and x is 0-2.

2. The bioavailable silicon compound as claimed in claim 1, wherein the silicon compound is a silicic acid (x=0), wherein the silicic acid is preferably orthosilicic acid and/or its oligomers.

3. The bioavailable silicon compound as claimed in claim 1, wherein the bioavailable silicon compound is stabilized with a stabilizing agent.

4. The bioavailable silicon compound as claimed in claim 3, wherein the bioavailable silicon compound is administered together with a choline compound as the stabilizing agent, and the choline compound is chosen from the group comprising choline, choline hydroxide, acetylcholine, betaine, glycerophosphorylcholine, sphingomyelin, phosphatidylcholine, lecithin or a salt thereof, wherein the choline compound salt is preferably chosen from the group comprising choline chloride, choline bitartate, choline dihydrogencitrate, 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′-diethyl dithiophosphate, choline dihydrogen phosphate; and choline phosphate.

5. The bioavailable silicon compound as claimed in claim 1, wherein the silicon compound is administered in the form of a capsule, tablet, liquid or granules.

6. The bioavailable silicon compound as claimed in claim 1, wherein the silicon compound is for absorption via the gastro-intestinal tract.

7. The bioavailable silicon compound as claimed in claim 1, wherein the silicon compound is administered in an amount of 1-50 mg Si per day, preferably 5-20 mg Si per day, for instance 8-15 mg Si per day, such as 10 mg Si per day.

8. The bioavailable silicon compound as claimed in claim 7, wherein the silicon compound is administered daily during a period of at least three months, and preferably during a period of at least six months and even more preferably during a period of at least one year.

9. The bioavailable silicon compound as claimed in claim 1, wherein the silicon compound is for use in a reduction of bleeding of probing (BOP), and/or probing pocket depth (PPD).

10. The bioavailable silicon compound as claimed in claim 9, wherein the compound is for reduction of probing pocket depth (PPD) in patients having a PPD value of at least 4 mm in one or more teeth.

11. The bioavailable silicon compound as claimed in claim 1 for the oral use in prevention, inhibition and/or treatment of peri-implantitis.

12. The bioavailable silicon compound as claimed in claim 1 for the oral use in inhibition and/or treatment of periodontitis.

13. A pharmaceutical composition for oral administration comprising the bioavailable silicon compound as claimed in claim 1, and at least one pharmaceutically acceptable excipient.

14. The pharmaceutical composition as claimed in claim 13, wherein the composition further comprises a trace element, preferably chosen from the group of magnesium, zinc, calcium, copper, boron and selenium, and/or a vitamin chosen from the group of Vitamin C, Vitamin D and Vitamin K.

15. A pharmaceutical combination comprising a bioavailable silicon compound as claimed in claim 1, and an antiseptic agent, an antimicrobial agent, a probioticum, prebiotics, and/or a trace element, preferably chosen from the group of magnesium, zinc, calcium, copper, boron and selenium, and/or a vitamin chosen from the group of Vitamin C, Vitamin D and Vitamin K.

16. The pharmaceutical combination as claimed in claim 15 for use in inhibition and/or treatment of periodontitis and/or peri-implantitis.

17. The pharmaceutical combination as claimed in claim 15, wherein the bioavailable silicon compound is combined with a probioticum for use in the prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis.

18. A pharmaceutical combination comprising a pharmaceutical composition as claimed in claim 13, and an antiseptic agent, an antimicrobial agent, a probioticum, prebiotics, and/or a trace element, preferably chosen from the group of magnesium, zinc, calcium, copper, boron and selenium, and/or a vitamin chosen from the group of Vitamin C, Vitamin D and Vitamin K.

19. The pharmaceutical combination as claimed in claim 18 for use in inhibition and/or treatment of periodontitis and/or peri-implantitis and wherein the bioavailable silicon compound is optionally combined with a probioticum for use in the prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis.

20. A method for prevention, inhibition and/or treatment of periodontitis and/or peri-implantitis in a patient comprising orally administering the bioavailable silicon compound of claim 1.

Description

BRIEF DESCRIPTION OF FIGURES

[0046] These and other aspects of the invention will be further elucidated with reference to the Examples and the Figures, wherein

[0047] FIG. 1 shows change in BOP scores of periodontitis patients after 6 months standard treatment in combination with administration of oral bioavailable silicic acid in comparison to standard treatment only (control).

