EP1458806A1

EP1458806A1 - Heteroxylan film-forming composition for making capsules and resulting capsules

Info

Publication number: EP1458806A1
Application number: EP02799119A
Authority: EP
Inventors: Serge Basquin; Fabien Darasse; Denis Despre; Arnaud Messager
Original assignee: Pierre Fabre Medicament SA; Ulice SA
Current assignee: Pierre Fabre Medicament SA; Ulice SA
Priority date: 2001-12-27
Filing date: 2002-12-26
Publication date: 2004-09-22
Also published as: JP2005513255A; FR2829142A1; AU2002364342A1; FR2829142B1; CA2470545A1; US20050037064A1; WO2003055942A1

Abstract

The invention concerns a heteroxylan composition for preparing capsules or tablets, in particular soft capsules or hard tablets. The invention concerns a film-forming composition for making hard or soft capsules, comprising: at least a heteroxylan compound; at least a softening agent; and at least a gelling agent. The invention also concerns a film obtained from said composition. The invention further concerns capsules obtained from said composition or said film.

Description

FILM-FORMING COMPOSITION OF HETEROXYLANES FOR THE MANUFACTURE OF CAPSULES AND CAPSULES THUS OBTAINED

The field of the present invention relates generally to film-forming compositions. More particularly, the present invention relates to a composition based on heteroxylans for the preparation of capsules.

By capsules, we mean hard or soft capsules, which are devices widely used nowadays to contain pharmaceutical, phytotherapeutic or even food products.

Hard pharmaceutical capsules, generally oblong, are classified as solid dosage forms (BOWMAN & OFNER, 2002) intended mainly for the ingestion of unit doses of solid active ingredients as opposed to soft capsules used for liquid and semi-solid drugs . The capsules also make it possible to preserve products, the taste and / or odor of which may prove to be unpleasant.

The preparation of hard capsules is traditionally carried out on the basis of animal gelatin, to which additives such as plasticizers, dyes, preservatives can be added. The preparation of these gelatin-based devices is described in

"Industrial Pharmacotechnie" (Rosetto, 1998, Ed. IMT).

However, since the appearance of public health problems linked to the epidemic of Bovine Spongiform Encephalitis (BSE) and the discovery of its vector in animal tissues which are traditionally used to isolate gelatin, the scientific community and the industrialists in the technical field have become aware of the risk arising from the use of gelatin of animal origin, in products intended for ingestion.

Updating a product capable of replacing gelatin has therefore become an important line of research for many companies in the technical field.

Gelatin substitutes have therefore been envisaged such as starches: by an extrusion process, we manage to produce starch capsules industrially (Targit® Technologies, VILIVALAM et al., 2000).

A patent has also been filed proposing the manufacture of hard capsules from κ-carrageenan as the main film-forming agent, associated with a variety of other hydrocolloids such as gellan gum and mannans (US-B-6,214,376) but this formula does not has no industrial future yet. Research has also been carried out to develop films whose formulation is based on cellulose ethers and which have the same mechanical properties and barriers to gases and lipids as gelatin films (KAMPER & FENNEMA, 1985).

In fact, native cellulose, mainly extracted from plant cell walls, is insoluble in water due to too high a quantity of intramolecular hydrogen bonds within the polymer and a high degree of crystallinity which limits its solvation.

On the other hand, by introducing along the chain of the substitutes which interfere with the formation of the crystalline units, it is then possible to solvate this polymer: this is achieved by etherification.

Thus by reacting the cellulose with a sodium hydroxide solution and then with methyl chloride, propylene oxide or sodium monochloroacetate, methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose are produced. (HPC) and sodium carboxymethylcellulose (CMC).

These compounds therefore make it possible to produce transparent, flexible but solid films, soluble in water and resistant to oils and greases (NISPEROS-CARPJEDO, 1994).

Of these cellulose derivatives, HPMC in particular is used as a gelatin substitute in applications of hard pharmaceutical capsules. Used industrially as a unique gelling agent (EP-A-0 056 825) or combined with carrageenans (EP-A-0 592 130, EP-A-1 029 539), it makes it possible to obtain capsules with the same properties as the capsules. except for the lower dissolution rates.

However, if these capsules are interesting, technically and commercially, they still have a defect: as chemical derivatives, interactions are possible with certain active compounds which the capsules may contain. The precautionary principle would therefore avoid their use in the food sector.

The pharmaceutical and food industries are therefore still awaiting capsules in which the gelatin has been replaced by one or more constituents of plant origin, which do not entail any risk for the consumer, the manufacture of which does not entail any prohibitive additional cost compared to gelatin capsules, which has mechanical and dissolving properties of the same order as the latter.

It is therefore to the credit of the applicant to have demonstrated that the use of heteroxylans, in particular arabinoxylans, as film-forming constituents in a composition for the manufacture of hard or soft capsules, could constitute a new outlet and an alternative advantageous for the use of the abovementioned compounds, in particular in terms of safety, manufacturing cost, quality of the films obtained.

