EP4041197A1

EP4041197A1 - Masking the taste of isosorbide

Info

Publication number: EP4041197A1
Application number: EP20796640.9A
Authority: EP
Inventors: Grégory Le Bihan; Sébastien CROQUET
Original assignee: Roquette Freres SA
Current assignee: Roquette Freres SA
Priority date: 2019-10-07
Filing date: 2020-10-07
Publication date: 2022-08-17
Also published as: FR3101546B1; JP2022550858A; FR3101546A1; WO2021069836A1; US20240050375A1

Abstract

The present technology relates to masking the taste of isosorbide, in particular its bitterness. The technology developed herein proposes a new dosage form allowing the taste of isosorbide to be improved, as well as a method for producing this dosage form.

Description

Masking the taste of isosorbide

Technical area

[1] The present technology relates to masking the taste of isosorbide, in particular its bitterness. The technology developed here thus provides a new dosage form to improve the taste of isosorbide, as well as a process for preparing this dosage form.

Prior art

[2] The majority of active substances used in pharmaceutical forms intended for the oral route are characterized by an unpleasant taste. Nowadays, taste appears to be an essential criterion making it possible to make the administration of a drug acceptable and thus to improve treatment compliance. Taste masking is therefore a real challenge for galenists, especially for drugs intended for pediatric and geriatric populations for whom oral administration is increasingly difficult. The taste masking techniques available in galenic formulation are numerous and are based on different approaches. There is no reference method, the choice of a technique depending mainly on the active substance to be masked, the pharmaceutical form and the cost of the technology considered. Among the techniques identified, there are easy-to-use methods, such as flavoring and sweetening; but which are often insufficient, requiring the use of more complex techniques such as the use of cyclodextrins or ion exchange resins.

[3] Isosorbide is an osmotic diuretic used in the treatment of Ménière's disease in several countries. This active principle, which needs to be ingested in large quantities, is known for its extremely unpleasant taste, in particular its strong bitterness. Typically, a dose of isosorbide consists of the oral absorption of sticks of 40 mL at 70% isosorbide (ie 28 g of isosorbide administered per dose). However, no method has until now been found which effectively masks the taste of isosorbide, in particular considering the concentrations and quantities ingested.

Objective of the invention

[4] The present invention thus aims to provide an effective means for masking the taste of isosorbide, in particular when this active principle is administered in large quantities, and / or at high concentrations.

Presentation of the invention

[5] The inventors here propose a galenic form which makes it possible to solve this problem. This oral dosage form is in the form of gelled isosorbide beads, preferably using alginate as a gelling agent.

[6] As will be seen from the examples below, this method allows the administration of isosorbide in large quantities, without the patient experiencing an unpleasant taste. The gelled beads thus obtained may contain more than 80% by dry weight of isosorbide.

[7] Still reading the examples below, it is found that this method is successful where conventional taste masking techniques fail, such as the use of sweeteners, flavors, or cyclodextrins.

[8] In addition, the dosage form proposed by the present invention is simple to implement, in that it does not require the use of a large number of materials.

[9] Since isosorbide is a small, highly soluble molecule, it is surprising that bitterness is not felt, especially considering the amounts and concentrations administered. Indeed, one would have expected that isosorbide would diffuse beads very quickly into the saliva of the oral cavity, where its bitterness would have been detected by the taste buds, and therefore felt by the panel of tasters.

[10] For example, document WO2006 / 001344 relates to a gelled mass based on alginate isosorbide and other gelling constituents. Such a composition is not suitable for making beads. In addition, this document teaches that taste masking is optimized by adding cocoa powder. Document US2010 / 120712 relates to a composition comprising these two ingredients, said composition being in the form of extruded granules or powders. Compositions in the form of beads are not described.

[11] The use of gel alginate beads to mask the taste of actives is mentioned in the prior art. However, it has never been proposed to apply this technology to isosorbide to mask the taste. Nothing in the prior art suggests that this technology applies to isosorbide, particularly considering that large amounts of isosorbide are administered.

