WO2009019571A2

WO2009019571A2 - Method of dissolving essential oils in water

Info

Publication number: WO2009019571A2
Application number: PCT/IB2008/002045
Authority: WO
Inventors: Claude Laruelle; Nacim Taleb; Thierry Breul
Original assignee: Claude Laruelle
Priority date: 2007-08-06
Filing date: 2008-07-29
Publication date: 2009-02-12
Also published as: FR2919802B1; FR2919802A1; MA30249B1; WO2009019571A3

Abstract

The invention relates to a method of preparing water-soluble granules containing at least one essential oil that is naturally insoluble or not very soluble in water, and also to the uses of this method and in particular for the preparation of pharmaceutical or aromatherapeutical compositions that are in dry form and that make it possible to extemporaneously produce solutions for mouthwashes or for body hygiene washes.

Description

PROCESS FOR SOLUBILIZATION OF ESSENTIAL OILS IN WATER

The invention relates to a process for the preparation of water-soluble granules containing at least one essential oil which is naturally of little or no water-soluble nature, as well as to the uses of this process and in particular for the preparation of pharmaceutical or aromatherapeutic compositions which are subject to dry form and allowing to realize extemporaneously solutions for mouthwashes, or for baths of corporal hygiene

Solutions for mouthwashes containing essential oils commercially available to date such as peppermint essential oil, tea tree melaleuca, clove, lavender, sage, eucalyptus, anise, or lemon, are hydro-ethanol solutions, which are packaged in glass or plastic bottles, with a capacity ranging from 5 to 500 ml, and which are impractical to use when it is necessary to move, given their size and risk of breakage and / or staining in case of improper closure of the bottle. This usually results in poor compliance by patients who avoid moving with their bottle of mouthwash solutions.

It would therefore be desirable, in order to enable patients to better follow their treatment, to offer them compositions in dry form, preferably packaged in unitary doses, easily transportable, and capable of giving, after dispersion in a suitable volume of water, solutions for mouthwashes.

However, it turns out that most antiseptic essential oils that can be used in mouthwash solutions, are soluble in organic solvents but are not soluble or very little in water. Also their dispersion in water leads to the formation of either a cloudy suspension, an unattractive appearance, or a biphasic liquid and in which the essential oil is not uniformly distributed, which can be translated by a decrease in the therapeutic or aromatherapeutic efficacy of mouthwashes. To obtain a satisfactory solubilization of these substances, it is appropriate to use an organic solvent, ethanol being most suitable for edible use. However, for obvious reasons of public health and also of convenience, it is not conceivable to propose compositions for mouthwashes to be reconstituted, partially or totally, in ethanol.

Effervescent tablets have long been known for the extemporaneous preparation of solutions for mouthwashes. Such tablets are, for example, described in U.S. Patent Nos. 3,772,431, 3,888,976 and 4,919,918. In any case, it is a question of general public products, having more vocation to allow a cleaning of the oral cavity and the teeth, by an effervescent effect, even foaming, that a disinfection. Therefore, in these patents, the presence of essential oils is only considered very incidentally. It should be noted that US Pat. No. 4,919,918 proposes, to ensure solubilization in water of little or no soluble substances that may be present in the tablets, to add an ionic surfactant of the laurylsulphate, n-laurylsarcosinate type. or sodium alkylsulfoacetate, which contributes to the desired foaming effect. Such a foaming effect is, however, not desirable for mouthwashes.

It has also already been proposed methods for rendering water soluble compounds naturally little or not soluble in water.

Thus, the patent application FR-A-2,649,611 proposes a method for preparing a therapeutic composition based on acetylsalicylic acid consisting of dissolving this active ingredient in a solvent and then impregnating the solution thus formed with a carbohydrate carrier. and then causing evaporation of the solvent to lead to the formation of microparticles or microcrystals of the active principle, the development of the crystals being limited by the matrix of the support.

