WO1997009967A1

WO1997009967A1 - Flavour-masking film-forming composition

Info

Publication number: WO1997009967A1
Application number: PCT/FR1996/001400
Authority: WO
Inventors: Gérard Trouve
Original assignee: Societe D'exploitation De Produits Pour L'industrie Chimique Seppic
Priority date: 1995-09-14
Filing date: 1996-09-12
Publication date: 1997-03-20
Also published as: FR2738833B1; FR2738833A1

Abstract

A film-forming composition for coating ingestible solid dosage forms containing at least one component with an off-flavour and odour is described. The composition of the invention includes a blend of water-soluble or dispersible film-forming polymers containing at least one hydroxyethylcellulose and at least one dextrin, and is useful for coating pharmaceutical tablets.

Description

Film-forming composition for masking taste.

The present invention relates essentially to a film forming composition for coating solid forms ingestible which one ^at least of the components has a taste and / or odor.

It finds particular application in the pharmaceutical field and aims to facilitate the oral administration of active ingredients having an unpleasant taste and / or odor.

It is known that certain constituents or active principles of medicaments intended for oral administration have an unpleasant taste and / or odor which can however be masked in particular by coating or by film-coating.

Although perfectly effective for this purpose, the coating processes are generally expensive because of the time required for their implementation.

The coating processes generally consist in spraying a film-forming solution on a solid form (or core) and simultaneously drying it by a current of hot air.

The film-coating processes, which are more economical than the coating processes, require the use of specific film-forming compositions insofar as these must make it possible to obtain a protective film which is not sufficiently soluble to remain intact for the duration of the passage in the mouth. (i.e. approximately one minute), but the disintegration of which is then sufficiently rapid in the stomach so as not to modify the bioavailability of the active principle.

It is under these conditions that a lot of research has been carried out for the development of original film-forming compositions capable of meeting this objective.

Most of the film-forming compositions resulting from this research consist of combinations of water-soluble polymers and specifically chosen water-insoluble polymers.

However, the preparation of film-coating solutions from these film-forming compositions requires the use of organic solvents due to the presence within these compositions of insoluble polymers. This constitutes a major drawback on the industrial level, given the dangers which organic solvents represent for health and the environment.

As examples of such compositions, there may be mentioned: - mixtures of acrylic polymers and cellulose esters used with an acetone-methanol solvent (document EP-0.523.847);

- mixtures of cellulose ethers (hydroxypropylcellulose) and cellulose esters (cellulose acetate or cellulose aceto-butyrate) used in solvents based on acetone

(documents EP-0.459.695 and EP-0.473.431);

- mixtures of ethylcellulose and hydroxypropylmethylcellulose (HPMC) used in an ethanol-dichloromethane solvent (BIOL. PHARM. BULL. 16, 2, 172-177, 1993); Film-forming compositions consisting exclusively of polymers soluble or dispersible in water and in particular of hydroxyethylcellulose (HEC) combined with hydroxypropylmethylcellulose have been proposed in document EP 0.411.952.

Such compositions can be used in the form of aqueous solutions, thus avoiding the attendant drawbacks to the use of organic solvents.

However, the aqueous solutions described in this prior document are viscous and cannot be used in concentrated form, which constitutes a serious handicap for their use on an industrial scale. Under these conditions, the present invenuon aims to solve the technical problem consisting in the supply of a new film-forming composition intended for the coating of ingestible solid forms of which at least one of the constituents has a taste and / or an odor. unpleasant, which has an efficiency with regard to masking the taste and / or odor at least equivalent to that of the compositions of the prior art, and which can be implemented on an industrial scale under form of concentrated aqueous solution to allow rapid filming.

The solution according to the present invention for solving this technical problem consists of a composition essentially comprising a mixture of film-forming polymers soluble or dispersible in water containing at least one hydroxyethylcellulose and at least one dextrin; and optionally one or more additives chosen from the group comprising plasticizing agents, coloring agents, agents promoting the adhesion of the film and sweetening agents.

It has been discovered, and this constitutes the basis of the present invention, that a film-forming composition combining a hydroxyethylcellulose and a dextrin could be used in the form of a concentrated aqueous film-coating solution in a completely satisfactory manner. industrial scale by providing effective taste masking.

In the context of the present invention, the effectiveness of the film-forming compositions is evaluated by the taste masking time, that is to say the time during which a product having an unpleasant taste and / or odor coated with the using a film-forming composition can remain in the mouth without this taste and / or odor appearing.