It turns out that heteroxylans are present in large quantities in maize bran (peripheral part of corn kernels), by-products of the semolina industry, but they are also found in significant quantities in rye and rice. The majority of this corn bran is currently used for animal feed, and a very small amount is used as a source of dietary fiber. Corn bran consists mainly of cellulose (10 to 20%) and heteroxylans (40 to 50%). High extraction yields (up to 90%) of the heteroxylans contained in the corn bran can be obtained without apparent decrease in the molecular weight of the polymer.

Heteroxylans are plant polysaccharides, located in cell walls (parietal polysaccharides) and belonging to the hemicellulose group. These are the most abundant non-cellulosic wall polysaccharides. They include a linear skeleton of xylopyranoses linked in β-1,4 substituted by side chains, of variable nature and number. The β-1,4 type glycolic bond provides the chain with a relatively wide conformation. The helical conformation of xylan β-1,4 is more flexible than that of cellulose, despite a similarity of xylose and glucose, because it is stabilized by only one hydrogen bond while there are two in the cellulose. This bond is established between the hydrogen of the hydroxyl group in position 3 of a xylose residue, and the oxygen in position 5 of the next. When the xyloses are substituted, they are substituted on their oxygen in position 3 and more rarely on their oxygen in position 2. The nature of the side chains, their proportion and their method of connection to the xylose skeleton are structural elements which differ from 'one heteroxylan to another.

In heteroxylans from maize bran, xylose constitutes approximately half of the dares presented, arabinose approximately one third, hence their name arabinoxylans. Galactose, glucuronic acid and ferulic acid are the other constituents. The molecular mass of heteroxylans varies between 100,000 and 250,000 g / mol, this variability being explained in particular by differences in the extraction method used or, in the analysis method used to determine the component sugars. heteroxylan analyzed. Their degree of polymerization is therefore between 700 and 1800. Heteroxylans are generally extracted in an alkaline medium; according to the variants of the heteroxylan extraction process, three main categories of heteroxylans can be obtained, namely grade C, B or A heteroxylans, corresponding respectively to non-purified, moderately purified and very purified products.

A first objective of the present invention is then to provide a composition intended to form a film used for the manufacture of capsules, usable in the pharmaceutical, phytotherapeutic or even food sector.

A second objective of the invention is to provide a film with the best possible visual appearance, capable of being molded and intended to be used for the manufacture of capsules.

A third objective of the invention is to obtain capsules from the present composition or from the present film.

These and other objectives are achieved by the present invention, which relates to a film-forming composition for the manufacture of capsules, comprising: at least one compound of the heteroxylan type, at least one plasticizing agent and at least one gelling agent. Preferably, such a composition is intended for the production of hard capsules.

Remarkably, the heteroxylan used in this composition is arabinoxylan.

Advantageously, the plasticizing agent preferably is chosen from the group of (poly) hydroxylated compounds and more preferably from the group consisting of glycerol, sorbitol, polyethylene glycol, propylene glycol, maltitol, triacetin or their mixtures.

Advantageously, this gelling agent, preferably of vegetable origin, is selected from the group comprising carrageenans (K and i carrageenans), gellan gum, pectins or their mixtures. According to a preferred variant, the dry base composition comprises: between 60 and 99% by weight of arabinoxylan, - between 5 and 40% by weight of plasticizer and between 0.1 and 20% by weight of gelling agent. Even more advantageously, the composition also comprises at least one bulking agent. This bulking agent is taken from the group comprising carbohydrates, such as sucrose, fructose, starch, cellulose, maltodextrins, cereal and non-cereal flours, mineral fillers such as calcium salts, sodium or potassium or their mixtures. Such a bulking agent can advantageously be a maltodextrin having a Dextrose Equivalent value of 5 to 40.

More preferably, the bulking agent is contained in the composition in a proportion of between 0 and 70% by dry weight. Remarkably, arabinoxylan is preferably extracted from corn bran, rye, rice or their mixtures.

According to another advantageous variant, the composition according to the invention further comprises an additive or a mixture of additives chosen from: - dyes, in particular chosen from the group consisting of titanium oxide, iron oxide, patent blue, quinoline yellow, orange yellow S, cochineal red A or cupric chlorophillin, antioxidants such as ascorbic acid, tocopherol, butylhydroxyanisol (BHA) or buthylhydroxytoluene (BHT). Thus, the composition comprises: between 0 and 3% by dry weight of dye and / or, - between 0 and 3% by dry weight of antioxidant.

Remarkably, the composition is in the form of a solution, preferably aqueous.

According to this remarkable characteristic, the composition comprises from 25 to 80% by weight of water.

Another subject of the invention relates to the use of the abovementioned composition for the production of a film. Another subject of the invention relates to a film obtained from the composition or according to the use of such a composition.

According to a remarkable characteristic, this film has the following mechanical properties: a breaking strength of between 30 and 250 N, - an elasticity of between 20 and 120 N. s ^"1 ,

- a deformation of between 2 and 20%.

