RO137277A0 - Mouthwash with β-cyclodextrin inclusion complex with clove essential oil - Google Patents

Abstract

The invention relates to a mouthwash with natural active principles of xylitol, β-cyclodextrin inclusion complex with essential oils of cloves, cinnamon, myrrh and tea tree, intended for the hygiene of the oral cavity, the mouthwash having an antimicrobial, antifungal, anti-inflammatory, immunomodulatory, soothing, odorizing and healing action. According to the invention, the mouthwash is made by combining distilled water with sodium bicarbonate, xylitol, beta-cyclodextrin inclusion complex with clove essential oil, solubilizer for essential oils, cinnamon essential oil, myrrh essential oil and tree tea essential oil, in the following association ratio expressed in parts by weight: 90...92.5 : 0.4...0.5 : 3...3.5 : 1...1.5 : 1. ..1.5 : 0.5...1 : 0.5...1 : 0.5...1.

Description

RO 137277 AO

STATE OFFICE FOR INVHÎ

Patent application of ίυ'

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MOUTHWASH WITH β CYCLODEXTRIN INCLUSION COMPLEX WITH VOLATILE OIL OF Cloves

The present invention relates to a mouthwash with natural active principles (xylitol, inclusion complex of β-cyclodextrin with volatile oil of cloves, solubilizer for essential oils, volatile oil of cinnamon, volatile oil of myrrh, volatile oil of tea) intended for oral cavity hygiene, with antimicrobial, antifungal, anti-inflammatory, immunomodulatory, calming, deodorizing and cicatrizing action.

There are various mouthwashes with natural extracts used to prevent or treat various oral and gum diseases: OSSIDENTA, ROMAZULAN, LISTERINE, ECO DENTA, etc.

Description: The invention refers to a mouthwash intended for the hygiene of the oral cavity, which consists of the combination of distilled water with sodium bicarbonate, xylitol, inclusion complex of β-cyclodextrin with volatile clove oil, solubilizer for essential oils , cinnamon volatile oil, myrrh volatile oil, tea tree volatile oil, in an association ratio, parts by weight of: 90...92.5 : 0.4...0.5 : 3. ..3.5 : 1...1.5 : 1...1.5 : 0.5...1 : 0.5...1 : 0.5...1.

The main advantages of the mouthwash according to the invention are the following:

- by combining natural principles, an effective antibacterial and antifungal action is obtained for oral cavity hygiene (βcyclodextrin inclusion complex with volatile clove oil, volatile cinnamon oil, volatile myrrh oil, volatile tea tree oil);

- a significant anti-inflammatory and cicatrizing effect (inclusion complex of β-cyclodextrin with volatile oil of cloves, volatile oil of cinnamon, volatile oil of myrrh, volatile oil of tea tree);

- immunomodulatory effect through non-specific mechanisms (β-cyclodextrin inclusion complex with clove volatile oil, cinnamon volatile oil, myrrh volatile oil, tea tree volatile oil);

- a calming and anesthetic action evident from the first use (β-cyclodextrin inclusion complex with volatile oil of cloves, volatile oil of cinnamon, volatile oil of myrrh, volatile oil of tea tree);

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- a feeling of freshness and a pleasant breath smell (inclusion complex of β-cyclodextrin with volatile oil of cloves, volatile oil of cinnamon, volatile oil of myrrh, volatile oil of tea tree);

- a tolerance and a good cleaning capacity of the oral cavity (xylitol recognized for its antitartar effect, solubilizer for essential oils with foaming capacity and surfactant effect).

This mouthwash enriches the range of pharmaceutical products with natural active principles used in the treatment of dental and gum diseases, as well as for maintaining the hygiene of the oral cavity, in that it is obtained by combining some natural products, each with known effects on the human body: xylitol, oil clove essential oil, cinnamon essential oil, rosemary essential oil, tea tree essential oil.