A composition is effective according to the invention, when the taste masking time is at least 60 seconds.

A film-forming composition according to the invention is therefore preferably in the form of a concentrated aqueous solution, that is to say containing at least 15% by weight of film-forming polymers.

However, it is obvious that such a composition can also be in other forms such as for example in the form of granules or a mixture of dry powders for later use (after addition of water) in the form of a solution. aqueous.

According to a particular characteristic, the mixture of film-forming polymers soluble or dispersible in water represents at least 60% of the dry matter of the film-forming composition and the weight ratio between the hydroxyethylcellulose and the dextrin within this mixture is between 1 : 75 and 1: 1, preferably between 1: 6 and 1: 2 and more preferably is approximately 1: 3.

A film-forming composition characteristic of the invention comprises, expressed by weight relative to the weight of its dry matter:

- from 1 to 20% and preferably from 5 to 12% by weight of hydroxyethylcellulose and;

- from 5 to 75%, preferably from 20 to 50% by weight of dextrin.

According to a currently preferred characteristic of the invention, the mixture of film-forming polymers consists of hydroxyethylcellulose, hydroxypropylmethylcellulose and dextrin, the weight ratio between hydroxyethylcellulose and hydroxypropylmethylcellulose being advantageously between 1: 4 and 1: 1, preferably between 1: 3 and 1: 2.

The dextrins which are particularly suitable for the aim sought in the context of the present invention are those having a low viscosity in aqueous solution, that is to say a viscosity less than or equal to 1000 mPas in 50% solution.

The yellow or white dextrins conforming to the monographs of the American FCC (Food Chemical Codex) or the white dextrins described in the European pharmacopoeia will preferably be chosen. A particularly preferred dextrin is cassava dextrin such as, for example, that marketed under the name CLEARGUM TA 90® by the company ROQUETTE.

As a currently preferred example of hydroxyethylcellulose capable of being used in the context of the invention, mention will be made in particular of pharmaceutical quality products currently available commercially under the names NATROSOL 250G® from the company AQUALON and CELLOSISE® from the company UNION CARBIDE CORPORATION.

In addition to hydroxyethylcellulose and hydroxypropylmethylcellulose, the mixture of film-forming polymers can also include other cellulose-based polymers, preferably of pharmaceutical quality, such as, for example, hydroxypropylcellulose, weakly substituted hydroxypropylcellulose, or methylcellulose.

Among the plasticizing agents capable of being used in the context of the present invention, mention will be made of polyethylene glycols, sorbitol, glycerol, fatty acids and their ethoxylated salts or derivatives, acetylated monoglycerides, or propylene glycol. A preferred plasticizer is ethoxylated stearic acid or triacetin.

An agent improving the adhesion of the film is for example microcrystalline cellulose or lactose. In a preferred variant of the invention, the composition comprises from 1 to 20% of microcrystalline cellulose and, preferably, approximately 10% by weight of dry matter.

A coloring agent can be a lacquer, a pigment or a food coloring. A sweetening agent may for example be aspartame or any other compound making it possible to reinforce the taste masking effect. The film-forming compositions which have just been described make it possible to film numerous ingestible solid forms such as, for example, tablets, candies or chews.

According to a second aspect, the present application aims to cover a process for the preparation of an ingestible solid form of which at least one of the constituents has an unpleasant taste and / or odor, characterized in that, in order to mask the taste and / or said odor, said solid form is coated with a film-forming composition as described above.

Advantageously, the coating is carried out by spraying and drying the film-forming composition, under conditions allowing the deposition of an amount of composition of between 3% and 7% relative to the total weight of the solid form.

The coating process used being in itself quite conventional, the skilled person will have no difficulty in determining the conditions for achieving the above objective.

The invention will be better understood with the aid of the following illustrative examples, given only without implied limitation.

In these examples, and unless otherwise indicated, the percentages are expressed by weight and the following abbreviations have been used: HPMC: hydroxypropylmethylcellulose

HEC: hydroxyethylcellulose

Tiθ2: Titanium dioxide

EXAMPLE 1 HIGHLIGHTING OF THE TASTE MASKING PROPERTIES OF FILM-FORMING COMPOSITIONS ACCORDING TO THE INVENTION.

The purpose of this example is to demonstrate the effectiveness with respect to the masking of taste of the film-forming compositions in accordance with the present invention, in particular by comparison with known film-forming compositions.

