A composition for the treatment of oral lesions

Field of the invention

The invention refers to a composition suitable for the treatment of oral lesions, especially periodontitis. More specifically, the invention refers to a pharmaceutical composition or an oral care composition suitable for the prevention or treatment of oral lesions and containing an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent. Background of the invention

Out of the diseases that occur in the oral cavity, gingivitis and periodontitis (periodontal disease) are extremely widespread, consequently, they can be considered as pandemic [Jenkins, W. M. and Papapanou, P. N.: Epidemiology of periodontal disease in children and adolescents, Periodontology 2000, 26, 16-32 (2001)]. Gingivitis occurs in 70 to 90 % of the population including children. In case of gingivitis, the gum (i.e. gingiva) is swollen, red and bleed easily. Untreated gingivitis subsisting permanently may lead to the formation of periodontitis.

Periodontitis extends to more than two thirds of the population [Murray, JJ. : The Prevention of Dental Disease, Oxford University Press, 1988, Chapter 10: The prevention and

control of chronic periodontal disease, 328-372]. Periodontitis is a disease of the tissues that support and attach the teeth and having different stages depending on the severity of the disease. Untreated periodontitis results in the formation of gaps between the gums and the teeth (i.e. periodontal pockets), the loss of periodontal ligaments that attach the tooth to the jaw, the loss of alveolar bone and, lastly, tooth loss. Above 30 of age, the number of tooth lost because of periodontitis is growing increasingly. Periodontitis can be extended to the whole set of teeth (generalized periodontitis) or it can occur locally (localized periodontitis or localized inflammation of the periodontal pocket). Significant risk factors of the formation of periodontitis include age, environmental factors (for example smoking) and various systemic diseases [Mealey, B. L.: Periodontal Implications: Medically Compromised Patients, Ann. Periodontal., 1, 256-321 (1996)].

Serious periodontitis occurs significantly more frequently among patients suffering from diabetes than within the average polulation [Axelsson, P.: Diagnosis and Risk Prediction of Periodontal Diseases, Quintessence Publishing Co., Inc., 2002, p. 175]. Periodontitis is a frequent complication of diabetes and it is probably connected with the chronic inflammation, reduced bone formation and micro-circulation disorder that reduces tissue regeneration, all of which are developped by diabetes. [Kathryn, E. et al.: Inflammation, stress, and diabetes, J. Clin. Invest, 115, 1111-1119 (2005); Hongbing, H. et al.: Diabetes causes decreased osteoclasto-

genesis, reduced bone formation and enhanced apoptosis of osteablastic cells in bacteria stimulated bone loss, Endocrinology, 145, 447 (2005); McMullen, J.A. et al.: Microangiopathy within the gingival tissues of diabetic subjects with special reference to the prediabetic state, Periodontics, 5, 61-69 (1967)]. The diabetic periodontitis is a grave problem especially in case of type I diabetes mellitus (IDDM) that occurs especially in young age since the patient can loose the teeth even before reaching thirty of age. However, the interaction between diabetes and periodontitis has two directions: in addition to the fact that the bad metabolic state that is typical in diabetes predisposes the patient to the periodontitis, the consequence of this latter is a worsened metabolic equilibrium [Losche, W. Et al.: Plasma lipid and blood glucose levels in patients with destructive periodontal disease, J. Clin. Periodontal., 2000 Aug. 27 (8), 537-41].

The ulcerative alterations of the gum (gingiva), lip and tongue (e.g. aphtha) may have several causes, however, such alterations can accompany systemic diseases, too. Around the ulcerative alteration, an inflammation forms that can be also extremely painful and long lasting.

Pericoronitis is a rather frequent local symptom that occurs typically around the wisdom tooth. Pericoronitis is characterized by a local inflammation around the tooth as well as bleeding, and, if untreated, may lead to an extensive inflammation in the oral cavity.

Lesions of the mucous membrane of the mouth may arise

from mechanical impacts, eating too hot food etc., the resulting lesions can be easily infected leading to the development of an inflammation.

The term ,,oral lesion" includes in the description and claims the following disorders:

- gingivitis,

- ulcerative gingivitis (gingivitis ulcerosa),

- generalized periodontitis including diabetic periodontitis,

- localized periodontitis (i.e. inflammation of the periodontal pocket),

- ulcerative alterations of the gum (gingiva), lip or tongue (e.g. aphtha)

- pericoronitis.

- lesion or inflammation of the mucous membrane of the mouth.

The aim of the invention is to provide a composition suitable for the prevention or treatment of oral lesions, especially of periodontitis.

