Pharmaceutical composition in form of chewable tablets of geranioside or flavonoid fraction

Abstract

The present invention relates to a pharmaceutical composition in the form of a chewable tablet of a geranioside or flavonoid fraction. The present invention discloses a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized geranioside. The pharmaceutical composition comprises micronized geranioside which accounts for 20%-80% of the total weight of the pharmaceutical composition. The disclosed pharmaceutical compositions are useful for the treatment of venous insufficiency and hemorrhoid attacks.

Description

[0001] This application is a divisional application of PCT application PCT / EP2019 / 069498, filed on July 19, 2019, with the invention name of “Pharmaceutical composition in the form of chewable tablets of dioscorea glycoside or flavonoid fraction”. The date on which the PCT application entered the Chinese national phase is January 15, 2021, and the application number is 201980047436.7. Technical Field

[0002] The present invention relates to a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized diosmine.

[0003] The present invention also relates to a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized purified flavonoid fraction (MPFF). Background Art

[0004] The flavonoid fraction is derived from an extract of rutaceae. The micronized purified flavonoid fraction used in the present invention contains 87% to 93% of diosmin and other flavonoids at the same time. The amount of these other flavonoids is about 10%, including 2.5% to 5.0% of hesperidin, 0.9% to 2.8% of isobarbitalin, 0.9% to 2.8% of linaloside and less than 1% of diosmin.

[0005] Diosmin and flavonoid fractions of the present invention are micronized. The micronization of active ingredients significantly increases their bioavailability. Flavonoids, including micronization of diosmin, are particularly valuable for enhancing the digestion and absorption of these substances, which are poorly soluble in water and are therefore not easily absorbed by the digestive mucosa. Therefore, it is preferred to develop a galenic form comprising micronized diosmin or micronized flavonoid fractions to improve bioavailability.

[0006] In addition, the flavonoid fraction of the present invention is used in a daily dose of 1000mg to 3000mg scope to treat the symptoms of chronic venous insufficiency of lower extremities. Due to the increase of daily dose in the treatment of the main therapeutic indications of flavonoid fraction and diosmin, these active ingredients must be administered in high doses at each application. In addition, the treatment based on flavonoid fraction is a long-term treatment, which must be easy to take to encourage the patient to partially comply with the treatment. Therefore, it is preferred to develop a galenic formulation that is easy to take for the elderly and does not need to add water for patients who go out to eat.

[0007] The therapeutic use of the flavonoid fraction extracted from Rutaceae according to the invention has been described in patent specification EP 0711 560. This patent specification describes an effervescent granule composition containing a high dose of 1000 mg of the flavonoid fraction. The effervescent granules are dispersed in water before consumption.

[0008] A pharmaceutical form of a chewable tablet, suckable tablet or tablet for chewing containing diosmin has been described in the international patent application WO 2004 / 032942. The pharmaceutical form according to the application WO 2004 / 032842 does not contain a high dose of diosmin and does not use the active ingredient in micronized form. Summary of the invention

[0009] Therefore, the present invention relates to a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized diosmin or micronized purified flavonoid fraction (MPFF).

[0010] The pharmaceutical composition of the chewable tablet of the present invention must have specific functional properties in order to solve the technical problems associated with chewable tablets containing high doses of micronized active ingredients.

[0011] Indeed, the pharmaceutical composition must be sufficiently compressible while avoiding cracking and brittle phenomena. A very high proportion of active ingredient and a small proportion of excipients (so as not to increase the final mass of the chewable tablet) have a negative impact on the desired mechanical properties of the chewable tablet.

[0012] Furthermore, the effect of micronizing the active ingredient powder is to reduce the flowability of said powder, since the forces between the particles are increased. The size of the particles is an important factor in the pourability of the powder, which can likewise be influenced by the shape and / or moisture of the particles.

[0013] The present invention provides a pharmaceutical composition in the form of a chewable tablet having a high dose of a micronized purified flavonoid fraction comprising diosmin, hesperidin, isorhinin, linaloside and diosminin.

[0014] According to the invention, the French term "comprimé à croquer" is understood to refer to the pharmaceutical form known in English by the term "chewable tablet." "Chewable" tablets or tablets "for chewing" are hereby meant to be equivalent pharmaceutical forms.

