WO2005018655A1

WO2005018655A1 - Use of noni in relation to oral pathologies, for example, in order to combat problems associated with asialia and hyposialia

Info

Publication number: WO2005018655A1
Application number: PCT/FR2004/001975
Authority: WO
Inventors: Jean-Claude Vezin; Gérard D'ARROS
Original assignee: Pierre Fabre Medicament
Priority date: 2003-07-25
Filing date: 2004-07-23
Publication date: 2005-03-03
Also published as: FR2857872B1; FR2857872A1

Abstract

The invention relates to the use of a Noni extract for the production of a medicament having a preventive or therapeutic effect on oral affections or diseases.

Description

TITLE: USE OF NONI IN DENTAL BUCCO PATHOLOGIES IN PARTICULAR TO COMBAT DASIALIA AND DYYPIALIA PROBLEMS The present invention relates to the use of a fruit extract of

Morinda citrifolia, NONI, in the treatment or prevention of oral diseases or ailments. NONI (also called NONO) is the fruit of MORINDA CITRIFOLIA RUBIACEAE, tropical shrub of the coffee tree family with a very wide distribution in the Polynesian islands with in particular populations in the Marquesas Islands, Huahine, Tahaa, Bora Bora, Tahiti and Hawaii. The fruit is a globular syncarp, sometimes rounded, sometimes elongated and has the shape and dimensions of a large potato when it has reached its final size. The Polynesians have differentiated the stages of fruit ripening according to the following stages:

NONO PI: dark green skin, very hard fruit; NONO PUU: yellow green skin, very hard fruit; NONO OMOTO: pale yellow skin, very hard fruit; NONO TOHEA: pale yellow skin, fairly hard fruit; NONO PE: white skin, soft fruit. The transition to the NONO TOHEA stage to the NONO PE stage occurs very quickly (within a few hours). At the same time as the pulp softens, there is a foul odor reminiscent of that of rotten cheese, linked to the appearance of saturated fatty acids. Two days after arriving at the maturation stage, the NONO PE falls and crashes, releasing the seeds. The different stages of ripening of the fruit take place over a period of approximately 21 days and the production of NONI is permanent throughout the year. The different chemical constituents present in NONI according to Alexandar DITTMAR (Journal of Herbs, Spices and Medical Plants, Vol.l (3) 1993) are the following: acacetin-7-0-D (+) - glucopyranoside, 5,7- dimethylapigenin-4-0-8-D (+) - galactopyranoside, 6,8-dimethoxy-3-methylanthraquinone-l-0-8- rhamnosylglucopyranoside, 8-D-glucopyranose pentaacetate and asperuloside tetraacetate, glycosides, caproic and caprylic acids, anthraquinones, ursolic acid, protein, amino acids (alanine, arginine, aspartic acid, cysteine, cystine, glycine, glutamic acid, leucine, isoleucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine), sterols, sitosterol, phenolics, resins, carbonate, phosphate, magnesium, ferric iron, sodium, damnacanthal, nordamnacanthal, rubiadin, monomethyl ether rubiadin, morindine, morindone, morindadiol, soranjidiol, alizarin, chlororubin, scopoletin, alkaloids and enzymes (xeronine, proxeronin, proxononase). Before the arrival of Europeans, NONI was used as a medicine in traditional Polynesian medicine. NONI has already been the subject of various medical studies, in particular that of Doctor Ralph HELNICKE of the University of Hawaii concerning xeronine. NONI is also used in the composition of a drug against viral hepatitis B and acquired immunodeficiency syndrome (patent application WO 8805304 A1). Finally the work of Paul PETARD, Pharmacist Commander of the Armies, carried out in 1965 with the assistance of Doctor SEGONNE, Director of the microbiology laboratory of the hospital of Papeete and of Mr. PICHON, entomologist of ORSTOM (Some useful plants of French Polynesia and RAAU TAHITI, ed. HAERE PO NO TAHITI, pp. 280-285) have highlighted the antibacterial action of NONI on strains of staphylococcus aureus and escherichia coli while the work of Professor Ralph HELNICKE of the University of Hawaii have shown that NONI has an antibacterial action on pseudomonas aeruginosa, proteus morganii, staphylococcus aureus, bacillis subtilis, escherichia coli, salmonella and shigela. However, no study specific to oral bacteria, that is to say on the pathogenic bacterial strains responsible for oral infectious diseases such as dental caries and periodontitis, has been carried out to date. Surprisingly, the inventors of the present application have discovered that the extracts of fruit of Morinda citrifolia, that is to say the extracts of NONI, had a preventive or therapeutic action on oral diseases or ailments. The advantage of the product used according to the present invention is that NONI does not present a risk of toxicity since the 100% natural fruit juice has been marketed in the USA for several years. On the other hand, NONI is marketed in the USA with the agreement of the Food and Drug Administration (FDA) as a food supplement in the form of a gel-coated tablet containing powder extract of NONI. The Commission of the European Communities, on 06/12/2003 authorized the marketing of NONI juice as a new food ingredient. No scientific publication to date has reported any toxicity of NONI despite daily consumption of NONI by thousands of people in different forms (fruit juice, food supplements etc.). NONI extract can therefore be administered daily without danger. The present invention therefore relates to the use of an extract of NONI for the manufacture of a medicament having a preventive or therapeutic action for oral diseases or ailments. By “NONI extract” is understood within the meaning of the present invention any extract of fruit of Morinda citrifolia, raw, purified or enriched in one of its active ingredients obtained by any conventional method such as, for example, the processes described in the application FR-2783137 and in US-5288491, from NONI at an advanced stage of maturation. Advantageously, it is a crude extract, advantageously obtained from NONI at the NONO TOHEA maturation stage (pale yellow epidermis, fairly hard fruit) or NONO PE (white epidermis, soft fruit), even more advantageously. at the NONO PE ripening stage (white skin, soft fruit). This extract can advantageously be in the form of a liquid or a powder. In a particular embodiment, the present invention relates to the use of an extract of NONI as defined above for the manufacture of a drug having an excito-secretory action on the salivary glands and advantageously intended for the treatment of hyposialia and / or asialia. In another particular embodiment, the present invention also relates to the use of an extract of NONI as defined above for the manufacture of a medicament having a cariogenic antibacterial action, advantageously on streptococcus mutans and lactobacilli. In a third particular embodiment, the present invention relates to the use of an extract of NONI as defined above for the manufacture of a medicament having an oral antifungal action, advantageously on candidas albicans. Advantageously, the present invention relates to the use of an extract of NONI as defined above for the manufacture of an oral antiseptic drug and / or an oral hygiene product. Advantageously, the present invention relates to the use of an extract of NONI as defined above for the manufacture of a medicament intended to prevent the appearance of caries and / or periodontitis. Advantageously, the medicament or the oral hygiene product according to the present invention is in the form suitable for its use, and in particular in the form of mouthwash, spray pump solution, gelled solution, suspension, sub-lingual tablet or chewing gum. Advantageously, said medicament or oral hygiene product comprises other components such as excipients, taste masks, fluorine, other active agents, sweeteners, etc. The following examples of preparation and use are given as a non-limiting indication.

Example 1: Preparation of the Raw NONI Extract: The preparation of the raw extract was carried out in the traditional way by grinding the fruit until a fluid mass was obtained which was then filtered through a very fine mesh screen. to obtain the 100% natural final liquid crude extract. The pH of the raw NONI extract is 3.5. The product is kept in the refrigerator in hermetically sealed glass bottles. NONI extract has the particularity of being stored for a very long time in a container without undergoing any alteration and without fermenting. Analyzes carried out by HPLC coupled with a UV detector made it possible to identify 3 classes of compounds: - Carotene - Tannins - Fatty acids Concerning fatty acids, 4 constituents are present between C6 and CIO, in particular capric, caproic and caprylic acids . The tannins have been dosed globally but it is possible to identify them specifically on a suitable column. Carotene is present in large quantities and can be used as a marker for further analyzes carried out during clinical studies.