Yet another object of the invention relates to a capsule obtained from a composition or a film according to the invention. These capsules can be hard or soft capsules.

Advantageously, soft capsules of heteroxylans are produced from a composition comprising a large amount of plasticizer and very little or no gelling agent. Such a capsule comprises for example: between 60 and 99% by dry weight of at least one heteroxylan, between 5 and 40% by dry weight of at least one plasticizer,

- between 0.1 and 20% by dry weight of at least one gelling agent,

- between 0 and 70% of at least one bulking agent. The capsules thus obtained have a final humidity of between 5 and 18%.

Heteroxylan hard capsules are made from a composition containing, on the contrary, little plasticizer and generally more gelling agent. Thus, a hard capsule can comprise: between 20 and 90% by dry weight of at least one heteroxylan, between 10 and 30% by dry weight of at least one plasticizer, between 5 and 20% by dry weight of at least less a gelling agent, between 0 and 70% by dry weight of at least one bulking agent. The capsules thus obtained also have a final humidity of between 5 and 18%.

The method used for the production of these capsules is chosen from the methods known to those skilled in the art and usually used.

The invention will be better understood with the aid of the nonlimiting examples which follow, with reference to the drawings in which:

FIG. 1 represents the flow curve of a quenching solution based on gelatin, at 30% dry matter.

FIG. 2 represents the flow curve of a quenching solution obtained from de-formulated gelatin capsules, at 30% dry matter.

FIG. 3 represents the flow curve of a quenching solution obtained from de-formulated HPMC capsules, at 30% dry matter.

FIG. 4 represents the flow curve of a quenching solution based on HPMC, at 35% of dry matter. FIG. 5 represents the flow curve of a quenching solution based on arabinoxylan at 32.5% of dry matter.

FIG. 6 represents the flow curve of a quenching solution based on arabinoxylan at 32% dry matter.

FIG. 7 represents the measurements of the gelation temperatures of different quenching solutions.

FIG. 8 represents the measurements of the gel times of different quenching solutions. FIG. 9 represents the gelation profiles of a quenching solution based on arabinoxylan at 32.5% of dry matter.

FIG. 10 shows the gelation profiles of a quenching solution based on arabinoxylan at 32% dry matter. FIG. 11 shows the gelation profiles of a quenching solution obtained from de-formulated gelatin capsules, 30% dry matter.

FIG. 12 represents the gelation profiles of a quenching solution based on gelatin, at 30% dry matter.

FIG. 13 represents the gelation profiles of a quenching solution obtained from de-formulated HPMC capsules, with 30% dry matter.

FIG. 14 represents the gelation profiles of a quenching solution based on HPMC, with 13% of dry matter.

EXAMPLES:

EXAMPLE 1 Weight Composition of Heteroxylans Isolated from Corn Bran

The extraction of heteroxylans is carried out according to the protocol described by Chanliaud et al. (Journal ofcereal Science, 21, pp. 195-203, 1995). Variants have been introduced in order to obtain an industrially exploitable process and allow access to the various grades of heteroxylans (heteroxylans of grade "A", "B" or "C").

1) Preparation of grade C heteroxylans

The corn bran heteroxylans are extracted in an alkaline medium (pH: 11-12), with lime (Ca (OH) ₂ at saturation, 1.5 M potash) and at high temperature (from about 90 ° C to about 100 ° C for two hours). A solid / liquid separation makes it possible to separate the solution rich in heteroxylans, from a mixture notably composed of cellulose, proteins and carbohydrates. The solution is neutralized by adding acid, and preferably sulfuric acid or hydrochloric acid.

A liquid extract of heteroxylans of grade "C" is thus obtained, which can be concentrated in order to obtain a dry extract of approximately 15%). The extract thus obtained can then be dried, preferably by atomization, in order to obtain a powder of heteroxylans of grade "C", containing from about 55% to about 70% by weight of heteroxylans of grade "C" , as well as a large amount of salt (from about 10% to about 20%) and other molecules such as polyphenols, tannins capable of coloring heteroxylans.

2) Preparation of grade "B" heteroxylans

The liquid extract of grade "C" heteroxylans as obtained above, at the end of the alkaline extraction, solid / liquid separation and neutralization steps, is subjected to a demineralization step, by ultrafiltration in order to obtain a liquid extract of grade "B" heteroxylans, containing a salt level of less than 3%.

The liquid extract of heteroxylans of grade "B" thus obtained or ultrafiltration retentate is then concentrated in order to obtain an extract of heteroxylans of grade "B" containing about 15% of heteroxylans by weight of dry matter. The extract thus obtained can then be dried, preferably by atomization, in order to obtain a grade “B” heteroxylan powder, containing approximately 71% to approximately 80% of heteroxylans, said powder being slightly colored and always containing polyphenols.

3) Preparation of grade "A" heteroxylans

The liquid extract of grade "B" heteroxylans containing a salt level of less than 3%, obtained as described above at the end of the steps of alkaline extraction, solid / liquid separation, neutralization and demineralization by ultrafiltration, is then purified by desalting and discoloration, with the aim of eliminating respectively the sediments present in the heteroxylan extract of grade "B" and its light brown color mainly linked to the presence of polyphenols.

