PHARMACEUTICAL COMPOSITION IN THE FORM OF A CHEWABLE TABLET OF DIOSMIN OR A FLAVONOID FRACTION COMPRISING IT.

Abstract

A pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized diosmin. This pharmaceutical composition comprises between 20% and 80% of the total mass of micronized diosmin or purified, micronized flavonoid fraction. This pharmaceutical composition is used in the treatment of venous insufficiency and hemorrhoidal crises.

Description

[0001] The present invention relates to a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized diosmin. The present invention also relates to a pharmaceutical composition in the form of a chewable tablet containing a high dose of purified and micronized flavonoid fraction (MPFF).

[0002] The flavonoid fraction is derived from an extract of Rutaceae. The purified and micronized flavonoid fraction used in the invention contains 87% to 93% diosmin and other flavonoids concomitantly. These other flavonoids, comprising approximately 10%, include 2.5% to 5.0% hesperidin, 0.9% to 2.8% isorhoifoline, 0.9% to 2.8% linarin, and less than 1% diosmetin.

[0003] Diosmin and the flavonoid fraction according to the invention are micronized. Micronization of the active ingredient significantly increases its bioavailability. Micronization of flavonoids, including diosmin, is particularly advantageous for enhancing the intestinal absorption of these substances, which have low water solubility and are therefore poorly absorbed by the digestive mucosa. Consequently, it is preferable to develop dosage forms containing micronized diosmin or flavonoid fraction to improve bioavailability.

[0004] Furthermore, the flavonoid fraction according to the invention is administered at daily doses ranging from 1000 mg to 3000 mg to treat the manifestations of chronic venous insufficiency of the lower limbs. Due to the increased daily dosages required for the main therapeutic indications of the flavonoid fraction and diosmin, these active ingredients must be administered at high doses with each administration. Moreover, flavonoid fraction-based treatments are long-term treatments requiring easy administration to promote patient adherence. Consequently, it is preferable to develop dosage forms that are easy to take for the elderly and do not require the addition of water for patients who consume alcohol outside the home.

[0005] The therapeutic use of the flavonoid fraction extracted from Rutaceae according to the invention has been described in patent EP 0 711 560. This patent describes a composition of effervescent granules with a high concentration of 1000 mg of the flavonoid fraction. These effervescent granules are to be dispersed in water before consumption.

[0006] Chewable, suckable or suckable tablet pharmaceutical forms containing diosmin were described in international patent application WO 2004 / 032942. The pharmaceutical forms according to application WO 2004 / 032942 are not highly dosed in diosmin and do not use the active ingredient in micronized form.

[0007] Thus the present invention relates to pharmaceutical compositions in the form of a chewable tablet with a high dosage of micronized diosmin or purified and micronized flavonoid fraction (MPFF).

[0008] The pharmaceutical composition of the chewable tablet according to the invention must have specific functional properties in order to meet the technological difficulties relating to chewable tablets with a high dosage of micronized active ingredient.

[0009] Indeed, it is necessary for the pharmaceutical composition to be sufficiently compressible, avoiding cleavage and friability. The very high proportion of active ingredient and the low proportion of excipients, intended to minimize the final mass of the chewable tablet, negatively impact the desired mechanical properties of the chewable tablet.

[0010] Furthermore, micronizing active ingredient powders reduces their flowability due to the increased forces between particles. Particle size is a key factor in powder flowability, which can also be influenced by particle shape and / or moisture content.

[0011] The object of the present invention is a pharmaceutical composition in the form of a chewable tablet with a high dosage of purified and micronized flavonoid fraction comprising diosmin, hesperidin, isorhoifoline, linarin and diosmetin.

[0012] The term "chewable tablet" refers, according to the invention, to a pharmaceutical form known in Anglo-Saxon terminology as a "chewable tablet." A "chewable tablet" or a "snuffable tablet" are equivalent pharmaceutical forms.

[0013] Chewable pharmaceutical forms are very well accepted by patients and improve their adherence despite the fact that these chewable forms are large tablets of at least 3000mg unit mass.