[12] For example, document WO 00/06122 describes pharmaceutical compositions for oral administration comprising particles of active principle and a gelling agent. The particles of active principle can optionally be in the form of alginate beads (Example 12). The particles of active ingredient obtained are mixed with a gelling agent and other substances, in order to obtain the final dosage form. When taking, this solid form is added with water to obtain a gelled composition and the undesirable taste of the active ingredient is masked. This document does not mention isosorbide, and the pharmaceutical compositions finally ingested contain very small amounts of the active ingredient.

Summary of the invention

[13] Thus, the invention relates firstly to gelled beads, in particular for oral administration, comprising isosorbide, the isosorbide content being at least 50% by dry weight of isosorbide relative to the weight. total of said gelled beads.

[14] The invention relates secondly to a pharmaceutical composition comprising or consisting of the gel beads of the invention.

[15] The invention relates thirdly to a process for preparing the gelled beads of the invention, said process comprising the following steps:

-step (a): preparation of a solution comprising isosorbide and one or more gelling agent (s);

-step (b): preparation of a gelation solution; -step (c): dropwise addition of the solution prepared in step (a), to the gelling solution prepared in step (b);

-step (d): collecting the gelled isosorbide beads thus obtained.

[16] Fourthly, the invention relates to a method of masking the unwanted taste of isosorbide, comprising putting said isosorbide in the form of gel beads.

Description of the embodiments

[17] The characteristics exposed in the following paragraphs can, optionally, be implemented. They can be implemented independently of one another or in combination with one another.

[18] The invention relates firstly to gelled beads, in particular for oral administration, comprising isosorbide, the isosorbide content being at least 50% by dry weight of isosorbide relative to the total weight of said. gel beads. Preferably, this dry weight content of isosorbide is at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%. This isosorbide dry weight content is generally less than or equal to 95%, or even less than or equal to 90%, or even less than or equal to 85%.

[19] This content by dry weight of isosorbide relative to the total weight of said gelled beads can be determined by a person skilled in the art, for example by gas chromatography with flame ionization detection and internal calibration, preferably using the methyl aD-glucopyranoside as internal standard, for example according to a protocol described in the examples below.

[20] The gelled beads of the invention typically comprise one or more gelling agent (s). Gelling agents capable of rapidly gelling at room temperature in the presence of water are particularly useful herein. They are preferably polymers capable of undergoing crosslinking gelation in the presence of polyvalent metal ions.

[21] Gelling agents include among others those agents which are capable of gelling when used in combination. Examples of gelling agents are alginates, pectates, carrageenans and gelatin. Preferably, gelatin will not be used, in particular due to the fact that it is a product of animal origin. Preferably, as gelling agent, at least the alginate will be used. When several gelling agents are present, the proportion by dry weight of alginate is then preferably at least 20% relative to the total dry weight of gelling agents, preferably at least 30%, preferably at least. at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%. More preferably, the alginate is the only gelling agent of the gelled beads.

[22] Generally, these gelling agents are in the form of salts, for example sodium, magnesium, potassium, preferably sodium. Particularly preferred is sodium alginate.

[23] Preferably, the gelling agents used have a Brookfield viscosity, as measured at 1% at 20 ° C, less than or equal to 2000 cps, preferably less than or equal to 1000 cps, preferably less than or equal to 800 cps , preferably less than or equal to 500 cps, preferably less than or equal to 400 cps, preferably less than or equal to 300 cps, preferably less than or equal to 250 cps, preferably less than or equal to 200 cps. Preferably, this Brookfield viscosity is greater than or equal to 10 cps, preferably greater than or equal to 20 cps, preferably greater than or equal to 30 cps, preferably greater than or equal to 35 cps, preferably greater than or equal to 50 cps, preferably greater than or equal to 80 cps, preferably greater than or equal to 100 cps. This viscosity is for example chosen from a range going from 35 to 65 cps, or from 100 to 200 cps, or from 300 to 400 cps.

[24] Preferably, the content by dry weight of gelling agents relative to the total dry weight of the gelled beads (dry / dry), in particular the content of alginate, is at least 0.1%, of preferably at least 0.3%, preferably at least 0.5%, preferably at least 0.7%, preferably at least 1.0%, preferably at least 1 , 2%, preferably at least 1.4%. This content by dry / dry weight of gelling agents or more particularly of alginate is preferably less than or equal to 5.0%, preferably less than or equal to 4.0%, preferably less than or equal to 3.0%, preferably less than or equal to 2.0%, preferably less than or equal to 1.8%, preferably less than or equal to 1.6%.