Thus after the demineralization step, the heteroxylans are purified by precipitation in ethanol or by successive passages over different ion exchange resins and / or adsorption resin. Other ways of discoloration exist, in particular by using a strong oxidant of the hydrogen peroxide (H ₂ O) type. The process used for the provision of heteroxylans intended for the agrifood markets does not use this type of agent, but uses methods which respect the consumer and the environment.

The heteroxylan extract obtained at the end of the purification step is dried, preferably by atomization, in order to obtain a powder of heteroxylans of grade "A", having a content of heteroxylans of grade "A" greater than 81%. White and neutral grade A heteroxylans correspond to highly purified products.

The compounds forming the purified heteroxylans are presented in the table below: Table 1

Among these grade "A" heteroxylans, the arabinoxylans (AX) are those which were used to produce the film-forming composition and the capsules according to the invention. These "A" grade AXs have a molar mass of 250,000 g / mole.

It may also be envisaged to use arabinoxylans of grade "H". These arabinoxylans are obtained from grade "A" arabinoxylans by enzymatic hydrolysis using hemicellulases, in particular xylanases. These arabinoxylans have a molar mass of the order of 100,000 g / mole.

Example 2: Choice of control capsules

The control formulation strategy implemented is based on both: - the de-formulation of commercial capsules, ie their dissolution in defined proportions, making it possible to obtain a quenching solution close to that used industrially. These are gelatin and HPMC capsules distributed by

CAPSUGEL; l ”- the formulation of capsules using commercial ingredients, approved by the pharmacopoeia, in accordance with the proportions indicated in the bibliography.

Example 3: Materials and methods

3.1 Preparation of the quench solution

By quenching solution, we mean the solution in which the supports for the formation of the capsules are immersed.

3.1.1 Equipment used The solution is prepared: - in a stainless steel beaker (diameter (0) = 7.5 cm) + lid (box of

Petri dish in pyrex 0 = 8 cm)> • with magnetic stirring (0-1300 rpm) by a magnetic bar ^ in a thermostatted water bath.

3.1.2 Mixing of ingredients In the case of deformulations, no problem arises: the capsules are simply dissolved in a given quantity of water.

In the case of capsule formulations, particularly the most complex, the order of incorporation of the ingredients making up the dry matter is important.

Indeed, there are different affinities of the ingredients for water; however, the hydration of a highly hydrophilic ingredient risks being at the expense of that of a less hydrophilic ingredient introduced in solution before it: the less hydrophilic molecules then tend to come together, which induces poor homogeneity of the mixture, or even lump formation.

In addition, a gelling agent will not be able to hydrate to the maximum if other ingredients have already interacted with water, which will have repercussions on the gelled network on cooling and therefore on the gel strength.

- The ingredients should therefore preferably be introduced into solution in the order of their affinity for water. In this case, it involves solubilizing: 1) the gelling agent, 2) the film-forming agent,

3) the load agent.

I Glycerol, used as a plasticizer, is in liquid form. Soluble in water, it is therefore incorporated before the introduction of any dry powdery substance into water (except in the case of gellan gum).

• Solubilization of dry matter

To allow good hydration and solubilization of the ingredients introduced in powder form, they must be granted a so-called maturation period in phase with the industrial process.

The ingredients must in fact undergo hydration prior to their solubilization, on the same principle as that mentioned above: if another ingredient is incorporated immediately after, the hydration phase is disturbed, which has consequences on the solubilization.

These ingredients are therefore left one by one to dissolve for a period of time following their introduction into solution.

• Compensation of evaporated water The cover covering the beaker is not sufficient to prevent any evaporation during the preparation of the quenching solution. However, the loss of water induces an increase in its viscosity and the increase in its gel strength on cooling. Since it is essential to properly control these two parameters, we have chosen to compensate for the evaporated water, which makes it possible to have good repeatability of the viscosities and gel strengths during the manufacture of the capsules.

Thus, knowing the total theoretical mass of the prepared quenching solution, it suffices to measure the missing mass by weighing and to compensate for it by adding water.

3.2 Making films by spreading

3.2.1 Equipment used

The films are produced using an automatic film applicator 1 137-SHEEN allowing spreading at controlled speed (40 mm / s), combined with a manual spreader for thin layer chromatography (DESAGA HEIDELBERG) allowing meanwhile, control the spreading thickness (0-2 mm).

The film-forming solution is poured into the tank and spread to the desired thickness. The film supports are glass plates (50 x 20 cm) previously covered with an adhesive polyvinyl chloride (PVC) film facilitating the release of the film.

3.2.2 Implementation conditions

The final thickness of the films must therefore be 100-110 μm, which requires regulation of the spreading thickness.

All formulas do not necessarily have the same proportions of dry matter (MS), nor the same water retention capacity at constant MS, the thickness of spreading may therefore vary depending on the products.