The action of the mouthwash is mainly determined by the natural principles that enter into its composition:

Xylitol is a white crystalline substance, it tastes very similar to sugar. It is found in nature, in the fibers of many fruits, vegetables, grains or the bark of some trees. Clinical studies have shown that xylitol is suitable as a sweetener from the point of view of dental health because it is an active anti-caries and anti-tartar ingredient. It is a product that can be used safely by adults and children alike. The chemical structure of xylitol prevents the metabolism of some bacteria. Xylitol reduces the acidity in the oral cavity, prevents fermentation processes, reduces the formation of dental plaque, relieves the dryness of the oral cavity, helps to eliminate bacteria from the oral cavity, helps to remineralize the teeth. It is recommended as a sweetener in dental hygiene products, reduces the formation of dental plaque, reduces acidity in the oral cavity, encourages enamel remineralization. Animal studies have shown that xylitol can increase calcium absorption in the digestive system, provide protection against osteoporosis, and strengthen teeth. Xylitol also plays an important role in the occurrence of tooth decay.

Xylitol from the company Elemental, a plant-based product with a taste similar to sugar, was used to prepare the mouthwash. Indicative dosage: 3-7% (m/m) in mouthwash.

The volatile oil of cloves was obtained by steam entrainment for 4 hours using a standard Neo-Clevenger type plant. Volatile oil a

RO 137277 AO was collected and kept in a refrigerator (approx. 4°C). The dried inflorescences of Eugenia caryophyllata from which the oil was extracted were purchased from Solaris Plant S.R.L.

The inclusion complex of β-cyclodextrin with the volatile oil of cloves:

Several encapsulation methods of clove volatile oil were initially tested and we applied the one using mortaring to make this pharmaceutical form. The β-cyclodextrin encapsulation efficiency of clove oil was determined spectrophotometrically according to the data of literature and was 99.40%.

The determination of the chemical composition of the volatile oil of Eugenia caryophyllata and the complex with β-cyclodextrin was carried out by gas chromatography coupled with mass spectrometry (CG-MS). The same method was applied for the other volatile oils used. It can be observed that the differences obtained in terms of the composition of the volatile oil of Eugenia caryophyllata and its inclusion complex with β-cyclodextrin are insignificant (Appendix 1, Table 1 and Appendix 2, Figures 2 And 3).

The major component of volatile clove oil is eugenol, along with β-caryophyllene and eugenium acetate (annex 1, table 1) which give it recognized antiseptic, antimicrobial, antiviral, anti-inflammatory, antioxidant, astringent, analgesic and anesthetic properties, which makes that its use in dentistry is effective in treating some diseases of the oral cavity as well as in relieving dental pain. It is known to use volatile clove oil in the preparation of DENTOCALM gum ointment used successfully in dentistry to treat tooth and gum pain, but also to flavor chewing gums due to its antiseptic properties and removal of unpleasant odors from the oral cavity. Volatile clove oil is used in some surgical interventions in the oral cavity (treatment of abscesses) due to its very intense antiseptic and antimicrobial effect.

The formation of the inclusion complex between cyclodextrin and volatile clove oil presents several advantages (figure 7): it allows the controlled release of its components, increases the solubility of some components of the oil in water, prevents volatilization and degradation of the active principles in the oil.

The solubilizer for volatile oils is a solution consisting of ingredients of vegetable origin that allows the incorporation of essential oils, fragrances and

RO 137277 AO of various oily ingredients in aqueous media such as: mouthwashes, toilet waters, fluid deodorants, skin, body or hair sprays, micellar waters.

The product allows the dispersion of essential oils, perfumes and other oily ingredients in aqueous media. It is a mixture formulated with vegetable raw materials from sustainable sources, a solubilizer with good results.

compared with other natural PEG-free solubilizers and also with the industry gold standard (PEG-40), hydrogenated castor oil as a solubilizer showed very good performance.

Volatile oils cannot be mixed with water. In order to be able to be incorporated into aqueous media for the purpose of preparing various water-based cosmetic formulas, such a solubilizing ingredient is needed.

The product is approved for use in organic cosmetics.

Ingredients (INCI): Caprylyl/Capryl Glucoside, Aqua, Sodium Cocoyl Glutamate, Glyceryl Caprylate; Citric Acid, Polyglyceryl-6 Oleate, Sodium Surfactin

Properties of the solubilizer:

- PEG-free, PPG-free

- vegetable origin

- provides transparent solutions in certain combinations and dosages

- has the ability to bind water and leaves a pleasant feeling on the skin, without feeling sticky

- it is strongly foaming if it is dosed in excess

- recommended pH range: 4.5 - 7.5.