Four film-forming compositions (respectively designated A, B, C and D), the qualitative and quantitative composition of which are given in Table I, were prepared as follows:

The polymers, pigments (titanium dioxide), plasticizer (ethoxylated stearic acid) were dispersed in water by means of an agitator provided with a deflocculating turbine, at a rate of 150 g of dry matter for 850 g of water. The viscosity of the solution obtained was measured using a 3-speed mobile Brookfield viscometer 60.

The solutions thus obtained were pulverized in a coating turbine of the Erweka type, using a 0.8 mm Binks gun on tablets containing different active ingredients having an unpleasant taste and / or odor (garlic, valerian, paracetamol, theophylline) under conditions allowing a deposit corresponding to 5% of the weight of the tablets to be obtained.

The film thus obtained is smooth and regular. To verify the effectiveness of the film-forming compositions in accordance with the present invention, the taste masking time, the hardness of the tablets and the disintegration times were evaluated.

The taste masking time was evaluated by a group of ten people, and the time after which the taste of the active ingredient appears in the mouth was measured, the value retained being the average of the times measured.

The hardness of the tablets was evaluated in the usual way using an Erweka TBH 28 durometer.

The disintegration times were evaluated according to the method recommended by the European Pharmacopoeia in aqueous solutions having a pH of 1 and 7.

The results obtained, which have been grouped in Table I, clearly show the effectiveness, with respect to masking of taste, of the compositions in accordance with the invention.

The control tablets, not dandruff, are rejected almost immediately by the tasters.

Composition A, the polymer of which consists exclusively of hydroxypropylmethylcellulose makes it possible to mask the taste of valerian and of paracetamol in a relatively satisfactory manner (taste masking time of approximately 1 minute), the effectiveness with respect to screw of theophylline and garlic being more limited.

Comparison composition B, the polymer of which consists exclusively of polymetacrylic acid (EUDRAGIT® E30D) is very effective as regards the masking of taste with respect to the four active ingredients used. However, this composition leads to tablets whose disintegration times are very greatly increased compared to the tablets. no dandruff, whatever the pH, which is harmful from the point of view of the bioavailability of the active ingredients.

Comparison composition C, the polymer of which consists of a combination of hydroxyethylcellulose and hydroxypropylmethylcellulose is effective for the four active ingredients tested with taste masking times slightly greater than two minutes.

However, the viscosity of this composition in 15% solution is very high (1720 mPa.s), which limits its possibilities of use on an industrial scale. Composition D according to the invention has an entirely satisfactory efficacy with regard to masking of taste and comparable to that of comparison composition C. On the other hand, this composition has a viscosity in solution at 15% of 680 mPa. s fully compatible with industrial use. These results therefore demonstrate that a film-forming composition in accordance with the invention makes it possible to satisfactorily resolve the problem posed.

TABLE I

EXAMPLE 2

DEMONSTRATION OF THE INTEREST OF DEXTRIN BY

RELATION TO OTHER SOLUBLE POLYMERS.

The effectiveness of the film-forming compositions in accordance with the present invention was evaluated by comparison with various combinations of hydroxyethylcellulose and water-soluble polymers such as shellac and polyethylene glycol.

Three film-forming compositions (respectively identified E, F and G), the qualitative and quantitative compositions of which are mentioned in Table II, were prepared by following the experimental protocol described in Example I.

By constitution, all of these compositions have a viscosity of approximately 900 mPa.s. in an aqueous solution containing 15% of dry matter.

Tablets incorporating paracetamol were prepared according to the experimental protocol of Example I.

The taste masking times were evaluated and the results obtained are collated in Table II.

These results show that composition G according to the invention combining dextrin with hydroxyethylcellulose is the most effective in masking the taste of paracetamol.

TABLE II

EXAMPLE 3

PREPARATION OF FILM-FORMING COMPOSITIONS ACCORDING TO

INVENTION IN GRANULATED FORM.

The various constituents of the film-forming compositions according to the invention are generally in the form of powders.

In order to avoid the formation of dust during the handling of these powders, it may be advantageous to produce the film-forming composition in granulated form.

A granule is generally defined as a cluster of particles with a diameter of between approximately 100 μ and approximately 2 mm, this cluster being homogeneous in the sense that all the granules statistically have a composition identical to that of the desired film-forming composition.