Some of the medicinal herbs belonging to the order of Violales have been widely used in popular medicine. It is known, for example, that the leaf and root of the species Viola odorata have mucolytic, sweltering, blood-cleansing effect, and the flower therof has mucolytic, depressant and blood pressure lowering effect. Based on the expectorant, diuretic, astringent, antiphlogistic and blood-cleansing effect of the species Viola tricolor [Keville K., The Illustrated Encyclopedia of Herbs, Chancellor Press, 302. (1992); Hansel, R., Keller, K., Rimpler

H., Schneider, G. 0: Hager's Handbuch der Pharmazeutischen Praxis, Springer Verlag, 6. Band, 1141-1153], teas or extracts prepared from the parts of the plant growing above the earth are often used in case of cold as well as inflammatory, skin and arthritic diseases [Leporatti, M. L., Ivancheva, S.: Preliminary comparative analysis of medicinal plants used in the traditional medicine of Bulgaria and Italy, J. Ethnopharm., 87, 123-142 (2003)]. Certain parts of the species Viola odorata are used, in general, for the treatment of chronic bronchitis, pertussis and asthma bronchiale due to the expectorant and antitussive properties of the plant, however, the relieving action of Viola odorata in case of migraine is also known. The leaves of Viola odorata are considered to be effective in case of hoarseness, sore throat, impairments of sleep and neurosis.

In summary, although some of the medicinal herbs belonging to the order of Violales have been used in the form of a herb tea or extract for the treatment of certain diseases, no pharmaceutical composition has been prepared from these medicinal herbs.

HU-P 205 708 described cosmetic compositions containing extracts of medicinal herbs including Violae Odoratae and/or Viola tricolor and/or Viola Arvensis Murr. The known cosmetic compositions are suitable for the protection, calming, regeneration and care of the skin surface. The examples of the description include a mouth wash containing an alcoholic extract of a Viola species, ethanol, water, menthol and artificial sweetening agent. In addition to the fact that the mouth wash is

not a typical cosmetic composition, the effect thereof on the oral cavity has not been described. Summary of the invention

It has been found that the above aim can be achieved by a pharmaceutical composition or an oral care composition containing an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent optionally in addition to one or more conventional carrier(s). The pharmaceutical composition or oral care composition of the invention is suitable for the effective prevention or treatment of oral lesions, mainly periodontitis. Description of preferred embodiments

Under the expression ,,a medicinal herb belonging to the order of Violales" the following medicinal plants are meant in terms of the taxonomical description: Order: Violales Families: - vϊoiaceae

Viola genus

Hybanthus genus -> H.calycinus

Hybanthus concolor (T. F. Forst) Spreng Hybanthus linearifolius (Vahl) Urban Rinorea genus -» ^■ Rinorea moagalensis Anchietea genus -» Anchietea salutans Corynostylis genus -» Corynostylis hybnanthus Hymenanthera genus -> Hymenanthera obovata - Flacourtiaceae

- Lacistemataceae

- Passifloraceae

- Turneraceae

- Malesherbiaceae

- Fouquieriaceae

- Caricaceae

- Bixaceae

- Cochlospermaceae

- Cistaceae

- Tamaricaceae

- Ancistrocladaceae

- Frankeniaceae

- Achaπaceae

- Begoniaceae (according to other sources Salicales) - Loasaceae

- Datiscaceae

- Samydaceae

- Cucurbitaceae

As for families, there are significant alterations in literature data, therefore, the following species are also considered to belong to the order of Violales:

Viola acuminata acuminate violet

Viola adunca hookedspur violet, western dog violet

Viola adunca var adunca hookedspur violet

Viola adunca var kirkii Kirk's violet

Viola adunca var oxyceras hookedspur violet, sharptail violet

Viola affinis sand violet

Viola appalachiensis Appalachian violet

Viola arvensis field pansy

Viola bakeri Baker's violet

Viola beckwithii Beckwith's violet, Great Basin violet

Viola beckwithii ssp beckwithii Beckwith's violet

Viola beckwithii ssp glabrata western pansy

Viola bicolor field pansy

Viola biflora

Viola biflora ssp biflora twoflower violet

Viola biflora ssp carlottae Carlott's violet

Viola blanda sweet white violet, willdenow violet, etc

Viola blanda var blanda sweet white violet

Viola blanda var palustriformis sweet white violet, marsh violet

Viola brevistipulata short stipule violet

Viola brittoniana northern coastal violet; coast violet

Viola brittoniana var. brittoniana northern coastal violet

Viola brittoniana var. pectinata combed northern coastal violet

Viola calaminaria Yellow calamine violet

Viola califorπica California violet

Viola canadensis Canadian white violet; Canada violet; etc.

