WO2013167742A1

WO2013167742A1 - Rapidly disintegrating monolayer film and use thereof in oral hygiene

Info

Publication number: WO2013167742A1
Application number: PCT/EP2013/059748
Authority: WO
Inventors: Michel Sournac; Isabel Ribeiro Dos Santos
Original assignee: Pierre Fabre Medicament
Priority date: 2012-05-11
Filing date: 2013-05-10
Publication date: 2013-11-14
Also published as: FR2990349A1; FR2990349B1

Abstract

The present invention relates to novel rapidly disintegrating monolayer films intended for the oral administration of a pharmaceutical composition, based on essential oil of parsley and on extract of green tea and containing water-soluble polymers, and also to the uses thereof.

Description

FAST DISINTEGRATING MONOLAYER FILM AND USE THEREOF

The present invention relates to novel fast-disintegrating monolayer films for oral administration of a pharmaceutical composition, based on parsley essential oil and green tea extract and containing water-soluble polymers, and as their uses.

During administration, the film disintegrates in the oral cavity and releases the active substances.

Halitosis (or bad breath) is a common pathology that can have significant psychological effects, such as self-depreciation, isolation, depression, besides these social impacts, it is dangerous for the health of teeth and even for general health.

The main origin of halitosis is oral in about 85% of cases. The other etiologies are digestive, in the esophagus (diverticula, stenosis, megaoesophagia), stomach (stenosis, gastroparesis, gastritis); pulmonary (food or drug), or even metabolic (ketoacidosis, renal or hepatic insufficiency).

The main cause of the oral origin is bacterial. Some bacteria such as Porphyromonas, Prevotella, Fusobacterium present on the dental surfaces, in the periodontal pockets, on the dorsal part of the tongue, in the presence of food debris of amino acids, and according to the pH (an alkaline salivary pH favors the halitosis) release volatile compounds driven outwardly by exhaled air. These Volatile compounds have a strong odor, very uncomfortable at extremely low concentrations. These are essentially sulfur derivatives and amino derivatives. Among the sulfur derivatives are present essentially:

hydrogen sulphide H ₂ S

- the metyl mercaptan CH ₃ SH

dimethyl mercaptan (CH ₃ ) ₂ S.

Proteins, diamines (putrescine, cadaverine) are also involved in bad breath.

Volatile sulfur derivatives are detectable by a "human nose" from the concentration of a few tens of ppb.

Hydrogen sulfide has a destructive effect on the tissues exposed to it, leading to apoptotic death of periodontal cells. Moreover, it accelerates the proliferation of bone-destructive cells (osteoclasts) that can be concretely translated into bone resorption problems leading to periodontal disease or loosening. A vicious circle then engages because loosening is a common cause of halitosis. Hydrogen sulfide is also harmful to pulp cells, a recent study (Kobayashi et al., 2011, Journal of Endodontics, vol 37 (4): 4479-4484) shows that this hydrogen sulphide profoundly affects the metabolism of mitochondrial membranes of cells of the dental pulp causing apoptotic cell death. Located in a cavity in the center of the tooth, the pulp is however not isolated from the outside because exchanges occur permanently through the dentine, porous tissue, and the enamel that behaves as a selective membrane. Hydrogen sulfide penetrates and diffuses through the hard tissue of the tooth to affect its vitality. This phenomenon could explain the appearance of pulpites or acute inflammation of the nerve of the tooth. In case of pulpitis, the devitalization (removal of the nerve) of the tooth is the only solution.

If people with halitosis risk losing their teeth, both by loosening and devitalization, they risk health problems much more consequent. Indeed, some compounds responsible for bad breath (putrescine, cadaverine) are growth factors, involved in the development of cancerous tumors.

