NL2005194C2

NL2005194C2 - Pharmaceutical composition for use in the prevention and treatment of gingivitis and parodontitis.

Info

Publication number: NL2005194C2
Application number: NL2005194A
Authority: NL
Inventors: Eric Jan Ostwald; Sebastiaan Bokhorst
Original assignee: Eric Jan Ostwald; Sebastiaan Bokhorst
Priority date: 2010-08-05
Filing date: 2010-08-05
Publication date: 2012-02-07
Also published as: BE1020183A3

Description

PHARMACEUTICAL COMPOSITION FOR USE IN THE PREVENTION AND TREATMENT OF GINGIVITIS AND PARODONTITIS

FIELD OF THE INVENTION 5

The present invention relates to a pharmaceutical composition comprising tocopherols and/or tocotrienols, ascorbic acid, polyphenols and pharmaceutically acceptable excipients and/or diluents. The invention further relates to a method for preparing such a pharmaceutical composition, to the use of such a pharmaceutical 10 composition in the treatment or prevention of gingivitis or parodontitis in humans or animals, and to a kit comprising such a pharmaceutical composition.

BACKGROUND OF THE INVENTION

15 Every inflammation reaction of tissue in an organism can be regarded as a response to tissue damage caused by chemical, physical or biological factors. The aim of such a reaction is to eliminate the causes of these reactions and to create favourable conditions for recovery of the damaged tissue.

During inflammation of tissue, so called polymorphic nuclear leukocytes 20 produce a considerable amount of free oxygen radicals. These radicals disrupt the equilibrium between the oxidative and anti-oxidative processes. Due to this disturbance of the equilibrium fibroblasts are stimulated to make collagenase, which leads to the breakdown of collagen fibres in the area of inflammation (Brenneisen et al., Hydrogen peroxide (H202) increases the steady-state mRNA levels of collagenease/MMP-1 in 25 human dermal fibroblasts. Free Radio Biol Med 1997:22: 515-524).

Furthermore, many of the inflammation cells die and release other enzymes such as cathepsine, gelatinise or elastase. These enzymes are able to breakdown various proteins in connective tissue, creating even more damage.

The living cells (and extra-cellular spaces) have certain protective mechanisms 30 against oxidative processes. The two most important protective mechanism are enzymes that break down free oxygen radicals, e.g. katalase, and the presence of anti-oxidative micronutrients in the area of the damaged tissue.

One of the most important anti-oxidative micronutrients is ascorbic acid (vitamin C). This compound is essential for the hydroxylation of proline and lysine and 2 is thus critical for the formation of collagen fibres. It has been shown in several studies that a low serum concentration of ascorbic acid increases the chances of developing parodontitis (Nishida et al., Dietary vitamin C and the risk for periodontal disease. J. Peridontol. 2000: 71: 1215-1223; Amaliya et al., Java project on periodontal diseases: 5 the relationship between vitamin C and the severity of peridontitis. J. Clin. Peridontol. 2007: 34: 299-304). However, the use of other anti oxidative micronutrients or combinations of micronutrients for the prevention or treatment of parodontitis has not been thoroughly investigated.

The individual use of polyphenols for use in the treatment op parodontitis has 10 been described in the literature (Makimura et al., Inhibitory effect of tea catechins on collagenese activity. J. Peridontol 1993: 64:630-636). However, the results obtained were poor. Combination of polyphenols with for example anti-oxidative micronutrients such as ascorbic acid have not previously been investigated.

From clinical and experimental research it has become clear that cholecalciferol 15 (vitamine D) could play an important role in the prevention of parodontitis (Krall et al., Calcium and vitamin D supplements reduce tooth loss in the elderly. Am. J. Med. 2001: 111: 452-456). The effect of cholecalciferol is probably not only based on the prevention of breakdown of periodontal bone, but also on its anti-microbial function (Jagelaviciene et al., The relationship between general osteoporosis of the organism 20 and periodontal diseases. Medicina Kaunas 2006: 42: 613-618).

Although different approaches have been followed to find a way to prevent or treat gingivitis or parodontitis the results obtained thus far are relatively poor. There is thus still an unmet need for a product that can prevent or treat gingivitis or parodontitis.

25 DETAILED DESCRIPTION OF THE INVENTION

As indicated above, a balanced pharmaceutical composition which can be used for the prevention or treatment of gingivitis or parodontitis has not yet been described, let alone been placed on the market. It is therefore an object of the present invention to 30 provide a medicament which can be used for the prevention or treatment of gingivitis or parodontitis. The term pharmaceutical composition used in the application means a composition which is suitable for human and animal use and is able to induce a health increasing reaction in or on the human or animal body. A food supplement having the 3 above mentions properties would thus also fall within the scope of the present application.