Viola canadensis var. canadensis Canadian white violet

Viola canadensis var. corymbosa Canadian white violet

Viola canadensis var. rugulosa creepingroot violet

Viola canadensis var. scariosa shriveled Canadian white violet

Viola canadensis var. scopulorum Canadian rock white violet

Viola canina heath violet; dog violet

Viola canina ssp. canina heath dog violet

Viola canina ssp. montana heath dog violet

Viola chamissoniana olopu

Viola chamissoniana ssp. chamissoniana olopu

Viola chamissoniana ssp. robusta large olopu

Viola chamissoniana ssp. tracheliifolia olopu

Viola charlestonensis Charleston Mountain violet

Viola chinensis China violet

Viola collina hillside violet

Viola conspersa American dog violet

Viola cornuta horned violet; bedding pansy

Viola cucullata marsh blue violet

Viola cuneata wedgeleaf violet

Viola diffusa spreading violet

Viola douglasii Douglas' golden violet

Viola egglestonii glade violet

Viola epipsila dwarf marsh violet; large marsh violet

Viola epipsila ssp. repens dwarf marsh violet; creeping marsh violet

Viola flettii Olympic violet; rock violet

Viola frank-smithii Frank-Smith's violet

Viola glabella pioneer violet; stream violet

Viola grypoceras Viola grypoceras

Viola guadalupensis Guadalupe violet

Viola guestphalica Violet calamine violet

Viola hallii Oregon violet

Viola hastata halberd leaf yellow violet

Viola hederacea Australian violet; trailing violet

Viola helenae Wahiawa stream violet

Viola hirsutula southern woodland violet

Viola hirsuta Hairy violet

Viola hispida Rouen pansy

Viola howellii Howell's violet

Viola incognita large leaved white violet

Viola japonica Japanese violet

Viola kauaensis pohe hiwa

Viola kauaensis var. kauaensis pohe hiwa

Viola kauaensis var. wahiawaensis pohe hiwa

Viola keiskei Viola kβiskei

Viola labradorica alpine violet; Labrador violet

Viola lactea pale dog violet

Viola lanaiensis Hawaii violet

Viola lanceolata bog white violet

Viola lanceolata ssp. lanceolata lanceleaf bog white violet

Viola lanceolata ssp. occidentalis eastern bog white violet

Viola lanceolata ssp. vittata bog white violet

Viola langsdorfii Aleutian violet; Alaska violet

Viola lithion rock violet

Viola lobata moosehorn violet; yellow wood violet

Viola lobata ssp. integrifolia moosehorn violet

Viola lobata ssp. lobata moosehorn violet

Viola lobata var. lobata moosehorn violet

Viola lovelliana Lovell's violet

Viola lutea mountain pansy

Viola macloskeyi small white violet; western sweet white violet

Viola macloskeyi ssp. macloskeyi Macloskey's violet; western sweet white violet

Viola macloskeyi ssp. pallens smooth white violet

Viola mandschurica Manchurian violet

Viola maviensis Hawaii bog violet

Viola mirabilis wonder violet

Viola missouriensis Missouri violet; banded violet

Viola nephrophylla var. nephrophylla northern bog violet

Viola novae-angliae New England blue violet

Viola nuttallii Nuttall's violet; yellow prairie violet

Viola oahuensis Oahu violet

Viola obliqua marsh blue violet

Viola obtusa blunt violet

Viola ocellata pinto violet; two eyed violet

Viola odorata sweet violet; garden violet; etc.

Viola orbiculata darkwoods violet; western round leaved violet

Viola orientalis Viola orientalis

Viola palmata early blue violet; palmate violet; wild okra

Viola palmata var. palmata early blue violet

Viola palustris marsh violet; alpine marsh violet

Viola palustris var. brevipes marsh violet

Viola palustris var. palustris marsh violet

Viola patrinii stemless violet

Viola pedata birdfoot violet; bird's foot violet; etc.

Viola pedatifida prairie violet; prairie birdfoot violet; etc.