[25] Preferably, the gelled beads of the invention exhibit an isosorbide / gelling agent dry weight ratio at least equal to 40, preferably at least equal to 50, preferably at least equal to 55, preferably at least equal to 60. This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 130, preferably less than 120, preferably less than or equal to 100, preferably less than or equal to 80, preferably less than or equal to 75.

[26] Preferably when the alginate is used, the gelled beads of the invention exhibit an isosorbide / alginate dry weight ratio at least equal to 40, preferably at least equal to 50, preferably at least equal to 55, preferably at least equal to 60. This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 130, preferably less than 120, preferably less than or equal to 100, preferably less than or equal to 80, preferably less than or equal to 75.

[27] The gelled beads of the present invention comprise a solvent, preferably water, even more preferably demineralized water. Preferably, the solvent content of the gelled beads is less than or equal to 30% by weight relative to the total weight of gelled beads, preferably less than or equal to 25%, preferably less than or equal to 20%, for example less than or equal to 18%. This solvent content is generally greater than or equal to 1%, or even greater than or equal to 5%, or even greater than or equal to 10%, for example greater than or equal to 13%, 14% or 15%.

[28] Gelled beads may contain ions, usually in the form of traces, depending on the process used for their preparation.

[29] Furthermore, the gelled beads may contain other substances than those listed above, as long as this does not contravene the desired properties, in particular as regards the taste quality of the gelled beads, and / or their stability, and / or the pharmacological activity of isosorbide. Of such other substances are, for example: flavorings; sweeteners, especially intense sweeteners; encapsulating agents such as cyclodextrins; active ingredients other than isosorbide; compounds aimed at modifying the bioavailability of the active principles of the beads, in particular aimed at modifying the bioavailability of isosorbide.

[30] Preferably the gelled beads comprise less than 30% by dry weight of other substances relative to the total weight of gelled beads, preferably less than 20%, preferably less than 10%, preferably less than 5%, preferably less than 1%, more preferably 0%. It has in fact been demonstrated in the examples below that the other substances are not necessary for solving the problem posed here.

[31] Most preferably, the gelled beads are free from other substances. In particular, this means that the gelled beads in this case consist only of isosorbide, gelling agents, and a solvent which is preferably water, more preferably demineralized water. In an advantageous embodiment, the gelled beads consist only of isosorbide, alginate and a solvent which is preferably water, more preferably demineralized water.

[32] Preferably, the gelled beads have an average diameter less than or equal to 5.0 mm, preferably less than or equal to 3.0 mm, preferably less than or equal to 2.0 mm, preferably less than or equal to 1.5 mm. This average diameter is generally greater than or equal to 0.1 mm, or even greater than or equal to 0.2 mm, or even greater than or equal to 0.3 mm, or even greater than or equal to 0.4 mm, or even greater than or equal to 0 , 5 mm.

[33] Preferably, the beads are insoluble in water at a temperature of 20 ° C.

[34] The invention also relates to a pharmaceutical composition comprising the gelled beads of the invention. In this pharmaceutical composition, isosorbide fulfills the role of active principle. [35] It is understood that by “pharmaceutical composition” is meant a composition in its final dosage form intended to be administered to a patient.

[36] This pharmaceutical composition can also consist only of the gel beads of the invention. Thus, the gelled beads can quite be administered as they are. Alternatively, the gel beads can be administered with other substances, for example in the form of a suspension of the gel beads in a syrup.

[37] Preferably, the pharmaceutical composition of the invention contains an amount of isosorbide per intake of at least 10 g, preferably at least 20 g, preferably at least 25 g, for example 28 g.

[38] Preferably the pharmaceutical composition of the invention is intended to be administered 1, 2 or 3 times per day, preferably 3 times per day.

[39] Preferably, the pharmaceutical composition of the invention contains an isosorbide content of at least 20% by dry weight relative to the total weight of said pharmaceutical composition, preferably at least 30% by dry weight, of preferably at least 40% by dry weight, preferably at least 50% by dry weight, preferably at least 60% by dry weight, preferably at least 70% by dry weight, preferably d at least 75% by dry weight, more preferably at least 80% by dry weight. This isosorbide dry weight content is generally less than or equal to 95%, or even less than or equal to 90%, or even less than or equal to 85%.

