FR2857872A1 - Use of extract of fruit of Morinda citrifolia having antimicrobial activity and stimulating secretion of saliva, for prevention and treatment of oral diseases and disorders, - Google Patents

Abstract

Use of an extract (A) of noni (fruit of Morinda citrifolia) is claimed for preparing a pharmaceutical composition for treatment or prevention of oral diseases and disorders. ACTIVITY : Antibacterial; Fungicide. In a test, a patient with severe hyposialia and associated nocturnal migraines following surgical removal of the tonsils, who had not responded well to usual sialogogs, used a noni-based mouthwash, after every meal, for a month. After this time, the patient no longer suffered from a dry mouth or migraines and was still well a month after stopping the treatment. A mastication test, using a block of paraffin, indicated that saliva production after treatment was double that before treatment. MECHANISM OF ACTION : None given.

Description

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USE OF NONI DURING BUCCO DENTAL PATHOLOGIES
NOTABLY TO COMBAT THE PROBLEMS OF ASIALIA AND
On hyposialia
The present invention relates to the use of a Morinda citrifolia fruit extract, NONI, in the treatment or prevention of oral diseases or conditions.

 NONI (also known as NONO) is the fruit of the MORINDA CITRIFOLIA RUBIACEAE, a tropical shrub of the coffee tree family with a very extensive 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 differentiated the ripening stages of the fruit in the following stages: NONO PI: dark green epidermis, very hard fruit; NONO PUU: greenish yellow epidermis, very hard fruit; NONO OMOTO: pale yellow epidermis, very hard fruit; NONO TOHEA: pale yellow epidermis, rather hard fruit; NONO PE: white epidermis, soft fruit.

 The transition to the NONO TOHEA stage at the NONO PE stage is very fast (in a few hours). At the same time that the pulp softens, it develops a foul odor reminiscent of rotten cheese, linked to the appearance of saturated fatty acids. Two days after arriving at the ripening stage, the NONO PE falls and crushes, releasing the seeds.

 The different stages of ripening of the fruit take place over a period of about 21 days and the production of NONI is permanent throughout the year.

The different chemical constituents present in the NONI according to Alexandar DITTMAR (Journal of Herbs, Spices and Medical Plants, Vol.l (3)
1993) are as follows: acacetin-7-0-D (+) - glucopyranoside, 5,7-dimethylapigenin-4-O-8-D (+) galactopyranoside, 6,8-dimethoxy-3-methylanthraquinone-1-0 -8rhamnosylglucopyranoside, 8-D-glucopyranose pentaacetate and tetraacetate

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 asperuloside, glycosides, caproic and caprylic acids, anthraquinones, ursolic acid, protein, amino acids (alanine, arginine, aspartic acid, cysteine, cystine, glycine, glutamic acid, histidine, leucine, isoleucine, methionine, phenylalanine, proline, serine , threonine, tryptophan, tyrosine, valine), sterols, sitosterol, phenolic bodies, resins, carbonate, phosphate, magnesium, ferric iron, sodium, damnacanthal, nordamnacanthal, rubiadin, monomethyl ether of rubiadin, morindine, morindone, morindadiol, soranjidiol, alizarin , chlororubin, scopoletin, alkaloids and enzymes (xeronine, proxeronine, proxeronase).

 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, including those of Dr. Ralph HEINICKE of the University of Hawaii concerning xeronine.

 NONI is also included 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, made in 1965 with the assistance of Dr. SEGONNE, Director of the microbiology laboratory of the Papeete Hospital and Mr. PICHON, entomologist of ORSTOM (Some useful plants of French Polynesia and RAAU TAHITI, HAERE PO NO TAHITI, pp. 280-285) have demonstrated the antibacterial action of NONI on strains of Staphylococcus aureus and Escherichia coli while the work of Professor Ralph HEINICKE of the University of Hawaii have shown that NONI has an antibacterial action on Pseudomonas aeruginosa, Proteus morganii, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella and Shigela.

 However, no studies specific to oral bacteria, that is to say on the pathogenic bacterial strains responsible for oral infectious diseases such as tooth decay and periodontitis, have been performed to date.

 Surprisingly, the inventors of the present application have discovered that the fruit extracts of Morinda citrifolia, that is to say the extracts of

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 NONI, had a preventive or therapeutic action on diseases or oral diseases.

 The advantage of the product used according to the present invention is that the NONI does not present a risk of toxicity since 100% natural fruit juice has been marketed in the US for several years. On the other hand, NONI is marketed in the USA with the approval of the Food and Drug Administration (FDA) as a dietary supplement in the form of a gelatin-coated tablet containing NONI powder extract.