The main cause of halitosis being well known, it may seem simple to fight it. One can imagine that strengthening hygiene is an effective remedy. The use of antiseptics known to be active in the oral field should make it possible to eradicate the responsible bacteria, but their location and their ability to colonize and grow oppose this purpose. The use of antiseptic solutions improves the disease state but does not completely eliminate the causes. The use of menthol flavors transiently masks bad smells, but this action is fleeting and the extreme sensitivity of people makes this concept random. Another method may be useful and effective, it consists of using molecules or complex extracts reacting with the sulfur compounds mentioned above to make them less or nonvolatile. These are essentially zinc salts, especially chlorides or lactates, green tea extracts and some essential oils. Parsley and green tea are known for their antimicrobial properties. According to a study by Lodhia et al., 2008 (J. Nutr.Sci./ Vitaminol 54, 89-94), green tea makes it possible to reduce the concentration of sulfur compounds. in the mouth breath. Similarly, the antibacterial and anti-infectious activities of the parsley essential oil have been described (El-Megeed Hashem and Farahat Sahab, 1999, Food Chemistry 65, 29-33). For example, according to patent EP 1053743 the combination of olive oil and parsley oil was claimed and according to the patent application WO 2008/068408 it is claimed the combination of parsley essential oil and green tea extract, in the treatment of halitosis. The main claims of this application concern the quantities (expressed by weight relative to the total weight of the composition) of essential oil of parsley (0.01% to 5%) and green tea (0.005% to 1%) and the composition according to this invention is preferably a cooked sugar or a lozenge to be sucked.

However these galenic forms can cause problems, the pellets can be swallowed before having completely melted and then we find the problems related to the ingestion of drugs (choking, suffocation by obstruction of the throat). Moreover, these disadvantages can be at the origin of the cessation of treatment. These problems particularly concern the elderly, children, patients with swallowing disorders or pathologies affecting salivary secretion. Another disadvantage is the time needed for the tablet to completely melt what goes against the discretion sought by the patient to improve his breath.

Fast-disintegrating films must respond to often contradictory conditions: they must have a binding character that allows them to be shaped and, secondly, have an almost instant disintegration capability. They must also present sufficient flexibility and resistance, but also some stability necessary for normal storage conditions. These qualities are essential for their packaging in sachets, blisters or dispenser boxes. The currently used soluble films consist mainly of hydrophilic polymers having film-forming properties, and whose thickness and specific surface area make it possible to envisage rapid disintegration in contact with saliva.

These hydrophilic film-forming polymers are most often glucans, natural gums, or povidone derivatives. The combination of at least two polymers is generally desired in order to find a compromise between the main characteristics of the film, ie the flexibility, the mechanical strength and the speed of disintegration.

Thus, in films based on cellulosic polymers, the combination of at least two water-soluble cellulosic polymers is often necessary. Those comprising the combination of water-soluble cellulosic polymers of high molecular weight (60,000 to 150,000 Da) and water-soluble cellulosic polymers of low molecular weight are most often encountered. The first type of polymer makes it possible to adjust the mechanical properties of the film, while the second type of polymer makes it possible to vary the disintegration time.

For example, International Application WO 05/039499 discloses a fast disintegrating pharmaceutical or cosmetic film formulation consisting of a combination of hydroxypropylcellulose (Klucel JF®) and hydroxypropylmethylcellulose (Methocel® grades E, E50, E4M and SGA16M). However, the films described in this application each contain many plasticizers (polyalcohols, sorbitan ester, citric acid esters, etc.) which are necessary for obtaining flexible films and which make the formulation complex.

On the other hand, glucan polymers such as pullulans are theoretically capable of forming fast disintegrating films because of their high solubility, rapid dissolution rate and taste properties. However, their low molecular weight is a drawback which has the consequence of not facilitating the formation of films for concentrations of less than 20%; indeed, under these conditions, the viscosity of the mixtures is low and makes them take a risk with respect to the homogeneity of the latter, when, for example, an insoluble filler (active ingredient in dispersion) is added to the mixture. It is therefore necessary to associate pullulans with other natural polymers such as carrageenates or certain gums.

Thus, the application WO 03/030881 describes a preparation, in the form of an edible film preferably comprising a glucan and a water-soluble polymer, in a ratio of between 40: 1 and 0.5: 1. This water-soluble polymer is characterized by a molecular weight This makes it possible to increase the naturally low viscosity of the pullulans and to stabilize the mixture when it comprises a suspension of active principle. Preferably this polymer is a polysaccharide or a natural gum, forming part of alginates, carrageenates, hydroxypropylmethylcellulose, locust bean gum, guar gum, xanthan gum, dextrans, gum arabic, gellan gum, alone or in combination. However the compositions described in this application contain anti ^¬ agents foams, necessary for obtaining films free of air bubbles. It is also possible to associate the cellulosic polymers with natural polymers such as carrageenates or certain gums. Thus, the international application WO 04/105758 describes a ternary polymeric preparation, in the form of fast release edible film containing triprolidine for the treatment of sleep disorders, and comprising xanthan gum, hydroxypropyl methylcellulose and carrageenan. .