A first aspect of the present invention relates to a pharmaceutical composition comprising: 5 - 2 to 25 wt% tocopherols and/or tocotrienols; - 15 to 40 wt% ascorbic acid; - 5 to 30 wt% polyphenols; and - 15 to 30 wt% pharmaceutically acceptable excipients and/or diluents.

As can be derived from the experimental part below, the composition according 10 the invention realizes a surprisingly great reduction in the occurrence of bleeding of the gingiva. Reducing the occurrence of bleeding is generally considered as an indication that the tissue is recovering from parodontitis. Clearly, the composition according to the invention is able to prevent or treat gingivitis or parodontitis.

Although some of the constituents of the present invention have previously been 15 used or tested for their efficacy in the prevention or treatment of gingivitis or parodontitis, they have never been used in combination. Moreover, the efficacy of the constituents separately is considerably lower than the efficacy of the composition according to the invention. In other words, there is a synergistic effect between the constituents of the claimed composition when the composition is used for the 20 prevention or treatment of gingivitis or parodontitis.

The ascorbic acid used in the composition according to the invention is believed to increase the favourable effect of tocopherols and/or tocotrienols. It helps to regenerate tocopherols and/or tocotrienols radicals and enhances thereby the antioxidant effect of tocopherols and/or tocotrienols (Niki, Action of ascorbic acid as a 25 scavenger of active and stable oxygen radicals, The American Journal of Clinical Nutrition, 1991; 54.1119S-24S).

Preferably the tocopherols used are alpha-, beta, gamma or delta tocopherol, or a mixture thereof. The polyphenols used are preferably derived from a green tea extract. Besides the above mentioned constituents the composition according to the 30 invention comprises in a preferred embodiment of cholecalciferol. The amount of cholecalciferol used in the composition is preferably 0,001 wt% to 0,5 wt%. The presence of cholecalciferol in the composition according to the invention is particularly relevant when the composition is used in humans. Generally, the human diet does not comprises sufficient amounts of cholecalciferol. Especially in the winter time the 4 cholecalciferol levels in humans are relatively low. Generally, the animal diet comprises more than enough cholecalciferol and extra addition thereof is most often not necessary.

In a composition which is particularly suitable for use in animals 5 to 10 wt% curcuma longa extract is used. Preferably the product Biocurcumax is used, although 5 other curcuma longa extracts may also be used. The advantage of using Biocurcumax is that its bio availability is very good. In addition to curcuma longa the composition specially suitable for animals also comprises 15 to 45 wt%, preferably 20-30 wt% SAMe ( S-adenosylmethionine) It is further preferred to also add to this composition 0,1 to 3 wt% zinc and/or traces of selenium. The amount of selenium used is preferably 10 0,0001 wt% to 0,01 wt%.

In a highly preferred embodiment of the composition for use in animals, although it may also be administered to humans, the composition comprises 2-5 wt% tocopherols and/or tocotrienols, 10-20 wt% ascorbic acid, 5 to 15 wt% polyphenols, 20-30 wt% excipients and/or diluents, 5-10 wt% curcuma longa extract and 30-45 wt%, 15 S-adenosylmethionine. Preferably the composition also comprises 0,1-3 wt% zinc or salts thereof and optionally traces of selenium. If the above mentioned composition is administered to humans, the composition comprises optionally also 0,1-1 wt% cholecalciferol.

In a preferred embodiment of the composition for use in humans the 20 composition comprises 20-25 wt% tocopherols and/or tocotrienols, 30-40wt% ascorbic acid, 20-30 wt% polyphenols, 15-25 wt% pharmaceutically acceptable excipients and/or diluents and optionally 0,1-1 wt% cholecalciferol.

In a further preferred embodiment the above mentioned composition for humans may also comprise S-adenosylmethionine. In such a composition preferably 15 to 45 25 wt%, more preferably 20-30 wt% S-adenosylmethionine is used.

The composition according to the invention also comprises excipients and/or diluents in order to have a formulation that can be administered or applied conveniently and remains stable over prolonged periods of time. Excipients used in the pharmaceutical composition according to the invention are for example microcrystalline 30 cellulose, hydroxypropylcellulose, magnesium stearate, or stearic acid. However, it is also possible to use other comparable excipients, as for example described in The Handbook of Pharmaceutical Excipients of Rowe et al., 2006.