 The Commission of the European Communities, on 12/06/2003 authorized the placing on the market 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. ..).

 The extract of NONI can therefore be administered daily without danger.

 The present invention thus relates to the use of an extract of NONI for the manufacture of a medicament having a preventive or therapeutic action of diseases or oral diseases.

 For the purposes of the present invention, the term "NONI extract" is intended to mean any Morinda citrifolia fruit extract, crude, purified or enriched in one of its active ingredients, obtained by any conventional method such as, for example, the processes described in the patent application. FR-2783137 and in US Pat. No. 5,288,491, from NONI at an advanced maturation stage. Advantageously, it is a crude extract, advantageously obtained from NONI at the NONO TOHEA maturation stage (pale yellow epidermis, rather hard fruit) or NONO PE (white epidermis, soft fruit), even more advantageously at the NONO PE maturation stage (white epidermis, soft fruit).

 This extract can advantageously be in the form of liquid or 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

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 drug having excito-secretory action on the salivary glands and advantageously for the treatment of hyposialia and / or asialia.

 In another particular embodiment, the present invention also relates to the use of a NONI extract as defined above for the manufacture of a medicament having a cariogenic antibacterial action, advantageously on streptococci mutans and lactobacilli.

 In a third particular embodiment, the present invention relates to the use of a NONI extract 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 a NONI extract 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 for preventing 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, pump spray solution, gelled solution, suspension, compressed sub -lingual 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 crude extract of NONI
The preparation of the crude extract was made in the traditional way by grinding the fruits until a fluid mass is obtained which is then filtered through a very fine mesh screen to obtain the final 100% natural raw liquid extract. The pH of the crude NONI extract is 3.5.

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 The product is stored in a refrigerator in hermetically sealed glass bottles. The extract of NONI has the peculiarity of being preserved very long in a container without undergoing any alteration and without fermenting.

Analyzes carried out by HPLC coupled to a UV detector have identified 3 classes of compounds: - Carotene - Tannins - Fatty acids
Regarding fatty acids, 4 constituents are present between C6 and CIO, including capric, caproic and caprylic acids.

 The tannins have been dosed globally but it is possible to specifically identify them on a suitable column.

 Carotene is present in significant amounts and can be used as a marker for subsequent analyzes conducted in clinical studies.

EXAMPLE 2 Excito-Secretory Action on the Salivary Glands of the NONI Extract
Saliva secreted by the salivary glands plays an important role in the maintenance of oral health, due to: - salivary flow that exerts a "cleaning" action on oral surfaces, - mineral ions that neutralize acids (buffering capacity) and promote the remineralization of early carious lesions, - antibacterial substances (lysozymes, sialoperoxidases, agglutins, cystatins, histatins, immunoglobulins, Tissue Inhibitors Metallo Proteinase) which inhibit the metabolism of oral pathogenic microorganisms.

 Saliva therefore plays a major role in the regulatory process that aims to counterbalance 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 diseases (caries, periodontitis).

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 The extreme example of the consequences of this decrease 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 lead to a decrease in salivary 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, liver diseases, pancreatic diseases, nutritional deficiencies, Sjogren syndrome (xerostomia).

- main causes of therapeutic origin of the decrease in salivary flow radiotherapy loco-regional, antidepressants, antipsychotics, tranquillizers, hypnotics, anticholinergics, antihistamines, antihypertensives, diuretics, antiparkinsonian, appetite suppressant.

 Saliva production after each meal is essential because saliva is the body's only natural defense against oral pathogens. Numerous studies show the important role of saliva as a factor involved in the development of caries and periodontal diseases (SOCRANSKY J periodontol 1992; 63: p 322-331). All the hyposialies must be "corrected" to avoid any risk of appearance of oral pathologies, especially as the modern lifestyle no longer allows to perform a toothbrushing after each meal and especially that of lunch. The absence of dental brushing associated with salivary deficiency will inevitably lead to the development of oral diseases and it is therefore essential to deal with this danger by stimulating salivary secretion after each meal, especially since the factors that trigger 'hyposialia are multiple' age, pregnancy, menopause, stress, addiction, diseases, drugs'.

 The salivary glands produce saliva continuously throughout the day and interrupted only during periods of sleep, with the bulk of salivary secretion occurring during periods of stimulation (chewing, excitement of taste). The salivary secretion at rest varies between 0.3 and 0.4 ml / minute (approximately 19 ml / hour). The secretion of stimulated saliva (by the

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 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 gender, age and ethnicity.