Natural gums (guar gum, locust bean gum, xanthan gum, alginates and carrageenans) or polyvinyl pyrrolidone are often considered as stabilizing polymers, which must be added to either cellulose derivatives or glucans to enable the production of movies. These conditions are not always satisfactory, which also leads to the use of the addition of a plasticizer compound, such as polyoxyethylenated esters of sorbitan, esters of fatty acids and glycerol, glycerol, acid esters. fatty and propylene glycol, propylene glycol, dibutyl sebacate, triacetin.

Finally, many applications are characterized by the presence of a large number of constituents. Thus, the international application WO 03/030883 describes a preparation in the form of an edible film based on the complex combination of hydroxypropylmethylcellulose.

(Methocel E15®), polyvinyl pyrrolidone, corn starch (Pure B792® grade), xanthan gum, surfactant (Cremophor EL®), plasticizer (propylene glycol) and preferably a taste-masking agent.

International Application WO 98/20862 discloses an immediate release film for the oral administration of medicinal or cosmetic active principles, composed of water-soluble polymers, one or more polyalcohols, plasticizers, surfactants, flavorings and dyes. Preferably, the polymers are water-soluble cellulosic derivatives, such as

Hydroxypropyl methylcellulose, hydroxyethylcellulose and hydroxypropylcellulose, alone or in combination. In the dry film, the concentration of cellulosic polymer is between 20 and 75% by weight. Other non-cellulosic polymers can also be used, such as polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums such as xanthan gum, gum tragacanth, guar gum acacia gum, gum arabic, water-dispersible polyacrylates such as polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers.

The international application WO 04/087084 describes a preparation, in the form of a fast release edible film composed of cellulosic film-forming polymers, more particularly of a mixture of high-viscosity polymers and low-viscosity polymers present at low concentration, which presents an economic advantage. The cellulosic polymers are of the hydroxypropyl methylcellulose type, preferably the Methocel®, K-series or E-series products, and more specifically the K4M, K100, K3, E50 and E4M grades. Here again, the presence of plasticizing agents, in proportions ranging from 0.01% to 30%, is necessary to obtain flexible and non-brittle films.

The international application WO 04/045537 describes a complex preparation in the form of an edible film intended for the treatment of pharyngitis, consisting of pullulans, guar gum, pectins, xanthan gum, alginates, of gelatin, starches, modified starches, maltodextrins, gluten, carboxymethylcellulose, locust bean gum, carrageenates.

Finally, international application WO 08/107301 describes fast disintegrating monolayer films whose matrix consists essentially of two water-soluble polymers. The advantage of these films lies in the fact that they are devoid of plasticizer while remaining sufficiently deformable without being brittle. The plasticizers are often hygroscopic, making the preservation and handling of the films obtained difficult. The film comprises a polymeric mixture of a hydrophilic film-forming agent consisting of a copolymer of polyvinyl alcohol and polyethylene glycol, an active substance and a hydrophilic gelling agent.

It therefore clearly appears that the state of the art refers to complex compositions. It is therefore necessary to design a rapidly disintegrating edible film having a simplified formulation and having rheological properties (flexibility, mechanical strength and disintegration speed) equivalent or improved over the prior art. But the film must also be compatible with green tea extract, a phenol-rich ingredient that can limit compatibility with polymers.

The object of the present invention is to provide novel fast disintegrating monolayer films based on green tea extract and parsley essential oil, as described below and illustrated in the examples, whose matrix is constituted essentially two water-soluble polymers. By fast-disintegrating film is meant flexible galenic forms having a thickness of less than 100 microns and whose disintegration, dissolution, dispersion or decomposition time in the oral cavity remains less than one minute, advantageously less than 30 seconds and even more advantageously from 10 to 20 seconds. The active substances contained in this film can thus be absorbed by passage of the oral mucosa or sublingual or by swallowing.

For the purposes of the present invention, the amounts of green tea extract in the composition are expressed by weight of dry extract of green tea relative to the total weight of said composition.

For the purposes of the present invention, the term "parsley essential oil" is intended to mean the essential oil obtained from leaves and / or stalks of parsley.

Preferably, the amount of green tea extract is between 1 and 15%, more preferably between 8 and 12% and even more preferably is equal to 10%.

Advantageously, the amount of parsley essential oil is between 0.05 and 1%, more advantageously between 0.1 and 0.4% and even more advantageously is equal to 0.3%.