A film-forming composition in the form of granules was prepared as follows: In a mixer-granulator of the Diosna type, the following are introduced:

4.8 kg Cassava Dextrin (CLEARGUM ® TA90 / Arugula)

3.6 kg HPMC (PHARMACOAT ® 603 / Shinestsu)

1.5 kg HEC (NATROSOL ® G250 / Aqualon)

1.5 kg Microcrystalline cellulose (AVICEL ® PH 105 / FMC Corp.) 2.25 kg Titanium dioxide (Wittaker)

These products, which are all in the form of powders, were mixed for 15 minutes at speed 1.

Then poured onto the mixture thus obtained 8.1 kg of an aqueous solution consisting of 1.3 kg of ethoxylated stearic acid (SIMULSOL® M52 sold by the company SEPPIC) and 6.8 kg of demineralized water, the mixer rotating at speed 1 for 10 minutes.

1 kg of finishing water is then added and the stirring is maintained for an additional 10 minutes, with the lump breaker in action.

The wet mass thus obtained is ground in a FORPLEX device fitted with a 2 mm grid, then dried in a fluidized air bed.

A product is thus obtained in the form of granules, the characteristics of which are grouped in Table III-1.

The effectiveness of this granulated product vis-à-vis the masking of taste was evaluated. To this end, tablets incorporating different active principles having an unpleasant taste and / or odor have been coated with a 15% aqueous solution prepared using this granulated product.

The filming was carried out under the conditions described in Example I.

The percentage of film-forming product deposited on the tablet was measured as well as the taste masking time, and the results obtained are collated in Table III-2.

These results show that the masking of taste is all the more effective the greater the percentage of film deposited.

At 3% deposit, taste masking can be considered acceptable.

At 5% dry deposition, it is very good.

TABLE III- 1

GRANULOMETRY

> 2000μ> 1600μ> 1000μ> 500μ> 250μ> 125μ

0.1% 16.6% 61.5 94.4 99.3 99.5

COLORING

L = 89.9 a = -0.1 b = 4.3

TABLE III-2

EXAMPLE 4

STABILITY OF FILM TABLETS USING

FILM-FORMING COMPOSITIONS ACCORDING TO THE INVENTION.

The purpose of this example is to demonstrate the stability of the film-coated tablets using the film-forming compositions according to the invention.

For this, tablets incorporating valerian as active ingredient were film-coated following the experimental process described in Example I, by means of the film-forming compositions H, I, J and K, the qualitative and quantitative compositions of which are mentioned in Table IV- 1.

The polymer constituting composition K contains neither hydroxyethylcellulose nor dextrin.

A commercial tablet incorporating valerian and in the form of a dragee and a non-film-coated tablet were also used as controls.

All of the aforementioned tablets were subjected to relatively difficult humidity (90% relative humidity) and temperature (40 ° C) conditions.

The stability of these tablets was evaluated by measuring over time the increase in weight, the hardness as well as the effectiveness of the taste masking.

The results obtained are collated in Table IV-2. These results show that the film-coated tablets using the film-forming compositions according to the invention containing a combination of hydroxyethylcellulose and dextrin are more stable than all of the controls. Thus, it can be seen that the hardness, weight and efficacy values for the masking of taste are substantially constant with the compositions H, I, J of the invention, which is not the case for the comparison products. .

It can also be seen from reading this table that the nature of the pigments used to color the film has little influence on the performance measured. TABLE IV- 1

TABLE IV-2

EXAMPLE S

COLORFUL FILM-FORMING COMPOSITIONS.

Four colored film-forming compositions (respectively designated L, M, N and O), the qualitative and quantitative compositions of which are mentioned in Table V were prepared by following the experimental protocol described in Example I.

These compositions were dispersed in water and then applied to tablets incorporating paracetamol as active ingredient, also following the experimental protocol of Example I.

The film-coated tablets thus obtained are smooth, without etching masking.

The taste masking times were evaluated and proved to be equivalent (of the order of 120 seconds) regardless of the coloring system used.

TABLE V

(1) Natrosol® G 250

(2) Pharmacoat® 603

(3) Cristalgum® S

(4) Simulsol® M52 EXAMPLE 6

INFLUENCE OF THE NATURE OF DEXTRIN ON THE PROPERTIES OF FILM-FORMING COMPOSITIONS ACCORDING TO THE INVENTION.