[40] Preferably, the pharmaceutical composition according to the invention is for use as a medicament, in particular for the treatment of Ménière's disease. Another object of the invention relates to a method of treatment, in particular of Ménière's disease, comprising the administration of a pharmaceutical composition of the invention. In other words, it is a composition for its use in the treatment of Ménière's disease. Furthermore, it is also the use of the composition according to the invention for the manufacture of a medicament intended for therapeutic use in Ménière's disease. Preferably, the patient to be treated is an individual suffering from Ménière's disease. [41] A subject of the present invention is also a process for preparing gelled beads according to the invention, said process comprising the following steps:

-step (b): preparation of a gelation solution;

-step (c): dropwise addition of the solution prepared in step (a), to the gelling solution prepared in step (b);

-step (d): collecting the gelled isosorbide beads thus obtained.

[42] Preferably, for the preparation of the solution of step (a), the gelling agent is solubilized first in a solvent which is preferably water, more preferably demineralized water, and the isosorbide is then added.

[43] Preferably, the solution of step (a) has an isosorbide content chosen from a range of 30 to 80% by weight relative to the total weight of said solution. Preferably, this content is at least equal to 40%, preferably at least equal to 45%, preferably at least equal to 50%, preferably at least equal to 55%. Preferably, this content is at most equal to 80%, preferably at most equal to 75%, preferably at most equal to 70%, preferably at most equal to 65%. This content is for example equal to 50%, or to 60%.

[44] Preferably, the solution of step (a) has a content of gelling agents, in particular an alginate content, chosen in a range ranging from 0.1 to 5.0% by weight relative to the total weight. of said solution. Preferably, this content is at least equal to 0.2%, preferably at least equal to 0.3%, preferably at least equal to 0.4%, preferably at least equal to 0.5%. Preferably, this content is maximum equal to 4.5%, preferably maximum equal to 4.0%, preferably maximum equal to 3.5%, preferably maximum equal to 3.0%, preferably at most equal to 2.5%, preferably at most equal to 2.0%, preferably at most equal to 1.5%, preferably at most equal to 1.0%.

[45] Preferably, the amounts of isosorbide and gelling agents in the solution of step (a) are chosen such that the weight ratio isosorbide / gelling agents is at least equal to 40, preferably at least equal to 50, preferably at least equal to 60. This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 110, preferably less than or equal to 100.

[46] Preferably, when the alginate is used, the amounts of isosorbide and alginate in the solution of step (a) are chosen such that the isosorbide / alginate weight ratio is at least equal to 40, preferably at least equal to 50, preferably at least equal to 60. This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 110, preferably less than or equal to 100.

[47] Preferably, the total amount of solids in the solution of step (a) is chosen from a range of 30 to 80% by weight relative to the total weight of said solution. Preferably, this amount of solids is chosen from a range of 50 to 70%, preferably 60 to 65%.

[48] Preferably, the gelation solution of step (b) comprises one or more polyvalent metal ion (s). Indeed, it is recalled that the gelling agents of the invention are preferably polymers capable of undergoing crosslinking gelation in the presence of polyvalent metal ions. Alternatively and depending on the gelling agents chosen, the gelling solution can be a solution having a temperature lower than that of the solution of step (a), so that gelling occurs by cooling.

[49] These polyvalent metal ions are for example chosen from calcium, aluminum, iron, copper, zinc ions or a mixture thereof. Calcium ions are particularly preferred. These calcium ions can preferably be in the form of inorganic salts such as calcium chloride, calcium sulfate, calcium monohydrogenophosphate or calcium carbonate. They can also be in the form of organic salts such as calcium lactate, calcium gluconate, calcium citrate. Preferably, it is a water soluble salt. Most preferably, the polyvalent metal ions useful in the invention comprise at least chloride of calcium. More preferably, calcium chloride is the only polyvalent metal ion used.

[50] If the polyvalent metal ions are in the form of water insoluble salts (as is the case for example of calcium carbonate), it will be necessary to add an acid to dissolve the salt, in particular an organic acid such as citric acid, adipic acid, glucono-delta-lactone acid etc. Therefore, calcium salts which are soluble in water, in particular calcium chloride, are preferably used.