[0015] Chewable drug forms are well accepted by patients and improve their compliance, despite the fact that these chewable forms are large tablets with a unit mass of at least 3000 mg.

[0016] In pharmaceutical composition of the present invention, diosmin and flavonoid fraction are micronized. Micronization is a method that can reduce the powder particle size. The micronization of active ingredients such as diosmin or flavonoid fraction can be carried out by different micronization systems. These micronization systems can be grinders, air jet mills or bead mill micronizers, wherein the pressure of air jet or the supply rate of powder are different according to the expected particle size of the micronized active ingredient.

[0017] Particle size is a particularly important property of pulverulent materials such as powders. If the particles have an irregular shape, the size of the particles is characterized in terms of their diameter or the diameter of an equivalent sphere. Particle size determination by laser diffraction granulometry allows the characterization of particle size distribution or particle size measurement. 50 d 90 (Particle size distribution).

[0018] In the present invention, “d below X μm” 50 " means that at least 50% of the particles of the micronized product have a size below X μm. In the present invention, "a particle size below X μm" means that at least 50% of the particles of the micronized product have a particle size below X μm. 90 ” means that at least 90% of the particles of the micronized product have a size below X μm.

[0019] In one embodiment, the micronized active ingredient has a d 90 Less than 5μM. Less than 5μm d 90 Including d below 4μm, 3μm, 2μm, 1.8μm, 1.6μm, 1.5μm 50 .

[0020] In one embodiment, the micronized active ingredient has a d 50 Less than 5μM. Less than 5μm d 50 Including d below 4μm, 3μm, 2μm, 1.8μm, 1.6μm, 1.5μm 50 .

[0021] In some embodiments, the micronized diosmin or micronized purified flavonoid fraction is characterized by the following particle size measurements:

[0022] -d below 2μm 50 , preferably below 1.6 μm d 50 , and / or

[0023] -d below 5μm 90 , preferably below 2 μm d 90 , more preferably below 1.6 μm 90 .

[0024] The average diameter of the particles of the micronized active ingredient in the pharmaceutical composition of the present invention is strictly below 5 μm, preferably strictly below 1.6 μm.

[0025] The percentage of micronized diosmin or micronized purified flavonoid fraction in the pharmaceutical composition is 20% to 80% of the total mass of the composition. Preferably, the percentage of micronized active ingredient is 30% to 60% of the total mass of the composition. The pharmaceutical composition of the present invention makes it possible to administer a large amount of flavonoids per unit dose by oral route. "High dose" pharmaceutical composition should be understood as a preparation containing at least 20% active ingredient. The amount of diosmin or flavonoid fraction in the pharmaceutical composition is 1000mg-3000mg, including 2000mg, 1500mg, 2500mg.

[0026] The pharmaceutical composition in the form of a high-dose chewable tablet comprises 30% to 60% by weight of micronized diosmin or a micronized purified flavonoid fraction, based on the total mass of the composition, and 40% to 70% by weight of a polyol, based on the total mass of the composition.

[0027] In order to address the industrial limitations inherent in the preparation of chewable tablets containing high doses of micronized active ingredients, it is necessary to select excipients that help to overcome said industrial limitations. An excipient must be understood as any compound forming part of a formulation which is intended to serve simply as a support, that is to say which is not intended to have biological activity.

[0028] The pharmaceutical composition of the present invention comprises at least one polyol as a diluent.

[0029] The diluent is used to obtain a powder volume sufficient to prepare a tablet of the desired size and whose physical properties are compatible with a preparation method such as by direct compression. One or more polyols are used as diluents. The polyol used is preferably sorbitol. Two different polyols can be advantageously used, and a mixture of mannitol and sorbitol is preferred. Polyols as diluents have the advantage of providing a sweet taste and have excellent adhesion and compressibility. Mannitol or sorbitol can be replaced by different polyols, particularly xylitol or maltitol.

[0030] In the pharmaceutical composition of the present invention, the ratio of the mass of one or more polyols to the mass of the active ingredient is strictly less than 2, preferably less than 1.6.

[0031] In addition to the micronized active ingredient and one or more polyols, the pharmaceutical composition of the present invention also comprises one or more pharmaceutically acceptable excipients. For example, the present invention can provide a pharmaceutical composition comprising a micronized active ingredient, one or more polyols and a binder, or a pharmaceutical composition comprising a micronized active ingredient, one or more polyols, a binder and a lubricant.