Two drops of a preservative, sodium sulfite, were added to the formulation of the samples to guarantee their good conservation.

3.3 Manufacture of hard capsules by draining

The industrial manufacturing conditions of the capsules have been reproduced using supports serving as molds for the formation of the capsules and by developing a system which allows vertical draining of samples followed by horizontal pre-drying.

• The choice of supports

The supports selected are the teflon and stainless steel supports usually used at the industrial level (production of male and female shells).

• The drainage system

The support is mobile in rotation during the steps of plunging, draining and drying the capsules: - The speed of rotation is fixed at 100 rpm (on the basis of control samples of de-formulated gelatin). • The rotation is ensured by a motor system secured to a rod on which the supports adapt. - The diving and the ascent of the supports is done by hand, slowly and smoothly.

The transition from vertical to horizontal is allowed by manual rotation of the system on its axis: this step allows the product accumulated at the end of the drip cap to distribute itself evenly on the support.

The conditions for producing the capsules are summarized in Table 2 below.

Table 2

The final thickness of the capsules depends directly on the draining time. However, draining is conditioned by the viscosity of the solution associated with its gelation kinetics: a solution of high viscosity and rapid gelation kinetics will thus drip much less than a solution which is not very viscous and which gels slowly.

Between the time when the sample has left the quenching solution (T _e0 ) and when no more drops fall due to product defect or due to gelation (T _emax ), it is possible to stop the draining by passage horizontal to the system.

3.4 Drying process

3.4.1 Equipment used Industrially, drying takes place:

> • a few degrees above room temperature (22-28 ° C), - at relative humidity (RH) between 35 and 85%>. We therefore used a ventilated oven, thermostatically controlled, and regulated in HR (WTP Binder Labotechnik)

3.4.2 Drying conditions

The drying conditions have a strong impact on the appearance of the capsules (especially brittle and thick) which directly depends on their water content. It is therefore essential to control the relative drying humidity. Drying is carried out at 30 ° C - 40% RH. In the case of films, it is often recommended to remove them from their PVC support before complete drying; in fact, this makes it possible to: - avoid breaking the samples due to their possible brittleness after drying; - to have less difficulty peeling them off than when they have strongly adhered to the plate.

Similarly, for capsules, it is preferable to peel them off as soon as possible from their Teflon or stainless steel support. To allow easier separation, the support can be oiled beforehand with edible vegetable fats.

The minimum time to take off the product, film or capsule, from its support is an important parameter to evaluate because it gives a first overview of its drying kinetics.

Finally, at controlled RH, drying is accomplished when the water content of the capsules stabilizes.

The capsules, once dry, are packaged at room temperature in plastic bottles closed by screw caps, which allows their properties to be preserved.

For films, once dry they are packaged in aluminum foil between two sheets of parchment paper so as not to stick. The properties of these films and capsules are analyzed during and after manufacture, from the quenching solution to the finished product.

Example 4: Formulation of the control capsules

4.1 De-formulation / re-formulation of commercial capsules

The de-formulation method consists of:

1) dissolving gelatin or HPMC capsules of known characteristics in water,

2) attempt to obtain capsules with the same characteristics by the manufacturing process established in the laboratory.

Indeed, commercial gelatin and HPMC capsules can be mainly characterized by:

^ Their water content (X _w in%), in the range [12-16%]. ^ Their thickness (e in μm), included in the range [100-110 μm].

We therefore tried to obtain capsules which have little different, if not similar, characteristics.

The operating conditions making it possible to obtain capsules based on gelatin and HPMC similar to those on the market are grouped in Table 3 below:

Table 3

4.2 Formulation from commercial ingredients

As before, the controls formulated with our ingredients must have the same properties as the commercial control capsules, in particular concerning appearance, water content and thickness. The formulations must therefore comply with it.

(a) Formulation of hard gelatin capsules • Choice of gelatin There are two different types of gelatins, types A and B. Each of these gelatins can be used independently for the manufacture of capsules but their combination is recommended to optimize their characteristics (AUGSBURGER, 1991).

Two Force Bloom gelatins between 150 and 280 Blooms were tested: ^ PS 240 gelatin, belonging to type A (Pig Skin 240 Blooms). I ”- LB 200 gelatin, belonging to type B (Limed Bone 200 Blooms).

• Choice of formulation

Numerous tests intended to complete the formulation making it possible to obtain capsules having characteristics closest to commercial capsules have been carried out.

The optimal formulation is presented in Table 4 below. :

Table 4

Glycerol is the most widely used plasticizer for the production of hard gelatin capsules and mineral water ensures that the repeatability of the results is not influenced by changing water quality.

The dry matter contents have been adapted according to the results obtained in the deformation of the gelatin capsules.

(b) Formulation of HPMC capsules

• Choice of HPMC

The HPMC used is as follows: METHOCEL® El 5 (DOW CHEMICAL®) This HPMC is approved by the European Pharmacopoeia.