[51] Preferably, the gelation solution of step (b) has a content of polyvalent metal ions, in particular a content of calcium chloride, chosen in a range ranging from 1 to 20% by dry weight relative to the content. total weight of said solution. Preferably, this content is at least equal to 3%, preferably at least equal to 5%, preferably at least equal to 7%, preferably at least equal to 9%. Preferably, this content is at most equal to 18%, preferably at most equal to 16%, preferably at most equal to 14%, preferably at most equal to 12%, preferably at most equal to 11%. This content is for example equal to 10%.

[52] To carry out step (c), it is possible to pump the solution of step (a) contained in a storage unit in order to bring it to the gelling solution contained in another. storage unit. The pump used will typically depend on the viscosity of the solution from step (a) containing the gelling agent (s). Adding the solution prepared in step (a) dropwise to the gelation solution prepared in step (b) allows the instantaneous formation of beads.

[53] Preferably, the process for preparing gelled beads further comprises, between steps (c) and (d), a step of washing the gelled beads, preferably with demineralized water. This step is typically carried out in order to rid the product of salts optionally used in the process, such as, for example, calcium chloride.

[54] The process for preparing gelled beads preferably comprises a step of drying the gelled beads, between steps (c) and (d). This step will preferably be subsequent to the washing step if the latter is carried out. This drying can be carried out in an oven. On an industrial scale, however, techniques using the action of a heated air flow applied to the moving balls will be preferred. An example is drying in a fluidized air bed.

[55] Drying, in addition to increasing the stability of the gel beads, also has the effect of reducing the diameter of the beads. So to control the desired diameter, in addition to choosing a suitable system for the formation of the drops to gel, it will be necessary to take into account the effect of this heating step.

[56] Preferably before drying, the gelled beads contain a liquid core. Indeed in this case, the drying step will advantageously be able to concentrate the isosorbide of the beads.

[57] Preferably after drying, the gelled beads do not contain a liquid core.

[58] The present invention also relates to gelled beads, in particular for oral administration, which may be obtained by or obtained by according to the process for preparing gelled beads of the invention. The preferred embodiments of these gelled beads are as described before, in the description relating to the gelled beads.

[59] Another object of the invention relates to a method for masking the unwanted taste of isosorbide, comprising putting said isosorbide in the form of gel beads.

[60] The term "undesirable tastes" is conventionally understood to mean the flavors and / or flavors which are perceived as such by a group of individuals. In this case, when it comes to isosorbide, this is typically its bitterness.

[61] Preferably, the gelled beads make it possible to statistically significantly reduce the bitterness of isosorbide, compared to an isosorbide solution having the same concentration and quantity of isosorbide, said bitterness being detected by an electronic tongue equipped with lipid membrane bitterness sensors for example using equipment such as Insent® Electronic Taste Sensing System TS-5000Z (Atsugi-Chi, Japan) equipped for example with bitterness sensors SB2AC0 (Bitterness 1, cationic substances), SB2AN0 (Bitterness 2, cationic substances) and SB2C00 (Bitterness 3, anionic substances).

[62] Preferably, the gelled beads make it possible to statistically significantly improve the taste of isosorbide, compared to an isosorbide solution having the same concentration and quantity of isosorbide, said improvement being determined using a panel of tasters.

[63] Alternatively, instead of comparing ourselves to an isosorbide solution of the same concentration, we could also compare ourselves to a 40 ml isosorbide solution comprising 28 g of isosorbide, which represents a reference galenic for the treatment. of Ménière's disease.

[64] Preferably, the gelled beads make it possible to completely mask the undesirable taste of the isosorbide, and in particular its bitterness.

[65] Preferably, the gelled beads are as described before.

[66] Preferably, the isosorbide is formed into gelled beads by the process for preparing gelled beads of the invention as described above.

[67] In the present description, it is understood that an amount by "dry weight" refers to an amount by weight of anhydrous substance. By contrast and unless otherwise indicated, an amount simply expressed in “weight” (typically in the part of the description relating to preparation processes) refers to amounts of so-called “commercial” materials, that is to say to quantities of generally powdery product used as such. These contents by weight therefore include the water which may be inherently present in these commercial powders. In this regard, it should be noted that the isosorbide and the salts typically and preferably contain 0% by weight of water, and that the gelling agents, in particular the alginate, comprise a maximum of 15% by weight of water.