Viola pedunculata California golden violet; grass pansy; yellow pansy

Viola pedunculata ssp. pedunculata California golden violet

Viola pedunculata ssp. tenuifolia threadleaf California golden violet

Viola pinetorum goosefoot yellow violet

Viola pinetorum ssp. grisea goosefoot violet

Viola pinetorum ssp. pinetorum goosefoot violet

Viola pinnata pinnate violet

Viola praemorsa canary violet

Viola praemorsa ssp. flavovirens upland yellow violet

Viola praemorsa ssp. linguifolia upland yellow violet

Viola praemorsa ssp. praemorsa canary violet

Viola primulifolia primrose leaved violet

Viola prionantha Viola prionantha

Viola psychodes butterfly violet

Viola pubescens downy yellow violet

Viola pubescens var. peckii Peck's downy yellow violet

Viola pubescens var. pubescens smooth yellow violet

Viola pubescens var. scabriuscula rough yellow violet

Viola purpurea goosefoot violet

Viola purpurea ssp. aurea goosefoot yellow violet

Viola purpurea ssp. dimorpha two formed goosefoot violet

Viola purpurea ssp. geophyta rock goosefoot violet

Viola purpurea ssp. integrifolia entire leaved goosefoot violet

Viola purpurea ssp. mesophyta goosefoot violet

Viola purpurea ssp. mohavensis Mojave yellow violet

Viola purpurea ssp. purpurea purple goosefoot violet; pine violet

Viola purpurea ssp. quercetorum goosefoot yellow violet

Viola purpurea ssp. venosa goosefoot yellow violet

Viola rafinesquii field pansy

Viola reichanbachiana slender wood violet

Viola renifolia northern white violet; kidney leaved white violet

Viola renifolia var. renifolia kidneyleaf white violet

Viola rivianawood violet; dog violet

Viola rostrata longspur violet

Viola rotundifolia eastern roundleaf yellow violet; early yellow violet

Viola rupestris Teesdale violet; rock violet

Viola sagittata arrowleaf violet

Viola selkirkii Selkirk's violet

Viola sempervirens evergreen violet; redwood violet

Viola septemloba southern coastal violet

Viola septentrionalis var. septentrionalis northern woodland violet; northern blue violet

Viola sheltonii Shelton's violet

Viola sororaria woolly blue violet

Viola striata striped cream violet; pale violet; striped violet

Viola subsinuata wavy leaf violet

Viola tokubuchiana Viola tokubuchiana

Viola tomentosa feltleaf violet

Viola tricolorJohnnyjump up; heart's-ease; etc.

Viola trinervata Rainier violet; sagebrush violet

Viola tripartita threepart violet

Viola umbraticola Ponderosa violet

Viola umbraticola var. glaberrima Ponderosa violet

Viola umbraticola var. umbraticola Ponderosa violet

Viola utahensis Utah violet

Viola vaginata sheathed violet

Viola vallicola valley violet

Viola vallicola var. major large valley violet

Viola vallicola var. vallicola sagebrush violet

Viola variegata Viola variegata

Viola verecunda hidden violet

Viola viarum twoflower violet; plains violet; wayside violet

Viola villosa Carolina violet; hairy violet; wrinkled violet

Viola violacea Viola violacea

Viola wailenalenae Alakai Swamp violet

Viola walteri prostrate blue violet; prostrate southern violet

Viola x bernardii Bernard's violet

Viola x bissellii Bissell's violet

Viola x brauniae Braun's violet

Viola x conjugens violet

Viola x consobrina violet

Viola x consocia violet

Viola x cooperrider Viola x cooperrider

Viola x cordifolia violet

Viola x davisii Davis' violet

Viola x eamesii Eames' violet

Viola x eclipes violet

Viola x filicetorum violet

Viola x hollickii Hollick's violet

Viola x insolita violet

Viola x luciaβ Lucy's violet

Viola x malteana violet

Viola x mistura violet

Viola x modesta violet

Viola x mollicula Viola x mollicula

Viola x mulfordiae Mulford's violet

Viola x notabilis violet

Viola x peckiana Peck's violet

Viola x porteriana Porter's violet

Viola x primulifolia violet

Viola x ravida violet

Viola x redacta violet

Viola x ryoniae Ryon's violet

Viola x slavinii Slavin's violet

Viola wittrockiana; ladies' delight; etc.

Viola x wujekii Viola x wujekii

Viola yedoensis Viola yedoeπsis

The most important species of the Viola genus include Viola tricolor, Viola arvensis and Viola odorata.

Under ,,a part of a plant or herb that has grown above the earth" the leaf and/or stem and/or flowers (inflorescence) of the plant is/are meant.

The extract is prepared in a manner known perse. For this purpose, the part of the herb that has grown above the earth, optionally after drying and size-reducing, is extracted. The extraction is carried out with water or an organic solvent such as an alcohol e.g. ethanol, or an aqueous solution of an organic solvent e.g. aqueous ethanol generally at 0-100 ⁰ C, preferably at 20-100 ⁰ C. During the extraction, in most cases,

mixing is applied, however, ultrasonication can be used, too. The extract is separated from the parts of the plant by known methods using e.g. sedimentation, pressing of the parts of the plant, filtration, centrifugation or the combination of the procedures listed. The extract obtained can be used as it is or it can be converted to a liquid composition or pharmaceutical composition such as an aqueous solution or syrup. However, it is preferred to remove the solvent content of the extract for example by evaporation, spray drying or freeze drying, and the solid residue is used as an active agent for the preparation of a composition or a pharmaceutical composition. (In the description and claims, the expression ,,active agent" is used in this sense and it refers to the solid residue that has been dissolved in the extract and can be obtained from the extract of the medicinal herb. Of course, the active agent consists of various chemical compounds having biological effects.) Both the extract and the solid residue obtained from the extract can be characterized by the determination of the flavonoid and polyphenol content. In general, the flavonoid content of the solid residue amounts to 2.8-3.4 g/100 g, and the total polyphenol content is 9.7-11.0 g/100 g.