Furthermore, the patent application FR-A-2,613,223 proposes a process for the preparation of a solid dosage form in the form of water-soluble grains containing Ginkgo biloba. According to this process, this compound is solubilized in a solvent in the presence of a surfactant, then this solution is then mixed with a water-soluble support which is then subjected to granulation. According to this document, the water-soluble support can be indifferently chosen from sucrose, lactose, mannitol and maltodextrins. However, if these methods make it possible to improve the solubility of these particular active ingredients, namely acetylsalicylic acid and Ginkgo biloba, whatever the nature of the water-soluble support used, they do not give complete satisfaction when they are applied to solubilize essential oils. The inventors have therefore set themselves the goal of providing a process which makes it possible to render water-soluble one or more essential oils naturally little or not soluble in water, so as to be able to prepare compositions in dry form and which, although containing one or more essential oils little or not water-soluble, are capable of forming homogeneous and stable solutions (without any phenomenon of phase shift) after dispersion in water.

The inventors have also set themselves the goal of providing a process which, while having these advantages, is simple to implement and does not require other equipment than those conventionally equipped with formulation laboratories.

The subject of the invention is therefore a process for the preparation of water-soluble granules containing at least one essential oil for mouthwash or bath for personal hygiene, comprising the successive stages of: a) wet granulation or impregnation mannitol as a water-soluble carrier in the form of granules by means of a solvent containing at least one essential oil; and of ; b) drying the granules; characterized in that the solvent is an aqueous solution of a nonionic surfactant. In the course of their work, the inventors have in fact observed that, surprisingly, when mannitol is subjected to wet granulation or to impregnation with a solvent containing an essential oil which is naturally little or not soluble in water, this oil binds to mannitol without being denatured and remains bound to the latter when the granules are subsequently dispersed in water. A solution is then obtained within which the oil is perfectly dissolved and able to exert its therapeutic effects as if its solubilization was made possible by the very hydrophilic property of the mannitol to which it is bound.

The inventors have not yet identified the nature of the bond which is established between the essential oil and mannitol during granulation.

On the other hand, the existence of this bond could clearly be demonstrated by tests showing that if a solution obtained by dispersing the granules in the water is subjected to filtrations and extractions, the oil is constantly found. essential in the fraction where mannitol is found without any trace of essential oil not linked to mannitol being detected.

On the other hand, when xylitol or sorbitol is subjected to wet granulation or impregnation by means of a solvent containing the same essential oil and then to the dispersion of the granules obtained in water, it can be seen that The essential oil does not remain completely bound to the latter when the granules are subsequently dispersed in the water.

Of the nonionic surfactants, polysorbate 80 is preferably used as a nonionic surfactant. However other nonionic surfactants such as other polysorbates or poloxamers, are also likely to be used for the implementation of the process according to the invention. A true essential oil is a natural product extracted from aromatic plants. Extraction can be done from flowers, leaves, roots or even seeds. Two manufacturing processes are mainly used: extraction or steam entrainment. The mouthwashes containing essential oils are commonly used in stomatology, namely for the treatment of canker sores, gingivitis, dental neuralgia, sore throat or to fight bad breath.

Among the essential oils suitable for use in mouthwashes according to the invention, there may be mentioned as examples: lemon oil, anise oil, laurel oil, bergamot essence, bitter almond, camphor , cedar leaf oil, cinnamon oil, citronella oil, clove oil, eucalyptus oil, lavender oil, mustard oil, peppermint oil, pine oil, pine needle oil, rosemary oil, spearmint oil, sassafras oil, lavender oil, thyme oil, wintergreen oil.

For example, it is commonly accepted that essential oils made from clove, lavender, peppermint, sage and / or eucalyptus purify and refresh the breath, preserve the vitality of the gums while respecting the oral flora. According to a preferred arrangement of this composition, the essential oil is chosen from the essential oils of peppermint, tea tree melaleuca, clove, lavender, sage, eucalyptus, anise, or lemon.

In a particularly preferred manner, the essential oil is chosen from the essential oils of peppermint, clove, or lavender. According to the invention, these essential oils can be associated, depending on the desired effect.

The solvent used for the granulation or impregnation of mannitol may also comprise one or more excipients such as a dye (amaranth, red cochineal, patent blue V, yellow quinoline, etc.) chosen for its compatibility with the oil used. and the optional additional oil (s) and intended to give a pleasant color to the solution resulting from the dispersion of the granules in water, or any other excipient which one wishes to associate with the oil and which also has a solubility in water low or zero.