Recommendations, explanations

- the dosage varies slightly depending on the ingredient to be solubilized and depending on the formulated preparation

- typical ratio (solvent: oil, m/m): 0.5 : 1 to 4 : 1

- the higher the ratio, i.e. more solubilizer is used, the clearer or even transparent the resulting solution will be, but also the more foamy

- recommended dosage for the oily ingredients to be solubilized: from 0.1% to 5% of the total weight of the formulated preparation (m/m)

- mouthwash - dosed up to 2% (m/m) can be used in oral hygiene.

Way of ussage

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- the procedure is simple: thoroughly mix the solubilizer with the oily ingredient by hand. Water and the rest of the ingredients provided in the formula or as indicated in the recipe are added to the resulting solution

- it may happen that the essential oil or a combination of volatile oils, oily ingredients or perfumes prove more difficult to solubilize and it is not possible to anticipate without tests, the resulting solution may tend to be biphasic. The problem is only an aesthetic one and the microbiological or functional stability of the solution is not affected. By simply shaking the bottle, the solution will homogenize for a while and can be applied.

When preparing the mouthwash, the solubilizer for natural volatile oils from the company MAYAM was used to disperse volatile oils in water.

The volatile oil of cinnamon occupies a very special place in the therapeutic field, due to the particular intensity of its therapeutic effects, among the volatile oils, cinnamon has among the strongest antioxidant and antimicrobial effects. Cinnamon has been a highly prized spice for thousands of years and has been an important trade commodity in the Orient. In Egypt, Cinnamomum zeylanicum was used in the embalming process. It was also added to foods to preserve them. Cinnamon was the most sought-after spice during the explorations of the 15th-16th centuries, and in China it is used in traditional medicine, in intensive cultivation there are currently two species: Ceylon cinnamon (Cinnamomum zeylanicum) and Chinese cinnamon (Cinnamomum cassia). The first is native to India and the island of Ceylon and expanded in culture in Malaysia, the African islands of Madagascar and Seychelles, and the second is native to southern China and taken over in culture in Vietnam and India. currently, cinnamon is mainly used in the culinary arts, but it also has a long history in traditional medicine, being included in topical preparations, in therapeutic massage products, as well as in systemic administration as an analgesic and antimicrobial.

The results of preclinical studies support the fact that cinnamon oil and extract have antifungal, antibacterial and antiparasitic properties, being remarkable for their potential to combat the Candida albicans strain, the etiological agent of some resistant vaginal and oral infections.

since the 1970s the antifungal potential of cinnamon has been demonstrated and studies have indicated it as an alternative to synthetic preservatives. The research was carried out on different bakery products inoculated with strains producing

RO 137277 AO toxic mycotoxins (known for their carcinogenic action, both in humans and animals). For example, one of the studies showed that in the absence of preservatives in bread supplemented with 20 mg of cinnamon there was an inhibition in the development of molds up to 97-99%.

Cinnamon oil stimulates circulation and reduces inflammation, relieving pain and movement difficulties caused by these conditions.

Due to the presence of volatile active principles, such as cinnamic aldehyde, some studies support the fact that the aroma and fragrance of cinnamon act as cognitive stimulants, which could improve memory and visual-motor ability. Preclinical studies in rodents administered cinnamic aldehyde showed improvements in stress-induced depressive-like behaviors. Thus, cinnamic aldehyde can be administered orally in the treatment of behavioral and psychiatric disorders.

Cinnamon essential oil can be obtained by steam distillation from the bark of young branches or leaves of the cinnamon tree. All cinnamon volatile oils contain cinnamic aldehyde in varying percentages (65-80%). The main constituents of the oil used are: cinnamic aldehyde (60-65%), caryophyllene, cymene, eugenol, linalool, methylaminoketone which gives the characteristic aroma, phelandrene, pinene (Annex 2 table 3, figure 4).