Under a ..pharmaceutical composition" a known formulation or dosage form is meant which is conventionally used for the prevention or treatment of diseases and which has either systemic or local action. In general, the pharmaceutical composition is suitable for peroral, parenteral, rectal or transdermal administration or for local treatment. Thus, the

pharmaceutical composition of the invention is solid or liquid and contains, in addition to the active agent obtained from the medicinal herb by extraction, optionally one or more pharmaceutical carrier(s). The pharmaceutical composition of the invention contains, in general, 0.1-100 % by mass, preferably 1-50 % by mass, suitably 5-30 % by mass of the active agent. It is to be noted that a 100 % content of active agent is possible only in certain cases e.g. in capsules where dilution is not absolutely necessary. In most dosage forms, carriers i.e. diluents and/or other auxiliary agents are needed for the preparation of the pharmaceutical composition.

The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules, lozenge etc., and can comprise binding iagents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.

Preferred dosage forms include tablets for either systemic or local treatment. Tablets contain e.g. one or more filling agent(s), binding agent(s), lubricant(s), flavouring agent(s) etc. as the carrier. The filling agent is, preferably, a sugar such as xylitol, mannitol, isomaltol or lactose providing for also a sweet flavour. In general, the filling agent is present in an amount of 30 to 60 % by mass. The filling agent may include a further carbohydrate such as starch or microcrystalline cellulose in an

amount of generally 10 to 40 % by mass. In most cases, the binding agent includes polyvinylpyrrolidone) or hydroxypropyl methylcellulose in an amount of generally 1 to 5 % by mass. Lubricants include e.g. 0.2 to 3 % by mass of magnesium stearate, 1 to 5 % by mass of talc or 0.1 to 2 % by mass of silica. If necessary, the flavouring agent is an artificial sweetener or an aroma substance in an amount of generally 0.01 to 1 % by mass. Artificial sweeteners include e.g. aspartame [N-L-α-aspartyl-L-phenylalanine 1 -methyl ester], saccharin sodium [1 ,2-benzisothiazol-3(2H)-one 1 ,1 -dioxide sodium salt], sodium cyclamate [sodium cyclohexylsulfamate] or acesulfame potassium salt [6-methyl-1 ,2,3-oxathiazin-4(3H)- one 2,2-dioxide potassium salt], the aroma substance is, usually, mint, menthol etc.

Capsules may contain only the active agent or one or more of the carriers detailed above in relation with the tablets.

A further preferred dosage form includes pharmaceutical compositions in the form of a gel that can be employed locally in the oral cavity. Carriers of the gel comprise, suitably, one or more solvent(s), agent(s) providing for a jelly-like consistency, preserving agent(s), artificial sweetener(s), aroma substances etc. The solvent is, in general, distilled water or demineralized water in an amount of generally 50 to 95 % by mass. Also further solvents including glycerol, ethyl alcohol or propylene glycol can be present in an amount of usually 1 to 20 % by mass. Agent(s) providing for a jelly-like consistency include e.g. hydroxypropyl cellulose, sodium carboxymethyl cellulose,

calcium carboxymethyl cellulose, poly(vinylpyrrolidone) or guar gum in an amount of generally 0.5 to 5 % by mass. A preferred agent providing for a jelly-like consistency is sodium carboxymethyl cellulose. The preserving agent is, for example, sorbic acid or methylparaben [methyl p-hydroxybenzoate] in an amount of generally 0.1 to 2 % by mass. The artificial sweeteners and aroma substances are usually the ones listed above in an amount of generally 0.1 to 2 % by mass.

The gel of the invention can be introduced into the periodontal pocket by means of a suitable device such as an injection needle to achieve a valuable local effect.

Lozenges are tablets, pills, microcapsules, dragees, biscuits, wafers etc.that dissolve slowly in the mouth, thus, the active agent is liberated in the oral cavity during a longer period. In general, lozenges contain carbohydrate(s) and gelatin as the carrier, furthermore lubricant(s), artificial sweetener(s) and aroma substances as given in relation to tablets. Lozenges contain essentially conventional ingredients in addition to 1 to 30 % by mass of the active agent.