[0014] Diosmin and the flavonoid fraction are micronized in the pharmaceutical compositions according to the invention. Micronization is a process for reducing the particle size of a powder. The micronization of the active ingredient, such as diosmin or a flavonoid fraction, can be carried out using various micronization systems. These micronization systems can be a mill, an air jet micronizer, or a ball micronizer, in which the air jet pressure or the powder feed rate varies according to the desired particle size of the micronized active ingredient.

[0015] Grain size is a particularly important characteristic of powdered materials. Particle size is characterized by its diameter, or the diameter of its equivalent spheres if the particle is irregularly shaped. Grain diameters determined by a laser diffraction particle size analyzer allow for the characterization of a particle size distribution (d50, d90).

[0016] In the present invention, "d 50 less than X µm" means that at least 50% of the particles in the micronized sample have a size less than X µm. In the present invention, "d 90 less than X µm" means that at least 90% of the particles in the micronized sample have a size less than X µm.

[0017] In one embodiment, the d90 of the micronized active ingredient is less than 5µm. A d90 less than 5µm encompasses a d50 less than 4µm, 3µm, 2µm, 1.8µm, 1.6µm, 1.5µm.

[0018] In one embodiment, the d50 of the micronized active ingredient is less than 5µm. A d50 less than 5µm includes a d50 less than 4µm, 3µm, 2µm, 1.8µm, 1.6µm, 1.5µm.

[0019] In some embodiments, micronized diosmin or micronized and purified flavonoid fraction are characterized by the following particle size distribution: a d 50 less than 2µm, preferably less than 1.6µm and / or a d 90 less than 5µm, preferably less than 2µm, even more preferably less than 1.6µm.

[0020] The average diameter of the micronized active ingredient particles in the pharmaceutical composition according to the invention is strictly less than 5µm, preferably strictly less than 1.6µm.

[0021] The percentage of micronized diosmin or purified and micronized flavonoid fraction in the pharmaceutical composition is between 20% and 80% of the total mass of the composition. Preferably, the percentage of micronized active ingredient is between 30% and 60% of the total mass of the composition. The pharmaceutical compositions according to the invention allow for the oral administration of a large quantity of flavonoids for each unit dose. "High-dose" pharmaceutical compositions are defined as formulations containing at least 20% of the active ingredient. The amount of diosmin or flavonoid fraction in the pharmaceutical composition is between 1000 mg and 3000 mg, including 2000 mg, 1500 mg, and 2500 mg.

[0022] Pharmaceutical compositions in the form of high-strength chewable tablets comprise 30% to 60% by weight of micronized diosmin or purified and micronized flavonoid fraction of the total mass of the composition and 40% to 70% by weight of polyols of the total mass of the composition.

[0023] To meet the industrial constraints inherent in manufacturing chewable tablets with a micronized and highly concentrated active ingredient, it is necessary to select excipients that help overcome these industrial constraints. An excipient should be understood as any compound forming part of the formulation that is intended to act as a simple carrier, that is, that is not intended to have biological activity. The pharmaceutical compositions according to the invention comprise at least one polyol having the function of a diluent.

[0024] A diluent is used to obtain a sufficient volume of powder to manufacture a tablet of the desired size and with physical characteristics compatible with manufacturing processes such as direct compression. One or more polyols are used as diluents. Preferably, the polyol used is sorbitol. Two different polyols can be advantageously used, preferably a mixture of mannitol and sorbitol. Polyols as diluents have the advantage of providing a sweet taste and excellent binding and compressibility properties. It is possible to substitute another polyol for mannitol or sorbitol, such as xylitol or maltitol.

[0025] In the pharmaceutical composition according to the invention, the ratio of the mass of the polyol or polyols to the mass of the active ingredient is strictly less than 2, preferably the ratio is less than 1.6.

[0026] In addition to the micronized active ingredient and the polyol(s), the pharmaceutical composition according to the invention contains one or more pharmaceutically acceptable excipients. For example, the object of the invention may be a pharmaceutical composition comprising the micronized active ingredient, one or more polyols, and a binder, or a pharmaceutical composition comprising the micronized active ingredient, one or more polyols, a binder, and a lubricant.