The present invention thus relates to a monolayer film with rapid disintegration for the oral administration of a composition based on green tea extract and parsley essential oil, characterized in that it comprises a mixture of water-soluble polymers, d an emulsifier, and at least one plasticizer.

In a preferred manner, the mixture of water-soluble polymers consists of sodium carboxymethylcellulose and hydroxypropylcellulose. Advantageously, the weight ratio of sodium carboxymethylcellulose and hydroxypropylcellulose is between 2 and 10, more advantageously this ratio is between 3 and 5 and even more advantageously this ratio is equal to 4.

The plasticizer makes it possible to increase the flexibility of the films, for example polyols, sorbitan esters or citric acid esters. The plasticizers can be added directly to the formulation during the manufacture of the films. Suitable plasticizers include polyethylene glycol, such as Lutrol E400, polyethylene oxide, polyoxamers, polyvinyl alcohol, or mixtures of these polymers; triacetin, glycerol, mannitol, xylitol and other polyols well known to those skilled in the art. Sorbitol and glycerol are particularly well suited. The amounts of plasticizers in the present invention are between 0.5 and 10% by weight of the dry film, and more particularly between 2 and 4%.

The homogeneous mixture further contains additional components such as one or more emulsifier (s) and / or a plurality of filler (s). The preferred emulsifiers are sugar esters, which the skilled person knows well. The preferred emulsifier is sucrose stearate. It is important to note that polysorbate 80 (also called "tween 80") at 1% and polyethylene glycol at 4% did not make the mixture sufficiently homogeneous at the concentrations tested, revealing the technical difficulty to obtain an adequate formulation . Indeed, the addition of Tween 80 at 1% as an emulsifier is responsible for the presence on the films of the phenomenon of "fish eyes", this emulsifier has not allowed to improve the result. Other tests were carried out by taking as emulsifier polyethylene glycol 40 at 4%, the product was found to be stable, without precipitate, but in stability studies, it was found that the films stick together, this emulsifier has also been ruled out. Finally, the studies conducted with sucrose stearate as an emulsifier were conclusive.

The filler may be chosen from the mineral fillers conventionally used, such as silica, talc or other silicate, titanium dioxide, but also from certain pharmaceutical diluents or lubricants such as magnesium stearates, calcium stearates, or zinc.

Additional optional compounds may be added according to the invention. For example, flavors and / or sweeteners may be added to the film formulation to improve the palatability of the films. Aromas and sweeteners can be added during the production of films. They can be natural or artificial, they are well known to those skilled in the art. The choice of flavors and / or sweeteners is not important for the invention.

The invention also relates to the use of an oral hygiene composition in the form of a fast disintegrating monolayer film comprising a green tea extract, parsley essential oil, a mixture of water-soluble polymers, an emulsifier, and less a plasticizer for the preparation of a medicament for preventing and / or treating halitosis.

The invention will now be illustrated by way of non-limiting example by the following examples. These examples particularly highlight the difficulty of developing the composition. Example 1

In this example, several axes of formulations (Table 1) were initiated so as to select one or more polymers of food status, characterized by their film-forming properties but also by their compatibility with the dry extract of green tea, indeed the wealth in phenols of this ingredient may limit its compatibility.

Table 1, compatibility of different food grade polymers with dry extract of green tea

ES TV: dry extract of green tea; AP: pea starch; CMC: carboxymethylcellulose; HPC: hydroxypropyl methylcellulose; MC: methylcellulose; P: pectin; PVP: polyvinylpyrrolidone. Tests carried out by combining Klucel Nutra W (hydroxypropylcellulose) and Blanose 7LF

(sodium carboxymethylcellulose) are the most satisfactory. In fact, they make it possible to obtain a film which is not too brittle and its mechanical properties are particularly adapted to the process constraints of the various stages of slitting, cutting and canning.

Example 2

In this example, numerous attempts have been made to compare the influence of soluble filler (sorbitol) or insoluble (titanium dioxide) on the disintegration of the film as well as on its mechanical properties and for different ratios between the polymers.

The characteristics of the film namely its transparency, its flexibility, its resistance, whether it is noisy or not, if it is sticky, elastic have been evaluated. Other parameters such as grammage, disintegration time, maximum force and elongation at break have also been quantified. Several concentrations of sorbitol in the presence or absence of titanium dioxide were evaluated by also varying the ratios between sodium carboxymethylcellulose and hydroxypropylcellulose.