The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethyl cellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl or propyl p-hydroxybenzoate etc. as the carrier.

Preferred liquid dosage forms suitable for peroral

administration include solutions containing, for example, solvent(s), preserving agent(s), sweetener(s), aroma substances etc. as the carrier. Solvents include, in general, distilled or demineralized water usually in an amount of 70 to 95 % by mass, furthermore glycerol, ethyl alcohol or propylene glycol as a cosolvent generally in an amount of 1 to 20 % by mass. Preserving agents, sweeteners and aroma substances include, mainly, the ones listed above. The solution can be administered in the form of a spray, thus, introducing an aerosol into the oral cavity.

Pharmaceutical compositions suitable for parenteral application contain, in general, a sterile solution of the active agent.

Pharmaceutical compositions suitable for local treatment include absorbing or non-absorbing threads or chips impregnated with the active agent. Such threads or chips are placed into the periodontal pockets by the dentist to treat periodontitis. In the periodontal pcket, the active agent is slowly absorbed, optionally together with the thread or chip. Non- absorbing threads or chips are later removed by the dentist.

The dosage forms listed above as well as other dosage forms are known perse, see e.g. the manual Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, USA (1990)

The pharmaceutical composition contains dosage unit, in general. The daily dose can be administered in one or more portions. The actual dosage depends on many factors and is

determined by the doctor. In general, a typical dose for adult patients of 70 kg body mass amounts to 0.01 to 10 g, preferably 0.1 to 5 g of active agent, daily.

In general, the pharmaceutical composition is prepared by admixing the active agent to one or more carrier(s) and transforming the mixture obtained into a pharmaceutical composition in a manner known perse. The methods that can be used are known from the literature e.g. the manual Remington's Pharmaceutical Sciences cited above. Of course, as a further possibility, the solid residue obtained from the extract can be directly filled into capsules or the extract itself can be converted to a liquid pharmaceutical composition by the addition of further carriers, if needed.

Under an ,,oral care composition" a conventional composition used for the treatment of the oral cavity is meant with the exception of mouth wash. Oral care compositions include, for example, tooth paste (dentrifice), tooth gel, tooth powder, chewing gum etc.

The tooth paste or tooth gel can be any paste or gel or a combination thereof useful in dental care. They contain, in addition to the conventional ingredients of such pastes and gels, generally 1 to 30 % by mass of the active agent.

A suitable oral care composition is the chewing gum containing, in addition to the conventional ingredients, in general, 1 to 30 % by mass of active agent. Since chewing gum is chewed for a relatively long time, the active substances liberating during chewing are in permanent contact with the

gingiva, thus, they may well exert their favourable effect.

The effect of an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, on periodontitis was examined in rat as given below. In the examination, the cervix of tooth was ligated in order to produce gingivitis and periodontitis artificially, then the effect of the active agent prepared from an extract of Viola tricolor on the periodontitis produced was studied according to Lohinai [Lohinai, Z., J. Dent. Res., 82, 987 (2003)]. The gravity of the periodontitis was evaluated on basis of the quantity of Evans blue dye fixed. The higher amount of dye is present in the gingivomucosal tissue, the graver the periodontitis is.

Male albino 330-380 g Wistar rats were divided into two test groups each consisting of 9 animals and a control goup consisting of also 9 animals. The rats were lightly anaesthetized with pentobarbital sodium [5-ethyl-5-(1-methyl- butyl)-2,4,6-(1 H,3H,5H)-pyrimidinetrione sodium salt] administered in a dose of 35 mg/kg. Sterile braided silk thread was placed around the cervix of the first bottom molar on the left side and knotted mesially. After recovery from anaesthesia, the rats were housed in a controlled laboratory environment and provided with rodent chow and tap water ad libitum. The animals of the first test group were gavaged with 10 mg/kg of of the lyophilized active agent prepared from Viola tricolor by process A of Example, while the animals of the second test group were gavaged with 30 mg/kg of the lyophilized active agent prepared from Viola tricolor by process A of Example 1