 The tests are carried out at least two hours after any food intake.

 The patient sits in an armchair, mouth open with the tip of the tongue resting on the palatal surfaces of the upper incisors, then 5 ml of crude extract of NONI prepared according to Example 1 is placed at the level of the orifice of Steno. The patient is asked to keep the product in the mouth in the sublingual area for 2 minutes and then the patient is asked to spit in a graduated glass all the saliva secreted during this period.

 The salivary flow results stimulated by the NONI extract vary between 4 and 6 ml, ie 2 to 3 ml / minute. These measurements are confirmed by monitoring the concentration of carotene in the crude extract and in the extract diluted in saliva.

 Knowing that stimulated salivary secretion (chewing, taste excitation) is 1 to 2 ml / minute, it can 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 the NONI Extract
This clinical study was performed on 30 volunteers.

 The salivary flow (SD) stimulated by chewing for 5 minutes of a paraffin cube devoid of flavor was measured, and 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 salivary flow results stimulated by the NONI extract were superior to those obtained by chewing a paraffin cube, which confirms the particularly effective salivary stimulating action of NONI.

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 On two of the volunteers showing signs of hyposialia (DS <5 ml), the salivary flow rate stimulated with the crude extract of NONI prepared according to Example 1 (upper DS 5 ml) was thus improved. The measurements were made by measuring the concentration of carotene before and after the use of NONI.

Example 4: Clinical Study of the Treatment of Hyposialy with the Extract of Noni CAS CLINIQ UE N 1
The study was performed on a volunteer patient with significant hyposialia following a surgical procedure concerning the removal of tonsils (tonsillectomy) performed at the Saint-Louis Hospital in Paris. The patient suffered from severe dryness at night, which resulted in insomnia and severe migraines. Despite all the treatments by conventional sialogogues, the patient continued to suffer from this hyposialie.

 Firstly, a test for measuring salivary flow by chewing a paraffin cube for 5 minutes was carried out in this patient.

The secretion of stimulated saliva was 4 ml, which confirms the diagnosis of hyposialie. For one month, the patient performed mouthwashes after each meal with a crude NONI extract prepared according to Example 1. After 2 weeks of treatment, the patient began to perceive an improvement in 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 salivary flow test by chewing a paraffin cube was performed at the end of treatment, and an 8 ml figure was obtained which confirms the patient's healing and the therapeutic action of the extract. NONI as a corrector of hyposialies.

 One month after stopping treatment, the patient was no longer suffering from dry mouth.

CLINICAL CASE N 2
The study was conducted on a voluntary patient with hyposialia due to regular consumption of local marijuana (pakalolo), which is a plant-based substance containing tetrahydrocannabinol (THC).

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 The salivary flow stimulated by chewing a paraffin cube before and after mouthwash treatment from a crude NONI extract 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: = 7.5 ml.

EXAMPLE 5 Cariogenic Antibacterial Action of the NONI Extract
The formation of tooth decay is due to the bacteria that produce acid on the surface of the enamel from the carbohydrates, thus causing a demineralization of the dental structure.

 The work of KNEIST (Evaluation of new caries risk test, Independent Dentistry, July / August 1999, pp. 76-85), showed that streptococci mutans (SM) and lactobacilli (LB) play a decisive role in initiation. cavities. A possible antibacterial action of the NONI extract on SM and LB bacteria was investigated by comparing the number of bacteria SM and LB present in the oral cavity before and after mouthwash applications of a crude extract of NONI prepared according to Example 1

 For the evaluation of the number of bacteria SM and LB and to study the salivary pH, salivary tests CRTbacteria and CRTbuffer of the company VIVADENT were respectively used. A volunteer patient with poor dental hygiene, with several dental caries in progress, was selected.

 The patient was asked to make mouthwashes with the crude extract of NONI prepared according to Example 1 after each meal and not to change during the test his dietary and hygienic habits.

RESULTS
The CRTbacteria performed before the mouthwashes shows a strong presence of SM and LB bacteria and the CRTbuffer shows an acidic salivary pH.

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 The CRTbacteria performed after one month of mouthwash with the extract of NONI shows a very strong decrease in SM and LB and a neutral salivary pH.

 Tests performed after three months of mouthwash confirmed the results obtained after one month of treatment.