Cinnamon essential oil can be obtained by steam distillation from the bark of young branches or leaves of the cinnamon tree. That is why the volatile oils of cinnamon can contain cinnamic aldehyde in variable percentages (65 80%) as the majority component, if it is extracted from the bark (and then it is used as a spice), or eugenol predominates if it is extracted from the leaves (when it is used for medicinal). The main constituents of the oil used are: eugenol (80.29%), β-caryophyllene (3.21%), eugenol acetate (3.91%), benzyl benzoate (3.44%), cinnamyl acetate (1 .19%), linalool (1.06%), safrole (1.03%), cinnamic aldehyde (0.89%) (Appendix 2 table 3, figure 4).

Cinnamon volatile oil is known for its antimicrobial effects (broad-spectrum antibacterial, antiviral, antifungal, antiparasitic), but also for its digestive stimulant and carminative properties. Its absorption is easily achieved topically, which is why it is used to activate local circulation but also to fight dermatological infections.

RO 137277 AO in dermato-cosmetics, cinnamon oil is included in the composition of mouthwashes, lipsticks, toothpastes, massage products, ointments and lotions for hands and feet, having the role of stimulating blood circulation and antiseptic effect against mycoses nails.

In the preparation of the mouthwash, the volatile oil of cinnamon from the MAYAM company was used, obtained by steam distillation from the leaves of the cinnamon tree (Cinnamomum zeylanicuni), which is presented in the form of a light yellowish clear liquid, with a characteristic, strong smell and pregnant.

Volatile oil of myrrh (Commiphora myrrhd) stands out for its cicatrizing, anti-infective and anti-inflammatory properties on the skin. Since ancient times myrrh resin has been used both for its aroma and remarkable therapeutic properties. Myrrh is a tree native to Somalia and Ethiopia that grows to about 5 meters tall. The viscous, yellowish resin is obtained by incisions made in the bark. By steam distillation of the resin, the volatile oil is obtained whose composition is: furanoeudesma-1,3-diene (40.35%), curzerene (24.76%), eudesma-4(15),7-diene- l-P-ol (9.97%), lindestrene (9.74%) (Annex 2, table 4 and figure 5) and which determines the anti-infective, antifungal, antiviral, intense parasiticide action very important for the healing ointment. Volatile myrrh oil stimulates skin regeneration according to the results of clinical studies, being indicated in the treatment of gum infections, eczema, fungal and viral infections. It is also considered to have immunostimulating activity. at the same time, some clinical studies have shown that essential oil of myrrh could also improve some forms of skin cancer.

In the preparation of the composition for the mouthwash, the volatile oil of organic myrrh, MAYAM, was used, obtained by distillation with water vapor from dry myrrh oleoresin, a natural and organic cosmetic product, Ecocert Greenlife certified in accordance with the ECOCERT standard available at http: //cosmetics.ecocert.com. Description: liquid of medium viscosity, yellow-brown color, strong, warm and slightly sweet smell, with woody and resinous notes.

Volatile tea tree oil is a therapeutic product with increased popularity in recent years because it is non-irritating topically and exhibits significant antimicrobial action even on some resistant strains.

Numerous studies over time have demonstrated the excellent ability of tea tree oil to act as an antiseptic, antibacterial, antiviral,

RO 137277 AO antifungal, but also as an anti-inflammatory agent. The terpenes in tea tree oil give it remarkable antiseptic properties, which is why it is recommended for healing wounds and fighting infections. A study published in the Journal of Investigative Dermatology in 2006 supports the effectiveness of tea tree oil in combating some common species of Staphyloccocus aureus, but also MRSA (methicillin-resistant Staphylococcus aureus, a strain resistant to many of the current antibiotics). For this reason, it is often used as a natural remedy to prevent infection of small wounds, cuts and burns.

Among the active principles present in tea tree oil are 1,8-cineole and terpinen-4-ol with insecticidal properties, the latter being also known for its anti-allergic properties. The volatile oil of tea tree (Melaleuca alternifolia) is obtained by steam distillation of the young leaves and branches of the tea tree. Tea tree oil is a pale yellow essential oil with a fresh camphor scent.