All these experiments show that a ratio of 80/20 sodium carboxymethylcellulose / hydroxypropylcellulose is finally chosen as well as a basis weight of 80 g / m ² .

Example 3

Main features of a fast disintegrating film which gave particularly satisfactory results. Table 2

Average

Area (cm ² ) 6, 5

Thickness (μπι) 54

Decay (s) 14.3

Loss on drying (%) 15

Max Force (MPa) 61.7

Tensile test Elongation at break (%) 7.3

EXAMPLE 4 Examples of Compositions According to the Invention Unit Composition of a Disintegrating Film (Table 3).

Raw material mg / unit% m / m

Sodium carboxymethylcellulose 27, 82 65, 5

Hydroxypropylcellulose 6, 95 16.4

Green tea extract 4, 14 9.7

Parsley essential oil 0, 13 0.3

Glycerol 0, 93 2.2

Sorbitol 0.31 0.7

Sucrose stearate 0.44 1.0

Sucralose 0, 04 0, 09

Saccharin sodium 0, 02 0, 05

Water Qsp

Total 44,100 Another unitary composition of a fast disintegrating film (Table 4).

Raw material mg / unit% m / m

Sodium carboxymethylcellulose 27, 82 65, 5

Hydroxypropylcellulose 6, 95 16.4

Green tea extract 4, 14 9.7

Parsley essential oil 0, 08 0,2

Glycerol 0, 93 2.2

Sorbitol 0.31 0.7

Sucrose stearate 0.44 1.0

Sucralose 0, 04 0, 09

Saccharin sodium 0, 02 0, 05

Acesulfam potassium 0, 02 0, 05

Chlorophylline cupro sodium 0, 10 0.2

Water Qsp

Total 44,100

Claims

claims

A rapidly disintegrating monolayer film for oral administration of a composition based on green tea extract and parsley essential oil, characterized in that it comprises a mixture of water-soluble polymers consisting of sodium carboxymethylcellulose and hydroxypropylcellulose, an emulsifier, and at least one plasticizer.

2. Film according to claim 1, characterized in that the mass ratio of sodium carboxymethylcellulose / hydroxypropylcellulose is between 2 and 10.

3. Film according to claim 1, characterized in that the mass ratio of sodium carboxymethylcellulose / hydroxypropylcellulose is between 3 and 5.

4. Film according to claim 1, characterized in that the mass ratio of sodium carboxymethylcellulose / hydroxypropylcellulose is equal to 4.

5. Film according to any one of claims 1 to 4, characterized in that the amounts of green tea extract and parsley essential oil are respectively between 1 and 15% and between 0.05 to 1% by weight. weight relative to the total weight of the composition.

6. Film according to any one of claims 1 to 4, characterized in that the amounts of green tea extract and parsley essential oil are respectively between 8 and 12% and between 0.1 to 0.4 % by weight relative to the total weight of the composition.

7. Film according to any one of claims 1 to 4, characterized in that the amounts of green tea extract and parsley essential oil are respectively 10% and 0.3%.

8. Use of an oral hygiene composition in the form of a fast-disintegrating monolayer film comprising a green tea extract, parsley essential oil, a mixture of water-soluble polymers consisting of sodium carboxymethylcellulose and hydroxypropylcellulose, a emulsifier, and at least one plasticizer for the preparation of a medicament for preventing and / or treating halitosis.

9. Use according to claim 8, characterized in that the mass ratio of sodium carboxymethylcellulose / hydroxypropylcellulose is between 2 and 10.

10. Use according to claim 8, characterized in that the mass ratio of sodium carboxymethylcellulose / hydroxypropylcellulose is between 3 and 5.

11. Use according to claim 8, characterized in that the mass ratio of sodium carboxymethylcellulose / hydroxypropylcellulose is equal to 4.

12. Use according to any one of claims 8 to 11, characterized in that the amounts of green tea extract and parsley essential oil are respectively between 1 and 15% and between 0.05 to 1% by weight. weight relative to the total weight of the composition.

13. Use according to any one of claims 8 to 11, characterized in that the amounts of green tea extract and parsley essential oil are respectively between 8 and 12% and between 0.1 to 0.4 % by weight relative to the total weight of the composition.

14. Use according to any one of claims 8 to 11, characterized in that the amounts of green tea extract and parsley essential oil are respectively 10% and 0.3%.