[0048] FIG. 2A and FIG. 2B show PPD scores (FIG. 2a) and BOP scores (FIG. 2b) of periodontitis patients (n=10) with residual pockets (following standard treatment) prior to oral administration of bioavailable silicic acid (baseline) and after 3 and 6 months of administration of bioavailable silicic acid; *p<0.05 versus baseline.

[0049] FIGS. 3A and 3B show schematically the scale of periodontitis for two individual patients. The situation is shown in the form of a map of dents, both in the baseline, and after a treatment during three and six months by oral administration of bioavailable silicic acid;

[0050] FIGS. 4A and 4B are X-ray photographs of an implant of a female patient having peri-implantitis, before and after a one year treatment by oral administration of bioavailable silicic acid;

[0051] FIG. 5A-5C are X-ray photographs of an implant of a female patient having peri-implantitis with severe bone loss (A) and damaged gingiva, as baseline, after 6 months and after 12 months treatment by oral administration of bioavailable silicic acid

[0052] FIG. 6 is a photograph of a mouth of a patient with an implantate showing the state after the treatment with the compound of the invention.

EXAMPLES

Example 1

[0053] A clinical test was carried out in a dental practice on periodontitis patients. 40 periodontitis patients were randomly selected. All 40 patients were given a standard treatment of scaling and root planning. The 40 patients were divided into two treatment groups of each 20 patients. The patients in the first treatment group were given a bioavailable form of silicon in solid form (bioavailable silicic acid) for oral administration twice a day. The 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 silicic acid is stabilized with choline chloride. The formulation furthermore contains microcrystalline cellulose as a carrier. The solid, encapsulated formulation is prepared by extrusion and is packaged in magnetic induced sealed high density polyethylene bottles to ensure a constant humidity level. The remaining 20 patients were the control group. Patients were instructed to take two capsules per day, each capsule containing 5 mg Si, during six months. The treatment was evaluated by measuring respectively probing pocket depth (PPD), the percentage of teeth with PPD and bleeding on probing (BOP), before the start of the treatment (t=0) and after the treatment (t=6 months). Probing of pocket depth was performed with a calibrated probe (North Carolina periodontal probe, Hu-Friedy, Chicago, Ill., USA).

[0054] The results of the treatment on the probing pocket depth (PPD) are summarized in Table 1. These results demonstrate that the use of the silicon product as an add-on to the standard therapy resulted in a better improvement for deep pockets, i.e. pockets >4 mm, reaching statistical significance for pockets >5 mm (see table 1: change control versus change treatment). After six months oral silicon treatment the percentage of teeth with deep pockets decreased with 10% more compared to controls (change in treatment group: −70%, change in control group: −60%). The improvement in BOP over six months treatment was also greater when the standard therapy was combined with the administration of bioavailable silicic acid, as shown in FIG. 1.

TABLE-US-00001 Treatment group Treatment with bioavailable Time Control (n = 20) silicic acid Variable (months) Mean* Change* Mean* Change* Overall 0 4.47 ± 0.83 4.89 ± 1.04 Overall 6 2.67 ± 0.34 −1.80 ± 0.81 2.75 ± 0.37 −2.14 ± 0.92 Undeep pockets (<4 mm) 0 3.39 ± 0.36 3.40 ± 0.26 Undeep pockets (<4 mm) 6 2.39 ± 0.27 −1.00 ± 0.47 2.46 ± 0.36 −0.94 ± 0.45 Deep pockets (4 ≤ P ≤ 7 mm) 0 5.00 ± 0.46 5.17 ± 0.63 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 (≥5 mm) 0 5.57 ± 0.41 5.69 ± 0.51 Deeper pockets (≥5 mm) 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 (≥6 mm) 6 3.34 ± 0.69 −2.94 ± 0.67 3.26 ± 0.63 −3.16 ± 0.59 Deepest pockets (≥7 mm) 0 7.17 ± 0.24 7.14 ± 0.19 Deepest pockets (≥7 mm) 6 4.01 ± 0.26 −3.16 ± 0.02 3.55 ± 0.95 −3.59 ± 1.03 Probing Pocket depth (PPD) in mm; *including standard deviation, **p < 0.05 versus control.

Example 2

[0055] A clinical test was carried out in a dental practice on periodontitis patients with residual pockets. 10 periodontitis patients were randomly selected who received the standard treatment (scaling and root planning) but remain to have deep pockets despite of the standard treatment.