Choice of formulation In accordance with the tests carried out for gelatin capsules, similar tests were carried out for HPMC capsules, in order to determine the formulation which made it possible to obtain capsules closest to those on the market.

This formulation is presented in the following table 5:

Table 5

The complementary gelling agent is the same as that used for the formulation based on arabinoxylans.

EXAMPLE 5 Formulation of the capsules based on arabinoxylans

Two different formulations of arabinoxylan-based capsules were produced and tested: - Formulation of hard AX capsules without maltodextrin. - Formulation of hard AX capsules with maltodextrin.

5.1 Formulation of hard capsules of AX without maltodextrin 5.1.1: Concentrations tested

Table 6 below presents the concentration ranges tested for the formulation of hard capsules of AX without maltodextrins.

Table 6

5.1.2: Dissolution of the AX

Less than 15% (total mass) of AX is easily dissolved in water (Volvic®) brought to 70 ° C but it is around 10%> that the capsules are most homogeneous.

As with gelatin, the strong affinity of AXs for water makes it possible: to pre-solubilize them by rapid introduction into solution, then to let them dissolve completely with stirring.

Unlike gelatin and HPMC, the AXs do not pose a problem of swelling of the quenching solution: the use of an anti-foaming agent is therefore a priori not necessary industrially.

5.1.3: Results Two formulations were chosen: the first, at around 25%) (m / m) of glycerol, makes it possible to produce soft capsules of AX; the second, at 2.4% (m / m) of glycerol, gives hard capsules of homogeneous appearance and flexible texture. These formulations are presented in Table 7 below: Table 7

Note: gellan gum is added to the AX 25%> glycerol formula in order to slightly increase the viscosity of the hot solution.

We can therefore conclude that AXs make it possible to manufacture not only hard capsules but also soft capsules by a simple formulation. Like the main controls for gelatin and HPMC, a draining time of

30 s is used to manufacture hard capsules 100 μm thick.

The capsules can be detached from their support from 2:30 am to 3 am, with great ease.

As for capsules formulated from HPMC, it can be considered that drying is accomplished as early as 3-4 h.

The water content stabilizes around 9-10%, ie below that measured on the control samples (11% on average): this is due to a lower water retention capacity of the "AX + association Gelcarin® "as gelatin or HPMC.

5.1.3: Conclusion

The hard capsules, more preferably studied, have an appearance and a texture in every respect similar to the controls of gelatin and HPMC. However, the MS content of the quenching solutions is lower than that of the controls, between 30 and 35% by total mass. The formulation based on AX and Gelcarin® being better defined, we sought to develop a formula incorporating a higher quantity of MS, by introducing bulking agents into the solution.

5.2 Formulation of hard capsules of AX with maltodextrin

5.2.1 Implementation

We have chosen to study two hard capsule formulations, one at 10%> glycerol, the other at 12% to compare the characteristics. The protocol used for making the quenching solution and manufacturing the capsules is identical for the three formulas.

Table 8 below groups together the optimal formulations based on AX for making hard capsules with a high DM content (rounded percentages).

Table 8

5.2.2. Results It is checked that the capsules prepared are similar in appearance and texture to the control capsules. The results obtained for FAX 9 show that draining for 30 s makes it possible to obtain conforming capsules.

The results are similar for the AX 10 capsules, the 2 formulas differing little.

EXAMPLE 8 Measurements of Viscosity and of Gelling Kinetics of Quenching Solutions

8.1 Viscosity measurements

The device used is the Rheometric Scientific SR 5000. It is a rheometer which can perform flow measurements as well as stress oscillations (Dynamic Stress Rheometer). Whatever the type of measurement, however, the mobile used is a geometry of the parallel plane type with a diameter of 5 cm. On the other hand, depending on the measurement made, the air gap differs: l * - 0.5 mm for flow measurements, - 2 mm for dynamic measurements.

8.1.1 Results The average viscosity results are given in the following table 9:

Table 9

Important note: the viscosities measured at 40 ° C give an average result of 900 mPa.s for the AX 2. However, although this value does not register exactly within the margins given by the bibliography at this temperature, we have judged that they were too wide (1000 and 8000 mPa.s) to be a valid reference. This is why we have chosen to carry out the measurements at 55 ° C.: this temperature being that of the quenching solution, the viscosities can be compared with industrial production.

8.1.2 Discussion Whatever the product considered, the curves obtained are typical of rheo-fluidifying behavior: the viscosity of the products decreases with increasing stress.

However, different behaviors are manifested according to the compositions, as shown in Figures 1 to 6.

The viscosity of the gelatin samples remains high at low speed gradients (γ) while the solutions of AX and HPMC have a viscosity is quite low as of low stresses. However, the AX and HPMC solutions have a viscosity which stabilizes quickly unlike gelatin solutions.

In addition, it is noted that the gelatin solutions can enter into turbulent regime from a speed gradient of 250 s ^"1 (in general beyond 300 s ^{" 1} ) while for the AX and the HPMC, the solutions resist higher speed gradients (in general, the turbulent entry does not take place before 600 s ^"1 )

AX and HPMC solutions are therefore more stable under high stresses than gelatin solutions

The stress threshold beyond which the behavior of the solutions can be compared to Newtonian behavior is less marked for the solutions of AX and of HPMC than for the solutions of gelatin. This is also manifested by a gradient index tending towards 1.