[0032] Binders or adhesives are substances whose function is to bind together the different particles of the pharmaceutical composition. Binders that may be mentioned are maltodextrin and povidone. The purpose of lubricants is to avoid clogging, adhesion and cohesion phenomena in different industrial processes. Lubricants are in particular chosen from stearic acid, magnesium stearate or talc.

[0033] Other pharmaceutically acceptable excipients may be added to the pharmaceutical compositions of the present invention, such as flavoring agents or sweetening agents.

[0034] As examples of excipients there may be mentioned:

[0035] Flavorings or spices, whose purpose is to mask unpleasant tastes and reduce earthy consistency: orange flavor, lemon flavor, soft caramel flavor, vanilla / lemon flavor;

[0036] Sweeteners enhance the sweetness of the composition: aspartame, acesulfame potassium, saccharin sodium, sodium cyclamate; and

[0037] Glidants, such as anhydrous colloidal silicon dioxide.

[0038] The composition of the present invention can be an immediate release, extended release or delayed release pharmaceutical composition. The composition of the present invention is preferably an immediate release composition.

[0039] The present invention also relates to a method for preparing the above-mentioned chewable tablet by wet granulation, which method comprises at least the following steps:

[0040] a) mixing micronized diosmin or a micronized purified flavonoid fraction, a polyol, a binder, a flavoring agent and a sweetener;

[0041] b) Wetting after mixing. The wet mass thus obtained is subsequently granulated, dried and then classified;

[0042] c) lubricating the granules obtained in step b) by means of colloidal silicon dioxide and magnesium stearate;

[0043] d) Pressing the lubricated mixture.

[0044] In a preferred embodiment, the chewable tablet of the present invention is prepared by a direct compression process, which comprises at least the following steps:

[0045] a) mixing micronized diosmin or a micronized purified flavonoid fraction, a polyol, a binder, a flavoring agent and a sweetener;

[0046] b) lubricating the mixture obtained in step a) by means of colloidal silicon dioxide and magnesium stearate;

[0047] c) Direct pressing of the lubricated mixture.

[0048] In a preferred embodiment, the chewable tablet of the present invention is prepared by a compaction granulation or dry granulation method, which comprises at least the following steps:

[0049] a) mixing micronized diosmin or a micronized purified flavonoid fraction, a polyol, a binder, a flavoring agent and a sweetener;

[0050] b) compacting after mixing to form granules;

[0051] c) lubricating the granules obtained in step b) by means of colloidal silicon dioxide and magnesium stearate;

[0052] d) Pressing the lubricated mixture.

[0053] Preferably, at the end of the process a chewable tablet is obtained, the hardness of which is between 180N and 220N (N=Newton), measured by diametric crushing. Preferably, the chewable tablet has a hardness of between 180N and 200N.

[0054] The invention also relates to the use of the pharmaceutical compositions of the invention in the treatment of venous diseases, more particularly venous insufficiency such as heaviness of the legs, pain, restless legs syndrome, capillary fragility and in the treatment of hemorrhoidal attacks. These pharmaceutical compositions are used as vein and blood vessel protective agents. DETAILED DESCRIPTION

[0055] The following examples illustrate the invention without limiting it.

[0056] Example 1: Pharmaceutical composition of chewable tablets

[0057]

[0058]

[0059] Element Mass (mg) content(%) Micronized Dioscorea 1000.0 33.3 Mannitol 409.13 13.6 Sorbitol 1227.37 40.9 Maltodextrin 300 10 Orange flavor 33 1.1 Acesulfame K 2 0.06 Magnesium Stearate 22.5 0.75 Anhydrous colloidal silica 6 0.2 Final Quality 3000.0

[0060] Preparation of the chewable tablet of Example 1:

[0061] The micronized diosmin or micronized purified flavonoid fraction is carefully mixed with the internal phase excipients, namely mannitol, sorbitol, maltodextrin, orange flavor, acesulfame K. The mixture is moistened with purified water by a pressurized vessel and then granulated.

[0062] The granules are dried to obtain a residual moisture that meets the specification, i.e. a residual moisture of about 2%. The granules are subsequently graded, homogenized, and then lubricated with magnesium stearate. Finally, the granules are sieved through a sieve with a mesh size of 0.8 mm and then compressed by a punch press.