[68] The drawings and the description below contain, for the most part, elements of a definite nature. They can therefore not only serve to better understand the present invention, but also contribute to its definition, if necessary.

Examples Materials

[69] Demineralized water; Isosorbide (Isosorbde C PHARMA, ROQUETTE, batch E2366), xylitol (XYLISORB® P90, ROQUETTE, batch E302Y); maltitol (SWEETPEARL® P90, ROQUETTE, batch EMM29); pea maltodextrin rich in amylose (KLEPTOSE® Linecaps, ROQUETTE, batch E4118); hydroxypropyl-beta-cyclodextrin (KLEPTOSE® HPB, ROCKET, lot E0262); yellow pectin (LOUIS FRANÇOIS, lot 342CS); a compound (“coprocessed compound”) of microcrystalline cellulose (MCC) and of carboxymethylcellulose (CMC) (Tabulose 591 F, ROQUETTE, lot 165004073); soluble hydrolyzed hydroxypropylated pea starch (LYCOAT® RS 720, ROQUETTE, batch E001 R); aspartame (AJINOMOTO); sodium saccharin (SIGMA); sucralose (NIUTANG); citric acid (SIGMA); low viscosity sodium alginate (Brookfield viscosity of 35-56 cps at 1.0%, 20 ° C) (sodium alginate IL6G, AGI); medium viscosity sodium alginate (Brookfield viscosity of 100-200 cps at 1.0%, 20 ° C) (sodium alginate I1G80, AGI); high viscosity sodium alginate (Brookfield viscosity of 300-400 cps at 1.0%, 20 ° C) (sodium alginate I3G80, AGI); calcium chloride (SIGMA); aromas (MANE): Banana / Bitter masking / Blackcurrant / Cherry / Herbal / Lemon / Mint / Orange Peach / Strawberry / Tutti frutti / chocolate / caramel.

Example 1: Masking of the taste of isosorbide using intense sweeteners (liquid medium)

[70] Various liquid formulations have been tested to examine the effectiveness of intense sweeteners in masking the taste of isosorbide. The formulations used are presented in Tables 1 and 2 below, and the percentages are expressed by weight relative to the total weight of the formulation. [71] [Table 1]

[72] [Table 2]

[73] The solutions thus prepared were administered orally to a panel of 5 tasters.

[74] The use of aspartame and sodium saccharin did not reduce the feeling of bitterness caused by isosorbide. Substitution of aspartame and sodium saccharin with sucralose also failed to reduce the feeling of bitterness caused by isosorbide, even when sucralose concentrations were increased. The addition of maltitol and xylitol in the formulations also did not improve the taste of the preparations.

Example 2: Masking of the taste of isosorbide using encapsulation techniques (liquid medium)

[75] Various liquid formulations were tested to examine the effectiveness of complexation encapsulation techniques in masking the taste of isosorbide. The formulations used are presented in Tables 3 and 4 below, and the percentages are expressed by weight relative to the total weight of the formulation.

[76] [Table 3]

[77] [Table 4]

[78] The solutions thus prepared were administered orally to a panel of 5 tasters.

[79] Regardless of the concentrations of hydroxypropyl-beta-cyclodextrin and pea maltodextrin used, the impact on bitterness was limited. A taste of burnt caramel was perceived by the panel for all formulations 9 to 14, but the bitterness was not removed.

Example 3: Masking of the taste of isosorbide using texturing techniques (gelled medium) [80] Various formulations in gel form were tested, in order to examine the effectiveness of texturing techniques for masking the taste. isosorbide. The formulations used are presented in Tables 5 and 6 below, and the percentages are expressed by weight relative to the total weight of the formulation. For the preparation of these formulations, isosorbide was ground (Moulin IKA) beforehand, in order to facilitate its solubilization.

[81] [Table 5]

[82] [Table 6] panel of

5 tasters.

[84] The use of a compound of MCC / CMC and soluble hydrolyzed hydroxypropyl pea starch made it possible to obtain a more or less viscous gel, in depending on the concentration used. The use of yellow pectin resulted in a better texture.