According to the invention, the composition may consist solely of granules as obtained by the method described above. However, although mannitol itself is a sweetener and contributes to the composition both sweetness and freshness in the mouth, it will most often be preferred to mix the granules with one or more sweeteners such as sodium cyclamate, sodium saccharin, aspartame or ammonium glycerinate, and / or optionally one or more flavors (mint, anise, lemon, raspberry ...) to make it even more pleasant both in terms of taste and its perfume, especially in the case where the essential oil used has poor organoleptic qualities.

According to yet another advantageous arrangement of the process according to the invention, the granulation or impregnation is carried out with a quantity of solvent corresponding to 5 to 60% and, preferably, to 10 to 40% by weight of the weight of mannitol, while this solvent has a weight content of oil of between 0.1 and 50% and preferably between 0.3 and 20%. Thus, at the end of the drying of the granules, the latter advantageously have a weight ratio between the mannitol and the essential oils of between 20 and 1500 and, preferably, between 300 and 1000.

According to the invention, the granulation of mannitol and the drying of the granules are preferably carried out in a planetary mixer and in a ventilated oven at a temperature which may vary between 20 and 60 ° C. depending on the degree of heat sensitivity of the product. or essential oils used. However, it is also possible to granulate mannitol in a fluidized air bed and to use an oven for drying the granules. This drying can also be carried out using a fluidized air bed.

According to yet another advantageous arrangement of the process according to the invention, the latter comprises, after drying of the granules, an operation of calibration of these granules, for example by sieving on a grid, this calibration being, preferably, conducted from in order to eliminate all the granules having a size greater than 5 mm.

The process just described has many advantages. Indeed, by making it possible to make water-soluble essential oils that naturally are not or little, it offers the possibility of producing, from essential oils with low or no water solubility, compositions in dry form. and able to form homogeneous and stable solutions after dispersion in water. Moreover, this process is simple to implement and uses only readily available raw materials (mannitol, water, nonionic surfactant) and a cost compatible with industrial scale operation. Finally, it does not require specific equipment and can be implemented by means of the apparatuses which are conventionally equipped formulation laboratories, wet granulation and impregnation are indeed commonly used for the manufacture of drugs proposed in capsules and tablets.

In the case where a galenic formulation in the form of a tablet is desired, a compression step will be carried out after the drying step previously described.

In this case, it will be appropriate to add beforehand to this compression step one or more excipients chosen from those conventionally used for the compression of powders or granules such as flow agents, fillers and lubricating agents. The subject of the invention is the use of a process as defined above for the preparation of a composition in dry form and able to give a mouthwash solution extemporaneously after dispersion in water.

The subject of the invention is therefore also a composition which is in a dry form and makes it possible to extemporaneously produce a solution for mouthwashes, by dispersion in water, which is characterized in that it comprises granules formed of mannitol linked to at least one essential oil.

Moreover, the composition may be in the form of a powder resulting from the mixing of the granules with the excipient (s), or in the form of tablets. According to another preferred arrangement of the composition according to the invention, the latter is packaged in unit doses each corresponding to a mouthwash. In a particularly preferred manner, each unit dose is packaged in an airtight and water-proof package, such as for example a bag made of an aluminum foil lined with a polyethylene film, and the dimensions of which are chosen to be able to contain once opened, a volume of water sufficient to perform a mouthwash, which thus avoids the use of a glass that is not always at hand especially when traveling. The composition according to the invention has many advantages. Indeed, it disperses easily in water to form a clear solution, homogeneous, stable and a very pleasant taste, even when it contains an essential oil with organoleptic properties unattractive. Being in a dry form, it eliminates the risk of degradation of essential oils tending to be unstable in solution as is mainly the case of essential oils sensitive to oxidation. Presented in single doses, it guarantees the use of an active dose during each mouthwash. Finally, by its presentation and ease of use, it offers the possibility of performing a mouthwash in all circumstances without having to move with a bottle likely to break or open unexpectedly.

The invention further relates to a solution for mouthwashes, characterized in that it is obtained by dispersing in water a composition as defined above.

The invention will be better understood with the aid of the additional description which follows, which refers to examples of preparation of dry compositions intended to be used for the extemporaneous production of solutions for mouthwashes and demonstration of the ability of these compositions to form homogeneous and stable solutions after dispersion in water.