[0027] Binders, or agglutinators, are agents whose role is to bind together the different particles of the pharmaceutical composition. Examples of binders include maltodextrin and povidone. Lubricants prevent seizing, adhesion, and cohesion during various industrial processes. Lubricants are selected from, among others, stearic acid, magnesium stearate, or talc.

[0028] Other pharmaceutically acceptable excipients may be added to the pharmaceutical composition according to the invention, such as flavorings, sweeteners, or binders.

[0029] Examples of excipients include: Flavorings or aromas, intended to mask unpleasant flavors and mitigate earthy consistencies: orange flavor, lemon flavor, soft caramel flavor, vanilla / lemon flavor; Sweeteners increase the sweet flavor of the composition: aspartame, acesulfame potassium, sodium saccharin, potassium cyclamate; and Flow agents such as anhydrous colloidal silica.

[0030] The composition according to the invention may be an immediate-release, extended-release, or delayed-release pharmaceutical composition. Preferably, the composition according to the invention is an immediate-release composition.

[0031] The invention extends to the wet granulation process for preparing a chewable tablet as described above, comprising at least the following steps: a) Mixture of micronized diosmin or purified and micronized flavonoid fraction, polyols, binders, flavorings, and sweeteners; b) After mixing, wet the mixture. The resulting wet mass is then granulated, dried, and calibrated; c) Lubrication of the granules obtained in step b) using colloidal silica and magnesium stearate; d) Compression of the lubricated mixture.

[0032] In a preferred embodiment, the chewable tablet according to the invention is prepared by a direct compression process comprising at least the following steps: a) mixture of micronized diosmin or purified and micronized flavonoid fraction, polyols, binders, flavorings and sweeteners; b) lubrication of the mixture obtained in step a) by means of colloidal silica and magnesium stearate; c) direct compression of the lubricated mixture.

[0033] In a preferred embodiment, the chewable tablet according to the invention is prepared by a granulation process by compaction or by dry granulation comprising at least the following steps: a) mixture of micronized diosmin or purified and micronized flavonoid fraction, polyols, binders, flavorings and sweeteners; b) after mixing, compact into granules; c) lubrication of the granule obtained in step b) using colloidal silica and magnesium stearate; d) compression of the lubricated mixture.

[0034] Preferably, the chewable tablets obtained at the end of the process have a hardness measured by diametrical crushing of between 180 N and 220 N (N = Newtons). Preferably, the chewable tablets have a hardness of between 180 N and 200 N.

[0035] The present invention also relates to the use of the pharmaceutical compositions according to the invention in the treatment of venous disease, more particularly venous insufficiency such as heavy legs, pain, restless legs syndrome, capillary fragility, and the treatment of hemorrhoidal crises. These pharmaceutical compositions are used as venotonics and vasculoprotectors.

[0036] The examples below illustrate the invention in a non-limiting manner. Example 1: Pharmaceutical compositions of chewable tablets

[0037] Ingredients Quantity (mg) Content (%) MPFF 1000.0 33.3 - Diosmin 90% 900.0 30 - Flavonoids 10% 100.0 3.3 mannitol 409.13 13.6 Sorbitol 1227.37 40.9 Maltodextrin 300 10 Orange flavor 33 1.1 Acesulfame potassium 2 0.06 Magnesium stearate 22.5 0.75 anhydrous colloidal silica 6 0.2 Final mass 3000.0 Micronized Diosmin 1000.0 33.3 mannitol 409.13 13.6 Sorbitol 1227.37 40.9 Maltodextrin 300 10 Orange flavor 33 1.1 Acesulfame potassium 2 0.06 Magnesium stearate 22.5 0.75 anhydrous colloidal silica 6 0.2 Final mass 3000.0

[0038] Manufacturing of the chewable tablets in Example 1: Micronized diosmin or the purified and micronized flavonoid fraction is thoroughly mixed with the excipients of the internal phase, i.e., mannitol, sorbitol, maltodextrin, orange flavor, and acesulfame potassium. The mixture is moistened with purified water using a pressure vessel and then granulated.

[0039] The granules are dried until a residual moisture content of approximately 2% is reached, conforming to specifications. They are then calibrated, homogenized, and lubricated with magnesium stearate. Finally, the granules are sieved through a 0.8 mm mesh sieve and then compressed using punches.