[85] Formulations with the MCC / CMC compound and pectin had limited impact on isosorbide bitterness, even when strong sweeteners were added to the formulation. Formulations based on soluble hydrolyzed hydroxypropyl pea starch failed to improve the taste of the isosorbide.

Example 4 Masking of the taste of isosorbide using texturing techniques (gelled medium) and the use of flavorings [86] In this example, the inventors attempted to improve the gels of Example 3 which had only a limited impact on the bitterness of the isosorbide. To do this, gels with added flavorings were tested. The formulations used are presented in Tables 7 and 8 below, and the percentages are expressed by weight relative to the total weight of the formulation. For the preparation of these formulations, the isosorbide was ground (Moulin IKA) beforehand, in order to facilitate its solubilization. All the flavors listed in the "Materials" section above have been tested, that is to say the following flavors: Banana / Bitter masking / Blackcurrant / Cherry / Herbal / Lemon / Mint / Orange Peach / Strawberry / Tutti frutti / chocolate / caramel. [87] [Table 7]

[88] [Table 8]

[89] The flavored gels thus prepared were administered orally to a panel of 5 tasters.

[90] Again, the results are inconclusive, regardless of the flavor tested, and regardless of its concentration. For all tests, strong bitterness continued to be detected by the panel.

Example 5: Masking of the taste of isosorbide by the formation of gelled beads

[91] Various formulations in the form of gel beads have been tested to examine the effectiveness of this technology in masking the taste of isosorbide. [92] The solutions [A] presented in tables 9 and 10 below were first prepared (the percentages are expressed by weight relative to the total weight of the formulation).

[93] [Table 9]

[94] [Table 10] [95] The sodium alginate was dispersed in demineralized water and the whole was mixed with a high shear force mixer (of the POLYTRON type). The isosorbide was added after being ground, in order to facilitate its solubilization.

[96] A gelation solution [B] was then prepared, consisting of 90% by weight of demineralized water, and 10% by weight of calcium chloride.

[97] For each solution [A], the following procedure was carried out: the solution [A] was withdrawn by means of a pipette and was then added dropwise to the solution [B], in order to instantly get gelled beads. The beads thus formed were removed and rinsed with deionized water in a beaker in order to remove the residual calcium chloride.

[98] The resulting beads had a diameter of about 2-3 mm. They were then dried in an oven, and then had a diameter of about 1 mm.

[99] In order to determine if the compounds of the solution [A] were completely put in the form of gelled beads, a test was carried out which consisted in introducing a blue dye into the solution [A] No coloration of the solution [B] during the formation of the beads, thus indicating that the compounds of the solution [A] are essentially contained in these beads.

[100] Three different sodium alginates were tested for formulations 33 to 37: a low viscosity alginate (35-65 cps), a medium viscosity alginate (100-200 cps) and a high viscosity alginate (300- 400 cps). The three alginates produced satisfactory beads. However, the inventors noted that the medium viscosity alginate represented an optimum, especially with regard to the drying efficiency of the gelled beads. It was this medium viscosity alginate that was used for formulation 38.

[101] The gelled isosorbide beads thus obtained completely masked the bitterness of the isosorbide. Compared to Formulation 33, when the isosorbide concentration was increased in solution (Formulations 34 and 35, the beads were less resistant. When the alginate concentration in the 50% isosorbide solutions was increased (Formulations 36 and 37 ), we obtained beads which did not exhibit a liquid core (the beads were totally gelled). However, at this stage, we recall that the presence of a liquid core is advantageous because drying will then make it possible to concentrate the isosorbide effectively. Finally, the best beads were obtained from a solution [A] containing 60% isosorbide, 39% demineralized water and 1.0% sodium alginate (Formulation 38 with an isosorbide / alginate ratio = 60; solids content = 61%), followed by beads obtained from a solution [A] containing 50% isosorbide, 49.5% deionized water and 0.5% sodium alginate ( Formulation 33 with isosorbide / alginate ratio = 100; solids content = 50.5%).

[102] Beads obtained from Formulation 38 were analyzed by gas chromatography with flame ionization detection and internal calibration to determine their isosorbide dry weight content.

[103] The capillary column used had a length of 30 meters, an internal diameter of 0.32 millimeters, a film thickness of 1 micron.