[0063] The hardness of the chewable tablets of the micronized diosmin and the micronized purified flavonoid fraction of Example 1 were 196 N and 192 N (N=Newton), respectively.

[0064] Example 2: Flow properties of the pharmaceutical composition of the present invention

[0065] The pourability of a powder is its ability to flow freely in the form of individual particles in a regular and constant manner. Therefore, the flowability of a powder determines the performance and correct operation of the manufacturing process and plays a role in the quality of the final product. Therefore, powders with good pourability flow without assistance. In contrast, sticky powders have poor pourability and mechanical (stirring, vibration) or chemical (coating) means must be provided in order to facilitate their movement.

[0066] The flowability of the powders and granules of the invention containing high doses of micronized diosmin and high doses of micronized purified flavonoid fractions determined by different methods (Carr index, Hausner ratio and Schultze flow function) shows that the pharmaceutical composition of the invention is very effective in the process of preparing chewable tablets. Despite the presence of factors that are very detrimental to the yield of the preparation process, such as micronization of the active ingredient and / or high doses of the active ingredient, the pourability of the pharmaceutical composition of the invention meets industrial and regulatory requirements.

[0067] The Carr Index (Ic) describes the flow of a powder bed as a function of density. It is determined by the following formula:

[0068] Ic=(ρ 振实 -ρ 堆 ) / ρ 振实

[0069] where ρ is the density and Ic is a dimensionless physical quantity.

[0070] The Carr index values ​​are interpreted as follows:

[0071] Ic<0.15Good dumping performance

[0072] 0.15<Ic<0.25Medium dumping

[0073] Ic>0.25 Positive dumping

[0074] The Hausner ratio (Hr) describes the compressibility and flowability of a powder based on density (ρ) measurements. The tap density (ρ) is given by the following formula: 振实 ) and bulk density (ρ 堆 ) is calculated by the ratio:

[0075] Hr=ρ 振实 / ρ 堆

[0076] Hr is a dimensionless physical quantity. If Hr is between 1.0 and 1.2, the powder has low compressibility, loose cohesion and good flowability; if Hr is between 1.2 and 1.4, the powder is compressible, cohesive and has poor flowability.

[0077] Finally, the Schultze apparatus is a shear cell used to measure the flow function (FFC). Good flow is characterized by an FFC between 4 and 10, and free flow is characterized by an FFC above 10.

[0078]

Claims

1. A pharmaceutical composition in the form of a chewable tablet comprising micronized diosmin as an active ingredient, characterized in that The percentage of active ingredients is 20% to 80% of the total mass of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that The active ingredient is a micronized purified flavonoid fraction, the percentage of which is 20% to 80% of the total mass of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 2, characterized in that The flavonoid fraction contains diosmin, hesperidin, isorhinin, linaloside and diosminin.

4. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that The average diameter of the particles of the micronized active ingredient is below 5 μm.

5. The pharmaceutical composition according to claim 4, characterized in that The average diameter of the particles of the micronized active ingredient is below 1.6 μm.

6. A pharmaceutical composition according to any one of claims 1 to 5, characterized in that The content of the high-dose active ingredient is 20% to 80% of the total weight of the composition.

7. The pharmaceutical composition according to claim 6, characterized in that The content of the active ingredient in the high dose is 30% to 60% of the total weight of the composition.

8. The pharmaceutical composition according to any one of claims 1 to 7, comprising at least one polyol.

9. A pharmaceutical composition according to any one of claims 1 to 8, characterized in that It contains: - 30% to 60% by weight of micronized diosmin or a micronized purified flavonoid fraction, based on the total mass of the composition; - 40% to 70% by weight of polyols, based on the total mass of the composition.

10. A pharmaceutical composition according to any one of claims 1 to 9, characterized in that The ratio of the mass of the polyol or polyols to the mass of the active ingredient is strictly less than 2.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the polyol is sorbitol.

12. A pharmaceutical composition according to any one of claims 1 to 11 comprising a polyol and a binder.

13. A pharmaceutical composition according to any one of claims 1 to 12, comprising a polyol, a binder and a lubricant.

14. A process for preparing a pharmaceutical composition according to any one of claims 1 to 13, characterized in that It is a process of wet granulation, dry granulation or direct compression.

15. Pharmaceutical composition according to any one of claims 1 to 14 for use in the treatment of venous insufficiency and hemorrhoidal attacks.

Images