5

The composition is preferably formulated into a tablet, sugar-coated pill, capsule, pastille, liquid, drinkable suspension or ointment. Most preferably the composition is formulated into a tablet.

Preferably the human or animal patients are administered a total daily dose 10-5 200 mg/kg body weight of the composition, preferably 25-150 mg/kg body weight, most preferably 75-125 mg/kg. This total daily dose is preferably obtained via a once or twice daily administration of the pharmaceutical composition according to the invention A particularly preferred single unit dosage of the composition according to the invention for humans comprises 400 mg to 2000 mg, preferably 500 mg to 1250 mg, 10 most preferably around 1000 mg.

Another single unit dosage of the composition according to the invention, which is particularly useful for administering to animals (e.g. dogs and cats), although it may also be administered to humans, comprises preferably 200 to 1000 mg, preferably 300 to 600 mg, most preferably around 550 mg.

15 It is preferred to administer the composition according to the invention to humans or animals having a history of suffering from gingivitis or parodontitis. A second aspect of the present invention relates to a method for preparing a pharmaceutical composition as described above.

A third aspect of the present invention relates to a kit comprising the above 20 mentioned pharmaceutical composition. Preferably the kit is a blister package or a container, such as for example a bottle.

The invention will now be described further by the following, non-limiting examples

25 EXAMPLES

Material and method

The pharmaceutical composition according to the invention was tested on 32 30 patients suffering from parodontitis. The patients were between 18 and 65 years old and had at least eight periodontal pockets of 4 mm or more, spread over at least four dentition elements. Exclusion criteria were diabetes mellitus, kidney insufficiency, pregnancy, use of anticoagulentia and regular use of immunosuppressive medicaments.

6

All patients received the same instructions with respect to dental care and also received the same toothpaste. The patients administered their selves either the composition according to the invention or a placebo. The total daily dosage of the active ingredients of the pharmaceutical composition used was: 5 - 200 mg D, L alpha-tocopherol acetate, - 600 mg ascorbic acid - 10 microgram cholecalciferol - 400 mg green tea extract, 98%. polyphenols 10 This total daily dosage was divided over four single unit dosages, namely capsules. Two capsules were taken in the morning and two in the evening. The capsules with the pharmaceutical composition according to the invention could not be distinguished visually from the placebo capsules.

15 The occurrence of bleeding of the gingiva as well as the amount and depth of periodontal pockets was assessed before the start of the trial by dentists. This was done again after three months and after six months. An evident improvement was defined as a decrease of the amount of gingival bleedings or as a reduction of the sum of the pocket depth by at least forty percent. For statistical analysis use was made of the so called 20 one-tailed t-test.

Results

After six months the amount of gingiva bleedings in the patients treated with the 25 composition according the invention decreased with 46% compared to 27% in the placebo group. In the group that received the composition according to the invention 38% of the patients showed a markedly decrease of the summed up pocketsize. In the placebo group this decrease was onlyl2,5% These results clearly show the beneficial effects of the composition according to the invention.

Claims

1. Farmaceutische samenstelling omvattende: - 2 to 25 gew% tocoferolen en/of tocotrienolen; 5 - 15 to 40 gew% ascorbinezuur; - 5 to 30 gew% polyfenolen; en -15 to 30 gew% farmaceutisch acceptabele excipienten en/of verdunmiddelen.A pharmaceutical composition comprising: - 2 to 25% by weight of tocopherols and / or tocotrienols; 5-15% to 40% by weight of ascorbic acid; - 5 to 30 wt% polyphenols; and -15 to 30% by weight pharmaceutically acceptable excipients and / or diluents.

2. Farmaceutische samenstelling volgens conclusie 1, verder omvattende 0,01 and 0,5 10 gew% cho lecalciferol.The pharmaceutical composition according to claim 1, further comprising 0.01 and 0.5% by weight of chocolate calciferol.

3. Farmaceutische samenstelling volgens conclusie 1, verder omvattende 5 tot 10 gew% curcuma longa extract.The pharmaceutical composition of claim 1, further comprising 5 to 10% by weight of curcuma longa extract.

4. Farmaceutische samenstelling volgens een van de conclusies 1-3 verder omvattende 15-45 gew% S-adenosylmethionine, bij voorkeur 20-30 gew% S-adenosylmethionine.Pharmaceutical composition according to any of claims 1-3, further comprising 15-45% by weight of S-adenosylmethionine, preferably 20-30% by weight of S-adenosylmethionine.