[104] The operating conditions were as follows: column temperature 140-250 ° C, at a rate of 3 ° C / minute, then up to 300 ° C at a rate of 10 ° C / min; injector temperature 300 ° C; detector temperature 300 ° C; helium carrier gas; constant flow rate 1.7 mL / min; split injection mode; split flow rate 80 mL / minute; hydrogen flow rate 30 mL / minute; air flow 400 mL / minute; volume injected 1 microliter

[105] In a 100 mL beaker, between 100 and 150 mg of gel beads and 30 mg of internal standard (methyl a-D-glucopyranoside) were placed. 10 ml of 10% sodium dodecyl sulphate and 50 ml of reverse osmosis water were added, and the whole placed under stirring in order to dissolve the gelled beads.

[106] In a 2 mL screw-cap cup, 1 mL of solution was placed, to which 1 mL of pyridine was added. The whole was evaporated to dryness under a stream of nitrogen. The residue was taken up in 1 ml of pyridine and 0.5 ml of BSTFA, and placed under stirring or sonication to detach the deposit. The whole was left in a dry bath thermostatically controlled at 70 ° C for 30 minutes before injecting 1 microliter.

[107] The isosorbide content is expressed in dry g per 100 g of gelled beads and is given by the following equation:

[108] [Math. 1] If Pe 100

% isosorbide = - x - x -

Se P Ki

[109] with:

- Si = area of isosorbide;

- Se = area of the internal standard peak; - Pe = Internal standard weight introduced into the beaker (in mg);

- P = weight of beads weighed (in mg);

- Ki = isosorbide response coefficient (approximately 0.8 under the analytical conditions used here.

[110] Two samples were tested which did not differ in the drying method employed. The turbine-dried sample had a dry weight content of isosorbide relative to the total weight of gelled beads of 81.7 ± 0.9% (average over 9 measurements). The oven-dried sample had a dry weight content of isosorbide relative to the total weight of gelled beads of 83.6 ± 1.0% (average carried out over 6 measurements)

Claims

[Claim 1] Gelled beads comprising isosorbide, the isosorbide content being at least 50% by dry weight of isosorbide relative to the total weight of said gelled beads.

[Claim 2] Gelled beads according to claim 1, characterized in that the isosorbide content is at least 60% by dry weight of isosorbide relative to the total weight of said gelled beads.

[Claim 3] Gelled beads according to any one of claims 1 or 2, comprising one or more gelling agent (s).

[Claim 4] Gelled beads according to claim 3, characterized in that the one or more gelling agent (s) comprises the alginate.

[Claim 5] Gelled beads according to any one of claims 3 or 4, characterized in that the content by dry weight of gelling agents relative to the total dry weight of the gelled beads is at least 0.1%, and less than or equal to 5.0%.

[Claim 6] Gelled beads according to any one of claims 3 to 5, characterized in that they have an isosorbide / gelling agent dry weight ratio of at least 40.

[Claim 7] Gelled beads according to any one of claims 1 to 6, characterized in that they have a water content of less than or equal to 30% by weight relative to the total weight of gelled beads.

[Claim 8] Gelled beads according to any one of claims 1 to 7, characterized in that they have an average diameter less than or equal to 5.0 mm.

[Claim 9] A pharmaceutical composition comprising or consisting of gelled beads as defined in any one of claims 1 to 8.

[Claim 10] A pharmaceutical composition according to claim 9, for use as a medicament.

[Claim 11] A process for preparing gelled beads as defined in any one of claims 1 to 8, said process comprising the following steps :

-step (d): collecting the gelled isosorbide beads thus obtained.

[Claim 12] A process for preparing gelled beads according to claim 11, wherein the gelling solution of step (b) comprises one or more polyvalent metal ion (s).

[Claim 13] Process for preparing gelled beads according to claim 12, characterized in that the said polyvalent metal ion (s) are chosen from calcium, aluminum, iron, copper or zinc ions, or a mixture of these.

[Claim 14] Process for preparing gelled beads according to any one of claims 11 to 13, characterized in that it further comprises a step of drying the gelled beads.

[Claim 15] A method of masking the unwanted taste of isosorbide, comprising putting said isosorbide in the form of gel beads.