[0056] Following the standard treatment, all 10 patients were administered orally a bioavailable form of silicon in solid form, as commercially available under the trade name BioSil®, from Bio Minerals N.V., Destelbergen, Belgium. This formulation contains choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride. The formulation furthermore contains microcrystalline cellulose as a carrier. The solid, encapsulated formulation is prepared by extrusion and is packaged in magnetic induced sealed high density polyethylene bottles to ensure a constant humidity level. The treatment was evaluated by measuring respectively probing pocket depth (PPD) and bleeding on probing (BOP), before the start of the treatment (t=0) and after the treatment (t=6 months). Probing of pocket depth was performed with a calibrated probe (North Carolina periodontal probe, Hu-Friedy, Chicago, Ill., USA).

[0057] The results are visualized in FIGS. 2a and 2b. As a result of only the oral ch-OSA supplementation, both the PPD and the BOP decreased already after 3 months. An additional benefit was seen for BOP after 6 months treatment. PPD was statistical significantly lower after 3 and 6 months oral ch-OSA supplementation versus baseline.

Example 3

[0058] Two individual patients with chronic periodontitis were administrated bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride. The first patient was a non-smoking male patient of 56 years old. The second patient was a non-smoking female patient of 36 years old. The results are shown in FIGS. 3A and 3B, wherein the color provides an indication of the pocket depth. The actual depth is also indicated for each tooth. The data were obtained by measuring the pocket depth around each tooth in the mouth 6 times. In both cases, the periodontitis reduced significantly. Before the treatment, patients had very deep pockets. After the treatment, this was reduced to low depth (less than 3 mm).

Example 4

[0059] A female peri-implantitis patient, 66 years old and non-smoker, had severe bone loss at two implant sites (as shown in FIG. 4A). The patient took during one year 5 drops of BioSil® liquid twice daily. This formulation contains choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride. The formulation furthermore contains glycerol as a diluent. After one year the bone level was significantly increased at the implant site (see FIG. 4B).

[0060] A second peri-implantitis patient, 73 years and non-smoker, with severe bone loss at the implant sites and damaged gingiva (FIG. 5a) took during one year 5 drops of BioSil® liquid twice daily. After one year the bone level was also significantly increased at the implant site (FIG. 5b, after 6 months, FIG. 5c, after 12 months). FIG. 6 shows that the gingiva regained its normal appearance with good color indicating improved vascularization in the course of the 1 year treatment.

[0061] The following treatment examples can be used as an adjunct to good mouth hygiene, scaling and root planing:

Example 5: Combination Treatment for the Prevention of Periodontitis

[0062] Daily oral administration of 5 mg of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride, for instance in the form of a capsule. [0063] Daily administration of a tablet containing 200 mg vitamin C, 150 microgram selenium, 10 mg zinc, 1 mg copper.

Example 6: Combination Treatment for the Prevention of Peri-Implantitis

[0064] Daily oral administration of 5 mg of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride, for instance in the form of a capsule; [0065] Daily administration of 1000 mg calcium, 6 microgram vitamin D, 50 microgram vitamin K, preferably in two formulations, such as tablets; [0066] Daily administration of 200 mg vitamin C, 100 microgram selenium, 10 mg zinc, 1 mg copper, 0.5 mg boron, 200 mg magnesium, for instance in the form of a single formulation, such as a tablet.

Example 6: Combination for Use in the Treatment of Periodontitis

[0067] 6 months oral administration of 10 mg of a bioavailable silicon compound per day, which bioavailable silicon compound is in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride; 10 mg bioavailable silicon is preferably administered as two dosage units, each containing 5 mg bioavailable silicon, for instance as a tablet; [0068] mouth rinsing with chlorhexidine 1% solution twice daily during 4 weeks.

[0069] It is herein preferable, that the administration of the bioavailable silicic acid and the mouth rinsing start simultaneously.

Example 7: Combination for Use in the Treatment of Periodontitis

[0070] Initial full mouth one-stage disinfection by rinsing for 2 minutes with a 0.12% chlorhexidine solution. [0071] 6 months oral administration of 10 mg of bioavailable silicic acid in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride, suitably in the form of two dosage units each containing 5 mg bioavailable silicic acid; [0072] Daily administration of two probiotic lozenges, each containing 2 viable strains of Lactobacillus reuteri (1 10.sup.8 CFU), for instance DSM17938 and ATCC PTA5289, during 6 months.

[0073] It is herein preferable, that the administration of the bioavailable silicic acid and the administration of the probiotic lozenges start simultaneously. Alternatively, the administration of the bioavailable silicic acid may precede the administration of the probiotic lozenges during a preparatory period of for instance 3 days up to 14 days, for instance 1 week.