once daily for 8 days. The animals of the control group obtained only vehicle. On day 8, the rats were re- anaesthetized as above and a cannula was inserted into the right femoral vein. To assess vascular permeability of the gingiva and periodontium which is increased in case of an inflammatory process, the animals received, intravenously, 50 mg/kg of Evans blue dye dissolved in physiological saline. Five minutes later another cannula was introduced into the abdominal aorta. After 10 minutes the right atria was cut and the dye remaining in the gingivomucosal capillaries was removed by retrograde intraaortic injection of 40 ml of isotonic saline. Then the mandibula was excised, separated from the surrounding tissues and cut in half in a sagittal plane between the incisors. An about 3 mm thick gingivomucosal tissue stripe from the half of the mesiolingual side of the second molar around the mandibular first molar to the half of the mesiobuccal side of the second molar was excised on both sides from the animals for the determination of the Evans blue content. The extravasated Evans blue from the excised gingivomucosal tissue samples was extracted with 0.5 ml of formamide for 48 hours at room temperature, then spectrophotometric determination was performed at 620 nm. The dye content was expressed in μg and related to 1 g of gingivomucosal tissue at the left and right side, respectively. The average of the results obtained were determined for both test groups and the control group, then the ratio of the value referring to the ligated side and the value that refers to the side without ligature was

calculated for each group. The results obtained are shown in Table 1.

Table 1

From Table 1 it can be seen that a serious periodontitis developed in the control group: the Evans blue content at the ligated cervix of the first molar on the left side was higher by 91 % than the dye content at the cervix without ligature at the right side. In the group treated with a dose of 10 mg/kg of the active agent obtained from the Viola tricolor extract, the Evans blue content at the ligated cervix on the left side was higher by only 33 % than the dye content at the cervix without ligature at the right side. In the group treated with a dose of 30 mg/kg of the active agent obtained from the Viola tricolor extract, the Evans blue content at the ligated cervix on the left side was higher by merely 21 % than the dye content at the cervix without ligature at the right side, thus, the ideal case when the ratio had a

value of 1.0 was fairly approximated.

Based on the above test, an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent can be used for the effective treatment of periodontitis.

Thus, an embodiment of the invention is a pharmaceutical composition for the prevention or treatment of oral lesions comprising an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent and optionally conventional pharmaceutical carriers.

A preferred pharmaceutical composition of the invention comprises an extract of a part of a Viola species such as Viola tricolor, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent.

A further preferred pharmaceutical composition of the invention is suitable for the prevention or treatment of gingivitis and periodontitis and, suitably, has a form of capsule, tablet, film-coated tablet, gel, lozenge or chip, wherein the periodontitis includes generalized, diabetic and localized periodontitis.

An especially preferred pharmaceutical composition of the invention is suitable for the prevention and treatment of periodontitis including generalized, diabetic and localized

periodontitis.

Another embodiment of the invention is an oral care composition comprising an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent and conventional carriers of such compositions with the proviso that the composition is other than a mouth wash.

A preferred oral care composition comprises an extract of a part of a Viola species such as Viola tricolor, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent.

A further preferred oral care composition of the invention is suitable for the prevention or treatment of gingivitis and periodontitis and, suitably, has a form of a tooth paste (dentrifice), tooth gel or chewing gum.

A further embodiment of the invention is a use of an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent for the preparation of a pharmaceutical composition suitable for the prevention or treatment of oral lesions.

It is preferred to use an extract of a part of a Viola species such as Viola tricolor, wherein said part has grown above the earth, or the solid residue remaining after the removal of the

solvent content of the extract as the active agent.

A preferred use refers to the preparation of a pharmaceutical composition suitable for the prevention or treatment of periodontitis.

A still further embodiment of the invention is a use of an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent for the preparation of an oral care composition with the proviso that the composition is other than a mouth wash.

It is preferred to use an extract of a part of a Viola species such as Viola tricolor, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent.

A preferred use refers to the preparation of a tooth paste, tooth gel or chewing gum.

A still further embodiment of the invention is a method for the treatment of oral lesions which comprises administering to the patient an effective non-toxic dose of an extract of a part of a medicinal herb belonging to the order of Violales, wherein said part has grown above the earth, or the solid residue remaining after the removal of the solvent content of the extract as the active agent.

The invention is further elucidated by means of the following Examples.

Example 1

Preparation of an extract

Process A

10O g of the dry, finely powdered parts of Viola tricolor grown over the earth (i.e. leaf, stem, flowers) are extracted with water in a mass ratio of 5:200 at 60 ⁰ C under intensive stirring over a water bath. The aqueous extract obtained is filtered, the plant matter is pressed, then the extract is sedimented for 4-8 hours, and filtered again. The dry matter content of the aqueous extract obtained amounts to 5.5-5.9 mg/ml. The water is removed by lyophilization while maintaining the temperature of the tray under -50 ⁰ C. The dry residue obtained is stored in darkness at room temperature and protected from moisture. The dry matter (i.e. the active agent) has a flavonoid content of 3.0-3.4 g/100 g, total polyphenol content of 9.7-10.0 g/100 g , and total content of polyphenol in the skin powder of 2.0-2.5 g/100 g.