Example 2: Excito-Secretory Action on the Salivary Glands of the NONI Extract The saliva secreted by the salivary glands plays an important role in maintaining oral health, due to: - the salivary flow which exerts a "cleaning" action "oral surfaces,

- mineral ions which neutralize acids (buffering capacity) and promote the remineralization of early carious lesions,

- antibacterial substances (lysozymes, sialoperoxidases, agglutins, cystatins, histatins, immunoglobulins, Tissue Inhibitors Metallo Protemase) which inhibit the metabolism of oral pathogenic microorganisms. Saliva therefore plays a major role in the regulatory process which aims to counteract the pathogenic action of bacteria in the oral flora. Saliva can only play its protective role when the salivary glands produce sufficient saliva. Any salivary deficiency is likely to lead to the appearance of oral infectious pathologies (caries, periodontitis). The extreme example of the consequences of this reduction in flow is that of patients who, having undergone cervico-facial radiotherapy, develop extensive polycaries in the absence of therapeutic vigilance. A number of pathologies and therapies cause a decrease in saliva flow:

- main causes of systemic origin of the decrease in salivary flow: senescence, hormonal changes (pregnancy, menopause), psychological factors (anxiety, anxiety), drug addiction, diabetes, lupus erythematosus, neurological pathologies, hepatic pathologies, pancreatic pathologies, nutritional deficiencies , Sjogren's syndrome (xerostomia).

- main causes of therapeutic orisine for the reduction of salivary flow: loco-regional radiotherapy, antidepressants, antipsychotics, tranquilizers, hypnotics, anticholinergics, antihistamines, antihypertensives, diuretics, antiparkinsonians, appetite suppressants. Saliva production after each meal is essential because saliva is the body's only natural defense system against oral pathogens. Numerous studies show the important role of saliva as a factor involved in the development of cavities and periodontal diseases (SOCRANSKY J periodontol 1992; 63: p 322-331). All hyposialias must be "corrected" to avoid any risk of occurrence of oral pathologies, especially since the modern lifestyle no longer allows dental brushing after each meal and especially that of lunch. The absence of dental brushing associated with a salivary deficiency will inevitably lead to the appearance of oral or dental pathologies and it is therefore essential to deal with this danger by stimulating salivary secretion after each meal, especially since the factors triggering the hyposialia are multiple "age, pregnancy, menopause, stress, drug addiction, disease, medication". The salivary glands produce saliva continuously throughout the day and interrupted only during periods of sleep, the bulk of salivary secretion occurring during periods of stimulation (chewing, arousal of taste). Salivary secretion at rest varies between 0.3 and 0.4 ml / minute (approximately 19 ml / hour). The secretion of saliva stimulated (by chewing gum for example) is 1 to 2 ml / minute. In 24 hours, the salivary flow varies from 600 to 1000 ml. A method of measuring salivary flow stimulated by NONI extract was developed and tested on 200 volunteers of different sex, age and ethnicity. The tests are carried out at least two hours after any food intake. The patient is seated in a chair, mouth open with the tip of the tongue resting on the palatal faces of the upper incisors, then 5 ml of crude NONI extract prepared according to Example 1 is placed at the level of the canal orifice. Steno. The patient is asked to keep the product in the mouth in the sublingual region for 2 minutes, then the patient is asked to spit out all the saliva secreted during this period in a graduated glass. The results of the salivary flow stimulated by the extract of NONI vary between 4 and 6 ml, or 2 to 3 ml / minute. These measurements are confirmed by monitoring the carotene concentration in the crude extract and in the extract diluted in saliva. Knowing that the stimulated salivary secretion (chewing, arousal of taste) is 1 to 2 ml / minute, it can therefore be deduced that the presence of NONI extract in the oral cavity stimulates salivary secretion.