Mayam essential tea tree oil, a natural and organic cosmetic product certified by Ecocert Greenlife, was used to create the composition for the mouthwash. The main compounds identified by gas chromatography coupled with mass spectrometry are: α- and γ-terpinene, α-terpinolene, α-terpineol, terpinen4-ol, p-cymene, γ-elemene, 1,8-cineole (eucalyptol), aromadendrene, (Annex 2, table 5 fig. 6).

The association of all these natural extracts in the mouthwash formula results in a synergistic remineralizing, regenerating, soothing, anti-inflammatory and antimicrobial effect.

The advantage of the formula for obtaining mouthwash with volatile oils is that it covers the whole range of problems related to ensuring effective hygiene of the oral cavity while also having therapeutic properties: it removes tooth and gum pain. Xylitol has a remineralizing effect on enamel. The mouthwash also has a strong anti-inflammatory, antimicrobial and cicatrizing action due to the combination of volatile oils in the formula. In addition, xylitol also provides an antitartar effect. This mouthwash formula, being free of alcohol, can also be used for oral cavity hygiene in children. The sodium bicarbonate in the formula plays a role in adjusting the pH of the final preparation.

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Several embodiments of the invention are presented below.

Example 1. The composition for lOOg mouthwash is as follows: 91 g distilled water, 0.5 g sodium bicarbonate, 3 g xylitol, 1 g β-cyclodextrin inclusion complex with volatile clove oil, 1.5 g solubilizer for essential oils , 1 g cinnamon volatile oil, 1 g myrrh volatile oil, 1 g tea tree volatile oil.

The process of obtaining the invention consists in the fact that, in a Berzelius glass, the exact amount of solubilizer for volatile oils is transferred over which the oils are added (volatile cinnamon oil, volatile myrrh oil, volatile tea tree oil). Mix well with a stick and then add the water in which sodium bicarbonate, xylitol, β-cyclodextrin inclusion complex with volatile oil of cloves have been dissolved and mix well. The solution is transferred to the conditioning bottle, tightly closed and stored in the dark and cool.

Example 2. The composition for lOOg mouthwash is as follows: 92.5 g distilled water, 0.4 g sodium bicarbonate, 3.5 g xylitol, 1.1 g inclusion complex of β-cyclodextrin with volatile clove oil, 1 g essential oil solubilizer, 0.5 g cinnamon volatile oil, 0.5 g myrrh volatile oil, 0.5 g tea tree volatile oil.

The obtaining procedure is the one presented in example 1.

Example 3. The composition for lOOg mouthwash is as follows: 90 g distilled water, 0.5 g sodium bicarbonate, 3.5 g xylitol, 1.5 g β-cyclodextrin inclusion complex with volatile clove oil, 1.5 g solubilizer for essential oils, 1 g cinnamon volatile oil, 1 g myrrh volatile oil, 1 g tea tree volatile oil.

The obtaining procedure is the one presented in example 1.

Characteristics of prepared mouthwash:

- homogeneous, transparent appearance;

- slightly yellowish color;

- aromatic-characteristic smell;

- sweet-flavored taste;

- pH 6.8-7.

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Store in brown glass bottles and store in a cool place away from light.

Administration: shake the bottle before administration, then rinse the mouth.

The tests carried out on volunteers showed a good tolerance and efficiency in oral cavity hygiene, a pleasant feeling when using it, but for better safety it is recommended to test the individual tolerance at the first use of the preparation.

Appendix 1 presents the results of testing the antimicrobial activity of the preparation on culture media by the diffusimetric method.

Annex 2 shows the chemical compositions established by gas chromatographic analysis for all volatile oils used in the preparation of mouthwash.

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ANNEX I

STUDY OF THE ANTIMICROBIAL ACTION OF THE MOUTHWATER WITH THE INCLUSION COMPLEX OF β-CYCLODEXTRIN WITH VOLATILE OIL OF Cloves

The testing of the antimicrobial activity of the mouthwash was carried out qualitatively, by the diffusimetric method: 10 pL of the preparation was spotted on the surface of the seeded plates. Suspensions adjusted to 0.5 McFarland of four species of the Candida genus were used for seeding, of which two ATCC strains: Candida albicans ATCC10231 and Candida kefir ATCC, and two strains isolated from biological samples: Candida albicans 5328, Candida parapsilopsis S14. in figure 1 the Petri dishes with the inhibition zones obtained are scanned, and in table 1 the inhibition diameters of microbial growth for the tested strains are listed.