Process B

100 g of the dry, powdered parts of Viola tricolor grown over the earth (i.e. leaf, stem, flowers) are extracted with water in a mass ratio of 5:150 by boiling at 100 ⁰ C. The aqueous extract obtained is worked up as described under process A. The aqueous extract has a dry matter content of 5.7-6.2 mg/ml. The lyophilized product (i.e. active agent) prepared as given under process A has a flavonoid content of 2.8-3.1 g/100 g, total polyphenol content of 10.1-11.0 g/100 g , and total content of polyphenol in the skin powder of 1.9-2.2 g/100 g.

Process C

100 g of the dry, powdered parts of Viola tricolor grown over the earth (i.e. leaf, stem, flowers) are extracted with aqueous ethanol containing 75 % by volume of ethanol in a mass ratio of 5:200 in a cold ultrasonic bath. The extract is filtered and the ethanol is removed by evaporation under reduced pressure. The remaining aqueous phase is dried by lyophilization as described under process A.

Example 2 Hard gelatine capsule

0.5 g portions of the lyophilized active agent prepared according to Example 1 , process B are filled into hard gelatin capsules, the capsules are closed, placed into a glass container that is sealed airtightly. Each capsule contains 500 mg of active agent.

Example 3 Hard gelatine capsule

75 g of the lyophilized active agent prepared according to Example 1 , process A and 40 g of carboxymethyl cellulose are homogenized, and the mixture is filled into hard gelatine capsules, the capsules are closed, placed into glass containers that are sealed airtightly. Each capsule contains 75 mg of active agent.

Example 4

Tablet

Tablets are prepared from the following ingredients: lyophilized active agent prepared according to Example 1 , process A 10.0 % by mass,

lactose 45.0 % by mass, microcrystalline cellulose 36.9 % by mass, polyvinylpyrrolidone 6.0 % by mass, magnesium stearate 2.0 % by mass, aspartame 0.1 % by mass.

The ingredients are homogenized and the mixture is compressed to tablets. Alternatively, the active agent can be homogenized with the lactose and microcrystalline cellulose, the mixture is wetted with an aqueous solution of polyvinylpyrrolidone, then, the magnesium stearate and aspartame are added to the mixture. Finally, the homogenized mixture is compressed to tablets of 500 mg.

The tablet obtained can be swallowed with water to transfer it to the gastrointestinal tract. As an alternative, the tablet can be kept sucking for a longer time in the oral cavity in which the active agent is liberated gradually.

Example 5 Gel

A gel is prepared from the following ingredients: lyophilized active agent prepared according to Example 1 , process A 5.0 % by mass, demineralized water 80.9 % by mass, glycerol 8.0 % by mass, sodium carboxymethyl cellulose 5.0 % by mass, methylparaben 1.0 % by mass, mentha 0.1 % by mass.

The active agent, methylparaben and mentha are dissolved

in the mixture of the water and glycerol, then sodium carboxy- methyl cellulose are admixed to the mixture to obtain the gel that is filled into tubes and used to treat the gum and/or the periodontal pockets.

Alternatively, the gel can be prepared by the following procedure: the active agent and mentha are dissolved in a portion of the water while to the residual water the glycerol is added. In the warm aqueous glycerol solution the methyl- paraben is dissolved, then the sodium carboxymethyl cellulose is added, the formed gel is stirred until cold, finally the aqueous solution of the active agent and aroma is admixed.

Example 6

Tooth paste

A tooth paste is prepared from the following ingredients: lyophilized active agent prepared according to Example 1 , process A 16.0 % by mass, demineralized water 62.5 % by mass, glycerol 14.0 % by mass, calcium carbonate 3.0 % by mass, titanium dioxide 2.0 % by mass, sodium lauryl sulfate 0.1 % by mass, sodium fluoride 0.1 % by mass, xylitol [xylo-pentane-1 ,2,3,4,5-pentol] 0.5 % by mass, ethylparaben 1.5 % by mass, menthol 0.3 % by mass.

The ingredients are admixed under continuous stirring and the paste obtained is filled into tubes. The tooth paste is used

for tooth-brushing in the usual manner.

Example 7

Tooth paste

A tooth paste is prepared from the following ingredients using the method described in Example 6: lyophilized active agent prepared according to Example 1 , process A 10 % by weight, demineralized water 67.5 % by weight, glycerol 15 % by weight, calcium carbonate 3 % by weight, titanium dioxide 2 % by weight, sodium lauryl sulfate 0.1 % by weight, sodium fluoride 0.1 % by weight, xylitol [xylo-pentane-1 ,2,3,4,5-pentol] 0.5 % by weight, ethylparaben 1.5 % by weight, menthol 0.3 % by weight.