[0040] Micronized diosmin chewable tablets and micronized purified flavonoid fraction chewable tablets according to example 1 have a hardness of 196 N and 192 N respectively (N=Newton). Example 2: Flow properties of pharmaceutical compositions according to the invention

[0041] The flowability of a powder is its ability to flow freely in a regular and consistent manner as individual particles. The flowability of powders therefore determines the performance and proper functioning of production processes and influences the quality of the final product. A powder with good flowability flows without assistance. Conversely, a cohesive powder has poor flowability, and a mechanical (agitation, vibration) or chemical (coating) device must be used to facilitate its movement.

[0042] The flowability of the powders and granules of highly concentrated micronized diosmin and purified, micronized, and highly concentrated flavonoid fraction according to the invention, measured by various methods (Carr index, Hausner ratio, and Schultze flow function), demonstrates that the pharmaceutical compositions according to the invention perform very well in the manufacturing processes of chewable tablets. Despite factors that are highly unfavorable to the yield of the manufacturing processes, such as the micronization of the active ingredient and / or a high concentration of the active ingredient, the flowability of the pharmaceutical compositions according to the invention meets industrial and regulatory requirements.

[0043] The Carr index (Ic) describes the flow of a powder bed as a function of density. It is determined by the equation below: Ic = ρ tassé − ρ vrac / ρ tassé where ρ is the density and Ic is a dimensionless physical quantity. Carr index quantities are interpreted as follows: Ic < 0.15 good flowability; 0.15 < Ic < 0.25 average flowability; Ic > 0.25 poor flowability

[0044] The Hausner ratio (Hr) characterizes the compressibility and flowability of a powder based on density measurements (ρ). It is calculated by dividing the packed density (ρ packed) by the bulk density (ρ bulk) according to the equation: Hr = ρ tassé / ρ vrac

[0045] Hr is a dimensionless physical quantity. If Hr is between 1.0 and 1.2, the powder is not very compressible, not very cohesive and has good flow; if Hr is between 1.2 and 1.4, the powder is compressible, cohesive and has poor flow.

[0046] Finally, the Schultze apparatus is a shear cell for measuring the flow function (FFC). Easy flow is characterized by an FFC between 4 and 10, and free flow is characterized by an FFC greater than 10. Methods Powders or Granules micronized diosmin purified and micronized flavonoid fraction Here 0.12-0.25 (average to good flowability) Hr 1.1-1.3 (good to fairly good flowability) FFC 7-13 (easy to free flow)

Claims

1. Pharmaceutical composition in the form of a chewable tablet comprising as active ingredient micronized diosmin or a purified and micronized flavonoid fraction derived from a rutaceae extract comprising from 87% to 93% diosmin and other flavonoids concomitantly at a level of approximately 10% comprising from 2.5% to 5.0% hesperidin, from 0.9% to 2.8% isorhoifolin, from 0.9% to 2.8% linarin and less than 1% diosmetin, characterized in that : - the composition comprises at least one polyol, - the composition comprises from 30% to 60% by weight of active ingredient relative to the total mass of the pharmaceutical composition.

2. Pharmaceutical composition according to claim 1, characterized in that it comprises from 40% to 70% by weight of polyols relative to the total mass of the composition.

3. Pharmaceutical composition according to any one of claims 1 or 2, characterized in thatthe ratio of the mass of the polyol or polyols to the mass of the active ingredient is strictly less than 2.

4. Pharmaceutical composition according to any one of claims 1 to 3, in which a polyol is sorbitol.

5. Pharmaceutical composition according to any one of claims 1 to 4, comprising a polyol and a binder.

6. Pharmaceutical composition according to any one of claims 1 to 5, comprising a polyol, a binder and a lubricant.

7. Process for manufacturing a pharmaceutical composition according to any one of claims 1 to 6, characterized in that This is a process by wet granulation, dry granulation or direct compression.

8. Pharmaceutical composition according to any one of claims 1 to 6 for its use in the treatment of venous insufficiency and hemorrhoidal crisis.