It goes without saying, however, that this additional description is given only as illustrations of the invention and does not constitute in any way a limitation. The following figures illustrate the invention: FIG. 1 shows the particle size distribution before dispersion in water of the composition provided in example 4; Figure 2 shows the particle size distribution after dispersion in water of the composition provided in Example 4.

EXAMPLE 1 Preparation of granules for mouthwashes based on essential oil of mint poiyrée

100,000 sachets each containing 555.0 mg of a composition in the form of granules and having the following formulation - per sachet:

Preparation process:

Solution A: solubilization of 4.5 kg of Polysorbate 80 (Montanox® 80 VG PHA) in 7.0 kg of purified water using a propeller mixer for 30 minutes at 100 rpm, Solution B: solubilization of 1.5 kg of peppermint essential oil, dyes (4.0 g of E131 patented blue and 150.0 g of yellow E 104 quinoline) and 0.3 kg of sodium saccharin in the solution A by mixing 10 minutes at 200 rpm with a propeller mixer. - Granulation of 49.046 kg of DC mannitol, previously sieved on a grid of 0.800 mm of mesh opening, in a planetary granulator using solution B (wetting in 2 minutes at 200 revolutions per minute then granulation for 5 minutes at 200 revolutions per minute),

Drying of the grain obtained at 25 ° C in a ventilated oven until a residual moisture of less than 2.00% is obtained (measurement of the residual humidity at 70 ° C at constant loss in an infra-red scale),

Calibration of the dry grain on a grid of 0.800 mm mesh opening.

EXAMPLE 2 Preparation of granules for mouthwashes based on essential oil of lavender

Preparation process:

Solution A: solubilization of 4.5 kg of Polysorbate 80 (Montanox® 80 VG PHA) in 7.0 kg of purified water using a propeller mixer for 30 minutes at 100 rpm,

Solution B: Solubilization of 0.5 kg of lavender essential oil, colorants (4.0 g of E131 patented blue and 150.0 g of yellow E104 quinoline) and 0.3 kg of sodium saccharin in solution A mixing 10 minutes at 200 rpm with a propeller mixer.

Granulation of 50.046 kg of DC mannitol, previously sieved on a grid of 0.800 mm of mesh opening, in a planetary granulator using solution B (wetting in 2 minutes at 200 revolutions per minute and then granulation for 5 minutes at 200 revolutions per minute), - drying of the grain obtained at 25 ° C. in a ventilated oven until a residual moisture of less than 2.00% is obtained (measurement of the residual humidity at 70 ^° C. at constant loss in a balance at infra red), Calibration of the dry grain on a grid of 0.800 mm mesh opening.

EXAMPLE 3 Preparation of granules for mouthwashes based on essential oil of clove

Preparation process:

Solution B: solubilisation of 1.0 kg of clove essential oil, dyes (4.0 g of El 31 patented blue and 150.0 g of yellow quinoline E 104) and 0.3 kg of sodium saccharin in solution A by mixing for 10 minutes at 200 rpm with a propeller mixer.

Granulation of 49.546 kg of DC mannitol, previously sieved on a grid of 0.800 mm of mesh opening, in a planetary granulator using solution B (wetting in 2 minutes at 200 rpm) then granulation for 5 minutes at 200 turns per minute),

Drying of the grain obtained at 25 ° C in a ventilated oven until a residual moisture of less than 2.00% is obtained (measurement of the residual humidity at 70 ° C at constant loss in an infrared balance), - Calibration dry grain on a grid of 0.800 mm mesh opening.

EXAMPLE 4 Preparation of granules for mouthwashes based on essential oils of mint, lavender and clove 100 000 sachets are made each containing 555 mg of a composition in the form of granules and having the following wording:

Preparation process:

Solution B: solubilization of essential oils (1.5 kg of peppermint essential oil, 0.05 kg of lavender essential oil and 0.1 kg of clove essential oil), dyes (4, 0 g of El 31 patented blue and 150.0 g of quinoline yellow E104) and of 0.3 kg of sodium saccharin in solution A by mixing for 10 minutes at 200 revolutions per minute using a propeller mixer.