Example 8: Combination for Use in the Treatment of Aggressive Periodontitis

[0074] 6 months oral administration of 10 mg of bioavailable silicic acid per day, in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride; [0075] Oral administration of amoxicillin (250 mg three times daily) with metronidazole (250 mg three times daily) during 1 week, and [0076] mouth rinsing with chlorhexidine 1% solution twice daily during 4 weeks.

Example 9: Aggressive Periodontitis Treatment

[0077] 6 months oral administration of 10 mg of bioavailable silicic acid per day, in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride, for instance in the form of 2 dosage units [0078] combined oral administration of amoxicillin (250 mg three times daily) with metronidazole (250 mg three times daily) during 1 week and [0079] Subgingival placement of 2.5 mg chlorhexidine gluconate in a hydrolyzed gelatin matrix chip (PerioChip). The chip degrades within 7-10 days.

[0080] It is herein preferable, that the administration of the bioavailable silicic acid and the administration of the antibiotic start simultaneously and concur with the subgingival placement. However, alternative protocols are not excluded.

Example 10: Aggressive Periodontitis Treatment

[0081] 6 months oral administration of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride; preferably in the form of two dosage units, such as tablets [0082] Local application of an ethylene/vinyl acetate copolymer fiber that contains tetracycline (12.7 mg per 9 inches) in the affected periodontal pocket for 10 days. [0083] mouth rinsing with chlorhexidine 1% solution twice daily during 4 weeks.

Example 11: Combination in the Treatment of Peri-Implantitis

[0084] 12 months oral administration of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride, preferably in the form of two dosage units, such as capsules. [0085] Daily administration of 1000 mg calcium, 6 microgram vitamin D, 50 microgram vitamin K, preferably in the form of two dosage units, such as tablets. [0086] Daily administration of 200 mg vitamin C, 100 microgram selenium, 10 mg zinc, 1 mg copper, 0.5 mg boron, 200 mg magnesium, preferably in the form of a table. [0087] irrigating the periodontal pockets and cleaning the implants with chlorhexidine 1% solution [0088] mouth rinsing with chlorhexidine 1% solution twice daily during 4 weeks.

Example 12: Combination for Use in the Treatment of Peri-Implantitis

[0089] 12 months oral administration of 10 mg of bioavailable silicic acid per day in the form of choline-stabilized orthosilicic acid (ch-OSA®), wherein silicic acid is stabilized with choline chloride, for instance in the form of two dosage units such as capsules. [0090] Surgical intervention to create an access flap, removal of subgingival bacterial and non-bacterial residues, irrigation of the periodontal pockets and cleaning the implants with chlorhexidine 1% solution. Use of de-proteinized bone mineral on a collagen membrane. [0091] Mouth rinsing with chlorhexidine 1% solution twice daily during 4 weeks. [0092] Daily administration of 1000 mg calcium, 6 microgram vitamin D, 50 microgram vitamin K, for instance in the form of two dosage units, such as tablets. [0093] Daily administration of 200 mg vitamin C, 100 microgram selenium, 10 mg zinc, 1 mg copper, 0.5 mg boron, 200 mg magnesium, for instance in the form of a tablet.

[0094] 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 preferred that the administration of the silicon compound starts simultaneous with the use of the antiseptic and/or antibiotics. However, alternatively, the administration of the bioavailable silicic acid may precede the administration of the antiseptic and/or antibiotics during a preparatory period of for instance 3 days up to 14 days, for instance 1 week.

[0095] In summary, these examples indicate that the oral administration of a bioavailable silicon compound, such as silicic acid during a period of at least 3 months daily leads to inhibition of periodontitis and peri-implantatis and is thus a therapeutic effective, non-invasive, non-surgical treatment. The treatment is particularly suitable in combination with appropriate cleaning of the mouth, by one or more antiseptic and/or antimicrobial agent(s), in case the plaques are subgingival and difficult to reach a surgical created access flap may be needed. The treatment may be further enhanced by simultaneous administration of vitamins, such as vitamin C, Vitamin D, vitamin K, and/or trace elements, such as magnesium, calcium, selenium, boron and copper, as well as by administration of a probioticum or the use of subgingival bioactive substances. The positive results for chronic periodontitis indicate the major benefit of the present invention. The positive results for peri-implantitis provide a non-invasive treatment for this disease. Both positive results are by themselves highly surprising, in view thereof that a daily dose of bioavailable silicic acid may inhibit and even heal the disease that is already in an advanced state. The invention further relates to a method of prevention, inhibition or treatment of periodontitis and/or peri-implantitis comprising the oral administration of a bioavailable silicic acid.