Cassava dextrins (CLEARGUM® TA90 sold by the company Roquette and CRISTALGUM® S sold by National Starch) and corn dextrins (C 8380 and C 8322 sold by the company Cerestar) were used to make four film-forming compositions having the composition next: Dextrin 46%

HPMC 25%

HEC 10% Cellulose 10%

Plasticizer 09%

These compositions were dispersed in water in order to form aqueous coating solutions with 15% of dry matter, which were sprayed on tablets incorporating paracetamol as active ingredient according to the protocol described in Example I .

The viscosity of the solutions thus formed as well as the taste masking times were evaluated and the results are reported in Table VI. These results show that the two types of dextrin used make it possible to obtain film-coating solutions of suitable viscosity, easily sprayable and stable for approximately 12 hours at room temperature.

Masking the taste of paracetamol is effective with both types of dextrin, the best results being obtained with cassava dextrins. TABLE VI

EXAMPLE 7

USE OF FILM-FORMING COMPOSITIONS ACCORDING TO THE INVENTION FOR THE MANUFACTURE OF EXTENDED-RELEASE TABLETS BASED ON THEOPHYLLIN. This example highlights the fact that the film-forming compositions in accordance with the invention make it possible to modulate the release of the active principles.

Four film-forming compositions (designated respectively P, Q, R and S), the qualitative and quantitative compositions of which are mentioned in Table VII were prepared by following the experimental protocol of Example I.

Aqueous solutions at 15% by weight prepared from these compositions were sprayed onto theophylline tablets under conditions allowing the obtaining of a dry deposit representing 5% by weight of total weight of the tablets.

The dissolution times of these tablets in distilled water at 37 ° C were measured using the method recommended in the European Pharmacopoeia.

The kinetics of theophylline release were determined by U.V. assay at 274 nm of the active principle.

The delay effect is characterized by the time after which 50% of the total amount of active ingredient has been released (TD 50).

The results obtained have been grouped in Table VIL. These results show that the film-forming compositions containing a combination of hydroxyethylcellulose and dextrin in accordance with the invention (Q, R, S) can modulate the release of the active principles unlike the comparison composition P.

TABLE VII

(1) HPC: Hydroxypropylcellulose

Claims

- Film-forming composition intended for coating ingestible solid forms of which at least one of the constituents has an unpleasant taste and / or odor, characterized in that it comprises a mixture of film-forming polymers soluble or dispersible in water containing at least one hydroxyethylcellulose and at least one dextrin; and optionally one or more additive (s) chosen from the group comprising plasticizing agents, coloring agents, agents promoting the adhesion of the film and sweetening agents. - Film-forming composition according to claim 1, characterized in that it is in the form of a concentrated aqueous solution, in the form of granules or in the form of a mixture of dry powders. - Film-forming composition according to claim 1 or 2, characterized in that the aforementioned mixture of film-forming polymers soluble or dispersible in water represents at least 60% of the dry matter of said film-forming composition and in that the weight ratio between hydroxyethylcellulose and dextrin within this mixture is between 1:75 and 1: 1, preferably between 1: 6 and 1: 2 and more preferably is approximately 1: 3. - Film-forming composition according to any one of claims 1 to 3, characterized in that it comprises, expressed by weight relative to the weight of its dry matter:

- from 1 to 20% and preferably from 5 to 12% by weight of hydroxyethylcellulose; and

- from 15 to 75%, preferably from 25 to 50% by weight of dextrin. - Film-forming composition according to any one of claims 1 to 3, characterized in that the above-mentioned mixture of film-forming polymers consists of hydroethylcellulose, hydroxypropylmethylcellulose and dextrin.

6- Film-forming composition according to claim 5, characterized in that the weight ratio between hydroxyethylcellulose and hydroxypropylmethylcellulose is between 1: 4 and 1: 1, preferably between 1: 3 and 1: 2. 7- Composition according to any one of claims 1 to 6 further comprising from 1 to 20% of microcrystalline cellulose and, from preferably about 10% expressed by weight relative to the weight of its dry matter. - Film-forming composition according to any one of claims 1 to 7, characterized in that the aforementioned dextrin has a viscosity less than or equal to 1000 mPas in 50% aqueous solution. - Process for the preparation of an ingestible solid form of which at least one of the constituents has an unpleasant taste and / or odor, characterized in that, in order to mask the taste and / or said odor, said solid form is coated with using a film-forming composition according to any one of claims 1 to 8. 0- A method according to claim 9, characterized in that the coating is carried out by spraying and drying the film-forming composition, under conditions allowing the depositing a quantity of composition of between 3% and 7% relative to the total weight of the solid form.