Granulation of 48.896 kg of DC mannitol, previously sieved on a grid of 0.800 mm of mesh opening, in a planetary granulator using solution B (wetting in 2 minutes at 200 revolutions per minute then granulation for 5 minutes at 200 turns per minute), Drying of the grain obtained at 25 ° C in a ventilated oven until a residual moisture of less than 2.00% is obtained (measurement of the residual humidity at 70 ° C at constant loss in an infra-red scale),

Calibration of the dry grain on a grid of 0.800 mm of mesh opening,

Packing the resulting mixture (555.00 mg unit).

Pharmacotechnical characterization (including visual and flow parameters of the final mixture) The results of the checks carried out during manufacture on the latter composition show that the granulation is homogeneous; that the grains are formed and of homogeneous coloration, an absence of phase shift phenomenon, and that the flow rate of the final mixture is less than 10 seconds.

Analysis of granulometry of granules by sieving

The particle size of the composition of Example 4 was measured according to the particle size classification by sieving powder method (European Pharmacopoeia 2.9.12 V ^th edition) which consists essentially in passing the granules through a series of sieves of various sizes, to weigh the various sieved particulate populations and to report the percentage weight of each of them with respect to the initial composition.

Figure 1 illustrates, in the form of a histogram, the particle size distribution obtained for the sample and the table below summarizes the grain size values.

The previous results show the obtaining of small granules whose diameter is less than 1 mm.

Analysis of granulometry of granules by laser diffraction granulometer

An analysis of the particle size of the composition of Example 4 was carried out using a laser diffraction granulometer (He-Ne red laser of at least 2 mW, 18 mm in diameter and 633 nm in length). wave) Mastersizer

Long Bank (Malvern Instruments SA Company) and an MS 1 sampler of the same Company, is provided in Figure 2.

Figure 2 shows that the composition of Example 4 shows results which confirm those obtained according to the sieving method described above. No measured particle has an average diameter greater than 1 mm, and the median value of the measured particle sizes is between 300 and 400 micrometers.

Visual analysis of the composition of Example 4 after dispersion Samples were prepared by dispersing the contents of a packet - either

555 mg of the compositions provided in Examples 1, 2, 3 and 4 in 20 ml of water and a visual analysis of the dispersion obtained made it possible to conclude that there were no particles in solution, thus revealing the formation of a true solution essential oils obtained by this process in water.

Claims

A process for the preparation of water-soluble granules containing at least one essential oil for mouthwash or for a personal hygiene bath, comprising the successive steps of: a) wet granulation or impregnation of mannitol as a water-soluble carrier in the form of granules using a solvent containing at least one essential oil, and; b) drying the granules, characterized in that the solvent is an aqueous solution of a nonionic surfactant.

2. Method according to claim 2, characterized in that the nonionic surfactant is a polysorbate or a poloxamer.

3. Method according to any one of the preceding claims, characterized in that the essential oil is selected from the essential oil of peppermint, tea tree melaleuca, clove, lavender, sage, d eucalyptus, anise, or lemon.

4. Method according to any one of the preceding claims, characterized in that the granulation or impregnation of mannitol is carried out with a quantity of solvent corresponding to 5 to 60% and, preferably, to 10 to 40% by weight of the mannitol.

5. Method according to any one of the preceding claims, characterized in that it comprises, subsequent to the drying of the granules, a calibration operation of these granules.

6. Process for the preparation of an oral tablet containing at least one essential oil for mouthwash or for a personal hygiene bath, characterized in that it contains the successive steps of: a) obtaining the water-soluble granules previously obtained according to one of the following: previous claims; b) adding one or more excipients selected from those conventionally used for compression of powders or granules such as flow agents, fillers, lubricating agents, flavorings and sweeteners; c) compression of the powder or granules obtained according to step b).

7. Composition in a dry form to achieve extemporaneously a solution by dispersion in water, characterized in that it comprises granules formed of mannitol bonded to at least one essential oil, said granules being prepared by a method according to any one of claims 1 to 5.

8. Composition according to Claim 7, characterized in that the composition is packaged in unit doses each corresponding to a mouthwash or a personal hygiene bath.

9. A composition according to claim 8, characterized in that each unit dose is packaged in a waterproof packaging and air, and whose dimensions are chosen so as to be able to contain, once opened, a volume of enough water to make a mouthwash.