5. Farmaceutische samenstelling volgens conclusie 3 of 4, verder omvattende 0,1 tot 3 gew% zink of zouten daarvan en/of sporen van selenium. 20The pharmaceutical composition according to claim 3 or 4, further comprising 0.1 to 3% by weight of zinc or salts thereof and / or traces of selenium. 20

6. Farmaceutische samenstelling volgens een van de conclusies 1-5, waarin de polyfenolen zijn verkregen uit een groene thee extract.Pharmaceutical composition according to any of claims 1-5, wherein the polyphenols are obtained from a green tea extract.

7. Farmaceutische samenstelling volgens een van de conclusies 1-6, waarin de 25 tocoferolen zijn alfa-, beta, gamma of delta tocoferol, of een mengsel daarvan.7. Pharmaceutical composition according to any of claims 1-6, wherein the tocopherols are alpha, beta, gamma or delta tocopherol, or a mixture thereof.

8. Farmaceutische samenstelling volgens een van de conclusies 1-7, waarin de excipienten die worden gebruikt zijn gekozen uit de groep die bestaat uit microkristallijn cellulose, hydroxypropylcellulose, magnesiumstearaat, of stearinezuur. 30A pharmaceutical composition according to any of claims 1-7, wherein the excipients used are selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, or stearic acid. 30

9. Farmaceutische samenstelling volgens een van de conclusies 1-8, waarin de samenstelling is geformuleerd als een tablet, een suiker bekleedde capsule, pastille, vloeistof of drinkbare suspensie of zalf.A pharmaceutical composition according to any of claims 1-8, wherein the composition is formulated as a tablet, a sugar coated capsule, pastille, liquid or drinkable suspension or ointment.

10. Farmaceutische samenstelling volgens een van de conclusies 1-9, voor gebruik in de preventie en behandeling van gingivitis of parodontitis in mensen of dieren.Pharmaceutical composition according to any of claims 1-9, for use in the prevention and treatment of gingivitis or periodontitis in humans or animals.

11. Farmaceutische samenstelling volgens conclusie 10, waarin de menselijke of 5 dierlijke patiënten een totale dagelijkse dosis krijgen toegediend van 10-200 mg/kg lichaamsgewicht van de samenstelling, bij voorkeur 25-150 mg/kg lichaamsgewicht, meest bij voorkeur 75-125 mg/kg.A pharmaceutical composition according to claim 10, wherein the human or animal patients are administered a total daily dose of 10-200 mg / kg body weight of the composition, preferably 25-150 mg / kg body weight, most preferably 75-125 mg / kg.

12. Farmaceutische samenstelling volgens conclusie 10 of 11, waarin de farmaceutische 10 samenstelling eenmaal of tweemaal per dag wordt toegediend.12. Pharmaceutical composition according to claim 10 or 11, wherein the pharmaceutical composition is administered once or twice a day.

13. Farmaceutische samenstelling volgens een van de conclusies 10-12, waarin een eenheidsdosering voor mensen omvat 400 mg tot 2000 mg, bij voorkeur 500 tot 1250 mg en meest bij voorkeur circa 1000 mg. 15A pharmaceutical composition according to any of claims 10-12, wherein a unit dose for humans comprises 400 mg to 2000 mg, preferably 500 to 1250 mg and most preferably about 1000 mg. 15

14. Farmaceutische samenstelling volgens een van de conclusies 10-12, waarin een eenheidsdosering voor dieren omvat 200 tot 1000 mg, bij voorkeur 300 tot 600 mg, meest bij voorkeur circa 550 mg.A pharmaceutical composition according to any of claims 10-12, wherein a unit dose for animals comprises 200 to 1000 mg, preferably 300 to 600 mg, most preferably about 550 mg.

15. Farmaceutische samenstelling volgens een van de conclusies 10-14, waarin de samenstelling wordt toegediend aan mensen die een geschiedenis hebben van het lijden aan gingivitis of parodontitis.The pharmaceutical composition according to any of claims 10-14, wherein the composition is administered to people who have a history of suffering from gingivitis or periodontitis.

16. Werkwijze voor het vervaardigen van een farmaceutische samenstelling volgens een 25 van de conclusies 1-9.A method for manufacturing a pharmaceutical composition according to any of claims 1-9.

17. Kit omvattende een farmaceutische samenstelling volgens een van de conclusies 1- 9.A kit comprising a pharmaceutical composition according to any of claims 1-9.

18. Kit volgens conclusie 17, waarin de kit is een doordrukverpakking of een houder.The kit of claim 17, wherein the kit is a blister pack or a container.