Example 3; comparative study of the excito-secretory power of NONI extract This clinical study was carried out on 30 volunteers. The salivary flow (DS) stimulated by chewing for 5 minutes of a paraffin cube without flavor was measured, then 24 hours later, the salivary flow stimulated by the presence of NONI extract in the oral cavity for a period of 5 minutes was measured. In all cases, the results of the salivary flow stimulated by the extract of NONI were superior to those obtained by chewing a paraffin cube, which confirms the particularly effective salivary stimulating action of NONI. On two of the volunteers showing signs of hyposialia (DS <5 ml), the salivary flow stimulated with the crude NONI extract prepared according to example 1 (superior DS 5 ml) was thus improved. The measurements were made by measuring the carotene concentration before and after the use of NONI.

EXAMPLE 4 Clinical Study of the Treatment of Hposposialia with the Extract of NONI CLINICAL CASE N ° 1 The study was carried out on a voluntary patient suffering from significant hyposialia following a surgical intervention concerning the ablation tonsils (tonsillectomy) performed at Saint-Louis hospital in Paris. The patient suffered from severe dry mouth which resulted in insomnia and violent migraines at night. Despite all the treatments with conventional sialogogues, the patient continued to suffer from this hyposialia. First, a test to measure saliva flow by chewing a paraffin cube for 5 minutes was carried out in this patient. The stimulated saliva secretion was 4 ml, which confirms the diagnosis of hyposialia. For one month, the patient carried out mouthwashes after each meal with a crude extract of NONI prepared according to example 1. After 2 weeks of treatment, the patient began to perceive an improvement concerning his nocturnal and daytime dry mouth. After a month of mouthwash treatment with NONI extract, the patient no longer complained of dry mouth or nocturnal migraine. A saliva flow measurement test by chewing a paraffin cube was carried out at the end of the treatment, and a figure of 8 ml was obtained which confirms the healing of the patient and the therapeutic action of the extract of NONI as a corrector for hyposialias. One month after stopping treatment, the patient still no longer suffered from dry mouth.

CLINICAL CASE N ° 2 The study was carried out on a voluntary patient suffering from hyposialia due to regular consumption of local marijuana (pakalolo), which is a substance of plant origin containing 9 tetrahydrocannabinol (THC). The salivary flow stimulated by the chewing of a paraffin cube before and after treatment by mouthwash from a crude extract of NONI prepared according to example 1 was compared.

RESULT:

Before treatment: DS = 4 ml,

After 1 month of treatment: DS = 6.5 ml,

After 3 months of treatment: DS = 7.5 ml.

EXAMPLE 5 Cariogenic Antibacterial Action of NONI Extract The formation of dental caries is due to bacteria which produce acid on the surface of the enamel from carbohydrates, thus causing demineralization of the dental structure. . The work of KNEIST (Evaluation of new caries risk test, Independent

Dentistry, July / August 1999, p. 76-85), have shown that streptococcus mutans (SM) and Iactobacilli (LB) play a decisive role in the initiation of caries. A possible antibacterial action of NONI extract on SM and LB bacteria was investigated by comparing the number of SM and LB bacteria present in the oral cavity before and after mouthwash applications of a crude NONI extract prepared according to Example 1. For the evaluation of the number of SM and LB bacteria and for studying the salivary pH, the salivary tests CRTbacteria and CRTbuffer from the company V ADENT were used respectively. A volunteer patient with poor dental hygiene, with several dental caries in progress, was selected. The patient was asked to rinse the mouth with the raw NONI extract prepared according to Example 1 after each meal and not to change his eating and hygienic habits during the test.

RESULTS The CRTbacteria produced before the mouthwashes shows a strong presence of bacteria SM and LB and the CRTbuffer shows an acid salivary pH. The CRTbacteria produced after a month of mouthwash with NONI extract shows a very strong decrease in SM and LB and a neutral salivary pH. The tests carried out after three months of mouthwash confirmed the results obtained after one month of treatment.

This clinical test proves that the NONI extract exerts an antibacterial action on SM and LB since we took care to take care that the patient does not change his hygienic and food habits during the duration of the test. The antibacterial action of NONI extract can be direct or indirect, since the patient's salivary secretion is considerably improved, as shown by the CRTbuffer and the salivary flow tests: before treatment: DS = 7 ml; after 1 month of treatment: DS = 9 ml; after 3 months of treatment: DS ≈ l l ml.