The AX and HPMC solutions have a more constant stress response behavior than gelatin.

The measurements carried out on deformulated gelatin and AX 9 were repeated nine times while only three to six repetitions were carried out for the other samples: this explains the wider confidence intervals.

Furthermore, this confidence interval is very important for the HPMC whose formulation we have developed (HPMC 35%). This is explained by a much greater increase in the viscosity of the solution over the measurements than for the other samples. This phenomenon can be explained by an evaporation of ethanol.

Overall, we therefore measure a viscosity of quenching solutions at 55 ° C for our various products: it ranges from 500 to 900 mPa.s.

However, the AX samples have a viscosity significantly lower than that of gelatin solutions: if we consider our most repeatable measurements (AX 9 compared to de-formulated gelatin) these viscosities are 600-800 mPa.s for the AX against 700-900 mPa.s for gelatin. In parallel, we also studied the gelation kinetics of our solutions.

8.2 Gelation kinetics By definition, two parameters are evaluated by measuring the gelation kinetics:

- the average gel time of the solutions,

- the temperature at which this gelation takes place.

8.2.1 Gelation times and temperatures These measurements were performed on Rheometrics on all of the samples. Figures 1 and 2 respectively represent the average times and the average gelation temperatures.

Figures 3 to 8 show the gelation profile as a function of time for each of the compositions tested.

8.2.3 Discussion

The cooling conditions being similar to the production of the capsules and in rheometric measurements, we verify a similarity between the measurement of the time of onset of gelation and that of the maximum draining time: in fact, with the production of the capsules, we can leave the solutions of HPMC and gelatin to drip a little less than 2 minutes while the solutions of AX no longer drip after 50 s, which is measured here.

The kinetics of cooling being the same for all the samples, we therefore obtain in parallel a higher gelation temperature for the AX solutions than for the controls.

We can measure a higher maximum gel strength (G ') for our AX solutions than for the controls (20 to 40,000 Pa compared to 10-20,000 for the de-formulated controls in particular). However, our AX gels, formed faster than those of gelatin or HPMC, take longer to stabilize at room temperature which explains a re-decrease in G ': the gel strength stabilizes after 5 minutes at 25 ° C around the same values as for the controls, ie 10 to 20,000 Pa.

8.3 Conclusion

We were thus able to manufacture capsules based on AX which have the same properties of appearance, texture and thickness as commercial controls. The production process is then substantially identical: only the draining time necessary for the manufacture of capsules of standard thickness is slightly lower for AX solutions, the other manufacturing parameters remaining unchanged. This difference is explained by a lower viscosity of the AX solutions compared to the control solutions. Furthermore, this low viscosity is compensated for by a significantly higher gelling kinetics, which can be significantly improved by varying the gelling power of the gelling agent used.

The formulation of our products being optimized for a standard thickness of the capsules, we then sought to complete this optimization on the criterion of water content.

Example 9 Comparison of the Mechanical and Dissolution Properties of the Hard Capsules

We have logically chosen to continue to characterize the capsules obtained by the AX 9 and AX 10 formulas, for which the study was the most thorough.

The mechanical and dissolving properties of these capsules were measured and, in some cases, compared with those of the control capsules of gelatin and HPMC by studying both capsules and films.

9.1 Mechanical properties

The study was carried out on films made by spreading from quenching solutions at 70 ° C. In the same way that we have established for each formula which duration of draining makes it possible to obtain a standard thickness of the capsules, we have sought what thickness of spreading makes it possible to manufacture films of standard thickness.

9.1.1 The thicknesses of spreading allowing the standardization of the thickness of the films after drying We tried to use thicknesses of spreading allowing to obtain after drying thicknesses equivalent to the standards for the capsules, that is to say thickness between 100 and 110 μm.

The results obtained are presented in the following table 10: Table 10

On average, the films obtained have a thickness of 110-115 μm. Only films based on HPMC at 13% DM have a thickness after drying of between 100 and 130 μm.

9.1.2. Mechanical properties of the films From the films obtained, we therefore carried out measurements of mechanical properties on the Instron 1122.

The results are presented in the following table 11:

Table 11

It is found that the elasticity of the film based on AX 10 is better than that of the film based on commercial HPMC. On the other hand, it is less good than that of films based on gelatin.

The deformation of the film based on AX 10 is on the other hand better than that of the films based on gelatin and de-formulated HPMC. However, it is lower than the deformation of the commercial HPMC-based film. However, it is important to note that the latter has a thickness of 130 μm, which may explain that it has such a large capacity for deformation.

9.1.3 Conclusion

It would be interesting to make measurements at the correct film thickness on the HMPC 13% DM sample, formulated in the same mode as our AX samples.