 This clinical test proves that the NONI extract has an antibacterial action on SM and LB since we took care to be careful that the patient does not change his hygienic and nutritional habits during the test. The antibacterial action of the NONI extract can be direct or indirect, since salivary secretion of the patient is considerably improved, as shown by CRTbuffer and salivary flow tests: before treatment: DS = 7 ml; 1 month of treatment: DS = 9 ml; 3 months of treatment: DS = 11 ml.

Example 6: Clinical Study of the Periodontal Antibacterial Action of the NONI Extract
The action of the crude extract of NONI prepared according to Example 1 was tested on certain bacteria thanks to the new Periodontitis Microbiology Test (PMT) tests from Laboral France, allowing the clinical evaluation of periodontal pathogens such as: actinobacillus actinomycetemcomitans, porphyromonas gingivalis, prevotella intermedia, forsythus bacteroides, 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 evaluated using the PMT test.

 The presence of the bacteria having been observed, the patient was treated with mouthwashes of an extract of NONI prepared according to Example 1, after each meal for a month.

 At the end of the treatment, the results of the PMT kits showed a decrease in the presence of periodontal pathogens.

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Example 7 Oral Antifungal Action of the Noni Extract
In a patient with recurrent atrophic oral candidiasis related to the presence of a partial resin prosthesis, complete healing after two weeks of mouthwash of crude extract of NONI prepared according to Example 1 was obtained.

 Encouraging results have also been obtained during maintenance treatment with mouthwashes of NONI extract prepared according to Example I of neuromeningeal cryptococcosis in a subject suffering from AIDS.

 The extract of NONI thus seems to have a therapeutic action on the CANDIDA ALBICANS of the oral cavity.

 The extract of NONI can therefore stimulate the body's natural defenses against oral microbial aggressions responsible for dental and periodontal diseases. The daily action of the extract of NONI thus makes it possible to protect the patients against the oral diseases consecutive to the hyposialie, whose causes are multiple and especially never taken into consideration by the medicine.

 Thus, the extract of NONI is an indispensable complement of hygiene to the oral brushing in the old people, the pregnant women, the addicts, the stressed persons whose hyposialie is absolutely not taken into consideration in the medical practice today.

 It can be used in the form of a sub-lingual tablet prepared by a process comprising a step of cryocrushing the NONI extract from the fruits collected in the NONO PE stage to obtain a powder and then preparing the tablet. The particular smell of the NONI extract can be masked more easily by adding a sweetening powder at the time of making the pellet.

 NONI powder extract can also be used as chewing gum as a dental hygiene product that can stimulate the body's natural salivary defenses after every meal thanks to the combined effect of chewing and stimulation of the body. the salivary secretion of the extract of NONI. NONI extract can also be used daily as an oral hygiene product in the form of mouthwash from a naturally sweetened liquid raw extract of hibiscus tiliaceus flowers "purau tahitien".

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 Other preparations have been used, in particular to treat hyposialies and asialies.

 They consist of adding mineral salts such as: - potassium chloride - sodium chloride - magnesium chloride - calcium chloride at concentrations of between 10 and 100 mg% ml to amounts of 2 to 80% of NONI juice. that - mucilages - caragghenates - 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 NONI-associated silica derivatives has also been prepared.

Claims (11)

1. Use of a NONI extract for the manufacture of a medicament having preventive or therapeutic action against oral diseases or conditions.  2. Use of a nonion extract according to claim 1 for the manufacture of a medicament having an excito-secretory action on the salivary glands.  3. Use of a nonion extract according to claim 2 for the manufacture of a medicament for the treatment of hyposialie and / or asialie.  4. Use of a nonion extract according to claim 1 for the manufacture of a medicament having a cariogenic antibacterial action.  5. Use of a nonion extract according to claim 4 for the manufacture of an antibacterial drug on streptococci mutans and lactobacilli.  6. Use of a nonion extract according to claim 1 for the manufacture of a medicament having oral antifungal action.  7. Use of a NONI extract according to claim 6 for the manufacture of an antifungal drug on candida albicans.  8. Use of a nonion extract according to claim 1 for the manufacture of an oral antiseptic medicament.  9. Use of a nonion extract according to claim 1 for the manufacture of an oral hygiene product.  10. Use of an extract of NONI according to any one of claims 1 to 9 for the manufacture of a medicament for preventing the occurrence of caries and / or periodontitis.  11. Use of a nonion extract according to any one of claims 1 to 10, characterized in that the drug or the oral hygiene product is in the form of mouthwash, pump spray solution, gelled solution, sub-lingual tablet or chewing gum, tixotropic gel.