EXAMPLE 6 Clinical Study of the Periodontal Antibacterial Action of the NONI Extract The action of the NONI crude extract prepared according to Example 1 was tested on certain bacteria using the new Periodontitis Microbiology Test (PMT) tests. from Laboral France, allowing clinical evaluation of periodontal pathogens such as: actinobacillus actinomycetemcomitans, porphyromonas gingivalis, prevotella intermedia, bacteroides forsythus, fusobacterium nucleatum, peptostreptococcus micros and treponema denticola. The PMT kit was used rather than the LABORAL Cultures kit. After selecting a patient with periodontitis, the presence of periodontal pathogens in the patient's periodontal pockets was assessed using the PMT test. The presence of bacteria having been observed, the patient underwent treatment with mouthwashes of an extract of NONI prepared according to Example 1, after each meal for one month. At the end of the treatment, it was found, with the results of the PMT kits, a decrease in the presence of periodontal pathogens. EXAMPLE 7 Oral Antifungal Action of the NONI Extract On a patient suffering from repetitive atrophic oral candidiasis linked to the presence of a partial resin prosthesis, total recovery after two weeks of mouthwashing with raw NONI extract prepared according to Example 1 was obtained. Encouraging results have also been obtained during maintenance treatment with mouthwashes of NONI extract prepared according to the example Neuromeningeal cryptococcosis in a subject suffering from AIDS. The NONI extract therefore seems to have a therapeutic action on CANDIDA ALBICANS in the oral cavity. NONI extract can therefore stimulate the body's natural defenses against oral microbial attacks responsible for dental and periodontal diseases. The daily action of the extract of NONI thus makes it possible to protect the patients against oral diseases consecutive to hyposialia, the causes of which are multiple and especially never taken into consideration by medicine. Thus, NONI extract is an essential hygiene supplement to oral brushing in the elderly, pregnant women, drug addicts, stressed people whose hyposialia is absolutely not taken into consideration in medical practice. today. It can be used in the form of a sub-lingual tablet prepared by a process comprising a step of freeze-grinding the NONI extract from the fruits collected at the NONO PE stage to obtain a powder and then preparation of the tablet. The special smell of NONI extract can be masked more easily by adding a sweetening powder when making the lozenge. The powdered NONI extract can also be used in the form of chewing gum as a dental hygiene product capable of stimulating the body's natural salivary defenses after each meal thanks to a combined effect of chewing and stimulation of salivary secretion of NONI extract. The NONI extract can also be used daily as an oral hygiene product in the form of mouthwashes from a raw liquid extract sweetened naturally by the flowers of hibiscus tiliaceus "Tahitian purau". Other preparations have been used, in particular to treat hyposialias and asialias. They consist in adding to amounts of 2 to 80% of NONI juice mineral salts such as: - potassium chloride - sodium chloride - magnesium chloride - calcium chloride at concentrations between 10 and 100 mg% ml as well only - mucilages - caraggenates - gum arabic - gluco and galacto mannan - methyl cellulose - hydroxypropyl methyl cellulose - gelatin - glycerin - lycasin syrup - maltitol syrup at concentrations of 0.1 to 20%. The preparation of tixotropic gels containing silica derivatives associated with NONI were also prepared.

Claims

1. Use of an extract of NONI for the manufacture of a medicament having an excito-secretory action on the salivary glands and / or a cariogenic antibacterial action.

2. Use of a NONI extract according to claim 1, for the manufacture of a medicament intended for the treatment of hyposialia and / or asialia.

3. Use of an extract of NONI according to claim 1, for the manufacture of an antibacterial drug on streptococcus mutans and lactobacilli.

4. Use of a NONI extract according to any one of claims 1 to 3, for the manufacture of a medicament intended to prevent the appearance of caries and / or periodontitis.

5. Use of a NONI extract according to any one of claims 1 to 4, characterized in that the medicament is in the form of mouthwash, pump spray solution, gelled solution, sub-lingual tablet or gum chewable, tixotropic gel.