(less maltodextrin). Indeed, the results obtained in elasticity at 130 μm are slightly higher than those obtained for the AX 10 at 115 μm. It is therefore possible that these new measurements give results close to those obtained for the AX 10.

9.2. Disintegration and dissolution kinetics

The first measurements carried out show that the capsules produced on the basis of AX satisfy the dissolutest and moreover have better dissolution properties than the gelatin capsules.

Conclusion:

Arabinoxylans therefore constitute the substitutes of choice for the industrial production of hard pharmaceutical capsules.

In fact, we were able to define a formulation based on natural ingredients of plant origin, based on the combination of arabinoxylans and a gelling agent, Gelcarin®: this formulation makes it possible to obtain hard capsules for a low of dry matter and according to a process identical to those used for commercial samples. These capsules have characteristics similar to industrial controls.

The capsules obtained have an appearance, texture and dimensions after drying close to standard industrial values.

For the desired texture, their water content stabilizes around 9%, ie a value lower than the usual industrial values but at which the gelatin and HPMC capsules are usually brittle. This property is interesting for the behavior in conservation.

Finally, it is notable that our capsules have better dissolving properties than gelatin. In this context, their mechanical properties can be improved by increasing their thickness. The ease with which soft capsules can be produced from arabinoxylans foreshadows the excellent quality of hard capsules which can be obtained by working more thoroughly on the process and by developing the formulation developed.

Claims

1. Film-forming composition for the manufacture of capsules, characterized in that it essentially comprises: - at least one compound of the heteroxylan type, at least one plasticizing agent, and at least one gelling agent.

2. Composition according to claim 1, characterized in that the heteroxylan is arabinoxylan.

3. Composition according to claim 1 or 2, characterized in that the plasticizing agent is preferably chosen from the group of (poly) hydroxylated compounds, and more preferably still from the group comprising glycerol, sorbitol, polyethylene glycol, propylene glycol, maltitol, triacetin or their mixtures.

4. Composition according to one of the preceding claims, characterized in that the gelling agent is selected from the group comprising carrageenans (K and i carrageenans), gellan gum, pectins or their mixtures.

5. Composition according to one of the preceding claims, characterized in that it comprises: from 20 to 99% by dry weight of heteroxylan, from 5 to 40% by dry weight of plasticizing agent and - from 0.1 to 20% by dry weight of gelling agent.

6. Composition according to one of the preceding claims, characterized in that it further comprises at least one bulking agent.

7. Composition according to the preceding claim, characterized in that the bulking agent is taken from the group comprising carbohydrates, such as sucrose, fructose, starch, cellulose, maltodextrins, cereal and non-cereal flours , mineral fillers such as calcium, sodium or potassium salts or their mixtures, and preferably a maltodextrin having a Dextrose Equivalent value of 5 to 40.

8. Composition according to the preceding claim, characterized in that it comprises from 0 to 70% by dry weight of bulking agent.

9. Composition according to one of the preceding claims, characterized in that the said heteroxylan-type compound (s) are preferably extracted from corn bran, rye, rice or their mixtures.

10. Composition according to one of the preceding claims, characterized in that the said heteroxylan-type compound (s) preferably have a molar mass of between 100,000 and 300,000 g / mole.

11. Composition according to one of the preceding claims, characterized in that it further comprises an additive or a mixture of additives chosen from: dyes, in particular chosen from the group consisting of titanium oxide, oxide iron, patent blue, quinoline yellow, orange yellow S, cochineal red A or cupric chlorophillin, antioxidants such as ascorbic acid, tocopherol, butylhydroxyanisol (BHA) or butylhydroxytoluene (BHT ).

12. Composition according to the preceding claim, characterized in that it comprises: - between 0 and 3% by dry weight of dye and / or,

- between 0 and 3% by dry weight of antioxidant.

13. Composition according to one of the preceding claims, characterized in that it is in the form of a solution, preferably aqueous.

14. Composition according to the preceding claim, characterized in that it comprises from 25 to 80% by weight of water.

15. Use of the composition according to one of claims 1 to 14, for the production of film.

16. Film obtained from the composition according to one of claims 1 to 14 or according to the use according to the preceding claim.

17. Film according to the preceding claim, characterized in that it has the following mechanical properties: tensile strength between 30 and 250 N, - elasticity between 20 and 120 Ns ^"1 , deformation between 2 and 20%>.

18. Capsule obtained from a composition according to one of claims 1 to or from a film according to one of claims 16 or 17.

19. Soft capsule, characterized in that it comprises: between 60 and 99%> by dry weight of at least one heteroxylan, between 5 and 40%> by dry weight of at least one plasticizer,

- between 0.1 and 20% by dry weight of at least one gelling agent, - between 0 and 70% of at least one bulking agent.

20. Hard capsule, characterized in that it comprises: between 20 and 90% by dry weight of at least one heteroxylan, between 10 and 30% by dry weight of at least one plasticizer, - between 5 and 20% by dry weight of at least one gelling agent,

- between 0 and 70% by dry weight of at least one bulking agent.