Table 1. Microbial growth inhibition diameters obtained for mouthwash enriched with clove volatile oil β-cyclodextrin inclusion complex (AGco) and mouthwash without complex (AG)

Samples tested Microbial strains Inhibition diameters (cm) AGco AG Candida albicans ATCC 10231 1.5 1.5 Candida kefir ATCC 1.5 0 Candida albicans 5328 1.0 ± Candida parapsilopsis S14 ± 0

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APPENDIX 2 ANALYSIS OF ACTIVE INGREDIENTS IN MOUTHWATER WITH β-CYCLODEXTRIN INCLUSION COMPLEX WITH VOLATILE OIL OF Cloves

The analysis of the main components in the composition of the volatile oils used in the preparation of the mouthwash was carried out by gas chromatography coupled with mass spectrometry using a Focus GC gas chromatograph coupled with a Polaris Q ion trap mass spectrometer.

Table 2. The main components of the volatile oil of cloves as such and in the form of an inclusion complex with β-cyclodextrin (results obtained by chromatography of

gas coupled with mass spectrometry) No. Crt. Compound RI' Relative Area % UV ² CIM ³ 1 Eugenol 1358 90.67 94.71 2 β-Caryophyllene 1417 3.98 0.33 3 Humulen 1449 0.41 0.06 4 Acetate of eugenics 1513 4.77 4.66 5 Caryophyllene oxide 1582 0.17 0.04

The legend'. ¹ Kovats indices; ² Volatile oil of cloves {Eugenia caryophyllata) unencapsulated; ³ Inclusion complex obtained by trituration in a mortar.

Table 3. Principal components of cinnamon volatile oil (results obtained by gas chromatography coupled to mass spectrometry)

No. Crt. Compound RI ¹ Relative Area % 1 Linalool 1088 1.06 2 Cinnamic aldehyde 1262 0.89 3 safrole 1279 1.03 4 Eugenol 1362 80.29 5 Cinnamyl acetate 1431 1.19 6 β-caryophyllene 1414 3.21 7 Eugenol acetate 1512 3.91 8 Benzoate of tapes 1702 3.44

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Table 4. Main components of myrrh volatile oil (results obtained by

gas chromatography coupled to mass spectrometry) No. Crt. Compound RI ¹ Relative Area % 1 β-Element 1379 2.63 2 Curzeren 1492 24.76 3 Furanoeudesma-1,3-diene 1620 40.35 4 Lindestren 1624 9.74 5 Eudesma-4(15),7-dien-l β -ol 1669 9.97

Legend: ¹ Index Kovats

Table 5. The main components of the volatile oil of tea tree (results

obtained by gas chromatography coupled with mass spectrometry) No. Crt. Compound RI ¹ Relative Area % 1 a-Terpinene 1009 10.85 2 p-cymene 1017 2.63 3 Eucalyptol 1026 3.76 4 γ-terpinene 1051 18.77 5 a -Terpinolene 1078 3.43 6 terpinene-4-ol 1175 36,32 7 a-Terpineol 1183 2.63 8 γ-Element 1430 1.95 9 Aromadendrons 1454 0.75 10 a-Muurolene 1490 3.88 11 γ-Cadinene 1512 3.48

Legend: ¹ Index Kovats

MC l

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Claims (1)

RO 137277 AO MOUTHWASH WITH β-CYCLODEXTRIN INCLUSION COMPLEX WITH VOLATILE OIL OF Cloves Claim Mouthwash intended for oral cavity hygiene, characterized by the fact that it consists of the combination of distilled water with sodium bicarbonate, xylitol, inclusion complex of β-cyclodextrin with volatile oil of cloves, solubilizer for essential oils, volatile oil of cinnamon, volatile oil of myrrh, volatile tea tree oil, in an association ratio, parts by weight of: 90...92.5 : 0.4...0.5 : 3...3.5 : 1. ..1.5:1...1.5:0.5...1:0.5...1:0.5...1.